Methods for treating hypertrophic obstructive cardiomyopathy

Abstract

Described herein are methods for treating symptomatic hypertrophic obstructive cardiomyopathy (oHCM). The treatment method includes administering a cardiac myosin inhibitor (CK-3773274, also known as CK-274 or aficamten) and may include titrating the administered daily dose based on one or more components of an echocardiogram. The daily dose may be increased, maintained, decreased, or discontinued based on the echocardiogram. The method may be useful for treating patients recently diagnosed with oHCM, treatment-naive patients for oHCM, or patients who previously received standard of care medication for oHCM and discontinued that treatment prior to administration of aficamten (e.g., patients with chronic oHCM).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 370,435, filed August 4, 2022, U.S. Provisional Application No. 63 / 405,310, filed September 9, 2022, U.S. Provisional Application No. 63 / 377,279, filed September 27, 2022, U.S. Provisional Application No. 63 / 427,067, filed November 21, 2022, U.S. Provisional Application No. 63 / 483,882, filed February 8, 2023, U.S. Provisional Application No. 63 / 485,215, filed February 15, 2023, and U.S. Provisional Application No. 63 / 524,559, filed June 30, 2023, the contents of which are incorporated herein by reference in their entirety for all purposes.

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

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

[0004] Current treatments for oHCM (e.g., beta-blockers, calcium channel blockers, and disopyramide) were developed for other medical conditions and later applied to oHCM due to their inherent negative inotropic properties. Beta-blockers have been shown to reduce symptom burden and improve hemodynamics, but they do not improve exercise capacity (Dybro 2021) and can be associated with poor tolerability. Treatments that improve exercise capacity compared to beta-blockers are needed in both recently diagnosed and chronic symptomatic oHCM patients. Summary of the Invention [Means for solving the problem]

[0005] Described herein are methods and compositions for treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM), comprising administering the cardiac myosin inhibitor aficamten or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods for improving exercise capacity in patients, e.g., patients suffering from oHCM, comprising administering or delivering the aficamten or a pharmaceutically acceptable salt thereof described herein. In some embodiments, the present disclosure provides methods for reducing symptom burden, improving hemodynamics, and improving exercise capacity in patients, e.g., patients suffering from oHCM, comprising administering or delivering the aficamten or a pharmaceutically acceptable salt thereof described herein. The methods disclosed herein may be useful for treating patients recently diagnosed with oHCM (diagnosed within 12 months prior to administering aficamten or a pharmaceutically acceptable salt thereof). Patients recently diagnosed with oHCM can include treatment-naïve patients and patients who have been treated with or are currently being treated with standard of care (SOC) medical therapy for oHCM. The methods disclosed herein can be useful for treating treatment-naïve patients (those not yet receiving oHCM treatment). The methods disclosed herein can be useful for treating patients with chronic oHCM. Patients with chronic oHCM include patients with a history of oHCM of more than 12 months who are currently receiving SOC therapy for oHCM, or patients who received SOC therapy for oHCM within the 12 months prior to administration of aficamten or a pharmaceutically acceptable salt thereof. SOC therapy includes treatments for oHCM that include administration of beta-blockers, calcium channel blockers, or disopyramide.

[0006] In some embodiments of the methods disclosed herein, the methods include administering aficamten, or a pharmaceutically acceptable salt thereof, as monotherapy for oHCM. It is understood that administration of monotherapy for oHCM indicates that the patient receives only one therapy (e.g., aficamten, or a pharmaceutically acceptable salt thereof) for the treatment of oHCM. However, it is understood that the patient may also receive one or more other therapies for the treatment of other diseases. As described herein, "one or more other therapies for the treatment of other diseases" excludes SOC therapies for oHCM (e.g., one or more of a beta-blocker, a calcium channel blocker, or disopyramide). As further described herein, the daily dose of aficamten may be titrated based on the results of an echocardiogram.

[0007] In some embodiments of the methods disclosed herein, the patient has one or more of the following before administration of aficamten, or a pharmaceutically acceptable salt thereof: LVEF ≧60%; resting LVOT-G ≧30 mmHg; post-Valsalva LVOT-G ≧50 mmHg; NYHA class II or class III. In some embodiments, the patient has a pVO2 <80%. In some embodiments, the patient has a predicted pVO2 <80%. In some embodiments, the patient is characterized as being in NYHA functional class II or III, with a resting LVOT-G ≧30 mmHg, a maximum post-Valsalva LVOT-G ≧50 mmHg, and a pVO2 (measured or predicted) less than 80%.

[0008] In some embodiments of the methods disclosed herein, administration of aficamten or a pharmaceutically acceptable salt thereof results in improvement in one or more of the following: exercise capacity; cardiac function as measured by improvement in NYHA functional class; resting LVOT-G; post-Valsalva LVOT-G; health status as measured by Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS); structural remodeling as measured by a reduction in one or more of mean left ventricular mass index (LVMI) and left atrial volume index (LAVI); N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels; high-sensitivity cardiac troponin I (hs-cTnI) levels; diastolic function as measured by a decrease in lateral wall E / e'; interventricular septal thickness (IV ventricular septum thickness remodeling as measured by changes in ST; CPET parameters selected from the following: ventilatory efficiency / carbon dioxide production (VE / VCO2 slope), circulatory power (VO2 × systolic blood pressure), ventilatory anaerobic threshold (VAT), total workload (Watts), and heart rate response; and health status and health-related quality of life as measured by the patient-reported outcomes (PRO) questionnaires EuroQol 5 Dimension 5 Level Instrument (EQ-5D-5L), Clinical Global Impression (CGI), Patient Global Impression of Change (PGI-C), and Seattle Angina Questionnaire-7 (SAQ-7). In some embodiments of the methods disclosed herein, administration with aficamten or a pharmaceutically acceptable salt thereof results in improvement in one or more of the following:Exercise capacity; cardiac function measured by improvement in NYHA functional class; resting LVOT-G; post-Valsalva LVOT-G; health status measured by the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS); structural remodeling measured by a reduction in one or more of the mean left ventricular mass index (LVMI) and left atrial volume index (LAVI); N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels; high-sensitivity cardiac troponin I (hs-cTnI) levels; diastolic function measured by a decrease in lateral wall E / e'; and change in interventricular septal thickness (IVST). ventricular septum thickness remodeling as determined by CPET parameters selected from the following: ventilatory efficiency / carbon dioxide production (VE / VCO2 slope), circulatory power (VO2 × systolic blood pressure), ventilatory anaerobic threshold (VAT), total workload (Watts), and heart rate response; and health status and health-related quality of life as measured by the patient-reported outcomes (PRO) questionnaires EuroQol 5 Dimension 5 Level Instrument (EQ-5D-5L), Clinical Global Impression (CGI), Patient Global Impression of Change (PGI-C), Seattle Angina Questionnaire-7 (SAQ-7), and Short Form Survey 36 (SF-36). In some embodiments, one or more improved outcomes are improved compared to treatment with SOC therapy (e.g., metoprolol). In some embodiments, administration with aficamten or a pharmaceutically acceptable salt thereof improves symptoms of HCM, such as reduced chest pain, dizziness, shortness of breath, fainting during physical activity, fatigue, lack of energy, and physical activity limitations.

[0009] A method for treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof can include administering a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof to the patient, where the therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof is selected by titrating the daily dose of aficamten 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 can be administered to the patient at a constant amount for about two weeks before the amount of the daily dose is titrated.

[0010] In some embodiments of the above method, aficamten or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 5 mg to about 20 mg. In some embodiments, the daily dose is about 5 mg. In some embodiments, the daily dose is about 10 mg. In some embodiments, the daily dose is about 15 mg. In some embodiments, the daily dose is about 20 mg. For example, as described herein, in some embodiments, a patient starts at 5 mg once daily, and at about weeks 2, 4, and 6, the patient undergoes echocardiograms to determine whether to titrate to a dose of 10 mg, 15 mg, or 20 mg. Additionally, if the patient's post-Valsalva LVOT-G is ≥ 30 mmHg and their biplane left ventricular ejection fraction (LVEF) is ≥ 55%, a dose escalation occurs. Patients who do not meet the escalation criteria may continue on their current dose or may have their dose tapered if their LVEF is less than 50%. For information on increasing, maintaining, reducing, or discontinuing a dose, see, e.g., Table 26. As will be understood by those skilled in the art and as described herein, unless otherwise specified, for example, dose amounts refer to the amount of aficamten free base, or, if a non-free base form, e.g., a pharmaceutically acceptable salt, is administered, the amount of the corresponding aficamten free base.

[0011] In some embodiments, the daily dose is administered as a single dose each day. In some embodiments, the daily dose is administered in two divided doses.

[0012] In some embodiments, a method for treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof includes administering a first daily dose of aficamten or a pharmaceutically acceptable salt thereof to the patient for a first period of time; and, based on one or more components of a first echocardiogram of the patient obtained after the first period of time, administering a second daily dose of aficamten or a pharmaceutically acceptable salt thereof to the patient for a second period of time or discontinuing administration of aficamten or a pharmaceutically acceptable salt thereof to the patient. The method may include selecting the second daily dose of aficamten or a pharmaceutically acceptable salt thereof based on the one or more components of the first echocardiogram. In some embodiments, the one or more components of the first echocardiogram include biplane LVEF, or biplane LVEF and post-Valsalva LVOT-G. In some embodiments, the one or more components of the first echocardiogram include biplane LVEF. In some embodiments, the one or more components of the first echocardiogram include biplane LVEF and post-Valsalva LVOT-G. In some embodiments of the methods described herein, the patient undergoes two or more echocardiograms within a first time period, and the second daily dose is selected based on the combined results of the two or more echocardiograms obtained within the first time period.

[0013] In some embodiments of the above method, one or more components of the first echocardiogram include a biplane LVEF, and if the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold, the second daily dose of aficamten or a pharmaceutically acceptable salt thereof is lower than the first daily dose of aficamten or a pharmaceutically acceptable salt thereof. For example, the predetermined biplane LVEF threshold may be 50%.

[0014] In some embodiments of the above method, one or more components of the first echocardiogram include a biplane LVEF, and if the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold, administration of aficamten or a pharmaceutically acceptable salt thereof to the patient is discontinued. For example, the predetermined biplane LVEF threshold can be 50%.

[0015] In some embodiments of the above method, one or more components of the first echocardiogram include a biplane LVEF, and if the biplane LVEF of the first echocardiogram is equal to or greater than a predetermined biplane LVEF threshold and less than a second predetermined biplane LVEF threshold, the second daily dose of aficamten or a pharmaceutically acceptable salt thereof is the same as the first daily dose of aficamten or a pharmaceutically acceptable salt thereof. In some embodiments, the predetermined biplane LVEF threshold is 50% and the second predetermined biplane LVEF threshold is 55%.

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

[0017] In some embodiments of the above method, one or more components of the first echocardiogram include biplane LVEF and post-Valsalva LVOT-G, and if the biplane LVEF is equal to or greater than a second predetermined biplane LVEF threshold and the post-Valsalva LVOT-G is equal to or greater than a predetermined post-Valsalva LVOT-G threshold, the second daily dose of aficamten or a pharmaceutically acceptable salt thereof is greater than the first daily dose of aficamten or a pharmaceutically acceptable salt thereof. In some embodiments, the predetermined biplane LVEF threshold is 55% and the post-Valsalva LVOT-G threshold is 30 mmHg.

[0018] In some embodiments of the above method, the first daily dose of aficamten, or a pharmaceutically acceptable salt thereof, is about 5 mg of aficamten. In some embodiments, the second daily dose of aficamten, or a pharmaceutically acceptable salt thereof, is about 5 mg or about 10 mg of aficamten. In some embodiments of the above method, the first daily dose of aficamten, or a pharmaceutically acceptable salt thereof, is about 5 mg of aficamten and the second daily dose is about 10 mg of aficamten.

[0019] In some embodiments of the above methods, the method further comprises measuring one or more components of the first echocardiogram.

[0020] In some embodiments 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. For example, as described herein, in some embodiments, the provided methods include: administering a first daily dose of aficamten or a pharmaceutically acceptable salt thereof to the patient for a first period of time, wherein the first daily dose is about 5 mg of aficamten and the first period of time is about 2 weeks; assessing the patient's post-Valsalva LVOT-G and LVEF (e.g., using an echocardiogram) after the first period of time; The method includes administering a second daily dose of aficamten or a pharmaceutically acceptable salt thereof to the patient if the patient has a post-Valsalva LVOT-G≧30mmHg and a LVEF≧55%, wherein the second daily dose is about 10 mg of aficamten; and administering a second daily dose of aficamten or a pharmaceutically acceptable salt thereof to the patient if the patient has a post-Valsalva LVOT-G<30mmHg or a LVEF<55%, wherein the second daily dose is about 5 mg of aficamten. As described herein, in some embodiments, a second daily dose is administered for a second period (e.g., about 2 weeks) before the patient is evaluated for post-Valsalva LVOT-G and LVEF.

[0021] In some embodiments of the above method, a second daily dose of aficamten or a pharmaceutically acceptable salt thereof is administered to the patient for a second period of time, and the method further includes administering a third daily dose of aficamten or a pharmaceutically acceptable salt thereof to the patient for a third period of time or discontinuing administration of aficamten or a pharmaceutically acceptable salt thereof to the patient based on one or more components of a second echocardiogram of the patient obtained after the second period of time and the second daily dose of aficamten or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes selecting the third daily dose of aficamten or a pharmaceutically acceptable salt thereof based on one or more components of the second echocardiogram and the second daily dose. In some embodiments, the one or more components of the second echocardiogram include biplane LVEF or post-Valsalva LVOT-G. In some embodiments, the one or more components of the second echocardiogram include biplane LVEF. In some embodiments, one or more components of the second echocardiogram include biplane LVEF and post-Valsalva LVOT-G. In some embodiments of the methods described herein, the patient undergoes two or more echocardiograms within the second time period, and the third daily dose is selected based on the combined results of the two or more echocardiograms obtained within the second time period.

[0022] In some embodiments of the above method, one or more components of the second echocardiogram include a biplane LVEF, and if the biplane LVEF of the second echocardiogram is below a predetermined biplane LVEF threshold, the third daily dose of aficamten or a pharmaceutically acceptable salt thereof is lower than the second daily dose of aficamten or a pharmaceutically acceptable salt thereof, or administration of aficamten or a pharmaceutically acceptable salt thereof to the patient is discontinued. In some embodiments, the predetermined biplane LVEF threshold is 50%.

[0023] In some embodiments of the above method, if the biplane LVEF of the second echocardiogram is below a predetermined biplane LVEF threshold and the second daily dose of aficamten or a pharmaceutically acceptable salt thereof is the same as or lower than the first daily dose of aficamten, administration of aficamten or a pharmaceutically acceptable salt thereof to the patient is discontinued. In some embodiments, the predetermined biplane LVEF threshold is 50%.

[0024] In some embodiments of the above method, if the second daily dose of aficamten or a pharmaceutically acceptable salt thereof is greater than the first daily dose of aficamten or a pharmaceutically acceptable salt thereof and the biplane LVEF of the second echocardiogram is below a predetermined biplane LVEF threshold, the third daily dose of aficamten or a pharmaceutically acceptable salt thereof is less than the second daily dose of aficamten or a pharmaceutically acceptable salt thereof. In some embodiments, the predetermined biplane LVEF threshold is 50%. In some embodiments, the third daily dose of aficamten or a pharmaceutically acceptable salt thereof is the same as the first daily dose of aficamten or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments of the above method, the one or more components of the second echocardiogram include a biplane LVEF, and if the biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold and less than a second predetermined biplane LVEF threshold, the third daily dose of aficamten or a pharmaceutically acceptable salt thereof is the same as the second daily dose of aficamten or a pharmaceutically acceptable salt thereof. In some embodiments, the predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the second predetermined post-Valsalva LVOT-G threshold is 30 mmHg.

[0026] In some embodiments of the above method, one or more components of the second echocardiogram include biplane LVEF and post-Valsalva LVOT-G, and if the biplane LVEF is equal to or greater than a second predetermined biplane LVEF threshold and the post-Valsalva LVOT-G is below a predetermined post-Valsalva LVOT-G threshold, the third daily dose of aficamten or a pharmaceutically acceptable salt thereof is the same as the second daily dose of aficamten or a pharmaceutically acceptable salt thereof. In some embodiments, the second predetermined biplane LVEF threshold is 55% and the predetermined post-Valsalva LVOT-G threshold is 30 mmHg.

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

[0028] In some embodiments of the above methods, the first daily dose of aficamten or a pharmaceutically acceptable salt thereof is about 5 mg of aficamten, the second daily dose of aficamten or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg of aficamten, and the third daily dose of aficamten or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, or about 15 mg of aficamten. For example, as described herein, in some embodiments, the provided methods include: administering to the patient a daily dose of aficamten or a pharmaceutically acceptable salt thereof (which may be referred to as the second daily dose) for a period of time (which may be referred to as the second period), wherein the daily dose is about 10 mg of aficamten and the period is about 2 weeks; After that period, assessing the patient's post-Valsalva LVOT-G and LVEF (e.g., using an echocardiogram); administering to the patient a daily dose of aficamten or a pharmaceutically acceptable salt thereof (sometimes referred to as the third daily dose) if the patient has a post-Valsalva LVOT-G≧30mmHg and an LVEF≧55%, wherein the daily dose is about 15 mg of aficamten; and administering to the patient a daily dose of aficamten or a pharmaceutically acceptable salt thereof (sometimes referred to as the third daily dose) if the patient has a post-Valsalva LVOT-G<30mmHg or an LVEF<55%, wherein the daily dose is about 10 mg of aficamten (e.g., LVEF≧50%) or about 5 mg of aficamten (e.g., LVEF<50% but≧40%), or discontinuing administration for a period of time if the LVEF<40%. Includes. For example, in some embodiments, provided methods include: administering a first daily dose of aficamten or a pharmaceutically acceptable salt thereof to the patient for a first period of time, wherein the first daily dose is about 5 mg of aficamten and the first period of time is about 2 weeks; assessing the patient's post-Valsalva LVOT-G and LVEF (e.g., using an echocardiogram) after the first period, wherein the patient has a post-Valsalva LVOT-G≧30 mmHg and an LVEF≧55%; administering to the patient a second daily dose of aficamten or a pharmaceutically acceptable salt thereof for a second period of time, wherein the second daily dose is about 10 mg of aficamten and the second period of time is about 2 weeks; assessing the patient's post-Valsalva LVOT-G and LVEF (e.g., using an echocardiogram) after the second period; administering to the patient a third daily dose of aficamten or a pharmaceutically acceptable salt thereof if the patient has a post-Valsalva LVOT-G≧30mmHg and a LVEF≧55%, wherein the third daily dose is about 15 mg of aficamten; and administering to the patient a third daily dose of aficamten or a pharmaceutically acceptable salt thereof if the patient has a post-Valsalva LVOT-G<30mmHg or a LVEF<55%, wherein the third daily dose is about 10 mg of aficamten (e.g., LVEF≧50%) or about 5 mg of aficamten (e.g., LVEF<50% but≧40%), or discontinuing administration for a period of time if the LVEF<40%. Includes. As described herein, in some embodiments, a third daily dose is administered for a third period of time (e.g., about 2 weeks) before the patient is evaluated for post-Valsalva LVOT-G and LVEF.

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

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

[0031] In some embodiments of the above method, a third daily dose of aficamten or a pharmaceutically acceptable salt thereof is administered to the patient for a third period of time, and the method further includes administering a fourth daily dose of aficamten or a pharmaceutically acceptable salt thereof to the patient for a fourth period of time or discontinuing administration of aficamten or a pharmaceutically acceptable salt thereof to the patient based on one or more components of a third echocardiogram of the patient obtained after the third period of time and the third daily dose of aficamten or a pharmaceutically acceptable salt thereof. In some embodiments, the method further includes selecting the fourth daily dose of aficamten or a pharmaceutically acceptable salt thereof based on one or more components of the third echocardiogram and the third daily dose. In some embodiments, the one or more components of the third echocardiogram include biplane LVEF or post-Valsalva LVOT-G. In some embodiments, the one or more components of the third echocardiogram include biplane LVEF. In some embodiments, one or more components of the third echocardiogram include biplane LVEF and post-Valsalva LVOT-G. In some embodiments of the methods described herein, the patient undergoes two or more echocardiograms within a third time period, and the fourth daily dose is selected based on the combined results of the two or more echocardiograms obtained within the third time period.

[0032] In some embodiments of the above method, one or more components of the third echocardiogram include a biplane LVEF, and if the biplane LVEF of the third echocardiogram is below a predetermined biplane LVEF threshold, the fourth daily dose of afficamten or a pharmaceutically acceptable salt thereof is lower than the third daily dose of afficamten or a pharmaceutically acceptable salt thereof, or administration of afficamten or a pharmaceutically acceptable salt thereof to the patient is discontinued. In some embodiments, if the biplane LVEF of the third echocardiogram is below a predetermined biplane LVEF threshold and the third daily dose of afficamten or a pharmaceutically acceptable salt thereof is the same as the first daily dose of afficamten or a pharmaceutically acceptable salt thereof, administration of afficamten or a pharmaceutically acceptable salt thereof to the patient is terminated. In some embodiments, the predetermined biplane LVEF threshold is 50%.

[0033] In some embodiments of the method, the one or more components of the third echocardiogram include a biplane LVEF, and if the biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold and less than a second predetermined biplane LVEF threshold, the fourth daily dose of aficamten or a pharmaceutically acceptable salt thereof is the same as the third daily dose of aficamten or a pharmaceutically acceptable salt thereof. In some embodiments of the method, the first predetermined biplane LVEF threshold is 50% and the second predetermined biplane LVEF threshold is 55%.

[0034] In some embodiments of the above method, one or more components of the third echocardiogram include biplane LVEF and post-Valsalva LVOT-G, and if the biplane LVEF is equal to or greater than a second predetermined biplane LVEF threshold and the post-Valsalva LVOT-G is below a predetermined post-Valsalva LVOT-G threshold, the fourth daily dose of aficamten or a pharmaceutically acceptable salt thereof is the same as the third daily dose of aficamten or a pharmaceutically acceptable salt thereof. In some embodiments, the second predetermined biplane LVEF threshold is 55% and the second predetermined post-Valsalva LVOT-G threshold is 30 mmHg.

[0035] In some embodiments of the above method, the one or more components of the third echocardiogram include biplane LVEF and post-Valsalva LVOT-G, and if the biplane LVEF of the third echocardiogram is above a second predetermined biplane LVEF threshold and the post-Valsalva LVOT-G of the third echocardiogram is equal to or greater than the second predetermined post-Valsalva LVOT-G threshold, the fourth daily dose of aficamten or a pharmaceutically acceptable salt thereof is greater than the third daily dose of aficamten or a pharmaceutically acceptable salt thereof. In some embodiments, the second predetermined biplane LVEF threshold is 55% and the second predetermined post-Valsalva LVOT-G threshold is 30 mmHg.

[0036] In some embodiments of the above methods, the first daily dose of aficamten or a pharmaceutically acceptable salt thereof is about 5 mg of aficamten, the second daily dose of aficamten or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg of aficamten, the third daily dose of aficamten or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, or about 15 mg of aficamten, and the fourth daily dose of aficamten or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, about 15 mg, or about 20 mg of aficamten. For example, as described herein, in some embodiments, the provided methods include: administering to the patient a daily dose of aficamten or a pharmaceutically acceptable salt thereof (which may be referred to as the third daily dose) for a period of time (which may be referred to as the third period), wherein the daily dose is about 15 mg of aficamten and the period is about 2 weeks; After that period, assessing the patient's post-Valsalva LVOT-G and LVEF (e.g., using an echocardiogram); administering to the patient a daily dose of aficamten or a pharmaceutically acceptable salt thereof (sometimes referred to as the fourth daily dose) if the patient has a post-Valsalva LVOT-G≧30mmHg and an LVEF≧55%, wherein the daily dose is about 20 mg of aficamten; and administering to the patient a daily dose of aficamten or a pharmaceutically acceptable salt thereof (sometimes referred to as the fourth daily dose) if the patient has a post-Valsalva LVOT-G<30mmHg or an LVEF<55%, wherein the daily dose is about 15 mg of aficamten (e.g., LVEF≧50%) or about 10 mg of aficamten (e.g., LVEF<50% but≧40%), or discontinuing administration for a period of time if LVEF<40%. Includes: For example, in some embodiments, provided methods include: administering a first daily dose of aficamten or a pharmaceutically acceptable salt thereof to the patient for a first period of time, wherein the first daily dose is about 5 mg of aficamten and the first period of time is about 2 weeks; assessing the patient's post-Valsalva LVOT-G and LVEF (e.g., using an echocardiogram) after the first period, wherein the patient has a post-Valsalva LVOT-G≧30 mmHg and an LVEF≧55%; administering to the patient a second daily dose of aficamten or a pharmaceutically acceptable salt thereof for a second period of time, wherein the second daily dose is about 10 mg of aficamten and the second period of time is about 2 weeks; assessing the patient's post-Valsalva LVOT-G and LVEF (e.g., using an echocardiogram) after the second period; administering to the patient a third daily dose of aficamten or a pharmaceutically acceptable salt thereof for a third period of time, wherein the third daily dose is about 15 mg of aficamten and the third period of time is about 2 weeks; assessing the patient's post-Valsalva LVOT-G and LVEF (e.g., using an echocardiogram) after a third period of time; administering a fourth daily dose of aficamten or a pharmaceutically acceptable salt thereof to the patient if the patient has a post-Valsalva LVOT-G≧30mmHg and an LVEF≧55%, wherein the third daily dose is about 20 mg of aficamten; and administering a fourth daily dose of aficamten or a pharmaceutically acceptable salt thereof to the patient if the patient has a post-Valsalva LVOT-G<30mmHg or an LVEF<55%, wherein the fourth daily dose is about 15 mg of aficamten (e.g., LVEF≧50%) or about 10 mg of aficamten (e.g., LVEF<50% but≧40%), or discontinuing administration for a period of time if the LVEF<40%. Includes. As described herein, in some embodiments, the fourth daily dose is administered for a fourth period (e.g., about two weeks) before the patient is evaluated for post-Valsalva LVOT-G and LVEF. In some embodiments, the fourth daily dose is administered for about two weeks or longer, e.g., about four weeks, about one month, about two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve months, or longer. In some embodiments, during the fourth period, e.g., during a fourth period longer than about two weeks, the patient may be evaluated one or more times for cardiac structure and / or function, e.g., post-Valsalva LVOT-G, LVEF, exercise capacity, etc. As described herein, the provided methods can, among other things, improve exercise capacity.

[0037] In some embodiments of the above method, the method further comprises measuring one or more components of a third echocardiogram.

[0038] In some embodiments of the above methods, the fourth period of time is about two weeks.

[0039] In some embodiments of the above method, the first predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the predetermined post-Valsalva LVOT-G threshold is 30 mmHg.

[0040] In some embodiments, the daily dose is about 15 mg of afficamten. In some embodiments, the third daily dose is about 15 mg of afficamten. In some embodiments, the fourth daily dose is about 15 mg of afficamten. In some embodiments, the daily dose is about 20 mg of afficamten. In some embodiments, the fourth daily dose is about 20 mg of afficamten. In some embodiments, the daily dose is administered as a tablet. In some embodiments, the amount of afficamten in the tablet, which may exist in multiple forms (e.g., free form, pharmaceutically acceptable salt form, polymorphic form, etc.), is approximately the daily dose described herein. In some embodiments, the amount of afficamten in the tablet is about 5 mg. In some embodiments, the amount of afficamten in the tablet is about 10 mg. In some embodiments, the amount of afficamten in the tablet is about 15 mg. In some embodiments, the amount of afficamten in the tablet is about 20 mg. In some embodiments, the amount of aficamten in the tablet is about half of the daily dose described herein. In some embodiments, the amount of aficamten in the tablet is about 2.5 mg. In some embodiments, the amount of aficamten in the tablet is about 5 mg. In some embodiments, the amount of aficamten in the tablet is about 7.5 mg. In some embodiments, the amount of aficamten in the tablet is about 10 mg.

[0041] In some embodiments of any of the above methods, aficamten or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, aficamten or a pharmaceutically acceptable salt thereof is administered as a tablet. In some embodiments, the tablet comprises one or more carriers or excipients selected from the group consisting of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, the tablet comprises (i) about 1% to about 50% by weight of aficamten or a pharmaceutically acceptable salt thereof, (ii-1) about 10% to about 60% by weight of mannitol, (ii-2) about 5% to about 45% by weight of microcrystalline cellulose, (iii) about 0.1% to about 10% by weight of hydroxypropyl cellulose, (iv) about 1% to about 10% by weight of croscarmellose sodium, (v) about 0.1% to about 10% by weight of sodium lauryl sulfate, and (vi) about 0.1% to about 10% by weight of magnesium stearate, where the weight percentages exclude the weight of a coating, if present. In some embodiments, the aficamten or a pharmaceutically acceptable salt thereof comprises one or more of aficamten polymorphic Form I, Form II, Form III, Form IV, Form V, and Form VI. [Brief explanation of the drawings]

[0042] [Figure 1] 1 illustrates an exemplary method for treating hypertrophic obstructive cardiomyopathy (oHCM) in a patient, comprising titrating the daily dose of aficamten or a pharmaceutically acceptable salt thereof.

[0043] [Figure 2]A schematic overview of the Phase 1 clinical trial of aficamten is shown. The study included the SAD cohort, MAD cohort, CYP2D6-PM cohort, and food effect cohort. The MAD and CYP2D6-PM cohorts were initiated when a tolerable pharmacologically active dose (approximately a 5% reduction in LVEF) was identified in the SAD cohort. The food effect cohort was initiated after the final SAD cohort was completed. The criteria for stopping dose escalation were met in the SAD 75 mg dose cohort, and the remaining patients in this cohort were administered 50 mg. The final SAD cohort was then completed using 40 mg of aficamten. CYP2D6-PM = cytochrome P450 2D6 poor metabolizer phenotype; d = day; LVEF = left ventricular ejection fraction; MAD = repeated escalating dose; qd = once daily; SAD = single escalating dose.

[0044] [Figure 3] A shows the mean (SE) maximum plasma concentration (Cmax) of aficamten, which increased dose-proportionally after single oral doses of 1 mg to 50 mg. B shows the dose-proportionally increased exposure (AUC24) of aficamten after single oral doses of 1 mg to 50 mg. AUC24 = area under the plasma drug concentration-time curve from 0 to 24 hours; Cmax = maximum plasma concentration; SE = standard error.

[0045] [Figure 4]This figure shows the plasma concentrations of aficamten over time with repeated doses from an exemplary clinical trial. Mean (SE) plasma concentrations of aficamten are shown. Data points are offset for clarity. Although aficamten plasma concentrations increased between the 5 mg dose and the two higher doses, there was no difference in mean concentrations between the 7.5 mg and 10 mg doses on Day 2. Clearance was similar for the 5 mg and 10 mg doses, and accumulation rates were similar for all three doses. Only trough measurements are shown for Days 7, 8, 10, 11, 12, and 13. For the 5 mg and 10 mg cohorts, the dosing period was 14 days with a 3-day follow-up. For the 7.5 mg cohort, dosing was extended to 17 days with a 3-day follow-up, confirming steady state was reached after 10–12 days. SE = standard error.

[0046] [Figure 5] A shows the SAD cohort from an exemplary aficamten clinical trial, and B shows the MAD cohort. Mean (SE) change from baseline in LVEF is displayed. Data points are offset for clarity. Both the SAD and MAD cohorts experienced LVEF reductions within the target range (5% to 15% reduction). In the SAD cohort, LVEF declines were generally small, with a mean maximum reduction of 5.8% in the 50 mg group (1.5 hours post-dose). In the MAD cohort, the greatest mean reduction in LVEF from baseline occurred in the 10 mg group (5.0% mean change at 1.5 hours post-dose on Day 14). LVEF = left ventricular ejection fraction; MAD = repeated escalating dose; qd = once daily; SAD = single escalating dose; SE = standard error.

[0047] [Figure 6](A) shows an analysis of the SAD cohort from an exemplary clinical trial, demonstrating a trend toward decreased LVEF with increasing aficamten plasma concentrations. (B) shows an analysis of the MAD cohort from an exemplary clinical trial, demonstrating minimal LVEF depression in most participants at aficamten plasma concentrations of ≦180 ng / ml. CI = confidence interval; LVEF = left ventricular ejection fraction; MAD = repeated ascending doses; SAD = single ascending dose.

[0048] [Figure 7] 1 shows resting LVOT-G for treatment and placebo cohorts from an exemplary clinical trial of aficamten.

[0049] [Figure 8] 1 shows post-Valsalva LVOT-G for treatment and placebo cohorts from an exemplary clinical trial of aficamten.

[0050] [Figure 9] 1 shows the change in left arterial volume index (LAVI) for treatment and placebo cohorts from an exemplary clinical trial of aficamten.

[0051] [Figure 10] 1 shows the change in lateral wall E / e' ratio for treatment and placebo cohorts from an exemplary clinical trial of aficamten.

[0052] [Figure 11] 1 shows changes to mitral valve characteristics including mitral regurgitation (MR), eccentric MR, and systolic anterior motion (SAM) in treatment and placebo cohorts from an exemplary clinical trial of Affycamten.

[0053] [Figure 12] 1 shows the change in resting LVOT-G for treatment and placebo cohorts from an exemplary clinical trial of aficamten.

[0054] [Figure 13] 1 shows the change in resting Valsalva LVOT-G for treatment and placebo cohorts from an exemplary clinical trial of aficamten.

[0055] [Figure 14] 1 shows the changes to LVEF for treatment and placebo cohorts from an exemplary clinical trial of aficamten.

[0056] [Figure 15] 1 shows NYHA functional class response for treatment and placebo cohorts from an exemplary clinical trial of aficamten.

[0057] [Figure 16] 1 shows the change in mean NT-proBNP for treatment and placebo cohorts from an exemplary clinical trial of aficamten.

[0058] [Figure 17] 1 shows the change in resting LVOT-G for treatment and placebo cohorts from an exemplary clinical trial of aficamten.

[0059] [Figure 18] 1 shows the change in resting Valsalva LVOT-G for treatment and placebo cohorts from an exemplary clinical trial of aficamten.

[0060] [Figure 19] 1 shows the changes to LVEF for treatment and placebo cohorts from an exemplary clinical trial of aficamten.

[0061] [Figure 20] 1 shows the hemodynamic responses of treatment and placebo cohorts from an exemplary clinical trial of aficamten.

[0062] [Figure 21]1 shows NYHA functional class response for treatment and placebo cohorts from an exemplary clinical trial of aficamten.

[0063] [Figure 22] 1 shows the change in mean NT-proBNP for treatment and placebo cohorts from an exemplary clinical trial of aficamten.

[0064] [Figure 23] 1 shows hs-troponin for treatment and placebo cohorts from an exemplary clinical trial of aficamten.

[0065] [Figure 24] 1 shows NYHA functional class response for treatment and placebo cohorts from an exemplary clinical trial of aficamten.

[0066] [Figure 25] 1 shows NYHA functional class response for treatment and placebo cohorts from an exemplary clinical trial of aficamten.

[0067] [Figure 26] 1 shows the open-label extension design of an exemplary clinical trial of aficamten (Example 3a).

[0068] [Figure 27] 1 shows the distribution of patients over time among doses in an open-label extension study of an exemplary clinical trial of aficamten (Example 3a).

[0069] [Figure 28] 3 shows resting LVOT-G of patients in an open-label extension study of an exemplary clinical trial of aficamten (Example 3a).

[0070] [Figure 29] 1 shows post-Valsalva LVOT-G in patients in the open-label extension of an exemplary clinical trial of aficamten (Example 3a).

[0071] [Figure 30] 1 shows the changes to LVEF in patients in the open-label extension of an exemplary clinical trial of aficamten (Example 3a).

[0072] [Figure 31] 1 shows the distribution of NYHA functional class at various time points for patients in an open-label extension study of an exemplary clinical trial of aficamten (Example 3a).

[0073] [Figure 32] FIG. 3 shows NYHA functional class response at various time points for patients in an open-label extension study of an exemplary clinical trial of aficamten (Example 3a).

[0074] [Figure 33] 3 shows the mean NT-proBNP change in patients in the open-label extension of an exemplary clinical trial of aficamten (Example 3a).

[0075] [Figure 34] 3 shows the change in mean cardiac troponin I for patients in the open-label extension of an exemplary clinical trial of aficamten (Example 3a).

[0076] [Figure 35] 1 shows the change from baseline in KCCQ scores for patients in the open-label extension of an exemplary clinical trial of aficamten (Example 3a).

[0077] [Figure 36] 1 shows the proportion of patients with various levels of change from baseline in KCCQ scores for patients in the open-label extension of an exemplary clinical trial of aficamten (Example 3a).

[0078] [Figure 37]1 shows the percent change from baseline in hs-troponin I for treatment and placebo cohorts from an exemplary clinical trial of aficamten (Example 3a).

[0079] [Figure 38] 1 shows an exemplary Phase 3 clinical trial design for Affycamten.

[0080] [Figure 39] 1 shows the change in resting LVOT-G from baseline at various time points in patients in an open-label extension study of an exemplary clinical trial of aficamten (Examples 3a and 3b).

[0081] [Figure 40] 1 shows the change in post-Valsalva LVOT-G from baseline at various time points in patients in an open-label extension study of an exemplary clinical trial of aficamten (Examples 3a and 3b).

[0082] [Figure 41] 1 shows the change in NYHA functional class distribution at various time points for patients in an open-label extension study of an exemplary clinical trial of aficamten (Examples 3a and 3b).

[0083] [Figure 42] 1 shows the change in LVEF at various time points in patients in an open-label extension study of an exemplary clinical trial of aficamten (Examples 3a and 3b).

[0084] [Figure 43] An exemplary Phase 3 clinical trial design for aficamten is shown (Example 5).

[0085] [Figure 44] 1 shows the baseline doses of beta-blockers and calcium channel blockers for 40 patients in an open-label extension study of an exemplary clinical trial of aficamten (Examples 3a and 3b).

[0086] [Figure 45A] 1 shows the interim change in NT-proBNP in patients in the open-label extension of an exemplary clinical trial of aficamten (Examples 3a and 3b). [Figure 45B] 1 shows the interim change in hs-troponin I in patients in the open-label extension of an exemplary clinical trial of aficamten (Examples 3a and 3b).

[0087] [Figure 46] 1 shows resting LVOT-G from baseline to week 12 in an exemplary clinical trial of aficamten (Example 2).

[0088] [Figure 47] 1 shows Valsalva LVOT-G from baseline to week 12 in an exemplary clinical trial of Aficamten (Example 2).

[0089] [Figure 48] 1 shows LVEF from baseline to week 12 in an exemplary clinical trial of aficamten (Example 2).

[0090] [Figure 49] 1 shows the distribution of patients who demonstrated hemodynamic response at week 10 in an exemplary clinical trial of aficamten (Example 2).

[0091] [Figure 50] 1 shows the distribution of patients who showed improvement in NYHA class at week 10 in an exemplary clinical trial of aficamten (Example 2).

[0092] [Figure 51] 1 shows the mean proportional change from baseline in NT-proBNP and hs-cTnI at week 10 of an exemplary clinical trial of aficamten (Example 2).

[0093] [Figure 52]1 shows the doses of aficamten achieved in patients in the open-label extension study of an exemplary clinical trial of aficamten (Examples 3a and 3b).

[0094] [Figure 53] 3A and 3B show the mean (SD) change in resting LVOT-G from baseline at various time points in patients in an open-label extension study of an exemplary clinical trial of aficamten (Examples 3a and 3b). The dashed horizontal line represents the threshold for designating severe obstruction.

[0095] [Figure 54] 3A and 3B show the mean (SD) change from baseline in core lab and site interpretation of Valsalva LVOT-G at various time points in patients in an open-label extension study of an exemplary clinical trial of aficamten. The dashed horizontal line represents the threshold for designating severe obstruction.

[0096] [Figure 55] 3A and 3B show the core laboratory and site-interpreted mean (SD) change in LVEF at various time points for patients in an open-label extension study of an exemplary clinical trial of aficamten (Examples 3a and 3b). The dashed horizontal line represents the lower LVEF threshold at 50 mmHg.

[0097] [Figure 56] 1 shows the percentage of patients who showed improvement in NYHA class at various weeks through week 48 in an open-label extension study of an exemplary clinical trial of aficamten (Examples 3a and 3b).

[0098] [Figure 57A] 1 shows the change in NYHA class from baseline to weeks 36-48 for 27 patients in the open-label extension of an exemplary clinical trial of aficamten (Examples 3a and 3b).

[0099] [Figure 57B]The changes in longitudinal global strain (GLS) from baseline to weeks 12 and 36-48 in 27 patients who underwent echocardiography at weeks 12 and 36-48 in an open-label extension study of an exemplary clinical trial of Aficamten are shown (Examples 3a and 3b).

[0100] [Figure 57C] In an open-label extension study of an exemplary clinical trial of Aficamten, patients who underwent echocardiography at Week 12 and Weeks 36-48 and demonstrated an optimal hemodynamic response (resting LVOT-G) were shown to have changes in longitudinal global strain (GLS) from baseline to Week 12 and Weeks 36-48 (Examples 3a and 3b).

[0101] [Figure 57D] In an open-label extension study of an exemplary clinical trial of Aficamten, patients who underwent echocardiography at Week 12 and Weeks 36-48 and demonstrated an optimal hemodynamic response (Valsalva LVOT-G) were shown to have changes in longitudinal global strain (GLS) from baseline to Week 12 and Weeks 36-48 (Examples 3a and 3b).

[0102] [Figure 58] 1 shows an exemplary Phase 3 clinical trial design for Affycamten.

[0103] [Figure 59A] 1 shows the experimental X-ray powder diffraction (XRPD) pattern of polymorphic Form I of Affycamten.

[0104] [Figure 59B] 1 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) graphs of polymorphic Form I of Affycamten.

[0105] [Figure 59C] 1 shows the dynamic vapor sorption (DVS) graph of polymorphic Form I of Affycamten.

[0106] [Figure 60A] 1 shows the experimental XRPD pattern of polymorphic Form II of Affycamten.

[0107] [Figure 60B] 1 shows DSC and TGA graphs of polymorphic Form II of Affycamten.

[0108] [Figure 61A] 1 shows an experimental XRPD pattern of a mixture of polymorphic forms I and III of Affycamten.

[0109] [Figure 61B] 1 shows DSC and TGA graphs of a mixture of polymorphic forms I and III of Affycamten.

[0110] [Figure 62A] 1 shows the experimental XRPD pattern of polymorphic Form IV of Affycamten.

[0111] [Figure 62B] 1 shows DSC and TGA graphs of polymorphic Form IV of Affycamten.

[0112] [Figure 63] 1 shows an experimental XRPD pattern and two simulated patterns of polymorphic Form V of Affycamten (top to bottom: simulated at 223 K, simulated at 273 K, experimental).

[0113] [Figure 64A] Two experimental XRPD patterns of polymorphic Form VI of aficamten are shown: (a) top, XRPD of Form VI taken before drying, and (b) bottom, after drying (oven, vacuum, 24 hours, 25°C).

[0114] [Figure 64B] 1 shows a TGA graph of polymorphic Form VI of Affycamten, showing the weight loss of a sample of Form VI oven dried (oven, vacuum, overnight, 25° C.) in the range of 25-300° C. [Figure 64C]1 shows a TGA graph of polymorphic Form VI of Affycamten. The graph shows a TGA plot over the range 25-300°C of a sample of Form VI that was oven dried (oven, vacuum, overnight, 25°C) and further heated at 150°C before thermogravimetric analysis.

[0115] [Figure 64D] 1 shows a DSC graph of polymorphic Form VI of Affycamten. 2 shows a DSC plot of a sample of Form VI oven dried (oven, vacuum, overnight, 25° C.) in the range of 25-300° C. [Figure 64E] 1 shows a DSC graph of polymorphic Form VI of Affycamten. 2 shows a TGA plot over the range 25-300°C of a sample of Form VI that was oven dried (oven, vacuum, overnight, 25°C) and further heated at 150°C before thermogravimetric analysis. DETAILED DESCRIPTION OF THE INVENTION

[0116] Described herein is the cardiac myosin inhibitor aficamten and various methods for treating, for example, obstructive hypertrophic cardiomyopathy in a subject in need thereof using aficamten or a pharmaceutically acceptable salt thereof.

[0117] Treatment methods may include adjusting the dose, e.g., increasing, decreasing, or maintaining the dose, or terminating administration, based on the results of one or more measured biplane left ventricular ejection fraction (LVEF) measurements and / or post-Valsalva left ventricular outflow tract pressure gradient (LVOT-G) measurements. These measurements may be obtained, for example, using an echocardiogram. The methods disclosed herein may be useful 1) as primary therapy for recently diagnosed and / or untreated subjects, or 2) as monotherapy for participants who have previously received standard of care (SOC) medical therapy for symptomatic oHCM. It should be understood that administration of monotherapy for oHCM indicates that the patient receives only one therapy (e.g., aficamten, or a pharmaceutically acceptable salt thereof) for the treatment of oHCM. However, it should be understood that the patient may also receive one or more other therapies for the treatment of other diseases. As described herein, "one or more other therapies for the treatment of another disease" excludes SOC therapies for oHCM (e.g., one or more of a beta-blocker, a calcium channel blocker, or disopyramide).

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

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

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

[0121] Throughout this application, unless the context indicates otherwise, references to aficamten include its amorphous form or any of its polymorphs, including any one of polymorphic forms I, II, III, IV, V, or VI described herein, or mixtures thereof.

[0122] Reference herein to "about" a value or parameter includes (and describes) the value or parameter itself, as well as any value or parameter 5% above or below that parameter. For example, a reference to "about X" includes the references "X" and "X + / - 5%." For example, a daily dose of "about 5 mg" includes "5 mg + / - 5%," which includes doses of 4.75 mg, 5.25 mg, or any amount therebetween.

[0123] "Recently diagnosed" patients were those with a history of oHCM of 12 months or less, regardless of use of standard treatment for oHCM.

[0124] "Untreated" patients are those who have not previously been treated with standard treatment for oHCM.

[0125] "Currently untreated" patients were those who had not received standard-of-care therapy for oHCM within the past 12 months.

[0126] Patients with "chronic oHCM" are those with a history of oHCM greater than 12 months who a) are currently being treated with standard of care for oHCM, or b) have received standard of care for oHCM within the past 12 months.

[0127] "NYHA classification" or "NYHA class" refers to the New York Heart Association functional classification of heart failure symptoms. Descriptions of each of the NYHA classes I, II, III, and IV can be found in: 1) Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart Association. Criteria Committee. "Nomenclature and criteria for diagnosis of diseases of the heart and great vessels", 9th ed. Boston, MA: Lippincott Williams and Wilkins; March 1, 1994; and 2) "Classes of Heart Failure", American Heart Association, https: / / www.heart.org / en / health-topics / heart-failure / what-is-heart-failure / classes-of-heart-failure, adapted from Criteria Committee, New York Heart Association, Inc. Diseases of the Heart and Blood Vessels. Nomenclature and Criteria for diagnosis, 6th ed. Boston, Little, Brown and Co. 1964, p 114. Briefly, NYHA class I indicates that the patient has no limitations in usual physical activity (e.g., shortness of breath when walking or climbing stairs). NYHA class II indicates that the patient has mild symptoms (e.g., mild shortness of breath and / or angina) and some limitations during usual activities. NYHA class III indicates that the patient is unable to perform even less than usual activities (e.g., walking short distances [20-100 m]) due to symptoms and is comfortable only at rest. NYHA class IV indicates that the patient has severe functional limitations and symptoms are present even at rest. Most patients are bedridden.

[0128] The term "pharmaceutically acceptable salt" refers to any salt of a compound herein that is known to be non-toxic and commonly used in the pharmaceutical literature. In some embodiments, a pharmaceutically acceptable salt of a compound retains the biological effectiveness of the compounds described herein and is not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0129] When the compounds described herein are obtained as acid addition salts, the solution of the acid salt can be basified to obtain free base.On the other hand, when the compound is a free base, addition salts, particularly pharmaceutically acceptable addition salts, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with acid according to the conventional procedure for preparing acid addition salts from basic compounds (see, for example, Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19).Those skilled in the art will recognize various synthetic methods that can be used to prepare pharmaceutically acceptable addition salts.

[0130] 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. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

[0131] The terms "patient," "individual," and "subject" refer to animals, e.g., mammals. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows, and humans. In some embodiments, a patient or subject is a human, e.g., a human who has been or will be the object of treatment, observation, or experimentation. The compounds, compositions, and methods described herein can be useful in both human therapy and veterinary applications.

[0132] The term "therapeutically effective amount" or "effective amount" refers to an amount of a compound disclosed and / or described herein that, when administered to a patient in need of treatment as defined herein, is sufficient to affect such treatment. A therapeutically effective amount of a compound may be an amount sufficient to treat a disease that responds to modulation of myocardial segments. A therapeutically effective amount will vary depending, for example, on the subject and condition being treated, the subject's weight and age, the severity of the condition, the particular compound, the dosing regimen to be followed, the timing of administration, and the mode of administration, all of which can be readily determined by one of ordinary skill in the art. A therapeutically effective amount can be ascertained experimentally, for example, by assaying blood levels of the chemical substance, or theoretically by calculating bioavailability.

[0133] "Treatment" (and related terms such as "treat," "treated," "treating") includes one or more of inhibiting a disease or disorder, delaying or preventing the onset of clinical symptoms of a disease or disorder, and / or alleviating a disease or disorder (i.e., causing a reduction or regression of clinical symptoms). The term encompasses both complete and partial reduction or prevention of a condition or disorder, and complete or partial reduction of clinical symptoms of a disease or disorder. Thus, the compounds described and / or disclosed herein may prevent the worsening of an existing disease or disorder, may assist in the management of a disease or disorder, or may reduce or eliminate a disease or disorder.

[0134] References to any dosage amount of a compound described herein or a pharmaceutically acceptable salt thereof (e.g., 5 mg, 10 mg, 20 mg, etc. of aficamten) refer to the amount of that compound without any salt (i.e., equivalent mass).

[0135] Treatment of hypertrophic obstructive cardiomyopathy As further described herein, a therapeutically effective amount of afficamten can be administered to a patient for the treatment of obstructive hypertrophic cardiomyopathy. The afficamten can be administered at a constant dose level. The afficamten can be administered at a dose-adjusted dose level. For example, the dose of afficamten can be adjusted depending on the patient's response to the drug. That is, the dose of afficamten can be periodically increased, decreased, maintained, or discontinued depending on measures of drug response, such as one or more of a biplane left ventricular ejection fraction (LVEF) measurement and a post-Valsalva LVOT-G measurement.

[0136] Results from a recent clinical trial (see Example 1) demonstrated that 10 weeks of aficamten treatment resulted in large and statistically significant reductions from baseline in mean resting left ventricular outflow tract gradient (LVOT-G) (p=0.0003, p=0.0004 for Cohort 1 and Cohort 2, respectively) and mean post-Valsalva LVOT-G (p=0.001, p<0.0001 for Cohort 1 and Cohort 2, respectively) compared to placebo. The majority of patients treated with aficamten (78.6% in Cohort 1 and 92.9% in Cohort 2) achieved the intended treatment goal, defined as a resting gradient of <30 mmHg and a post-Valsalva gradient of <50 mmHg at 10 weeks, compared to placebo (7.7%). The reduction in LVOT-G occurred within 2 weeks of initiating aficamten treatment, peaked within 2 to 6 weeks after the end of dose titration, and persisted until the end of treatment at week 10. The observed reduction in LVOT-G was dose-dependent, with patients achieving greater reductions in LVOT-G with increasing aficamten doses.

[0137] Treatment with aficamten in the clinical trial was well tolerated. Overall, the incidence of adverse events was similar between treatment arms. There were no serious adverse events attributable to aficamten, and no treatment discontinuations of aficamten occurred. No new cases of atrial fibrillation were reported by investigators. In this dose-ranging study, one patient experienced a transient decrease in left ventricular ejection fraction (LVEF) that required dose adjustment but not dose interruption. LVEF returned toward baseline within 2 weeks after the end of treatment in both cohorts, confirming the reversibility of the aficamten effect, as also observed in healthy participants in the phase 1 aficamten trial.

[0138] Aficamten is administered at a therapeutically effective dose, e.g., a dose sufficient to provide treatment for a disease state. In humans, the daily dose can be about 1 mg to about 50 mg. For example, the daily dose can be about 5 mg, about 10 mg, about 15 mg, about 20 mg, or any amount therebetween. The daily dose is the total amount administered in one day. The daily dose can be administered daily, every other day, weekly, every two weeks, monthly, or at various intervals, without limitation. In some embodiments, the daily dose is administered for a period ranging from one day to the lifespan 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., two, three, or four divided doses. In some embodiments, the daily dose is administered in two divided doses.

[0139] In one example, oHCM is treated in a patient by administering a daily dose of about 5 mg to about 20 mg of aficamten to the patient. In one example, hypertrophic obstructive cardiomyopathy is treated in a patient by administering a daily dose of about 5 mg of aficamten to the patient. In one example, hypertrophic obstructive cardiomyopathy is treated in a patient by administering a daily dose of about 10 mg of aficamten to the patient. In one example, hypertrophic obstructive cardiomyopathy is treated in a patient by administering a daily dose of about 15 mg of aficamten to the patient. In one example, hypertrophic obstructive cardiomyopathy is treated in a patient by administering a daily dose of about 20 mg of aficamten to the patient.

[0140] In some embodiments, methods for treating oHCM are provided that include administering, as monotherapy, aficamten or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing aficamten or a pharmaceutically acceptable salt thereof, wherein the patient has recently been diagnosed with oHCM, the patient is treatment-naive, or the patient has chronic oHCM. In some embodiments, methods for treating oHCM are provided that include administering, as monotherapy, aficamten or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing aficamten or a pharmaceutically acceptable salt thereof, wherein the patient has chronic oHCM and previously received SOC medication for oHCM prior to administration of aficamten or a pharmaceutically acceptable salt thereof. In some embodiments, a method for treating oHCM is provided, comprising administering aficamten or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing aficamten or a pharmaceutically acceptable salt thereof, as monotherapy, wherein the patient has chronic oHCM, has previously received SOC medication for oHCM prior to administering aficamten or a pharmaceutically acceptable salt thereof, and has discontinued SOC medication for oHCM prior to administering aficamten or a pharmaceutically acceptable salt thereof.

[0141] In some embodiments, the patient has an LVEF ≧60% and a resting LVOT-G ≧30 mmHg before administering aficamten or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has an LVEF ≧60% and a post-Valsalva LVOT-G ≧50 mmHg before administering aficamten. In some embodiments, the patient has an LVEF ≧60%, a resting LVOT-G ≧30 mmHg, and a post-Valsalva LVOT-G ≧50 mmHg before administering aficamten. In some embodiments, the patient has an LVEF ≧60%, a resting LVOT-G ≧30 mmHg, and a NYHA class II or III before administering aficamten or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has an LVEF ≧60%, a post-Valsalva LVOT-G ≧50 mmHg, and a NYHA class II or III before administering aficamten. In some embodiments, the patient has an LVEF > 60%, a resting LVOT-G > 30 mmHg, a post-Valsalva LVOT-G > 50 mmHg, and NYHA class II or III prior to administration of aficamten.

[0142] During the course of treatment for oHCM, the dose of aficamten administered to a patient may be titrated, e.g., by increasing, decreasing, or maintaining the dose. Dose adjustments may occur once during treatment or may be repeated over time. For example, in some embodiments, the dose of aficamten is titrated two or more times (e.g., three, four, five, or more times) during the course of treatment. In some embodiments, a new daily dose amount is administered to the patient at a stable amount for about one week to about eight weeks (or about two weeks to about six weeks, or about four weeks) before the daily dose amount is titrated. In some embodiments, a new daily dose amount is administered to the patient at a stable amount for about two weeks before the daily dose amount is titrated. For example, a first daily dose may be administered to the patient for about two weeks before the first dose adjustment, during which the daily dose amount is increased, decreased, or maintained. A second dose adjustment may then occur approximately two weeks after the first dose adjustment. Dose titration allows for the dosage to be individualized to the patient's response to the drug, thereby maximizing the potential therapeutic benefit to the patient.

[0143] Dose adjustment can be based on one or more of the patient's measured biplane left ventricular ejection fraction (LVEF) and post-Valsalva LVOT-G. These measurement(s) can be determined, for example, using an echocardiogram. The echocardiogram is taken after administration of the daily dose, for example, about 1 hour to about 3 hours after administration of the dose. In some embodiments, the echocardiogram is taken about 2 hours after administration of the daily dose.

[0144] In some embodiments, an initial daily dose of about 5 mg, about 10 mg, about 15 mg, or about 20 mg of aficamten, or any amount therebetween, is administered to the patient. After a period of time (e.g., about two weeks), biplane LVEF and / or post-Valsalva LVOT-G are measured, e.g., by echocardiography, after dose administration (e.g., about 1-3 hours or about 2 hours after dose administration). If the biplane LVEF falls below a predetermined biplane LVEF threshold (e.g., less than 50%), the dose can be reduced or terminated. For example, if the biplane LVEF falls below the biplane LVEF threshold and the current dose is not the lowest (e.g., first) dose, the dose can be reduced. If the biplane LVEF falls below the biplane LVEF threshold and the current dose is the lowest (e.g., first) dose, the dose can be discontinued. If the biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold and less than a second predetermined biplane LVEF threshold (e.g., 50%≦LVEF<55%), the dosage may be maintained, or if the biplane LVEF is equal to or greater than a second predetermined biplane LVEF threshold (e.g., 55% or greater) and the post-Valsalva LVOT-G is less than a predetermined LVOT-G threshold (e.g., less than 30%), the dosage may be maintained. If the post-Valsalva LVOT-G is equal to or greater than a predetermined LVOT-G threshold (e.g., about 30 mmHg or greater) and the biplane LVEF is equal to or greater than a second predetermined biplane LVEF threshold (e.g., about 55% or greater), the daily dose is increased. In some embodiments, the biplane LVEF threshold is about 50%, and the post-Valsalva LVOT-G threshold is about 30 mmHg. If the LVEF is consistently less than 40%, the administration of the daily dose is temporarily suspended. In some embodiments, titration of the dose of aficamten includes maintaining the dose at the current dose; increasing the dose by about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 10 mg, or any amount therebetween; decreasing the dose by about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 10 mg, or any amount therebetween; or discontinuing administration.In some embodiments, dose titration includes maintaining the dose at the current dose; increasing the dose by about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 10 mg, or any amount therebetween; or decreasing the dose by about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 10 mg, or any amount therebetween.

[0145] After a period of time (e.g., about two weeks) during which the patient is administered the first titrated dose, the dose may again be titrated (i.e., increased, decreased, or maintained) based on the patient's biplane LVEF and / or post-Valsalva LVOT-G, e.g., using the same threshold parameters described above. Exemplary titration schedules include administering the first titrated dose for about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about eight weeks, about ten weeks, or about twelve weeks, or any period therebetween, followed by titration based on the patient's biplane LVEF and / or post-Valsalva LVOT-G, e.g., using the same threshold parameters described above. Further iterations of administration and titration may occur as appropriate.

[0146] Provided herein are methods for reducing post-Valsalva LVOT-G to below a specific value in patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM), comprising administering a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof to the patient, wherein the patient has recently been diagnosed with oHCM, the patient is treatment-naive, or the patient has chronic oHCM. The reduction in post-Valsalva LVOT-G to below the specific value can occur within 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 9 weeks, or 10 weeks of initiating treatment with aficamten or a pharmaceutically acceptable salt thereof. The reduction in post-Valsalva LVOT-G can be sustained for at least 10 weeks of treatment. In some embodiments, the reduction in post-Valsalva LVOT-G occurs within 2 to 6 weeks of the end of titration. In some embodiments, the reduction in post-Valsalva LVOT-G peaks within 2 to 6 weeks of the end of titration. In some embodiments, the specific post-Valsalva LVOT-G value is 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, or 30 mmHg.

[0147] Further provided herein are methods for treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient with heart failure symptoms, wherein the patient has recently been diagnosed with oHCM, the patient is treatment-naive, or the patient has chronic oHCM, comprising administering a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof to the patient, wherein the method results in a reduction in heart failure symptoms as assessed by NYHA classification. In some embodiments described above, the method improves the heart failure symptoms of the patient by at least one NYHA class, e.g., by one or two NYHA class(es). In some embodiments described above, the method changes the patient's NYHA class from III to II or I. In some embodiments described above, the method changes the patient's NYHA class from III to II. In some embodiments described above, the method changes the patient's NYHA class from III to I. In some embodiments described above, the method changes the patient's NYHA class from II to I. In some of the foregoing embodiments, the reduction in heart failure symptoms occurs within 10 weeks of initiating treatment with aficamten or a pharmaceutically acceptable salt thereof.

[0148] FIG. 1 illustrates an exemplary method for treating a patient with obstructive hypertrophic cardiomyopathy (oHCM), where the patient has recently been diagnosed with oHCM (e.g., within the past 12 months), the patient has not been treated for oHCM, or the patient has previously received standard medical therapy for oHCM and discontinued that treatment before administering aficamten, the method comprising titrating a daily dose of aficamten or a pharmaceutically acceptable salt thereof. The exemplary method illustrated in FIG. 1 provides four daily dose levels (e.g., about 5 mg, 10 mg, 15 mg, and 20 mg), with the first daily dose level being the lowest daily dose level (e.g., about 5 mg) but can be easily modified to include additional or lower dose levels. The exemplary method illustrated in FIG. 1 can be further modified so that the first daily dose level is not the lowest daily dose level. At 102, a first daily dose level (e.g., about 5 mg) of aficamten or a pharmaceutically acceptable salt thereof is administered to the patient. After the first period of time, the daily dose level is increased or maintained, or administration is terminated, at 104. This selection may be based on a first echocardiogram obtained for the patient after the first period of time. End administration 106 may be selected if the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold (e.g., 50%), and no further doses of aficamten or a pharmaceutically acceptable salt thereof are administered to the patient. If either of the following conditions is met on the first echocardiogram: (1) the biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold (e.g., 50%) and less than a second predetermined biplane LVEF threshold (e.g., 55%), or (2) the biplane LVEF is equal to or greater than a second predetermined biplane LVEF threshold (e.g., 55%) and the post-Valsalva LVOT-G on the first echocardiogram is less than a predetermined post-Valsalva LVOT-G threshold (e.g., 30 mmHg), maintenance of the first daily dose level (e.g., about 5 mg) can be selected. If maintenance is selected, the first daily dose level of aficamten or a pharmaceutically acceptable salt thereof is administered to the patient for a second period of time at 102, and optionally, the daily dose can be titrated again at 104 after the second period of time.If either of the following conditions is met on the first echocardiogram: (1) the biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold (e.g., 50%) and is less than a second predetermined biplane LVEF threshold (e.g., 55%), or (2) the biplane LVEF is equal to or greater than a second predetermined biplane LVEF threshold (e.g., 55%) and the post-Valsalva LVOT-G on the first echocardiogram exceeds a predetermined post-Valsalva LVOT-G threshold (e.g., 30 mmHg), the daily dose level may be increased to a second daily dose level (e.g., 10 mg). If an increase in the daily dose level is selected, a second daily dose level of aficamten or a pharmaceutically acceptable salt thereof is administered to the patient for a second period at 108.

[0149] If a second daily dose level (e.g., 10 mg) of aficamten or a pharmaceutically acceptable salt thereof is administered to the patient at 108, the daily dose may be titrated again (i.e., selecting to increase, decrease, or maintain the daily dose) based on the echocardiogram at 110. If the biplane LVEF of the echocardiogram is below a predetermined biplane LVEF threshold (e.g., 50%), the daily dose may be reduced to the first daily dose level (e.g., from about 10 mg to about 5 mg). If the daily dose is reduced to the first daily dose level, the first daily dose level (e.g., about 5 mg) is administered to the patient at 102. If either of the following conditions is met on the echocardiogram: (1) the biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold (e.g., 50%) and is less than a second predetermined biplane LVEF threshold (e.g., 55%), or (2) the biplane LVEF is equal to or greater than a second predetermined biplane LVEF threshold (e.g., 55%) and the echocardiogram post-Valsalva LVOT-G is less than a predetermined post-Valsalva LVOT-G threshold (e.g., 30 mmHg), maintenance of the second daily dose level (e.g., about 10 mg) can be selected. If maintenance is selected, the second daily dose level of aficamten or a pharmaceutically acceptable salt thereof is administered to the patient for a further period at 108, and optionally, the daily dose can be titrated again at 110 after the second period. If the biplane LVEF is equal to or greater than a second predetermined biplane LVEF threshold (e.g., 55%) and the echocardiographic post-Valsalva LVOT-G exceeds a predetermined post-Valsalva LVOT-G threshold (e.g., 30 mmHg), the daily dose may be increased to a third daily dose level (e.g., 15 mg). If an increase in the daily dose level is selected, a second daily dose level of aficamten or a pharmaceutically acceptable salt thereof is administered to the patient for a period of time at 112.

[0150] If a third daily dose level (e.g., 10 mg) of aficamten or a pharmaceutically acceptable salt thereof is administered to the patient at 112, the daily dose may be titrated again (i.e., selecting to increase, decrease, or maintain the daily dose) based on the echocardiogram at 114. If the biplane LVEF of the echocardiogram is below a predetermined biplane LVEF threshold (e.g., 50%), the daily dose may be reduced to a second daily dose level (e.g., from 15 mg to 10 mg). If the daily dose is reduced to the second daily dose level, the second daily dose level is administered to the patient at 108. If either of the following conditions is met on the echocardiogram: (1) the biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold (e.g., 50%) and is below a second predetermined biplane LVEF threshold (e.g., 55%), or (2) the biplane LVEF is equal to or greater than a second predetermined biplane LVEF threshold (e.g., 55%) and the echocardiogram post-Valsalva LVOT-G is below a predetermined post-Valsalva LVOT-G threshold (e.g., 30 mmHg), maintenance of the third daily dose level (e.g., about 15 mg) can be selected. If maintenance is selected, the third daily dose level of aficamten or a pharmaceutically acceptable salt thereof is administered to the patient for a further period of time at 112, and optionally the daily dose can be titrated again at 114 after that period of time. If the biplane LVEF is equal to or greater than a second predetermined biplane LVEF threshold (e.g., 55%) and the echocardiographic post-Valsalva LVOT-G exceeds a second predetermined post-Valsalva LVOT-G threshold (e.g., 30 mmHg), the daily dose may be increased to a fourth daily dose level (e.g., 20 mg). If an increase in the daily dose level is selected, the fourth daily dose level of aficamten or a pharmaceutically acceptable salt thereof is administered to the patient for a second period of time at 116.

[0151] 1, the first daily dose level is a minimum dose and therefore will not be further reduced. Nevertheless, in other embodiments, the first daily dose level may be other than a minimum dose and may be reduced to a lower dose level (e.g., from 10 mg to 5 mg) if the echocardiographic biplane LVEF falls below a predetermined biplane LVEF threshold (e.g., 50%).

[0152] In the exemplary method shown in Figure 1, the fourth daily dose level is the maximum dose and therefore is not further increased. Nevertheless, in other embodiments, additional dose levels may be available and the daily dose may be further increased at 118. In the method shown in Figure 1, a selection is made at 118 to maintain the fourth daily dose level or to decrease the daily dose level based on the echocardiogram. If the biplane LVEF of the echocardiogram is below a predetermined biplane LVEF threshold (e.g., 50%), the daily dose may be decreased to a third daily dose level (e.g., from 20 mg to 15 mg). If the daily dose is decreased to the third daily dose level, the second daily dose level is administered to the patient at 112. If either of the following conditions is met on the echocardiogram: (1) the biplane LVEF is equal to or greater than a predetermined biplane LVEF threshold (e.g., 50%) and is below a second predetermined biplane LVEF threshold (e.g., 55%), or (2) the biplane LVEF is equal to or greater than a second predetermined biplane LVEF threshold (e.g., 55%) and the echocardiogram post-Valsalva LVOT-G is below a predetermined post-Valsalva LVOT-G threshold (e.g., 30 mmHg), maintenance of the third daily dose level (e.g., about 15 mg) can be selected. If maintenance is selected, the third daily dose level of aficamten or a pharmaceutically acceptable salt thereof is administered to the patient for a further period of time at 116, and optionally the daily dose can be titrated again at 118 after that period of time.

[0153] Exemplary daily dose increases include an increase from about 5 mg to about 10 mg of aficamten, an increase from about 10 mg to about 15 mg of aficamten, or an increase from about 10 mg to about 20 mg of aficamten. Other dose increases are readily envisioned, such as increasing a given initial daily dose by about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 10 mg, or any amount therebetween. Exemplary daily dose decreases include a decrease from about 20 mg to about 10 mg, a decrease from about 15 mg to about 10 mg, or a decrease from about 10 mg to about 5 mg. Other dose decreases are readily envisioned, such as decreasing a given initial daily dose by about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 10 mg, or any amount therebetween.

[0154] An exemplary embodiment of the methods described herein involves administering a first daily dose of aficamten or a pharmaceutically acceptable salt thereof (e.g., about 1 mg to about 20 mg, e.g., a first daily dose of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, or 20 mg, or any amount therebetween) for a first period of time (e.g., about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 12 weeks, or any length of time therebetween), followed by measuring the patient's biplane LVEF and / or post-Valsalva LVOT-G. Based on this, the daily dose can be maintained, the daily dose can be decreased (e.g., the daily dose can be decreased by about 1 mg to about 10 mg, e.g., the daily dose can be decreased by 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg, or any amount therebetween), the daily dose can be increased (e.g., the daily dose can be increased by about 1 mg to about 10 mg, e.g., the daily dose can be increased by 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg, or any amount therebetween), or administration can be discontinued to reach the second daily dose. Another exemplary embodiment of the methods described herein includes administering a first daily dose of aficamten or a pharmaceutically acceptable salt thereof for about two weeks, followed by maintaining the daily dose, decreasing the daily dose by about 5 mg, increasing the daily dose by about 5 mg, or discontinuing administration to reach the second daily dose based on the patient's biplane LVEF and / or post-Valsalva LVOT-G. Another exemplary embodiment of the methods described herein includes administering a first daily dose of aficamten or a pharmaceutically acceptable salt thereof for about three weeks, followed by maintaining the daily dose, decreasing the daily dose by about 5 mg, increasing the daily dose by about 5 mg, or discontinuing administration to reach the second daily dose based on the patient's resting LVOT-G, biplane LVEF, and / or post-Valsalva LVOT-G.Another exemplary embodiment of the methods described herein includes administering a first daily dose of aficamten or a pharmaceutically acceptable salt thereof for about two weeks, followed by maintaining the daily dose, decreasing the daily dose by about 10 mg, increasing the daily dose by about 10 mg, or discontinuing administration to reach the second daily dose, based on the patient's biplane LVEF and / or post-Valsalva LVOT-G. Another exemplary embodiment of the methods described herein includes administering a first daily dose of aficamten or a pharmaceutically acceptable salt thereof for about three weeks, followed by maintaining the daily dose, decreasing the daily dose by about 10 mg, increasing the daily dose by about 10 mg, or discontinuing administration to reach the second daily dose, based on the patient's biplane LVEF and / or post-Valsalva LVOT-G. Another exemplary embodiment of the methods described herein includes administering a first daily dose of aficamten or a pharmaceutically acceptable salt thereof for about 2 weeks to about 12 weeks, followed by maintaining the daily dose, decreasing the daily dose by about 10 mg, increasing the daily dose by about 10 mg, or discontinuing administration to reach the second daily dose based on the patient's biplane LVEF and / or post-Valsalva LVOT-G.

[0155] Treatment of oHCM may result in improved exercise capacity and / or symptomatic relief in patients with hyperdynamic ventricular contractions due to obstructive hypertrophic cardiomyopathy. The methods disclosed herein may be useful in treating recently diagnosed, untreated, or patients with chronic oHCM.

[0156] In some embodiments, a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy, thereby reducing the patient's post-Valsalva LVOT-G. The patient may have been recently diagnosed with oHCM (e.g., within the past 12 months), may not have been treated for oHCM, or may have previously received standard medical therapy for oHCM and discontinued that treatment prior to administering aficamten. In some embodiments, the patient has a baseline post-Valsalva LVOT-G of about 30 mmHg or greater, about 40 mmHg or greater, 50 mmHg or greater, about 60 mmHg or greater, or about 70 mmHg or greater. In response to administration of a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof, the post-Valsalva LVOT-G may decrease to less than 50 mmHg, e.g., about 45 mmHg or less, about 40 mmHg or less, about 35 mmHg or less, or about 30 mmHg or less. In some embodiments, in response to administration of a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof, post-Valsalva LVOT-G decreases by about 10 mmHg or more, about 15 mmHg or more, about 20 mmHg or more, about 25 mmHg or more, about 30 mmHg or more, or about 35 mmHg or more. In some embodiments, in response to administration of a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof, post-Valsalva LVOT-G decreases by about 10 mmHg to about 40 mmHg. The decrease in post-Valsalva LVOT-G can occur about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after administration of the daily dose.

[0157] In some embodiments, a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy, thereby decreasing the patient's left ventricular mass index (LVMI), where the patient has recently been diagnosed with oHCM (e.g., within the past 12 months), the patient has not been treated for oHCM, or the patient previously received standard of care medical therapy for oHCM and discontinued that treatment prior to administering aficamten. In response to administration of a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof, the LVMI decreases to about 1 g / m or less. 2More than about 1.5g / m 2 More than about 2g / m 2 More than about 2.5g / m 2 More than about 3g / m 2 Above, about 3.5g / m 2 or more, or about 4 g / m 2 In some embodiments, in response to administration of a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof, the LVMI can be reduced by about 1 g / m 2 ~about 10g / m 2 , for example, about 1 g / m 2 ~about 6g / m 2 or approximately 2 g / m 2 ~about 5g / m 2 The reduction in LVMI can occur at about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after administration of the daily dose.

[0158] In some embodiments, a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy, thereby decreasing the patient's left arterial volume index (LAVI), where the patient has recently been diagnosed with oHCM (e.g., within the past 12 months), the patient has not been treated for oHCM, or the patient previously received standard of care medical therapy for oHCM and discontinued that treatment prior to administering aficamten. In response to administration of a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof, the LAVI decreases to about 0.5 mL / m 2 Approximately 1mL / m 2 Approximately 1.5mL / m 2 Approximately 2mL / m 2 or more, or approximately 2.5 mL / m 2 In some embodiments, in response to administration of a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof, the LAVI can be reduced by about 0.5 mL / m 2 ~about 5mL / m 2 mmHg, e.g., about 0.5 mL / m 2 ~approx. 4g / m 2 or approximately 1 mL / m 2 ~about 3mL / m 2The reduction in LAVI can occur at about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after administration of the daily dose.

[0159] In some embodiments, a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy, thereby decreasing the patient's e' value. The patient may have been recently diagnosed with oHCM (e.g., within the past 12 months), may not have been treated for oHCM, or may have previously received standard medical therapy for oHCM and discontinued that treatment prior to administering afficamten. In response to administration of a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof, the e' value may decrease by about 0.1 cm / s or more, about 0.15 cm / s or more, about 0.2 cm / s or more, or about 0.25 cm / s or more. In some embodiments, in response to administration of a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof, the e' value decreases by about 0.05 cm / s to about 0.3 cm / s, e.g., about 0.1 cm / s to about 0.25 cm / s or about 0.15 cm / s to about 0.25 cm / s. The decrease in the e' value can occur after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after administration of the daily dose.

[0160] In some embodiments, a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy, thereby decreasing the patient's lateral wall E / e' ratio. The patient may have been recently diagnosed with oHCM (e.g., within the past 12 months), may not have been treated for oHCM, or may have previously received standard medical therapy for oHCM and discontinued that treatment prior to administering aficamten. In response to administration of a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof, the lateral wall E / e' ratio may decrease by about 0.5 or more, 1 or more, about 1.2 or more, about 1.5 or more, or about 1.8 or more. In some embodiments, in response to administration of a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof, the lateral wall E / e' ratio decreases by about 0.5 to about 2, e.g., about 1 to about 1.8, or about 1.5 to about 1.8. The decrease in the lateral wall E / e' ratio can occur after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after administration of the daily dose.

[0161] In some embodiments, a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy, thereby reducing the patient's brain natriuretic peptide or N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels. The patient may have recently been diagnosed with oHCM (e.g., within the past 12 months), may not be receiving treatment for oHCM, or may have previously received standard medical therapy for oHCM and discontinued that treatment prior to administering aficamten. The reduction in the patient's brain natriuretic peptide or N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels may occur about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after administration of the daily dose.

[0162] In some embodiments, a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy, thereby decreasing the patient's cardiac troponin I levels. The patient may have recently been diagnosed with oHCM (e.g., within the past 12 months), the patient has not been treated for oHCM, or the patient previously received standard medical therapy for oHCM and discontinued that treatment prior to administering aficamten. The decrease in the patient's cardiac troponin I levels may occur about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after administration of the daily dose.

[0163] In some embodiments of any of the foregoing, the patient with obstructive hypertrophic cardiomyopathy is classified as NYHA class III when administration of aficamten or a pharmaceutically acceptable salt thereof is initiated, and the patient has recently been diagnosed with oHCM (e.g., within the past 12 months), the patient has not been treated for oHCM, or the patient previously received standard of care medical therapy for oHCM and discontinued that treatment prior to administration of aficamten. In some embodiments, the patient with obstructive hypertrophic cardiomyopathy is classified as NYHA class II when administration of aficamten or a pharmaceutically acceptable salt thereof is initiated.

[0164] In some embodiments of any of the foregoing, administration of aficamten or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in an improvement in the patient's exercise capacity, where the patient has recently been diagnosed with oHCM (e.g., within the past 12 months), the patient has not been treated for oHCM, or the patient previously received standard of care medical therapy for oHCM and discontinued that treatment prior to administering aficamten. In some embodiments of any of the foregoing, administration of aficamten or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in an improvement in the patient's exercise capacity, as measured, for example, by change in maximal oxygen uptake (pVO2) or change in maximal oxygen uptake (pVO2) by cardiopulmonary exercise testing (CPET).

[0165] In some embodiments of any of the foregoing, aficamten or a pharmaceutically acceptable salt thereof results in an improvement in total workload during CPET when administered to a patient with obstructive hypertrophic cardiomyopathy, where the patient has recently been diagnosed with oHCM (e.g., within the past 12 months), the patient is not receiving treatment for oHCM, or the patient has previously received standard of care medical therapy for oHCM and discontinued that treatment prior to administering aficamten.

[0166] In some embodiments of any of the foregoing, administration of aficamten or a pharmaceutically acceptable salt thereof to patients with obstructive hypertrophic cardiomyopathy results in improvement of other CPET parameters, including, but not limited to, one or more of: (1) ventilatory efficiency (VE / VCO2 slope), (2) circulatory power (VO2 × systolic BP), and (3) ventilatory anaerobic threshold (VAT), where the patient has recently been diagnosed with oHCM (e.g., within the past 12 months), the patient is not being treated for oHCM, or the patient has previously received standard of care medical therapy for oHCM and discontinued that treatment prior to administering aficamten.

[0167] In some embodiments of any of the foregoing, administration of aficamten or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in an improvement in the patient's health status, where the patient has recently been diagnosed with oHCM (e.g., within the past 12 months), the patient has not been treated for oHCM, or the patient previously received standard of care medical therapy for oHCM and discontinued that treatment prior to administering aficamten. In some embodiments of any of the foregoing, administration of aficamten or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in an improvement in the patient's health status as measured by a change in the Kansas City Cardiomyopathy Questionnaire-Overall Summary Score (KCCQ-OSS). In some embodiments of any of the foregoing, administration of aficamten or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in an improvement in the patient's health status as measured by a change in the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS). In some embodiments of any of the foregoing, administration of aficamten or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in an improvement in the patient's health status as measured by a change in the Kansas City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS). In some embodiments of any of the foregoing, administration of aficamten or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in an improvement in the patient's health status as measured by a change in the Kansas City Cardiomyopathy Questionnaire-Physical Limitation Score (KCCQ-PLS). In some embodiments of any of the foregoing, administration of aficamten or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in an improvement in the patient's health status as measured by a change in the Kansas City Cardiomyopathy Questionnaire-Social Limitation Score (KCCQ-SLS). In some embodiments of any of the foregoing, administration of aficamten or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in an improvement in the patient's health status as measured by a change in the Kansas City Cardiomyopathy Questionnaire-Quality of Life (KCCQ-QoL).In some embodiments, administration of aficamten or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in an improvement of at least about 5 points, at least about 10 points, or at least about 20 points in one or more KCCQ domain scores (e.g., KCCQ-OSS, KCCQ-CSS, KCCQ-TSS, KCCQ-PLS, KCCQ-SLS, or KCCQ-QoL). In some embodiments, administration of aficamten or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in an improvement of about 5 to less than 10 points, about 10 to less than 20 points, or at least 20 points in one or more KCCQ scores (e.g., KCCQ-OSS, KCCQ-CSS, KCCQ-TSS, KCCQ-PLS, KCCQ-SLS, or KCCQ-QoL). In some such embodiments, the improvement in one or more KCCQ domain scores is an improvement in KCCQ-OSS. In some embodiments, the improvement in one or more KCCQ domain scores persists for about 6 months. In some embodiments, administration of aficamten or a pharmaceutically acceptable salt thereof to patients with obstructive hypertrophic cardiomyopathy results in an improvement of 1, 2, 3, 4, 5, or more than 5 points on the KCCQ-CSS. In some embodiments of any of the foregoing, administration of aficamten or a pharmaceutically acceptable salt thereof to patients with obstructive hypertrophic cardiomyopathy results in an improvement in the patient's health status and health-related quality of life as measured by a PRO questionnaire, as determined by a change in response to the EuroQol 5 Dimension 5 Level instrument (EQ-5D-5L). In some embodiments, administration of aficamten or a pharmaceutically acceptable salt thereof results in an improvement in one or more HCM symptoms. In some embodiments, the improvement in one or more HCM symptoms includes a decrease in the severity and / or frequency of chest pain, dizziness, shortness of breath, fainting during physical activity, fatigue, lack of energy, or limitations in physical activity.

[0168] Combinations of the foregoing results are also contemplated. In some embodiments of any of the foregoing, administration of aficamten or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy (wherein the patient has recently been diagnosed with oHCM (e.g., within the past 12 months), the patient is not receiving treatment for oHCM, or the patient previously received standard of care medical therapy for oHCM and discontinued that treatment prior to administration of aficamten) results in an improvement in exercise capacity and functional class, as determined by, for example, (1) a change from baseline in pVO2 of ≥ 1.5 mL / kg / min and an improvement in NYHA functional class of ≥ 1 class, or (2) a change from baseline in pVO2 of ≥ 3.0 mL / kg / min and no worsening of NYHA functional class. In some embodiments of any of the foregoing, administration of aficamten or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in the patient having a resting LVOT-G of < 30 mmHg, a post-Valsalva LVOT-G of < 50 mmHg, and a NYHA functional class of I. In some embodiments of any of the foregoing, administration of aficamten or a pharmaceutically acceptable salt thereof to a patient with hypertrophic obstructive cardiomyopathy results in the patient having a resting LVOT-G of <30 mmHg, a post-Valsalva LVOT-G of <50 mmHg, and an improvement in NYHA functional class by at least one class.

[0169] In some embodiments, the methods disclosed herein include reducing resting LVOT-G to less than 30 mmHg, reducing post-Valsalva LVOT-G to less than 50 mmHg, improving mitral regurgitation, improving cardiac relaxation, beneficial cardiac remodeling, reverse cardiac remodeling, beneficial structural cardiac remodeling, beneficial functional cardiac remodeling, reversing adverse cardiac remodeling, reducing mean left ventricular mass index (LVMI), improving left ventricular (LV) filling pressures, reducing left atrial volume index (LAVI), and systolic anterior motion of the mitral valve leaflets. reduction in mitral valve regurgitation, reduction in lateral wall E / e', reduction in lateral wall E / E, reduction in brain natriuretic peptide (BNP) levels, reduction in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels, reduction in cardiac troponin I levels, reduction in left ventricular wall stress, reduction in myocardial damage, and reduction in heart failure symptoms (e.g., reduction in NYHA classification).

[0170] How to reduce foundational therapy for oHCM Standard-of-care (SoC) medications are currently recommended as first-line therapy for the treatment of obstructive hypertrophic cardiomyopathy (oHCM). These medications include one or more of the following: beta-blockers, calcium channel blockers, disopyramide, and ranolazine. However, off-target side effects often make them unattractive to patients. These side effects may include hypotension, bradycardia, fatigue, insomnia, and sexual dysfunction. Reduction and / or withdrawal of baseline therapy (BTR / W) may be beneficial for patients. Weaning off beta-blocker therapy in patients with heart failure with preserved ejection fraction (HFpEF) and chronotropic heart failure has been shown to result in functional benefits, such as improved pVO2 and improved health status as measured by the Minnesota Heart Failure Living Questionnaire (MLHFQ) score (Palau et al., Clin. Cardiol. 2020:45(5):423-429).

[0171] In some aspects, methods of treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof are provided, wherein the patient is receiving one or more baseline therapies for oHCM. In some embodiments, methods of treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof are provided, wherein the patient is receiving baseline therapies for oHCM, comprising: (1) administering a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof to the patient; and (2) reducing and / or ceasing at least one baseline therapy. In some embodiments, the patient is receiving one, two, or three baseline therapies for oHCM. In some embodiments, the method comprises reducing at least one baseline therapy. In some embodiments, the method comprises reducing all of the one or more baseline therapies. In some embodiments, the method comprises ceasing at least one baseline therapy. In some embodiments, the method comprises ceasing all of the one or more baseline therapies. In some embodiments, at least one of the baseline therapies comprises administering at least one standard of care therapy selected from the group consisting of a beta-blocker, a non-dihydropyridine calcium channel blocker, and disopyramide. In some embodiments, the patient is receiving one or more of a beta-blocker, a non-dihydropyridine calcium channel blocker, and disopyramide as a baseline therapy. In some embodiments, reducing at least one baseline therapy comprises administering a lower dose of the at least one baseline therapy. In some embodiments, the lower dose is 50% or less of the original dose of the baseline therapy. In some embodiments, (i) initiating administration of a therapeutically effective amount of aficamten, or a pharmaceutically acceptable salt thereof, to the patient and (ii) reducing and / or stopping the at least one baseline therapy are performed simultaneously. In some embodiments, (i) initiating administration of a therapeutically effective amount of aficamten, or a pharmaceutically acceptable salt thereof, to the patient and (ii) reducing and / or stopping the at least one baseline therapy are performed sequentially.In some embodiments, at least one baseline therapy is reduced and / or discontinued at the start of administration of aficamten or a pharmaceutically acceptable salt thereof. In some embodiments, the reduction and / or discontinuation of at least one baseline therapy is performed 2 weeks or more after initiation of administration of aficamten or a pharmaceutically acceptable salt thereof, for example, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 8 weeks, 10 weeks, 12 weeks, 15 weeks, 18 weeks, or 24 weeks after initiation of administration of aficamten or a pharmaceutically acceptable salt thereof, or any time period therebetween. In some embodiments, the reduction and / or discontinuation of at least one baseline therapy is performed 12 weeks or more after initiation of administration of aficamten or a pharmaceutically acceptable salt thereof. In some embodiments, the reduction and / or cessation of at least one background therapy occurs when the patient has received a stable dose of afficamten or a pharmaceutically acceptable salt thereof for 2 weeks or more, e.g., 2, 3, 4, 5, 8, 10, 12, 15, 18, or 24 weeks, or any period therebetween, after initiation of administration of afficamten or a pharmaceutically acceptable salt thereof. In some embodiments, the reduction and / or cessation of at least one background therapy occurs when the patient has received a stable dose of afficamten or a pharmaceutically acceptable salt thereof for 4 weeks or more, e.g., 4, 5, 8, 10, 12, 15, 18, or 24 weeks, or any period therebetween, after initiation of administration of afficamten or a pharmaceutically acceptable salt thereof.

[0172] In another aspect, a method of treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof is provided, comprising: (1) administering a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof to the patient for a first period of time in combination with a first dose of standard of care therapy for oHCM; and (2) administering a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof to the patient for a second period of time in combination with a second dose of standard of care therapy for oHCM. In some embodiments, the second dose of standard of care therapy for oHCM is less than the first dose of standard of care therapy. In some embodiments, the second dose of standard of care therapy for oHCM is 50% or less of the first dose of standard of care therapy. In some embodiments, the first period of time is at least 12 weeks. In some embodiments, aficamten or a pharmaceutically acceptable salt thereof is administered at a constant dose for at least about 4 weeks prior to the start of the second period of time.

[0173] In another aspect, methods are provided for treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, comprising: (1) administering a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof in combination with standard of care therapy for oHCM to the patient for a first period of time; and (2) administering a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof to the patient as monotherapy for a second period of time. In some embodiments, the second dose of the standard of care therapy for oHCM is no more than 50% of the first dose of the standard of care therapy. In some embodiments, the first period of time is at least 12 weeks. In some embodiments, the aficamten or a pharmaceutically acceptable salt thereof is administered at a constant dose for at least about 4 weeks prior to the start of the second period of time.

[0174] In another aspect, a method of treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof is provided, comprising: (1) administering to the patient a background therapy comprising at least one standard of care therapy selected from the group consisting of a beta-blocker, a non-dihydropyridine calcium channel blocker, and disopyramide; (2) administering to the patient a therapeutically effective amount of aficamten, or a pharmaceutically acceptable salt thereof, in combination with the background therapy for a first period of time; and (3) administering to the patient a therapeutically effective amount of aficamten, or a pharmaceutically acceptable salt thereof, in combination with a second dose of standard of care therapy for oHCM for a second period of time, wherein the second dose of standard of care therapy for oHCM is less than the first dose of standard of care therapy. In some embodiments, the second dose of standard of care therapy for oHCM is no more than 50% of the first dose of standard of care therapy. In some embodiments, the first period of time is at least 12 weeks. In some embodiments, aficamten or a pharmaceutically acceptable salt thereof is administered at a steady rate for at least about four weeks prior to the start of the second period.

[0175] In another aspect, a method of treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof is provided, comprising: (1) administering to the patient a background therapy comprising at least one standard of care therapy selected from the group consisting of a beta-blocker, a non-dihydropyridine calcium channel blocker, and disopyramide; (2) administering to the patient a therapeutically effective amount of aficamten, or a pharmaceutically acceptable salt thereof, in combination with the background therapy for a first period of time; and (3) administering to the patient a therapeutically effective amount of aficamten, or a pharmaceutically acceptable salt thereof, as monotherapy for a second period of time. In some embodiments, the first period of time is at least 12 weeks. In some embodiments, the aficamten, or a pharmaceutically acceptable salt thereof, is administered at a constant dose for at least about 4 weeks prior to the start of the second period of time.

[0176] In another aspect, a method for improving myocardial mechanics in a patient in need thereof is provided, comprising administering a therapeutically effective amount of afficamten or a pharmaceutically acceptable salt thereof to the patient. In some aspects, a method for improving myocardial mechanics in a patient with obstructive hypertrophic cardiomyopathy is provided, comprising administering a therapeutically effective amount of afficamten or a pharmaceutically acceptable salt thereof to the patient. In some embodiments, the method comprises chronic administration of afficamten or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the method comprises administering afficamten for at least about 12 weeks, at least about 24 weeks, at least about 36 weeks, at least about 48 weeks, at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, or at least about 10 years. In some embodiments, the method comprises administering afficamten for at least about 12 weeks. In some embodiments, the method comprises administering afficamten for at least about 36 weeks. In some embodiments, the method comprises administering afficamten for at least about 48 weeks. In some embodiments, the method further results in an improvement in resting LVOT-G. In some embodiments, the method results in a resting LVOT-G of less than 30 mmHg. In some embodiments, the method further results in an improvement in Valsalva LVOT-G. In some embodiments, the method results in a Valsalva LVOT-G of less than 50 mmHg. In some embodiments, the method comprises administering aficamten or a pharmaceutically acceptable salt thereof to a patient who exhibits an optimal hemodynamic response to treatment with aficamten or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the method comprises administering aficamten to a patient whose resting LVOT-G is less than 30 mmHg. In some embodiments, the method comprises administering aficamten to a patient whose Valsalva LVOT-G is less than 50 mmHg. In some embodiments, the patient has a resting LVOT-G of less than 30 mmHg as a result of treatment with aficamten or a pharmaceutically acceptable salt thereof.In some embodiments, the patient has a Valsalva LVOT-G of less than 50 mmHg as a result of treatment with aficamten or a pharmaceutically acceptable salt thereof. In some embodiments, the patient exhibits an optimal hemodynamic response to treatment with aficamten or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement in myocardial mechanics occurs after the patient exhibits an optimal hemodynamic response to treatment with aficamten or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement in myocardial mechanics occurs about 4 weeks, about 6 weeks, about 8 weeks, about 12 weeks, or about 36 weeks (or any number of weeks therebetween) after the patient achieves a resting LVOT-G of less than 30 mmHg and / or a Valsalva LVOT-G of less than 50 mmHg in response to treatment with aficamten or a pharmaceutically acceptable salt thereof.

[0177] In another aspect, a method for improving global longitudinal strain (GLS) in a patient in need thereof is provided, comprising administering a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof to the patient. In some aspects, a method for improving global longitudinal strain (GLS) in a patient with hypertrophic obstructive cardiomyopathy is provided, comprising administering a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof to the patient. In some embodiments, the method comprises chronic administration of aficamten or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the method comprises administering aficamten for at least about 12 weeks, at least about 24 weeks, at least about 36 weeks, at least about 48 weeks, at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, or at least about 10 years. In some embodiments, the method comprises administering aficamten for at least about 12 weeks. In some embodiments, the method comprises administering aficamten for at least about 36 weeks. In some embodiments, the method comprises administering aficamten for at least about 48 weeks. In some embodiments, the method further results in an improvement in resting LVOT-G. In some embodiments, the method results in a resting LVOT-G of less than 30 mmHg. In some embodiments, the method further results in an improvement in Valsalva LVOT-G. In some embodiments, the method results in a Valsalva LVOT-G of less than 50 mmHg. In some embodiments, the method comprises administering aficamten or a pharmaceutically acceptable salt thereof to a patient who exhibits an optimal hemodynamic response to treatment with aficamten or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the method comprises administering aficamten to a patient with a resting LVOT-G of less than 30 mmHg. In some embodiments, the method comprises administering aficamten to a patient with a Valsalva LVOT-G of less than 50 mmHg.In some embodiments, the patient has a resting LVOT-G of less than 30 mmHg as a result of treatment with aficamten or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has a Valsalva LVOT-G of less than 50 mmHg as a result of treatment with aficamten or a pharmaceutically acceptable salt thereof. In some embodiments, the patient exhibits an optimal hemodynamic response to treatment with aficamten or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement in GLS occurs after the patient exhibits an optimal hemodynamic response to treatment with aficamten or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement in GLS occurs about 4 weeks, about 6 weeks, about 8 weeks, about 12 weeks, or about 36 weeks (or any number of weeks therebetween) after the patient achieves a resting LVOT-G of less than 30 mmHg and / or a Valsalva LVOT-G of less than 50 mmHg in response to treatment with aficamten or a pharmaceutically acceptable salt thereof.

[0178] In some embodiments of any of the foregoing, the therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof is selected by titrating the daily dose of aficamten or a pharmaceutically acceptable salt thereof administered to the patient, as described herein with respect to the methods of treating oHCM.

[0179] In some embodiments, the patient suffers from a co-morbidity, ie, one or more of hypertension, diabetes, permanent atrial fibrillation, and paroxysmal atrial fibrillation.

[0180] Administration of the compounds and compositions disclosed and / or described herein can be via any accepted mode of administration for a therapeutic agent, including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. In some embodiments, the compounds or compositions are administered orally or intravenously. In some embodiments, the compounds or compositions disclosed and / or described herein are administered orally. In some embodiments, the compounds or compositions disclosed and / or described herein are administered by injection. In some embodiments, the compounds or compositions disclosed and / or described herein are administered intranasally. In some embodiments, the compounds or compositions disclosed and / or described herein are administered transdermally.

[0181] Pharmaceutically acceptable compositions include solid, semi-solid, liquid, and aerosol dosage forms, such as tablets, capsules, powders, solutions, suspensions, suppositories, and aerosol forms. The compounds disclosed and / or described herein may be administered in sustained- or controlled-release dosage forms (e.g., controlled-release / sustained-release pills, depot injections, osmotic pumps, or transdermal patch forms (including electrotransport)) for timed administration over an extended period of time and / or for pulsed administration at a predetermined rate. In some embodiments, the compositions are provided in unit dosage forms suitable for single administration of precise doses.

[0182] Aficamten may be administered alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, saccharin sodium, 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). Generally, pharmaceutical compositions contain about 0.005% to 95% by weight or about 0.5% to 50% by weight of a compound disclosed and / or described herein, depending on the intended mode of administration. Actual methods for preparing such dosage forms are known, or will become apparent, to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania. Suitable formulations of aficamten are disclosed in WO2021 / 011808, which is incorporated herein by reference in its entirety.

[0183] In some embodiments, aficamten is provided in a formulation comprising (i) aficamten or a pharmaceutically acceptable salt thereof, (ii) a filler, (iii) a binder, (iv) a disintegrant, (v) a surfactant, and (vi) a lubricant. In some embodiments, aficamten is provided in a formulation comprising (i) aficamten, (ii) a filler, (iii) a binder, (iv) a disintegrant, (v) a surfactant, and (vi) a lubricant. In some embodiments, the filler is selected from the group consisting of powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, kaolin, corn starch, maize starch, starch derivatives, pregelatinized starch, calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate, tricalcium phosphate, compressible sugars, sugar alcohols, mannitol, sorbitol, maltitol, xylitol, lactitol, lactose, dextrose, maltose, sucrose, glucose, fructose, saccharose, raffinose, dextrates, trehalose, maltodextrin, and mixtures of any of the foregoing.

[0184] In some embodiments, the binder is selected from the group consisting of gum arabic, gum acacia, alginate, alginic acid, corn starch, copolyvidone, polyvinylpyrrolidone, gelatin, glyceryl behenate, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hypromellose, lactose, polyvinyl alcohol, povidone, polyethylene oxide, polyacrylates, potato starch, pregelatinized starch, sodium alginate, sodium starch, sodium carboxymethyl cellulose, starch, and mixtures of any of the foregoing.

[0185] In some embodiments, the disintegrant is selected from the group consisting of alginic acid, croscarmellose sodium, cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, polacrilin potassium, pregelatinized starch, partially hydrolyzed starch, carboxymethylstarch sodium, starch, sodium alginate, carboxymethylcellulose sodium, and mixtures of any of the foregoing.

[0186] In some embodiments, the surfactant is cetylpyridine chloride, heptadecaethyleneoxycetanol, lecithin, polyoxyethylene stearate, nonoxynol 9, nonoxynol 10, octoxynol 9, sorbitan fatty acid esters, span 20, span 40, span 60, span 80, span 85, polysorbate, polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, fatty alcohol sulfate The surfactant is selected from the group consisting of sodium salts of hydroxypropyl methylcellulose, sodium lauryl sulfate, sodium salts of sulfosuccinic acid, dioctyl sodium sulfosuccinate, partial esters of fatty acids and alcohols, glycerin monostearate, glyceryl monooleate, ethers of polyoxyethylene and fatty alcohols, esters of polyoxyethylene and fatty acids, copolymers of ethylene oxide and propylene oxide (Pluronic®), benzalkonium chloride, ethoxylated triglycerides, and mixtures of any of the foregoing.

[0187] In some embodiments, the lubricant is selected from the group consisting of hydrogenated castor oil, magnesium stearate, glyceryl monostearate, calcium stearate, glyceryl behenate, glycerol distearate, glyceryl dipalmitostearate, behenoyl polyoxyl-8 glyceride, sodium stearyl fumarate, stearic acid, talc, zinc stearate, mineral oil, polyethylene glycol, polaxamer, sodium lauryl sulfate, and mixtures of any of the foregoing.

[0188] In some embodiments, the formulation comprises (i) about 1% to about 80% by weight of aficamten or a pharmaceutically acceptable salt thereof, (ii) about 15% to about 90% by weight of a filler, (iii) about 0.1% to about 10% by weight of a binder, (iv) about 1% to about 10% by weight of a disintegrant, (v) about 0.1% to about 10% by weight of a surfactant, and (vi) about 0.1% to about 10% by weight of a lubricant.

[0189] In some embodiments, the formulation comprises (i) about 1% to about 50% by weight of aficamten or a pharmaceutically acceptable salt thereof, (ii) about 40% to about 80% by weight of a filler, (iii) about 0.5% to about 5% by weight of a binder, (iv) about 2% to about 8% by weight of a disintegrant, (v) about 0.5% to about 5% by weight of a surfactant, and (vi) about 0.5% to about 5% by weight of a lubricant.

[0190] In some embodiments, the formulation comprises (i) about 10% to about 30% by weight of aficamten or a pharmaceutically acceptable salt thereof, (ii) about 60% to about 80% by weight of a filler, (iii) about 1% to about 3% by weight of a binder, (iv) about 4% to about 6% by weight of a disintegrant, (v) about 1% to about 3% by weight of a surfactant, and (vi) about 0.5% to about 1.5% by weight of a lubricant.

[0191] In some embodiments, the formulation comprises (i) about 1% to about 10% by weight of aficamten or a pharmaceutically acceptable salt thereof, (ii) about 70% to about 90% by weight of a filler, (iii) about 1% to about 3% by weight of a binder, (iv) about 4% to about 6% by weight of a disintegrant, (v) about 1% to about 3% by weight of a surfactant, and (vi) about 0.5% to about 1.5% by weight of a lubricant.

[0192] In some embodiments, the formulation comprises (i) about 5% by weight of aficamten or a pharmaceutically acceptable salt thereof, (ii) about 85% by weight of a filler, (iii) about 2% by weight of a binder, (iv) about 5% by weight of a disintegrant, (v) about 2% by weight of a surfactant, and (vi) about 1% by weight of a lubricant.

[0193] In some embodiments, the formulation comprises (i) about 10% by weight of aficamten or a pharmaceutically acceptable salt thereof, (ii) about 80% by weight of a filler, (iii) about 2% by weight of a binder, (iv) about 5% by weight of a disintegrant, (v) about 2% by weight of a surfactant, and (vi) about 1% by weight of a lubricant.

[0194] In some embodiments, the formulation comprises (i) about 1% to about 50% by weight of aficamten or a pharmaceutically acceptable salt thereof, (ii-1) about 10% to about 60% by weight of mannitol, (ii-2) about 5% to about 45% by weight of microcrystalline cellulose, (iii) about 0.1% to about 10% by weight of hydroxypropyl cellulose, (iv) about 1% to about 10% by weight of croscarmellose sodium, (v) about 0.1% to about 10% by weight of sodium lauryl sulfate, and (vi) about 0.1% to about 10% by weight of magnesium stearate.

[0195] In some embodiments, the formulation comprises (i) about 10% to about 30% by weight of aficamten or a pharmaceutically acceptable salt thereof, (ii-1) about 40% to about 50% by weight of mannitol, (ii-2) about 20% to about 30% by weight of microcrystalline cellulose, (iii) about 1% to about 3% by weight of hydroxypropyl cellulose, (iv) about 4% to about 6% by weight of croscarmellose sodium, (v) about 1% to about 3% by weight of sodium lauryl sulfate, and (vi) about 0.5% to about 1.5% by weight of magnesium stearate.

[0196] In some embodiments, the formulation comprises (i) about 1% to about 10% by weight of aficamten or a pharmaceutically acceptable salt thereof, (ii-1) about 50% to about 60% by weight of mannitol, (ii-2) about 25% to about 35% by weight of microcrystalline cellulose, (iii) about 1% to about 3% by weight of hydroxypropyl cellulose, (iv) about 4% to about 6% by weight of croscarmellose sodium, (v) about 1% to about 3% by weight of sodium lauryl sulfate, and (vi) about 0.5% to about 1.5% by weight of magnesium stearate.

[0197] In some embodiments, the formulation comprises (i) about 20% by weight of aficamten or a pharmaceutically acceptable salt thereof, (ii-1) about 44% by weight of mannitol, (ii-2) about 26% by weight of microcrystalline cellulose, (iii) about 2% by weight of hydroxypropyl cellulose, (iv) about 5% by weight of croscarmellose sodium, (v) about 2% by weight of sodium lauryl sulfate, and (vi) about 1% by weight of magnesium stearate.

[0198] In some embodiments, the formulation comprises (i) about 10% by weight of aficamten or a pharmaceutically acceptable salt thereof, (ii-1) about 50% by weight of mannitol, (ii-2) about 30% by weight of microcrystalline cellulose, (iii) about 2% by weight of hydroxypropyl cellulose, (iv) about 5% by weight of croscarmellose sodium, (v) about 2% by weight of sodium lauryl sulfate, and (vi) about 1% by weight of magnesium stearate.

[0199] In some embodiments, the formulation comprises (i) about 5% by weight of aficamten or a pharmaceutically acceptable salt thereof, (ii-1) about 54% by weight of mannitol, (ii-2) about 31% by weight of microcrystalline cellulose, (iii) about 2% by weight of hydroxypropyl cellulose, (iv) about 5% by weight of croscarmellose sodium, (v) about 2% by weight of sodium lauryl sulfate, and (vi) about 1% by weight of magnesium stearate.

[0200] In some embodiments, the formulation is in the form of a tablet. In some embodiments, the tablet further comprises a coating (e.g., a film coating as described elsewhere herein). In such embodiments, the weight percentages herein are provided relative to the core tablet, not including the weight of the coating.

[0201] In some embodiments, aficamten or a pharmaceutical composition containing aficamten takes the form of a pill or tablet, and thus the composition may contain one or more of a diluent (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesium stearate), and / or a binder (e.g., starch, gum arabic, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives) along with a compound disclosed and / or described herein. Other solid dosage forms include powders, marume, solutions, or suspensions (e.g., in propylene carbonate, vegetable oils, or triglycerides) enclosed in gelatin capsules.

[0202] In some embodiments, aficamten is provided in a tablet comprising: (i) a core having a total core weight comprising: (a) (ai) aficamten, or a pharmaceutically acceptable salt thereof, (a-ii) an intragranular filler, (a-iii) an intragranular binder, (a-iv) an intragranular disintegrant, and (av) an intragranular surfactant; and (b) an extragranular component comprising: (bi) an extragranular filler, (b-ii) an extragranular disintegrant, and (b-iii) an extragranular lubricant; and optionally (ii) a coating layer comprising a coating agent.

[0203] In some embodiments, the intragranular filler is selected from the group consisting of powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, kaolin, corn starch, maize starch, starch derivatives, pregelatinized starch, calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate, tricalcium phosphate, compressible sugars, sugar alcohols, mannitol, sorbitol, maltitol, xylitol, lactitol, lactose, dextrose, maltose, sucrose, glucose, fructose, saccharose, raffinose, dextrates, trehalose, maltodextrin, and mixtures of any of the foregoing.

[0204] In some embodiments, the intragranular binder is selected from the group consisting of gum arabic, gum acacia, alginate, alginic acid, corn starch, copolyvidone, polyvinylpyrrolidone, gelatin, glyceryl behenate, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hypromellose, lactose, polyvinyl alcohol, povidone, polyethylene oxide, polyacrylates, potato starch, pregelatinized starch, sodium alginate, sodium starch, sodium carboxymethyl cellulose, starch, and mixtures of any of the foregoing.

[0205] In some embodiments, the intragranular disintegrant is selected from the group consisting of alginic acid, croscarmellose sodium, cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, polacrilin potassium, pregelatinized starch, partially hydrolyzed starch, carboxymethylstarch sodium, starch, sodium alginate, carboxymethylcellulose sodium, and mixtures of any of the foregoing.

[0206] In some embodiments, the intragranular surfactant is cetylpyridine chloride, heptadecaethyleneoxycetanol, lecithin, polyoxyethylene stearate, nonoxynol 9, nonoxynol 10, octoxynol 9, sorbitan fatty acid esters, span 20, span 40, span 60, span 80, span 85, polysorbate, polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, fatty alcohol Selected from the group consisting of sodium salts of sulfates, sodium lauryl sulfate, sodium salts of sulfosuccinic acid, dioctyl sodium sulfosuccinate, partial esters of fatty acids and alcohols, glycerin monostearate, glyceryl monooleate, ethers of polyoxyethylene and fatty alcohols, esters of polyoxyethylene and fatty acids, copolymers of ethylene oxide and propylene oxide (Pluronic®), benzalkonium chloride, ethoxylated triglycerides, and mixtures of any of the foregoing.

[0207] In some embodiments, the extragranular filler is selected from the group consisting of powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, kaolin, corn starch, maize starch, starch derivatives, pregelatinized starch, calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate, tricalcium phosphate, compressible sugars, sugar alcohols, mannitol, sorbitol, maltitol, xylitol, lactitol, lactose, dextrose, maltose, sucrose, glucose, fructose, saccharose, raffinose, dextrates, trehalose, maltodextrin, and mixtures of any of the foregoing.

[0208] In some embodiments, the extragranular disintegrant is selected from the group consisting of alginic acid, croscarmellose sodium, cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, polacrilin potassium, pregelatinized starch, partially hydrolyzed starch, carboxymethylstarch sodium, starch, sodium alginate, carboxymethylcellulose sodium, and mixtures of any of the foregoing.

[0209] In some embodiments, the extragranular lubricant is selected from the group consisting of hydrogenated castor oil, magnesium stearate, glyceryl monostearate, calcium stearate, glyceryl behenate, glycerol distearate, glyceryl dipalmitostearate, behenoyl polyoxyl-8 glyceride, sodium stearyl fumarate, stearic acid, talc, zinc stearate, mineral oil, polyethylene glycol, polaxamer, sodium lauryl sulfate, and mixtures of any of the foregoing.

[0210] In some embodiments, the core comprises (a) an intragranular component including (ai) aficamten or a pharmaceutically acceptable salt thereof in an amount of about 1% to about 80% of the total core weight, (a-ii) an intragranular filler in an amount of about 10% to about 80% of the total core weight, (a-iii) an intragranular binder in an amount of about 0.1% to about 10% of the total core weight, (a-iv) an intragranular disintegrant in an amount of about 0.1% to about 5% of the total core weight, and (av) an intragranular surfactant in an amount of about 0.1% to about 5% of the total core weight, and (b) an extragranular component including (bi) an extragranular filler in an amount of about 5% to about 15% of the total core weight, (b-ii) an extragranular disintegrant in an amount of about 0.1% to about 5% of the total core weight, and (b-iii) an extragranular lubricant in an amount of about 0.1% to about 5% of the total core weight. In some embodiments, the total core weight is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0211] In some embodiments, the core comprises (a) an intragranular component including (ai) aficamten or a pharmaceutically acceptable salt thereof in an amount of about 1% to about 80% of the total core weight, (a-ii) an intragranular filler in an amount of about 10% to about 80% of the total core weight, (a-iii) an intragranular binder in an amount of about 0.1% to about 10% of the total core weight, (a-iv) an intragranular disintegrant in an amount of about 0.1% to about 5% of the total core weight, and (av) an intragranular surfactant in an amount of about 0.1% to about 5% of the total core weight, and (b) an extragranular component including (bi) an extragranular filler in an amount of about 5% to about 15% of the total core weight, (b-ii) an extragranular disintegrant in an amount of about 0.1% to about 5% of the total core weight, and (b-iii) an extragranular lubricant in an amount of about 0.1% to about 5% of the total core weight. In some embodiments, the total core weight is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0212] In some embodiments, the core comprises (a) an intragranular component including (ai) aficamten or a pharmaceutically acceptable salt thereof in an amount of about 1% to about 50% of the total core weight, (a-ii) an intragranular filler in an amount of about 40% to about 80% of the total core weight, (a-iii) an intragranular binder in an amount of about 1% to about 5% of the total core weight, (a-iv) an intragranular disintegrant in an amount of about 1% to about 5% of the total core weight, and (av) an intragranular surfactant in an amount of about 1% to about 5% of the total core weight, and (b) an extragranular component including (bi) an extragranular filler in an amount of about 5% to about 15% of the total core weight, (b-ii) an extragranular disintegrant in an amount of about 1% to about 5% of the total core weight, and (b-iii) an extragranular lubricant in an amount of about 0.1% to about 2% of the total core weight. In some embodiments, the total core weight is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0213] In some embodiments, the core comprises (a) an intragranular component including (ai) aficamten or a pharmaceutically acceptable salt thereof in an amount of about 10% to about 30% of the total core weight, (a-ii) an intragranular filler in an amount of about 50% to about 70% of the total core weight, (a-iii) an intragranular binder in an amount of about 1% to about 3% of the total core weight, (a-iv) an intragranular disintegrant in an amount of about 2% to about 4% of the total core weight, and (av) an intragranular surfactant in an amount of about 1% to about 3% of the total core weight, and (b) an extragranular component including (bi) an extragranular filler in an amount of about 5% to about 15% of the total core weight, (b-ii) an extragranular disintegrant in an amount of about 1% to about 3% of the total core weight, and (b-iii) an extragranular lubricant in an amount of about 0.1% to about 1.5% of the total core weight. In some embodiments, the total core weight is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0214] In some embodiments, the core comprises (a) an intragranular component including (ai) aficamten or a pharmaceutically acceptable salt thereof in an amount of about 1% to about 10% of the total core weight, (a-ii) an intragranular filler in an amount of about 60% to about 80% of the total core weight, (a-iii) an intragranular binder in an amount of about 1% to about 3% of the total core weight, (a-iv) an intragranular disintegrant in an amount of about 2% to about 4% of the total core weight, and (av) an intragranular surfactant in an amount of about 1% to about 3% of the total core weight, and (b) an extragranular component including (bi) an extragranular filler in an amount of about 5% to about 15% of the total core weight, (b-ii) an extragranular disintegrant in an amount of about 1% to about 3% of the total core weight, and (b-iii) an extragranular lubricant in an amount of about 0.1% to about 1.5% of the total core weight. In some embodiments, the total core weight is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0215] In some embodiments, the core comprises (a) an intragranular component including (ai) about 5% of the total core weight of aficamten or a pharmaceutically acceptable salt thereof, (a-ii) about 74% of the total core weight of an intragranular filler, (a-iii) about 2% of the total core weight of an intragranular binder, (a-iv) about 3% of the total core weight of an intragranular disintegrant, and (av) about 2% of the total core weight of an intragranular surfactant, and (b) an extragranular component including (bi) about 11% of the total core weight of an extragranular filler, (b-ii) about 2% of the total core weight of an extragranular disintegrant, and (b-iii) about 1% of the total core weight of an extragranular lubricant. In some embodiments, the total core weight is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0216] In some embodiments, the core comprises (a) an intragranular component including (ai) about 10% of the total core weight of aficamten or a pharmaceutically acceptable salt thereof, (a-ii) about 69% of the total core weight of an intragranular filler, (a-iii) about 2% of the total core weight of an intragranular binder, (a-iv) about 3% of the total core weight of an intragranular disintegrant, and (av) about 2% of the total core weight of an intragranular surfactant, and (b) an extragranular component including (bi) about 11% of the total core weight of an extragranular filler, (b-ii) about 2% of the total core weight of an extragranular disintegrant, and (b-iii) about 1% of the total core weight of an extragranular lubricant. In some embodiments, the total core weight is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0217] In some embodiments, the core comprises (a) an intragranular component including (ai) about 20% of the total core weight of aficamten or a pharmaceutically acceptable salt thereof, (a-ii) about 59% of the total core weight of an intragranular filler, (a-iii) about 2% of the total core weight of an intragranular binder, (a-iv) about 3% of the total core weight of an intragranular disintegrant, and (av) about 2% of the total core weight of an intragranular surfactant, and (b) an extragranular component including (bi) about 11% of the total core weight of an extragranular filler, (b-ii) about 2% of the total core weight of an extragranular disintegrant, and (b-iii) about 1% of the total core weight of an extragranular lubricant. In some embodiments, the total core weight is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0218] In some embodiments, the core comprises (a) an intragranular component comprising: (ai) aficamten or a pharmaceutically acceptable salt thereof at about 1% to about 50% of the total core weight; (a-ii-1) mannitol at about 40% to about 60% of the total core weight; (a-ii-2) microcrystalline cellulose at about 10% to about 30% of the total core weight; (a-iii) hydroxypropyl cellulose at about 1% to about 5% of the total core weight; (a-iv) croscarmellose sodium at about 1% to about 5% of the total core weight; and (av) sodium lauryl sulfate at about 1% to about 5% of the total core weight; and (b) an extragranular component comprising: (bi) microcrystalline cellulose at about 5% to about 15% of the total core weight; (b-ii) croscarmellose sodium at about 1% to about 5% of the total core weight; and (b-iii) an extragranular lubricant at about 0.1% to about 2% of the total core weight. In some embodiments, the extragranular lubricant is magnesium stearate. In some embodiments, the total core weight is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0219] In some embodiments, the core comprises (a) an intragranular component including (ai) about 10% to about 30% of the total core weight of aficamten or a pharmaceutically acceptable salt thereof, (a-ii-1) about 40% to about 50% of the total core weight of mannitol, (a-ii-2) about 10% to about 20% of the total core weight of microcrystalline cellulose, (a-iii) about 1% to about 3% of the total core weight of hydroxypropyl cellulose, (a-iv) about 2% to about 4% of the total core weight of croscarmellose sodium, and (av) about 1% to about 3% of the total core weight of sodium lauryl sulfate, and (b) an extragranular component including (bi) about 5% to about 15% of the total core weight of microcrystalline cellulose, (b-ii) about 1% to about 3% of the total core weight of croscarmellose sodium, and (b-iii) about 0.1% to about 1.5% of the total core weight of an extragranular lubricant. In some embodiments, the extragranular lubricant is magnesium stearate. In some embodiments, the total core weight is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0220] In some embodiments, the core comprises (a) an intragranular component including (ai) about 1% to about 10% by weight of aficamten or a pharmaceutically acceptable salt thereof of the total core weight, (a-ii-1) about 50% to about 60% by weight of mannitol of the total core weight, (a-ii-2) about 15% to about 25% by weight of microcrystalline cellulose of the total core weight, (a-iii) about 1% to about 3% by weight of hydroxypropyl cellulose of the total core weight, (a-iv) about 2% to about 4% by weight of croscarmellose sodium of the total core weight, and (av) about 1% to about 3% by weight of sodium lauryl sulfate of the total core weight, and (b) an extragranular component including (bi) about 5% to about 15% by weight of microcrystalline cellulose of the total core weight, (b-ii) about 1% to about 3% by weight of croscarmellose sodium of the total core weight, and (b-iii) about 0.1% to about 1.5% by weight of an extragranular lubricant of the total core weight. In some embodiments, the extragranular lubricant is magnesium stearate. In some embodiments, the total core weight is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0221] In some embodiments, the core comprises (a) an intragranular component comprising: (ai) about 20% aficamten or a pharmaceutically acceptable salt thereof by weight of the total core; (a-ii-1) about 44% mannitol by weight of the total core; (a-ii-2) about 15% microcrystalline cellulose by weight of the total core; (a-iii) about 2% hydroxypropyl cellulose by weight of the total core; (a-iv) about 3% croscarmellose sodium by weight of the total core; and (av) about 2% sodium lauryl sulfate by weight of the total core; and (b) an extragranular component comprising: (bi) about 11% microcrystalline cellulose by weight of the total core; (b-ii) about 2% croscarmellose sodium by weight of the total core; and (b-iii) about 1% extragranular lubricant by weight of the total core. In some embodiments, the extragranular lubricant is magnesium stearate. In some embodiments, the total core weight is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0222] In some embodiments, the core comprises (a) an intragranular component comprising: (ai) about 10% aficamten or a pharmaceutically acceptable salt thereof by weight of the total core; (a-ii-1) about 50% mannitol by weight of the total core; (a-ii-2) about 19% microcrystalline cellulose by weight of the total core; (a-iii) about 2% hydroxypropyl cellulose by weight of the total core; (a-iv) about 3% croscarmellose sodium by weight of the total core; and (av) about 2% sodium lauryl sulfate by weight of the total core; and (b) an extragranular component comprising: (bi) about 11% microcrystalline cellulose by weight of the total core; (b-ii) about 2% croscarmellose sodium by weight of the total core; and (b-iii) about 1% extragranular lubricant by weight of the total core. In some embodiments, the extragranular lubricant is magnesium stearate. In some embodiments, the total core weight is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0223] In some embodiments, the core comprises (a) an intragranular component comprising (ai) about 5% by weight of aficamten or a pharmaceutically acceptable salt thereof, (a-ii-1) about 54% by weight of mannitol, (a-ii-2) about 20% by weight of microcrystalline cellulose, (a-iii) about 2% by weight of hydroxypropyl cellulose, (a-iv) about 3% by weight of croscarmellose sodium, and (av) about 2% by weight of sodium lauryl sulfate; and (b) an extragranular component comprising (bi) about 11% by weight of microcrystalline cellulose, (b-ii) about 2% by weight of croscarmellose sodium, and (b-iii) about 1% by weight of an extragranular lubricant. In some embodiments, the extragranular lubricant is magnesium stearate. In some embodiments, the total core weight is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

[0224] In some embodiments, the tablet includes a coating layer comprising a coating agent. In some embodiments, the coating layer surrounds the entire tablet core. In some embodiments, the coating agent is selected from the group consisting of Opadry QX White 21A180025, Opadry I, and Opadry II. In some embodiments, the coating agent is Opadry QX White 21A180025. In some embodiments, the tablet includes about 0.5% to about 10% of the total core weight of the coating agent. In some embodiments, the tablet includes about 1% to about 5% of the total core weight of the coating agent. In some embodiments, the tablet includes about 2% to about 4% of the total core weight of the coating agent. In some embodiments, the tablet includes about 3% of the total core weight of the coating agent. In some embodiments, the tablet includes about 0.5% to about 10% of the total core weight of Opadry QX White 21A180025. In some embodiments, the tablet comprises about 1% to about 5% of the total core weight of Opadry QX White 21A180025. In some embodiments, the tablet comprises about 2% to about 4% of the total core weight of Opadry QX White 21A180025. In some embodiments, the tablet comprises about 3% of the total core weight of Opadry QX White 21A180025.

[0225] In some embodiments, the amount of aficamten (which may exist in various forms) in a formulation, e.g., a tablet, is approximately the daily dose described herein, e.g., about 5 mg, about 10 mg, about 15 mg, or about 20 mg of aficamten. In some embodiments, the amount of aficamten (which may exist in various forms) in a formulation (e.g., a tablet) is about half the daily dose described herein. In some embodiments, the amount of aficamten in a formulation (e.g., a tablet) is about 2.5 mg, about 5 mg, about 7.5 mg, or about 10 mg of aficamten.

[0226] In some embodiments, aficamten is present in free base form in various formulations, such as tablets. In some embodiments, methods, such as those described in the Examples, use such tablets.

[0227] Liquid pharmaceutically administrable compositions can be prepared, for example, by dissolving, dispersing, or suspending a compound disclosed and / or described herein and optional pharmaceutical additives in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycol, ethanol, etc.) to form a solution or suspension. Injectables can be prepared in conventional forms: as liquid solutions or suspensions, as emulsions, or as solid forms suitable for dissolution or suspension in liquid prior to injection. The percentage of compound contained in such parenteral compositions depends, for example, on the physical properties of the compound, the activity of the compound, and the needs of the subject. However, percentages of active ingredient ranging from 0.01% to 10% in solution are usable, and may be higher if the composition is a solid that is subsequently diluted to another concentration. In some embodiments, the composition contains about 0.2-2% of a compound disclosed and / or described herein in solution.

[0228] Pharmaceutical compositions of the compounds disclosed and / or described herein may be administered to the respiratory tract as aerosols or solutions for nebulizers, or as ultrafine powders for inhalation, either alone or in combination with an inert carrier such as lactose.In such cases, the particles of the pharmaceutical composition may have a diameter of less than 50 microns, or in some embodiments, less than 10 microns.Pharmaceutical compositions of the compounds disclosed and / or described herein may also be administered transdermally, for example, in the form of patches, creams, ointments, or other formulations suitable for administration to the skin.

[0229] Additionally, pharmaceutical compositions may include a compound disclosed and / or described herein, as well as one or more additional drugs, pharmaceutical agents, adjuvants, etc. Suitable drugs and pharmaceutical agents include those described herein.

[0230] Polymorph In some embodiments, aficamten is a polymorphic form of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Suitable polymorphs of aficamten include those disclosed in, and may be prepared in accordance with, WO2021 / 011807, which is incorporated herein by reference in its entirety. Polymorphs may have properties such as bioavailability and stability under specific conditions suitable for medical or pharmaceutical use. Differences in the crystalline structure of a drug substance can affect the drug's dissolution rate (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ease of purification, ability to prepare uniform doses of known strengths, etc.), and stability (e.g., thermal stability, shelf life (including resistance to degradation), etc.). Such differences may affect the preparation or formulation of pharmaceutical compositions in different dosage or delivery forms, such as solid oral dosage forms, including tablets and capsules. Compared to other forms, such as non-crystalline or amorphous forms, polymorphs may provide desirable or suitable hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, reproducibility, and / or process control. Thus, a polymorph of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide may provide advantages such as improved manufacturing processes for the active agent, improved stability or shelf life of pharmaceutical forms of the active agent, or favorable bioavailability and / or stability for the active agent. In some embodiments, the aficamten in a formulation, e.g., a tablet, is one of polymorphic Form I, Form II, Form III, Form IV, Form V, or Form VI, or a combination thereof. In some embodiments, the aficamten is one of polymorphic Form I, Form II, Form III, Form IV, Form V, or Form VI. In some embodiments, the aficamten is polymorphic Form I or Form IV. In some embodiments, the aficamten is polymorphic Form I.In some embodiments, the aficamten is polymorphic form IV.

[0231] Form I In some embodiments, Aficamten is polymorphic Form I of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. The angles 2θ and relative peak intensities that may be observed for Form I using XRPD are shown in Table P-1. In some embodiments, Form I has an XRPD pattern substantially as shown in Figure 59A. [Table 1]

[0232] In some embodiments, polymorph Form I has an XRPD pattern substantially as shown in Figure 59A or as shown in Table P-1, exhibiting at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks at angles 2θ with maximum intensity in the XRPD pattern. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting, and the instrumentation and analytical procedures and settings used to acquire the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including polymorph Form I, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2θ.

[0233] In some embodiments, polymorphic Form I is 3.7±0.2, 11.2±0.2, 12.9±0.2, 13.5±0.2, 14.4±0.2, 14.9±0.2, 16.6±0.2, 17.8±0.2, 18.6±0.2, 21.6±0.2, 22.2±0.2, 22.4±0.2, 22.8±0.2, 23.2±0.2, 23.9±0.2, 24.4±0.2 0.2, 24.7±0.2, 25.0±0.2, 25.8±0.2, 26.1±0.2, 28.6±0.2, 29.0±0.2, 29.4±0.2, 29.9±0.2, 30.6±0.2, 33.8±0.2, 36.1±0.2, 36.8±0.2, 37.8±0.2, and 39.8±0.2 degrees 2θ. In some embodiments, polymorphic Form I has an XRPD pattern comprising peaks at 3.7±0.2, 11.2±0.2, 12.9±0.2, 13.5±0.2, 14.4±0.2, 18.6±0.2, 22.4±0.2, 24.7±0.2, 25.0±0.2, and 26.1±0.2 degrees 2θ. In some embodiments, polymorphic Form I has an XRPD pattern comprising peaks at 3.7±0.2, 11.2±0.2, 12.9±0.2, 14.4±0.2, and 22.4±0.2 degrees 2θ. It is understood that peaks in an XRPD pattern other than those shown in Figure 59A or provided in Table P-1 may be observed due to, for example, the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0234] In some embodiments, Form I has a derivative DSC graph substantially as shown in Figure 59B. In some embodiments, Form I is characterized by having an endothermic onset at about 199°C as determined by DSC. In some embodiments, Form I is characterized by having an endothermic onset at 199±2°C (e.g., 199±1.9°C, 199±1.8°C, 199±1.7°C, 199±1.6°C, 199±1.5°C, 199±1.4°C, 199±1.3°C, 192±1.2°C, 199±1, 199±0.9°C, 199±0.8°C, 199±0.7°C, 199±0.6°C, 199±0.5°C, 199±0.4°C, 199±0.3°C, 199±0.2°C, or 199±0.1°C) as determined by DSC.

[0235] In some embodiments, Form I has a TGA graph substantially as shown in Figure 59B.

[0236] In some embodiments, Form I has a DVS graph substantially as shown in Figure 59C.

[0237] In some embodiments of Form I, at least one, at least two, at least three, at least four, at least five, or all of the following (a)-(f) apply: (a) Form I has an XRPD pattern containing peaks at 3.7±0.2, 11.2±0.2, 12.9±0.2, 14.4±0.2, and 22.4±0.2 degrees 2θ; or has an XRPD pattern containing peaks at 3.7±0.2, 11.2±0.2, 12.9±0.2, 13.5±0.2, 14.4±0.2, 18.6±0.2, 22.4±0.2, 24.7±0.2, 25.0±0.2, and 26.1±0.2 degrees 2θ; or ±0.2, 16.6±0.2, 17.8±0.2, 18.6±0.2, 21.6±0.2, 22.2±0.2, 22.4±0.2, 22.8±0.2, 23.2±0.2, 23.9±0.2, 24.4±0.2, 24.7±0.2, 25.0±0.2, 25.8±0.2, 26.1±0.2, 28.6±0.2, 29.0±0.2, 29.4±0.2, 29.9±0.2, 30.6±0.2, 33.8±0.2, 36.1±0.2, 36.8±0.2, 37.8±0.2, and 39.8±0.2 degrees 2θ. (b) Form I has an XRPD pattern substantially as shown in Figure 59A. (c) Form I has a DSC graph substantially as shown in Figure 59B. (d) Form I is characterized by an endothermic onset at about 199°C as determined by DSC. (e) Form I has a TGA graph substantially as shown in Figure 59B. (f) Form I has a DVS graph substantially as shown in Figure 59C.

[0238] Form II In some embodiments, Aficamten is polymorphic Form II of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. The angles 2θ and relative peak intensities that may be observed for Form II using XRPD are shown in Table P-2. In some embodiments, Form II has an XRPD pattern substantially as shown in Figure 60A. [Table 2]

[0239] In some embodiments, polymorph Form II has an XRPD pattern substantially as shown in Figure 60A or as shown in Table P-2, exhibiting at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks at angles 2θ with maximum intensity in the XRPD pattern. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting, and the instrumentation and analytical procedures and settings used to acquire the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including polymorph Form II, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2θ.

[0240] In some embodiments, polymorph Form II has an XRPD pattern comprising peaks at 3.7±0.2, 7.4±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, 13.5±0.2, 14.4±0.2, 14.7±0.2, 16.1±0.2, 17.0±0.2, 18.5±0.2, 20.4±0.2, 21.6±0.2, 22.3±0.2, 23.3±0.2, 24.0±0.2, 24.3±0.2, 24.8±0.2, 25.8±0.2, 27.4±0.2, 28.8±0.2, 29.5±0.2, and 30.5±0.2 degrees 2θ. In some embodiments, polymorph Form II has an XRPD pattern comprising peaks at 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, 14.7±0.2, 16.1±0.2, 18.5±0.2, 20.4±0.2, 22.3±0.2, and 23.3±0.2 degrees 2θ. In some embodiments, polymorph Form II has an XRPD pattern comprising peaks at 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, and 20.4±0.2 degrees 2θ. It is understood that peaks in an XRPD pattern other than those shown in Figure 60A or provided in Table P-2 may be observed due to, for example, the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0241] In some embodiments, Form II has a DSC graph substantially as shown in Figure 60B. In some embodiments, Form II is characterized by having an endothermic onset at about 199°C as determined by DSC. In some embodiments, Form II is characterized by having an endothermic onset at about 199±2°C (e.g., 199±1.9°C, 199±1.8°C, 199±1.7°C, 199±1.6°C, 199±1.5°C, 199±1.4°C, 199±1.3°C, 199±1.2°C, 199±1, 199±0.9°C, 199±0.8°C, 199±0.7°C, 199±0.6°C, 199±0.5°C, 199±0.4°C, 199±0.3°C, 199±0.2°C, or 199±0.1°C) as determined by DSC.

[0242] In some embodiments, Form II has a TGA graph substantially as shown in Figure 60B.

[0243] In some embodiments of Form II, at least one, at least two, at least three, at least four, or all of the following (a)-(e) apply: (a) Form II has an XRPD pattern containing peaks at 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, and 20.4±0.2 degrees 2θ; or has an XRPD pattern containing peaks at 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, 14.7±0.2, 16.1±0.2, 18.5±0.2, 20.4±0.2, 22.3±0.2, and 23.3±0.2 degrees 2θ; or 3.7±0.2, 7.4±0.2, 9.8±0.2. 2, 11.1±0.2, 12.8±0.2, 13.5±0.2, 14.4±0.2, 14.7±0.2, 16.1±0.2, 17.0±0.2, 18.5±0.2, 20.4±0.2, 21.6±0.2, 22.3±0.2, 23.3±0.2, 24.0±0.2, 24.3±0.2, 24.8±0.2, 25.8±0.2, 27.4±0.2, 28.8±0.2, 29.5±0.2, and 30.5±0.2 degrees 2θ. (b) Form II has an XRPD pattern substantially as shown in Figure 60A. (c) Form II has a DSC graph substantially as shown in Figure 60B. (d) Form II is characterized by a melting endotherm onset at about 199°C as determined by DSC. (e) Form II has a TGA graph substantially as shown in Figure 60B.

[0244] Form III In some embodiments, Aficamten is polymorphic Form III of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. The angles 2θ and relative peak intensities that may be observed for a mixture of Form I and Form III using XRPD are shown in Table P-3. In some embodiments, a mixture of Form I and Form III has an XRPD pattern substantially as shown in Figure 61A. [Table 3-1] [Table 3-2]

[0245] In some embodiments, polymorphic Form III has an XRPD pattern comprising peaks at 9.6±0.2, 10.9±0.2, 15.8±0.2, and 18.1±0.2 degrees 2θ. In some embodiments, polymorphic Form III has an XRPD pattern comprising peaks at 9.6±0.2, 10.9±0.2, 14.5±0.2, 15.8±0.2, and 18.1±0.2 degrees 2θ. In some embodiments, polymorphic Form III has an XRPD pattern comprising peaks at 9.6±0.2, 10.9±0.2, 14.5±0.2, 15.8±0.2, 18.1±0.2, and 20.2±0.2 degrees 2θ. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting, and the instrument and analytical procedures and settings used to acquire the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including polymorph Form III, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2θ.

[0246] In some embodiments, a mixture of polymorphic Form I and polymorphic Form III has a DSC graph substantially as shown in Figure 61B.

[0247] In some embodiments, a mixture of polymorphic Form I and polymorphic Form III has a TGA graph substantially as shown in Figure 61B.

[0248] Form IV In some embodiments, Aficamten is polymorphic Form IV of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. The angles 2θ and relative peak intensities that may be observed for Form IV using XRPD are shown in Table P-4. In some embodiments, Form IV has an XRPD pattern substantially as shown in Figure 62A. [Table 4-1] [Table 4-2]

[0249] In some embodiments, polymorph Form IV has an XRPD pattern substantially as shown in Figure 62A or as shown in Table P-4, exhibiting at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks at angles 2θ with maximum intensity in the XRPD pattern. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting, and the instrumentation and analytical procedures and settings used to acquire the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including polymorph Form IV, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2θ.

[0250] In some embodiments, polymorph IV is 3.7±0.2, 7.7±0.2, 11.1±0.2, 12.4±0.2, 12.8±0.2, 13.5±0.2, 14.3±0.2, 15.5±0.2, 16.6±0.2, 17.9±0.2, 18.5±0.2, 18.6±0.2, 19.1±0.2, 19.9±0.2, 20.9±0.2, 21.5±0.2, 21.6±0.2, 21.9±0.2, 22.3±0.2, 22.4±0.2, 22.8±0.2, 23.1±0.2, 23.5±0.2, 23.9±0.2, 24.4±0.2 0.2, 24.8±0.2, 25.0±0.2, 25.3±0.2, 25.8±0.2, 26.2±0.2, 27.1±0.2, 27.4±0.2, 28.0±0.2, 28.6±0.2, 29.0±0.2, 30.0±0.2, 30.5±0.2, 30.8±0.2, 31.0±0.2, 31.4±0.2, 33.8±0.2, 35.0±0.2, 35.7±0.2, 36.1±0.2, 36.7±0.2, 37.9±0.2, 38.1±0.2, and 39.8±0.2 degrees 2θ. In some embodiments, polymorphic Form IV has an XRPD pattern comprising peaks at 3.7±0.2, 11.1±0.2, 12.8±0.2, 13.5±0.2, 21.9±0.2, 22.8±0.2, 23.1±0.2, 23.5±0.2, 24.4±0.2, and 24.8±0.2 degrees 2θ. In some embodiments, polymorphic Form IV has an XRPD pattern comprising peaks at 11.1±0.2, 12.8±0.2, 13.5±0.2, 22.8±0.2, and 24.4±0.2 degrees 2θ. It is understood that peaks in an XRPD pattern other than those shown in Figure 62A or provided in Table P-4 may be observed due to, for example, the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0251] In some embodiments, Form IV has a DSC graph substantially as shown in Figure 62B. In some embodiments, Form IV is characterized by having an endothermic onset at about 200°C as determined by DSC. In some embodiments, Form IV is characterized by having a melting endothermic onset at about 200±2°C (e.g., 200±1.9°C, 200±1.8°C, 200±1.7°C, 200±1.6°C, 200±1.5°C, 200±1.4°C, 200±1.3°C, 200±1.2°C, 200±1, 200±0.9°C, 200±0.8°C, 200±0.7°C, 200±0.6°C, 200±0.5°C, 200±0.4°C, 200±0.3°C, 200±0.2°C, or 200±0.1°C) as determined by DSC.

[0252] In some embodiments, Form IV has a TGA graph substantially as shown in Figure 62B.

[0253] In some embodiments of Form IV, at least one, at least two, at least three, at least four, or all of the following apply: (a) to (e) above; (a) Form IV has an XRPD pattern containing peaks at angles 2θ of 11.1±0.2, 12.8±0.2, 13.5±0.2, 22.8±0.2, and 24.4±0.2 degrees, and having an XRPD pattern containing peaks at an angle 2θ of 24.8±0.2 degrees, or 3.7±0.2, 7.7±0.2, 11.1±0.2, 12.4±0.2, 12.8±0.2, 13.5±0.2, 14.3±0.2, 15.5±0.2, 16.6±0.2, 17.9±0.2, 18.5±0.2, 18.6±0.2, 19.1±0.2, 19.9±0.2, 20. 9±0.2, 21.5±0.2, 21.6±0.2, 21.9±0.2, 22.3±0.2, 22.4±0.2, 22.8±0.2, 23.1±0.2, 23.5±0.2, 23.9±0.2, 24.4±0.2, 24.8±0.2, 25.0±0.2, 25.3±0.2, 25.8±0.2, 26.2±0.2, 27.1±0.2, 27.4±0.2, 28.0±0.2 0.2, 28.6±0.2, 29.0±0.2, 30.0±0.2, 30.5±0.2, 30.8±0.2, 31.0±0.2, 31.4±0.2, 33.8±0.2, 35.0±0.2, 35.7±0.2, 36.1±0.2, 36.7±0.2, 37.9±0.2, 38.1±0.2, and 39.8±0.2 degrees 2θ. (b) Form IV has an XRPD pattern substantially as shown in Figure 62A. (c) Form IV has a DSC graph substantially as shown in Figure 62B. (d) Form IV is characterized by a melting endotherm onset at about 200° C. as determined by DSC. (e) Form IV has a TGA graph substantially as shown in Figure 62B.

[0254] Form V In some embodiments, Aficamten is polymorphic Form V of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. The angles 2θ and relative peak intensities that may be observed for Form V using XRPD are shown in Table P-5. In some embodiments, Form V has an XRPD pattern substantially as shown in Figure 63. [Table 5-1] [Table 5-2]

[0255] In some embodiments, polymorph Form V has an XRPD pattern substantially as shown in Figure 63 or as shown in Table P-5, exhibiting at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks at angles 2θ with maximum intensity in the XRPD pattern. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting, and the instrumentation and analytical procedures and settings used to acquire the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including polymorph Form V, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2θ.

[0256] In some embodiments, polymorphic Form V is 5.7±0.2, 8.3±0.2, 11.5±0.2, 13.8±0.2, 15.5±0.2, 15.8±0.2, 16.3±0.2, 16.6±0.2, 17.2±0.2, 17.8±0.2, 18.5±0.2, 18.9±0.2, 19.1±0.2, 19.8±0.2, 20.0±0.2, 20.2±0.2, 20.7±0.2, 21.2±0.2. 2, 21.6±0.2, 23.0±0.2, 23.1±0.2, 23.3±0.2, 24.0±0.2, 24.2±0.2, 24.3±0.2, 24.6±0.2, 24.7±0.2, 25.2±0.2, 25.6±0.2, 26.7±0.2, 27.1±0.2, 27.3±0.2, 27.5±0.2, 27.9±0.2, 28.1±0.2, 28.4±0.2, 28.9±0.2, 29. 2±0.2, 29.7±0.2, 29.8±0.2, 29.9±0.2, 30.4±0.2, 30.6±0.2, 31.1±0.2, 31.3±0.2, 31.5±0.2, 32.0±0.2, 32.9±0.2, 33.0±0.2, 33.2±0.2, 33.5±0.2, 34.4±0.2, 34.6±0.2, 34.9±0.2, 35.3±0.2, 35.7±0.2, 36.0±0.2. 2, 36.2±0.2, 36.5±0.2, 36.6±0.2, 37.0±0.2, 37.1±0.2, 37.5±0.2, 37.8±0.2, 37.9±0.2, 38.3±0.2, 38.4±0.2, 38.7±0.2, 38.8±0.2, 39.3±0.2, 39.4±0.2, 39.6±0.2, and 39.9±0.2 degrees 2θ. In some embodiments, polymorphic Form V has an XRPD pattern comprising peaks at 5.7±0.2, 8.3±0.2, 11.5±0.2, 16.3±0.2, 17.2±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 20.7±0.2, 21.2±0.2, 23.3±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, 26.7±0.2, 28.1±0.2, 29.2±0.2, 29.7±0.2, 29.9±0.2, and 31.1±0.2 degrees 2θ.In some embodiments, polymorphic Form V has an XRPD pattern comprising peaks at 11.5±0.2, 16.3±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 21.2±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, and 26.7±0.2 degrees 2θ. In some embodiments, polymorphic Form V has an XRPD pattern comprising peaks at 11.5±0.2, 16.3±0.2, 20.0±0.2, 21.2±0.2, and 24.7±0.2 degrees 2θ. It is understood that peaks in an XRPD pattern other than those shown in Figure 63 or provided in Table P-5 may be observed due to, for example, the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0257] In some embodiments of Form V, at least one or both of the following apply: (a) to (b) of the formula: (a) Form V has an XRPD pattern containing peaks at 11.5±0.2, 16.3±0.2, 20.0±0.2, 21.2±0.2, and 24.7±0.2 degrees 2θ; or 5. Form V has an XRPD pattern containing peaks at 11.5±0.2, 16.3±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 21.2±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, and 26.7±0.2 degrees 2θ; or 5. having an XRPD pattern containing peaks at 7±0.2, 8.3±0.2, 11.5±0.2, 16.3±0.2, 17.2±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 20.7±0.2, 21.2±0.2, 23.3±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, 26.7±0.2, 28.1±0.2, 29.2±0.2, 29.7±0.2, 29.9±0.2, and 31.1±0.2 degrees 2θ. (b) Form V has an XRPD pattern substantially as shown in FIG.

[0258] Form VI In some embodiments, Aficamten is polymorphic Form VI of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. The angles 2θ and relative peak intensities that may be observed for Form VI using XRPD are shown in Table P-6. In some embodiments, Form VI has an XRPD pattern substantially as shown in Figure 64A. [Table 6-1] [Table 6-2]

[0259] In some embodiments, polymorph Form VI has an XRPD pattern substantially as shown in Figure 64A or as shown in Table P-6, exhibiting at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks at angles 2θ with maximum intensity in the XRPD pattern. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting, and the instrumentation and analytical procedures and settings used to acquire the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including polymorph Form VI, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2θ.

[0260] In some embodiments, polymorph VI is 3.0±0.2, 5.0±0.2, 5.4±0.2, 5.9±0.2, 7.2±0.2, 8.1±0.2, 8.9±0.2, 9.6±0.2, 9.9±0.2, 10.6±0.2, 12.1±0.2, 13.3±0.2, 14.0±0.2, 14.4±0.2, 14.7±0.2, 15.0±0.2, 15.4±0.2, 16.1±0.2, 16.5±0.2, 17.8±0.2, 18.9±0.2, 19.0±0.2, 19.2±0.2, 19.6±0.2, 20.0±0.2, 20.3±0.2, 20.7±0.2, 21.1±0.2, 21.9±0.2, 2 2.6±0.2, 22.9±0.2, 23.6±0.2, 23.8±0.2, 24.4±0.2, 24.8±0.2, 25.5±0.2, 26.4±0.2, 26.7±0.2, 27.3±0.2, 27.6±0.2, 28.2±0.2, 28.5±0.2, 29.0±0.2, 29.6±0.2, 29 In some embodiments, polymorphic Form VI has an XRPD pattern comprising peaks at 5.4±0.2, 5.9±0.2, 8.1±0.2, 9.6±0.2, 10.6±0.2, 12.1±0.2, 14.0±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2 degrees 2θ. In some embodiments, polymorphic Form VI has an XRPD pattern comprising peaks at angles 2θ of 10.6±0.2, 12.1±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2 degrees. It is understood that peaks in an XRPD pattern other than those shown in Figure 64A or provided in Table P-6 may be observed due to, for example, the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0261] In some embodiments, Form VI has a TGA graph substantially as shown in Figure 64B, or a TGA graph substantially as shown in Figure 64C. In some embodiments, Form VI exhibits a weight loss of about 2%±0.5% from 25°C to 200°C as determined by TGA.

[0262] In some embodiments, Form VI has a DSC graph substantially as shown in Figure 64D or a DSC graph substantially as shown in Figure 64E. In some embodiments, Form VI is characterized by a melting endotherm onset at about 200±2°C (e.g., 200±1.9°C, 200±1.8°C, 200±1.7°C, 200±1.6°C, 200±1.5°C, 200±1.4°C, 200±1.3°C, 200±1.2°C, 200±1, 200±0.9°C, 200±0.8°C, 200±0.7°C, 200±0.6°C, 200±0.5°C, 200±0.4°C, 200±0.3°C, 200±0.2°C, or 200±0.1°C) as determined by DSC. In some embodiments, Form VI can be obtained at about 200±2°C (e.g., 200±1.9°C, 200±1.8°C, 200±1.7°C, 200±1.6°C, 200±1.5°C, 200±1.4°C, 200±1.3°C, 200±1.2°C, 200±1, 200±0.9°C, 200±0.8°C, 200±0.7°C, 200±0.6°C). Endothermic reaction begins at approximately 115±2°C (e.g., 115±1.9°C, 115±1.8°C, 115±1.7°C, 115±1.6°C, 115±1.5°C, 115±1.4°C, 115±1.3°C, 115±1.2°C, 115±1.3°C, 115±1.4°C, 115±1.5°C, 115±1.6°C, 115±1.7°C, 115±1.8°C, 115±1.9 ... Fever onset at 115±0.9°C, 115±0.8°C, 115±0.7°C, 115±0.6°C, 115±0.5°C, 115±0.4°C, 115±0.3°C, 115±0.2°C, or 115±0.1°C, or at approximately 41±2°C (e.g., 41±1.9°C, 41±1.8°C, 41±1.7°C, 41±1.6°C, 41± 41±0.1.5°C, 41±1.4°C, 41±1.3°C, 41±1.2°C, 41±1, 41±0.9°C, 41±0.8°C, 41±0.7°C, 41±0.6°C, 41±0.5°C, 41±0.4°C, 41±0.3°C, 41±0.2°C, or 41±0.1°C), or any combination thereof.

[0263] In some embodiments of Form VI, at least one, at least two, at least three, at least four, at least five, at least six, or all of the following apply: (a) a) a hydroxyl group; (a) Form VI has an XRPD pattern containing peaks at 10.6±0.2, 12.1±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2 degrees 2θ, and has peaks at 5.4±0.2, 5.9±0.2, 8.1±0.2, 9.6±0.2, 10.6±0.2, 12.1±0.2, 14.0±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2 degrees 2θ. or have an XRPD pattern containing peaks of 3.0±0.2, 5.0±0.2, 5.4±0.2, 5.9±0.2, 7.2±0.2, 8.1±0.2, 8.9±0.2, 9.6±0.2, 9.9±0.2, 10.6±0.2, 12.1±0.2, 13.3±0.2, 14.0±0.2, 14.4±0.2, 14.7±0.2, 15.0±0.2, 15.4±0.2, 16.1±0.2, 16.5±0.2, 17.8±0.2, 18.9±0.2, 19.0±0.2, 19.2±0.2, 19.6±0.2, 20.0±0.2, 20.3±0.2, 20.7±0.2, 21.1±0.2, 21.9±0.2, 22.6±0.2, 22.9±0.2, 23.6±0.2, 23.8±0.2, 24.4±0.2, 24.8±0.2, 25.5±0.2, 26.4±0.2, 26.7±0.2, 27.3±0.2, 28.2±0.2 having an XRPD pattern containing peaks at 7.6±0.2, 28.2±0.2, 28.5±0.2, 29.0±0.2, 29.6±0.2, 29.9±0.2, 30.4±0.2, 30.9±0.2, 31.6±0.2, 32.2±0.2, 32.6±0.2, 33.1±0.2, 33.3±0.2, 34.5±0.2, 35.0±0.2, 35.5±0.2, and 38.5±0.2 degrees 2θ. (b) Form VI has an XRPD pattern substantially as shown in Figure 64A. (c) Form VI has a TGA graph substantially as shown in Figure 64B or Figure 64C. (d) Form VI has a weight loss of approximately 2% ± 0.5% from 25°C to 200°C as determined by TGA. (e) Form VI has a DSC graph substantially as shown in Figure 64D or Figure 64E. (f) Form IV is characterized by a melting endotherm onset at about 200° C. as determined by DSC. (g) Form VI is characterized by having an endotherm onset at about 200° C., an exotherm onset at about 115° C., or an endotherm onset at about 41° C., or any combination thereof, as determined by DSC.

[0264] kit Also provided are articles of manufacture and kits containing any of the compounds or pharmaceutical compositions provided herein. The articles of manufacture may include a labeled container. Suitable containers include, for example, bottles, vials, and test tubes. The container may be formed from a variety of materials, such as glass or plastic. The container may hold a pharmaceutical composition provided herein. The label on the container may indicate that the pharmaceutical composition is used to prevent, treat, or suppress a condition described herein, and may indicate instructions for either in vivo or in vitro use.

[0265] In one aspect, the present specification provides a kit containing the compound or composition described herein and instructions for use.The kit can include instructions for use in treating heart disease in individuals or subjects in need thereof.The kit can also include any material or equipment that can be used to administer the compound or composition, such as a vial, a syringe, or an IV bag.The kit can also include a sterile package.

[0266] In some embodiments, the present disclosure provides a method for manufacturing a medicament comprising aficamten, the method comprising: producing a first collection of tablets having an amount of aficamten (which may exist in various forms) that is approximately the first daily dose or about half of the first daily dose; producing a second set of tablets in which the amount of aficamten (which may be in various forms) is approximately the second daily dose or about half of the second daily dose; Optionally, preparing a third collection of tablets in which the amount of aficamten (which may be in various forms) is approximately the third daily dose or about half of the third daily dose; Optionally, preparing a fourth collection of tablets in which the amount of aficamten (which may be in various forms) is approximately the fourth daily dose or about half of the fourth daily dose; The present invention provides a method comprising: In some embodiments, the method includes producing a third collection of tablets having an amount of aficamten (which may exist in various forms) that is approximately the third daily dose or about half of the third daily dose. In some embodiments, the method includes producing a fourth collection of tablets having an amount of aficamten (which may exist in various forms) that is approximately the fourth daily dose or about half of the fourth daily dose.

[0267] In some embodiments, the present disclosure provides a method for manufacturing a medicament comprising aficamten, the method comprising: producing a first collection of tablets having an amount of aficamten (which may exist in various forms) of approximately a first daily dose; producing a second set of tablets having an amount of aficamten (which may be present in various forms) of approximately the second daily dose; Optionally, preparing a third collection of tablets having an amount of aficamten (which may be present in various forms) of about the third daily dose; Optionally, preparing a fourth collection of tablets having an amount of aficamten (which may be present in various forms) of about the fourth daily dose; The present invention provides a method comprising:

[0268] In some embodiments, the method includes producing a third collection of tablets having an amount of aficamten (which may exist in various forms) that is about the third daily dose. In some embodiments, the method includes producing a fourth collection of tablets having an amount of aficamten (which may exist in various forms) that is about the fourth daily dose.

[0269] Various first daily doses, second daily doses, third daily doses, and fourth daily doses are described herein. In some embodiments, the daily dose is about 5 mg of afficamten. In some embodiments, the first daily dose is about 5 mg of afficamten. In some embodiments, the daily dose is about 10 mg of afficamten. In some embodiments, the daily dose is about 15 mg of afficamten. In some embodiments, the daily dose is about 20 mg of afficamten. In some embodiments, tablets are produced with at least two different daily doses. In some embodiments, tablets are produced with an amount of afficamten (which may exist in various forms) of about 15 mg. In some embodiments, tablets are produced with an amount of afficamten (which may exist in various forms) of about 2.5 mg. In some embodiments, tablets are produced with an amount of afficamten (which may exist in various forms) of about 7.5 mg. Those skilled in the art will appreciate that in addition to aficamten, tablets may contain a variety of other ingredients, such as fillers, binders, disintegrants, surfactants, lubricants, etc., as described herein, In some embodiments, the tablets are film coated. [Example]

[0270] The present application can be better understood by reference to the following non-limiting examples, which are provided as exemplary embodiments of the present application. The following examples are presented to more fully illustrate the embodiments, but should in no way be construed as limiting the broad scope of the present application. While specific embodiments of the present application have been shown and described herein, it will be apparent that such embodiments are provided by way of example only. Those skilled in the art will be able to envision numerous variations, modifications, and substitutions without departing from the spirit and scope of the present invention. It will be understood that various alternatives to the embodiments described herein may be employed in practicing the methods described herein.

[0271] Example 1 This first-in-human study of aficamten (also known as CK-274) was conducted to evaluate its safety, pharmacokinetic, and pharmacodynamic profile, including the effects of diet and the CYP2D6 poor metabolizer (CYP2D6-PM) phenotype. Aficamten, a selective cardiac myosin inhibitor, reduced measures of left ventricular contractility preclinically in vitro and in vivo and may therefore have therapeutic potential for the management of hypertrophic obstructive cardiomyopathy. This phase 1, double-blind, randomized, placebo-controlled study enrolled healthy adults aged 18 to 55 years who received a single ascending dose or multiple ascending doses of aficamten or placebo (for 14 or 17 days). In addition to standard safety and pharmacokinetic assessments, pharmacodynamic effects were assessed by echocardiography. This study enrolled 102 participants (57 in the single-dose cohort, 24 in the multiple-dose cohort, 9 in the CYP2D6-PM cohort, and 12 in the food effect cohort). Adverse events were generally mild and no more frequent than those with placebo at single doses of 50 mg or less and multiple doses of 10 mg or less of aficamten. In the single ascending-dose cohort, aficamten plasma concentrations increased dose-proportionally, and the half-life of aficamten was 75 to 85 hours. Neither food nor CYP2D6-PM phenotype had a clinically meaningful effect on pharmacokinetics. At a single 50 mg dose, mean left ventricular ejection fraction (LVEF) decreased by 5.5% from baseline (p=0.0001). Repeated doses of 10 mg aficamten once daily resulted in a mean 5.0% reduction in LVEF after 14 days. Aficamten appears to be safe and well tolerated at the doses evaluated. A pharmacodynamic effect on LVEF was demonstrated, providing support for further clinical studies of aficamten.

[0272] method Study Overview and Ethics. This study used a randomized, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) design (Figure 2). The study was not designed to identify a maximum tolerated dose, but rather to identify a pharmacologically active dose range, defined as producing an absolute reduction in left ventricular ejection fraction (LVEF) from baseline within a range of 5% to 15% (e.g., a reduction from a baseline LVEF value of 70% to 55% to 65%). Dose escalation was to be stopped when this range was reached or earlier when an intolerable dose was identified.

[0273] Participants and Treatment. To be eligible for this study, participants were healthy adults aged 18-55 years with a body mass index of 18.0-32.0 kg / m 2 Participants were required to have normal electrocardiograms (ECGs) and clinical laboratory values, or only minor abnormalities deemed clinically insignificant. Participants were also required to have normal cardiac structure and function, with LVEF ≥ 60% in the first four SAD cohorts, ≥ 65% in subsequent SAD cohorts, all MAD cohorts, and the dietary influence cohort, and ≥ 55% in the CYP2D6-PM cohort. Prior to the study, participants were prohibited from using prescription medications within 14 days, over-the-counter medications (except acetaminophen) within 7 days, or tobacco or nicotine within 3 months. Additionally, participants were prohibited from consuming alcohol, caffeine, or grapefruit within 48 hours before study check-in.

[0274] Randomization schedules were centrally generated for each cohort and treatment period. All cohorts received aficamten or matching placebo in capsuled granule form with approximately 240 ml of water. Study medication was administered after an overnight fast, except during the postprandial period in the food-effect cohort.

[0275] Single Ascending Dose (SAD) Cohorts. The SAD portion of the study used a randomized, double-blind, placebo-controlled, sequential, dose-escalation design, in which participants received single ascending oral doses of the study medication. Seven cohorts were dosed sequentially (Figure 2). Of the eight participants within each cohort, the first two were randomly assigned (1:1) to receive aficamten or placebo and were followed for a minimum of two days before dosing the remaining participants in the group. The remaining six participants were then randomly assigned (5:1) to receive a single oral dose of either aficamten (1, 3, 10, 25, 40, 50, or 75 mg) or placebo.

[0276] The initial dose of aficamten was selected using criteria from the U.S. Food and Drug Administration (FDA) guidance based on previous animal studies, with a safety margin of at least 10. Dose escalation was to be stopped when the results identified a pharmacologically active dose range that reduced LVEF by 5% to 15% or an intolerable dose, whichever occurred first.

[0277] Recommendations for dose escalation in the SAD cohort (and the MAD cohort described below) were made by the treating investigator (blinded to treatment group) and were either approved or not by an unblinded Dose Level Review Committee (DLRC). Decisions were made once ≥6 participants had been treated and followed for ≥3 days, including collection of clinical, laboratory, ECG, and telemetry data, and maximum plasma drug concentrations (C max(2) Suitable echocardiograms for assessment of LV function were included before and after the dose-escalation study. Escalation criteria included no more than two participants in a dose group experiencing an LVEF less than 50% and no individual experiencing an LVEF less than 45%. Dose escalation criteria were as follows: (1) no individual experienced a serious cardiac adverse event related to the study drug; (2) no two individuals experienced a similar serious non-cardiac adverse event in the same organ system that was considered related to the study drug; (3) no two aficamten-treated individuals experienced a decrease in left ventricular ejection fraction (LVEF) of more than 15% compared to the most recent pre-dose value (as determined by the Dose Level Review Committee [DLRC]); (4) no individual experienced an LVEF less than 45% (unless determined by the DLRC and treating investigator to be unrelated to the study drug); and (5) both the treating investigator and DLRC approved the escalation and next-level dose based on clinical judgment.

[0278] Multiple Ascending Dose (MAD) Cohorts. The MAD cohorts also used a randomized, double-blind, placebo-controlled, sequential design. Enrollment for the MAD cohorts began once a single oral dose that was well tolerated and associated with observed PD effects was identified in the SAD cohort. Each of the three MAD cohorts included eight participants randomized 6:2 to aficamten or placebo. Participants received a once-daily oral dose of study medication for 14 days (for cohorts comparing 5 mg or 10 mg aficamten with placebo) or 17 days (for cohorts comparing 7.5 mg aficamten with placebo).

[0279] CYP2D6 Poor Metabolizer Cohort. A separate cohort was enrolled to evaluate the potential impact of CYP2D6 genetic variants on the PK properties of aficamten. The CYP2D6 gene encodes the cytochrome P450 2D6 enzyme, described as the most extensively characterized polymorphic drug-metabolizing enzyme, and previous in vitro studies suggested that CYP2D6 is a potential metabolizer of aficamten.

[0280] CYP2D6 genotype was determined for all study participants at screening. Participants identified as CYP2D6-PM were excluded from the SAD and MAD cohorts, but these participants were invited to participate in the CYP2D6-PM cohort. Following the SAD 25 mg cohort, the first individual in the CYP2D6-PM cohort was dosed (Figure 2). Each participant received a single dose of aficamten (10 mg) or placebo. Nine participants were randomized (7:2), including a sentinel group consisting of the first two participants treated.

[0281] Food Effect Cohort. To evaluate the effect of food on the PK of aficamten, a separate cohort was enrolled after the completion of the final SAD cohort and was planned to enroll 8 to 12 participants. In an open-label, 2-way crossover design, participants received two single 10 mg doses of aficamten, at least 14 days apart. Participants were randomized 1:1 to one of two sequences: fasting / postprandial or postprandial / fasting. In the fasting period, aficamten was administered after an overnight fast, and in the postprandial period, aficamten was administered 30 minutes after the start of a high-fat breakfast.

[0282] evaluation Safety and Tolerability. Safety was assessed by the incidence of adverse events (AEs) and the incidence of LVEF reduction. Treatment-emergent AEs (TEAEs) were defined as AEs that began or increased after administration of study drug. All AEs were coded using the Regulatory Terminology of Pharmaceuticals and Medical Devices version 21.1 and graded using the 5-point severity scale of the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Each AE was judged by the treating investigator as either related or unrelated to study drug. Clinical examinations were performed at regular intervals in all cohorts.

[0283] For safety monitoring, participants in all cohorts underwent periodic echocardiograms, which were evaluated by a cardiologist. In the SAD and MAD cohorts, echocardiograms were also reviewed at a central echocardiographic laboratory for PD assessment, as described below. In addition, participants in all cohorts were monitored with continuous 12-lead ECG recordings using a Holter monitor. For safety monitoring, single 12-lead ECGs were obtained at screening, pre-dose, and periodically throughout follow-up and interpreted by the investigator. In the SAD, MAD, and CYP2D6-PM cohorts, a cardiac dynamic ECG (three 10-second 12-lead ECG recordings) was obtained before the corresponding PK blood draw, and ECG intervals were quantified by a qualified radiologist.

[0284] Pharmacokinetic Analysis. For all study groups, blood samples for PK evaluation were obtained pre-dose and up to 12 times daily on Day 1, and then at regular intervals throughout the study. Blood samples were collected according to the following schedule: SAD cohort: Day 1: pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, and 216 hours post-dose. MAD cohort (14-day dosing): Day 1: pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours after dosing; Days 2, 4, 5, 6, and 9: pre-dose (corresponding to post-dose trough samples on days 1, 3, 4, 5, and 8) and 1.5 hours after dosing; Days 3, 7, 8, 10, 11, 12, and 13: pre-dose (corresponding to post-dose trough samples on days 2, 6, 7, 9, 10, 11, and 12); Day 14: pre-dose and 0.25, 0.5, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 168 hours after dosing. MAD cohort (17-day dosing): Day 1: pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post-dose; Days 2, 4, 5, 6, and 9: pre-dose (corresponding to post-dose trough samples on days 1, 3, 4, 5, and 8) and 1.5 hours post-dose; Days 3, 7, 8, 10, 11, 12, 13, 14, 15, and 16: pre-dose (corresponding to post-dose trough samples on days 2, 6, 7, 9, 10, 11, and 12); Day 17: pre-dose and 0.25, 0.5, 1.5, 2, 2.5, 3, 5, 7, 9, 12, 24, 36, 48, 72, and 168 hours post-dose. CYPD6-PM cohort: Day 1: pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 216, 312, and 552 hours post-dose. Food effect cohort: Day 1: pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 216 hours post-dose. PK parameters were calculated using standard non-compartmental methods using Phoenix® WinNonlin® version 7.0. Actual sample collection times were utilized.

[0285] Plasma concentrations of aficamten were measured using a high-performance liquid chromatography-tandem mass spectrometry method validated at Celerion (Lincoln, Nebraska) for accuracy, precision, linearity, sensitivity, and specificity. The analytical range (lower to upper limit of quantification) for aficamten was 1.00 to 500 ng / mL.

[0286] Echocardiograms. For PD assessment of LVEF, echocardiograms of the SAD and MAD cohorts were interpreted at a central echocardiographic laboratory and used for all data analyses and dose-level review decisions. Meanwhile, immediate echocardiogram interpretation was performed locally for safety monitoring. For the SAD cohorts receiving 1, 3, or 10 mg of aficamten, echocardiograms were obtained on day -1, predose on day 1, and 1.5, 4, and 24 hours postdose. For the SAD cohorts receiving 25, 40, 50, or 75 mg of aficamten, echocardiograms were obtained on day -1, predose on day 1, and 1.5, 6, and 24 hours postdose. An echocardiogram on day 3 (48 hours postdose) was obtained only if the 24-hour LVEF had not returned near or above baseline, as determined by the investigator. In the MAD cohort, echocardiograms were obtained on day -1, pre-dose on day 1, and 1.5 hours post-dose on days 2, 4, and 9, and 1.5, 24, and 72 hours post-dose on day 14 (for the 5 mg and 10 mg cohorts) or day 17 (for the 7.5 mg cohort). Echocardiograms were obtained 3 days after the final dose (day 17 or day 20) only if the participant's prior LVEF was not near or above baseline, as determined by the investigator.

[0287] Statistical Analysis: The sample size selected for this study was based on precedent set in other first-in-human PK studies of similar nature and not on power calculations. All participants who received at least one dose of study drug (aficamten or placebo) were included in the safety analysis. All participants who received at least one dose of study drug and had at least one evaluable PK plasma profile were included in the PK analysis set.

[0288] PK analyses were conducted to assess single-dose kinetics, repeated-dose (steady-state) kinetics, the effect of CYP2D6 phenotype on aficamten absorption and excretion, and the effect of food on aficamten absorption and excretion. For the SAD cohort, dose proportionality of aficamten was assessed using a power model on day 1. For the MAD cohort, dose proportionality was assessed using a power model on days 1 and 14 or 17. Several considerations were taken into account when assessing drug dose proportionality, including results derived from the statistical analysis of the power model (e.g., slope estimate and width of the two-sided 95% confidence interval [CI]), qualitative assessments specific to the drug's PK, and clinical relevance. For the SAD cohort, the parameter used to assess dose proportionality was the area under the plasma drug concentration-time curve (AUC) from time 0 to the time of the last measurable concentration (AUC last ), AUC extrapolated from time 0 to infinity (AUC inf ), AUC from time 0 to 24 hours (AUC 24 ), and maximum plasma concentration (C max In the MAD cohort, the parameters were AUC 24 and C max On the 14th or 17th day, the AUC (AUC tau ) and C max The statistical linear relationship between the ln-transformed PK parameters and the ln-transformed dose was calculated as quadratic (ln dose) 2 and tertiary (ln dose). 3 The statistical significance of the effects was verified by including the variance in the variance in the variance in the dose-dependent parameter. A statistically linear relationship was established if the quadratic and cubic effects were not statistically significant using a 5% significance level, or if the effects were statistically significant but small enough to be clinically inconsequential. Dose-proportionality analysis was performed using SAS® PROC MIXED. Dose-proportionality was established if a statistically linear relationship was demonstrated and the two-sided 95% CI around the estimated parameter of the slope included a value of 1 for the dose-dependent parameter.

[0289] In the MAD cohort, Helmert contrasts were used to evaluate ln-transformed plasma trough concentrations (C trough Afficamten steady-state analysis was performed on the α (α = 0.05) values. Separate analysis of variance (ANOVA) models were performed for each dose level. Day was included as a fixed effect. Helmert contrasts were constructed to compare each time point with the mean of subsequent time points. Steady state was established when subsequent time points were not statistically different (alpha = 5%, two-tailed).

[0290] All participants who received at least one dose of study drug and had at least one pre-dose and at least one post-dose echocardiographic measurement were included in the PD analysis set. Descriptive analyses included absolute reduction in LVEF relative to baseline and categorical LVEF response (the percentage of participants with a reduction in LVEF from baseline of ≥ 5%, ≥ 10%, and > 15%, and the percentage of participants with an LVEF of < 50% and < 45%). Descriptive statistics of echocardiographic parameters were generated using SAS® version 9.3 or higher.

[0291] Dose-response analysis was performed using analysis of covariance (ANCOVA) to determine the least-squares mean difference (aficamten minus placebo). To analyze the effect of drug dose on echocardiographic parameters in the SAD and MAD cohorts, inferential analysis was performed on the PD analysis set using a linear mixed model for repeated measures analysis of covariance (ANCOVA). The ANCOVA used baseline values as covariates, included treatment, time point, and time point x treatment interaction as fixed effects, and included change from baseline as the dependent variable. An unstructured variance-covariance structure was used, and the model accounted for repeated measurements of time point. Separate ANCOVA analyses were performed for each study part and each PD parameter. For each comparison, least-squares means, least-squares mean differences (active minus placebo), and associated two-sided 95% CIs are presented.

[0292] Concentration "bin" and exposure-response analyses were also performed using ANCOVA. SAS® PROC MIXED was used for all comparative analyses. Additional inferential analyses were performed in the SAD and MAD cohorts to evaluate the relationship between aficamten concentrations and LVEF for participants in the PK / PD analysis set. Concentration bin ANCOVA was performed using a linear mixed model for repeated measures analysis, with concentration bin group as the fixed effect, baseline PD parameters as covariates, and change from baseline as the dependent variable, with a random intercept to adjust for repeated measures. An unstructured variance-covariance structure was used. Aficamten plasma concentrations were paired with contemporaneous PD parameters. ANCOVA compared the change in PD parameters between each bin and the combined placebo group. For each comparison, least-squares means, least-squares mean differences (bin group minus placebo), and associated two-sided 95% CIs are presented. ANCOVA analyses were performed separately for each study part. For all time points for which both PK data and PD measurements were available, the time points were combined for analysis. For each part of the study, aficamten concentrations with time-matched PD data were pooled and sorted in ascending order. The data were then divided into five observation groups ("bins"), from lowest to highest. Each observation group consisted of 20% of the data points. Each bin was treated as a separate group. The concentration bins consisted of a placebo group and five bin groups based on pooling concentrations from all time points of aficamten treatment.

[0293] The above analysis was then repeated using concentration as a continuous variable to estimate exposure-response trends. Both random intercept and random concentration effects were included in the ANCOVA. Concentration slope estimates and ANCOVA analyses with corresponding two-sided 95% CIs are presented for each study part.

[0294] For all time points where both PK data and PD measurements were available, time points were combined for analysis. A nominal significance level of 5% was used for statistical comparisons without adjusting for multiplicity.

[0295] result Study population. A total of 102 participants were enrolled (57 in the SAD cohort, 24 in the MAD cohort, 9 in the CYP2D6-PM cohort, and 12 in the dietary influence cohort). All participants completed the study. The mean age ranged from 32 to 40 years across cohorts, and the majority of participants were male (Table 1). [Table 7]

[0296] In the SAD cohort, there were no safety concerns prohibiting dose escalation between 1 mg and 25 mg. At the next planned dose (50 mg), one participant had a post-dose LVEF of less than 50% (46.2%), which did not meet the dose escalation stopping rule, and the 75 mg cohort was initiated. A sentinel participant in the 75 mg cohort had a post-dose LVEF of less than 45%, and as a result, no further participants were dosed with 75 mg. As a result, the 50 mg group was expanded, and five additional participants were dosed within this cohort. After expansion, one participant in the 50 mg dose group experienced a LVEF of less than 45%, again a decline of more than 15%. Therefore, no further participants were dosed with more than 50 mg. The DLRC determined that the appropriate dose for the final single-dose cohort was 40 mg.

[0297] Following the results from the 1 mg to 25 mg SAD cohort, the first MAD cohort was initiated at 5 mg aficamten once daily for 14 days. Without any safety concerns, the next cohort was initiated at 10 mg once daily for 14 days. In this cohort, two participants met echocardiographic stopping criteria. The DLRC determined that the next treatment level should be 7.5 mg to better characterize steady-state PK. Therefore, the dosing period was extended from 14 to 17 days to ensure steady-state PK was reached by the final day of dosing.

[0298] Safety and Tolerability. There were no serious AEs, and no participants discontinued the study due to an AE. TEAEs observed were generally mild (Grade 1) and were not more frequent with aficamten than placebo for both single-dose and multiple-dose administration (Tables 2 and 3). Overall, the most common TEAE in both the SAD and MAD cohorts was headache (Tables 2 and 3). [Table 8] [Table 9]

[0299] Echocardiography-related AEs of a decrease in ejection fraction to <45%, based on assessment by the study's echocardiography expert, were reported in three participants (one each in the 40 mg, 50 mg, and 75 mg SAD cohorts) (Table 4). All were Grade 1 and all resolved at the next echocardiography evaluation (within 2.5–4.6 hours). One participant receiving 75 mg aficamten had an LVEF of 34.6% 1.5 hours after administration, representing a 31.5% decrease in LVEF, which led to the termination of dose escalation in the SAD portion of the study, as previously described. At the next evaluation 2.5 hours later, the LVEF had returned to 51.9%. No AEs of a decrease in ejection fraction to <45% were reported in the MAD, CYP2D6-PM, or food-effect cohorts.

[0300] In all cohorts, mean safety ECG parameters were within the normal range at the time points evaluated. No clinically significant changes from baseline were observed for any parameter. The QT interval (QTcF), corrected for heart rate using the Fridericia formula, did not exceed 450 ms at baseline or at any evaluation time during the dosing interval (except for two individuals with a baseline QTcF of ≥440 ms who experienced increases of 3 ms and 13 ms, respectively). In all cohorts, there was no increase in the QTcF interval of >30 ms (except for one participant in the SAD placebo group whose QTcF interval increased by 33 ms on Day 5 (427 ms compared to a baseline value of 394 ms)). In the cardiodynamic evaluation, categorical analysis of ECG parameters revealed no cardiac safety concerns, and there was no evidence of a positive QT effect after single or repeated doses of aficamten.

[0301] All vital signs were within normal limits at post-dose time points. No clinically significant serum chemistry, hematology, or urinalysis findings were observed during the study. [Table 10]

[0302] Pharmacokinetics Single-Dose Kinetics. The plasma profile of aficamten was generally well characterized at all dose levels, except for the lowest dose of 1 mg (due to concentrations close to the lower limit of quantitation) and the highest dose of 75 mg, which was administered to only one participant as previously mentioned. Across the dose range of 1 mg to 50 mg, mean maximum plasma concentrations and exposures were C max and the area under the plasma concentration-time curve from time 0 to 24 hours (AUC 24The increase was dose-proportional, as evidenced by an increase in β-glucan (β) with increasing dose (Figures 3A-3B and Table 5). Mean clearance and volume of distribution were similar across doses. The median time to peak plasma concentration ranged from 0.5 to 2.8 hours, with the longest time across all participants being 4.0 hours. The mean half-life ranged from 75 to 85 hours. [Table 11]

[0303] Repeat-Dose Kinetics. With once-daily dosing, mean plasma concentrations increased between the 5 mg dose and the two higher doses (7.5 mg and 10 mg), but there was little difference in mean concentrations between the 7.5 mg and 10 mg doses on Day 2 (Figure 4). Plasma PK parameters are displayed in Table 6. By the end of the treatment period (Day 14 or 17), mean plasma concentrations were 2- to 2.5-fold higher than those on Day 1. Estimates of terminal elimination half-lives were consistent across doses, ranging from 77 to 86 hours. Clearance was similar at the 5 mg and 10 mg doses, and accumulation rates were similar across the three doses. Steady state was reached after 10 to 12 days, consistent with the observed estimates of terminal elimination half-lives (Figure 4). [Table 12]

[0304] CYP2D6 poor metabolizer cohort. In CYP2D6-PMs, the mean half-life was prolonged to 110 hours compared with 85 hours in extensive metabolizers (i.e., the 10 mg SAD cohort), but no increase in AUC was observed in this group, and the geometric mean AUC 24 was 495 ng·h / ml (19 geometric CV%) (Table 7) compared with 679 ng·h / ml (35 geometric coefficient of variation percent [CV%]) for normal metabolizers (Table 5). CYP2D6-PMs did not appear to have a reduction in clearance that resulted in a clinically meaningful difference in exposure. [Table 13]

[0305] Food Effects. PK parameters of aficamten in the food effect cohort are displayed in Table 8. When taken with food, the C max The AUC increased by approximately 30%, and the time to peak plasma concentration decreased (1.5 hours vs. 2.3 hours). However, food had little effect on the AUC, and the geometric mean AUC in the fasted state was 24 (geometric CV%) was 601 (33) ng·h / ml in the postprandial state, compared with 631 (25) in the postprandial state. [Table 14]

[0306] Pharmacodynamics Left ventricular ejection fraction. At baseline, mean LVEF ranged from 61.0% to 67.5% across cohorts (Table 1). In the SAD cohort, a decrease in mean LVEF was observed in the group receiving the highest dose of aficamten (Figure 5A). The greatest mean reduction from baseline was observed 1.5 hours after administration in the 50 mg cohort (least squares mean difference 5.5%, p = 0.0001). LVESV and LVEDV statistically significantly increased by 8.1 mL and 6.6 mL, respectively (Table 9). Other echocardiographic parameters, such as stroke volume, cardiac output, cardiac time intervals, and measures reflecting diastolic function, did not change significantly (Table 9). One participant receiving 75 mg aficamten showed a 31.5% decrease in LVEF 1.5 hours after administration, which recovered 2.5 hours after its occurrence, leading to the end of dose escalation in the SAD portion of the study, as previously described. In the MAD cohort, a clear decline in LVEF emerged as dosing continued in the 10 mg cohort (Figure 5B). The greatest mean maximum decrease from baseline, 5.0%, was seen 1.5 hours after dosing in the 10 mg cohort on Day 14 (Figure 5B). The placebo-corrected decrease of 3.2% (least squares mean difference) did not reach statistical significance (p=0.21), likely due to a lack of power in this small group comparison. [Table 15-1] [Table 15-2]

[0307] Categorical LVEF response. In the SAD cohort, absolute declines in LVEF of 5% or greater from baseline occurred in 1 of 15 participants (7%) in the placebo cohort, 1 of 6 (17%) in the 3 mg cohort, 2 of 6 (33%) in the 40 mg cohort, 7 of 11 (64%) in the 50 mg cohort, and 1 of 1 (100%) in the 75 mg cohort, whereas no participants in the 1 mg, 10 mg, or 25 mg cohorts experienced declines of 5% or greater. Absolute declines in LVEF of 10% or greater occurred in 1 of 6 (17%) in the 40 mg cohort, 2 of 11 (18%) in the 50 mg cohort, and 1 (100%) in the 75 mg cohort. Reductions in LVEF below 50% were observed in 2 of 11 participants (18%) in the 50 mg cohort (48.2% and 45.5% by central laboratory assessment) and 1 of 1 (100%) in the 75 mg cohort. Only participants in the 75 mg cohort experienced an LVEF below 45%.

[0308] In the MAD cohort, four participants (1 of 6 participants (17%) receiving placebo, 1 of 6 participants (17%) receiving 7.5 mg aficamten once daily, and 2 of 6 participants (33%) receiving 10 mg aficamten once daily) experienced an absolute decrease in LVEF of 5% or more from baseline. Of these, two participants in the 10 mg cohort experienced a decrease of 10% or more. No decrease in LVEF below 50% was observed in any of the MAD cohorts by central laboratory assessment.

[0309] Relationship of Plasma Concentration to Changes in LVEF. The PK / PD relationship of aficamten is illustrated by plotting the plasma concentration of aficamten against the change in LVEF for the SAD and MAD cohorts (Figures 6A and 6B). In the SAD cohort, there was a trend toward a decrease in LVEF with increasing aficamten plasma concentration. The relationship of LVEF to aficamten plasma concentration was statistically significant in both bin concentration analysis (122–524 ng / mL, p<0.0001) and concentration-slope analysis (p=0.0027) for the highest plasma concentration bin. In the MAD cohort, the relationship of LVEF to plasma aficamten did not reach statistical significance in bin concentration analysis or linear regression analysis. This is likely due to the more limited range of plasma concentrations investigated and the small group size.

[0310] Consideration This phase 1, first-in-human study established the doses of aficamten that are physiologically effective in reducing LVEF and well-tolerated in healthy participants (up to 50 mg as a single oral dose or up to 10 mg after repeated doses) and identified the pharmacologically active dose that would serve as the starting dose for studies in patients with HCM. In addition, a single 10 mg oral dose was well-tolerated among individuals with the CYP2D6-PM phenotype, and food did not significantly affect the PK of aficamten. Taken together, these observations support the continued development of aficamten for patients with HCM and provide a roadmap for phase 2 trials.

[0311] Safety of Aficamten. No serious AEs were observed in this study, and all participants completed the intended dose as planned. AEs were generally mild and similar in frequency between Aficamten- and placebo-treated participants. Importantly, participants whose LVEF fell below 50% and whose LVEF returned to baseline within 24 hours did not have any associated symptoms or adverse changes in vital signs. This study was not intended to identify a maximum tolerated dose; therefore, dose escalation was halted once clear PD effects were observed during the SAD and MAD portions of the study. Therefore, no doses intolerable due to AEs were identified.

[0312] Effect on LVEF. In the SAD cohort, the 50 mg dose resulted in a mean 5.8% decrease in LVEF, whereas in the MAD cohort, the 10 mg dose once daily for 14 days resulted in a mean absolute decrease in LVEF of approximately 5%. The proportion of participants with a ≥5% absolute decrease in LVEF from baseline increased with increasing dose. Up to 64% of participants in the 50 mg SAD cohort and 33% of participants in the 10 mg MAD cohort experienced a ≥10% absolute decrease in LVEF from baseline. In the SAD cohort, which explored the widest range of aficamten exposure, there was a statistically significant decrease in LVEF as aficamten plasma concentrations increased. Thus, this study achieved its secondary objectives of identifying the pharmacologically active dose and describing its PK / PD relationship.

[0313] Three participants experienced a decrease in LVEF below 50%, which was rapidly reversible after discontinuation of study drug. After a single 50 mg dose, two participants (18%) experienced an LVEF below 50% (48.2% and 45.5%). After a single 75 mg dose, one participant experienced a decrease in LVEF to 34.1%. In both cases, the event occurred approximately 1.5 hours after administration, and LVEF recovered to above 50% 4 to 6 hours after administration. The SAD results informed dose selection for other parts of the study; there were no echocardiographic AEs in the MAD, CYP2D6-PM, or food effect cohorts.

[0314] Significance of PK Results: Aficamten demonstrated linear kinetics over the dose range of 1 mg to 50 mg, with a concentration-independent half-life and dose-independent clearance. Steady state was reached by the end of day 10 for the 10 mg dose and by the end of day 12 for the 5 mg and 7.5 mg doses. There was no food effect suggesting the need for dosing modifications. These findings support once-daily dosing in either the fasted or fed state.

[0315] The relationship between plasma concentrations and LVEF suggests a wide therapeutic index, facilitating individual dose optimization for patients with HCM, which is expected to be titrated over an escalating dose range until the desired PD effect is achieved. Additionally, the half-life of aficamten (75-85 hours after a single dose; 77-86 hours after multiple doses) and the reversibility of the observed effects offer potential advantages in that steady state is reached within 2 weeks and any excessive effects on LVEF are easily reversed.

[0316] Conclusions: Aficamten demonstrated a favorable safety profile in healthy participants, with no serious AEs or meaningful changes in clinical laboratory tests, ECGs, or health assessments. A decrease in LVEF below 50% was reversible within 6 hours after a single dose. A pharmacologically active dose of aficamten was identified, which could serve as the starting dose for trials in patients with HCM.

[0317] Example 2 A multicenter, randomized, placebo-controlled, double-blind, dose-finding phase 2 clinical trial of aficamten in patients with symptomatic obstructive hemoglobinuria (oHCM) was conducted. The primary objective of the study was to determine the safety and tolerability of aficamten. Secondary objectives were to describe the concentration-response relationship of aficamten on resting and post-Valsalva left ventricular outflow tract gradients measured by echocardiography during 10 weeks of treatment, to describe the dose-response relationship of aficamten, and to evaluate the plasma concentrations of aficamten in patients with oHCM. Patients were screened for enrollment in cohorts 1 and 2 at 17 clinical trial sites in North America and Europe. A third cohort (cohort 3) was also studied to evaluate the safety and efficacy of aficamten in combination with disopyramide, a Class 1 antiarrhythmic drug.

[0318] The first two cohorts (Cohort 1 and Cohort 2) excluded patients receiving disopyramide. Cohort 3 included patients receiving disopyramide. In each of the first two cohorts, patients were randomized 2:1 to active or placebo treatment and received up to three ascending doses of aficamten or placebo guided by echocardiography. In the third cohort, all patients received up to three ascending doses of aficamten guided by echocardiography. Overall, treatment duration was 10 weeks, with a 4-week follow-up period after the final dose.

[0319] Because patient characteristics vary widely in this disease, individualized dose adjustment to pharmacodynamic (PD) response (reducing LVOT-G to <30 mmHg while maintaining LVEF >50%) was employed to maximize efficacy and safety.

[0320] Patients were eligible for inclusion in this study only if they met all of the following criteria: 1. Able to understand and willing to sign the Informed Consent Form (ICF) and willing to comply with all study procedures and restrictions during the period specified in the assessment schedule; 2. Male or female, aged 18 to 85 years at screening; 3. Weight ≥ 45 kg at screening; 4. Diagnosed with oHCM according to the following criteria: (a) LV hypertrophy and non-dilated LV chambers without other cardiac disease; and (b) minimum wall thickness ≥ 15 mm (a minimum wall thickness of ≥ 13 mm was allowed if there was a positive family history of HCM or a known disease-causing genetic mutation); 5. Suitable acoustic window for echocardiography; 6. Had LVOT-G during screening as follows:For Cohorts 1 and 2: (a) resting gradient ≥ 50 mmHg; or (b) resting gradient ≥ 30 mmHg but < 50 mmHg and post-Valsalva LVOT-G ≥ 50 mmHg; or for Cohort 3: persistent resting LVOT obstruction (≥ 30 mmHg) and provoked LVOT obstruction (≥ 50 mmHg); 7. left ventricular ejection fraction (LVEF) ≥ 60% at screening; 8. New York Heart Association (NYHA) class II or III at screening; 9. patients taking beta-blockers, verapamil, diltiazem, or ranolazine must have been on a stable dose for more than 4 weeks before randomization and expected to maintain the same medication regimen during the study; 10. male patients were eligible to participate if they agreed to the following during the study and for at least 10 weeks after the final dose: (a) abstain from sperm donation; and (b)(i) engage in heterosexual intercourse as their preferred and usual lifestyle. abstinent (long-term sustained abstinence) and agree to remain abstinent; or (b)(i) must agree to use male condoms and, if the male patient's female partner is of childbearing potential, have the female partner use a highly effective method of contraception; 11. Female patients were eligible to participate if they were not pregnant or lactating and met at least one of the following conditions: (a)(i) not a woman of childbearing potential, or (a)(ii) a woman of childbearing potential and using a highly effective method of contraception during the study and for at least 4 weeks after the final dose; and (b) women of childbearing potential must have a negative pregnancy test (urine or serum, as required by local regulations) within 3 days prior to the first dose of the study intervention; 12. Able to complete all screening procedures; 13. Taking a stable dose of disopyramide for more than 4 weeks prior to screening (Cohort 3 only).

[0321] Patients were excluded from the study if they met any of the following criteria: 1. aortic stenosis or fixed subaortic obstruction; 2. known infiltrative or storage disorders causing cardiac hypertrophy similar to oHCM (e.g., Noonan syndrome, Fabry disease, amyloidosis); 3. history of left ventricular (LV) systolic dysfunction (LVEF < 45%) at any time during the clinical course; 4. documented history of current obstructive coronary artery disease (> 70% stenosis in one or more epicardial coronary arteries) or documented history of myocardial infarction; 5. treated with septal reduction therapy (surgical myectomy or percutaneous alcohol septal ablation) or planned for either therapy during the study period; 6. previous treatment with cardiotoxic agents such as doxorubicin or similar; 7. for cohorts 1 and 2: treatment with disopyramide or antiarrhythmic drugs with negative inotropic effects within 4 weeks prior to screening.For Cohort 3: Treatment with an antiarrhythmic drug other than disopyramide with negative inotropic effects within 4 weeks prior to screening; 8. Any ECG abnormality (e.g., type II second-degree atrioventricular block) deemed by the investigator to pose a risk to patient safety; 9. Proven paroxysmal atrial fibrillation or flutter during the screening period; 10. Paroxysmal or persistent atrial fibrillation requiring rhythm restoration therapy (e.g., direct current cardioversion, ablation procedures, or antiarrhythmic therapy) within 6 months prior to screening (this exclusion does not apply if the atrial fibrillation is treated with anticoagulation and has been adequately rate controlled for more than 6 months); 11. Within 6 months prior to screening 11. History of syncope on exercise or sustained ventricular tachyarrhythmia; 12. Implantable cardioverter-defibrillator (ICD) placement within 3 months prior to screening or planned ICD placement during the study; 13. History of appropriate ICD shocks for life-threatening ventricular arrhythmias within 6 months prior to screening; 14. Recipient of a major organ transplant (e.g., heart, lung, liver, bone marrow, kidney) or anticipated transplant within 12 months of randomization; 15. Hepatic dysfunction defined as total bilirubin (TBL) ≥ 1.5 times the upper limit of normal (ULN) or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 times the ULN at screening. However, patients with documented Gilbert's syndrome due to unconjugated hyperbilirubinemia without other liver disease and a TBL ≥ 1.5 times the ULN are permitted; 16. History or evidence of any other clinically significant disorder, malignancy, active infection, other condition or disease that, in the opinion of the investigator or medical monitor, poses a risk to the participant's safety or interferes with the study assessments, procedures, or completion; 17. Hemoglobin < 10.0 g / dL at screening; 18. Estimated glomerular filtration rate (eGFR) < 30 mL / min / 1.73 m at screening. 2(according to the Modification of Dietary Renal Disease (MDRD) formula); 19. Currently involved in another investigational device or drug trial or received an investigational device or drug less than 1 month (or 5 half-lives of the drug, whichever is longer) prior to screening; 20. Previously treated with aficamten or currently receiving mavacamten; 21. Known hypersensitivity to any of the excipients in film-coated aficamten tablets (e.g., mannitol, microcrystalline cellulose, croscarmellose, hydroxypropyl cellulose, sodium lauryl sulfate, magnesium stearate, Opadry QX White 21A180025).

[0322] In each cohort, patients received up to three escalating doses of aficamten, as shown in Table 11. Dose 1 was administered once daily to each patient for two weeks. At week 2, patients underwent echocardiography two hours after dose administration. Patients were titrated to dose 2 if either of the following conditions was met on echocardiography: (1) resting LVOT-G ≥ 30 mmHg and biplane LVEF ≥ 50%; or (2) resting LVOT-G < 30 mmHg, post-Valsalva LVOT-G ≥ 50 mmHg, and biplane LVEF ≥ 50%. Otherwise, patients continued on dose 1. If LVEF was less than 50% at week 2, patients were tapered to placebo. The dose adjustment algorithm is shown in Table 10 below.

[0323] After receiving the assigned dose for an additional 2 weeks (i.e., Week 4), each patient underwent echocardiography 2 hours after dose administration. If the echocardiogram met either of the following criteria: (1) resting LVOT-G ≥ 30 mmHg and biplane LVEF ≥ 50%; or (2) resting LVOT-G < 30 mmHg, post-Valsalva LVOT-G ≥ 50 mmHg, and biplane LVEF ≥ 50%, patients were escalated to the next higher dose. Otherwise, patients remained on the same dose. If LVEF was < 50% at Week 4, patients were returned to their previous dose level or, if they were receiving Dose 1, to placebo.

[0324] After two more weeks of receiving the assigned dose (i.e., week 6), each patient underwent an echocardiogram 2 hours after dose administration. If the LVEF was less than 50% at week 6, the patient was tapered to their previous dose level or, if the patient was on dose 1, to placebo. [Table 16]

[0325] Whenever a patient's dose was tapered to placebo, the patient continued on placebo for the duration of the study. [Table 17]

[0326] The baseline characteristics of patients in Cohort 1, Cohort 2, and Cohort 3 are shown in Tables 12 and 13. [Table 18] [Table 19-1] [Table 19-2]

[0327] Echocardiograms obtained every 2 weeks and 2 weeks after the final dose were analyzed for several important structural and physiological indices, as well as N-terminal prohormone of brain natriuretic peptide (NT-proBNP).

[0328] Initial results from the clinical trial included data from two sequential cohorts: Cohort 1 (n=21) and Cohort 2 (n=20), in which patients were randomized 2:1 to receive aficamten or placebo. Patients received up to three escalating doses of aficamten once daily (5, 10, and 15 mg in Cohort 1 and 10, 20, and 30 mg in Cohort 2) or placebo. To determine the feasibility of escalating to the next higher dose, patients underwent echocardiograms after two weeks of treatment at each dose. Overall, each patient in the study was treated for 10 weeks, with echocardiograms performed two weeks after the final dose.

[0329] In patients receiving aficamten in cohort 1 (n=14), mean resting LVOT-G changed from 53.8 mmHg at baseline to 13.4 mmHg at week 10; in patients receiving aficamten in cohort 2 (n=14), mean resting LVOT-G changed from 58.2 mmHg at baseline to 15.1 mmHg at week 10; and in patients in the combined placebo group (n=13), mean resting LVOT-G changed from 52.1 mmHg at baseline to 44.0 mmHg at week 10 (Figure 7; p=0.0003 for cohort 1 and p=0.0004 for cohort 2 compared with placebo at week 10).

[0330] In patients receiving aficamten in cohort 1 (n = 14), the mean Valsalva LVOT-G changed from 77.4 mmHg at baseline to 38.1 mmHg at week 10; in patients receiving aficamten in cohort 2 (n = 14), the mean Valsalva LVOT-G changed from 82.3 mmHg at baseline to 29.8 mmHg at week 10; and in patients in the combined placebo group (n = 13), the mean Valsalva LVOT-G changed from 84.6 mmHg at baseline to 76.0 mmHg at week 10 (Figure 8; p = 0.001 for cohort 1 and p < 0.0001 for cohort 2 compared with placebo at week 10).

[0331] In patients receiving aficamten in cohort 1 (n=14), the mean ejection fraction changed from 72.8% at baseline to 67.3% at week 10; in patients receiving aficamten in cohort 2 (n=14), the mean ejection fraction changed from 75.4% at baseline to 64.1% at week 10; and in patients in the combined placebo group (n=13), the mean ejection fraction changed from 74.5% at baseline to 74.9% at week 10 (p=0.01 for cohort 1, p=<0.0001 for cohort 2 compared with placebo at week 10).

[0332] Overall, the incidence of adverse events was similar between treatment arms. Treatment with aficamten in this study was well tolerated, and adverse events were reported as mild or moderate in severity. No treatment-related serious adverse events were reported by the investigators.

[0333] No patients receiving aficamten in cohort 1 had an LVEF <50%. In cohort 2, one patient with a baseline LVEF of 58% was titrated to 20 mg aficamten and experienced a transient decrease in LVEF to <50% (maintained >40%), necessitating tapering. No interruptions or discontinuations of aficamten treatment occurred in any patient across both cohorts.

[0334] The patient distribution among doses of aficamten in this study (Cohorts 1 and 2) is shown in Table 14. The patient distribution among doses of aficamten in Cohort 3 of this study is shown in Table 15. [Table 20] [Table 21]

[0335] Secondary outcomes of this clinical trial included data from Cohort 3 (n=13). All patients received up to three escalating doses of aficamten once daily (5, 10, and 15 mg). To determine the possibility of escalating to the next higher dose, patients underwent echocardiography after 2 weeks of treatment at each dose. Overall, each patient in this study was treated for 10 weeks, with echocardiography performed 2 weeks after the final dose. Efficacy endpoints included resting and induced LVOT gradients, NYHA class, and NT-proBNP.

[0336] Cohort 3 enrolled 13 patients (59 ± 14 years old; 54% female) with NYHA class II (n = 5) and III (n = 8). Patients in Cohort 3 had similar demographics, LVEF, and obstruction severity compared with Cohorts 1 and 2, but were more symptomatic and had higher baseline NT-proBNP. Patients in Cohort 3 had symptomatic obstructive HCM, a resting or post-Valsalva left ventricular outflow tract gradient (LVOT-G) of ≥ 50 mmHg, and had been previously treated with disopyramide and, most likely, a beta-adrenergic blocker. All patients received up to three escalating doses of aficamten once daily (5, 10, or 15 mg), titrated based on echocardiographic guidance as previously described. Overall, treatment duration was 10 weeks, with a 4-week follow-up period after the final dose. A total of 13 patients were enrolled, and all patients completed the treatment study.

[0337] Results from Cohort 3 demonstrated that significant reductions in mean resting LVOT-G and post-Valsalva LVOT-G (defined as a resting gradient of <30 mmHg and a post-Valsalva gradient of <50 mmHg) were achieved. These clinically important reductions in pressure gradients were achieved with only modest decreases in mean left ventricular ejection fraction (LVEF), with no patients experiencing a drop in LVEF below the predefined safety threshold of 50%. The majority of patients in Cohort 3 of this study experienced improvements in their New York Heart Association functional class. Pharmacokinetic data were similar to those observed in Cohorts 1 and 2. Additionally, the safety and tolerability of aficamten were consistent with no treatment-related discontinuations or serious adverse events reported by investigators.

[0338] Aficamten in combination with disopyramide may represent a treatment option for patients with the most severe and treatment-resistant oHCM.

[0339] Results after 10 weeks of therapy At baseline, there were no significant differences between aficamten and placebo in important echocardiographic indices and NT-proBNP levels. Patients taking aficamten had a trend toward a reduction in mean left ventricular mass index (LVMI) compared with placebo (-4.8 g / m 2 (±2.4) vs. 3.3g / m 2 (±3.6); Average difference: 8.1g / m 2 , p=0.063). Indices of left ventricular (LV) filling pressure significantly increased from baseline to week 10, including left atrial volume index (LAVI) (-2.9 mL / m 2 (±1.5) vs. 2.2 mL / m 2Improvements in the Affycamten-treated group included e' (0.5 cm / s (±0.4) vs. -0.5 cm / s (±0.3), p=0.03), and lateral wall E / e' (-2.0 (±1.1) vs. 1.8 (±0.8), p=0.006) (Figure 10). Similarly, reductions from baseline in categorical assessments of mitral valve leaflet systolic anterior motion (SAM; -50% vs. -17.3%) (Figure 11) and frequency of eccentric mitral regurgitation (MR; -35.8% vs. +13.3%) (Figure 11) were observed with Affycamten versus placebo at week 10. At week 10, aficamten resulted in a significantly greater reduction in NT-proBNP compared with placebo (geometric least squares mean ratio 0.38 (0.25 to 0.56), p=0.0002).

[0340] Figure 12 shows the change in resting LVOT-G for the treatment and placebo cohorts. Figure 13 shows the change in resting Valsalva LVOT-G for the treatment and placebo cohorts. In patients treated with disopyramide (Cohort 3), treatment with aficamten largely attenuated the effect on LVOT-G compared to patients in Cohort 1 (same aficamten dose). Figure 14 shows the change in LVEF for the treatment and placebo cohorts. Figure 15 shows the NYHA functional class response for the treatment and placebo cohorts. Figure 16 shows the change in mean NT-proBNP for the treatment and placebo cohorts.

[0341] The safety profiles of all three treatment cohorts are shown in Table 16. Six moderate adverse events were recorded in Cohort 3, including pneumonia, whooping cough, pulmonary mass, back pain, shortness of breath, and orthopnea. One adverse event of asymptomatic atrial fibrillation was recorded in a patient with a known history. The remaining adverse events included gastrointestinal symptoms (a known side effect of disopyramide) and other adverse events (headache, dizziness) seen in Cohorts 1 and 2. The overall safety profile in Cohort 3 supports the combination of aficamten and disopyramide. [Table 22]

[0342] These findings indicate that aficamten treatment results in beneficial early cardiac remodeling associated with increased e' velocity, reduced LVMI, LAVI, lateral wall E / e', SAM, eccentric mitral regurgitation, and brain natriuretic peptide, further demonstrating that aficamten favorably influences cardiac remodeling in oHCM.

[0343] Results of Cohort 1 and Cohort 2 For Cohorts 1 and 2, a complete hemodynamic response (resting LVOT gradient <30 mmHg and Valsalva gradient <50 mmHg at week 10) occurred in 11 of 14 patients (79%) in Aficamten Cohort 1 and 13 of 14 patients (93%) in Aficamten Cohort 2, compared with only 1 of 12 patients (8%) in the placebo pool (Figures 17, 18, 20).

[0344] Over the treatment period, EF decreased from 73 ± 6% to 67 ± 9% in aficamten cohort 1 (LS mean difference vs. placebo p = 0.007), from 75 ± 6% to 64 ± 8% in aficamten cohort 2 (LS mean difference vs. placebo p < 0.001), and remained unchanged in the placebo group (75 ± 6% to 75 ± 4%; p = 0.5) (Figure 19). Analysis of the relationship between aficamten dose and EF over time revealed a dose-dependent decline, with a mean reduction in EF per mg of aficamten of -0.6% (SE 0.084).

[0345] In the Afficamten treatment-integrated group (Cohorts 1 and 2), 15 of 28 patients (53%) experienced a change in NYHA class of 1 or more classes (Figure 21), including 6 patients who improved from class III to II, 8 from class II to I, and 1 from class III to I (Figure 24).

[0346] Aficamten treatment was associated with a 62% proportional reduction in NT-proBNP levels compared with placebo at week 10 (p<0.001). Importantly, 25 of 27 patients (93%) taking aficamten experienced at least some reduction in NT-proBNP levels compared with only 6 of 12 (50%) placebo-treated patients.

[0347] Baseline levels of hs-troponin I were 17 ng / L (290% CV) in the Aficamten pooled group and 17 ng / L (290% CV) in the placebo pooled group (Figure 23). At week 10, Aficamten-treated patients in Cohort 1 experienced an 18% relative reduction compared to placebo pooled (p=0.29), and patients in Cohort 2 experienced a 26% relative reduction compared to placebo pooled (p=0.097). Changes in hs-troponin I levels in the placebo pooled group and Aficamten-treated patients in Cohorts 1, 2, and 3 are shown in Figure 37.

[0348] The early and sustained hemodynamic effects of Aficamten were accompanied by significant clinical benefit in heart failure symptoms in the majority of patients. Symptom improvement of one or more NYHA classes occurred in more than half of the Aficamten-treated patients, with the majority of improvements converting patients from Class II to completely asymptomatic (Class I) in 64% of Cohort 2. Notably, Aficamten converted seven patients from advanced heart failure symptoms (Class III) to a less symptomatic state (Class II or I).

[0349] This robust hemodynamic response is particularly noteworthy because Afficamten shifted the majority of patients with obstructive HCM to gradient levels below the current threshold for considering septal reduction therapy, such as myectomy or alcohol septal ablation. This is particularly important because one of the advantages of septal reduction therapy is the opportunity to convert patients with limiting, advanced symptoms (Class III) to an asymptomatic or mildly symptomatic state.

[0350] Aficamten was also associated with significant reductions in NT-proBNP and hs-troponin, highlighting that this compound may have other potential downstream pathophysiological benefits, including reduced LV wall stress and reduced myocardial injury.

[0351] Cohort 3 results Symptomatic (New York Heart Association [NYHA] class II / III) patients with oHCM (resting or Valsalva LVOT gradient ≥ 50 mmHg and LVEF ≥ 60%) receiving standard-of-care medical therapy, including a combination of a calcium channel blocker (BB) and / or a calcium channel blocker (CBB), and disopyramide, were enrolled in an open-label study. Thirteen patients (mean age 59.4 (SD 14.4); 53.8% were women) were enrolled. Ten (77%) received a BB, two (15.4%) received a CCB, and one (7.7%) received both. The median (minimum, maximum) disopyramide dose was 300 mg / day (100, 600 mg / day). The mean (SD) LVEF at baseline was 74 (7.5%). Resting and Valsalva LVOT gradients were 50 (25) mmHg and 78 (27) mmHg, respectively. Five patients (38.5%) had NYHA class II, and eight patients (62%) had NYHA class III baseline serum NT-proBNP (geometric mean 1050 pg / mL, %CV 110). The final dose achieved was 5 mg in two patients, 10 mg in five patients, and 15 mg in six patients. Resting and Valsalva LVOT gradients (Figures 46 and 47) significantly decreased over the 10-week treatment period, with mean (SD) resting LVOT gradients at week 10 decreasing by 27 mmHg (22) [p<0.0001] and mean Valsalva LVOT gradients decreasing by 28 mmHg (32) [p=0.0002]. Mean LVEF decreased slightly from 74 ± 7.5% to 69 ± 7.2% [p = 0.018] (Figure 48) but returned to baseline after a 2-week washout. Ten of 13 patients (77%) demonstrated a complete or partial response in LVOT gradient at the end of treatment (Figure 49). Three patients (23%) achieved a transient complete or partial response during the treatment period, with overall improvement in gradient and symptoms at the end of treatment. Eleven patients (85%) demonstrated an improvement of 1 or more NYHA class, including all eight patients with baseline NYHA class III (Figure 50). Two patients who did not report an improvement in NYHA class experienced a partial hemodynamic response.Hemodynamic and NYHA class changes, reflected by reductions in cardiac biomarkers, were similar to those observed in cohorts 1 and 2 (patients receiving beta-blockers and / or calcium channel blockers but not disopyramide) (Figure 51). There were no dose interruptions, treatment discontinuations, or serious adverse events. No patients experienced an LVEF <50%, and there were no significant changes in QTc interval or vital signs.

[0352] In this open-label study, primarily involving patients with NYHA class III, the addition of aficamten significantly reduced LVOT gradient in 77% of patients, improved symptoms in 85% of patients, and improved LVOT by at least one class in all patients with baseline NYHA class III. Importantly, aficamten was well tolerated and reversible in this severely obstructive patient cohort. The decline in LVEF was similar to that observed in patients in Cohort 2 who were not receiving disopyramide. Aficamten has demonstrated efficacy as add-on therapy in patients with oHCM refractory to medical therapy and may be an alternative to SRT. Example 3a An open-label extension clinical trial of aficamten in patients with symptomatic oHCM was initiated. The primary objective of the study was to determine the safety and tolerability of aficamten over a 5-year period.

[0353] Patients were eligible for enrollment in this study if they completed the study as described in Example 2 and did not develop atrial fibrillation. Echo-guided dose adjustments based on on-site reading were administered by the investigator and could occur at any time during the study, as described below.

[0354] Study design Each patient received aficamten at dose 1 once daily for 2 weeks. During the second week, each patient underwent abbreviated echocardiography 2 hours after dose administration. If the echocardiogram met either of the following criteria: (1) resting LVOT-G ≥ 30 mmHg and biplane LVEF ≥ 50%; or (2) resting LVOT-G < 30 mmHg, post-Valsalva LVOT-G ≥ 50 mmHg, and biplane LVEF ≥ 50%, patients were titrated to dose 2. Otherwise, patients continued on 5 mg of aficamten. If LVEF was < 50%, treatment was discontinued. If LVEF was < 40%, treatment was interrupted.

[0355] At weeks 4, 6, 12, and every 12 weeks thereafter, each patient underwent an echocardiogram or abbreviated echocardiogram (abbreviated echocardiogram at weeks 4 and 6, and echocardiogram at week 12 and every 12 weeks thereafter) 2 hours after dose administration to determine if further dose adjustments were necessary (see Tables 17 and 18). Ambulatory cardiac monitoring will be performed at weeks 48, 96, 144, 192, and 240. Cardiac magnetic resonance will be monitored at weeks 48, 144, and 240. (See Figure 26). Baseline characteristics of patients enrolled in this open-label extension study are shown in Table 19. [Table 23] [Table 24] [Table 25]

[0356] Preliminary results Preliminary results are shown in Figures 27-34. Figure 27 shows the patient distribution across doses over time. At the time of data collection, 38 patients were enrolled in the study; all 38 patients had reached at least 2 weeks of dosing, 37 of 38 patients had reached at least 6 weeks of dosing, 30 of 38 patients had reached at least 12 weeks of dosing, and 19 of 38 patients had reached at least 24 weeks of dosing. Figure 27 shows the percentage of patients receiving each dose level (5, 10, or 15 mg) at each time point. Significant reductions in resting LVOT-G and Valsalva LVOT-G over time based on on-site echocardiographic data from these patients are shown in Figures 28 and 29. Significant and sustained reductions in LVOT gradient were observed from weeks 2 to 24. Additionally, minimal and stable reductions in LVEF were observed through week 24, as shown in Figure 30.

[0357] At baseline, 53% of patients were in NYHA class III and 47% were in NYHA class II.

[0358] Of patients who reached at least 12 weeks of treatment, only 7% of patients were in NYHA class III, 52% were in NYHA class II, and 41% were in NYHA class I at week 12 (Figure 31). Relative to baseline, 72% of patients experienced a one-class improvement in NYHA class, and 7% experienced a two-class improvement in NYHA class (Figure 32).

[0359] Of patients who reached at least Week 24 of treatment, only 6% of patients were in NYHA class III, 39% were in NYHA class II, and 56% were in NYHA class I at Week 24 (Figure 31). Relative to baseline, 61% of patients experienced a one-class improvement in NYHA class, and 17% experienced a two-class improvement in NYHA class (Figure 32).

[0360] No patients in this study showed a worsening of NYHA class from baseline. Preliminary Safety [Table 26]

[0361] One patient with a LVEF less than 50% and a TESAE had a history of alcohol-induced atrial fibrillation before the study, resulting in a reduction in LVEF to less than 50%. The patient experienced a recurrence of alcohol-induced atrial fibrillation episodes while taking 15 mg of aficamten, which also reduced LVEF to 47%, and aficamten was tapered. The patient subsequently experienced worsening atrial fibrillation and failed electrical cardioversion, leading to aficamten discontinuation. The patient returned to sinus rhythm with amiodarone, abstained from alcohol, and resumed aficamten at dose 1 (5 mg) because the LVEF was 60% with evidence of obstruction.

[0362] One patient underwent a temporary tapering due to investigator concerns about QTc prolongation in a subject with an abnormal baseline EKG. A temporary aficamten tapering was performed until the central laboratory interpreted the QTc. A normal QTc was confirmed, and aficamten was then increased.

[0363] One subject with severe TESAE presented with altered mental status prior to planned cardioversion for worsening atrial fibrillation while taking a DOAC (direct-acting oral anticoagulant), resulting in hospitalization. MRI demonstrated a presumed embolic stroke. The patient was subsequently diagnosed with a congenital heart abnormality (ostium secundum atrial septal defect). No tapering or discontinuation of aficamten was necessary.

[0364] Kansas City Cardiomyopathy Questionnaire (KCCQ) Participants' health status was assessed with the KCCQ before starting Aficamtene in the OLE and at weeks 12 and 24 of treatment. Changes from baseline in KCCQ scores, including OSS = Global Summary Score, CSS = Clinical Summary Score, TSS = Total Symptom Score, PLS = Physical Limitation Score, SLS = Social Limitation Score, and QoL = Quality of Life, were determined. Patients were categorized as worsening (<-5 points), unchanged (<-5 to <5 points), slightly improved (<5 to <10 points), moderately to significantly improved (<10 to <20 points), and significantly to very significantly improved (>20 points) compared to baseline.

[0365] These results demonstrate significant improvements in KCCQ scores among OLE participants at week 12 that were sustained through 24 weeks. The percentage of participants with clinically important improvement (global summary score ≥ 5 points) was 72.7% at week 12 and 72.0% at week 24. Highly significant clinical improvement (≥ 20 points) was seen in 36.4% at week 12 and 40.0% at week 24 (Figures 35 and 36). Treatment with Aficamten resulted in significant and sustained improvements in all KCCQ domain scores for up to 6 months.

[0366] conclusion In this open-label extension study of patients with obstructive HCM treated with background medical therapy (with or without disopyramide), aficamten was associated with significant and sustained reductions in LVOT gradient (Figures 28 and 29) and substantial improvements in heart failure symptoms (improvement of NYHA class by ≥1 in approximately 80% of patients) (Figures 31 and 32), as well as significant reductions in cardiac biomarkers (NT-proBNP and hs-cTnI) (Figures 33 and 34). Aficamten was well tolerated, and there were no events of LVEF <50% attributable to aficamten. These data demonstrate that the therapeutic effect of aficamten is sustained for up to 6 months.

[0367] Example 3b An open-label extension clinical trial of aficamten has been initiated in patients with symptomatic oHCM. Treatment duration is expected to be several years. The primary objective of the study was to determine the safety and tolerability of aficamten over a 5-year period.

[0368] Approximately 275 patients may be enrolled in the study. After up to 56 days of screening, eligible patients will receive a daily dose of aficamten. The maximum tolerated dose will be informed by the performance of other ongoing aficamten studies. Each patient will be started on the lowest pre-specified dose and titrated to the maximum tolerated dose (not to exceed the pre-specified maximum dose) under echocardiographic guidance. Dose adjustments cannot occur more frequently than every two weeks. The study will involve approximately 95 study sites in the United States, Europe, and the Middle East.

[0369] Inclusion criteria: (1) completion of a study investigating aficamten (i.e., according to Example 2 or Example 5); (2) ability to understand and willingness to sign the ICF and willingness to comply with all study procedures and restrictions for the period specified in the activity schedule; (3) left ventricular ejection fraction ≥ 55%.

[0370] Exclusion Criteria: (1) Previous treatment with mavacamten. (2) Participation in a study of another investigational device or drug or receipt of an investigational device or drug for less than 1 month (or 5 half-lives for drugs, whichever is longer) prior to screening. No other study procedures were permitted during participation in this study. (3) The presence of acute or serious comorbid conditions (e.g., serious infection, hematological, oncological, cardiological, nephrological, metabolic, gastrointestinal, or endocrinological dysfunction) that the investigator / subinvestigator or medical monitor at the study site determined to pose a risk to patient safety or interfere with the evaluation, procedures, or completion of the study. (4) New-onset paroxysmal or persistent atrial fibrillation requiring rhythm restoration therapy (e.g., direct current cardioversion, ablation therapy, or antiarrhythmic therapy) within 30 days prior to screening. Patients may be rescreened after 30 days if their heart rate (HR < 100 bpm) and / or rhythm remain stable for more than 30 days. (This exclusion does not apply if atrial fibrillation is treated with anticoagulation and heart rate has been adequately controlled for at least 14 days.) (5) Received ventricular septum reduction therapy (surgical myectomy or transcatheter alcohol ablation) since completion of a prior study of Aficamten. (6) Active obstructive coronary artery disease (confirmed stenosis of greater than 70% in one or more arteries). (7) Moderate or severe aortic stenosis. (8) Confirmed LVEF <40% with associated dose interruption during a previous study investigating Aficamten (i.e., according to Example 2 or Example 5). Patients may be considered for enrollment if data from the participant cohort are unblinded. (9) History of exercise-induced syncope or sustained ventricular tachyarrhythmia within 30 days prior to screening. (10) History of ICD placement within 30 days prior to screening. (11) Hypersensitivity to excipients in Aficamten tablets (e.g., mannitol, microcrystalline cellulose, croscarmellose, hydroxypropyl cellulose, sodium lauryl sulfate, magnesium stearate, Opadry QX White 21A180025).

[0371] Study design On day 1, each patient will undergo an echocardiogram and will receive dose 1 of aficamten once daily for 2 weeks. On week 2, each patient will undergo an abbreviated echocardiogram after dose administration. If LVOT-G after the Valsalva maneuver is 30 mmHg or greater and the biplane LVEF is 55% or greater, patients will be titrated to dose 2. Otherwise, patients will continue on 5 mg of aficamten. If LVEF is <50%, treatment will be discontinued.

[0372] At weeks 4, 6, 12, and every 12 weeks thereafter, each patient underwent an echocardiogram or abbreviated echocardiogram (abbreviated echocardiogram at weeks 4 and 6, and echocardiogram at week 12 and every 12 weeks thereafter) after dose administration to determine whether further dose adjustments were necessary (see Tables 21 and 22). Patient-reported outcomes, clinical laboratory assessments, NT-proBNP, hs-cTnI, and other biomarker measurements will be performed at week 12 and every 12 weeks thereafter. Ambulatory cardiac monitoring will be performed at weeks 48, 96, 144, 192, and 240, and cardiac magnetic resonance will be monitored at weeks 48, 144, and 240. If the patient has an LVEF <40% after the week 2 visit, a repeat echocardiogram (preferably within 24 hours) may be performed to confirm the initial findings. If the echocardiographic findings are confirmed, the patient will undergo a washout period of at least 2 days. If regional echocardiography demonstrates an LVEF ≥ 55%, patients may continue receiving aficamten at the reduced previously tolerated dose. [Table 27] [Table 28]

[0373] Echocardiogram The echocardiographic parameters to be measured include at least left ventricular parameters (left ventricular outflow tract pressure gradient at rest (LVOT-G), LVOT-G after Valsalva, LVEF, LVFS, left ventricular strain, left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left ventricular output), septal wall thickness and free wall thickness, E / e', E / A, and LA volume.

[0374] cardiac magnetic resonance The cardiac magnetic resonance (CMR) imaging substudy will evaluate the effects of long-term aficamten administration on cardiac morphology, function, and fibrosis in eligible and electing patients. CMR will be performed at baseline any time during the screening period and may be performed within 8 weeks prior to the first dose of aficamten, administered on Day 1. Patients who fail screening and are rescreened will not need to undergo a repeat baseline CMR. If a subject enrolls in the CMR substudy of Example 5, they will not need to undergo a repeat baseline CMR. Patients with an eGFR less than 30 mL / min / 1.73 m2 or who are allergic to gadolinium will undergo only non-contrast CMR. Patients may also elect to undergo only non-contrast CMR evaluation for any other reason. Subsequent CMR examinations will be performed within ±30 days of the Week 48 and Week 144 visits or within 60 days prior to the Week 240 or end-of-treatment (EOT) visit.

[0375] Record NYHA functional class. When available, patients complete patient-reported outcome (PRO) questionnaires: Kansas City Cardiomyopathy Questionnaire (KCCQ) as specified in Table 23, Seattle Angina Questionnaire-7 (SAQ-7), EuroQol 5-Dimension 5-Point Scale (EQ-5D-5L), Patient Global Impression of Change (PGI-C) scale, Clinical Global Impression (CGI) scale, and SF-36 Physical Function Subscale (SF-36PFS). [Table 29]

[0376] Primary endpoint The primary objective of this study was to determine the safety and tolerability of aficamten over a 5-year period, including assessment of cardiac structure and function during long-term administration of aficamten. Safety and tolerability will be assessed by (i) the incidence of adverse events, (ii) the incidence of serious adverse events, and (iii) the incidence of patients with LVEF <50%.

[0377] Secondary endpoints Secondary objectives were to assess the long-term effects of aficamten on LVOT-G in patients with oHCM, measured at rest and during Valsalva provocation, and to assess the proportion of patients who: a) Resting LVOT-G < 50mmHg, b) Resting LVOT-G < 30mmHg, c) Post-Valsalva LVOT-G < 50mmHg, d) Post-Valsalva LVOT-G < 30mmHg, or e) LVEF ≥ 50%, resting LVOT-G < 30mmHg, and post-Valsalva LVOT-G < 50mmHg, time to first resting LVOT-G < 30mmHg, time to first post-Valsalva LVOT-G < 50mmHg, time to first post-Valsalva LVOT-G < 30mmHg, and time to first LVEF ≥ 50%, resting LVOT-G < 30mmHg, and post-Valsalva LVOT-G < 50mmHg.

[0378] Exploratory Endpoints Exploratory objectives of this study include: (i) C at 1-year intervals until the end of participation; trough(ii) to evaluate the steady-state pharmacokinetics of aficamten during chronic administration as monitored by MRI; (ii) to evaluate the long-term effects of aficamten on cardiac biomarkers as assessed by change from baseline in NT-proBNP, hs-cTnI, galectin-3, PINP, TIMP-1, CITP, soluble ST2, and other biomarkers at 12-week intervals until the end of participation; (iii) to evaluate the impact on functional outcomes, such as change from baseline in NYHA functional class at 12-week intervals until the end of participation; (iv) to evaluate the impact on oHCM symptoms by assessing change from baseline to the end of participation in EQ-5D-5L, PGI-C, CGI, Kansas City Cardiomyopathy Questionnaire (KCCQ), SAQ-7, and SF-36 Physical Function Subscale (SF-36PFS) at 12-week intervals; and (v) to evaluate the pharmacodynamic effects of aficamten on cardiac function and structure. This will be assessed by changes from baseline to the end of participation in the following echocardiographic cardiac function and structure measures at 12-week intervals: LVEF; left ventricular fractional shortening (LVFS); left ventricular stroke volume (LVSV); left ventricular end-systolic and end-diastolic volumes (LVESV and LVEDV, respectively); septal, free wall, and maximum wall thickness; left atrial volume; left ventricular strain (longitudinal, circumferential, radial); diastolic indices: E / e', E / A; (vi) the effect of aficamten on electrocardiographic indices of myocardial repolarization abnormalities, as assessed by changes from baseline to the end of participation in the proportion of patients with electrocardiographic left ventricular strain patterns at 12-week intervals; and (vii) the effect of aficamten on cardiac structure. (viii) the effect of aficamten on cardiac function, assessed by change from baseline to 1, 3, 5 years and end of participation, and biventricular function, assessed by CMR imaging ... CMR imaging to biventricular function, assessed by CMR imaging, assessed by change from baseline to 1, 3, 5 years and end of participation, assessed by change from baseline to 1, 3, 5 years and end of participation, assessed by change from CMR imaging to biventricular function, assessed by change from baseline to 1, 3, 5 years and end of participation, assessed by change from CMR imaging to biventricular function, assessed by change from baseline to 1, 3, 5 years and end of participation, assessed by change from CMR imaging to biventricular function, assessed by change from CMR imaging to biventricular function, assessed by change from baseline to 1, 3, 5 years and end of participation, assessed by change from CMR imaging to biventricular function, assessed by change from CMR imaging to biventricular function, assessed by change from baseline to 1, 3, 5 years and end of participation, assessed by change from CMR to biventricular function, assessed by change from CMR to biventricular function, assessed by change from CMR to biventricular function, assessed by change from CMR to biventricular function, assessed by change from CMR to biventricular function, assessed by change from CMR to biventricular function, assessed by change from CMR to biChanges from baseline to 1, 3, 5 years, and end of participation were assessed using the following parameters by CMR late gadolinium enhancement (LGE): LGE mass (g); LGE mass % (% of LV mass);

[0379] Interim Results of Examples 3a and 3b Patients were treated according to the protocol in Example 3a or Example 3b. Patients were classified as receiving SoC therapy (both first-line and second-line) if they were receiving treatment with at least one beta-blocker (BB), non-dihydropyridine calcium channel blocker (CCB), or disopyramide. Patients were eligible for baseline therapy reduction / withdrawal (BTR / W) at the discretion of the site investigator after receiving a stable dose of aficamten for at least 4 weeks and after week 12 of the study. Successful BTR / W was defined as reducing the dose of at least one medication to 50% or less of baseline. Serial measurements were collected per protocol, but side effects specific to SoC therapy were not collected.

[0380] Of the first 42 patients enrolled, 39 (93%) were taking one or more SoC medications: 27 (69%) were receiving BB alone, 4 (10%) were receiving CCB alone, 7 (18%) were receiving a CCB or BB in combination with disopyramide, and 1 patient (3%) was receiving triple therapy. Among patients (N = 35) who received aficamten treatment for 12 weeks or more, 20 (57%) attempted BTR / W, and 17 (85%) achieved some form of BTR / W success. Ten patients permanently discontinued at least one medication, and five discontinued all SoC (afficamten monotherapy). Three patients attempted BTR / W but failed, and BB was restarted as a result of recurrence of symptoms or elevated left ventricular outflow tract gradient (LVOT-G). Baseline characteristics of all enrolled patients and the subgroups included in this analysis are shown in Table 24A. The median baseline doses of beta-blockers and calcium channel blockers are shown in FIG.

[0381] All subgroups demonstrated rapid and sustained relief of obstruction, improvement in cardiac biomarkers, and symptomatic improvement with a modest decline in LVEF (Figures 39-42). In patients available for assessment before and after BTR / W (N=14), BTR / W increased resting HR by 12 bpm (mean HR=74±10 bpm, p=0.0001) and Valsalva LVOT-G by 15 mmHg (mean Valsalva LVOT-G=42±26 mmHg, p=0.02). All other measures, including NT-pro B-type natriuretic peptide (321±424 pg / dL before BTR / W and 532±934 pg / mL after BTR / W, p=0.43) and high-sensitivity troponin I levels (4.8±1.8 ng / mL before BTR / W and 5.1±1.6 ng / mL after BTR / W, p=0.56), were similar. No safety events were considered related to aficamten therapy by the investigators. NT-proBNP and hs-troponin I levels are shown in Figures 45A and 45B. [Table 30-1] [Table 30-2]

[0382] A delineation of the baseline characteristics of the first 45 patients enrolled is shown in Table 24B. [Table 31]

[0383] The number of patients and the dose achieved at each time point are shown in Figure 52. From baseline to week 48, there was a significant decrease in resting peak blood pressure and Valsalva LVOT-G [Δresting mean: -32 mmHg (±28), ΔValsalva mean: -47 mmHg (±28)] (see Figures 53 and 54, respectively). There was a moderate decrease in LVEF from baseline to week 48 (Δ-5±3%), with no patients experiencing an aficamten-associated LVEF decrease of less than 50% (see Figure 55). There was a significant improvement in NYHA class. By week 48, 88% of patients experienced an improvement in NYHAFC of ≥1, while no patients experienced a worsening of NYHAFC (see Figure 56). Despite receiving beta-blockers (78%), calcium channel blockers (18%), and disopyramide (22%) at baseline, 19 patients (42%) were eligible for SRT according to symptom and hemodynamic guideline criteria (SRT eligibility: NYHA class III or IV with a LVOT gradient of 50 mmHg or greater at rest or during exertion with Valsalva or exercise, or NYHA class II with syncope or presyncope during exertion and an increasing gradient). No patients met these criteria by the 48-week visit. NTpro-BNP decreased from baseline to week 48 (geometric mean [CV%] 651.0 [160.4] to 111.1 [93.4] pg / mL), representing a 70% decrease from baseline (p<0.0001).

[0384] Mid-longitudinal global strain (GLS) results Patients (n=27, baseline characteristics in Table 24C) enrolled in the open-label extension study of aficamten (FOREST HCM) underwent echocardiography (GE E-95 ultrasound system) at baseline, week 12, and weeks 36 to 48. GLS analysis was performed using a vendor-neutral analysis package (TOMTEC® Imaging System).

[0385] Changes in NYHA functional class are shown in Figure 57A. Compared to baseline, GLS was similar at 12 weeks (-13.9% ± 3.2 vs. -14.3 ± 3.0, p 0.32), followed by significant improvements in GLS at 36-48 weeks (-13.9% ± 3.2 vs. -14.9% ± 2.7, p 0.012) (see Figure 57B). These improvements were more pronounced in patients with optimal hemodynamic responses (resting LVOTg < 30 and Valsalva LVOTg < 50 mmHg, n = 21) (see Figures 57C and 57D). [Table 32]

[0386] conclusion Interim results show that withdrawal or reduction of SoC medications after treatment with aficamten was generally effective and safe and associated with sustained significant improvements in clinically relevant efficacy metrics.

[0387] Treatment with aficamten was associated with rapid and sustained improvement in echocardiographic hemodynamics, paralleled by significant improvement in NYHA class. Aficamten precluded eligibility for SRT in all patients who were guideline-eligible at baseline. There were no cases of systolic dysfunction (LVEF <50%) attributable to aficamten.

[0388] Aficam therapy favorably affected myocardial mechanics (e.g., GLS) after long-term treatment, and these changes were most pronounced when the hemodynamic response was optimal (resting LVOTg < 30 and Valsalva LVOTg < 50 mmHg). Without being bound by theory, potential causative mechanisms include a reduction in LVOTg followed by a reduction in long-term afterload, which may result in other pathologic biological changes, given the improvement in strain that occurred several weeks after gradient reduction.

[0389] Example 4 This study is a phase 3, multicenter, randomized, double-blind, active-controlled trial in participants with symptomatic oHCM and elevated LVOT-G (see Figures 38 and 58). Approximately 170 eligible participants will be randomly assigned in a 1:1 ratio to aficamten or metoprolol. Randomization will be stratified by CPET exercise modality (treadmill / bicycle) to compare recently diagnosed patients with chronic oHCM. Randomization will be stratified as follows: 1) untreated or currently untreated participants (no SOC medication within the past 12 months) or recently diagnosed participants (history of oHCM ≤ 12 months with or without use of SOC therapy), and 2) participants with chronic oHCM (> 12 months) who are currently being treated or have received SOC therapy within the past 12 months. The number of participants utilizing the bicycle CPET exercise modality will be limited to approximately 50%.

[0390] The overall objective of this active-controlled trial is to evaluate the safety and efficacy of aficamten as 1) first-line therapy in recently diagnosed or treatment-naive participants, or 2) monotherapy in participants previously receiving standard of care (SOC) for symptomatic oHCM.

[0391] The primary objective of this study was to evaluate the effect of aficamten on exercise capacity in patients with symptomatic oHCM. The endpoint presented was change in maximal oxygen uptake (pVO2) from cardiopulmonary exercise testing (CPET) from baseline to week 24.

[0392] A secondary objective of the study was to evaluate the effect of aficamten on New York Heart Association (NYHA) functional class, as determined by the proportion of patients who achieved an improvement of ≥1 NYHA class from baseline to weeks 12 and 24.

[0393] A further secondary objective of the study is to evaluate the effect of aficamten on patient health status as determined by change from baseline to weeks 12 and 24 in the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS).

[0394] A further secondary objective of the study is to evaluate the effect of aficamten on structural remodeling as determined by the change in left ventricular mass index (LVMI) or left atrial volume index (LAVI) from baseline to 24 weeks.

[0395] A further secondary objective of this study is to evaluate the effect of aficamten on N-terminal prohormone brain natriuretic peptide (NT-proBNP) levels from baseline to 24 weeks.

[0396] A further secondary objective of this study is to assess the effect of aficamten on post-Valsalva left ventricular outflow tract gradient (LVOT-G) from baseline to 24 weeks.

[0397] To evaluate the safety and tolerability profile of aficamten in patients with symptomatic oHCM, the following will be recorded: (1) incidence of reported serious adverse cardiac events (cardiovascular [CV] death, cardiac arrest, nonfatal stroke, nonfatal myocardial infarction, CV hospitalization); (2) incidence of adverse events (AEs); and (3) incidence of left ventricular ejection fraction (LVEF) <50%.

[0398] The exploratory objective of this study was to evaluate the effect of aficamten on exercise capacity and functional class, as determined by comparing the number of patients at 24 weeks with baseline who achieve either: (1) a change from baseline in pVO2 of ≥ 1.5 mL / kg / min and an improvement in NYHA functional class of ≥ 1; or (2) a change from baseline in pVO2 of ≥ 3.0 mL / kg / min and no worsening of NYHA functional class.

[0399] Further exploratory objectives of this study are to evaluate the effect of aficamten on patient response over time, as determined by: (1) the proportion of patients with an improvement in KCCQ-CSS at weeks 12 and 24; (2) the proportion of patients with a resting LVOT-G <30mmHg, a post-Valsalva LVOT-G <50mmHg, and an NYHA functional class of I at weeks 12 and 24; and (3) the proportion of patients with a resting LVOT-G <30mmHg, a post-Valsalva LVOT-G <50mmHg, and an improvement in NYHA functional class of ≥1 at weeks 12 and 24.

[0400] A further exploratory objective of this study is to evaluate the effect of aficamten on cardiac troponin levels, as determined by the change in high-sensitivity cardiac troponin I (hs-cTnI) from baseline to 24 weeks.

[0401] A further exploratory objective of the study is to evaluate the effect of aficamten on metrics of diastolic function, as determined by the change in the ratio of early mitral inflow velocity to early mitral annular diastolic velocity (E / e' [lateral wall]) from baseline to 24 weeks.

[0402] A further exploratory objective of this study is to evaluate the effect of aficamten on interventricular septal thickness (IVST) remodeling, as determined by change in IVST from baseline to 24 weeks.

[0403] Further exploratory objectives of this study are to evaluate the effect of aficamten on other CPET parameters as determined by the change from baseline to week 24 in: (1) ventilatory efficiency / carbon dioxide production (VE / VCO2 slope), (2) circulatory power (VO2 × systolic blood pressure [SBP]), (3) ventilatory anaerobic threshold (VAT), total workload (watts), and heart rate response.

[0404] Further exploratory objectives of the study are to evaluate the effect of aficamten on health status and health-related quality of life as measured by PRO questionnaires, as determined by changes from baseline to week 24 in individual responses to the EuroQol 5 Dimension 5 Level instrument (EQ-5D-5L), Clinical Global Impression (CGI), Patient Global Impression of Change (PGI-C), and Seattle Angina Questionnaire-7 (SAQ-7).

[0405] A further exploratory objective of this study is to evaluate the pharmacokinetics of aficamten and its metabolites as determined by pharmacokinetic parameters through 24 weeks.

[0406] Selection Criteria Patients were eligible for inclusion in this study only if they met all of the following criteria: (1) were able to understand and willing to sign the ICF and comply with all study procedures and restrictions during the time period specified in the assessment schedule, (2) were male or female and aged 18–85 years (inclusive) at the time of screening, and (3) had a body mass index of <35 kg / m. 2(4) Diagnosis of oHCM by cardiac magnetic resonance imaging (CMR) or echocardiography according to the following criteria: (a) absence of other cardiac disease, left ventricular hypertrophy, and no dilated left ventricular cavity; (b) minimum wall thickness of 15 mm or greater (a minimum wall thickness of 13 mm or greater is acceptable if there is a known disease-causing genetic mutation or family history of HCM); (5) Resting LVOT-G of ≥ 30 mmHg and post-Valsalva LVOT-G of ≥ 50 mmHg during screening, as determined by a central echocardiographic laboratory; (6) LVEF of ≥ 60% at screening, as determined by a central echocardiographic laboratory; (7) New York Heart Association (NYHA) functional class II or III at the second screening visit; (8) Hemoglobin of ≥ 10 g / dL at screening; (9) Respiratory exchange ratio (RER) of ≥ 1.05 and pVO2 of < 100% predicted by central screening CPET at screening visit 2. (10) Have an acoustic window sufficient for echocardiography. (11) Male patients are eligible to participate if they agree to the following during the study and for at least 4 weeks after the final dose of aficamten: (a) abstain from sperm donation, and (b) either (i) abstain from heterosexual intercourse as a preferred and usual lifestyle (long-term sustained abstinence) and agree to continue abstinence, or (ii) agree to use male condoms and, if the male patient's female partner is of childbearing potential, have her use a highly effective method of contraception. (12) Female patients were eligible for participation if they were not pregnant, breastfeeding, or planning egg donation and met at least one of the following criteria: (a) they were not women of childbearing potential (WOCBP) or were WOCBP and used highly effective contraception during the study and for at least 4 weeks after the final dose of aficamten, and their male partners agreed to use condoms; and (b) WOCBPs must have a negative pregnancy test (urine or serum, as required by local regulations) on day 1 before the first dose of study aficamten. (13) They were able to complete all screening procedures. (14) Their KCCQ-CSS score at screening was ≥35 and ≤90.(15) Patients previously exposed to mavacamten can participate, but they must discontinue mavacamten for at least 8 weeks before signing informed consent and obtain approval from the medical monitor before enrollment. Approximately 10% of patients with oHCM previously treated with mavacamten can participate in this study with approval from the medical monitor.

[0407] Exclusion criteria Patients will be excluded from the study if they meet any of the following criteria: (1) a medical indication for either a beta-blocker or calcium channel blocker that prohibits discontinuation of the medication other than for oHCM; (2) a history of intolerance or medical contraindication to beta-blocker therapy; (3) a resting SBP greater than 160 mmHg at screening; (4) a resting heart rate greater than 100 bpm at screening; (5) significant valvular disease (as determined by the investigator), including moderate to severe aortic stenosis or fixed subaortic obstruction and / or mitral regurgitation not due to systolic anterior motion of the mitral valve; (6) known or suspected infiltrative, hereditary, or storage disorders that cause cardiac hypertrophy similar to oHCM (e.g., Noonan syndrome, Fabry disease, amyloidosis); (7) a history of LV systolic dysfunction (LVEF < 45%) or stress cardiomyopathy at any time during the clinical course. (8) Inability to exercise on a treadmill or bicycle (e.g., orthopedic limitations). (9) Treatment with septal reduction therapy (surgical myectomy or percutaneous alcohol septal ablation) within 6 months of screening (note that patients who underwent septal reduction therapy more than 6 months before screening may be admitted, totaling approximately 10% of patients), or planned to receive either therapy during the study period, which cannot be postponed. (10) History of paroxysmal or persistent atrial fibrillation or atrial flutter (atrial flutter treated with radiofrequency ablation within the past 6 months before screening without recurrence is permitted). (11) Current or recent (<4 weeks) treatment with disopyramide. (12) History of exercise-induced syncope, symptomatic ventricular arrhythmia, or sustained ventricular tachyarrhythmia within 6 months before screening. (13) ICD implantation within 3 months before screening or planned ICD implantation during the study. (14) Estimated glomerular filtration rate (eGFR) at screening <30 mL / min / 1.73 m 2 (15) Previous treatment with aficamten or previous intolerance to mavacamten (reduced LVEF requiring permanent drug discontinuation).

[0408] General design. The screening period begins at the time of informed consent and includes clinical assessments both pre-washout (Screening Visit 1) and post-washout (Screening Visit 2) periods. Participants not currently receiving medical therapy for oHCM will not require a washout period and will only attend Screening Visit 2. After meeting the eligibility criteria, participants will be randomized to receive either aficamten and placebo instead of metoprolol, or metoprolol and placebo instead of aficamten.

[0409] Participants enrolled in this study must have an LVEF ≥ 60% prior to randomization. Randomization will be stratified by CPET exercise modality (treadmill / bicycle) and recently diagnosed vs. chronic oHCM patients as follows: 1) untreated or currently untreated participants (no SOC medication within the past 12 months) or recently diagnosed participants (history of oHCM ≤ 12 months with or without SOC therapy use), and 2) participants with chronic oHCM (> 12 months) who are currently being treated or have received SOC therapy within the past 12 months. Participants randomized to aficamten may receive up to four escalating IP doses over the first 6 weeks of the study, as shown in Table 27 below.

[0410] Participants will receive IP in a double-blind manner at each study visit. During the first 6 weeks of the treatment period, IP doses will be individually adjusted at weeks 2, 4, and 6 according to echocardiographic and vital sign criteria (see Table 26). At these visits, an unblinded echocardiologist will review echocardiogram (LVEF and LVOT-G) and vital sign (SBP and resting heart rate) data, and either the unblinded echocardiologist or an unblinded designated physician will enter the data into an interactive web response system (IWRS), where dose adjustments will be made in a blinded manner according to a pre-specified algorithm.

[0411] Participants receiving aficamten will start at a dose of 5 mg once daily (Dose 1) and may be titrated to doses of 10, 15, and 20 mg once daily if they consistently meet two echocardiographic dose-escalation criteria, or maintain their current dose if the criteria are not met. If LVEF falls below 50%, the aficamten dose will be tapered, and if LVEF falls below 40% at any time, aficamten administration will be temporarily interrupted.

[0412] Patients receiving metoprolol will be initiated at a dose of 5 mg once daily (Dose 1) and may be titrated up to doses of 100, 150, and 200 mg once daily if they continue to meet two echocardiographic and two vital sign titration criteria, or stopped at the current dose if they do not meet the titration criteria.

[0413] During the study, if a participant experiences an intolerable adverse event (AE) that, in the investigator's judgment, is drug-related and necessitates the participant requesting discontinuation of IP, the IP dose may be reduced to the previous dose level. For participants receiving Dose 1, IP will be discontinued.

[0414] The treatment period will be up to 24 weeks, with a 4-week follow-up period (weeks 24 to 28) after the last dose. The primary endpoint, pVO2, will be measured by CPET at randomization and at week 24. [Table 33] [Table 34] [Table 35]

[0415] After randomization, each patient will receive Dose 1 (aficamten 5 mg, metoprolol 50 mg) once daily for 2 weeks. At the Week 2 visit, patients will undergo an echocardiogram 2 hours after dose administration. I...

Claims

1. A method for treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, comprising administering a therapeutically effective amount of aficamten. 【Chemical 1】 or a pharmaceutically acceptable salt thereof to said patient, wherein said patient has been diagnosed with oHCM within 12 months prior to administering aficamten or a pharmaceutically acceptable salt thereof.

2. A method for treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, comprising administering a therapeutically effective amount of aficamten. 【Chemistry 2】 or a pharmaceutically acceptable salt thereof to said patient, wherein said patient is not currently undergoing treatment for oHCM.

3. 3. The method of claim 1 or 2, comprising administering aficamten or a pharmaceutically acceptable salt thereof as monotherapy for oHCM.

4. A method for treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, comprising administering a therapeutically effective amount of aficamten. 【Chemistry 3】 or a pharmaceutically acceptable salt thereof, as monotherapy for oHCM to the patient, wherein the patient has chronic oHCM and has previously received standard of care medical therapy for oHCM, and has discontinued said therapy prior to administering aficamten or a pharmaceutically acceptable salt thereof.

5. 5. The method of claim 4, wherein the standard of care medical therapy comprises treatment with one or more therapies selected from beta-blockers, calcium channel blockers, and disopyramide.

6. The method of any one of claims 1 to 5, wherein the patient has a LVEF > 60% prior to administration of aficamten or a pharmaceutically acceptable salt thereof.

7. The method according to any one of claims 1 to 6, wherein the patient has a resting LVOT-G > 30 mmHg before administration of aficamten or a pharmaceutically acceptable salt thereof.

8. The method of any one of claims 1 to 7, wherein the patient has a post-Valsalva LVOT-G > 50 mmHg before administration of aficamten or a pharmaceutically acceptable salt thereof.

9. The method of any one of claims 1 to 8, wherein the patient is characterized as being in NYHA class II or class III prior to administration of aficamten or a pharmaceutically acceptable salt thereof.

10. Exercise capacity; cardiac function measured by improvement in NYHA functional class; LVOT-G at rest; LVOT-G after Valsalva; health status measured by Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS); structural remodeling measured by reduction in one or more of mean left ventricular mass index (LVMI) and left atrial volume index (LAVI); N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels; high-sensitivity cardiac troponin I (hs-cTnI) levels; diastolic function measured by reduction in lateral wall E / e'; and ventricular septum measured by change in interventricular septal thickness (IVST).

10. The method of any one of claims 1-9, wherein the method results in an improvement in one or more of: thickness remodeling; CPET parameters selected from the following: ventilatory efficiency / carbon dioxide production (VE / VCO2 slope), circulatory power (VO2 x systolic blood pressure), ventilatory anaerobic threshold (VAT), total workload (Watts), and heart rate response; and health status and health-related quality of life as measured by the Patient-Reported Outcomes (PRO) questionnaire EuroQol 5 Dimension 5 Level instrument (EQ-5D-5L), Clinical Global Impression (CGI), Patient Global Impression of Change (PGI-C), and Seattle Angina Questionnaire-7 (SAQ-7).

11. 11. The method of claim 10, wherein the results are improved compared to treatment with metoprolol.

12. 12. The method of any one of claims 10 or 11, which results in an improvement in exercise capacity as measured by an increase in maximal oxygen uptake (pVO2) by cardiopulmonary exercise testing (CPET).

13. 13. The method of any one of claims 10 to 12, which results in an improvement in cardiac function as measured by an improvement in NYHA functional class by one or more class(es).

14. 14. The method of any one of claims 10-13, which results in an improvement in exercise capacity as measured by an increase in pVO2 of at least 1.5 mL / kg / min from baseline and an improvement in at least one NYHA functional class.

15. 14. The method of any one of claims 10-13, which results in an improvement in exercise capacity as measured by an increase in pVO2 of at least 3.0 mL / kg / min from baseline and no worsening of at least one NYHA functional class.

16. 14. The method of any one of claims 10 to 13, which results in a resting LVOT-G of less than 30 mmHg, a post-Valsalva LVOT-G of less than 50 mmHg, and NYHA class I.

17. 14. The method of any one of claims 10-13, wherein the method results in a resting LVOT-G of less than 30 mmHg, a post-Valsalva LVOT-G of less than 50 mmHg, and an improvement in at least one NYHA functional class.

18. 18. The method of any one of claims 10 to 17, which results in an improvement in health status as measured by the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS).

19. 19. The method of any one of claims 10 to 18, which results in structural remodeling as measured by a reduction in one or more of the mean left ventricular mass index (LVMI) and left atrial volume index (LAVI).

20. 20. The method of any one of claims 10 to 19, which results in a reduction of N-terminal prohormone of brain natriuretic peptide (NT-proBNP).

21. 21. The method of any one of claims 10 to 20, which results in an improvement in post-Valsalva left ventricular outflow tract gradient (LVOT-G).

22. 22. The method of any one of claims 10 to 21, which results in a reduction of high-sensitivity cardiac troponin I (hs-cTnI).

23. 23. The method of any one of claims 10 to 22, resulting in improved diastolic function as measured by a reduction in sidewall E / e'.

24. 24. The method of any one of claims 10 to 23, which results in ventricular septal thickness remodeling as measured by changes in interventricular septal thickness (IVST).

25. 25. The method of any one of claims 10 to 24, which results in an improvement in one or more CPET parameters selected from ventilatory efficiency / carbon dioxide production (VE / VCO2 slope), circulatory power (VO2 x systolic blood pressure), ventilatory anaerobic threshold (VAT), total workload (Watts), and heart rate response.

26. 26. The method of any one of claims 10 to 25, which results in an improvement in health status and health-related quality of life as measured by the Patient Reported Outcomes (PRO) questionnaire EuroQol 5 Dimension 5 Level Instrument (EQ-5D-5L), Clinical Global Impression (CGI), Patient Global Impression of Change (PGI-C), and Seattle Angina Questionnaire-7 (SAQ-7).

27. 27. The method of any one of claims 1 to 26, wherein the therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof is selected by titrating the daily dose of aficamten or a pharmaceutically acceptable salt thereof administered to the patient.

28. 28. The method of claim 27, wherein the dose is titrated once during the course of treatment.

29. 28. The method of claim 27, wherein the dose is titrated two or more times during the course of treatment.

30. 30. The method of any one of claims 27-29, wherein the daily dose is administered to the patient at a constant amount for about two weeks before the amount of the daily dose is titrated.

31. 31. The method of any one of claims 1 to 30, wherein aficamten or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 5 mg to about 20 mg.

32. 32. The method of claim 31, wherein the daily dose is about 5 mg, about 10 mg, about 15 mg, or about 20 mg.

33. administering to said patient a first daily dose of aficamten or a pharmaceutically acceptable salt thereof for a first period of time; administering a second daily dose of aficamten or a pharmaceutically acceptable salt thereof to the patient for a second period of time or discontinuing administration of aficamten or a pharmaceutically acceptable salt thereof to the patient based on one or more components of a first echocardiogram of the patient obtained after the first period of time; The method of any one of claims 1 to 32, comprising:

34. 34. The method of claim 33, further comprising measuring the one or more components of the first echocardiogram.

35. 35. The method of claim 33 or 34, wherein the one or more components of the first echocardiogram include (a) biplane LVEF, or (b) biplane LVEF and post-Valsalva LVOT-G.

36. 36. The method of any one of claims 33 to 35, further comprising selecting a second daily dose of aficamten or a pharmaceutically acceptable salt thereof based on the one or more components of the first echocardiogram.

37. 37. The method of any one of claims 33 to 36, wherein the one or more components of the first echocardiogram include a biplane LVEF, and wherein the second daily dose of aficamten or a pharmaceutically acceptable salt thereof is less than the first daily dose of aficamten or a pharmaceutically acceptable salt thereof when the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold.

38. 37. The method of any one of claims 33 to 36, wherein the one or more components of the first echocardiogram include a biplane LVEF, and when the biplane LVEF of the first echocardiogram is equal to or greater than the predetermined biplane LVEF threshold and less than a second predetermined biplane LVEF threshold, the second daily dose of aficamten or a pharmaceutically acceptable salt thereof is the same as the first daily dose of aficamten or a pharmaceutically acceptable salt thereof.

39. 37. The method of any one of claims 33 to 36, wherein the one or more components of the first echocardiogram include biplane LVEF and post-Valsalva LVOT-G, and wherein if (i) the biplane LVEF of the first echocardiogram is equal to or greater than the second predetermined biplane LVEF threshold, and (ii) the post-Valsalva LVOT-G of the first echocardiogram is less than a predetermined post-Valsalva LVOT-G threshold, the second daily dose of aficamten or a pharmaceutically acceptable salt thereof is the same as the first daily dose of aficamten or a pharmaceutically acceptable salt thereof.

40. 37. The method of any one of claims 33 to 36, wherein the one or more components of the first echocardiogram include biplane LVEF and post-Valsalva LVOT-G, and wherein the second daily dose of aficamten or a pharmaceutically acceptable salt thereof is greater than the first daily dose of aficamten or a pharmaceutically acceptable salt thereof if (i) the biplane LVEF is greater than or equal to the second predetermined biplane LVEF threshold, and (ii) the post-Valsalva LVOT-G is greater than or equal to the predetermined post-Valsalva LVOT-G threshold.

41. 41. The method of any one of claims 33 to 40, wherein the first daily dose of aficamten or a pharmaceutically acceptable salt thereof is about 5 mg of aficamten and the second daily dose of aficamten or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg of aficamten.

42. 42. The method of any one of claims 33-41, wherein (i) the first period of time is about 2 weeks, (ii) the second period of time is about 2 weeks, or (iii) the first period of time is about 2 weeks and the second period of time is about 2 weeks.

43. 36. The method of any one of claims 33 to 35, wherein the one or more components of the first echocardiogram include a biplane LVEF, and when the biplane LVEF of the first echocardiogram falls below a predetermined biplane LVEF threshold, administration of aficamten or a pharmaceutically acceptable salt thereof to the patient is terminated.

44. 44. The method of claim 43, wherein the first daily dose of aficamten or a pharmaceutically acceptable salt thereof is about 5 mg of aficamten.

45. 45. The method of claim 43 or 44, wherein the first period of time is about two weeks.

46. The method of any one of claims 33 to 42, wherein a second daily dose of afficamten or a pharmaceutically acceptable salt thereof is administered to the patient for the second period of time, and further comprising administering a third daily dose of afficamten or a pharmaceutically acceptable salt thereof to the patient for a third period of time or terminating administration of the afficamten or a pharmaceutically acceptable salt thereof to the patient based on (i) one or more components of a second echocardiogram of the patient obtained after the second period of time and (ii) the second daily dose of afficamten or a pharmaceutically acceptable salt thereof.

47. 47. The method of claim 46, further comprising measuring the one or more components of the second echocardiogram.

48. 48. The method of claim 46 or 47, wherein the one or more components of the second echocardiogram include (a) biplane LVEF, or (b) biplane LVEF and post-Valsalva LVOT-G.

49. 49. The method of any one of claims 46 to 48, further comprising selecting a third daily dose of aficamten or a pharmaceutically acceptable salt thereof based on (i) the one or more components of the second echocardiogram and (ii) the second daily dose.

50. 50. The method of any one of claims 46 to 49, wherein the one or more components of the second echocardiogram include a biplane LVEF, and (i) the biplane LVEF of the second echocardiogram is less than the predetermined biplane LVEF threshold, and (ii) if the second daily dose of aficamten or a pharmaceutically acceptable salt thereof is greater than the first daily dose of aficamten or a pharmaceutically acceptable salt thereof, then the third daily dose of aficamten or a pharmaceutically acceptable salt thereof is less than the second daily dose of aficamten or a pharmaceutically acceptable salt thereof.

51. 51. The method of claim 50, wherein the third daily dose of aficamten or a pharmaceutically acceptable salt thereof is the same as the first daily dose of aficamten or a pharmaceutically acceptable salt thereof.

52. 50. The method of any one of claims 46 to 49, wherein the one or more components of the second echocardiogram include a biplane LVEF, and when the biplane LVEF of the second echocardiogram is equal to or greater than the predetermined biplane LVEF threshold and less than the second predetermined biplane LVEF threshold, the third daily dose of aficamten or a pharmaceutically acceptable salt thereof is the same as the second daily dose of aficamten or a pharmaceutically acceptable salt thereof.

53. 50. The method of any one of claims 46 to 49, wherein the one or more components of the second echocardiogram include biplane LVEF and post-Valsalva LVOT-G, and wherein if (i) the biplane LVEF of the second echocardiogram is equal to or greater than the second predetermined biplane LVEF threshold, and (ii) the post-Valsalva LVOT-G of the second echocardiogram is less than the predetermined post-Valsalva LVOT-G threshold, the third daily dose of aficamten or a pharmaceutically acceptable salt thereof is the same as the second daily dose of aficamten or a pharmaceutically acceptable salt thereof.

54. 50. The method of any one of claims 46 to 49, wherein the one or more components of the second echocardiogram include biplane LVEF and post-Valsalva LVOT-G, and wherein the third daily dose of aficamten or a pharmaceutically acceptable salt thereof is greater than the second daily dose of aficamten or a pharmaceutically acceptable salt thereof if (i) the biplane LVEF is greater than or equal to the second predetermined biplane LVEF threshold, and (ii) the post-Valsalva LVOT-G is greater than or equal to the predetermined post-Valsalva LVOT-G threshold.

55. 55. The method of any one of claims 46 to 54, wherein the first daily dose of aficamten or a pharmaceutically acceptable salt thereof is about 5 mg of aficamten, the second daily dose of aficamten or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg of aficamten, and the third daily dose of aficamten or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, or about 15 mg of aficamten.

56. 56. The method of any one of claims 46 to 55, wherein the third period of time is about two weeks.

57. The method of any one of claims 46 to 48, wherein the one or more components of the second echocardiogram include a biplane LVEF, and wherein administration of the aficamten or a pharmaceutically acceptable salt thereof to the patient is terminated if (i) the biplane LVEF of the second echocardiogram is less than the predetermined biplane LVEF threshold, and (ii) the second daily dose of aficamten or a pharmaceutically acceptable salt thereof is the same as the first daily dose of aficamten or a pharmaceutically acceptable salt thereof.

58. The method of any one of claims 46 to 56, wherein a third daily dose of afficamten or a pharmaceutically acceptable salt thereof is administered to the patient for the third period of time, and further comprising administering a fourth daily dose of afficamten or a pharmaceutically acceptable salt thereof to the patient for a fourth period of time or terminating administration of the afficamten or a pharmaceutically acceptable salt thereof to the patient based on (i) one or more components of a third echocardiogram of the patient obtained after the third period of time and (ii) the third daily dose of afficamten or a pharmaceutically acceptable salt thereof.

59. 59. The method of claim 58, further comprising measuring the one or more components of the third echocardiogram.

60. 60. The method of claim 58 or 59, wherein the one or more components of the third echocardiogram include (a) biplane LVEF, or (b) biplane LVEF and post-Valsalva LVOT-G.

61. 59. The method of claim 58, further comprising selecting a fourth daily dose of aficamten or a pharmaceutically acceptable salt thereof based on (i) the one or more components of the third echocardiogram and (ii) the third daily dose.

62. The method of any one of claims 58 to 61, wherein the one or more components of the third echocardiogram include a biplane LVEF, and (i) the biplane LVEF of the third echocardiogram is less than the predetermined biplane LVEF threshold, and (ii) if the third daily dose of aficamten or a pharmaceutically acceptable salt thereof is greater than the first daily dose of aficamten or a pharmaceutically acceptable salt thereof, then the fourth daily dose of aficamten or a pharmaceutically acceptable salt thereof is less than the third daily dose of aficamten or a pharmaceutically acceptable salt thereof.

63. 62. The method of any one of claims 58 to 61, wherein the one or more components of the third echocardiogram include a biplane LVEF, and when the biplane LVEF of the second echocardiogram is equal to or greater than the predetermined biplane LVEF threshold and less than the second predetermined biplane LVEF threshold, the fourth daily dose of aficamten or a pharmaceutically acceptable salt thereof is the same as the third daily dose of aficamten or a pharmaceutically acceptable salt thereof.

64. 62. The method of any one of claims 58 to 61, wherein the one or more components of the third echocardiogram include biplane LVEF and post-Valsalva LVOT-G, and wherein if (i) the biplane LVEF of the third echocardiogram is equal to or greater than the second predetermined biplane LVEF threshold, and (ii) the post-Valsalva LVOT-G of the third echocardiogram is less than the predetermined post-Valsalva LVOT-G threshold, the fourth daily dose of aficamten or a pharmaceutically acceptable salt thereof is the same as the third daily dose of aficamten or a pharmaceutically acceptable salt thereof.

65. 62. The method of any one of claims 58 to 61, wherein the one or more components of the third echocardiogram include biplane LVEF and post-Valsalva LVOT-G, and wherein the fourth daily dose of aficamten or a pharmaceutically acceptable salt thereof is greater than the third daily dose of aficamten or a pharmaceutically acceptable salt thereof if (i) the biplane LVEF of the third echocardiogram is equal to or greater than the second predetermined biplane LVEF threshold, and (ii) the post-Valsalva LVOT-G of the third echocardiogram is equal to or greater than the predetermined post-Valsalva LVOT-G threshold.

66. 66. The method of any one of claims 58 to 65, wherein the first daily dose of afficamten or its pharmaceutically acceptable salt is about 5 mg of afficamten, the second daily dose of afficamten or its pharmaceutically acceptable salt is about 5 mg or about 10 mg of afficamten, the third daily dose of afficamten or its pharmaceutically acceptable salt is about 5 mg, about 10 mg, or about 15 mg of afficamten, and the fourth daily dose of afficamten or its pharmaceutically acceptable salt is about 5 mg, about 10 mg, about 15 mg, or about 20 mg of afficamten.

67. 67. The method of any one of claims 58 to 66, wherein the fourth period of time is about two weeks.

68. The method of any one of claims 58 to 60, wherein the one or more components of the third echocardiogram include biplane LVEF, and wherein administration of the aficamten or pharmaceutically acceptable salt thereof to the patient is terminated if (i) the biplane LVEF of the second echocardiogram is less than the predetermined biplane LVEF threshold, and (ii) the third daily dose of aficamten or a pharmaceutically acceptable salt thereof is the same as the first daily dose of aficamten or a pharmaceutically acceptable salt thereof.

69. (a) the predetermined biplane LVEF threshold is 50%; (b) the predetermined biplane LVEF threshold is 50% and the second predetermined biplane LVEF threshold is 55%; (c) the predetermined biplane LVEF threshold is 50% and the predetermined post-Valsalva LVOT-G threshold is 30 mmHg; (d) the predetermined biplane LVEF threshold is 55% and the predetermined post-Valsalva LVOT-G threshold is 30 mmHg; or (c) the predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the predetermined post-Valsalva LVOT-G threshold is 30 mmHg.

70. 1. A method for treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, the patient being treated with one or more baseline therapies for oHCM, the method comprising administering a therapeutically effective amount of aficamten. 【Chemistry 4】 or a pharmaceutically acceptable salt thereof; and (2) reducing and / or ceasing at least one baseline therapy.

71. 71. The method of claim 70, comprising reducing at least one baseline therapy.

72. 72. The method of claim 70 or 71, comprising discontinuing at least one baseline therapy.

73. 73. The method of any one of claims 70-72, wherein at least one of the background therapies is selected from the group consisting of beta-blockers, non-dihydropyridine calcium channel blockers, and disopyramide.

74. 74. The method of any one of claims 70-73, wherein reducing the at least one basal therapy comprises administering a lower dose of the at least one basal therapy, wherein the lower dose is no more than 50% of the original dose of the basal therapy.

75. 75. The method of any one of claims 70 to 74, wherein all of the one or more baseline therapies are stopped.

76. 75. The method of any one of claims 70 to 74, wherein all of the one or more background therapies are reduced.

77. 75. The method of any one of claims 70 to 74, wherein all of the one or more baseline therapies are reduced or stopped.

78. 78. The method of any one of claims 70 to 77, wherein the reduction and / or cessation of at least one baseline therapy occurs at the start of the administration of aficamten or a pharmaceutically acceptable salt thereof.

79. 78. The method of any one of claims 70 to 77, wherein the reduction and / or cessation of the at least one background therapy is performed at least two weeks after the start of the administration of aficamten or a pharmaceutically acceptable salt thereof.

80. 78. The method of any one of claims 70 to 77, wherein the reduction and / or cessation of the at least one background therapy is performed 12 weeks or more after the start of the administration of aficamten or a pharmaceutically acceptable salt thereof.

81. The method of any one of claims 70 to 77, wherein reducing and / or stopping the at least one baseline therapy occurs when the patient has been receiving a stable dose of aficamten or a pharmaceutically acceptable salt thereof for at least two weeks.

82. The method of any one of claims 70 to 77, wherein reducing and / or ceasing the at least one baseline therapy occurs when the patient has been receiving a stable dose of aficamten or a pharmaceutically acceptable salt thereof for at least four weeks.

83. 83. The method of any one of claims 70-82, wherein the patient is administered one, two, or three background therapies for oHCM.

84. 84. The method of any one of claims 70 to 83, wherein the patient receives one or more of the following as background therapy: a beta-blocker, a non-dihydropyridine calcium channel blocker, and disopyramide.

85. 85. The method of any one of claims 70 to 84, wherein the therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof is selected by titrating the daily dose of aficamten or a pharmaceutically acceptable salt thereof administered to the patient.

86. 86. The method of claim 85, wherein the dose is titrated once during the course of treatment.

87. 86. The method of claim 85, wherein the dose is titrated two or more times during the course of treatment.

88. 88. The method of any one of claims 70-87, wherein the daily dose of aficamten or a pharmaceutically acceptable salt thereof is administered to the patient at a constant amount for about two weeks before the amount of the daily dose is titrated up.

89. 89. The method of any one of claims 70 to 88, wherein aficamten or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 5 mg to about 20 mg.

90. 90. The method of claim 89, wherein the daily dose is about 5 mg, about 10 mg, about 15 mg, or about 20 mg.

91. 1. A method of treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, comprising: (1) A therapeutically effective amount of aficamten 【Chemistry 5】 or a pharmaceutically acceptable salt thereof to said patient in combination with a first dose of a standard of care therapy for oHCM for a first period of time; (2) administering to the patient a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof in combination with a second dose of the standard of care therapy for oHCM for a second period of time; Including, The method, wherein the second dose of the standard of care therapy for oHCM is less than the first dose of the standard of care therapy.

92. 92. The method of claim 91, wherein the second dose of the standard of care therapy for oHCM is no more than 50% of the first dose of the standard of care therapy.

93. 1. A method of treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, comprising: (1) A therapeutically effective amount of aficamten 【Chemistry 6】 or a pharmaceutically acceptable salt thereof to said patient in combination with a standard of care therapy for oHCM for a first period of time; (2) administering to the patient a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof as monotherapy for a second period of time; The method comprising:

94. 94. The method of any one of claims 91 to 93, wherein the patient in need of treatment for symptomatic oHCM is receiving standard of care therapy for oHCM prior to administering aficamten.

95. 1. A method of treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, comprising: (1) administering to the patient a baseline therapy comprising at least one standard of care therapy selected from the group consisting of a beta-blocker, a non-dihydropyridine calcium channel blocker, and disopyramide; (2) a therapeutically effective amount of aficamten 【Chemistry 7】 or a pharmaceutically acceptable salt thereof to said patient for a first period of time; (3) administering to the patient a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof in combination with a second dose of the standard of care therapy for oHCM for a second period of time; Including, The method, wherein the second dose of the standard of care therapy for oHCM is less than the first dose of the standard of care therapy.

96. 96. The method of claim 95, wherein the second dose of the standard of care therapy for oHCM is no more than 50% of the first dose of the standard of care therapy.

97. 1. A method of treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, comprising: (1) administering to the patient a baseline therapy comprising at least one standard of care therapy selected from the group consisting of a beta-blocker, a non-dihydropyridine calcium channel blocker, and disopyramide; (2) a therapeutically effective amount of aficamten 【Chemistry 8】 or a pharmaceutically acceptable salt thereof to said patient for a first period of time; (3) administering to the patient a therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof as monotherapy for a second period of time; The method comprising:

98. 98. The method of any one of claims 91 to 97, wherein the first period of time is at least 12 weeks.

99. The method of any one of claims 91 to 98, wherein the therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof is selected by titrating the daily dose of aficamten or a pharmaceutically acceptable salt thereof administered to the patient.

100. 100. The method of any one of claims 91 to 99, wherein aficamten or a pharmaceutically acceptable salt thereof is administered at a constant dose for at least 4 weeks prior to the start of said second period.

101. 101. The method of claim 100, wherein the dose is titrated once during the course of treatment.

102. 101. The method of claim 100, wherein the dose is titrated two or more times during the course of treatment.

103. 103. The method of any one of claims 99-102, wherein the daily dose of aficamten or a pharmaceutically acceptable salt thereof is administered to the patient at a constant amount for about two weeks before the amount of the daily dose is titrated up.

104. 104. The method of any one of claims 91 to 103, wherein aficamten or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 5 mg to about 20 mg.

105. 105. The method of claim 104, wherein the daily dose is about 5 mg, about 10 mg, about 15 mg, or about 20 mg.

106. A method for improving myocardial mechanics in a patient in need thereof, comprising administering a therapeutically effective amount of aficamten. 【Chemistry 9】 or a pharmaceutically acceptable salt thereof to said patient, wherein said patient is suffering from obstructive hypertrophic cardiomyopathy (oHCM).

107. A method for improving longitudinal global strain (GLS) in a patient in need thereof, comprising administering a therapeutically effective amount of aficamten. 【Chemistry 10】 or a pharmaceutically acceptable salt thereof to said patient, wherein said patient is suffering from obstructive hypertrophic cardiomyopathy (oHCM).

108. The method of claim 106 or 107, wherein the therapeutically effective amount of aficamten or a pharmaceutically acceptable salt thereof is selected by titrating the daily dose of aficamten or a pharmaceutically acceptable salt thereof administered to the patient.

109. 109. The method of claim 108, wherein the dose is titrated once during the course of treatment.

110. 109. The method of claim 108, wherein the dose is titrated two or more times during the course of treatment.

111. 111. The method of any one of claims 106 to 110, wherein aficamten or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 5 mg to about 20 mg.

112. 112. The method of claim 111, wherein the daily dose is about 5 mg, about 10 mg, about 15 mg, or about 20 mg.

113. 113. The method of any one of claims 106 to 112, wherein the aficamten or a pharmaceutically acceptable salt thereof is administered once a day.

114. 114. The method of any one of claims 111 to 113, comprising administering afficamten or a pharmaceutically acceptable salt thereof for at least about 12 weeks.

115. 114. The method of any one of claims 111 to 113, comprising administering afficamten or a pharmaceutically acceptable salt thereof for at least about 36 weeks.

116. 114. The method of any one of claims 111 to 113, comprising administering afficamten or a pharmaceutically acceptable salt thereof for at least about 48 weeks.

117. 117. The method of any one of claims 111 to 116, which results in a resting LVOT-G of less than 30 mmHg.

118. 118. The method of any one of claims 111 to 117, which results in a Valsalva LVOT-G of less than 50 mmHg.

119. 117. The method of any one of claims 111 to 116, wherein the patient has a resting LVOT-G of less than 30 mmHg as a result of the treatment with aficamten or a pharmaceutically acceptable salt thereof.

120. 120. The method of any one of claims 111-116 or 119, wherein the patient has a Valsalva LVOT-G of less than 50 mmHg as a result of the treatment with aficamten or a pharmaceutically acceptable salt thereof.

121. 121. The method of any one of claims 111 to 120, wherein the patient exhibits an optimal hemodynamic response to treatment with aficamten or a pharmaceutically acceptable salt thereof.

122. 122. The method of any one of claims 1 to 121, wherein the aficamten or a pharmaceutically acceptable salt thereof is administered orally.

123. 123. The method of claim 122, wherein the aficamten or a pharmaceutically acceptable salt thereof is administered as a tablet.

124. 124. The method of claim 123, wherein the tablet comprises one or more carriers or excipients selected from the group consisting of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, and magnesium carbonate.

125. The tablet comprises: (i) about 1% to about 50% by weight of said aficamten or a pharmaceutically acceptable salt thereof; (ii-1) about 10% by weight to about 60% by weight of mannitol; (ii-2) about 5% to about 45% by weight of microcrystalline cellulose; (iii) about 0.1% to about 10% by weight of hydroxypropyl cellulose; (iv) about 1% to about 10% by weight of croscarmellose sodium; and (v) about 0.1% to about 10% by weight of sodium lauryl sulfate; (vi) about 0.1% to about 10% by weight of magnesium stearate; Including, However, the weight percentage does not include the weight of a coating, if present.

126. 126. The method of any one of claims 1 to 125, wherein the aficamten or a pharmaceutically acceptable salt thereof comprises one or more of the polymorphic forms I, II, III, IV, V, and VI of aficamten.

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