Methods for treating obstructive hypertrophic cardiomyopathy

Abstract

Described herein are methods for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (oHCM). The methods of treatment comprise the administration of a cardiac myosin inhibitor (CK-3773274, also known as CK-274 or Aficontan) and may comprise the titration of the daily dose administered based on one or more components of echocardiography. The daily dose may be increased, maintained, decreased, or terminated based on the echocardiography. The methods are useful for treating patients who have recently diagnosed with oHCM, patients who have not received oHCM treatment, or patients who have previously received SOC medical therapy of oHCM and have suspended the therapy prior to administration of aficontan, such as patients with chronic oHCM.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 370,435 filed on August 4, 2022; U.S. Provisional Application No. 63 / 405,310 filed on September 9, 2022; U.S. Provisional Application No. 63 / 377,279 filed on September 27, 2022; U.S. Provisional Application No. 63 / 427,067 filed on November 21, 2022; U.S. Provisional Application No. 63 / 483,882 filed on February 8, 2023; U.S. Provisional Application No. 63 / 485,215 filed on February 15, 2023; and U.S. Provisional Application No. 63 / 524,559 filed on June 30, 2023; the contents of which are hereby incorporated by reference in their entirety for all purposes. Technical Field

[0003] The disclosure herein relates to treatments for obstructive hypertrophic cardiomyopathy and compounds and compositions useful for treating obstructive hypertrophic cardiomyopathy. Background Art

[0004] Hypertrophic cardiomyopathy (HCM) is a disease in which the heart muscle (myocardium) becomes abnormally thick (hypertrophy). The thickening of the heart muscle causes the inside of the left ventricle to become smaller and stiffer, and therefore the ventricle becomes less able to relax and fill with blood. Therefore, patients with obstructive hypertrophic cardiomyopathy may suffer from diastolic abnormalities and mitral regurgitation (MR). This ultimately limits the heart's ability to pump blood, leading to symptoms including chest pain, dizziness, shortness of breath, or fainting during physical activity. A subgroup of patients with HCM are at high risk for progressive disease, which can lead to atrial fibrillation, stroke, and death caused by arrhythmias. The adverse cardiac remodeling of oHCM is a known risk factor for progression to arrhythmias and heart failure. Therefore, there is a need for a therapy to address this condition.

[0005] Current treatments for oHCM (e.g., beta-blockers, calcium channel blockers, and disopyramide) were developed for other medical conditions and subsequently applied to oHCM due to their potential negative inotropic profile. Although beta-blockers have been shown to reduce symptom burden and improve hemodynamics, they do not improve exercise capacity (Dybro 2021) and may be associated with poor tolerability. Both patients with recently diagnosed oHCM and those with chronic symptomatic oHCM require treatments that improve exercise capacity compared to beta-blockers. Summary of the invention

[0006] Described herein are methods and compositions for treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM), including administering aficamten, a cardiac myosin inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure provides methods for improving the motor ability of a patient, such as a patient with oHCM, including administering or delivering aficamten or a pharmaceutically acceptable salt thereof as described herein to the patient. In some embodiments, the disclosure provides methods for reducing the symptom load of a patient, such as a patient with oHCM, improving hemodynamics, and improving motor ability, including administering or delivering aficamten or a pharmaceutically acceptable salt thereof as described herein to the patient. The methods disclosed herein can be used to treat patients recently diagnosed with oHCM (diagnosed within 12 months prior to administering aficamten or a pharmaceutically acceptable salt thereof). Patients recently diagnosed with oHCM may include patients who have not received treatment, as well as patients who have received or are receiving standard of care (SOC) medical therapy for oHCM. The methods disclosed herein can be used to treat patients who have not received treatment (oHCM has not yet been treated). The methods disclosed herein can be used to treat patients with chronic oHCM. Patients with chronic oHCM include patients with a history of oHCM >12 months and currently receiving SOC therapy for oHCM, or patients who have received SOC therapy for oHCM within 12 months prior to administration of aficontan or a pharmaceutically acceptable salt thereof. SOC therapy includes treatment of oHCM including administration of beta-blockers, calcium channel blockers, or disopyramide.

[0007] In some implementations of the methods disclosed herein, the methods include administering aficontan or a pharmaceutically acceptable salt thereof as a monotherapy for oHCM. It should be understood that administering oHCM monotherapy indicates that the patient receives only one therapy for treating oHCM (e.g., aficontan or a pharmaceutically acceptable salt thereof); however, it should be understood that the patient may also receive other therapies or therapies for treating other diseases. As described herein, "other therapies or therapies for treating other diseases" exclude SOC therapies for oHCM (e.g., one or more of beta-blockers, calcium channel blockers, or disopyramide). As further described herein, the daily dose of aficontan can be titrated based on the results of an echocardiogram.

[0008] In some embodiments of the methods disclosed herein, the patient has one or more of the following prior to administration of afecontan or a pharmaceutically acceptable salt thereof: LVEF ≥ 60%; resting LVOT-G ≥ 30 mm Hg; LVOT-G ≥ 50 mmHg after Valsalva; NYHA class II or class III. In some embodiments, the patient's pVO2 < 80%. In some embodiments, the patient's predicted pVO2 < 80%. In some embodiments, the patient's resting LVOT-G ≥ 30 mmHg, peak LVOT-G ≥ 50 mmHg after Valsalva, characterized as being in NYHA functional class II or III, and pVO2 < 80% (measured or predicted).

[0009] In some implementations of the methods disclosed herein, administration of aficontan or a pharmaceutically acceptable salt thereof improves one or more of the following: exercise capacity; cardiac function as measured by improvement in NYHA functional class; resting LVOT-G; LVOT-G after Valsalva maneuver; health status as measured by the 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 pro-brain natriuretic peptide hormone (NT-proBNP) level; high-sensitivity cardiac troponin I (hs-cTnI) level; diastolic function as measured by a reduction in lateral E / e'; ventricular septal thickness remodeling as measured by changes in ventricular septal thickness (IVST); CPET parameters selected from the group consisting of ventilatory efficiency / carbon dioxide production (VE / VCO2 slope), circulatory power (VO2×systolic pressure), ventilatory anaerobic threshold (VAT), total workload (watts), and heart rate response; and improvement in heart rate as measured by the patient-reported outcomes (PRO) questionnaire EuroQol Health status and health-related quality of life measured by the 5-dimensional 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 implementations of the methods disclosed herein, administration of aficontan or a pharmaceutically acceptable salt thereof improves one or more of the following: exercise capacity; cardiac function as measured by improvement in NYHA functional class; resting LVOT-G; LVOT-G after Valsalva maneuver; health status as measured by the 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 pro-brain natriuretic peptide hormone (NT-proBNP) level; high-sensitivity cardiac troponin I (hs-cTnI) level; diastolic function as measured by a reduction in lateral E / e'; ventricular septal thickness remodeling as measured by changes in ventricular septal thickness (IVST); CPET parameters selected from the group consisting of ventilatory efficiency / carbon dioxide production (VE / VCO2 slope), circulatory power (VO2×systolic pressure), ventilatory anaerobic threshold (VAT), total workload (watts), and heart rate response; and improvement in heart rate as measured by the patient-reported outcomes (PRO) questionnaire EuroQol Health status and health-related quality of life measured by the 5-dimensional 5-level tool (EQ-5D-5L), Clinical Global Impression (CGI), Patient Global Impression of Change (PGI-C), Seattle Angina Questionnaire-7 (SAQ-7), and Short Form Survey (SF-36). In some embodiments, one or more improved outcomes are improved compared to treatment with a SOC therapy (e.g., metoprolol).In some embodiments, administration with aficontan or a pharmaceutically acceptable salt thereof improves HCM symptoms, such as reduction in chest pain, dizziness, shortness of breath, fainting during physical activity, fatigue, lack of energy, and limitation of physical activity.

[0010] A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof may comprise administering to the patient a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof is selected by titrating the daily dose of aficontan or a pharmaceutically acceptable salt thereof administered to the patient. In some embodiments, the dose is titrated once during the course of treatment. In some embodiments, the dose is titrated two or more times during the course of treatment. Prior to titrating the daily dose, the daily dose may be administered to the patient at a constant amount for about two weeks.

[0011] In some implementations of the above methods, aficontan or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 5 mg to about 20 mg. In some embodiments, the daily dose is about 5 mg. In some embodiments, the daily dose is about 10 mg. In some embodiments, the daily dose is about 15 mg. In some embodiments, the daily dose is about 20 mg. For example, as described herein, in some embodiments, patients start with 5 mg once a day; at about weeks 2, 4, and 6, patients undergo an echocardiogram to determine whether to titrate the dose upward to 10, 15, or 20 mg; if the patient's LVOT-G after the Valsalva maneuver is ≥30 mmHg and the biplane left ventricular ejection fraction (LVEF) is ≥55%, then dose escalation will occur, and patients who do not meet the escalation criteria will continue to receive the current dose or if their LVEF is less than 50%, they can be titrated downward. For increasing, maintaining, reducing, or discontinuing doses, see, for example, Table 26. As understood by those skilled in the art and described herein, unless otherwise indicated, amounts (e.g., in dosages) are those of aficontan free base, or the corresponding amount of aficontan free base when a non-free base form, such as a pharmaceutically acceptable salt, is administered.

[0012] In some implementations, the daily dose is administered as a single dose per day. In some implementations, the daily dose is administered in 2 divided doses.

[0013] In some embodiments, a method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof comprises administering a first daily dose of aficontan or a pharmaceutically acceptable salt thereof to the patient for a first period of time; and administering a second daily dose of aficontan or a pharmaceutically acceptable salt thereof to the patient for a second period of time, or terminating administration of aficontan 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 may include selecting a second daily dose of aficontan or a pharmaceutically acceptable salt thereof based on one or more components of the first echocardiogram. In some embodiments, the one or more components of the first echocardiogram comprise a biplane LVEF, or a biplane LVEF and a post-Valsalvarez LVOT-G. In some embodiments, the one or more components of the first echocardiogram comprise a biplane LVEF. In some embodiments, the one or more components of the first echocardiogram comprise a biplane LVEF. In some embodiments, the one or more components of the first echocardiogram comprise a biplane LVEF and a post-Valsalvarez LVOT-G. In some embodiments of the methods described herein, the patient undergoes two or more echocardiograms during the first time period, and the second daily dose is selected based on combined results of the two or more echocardiograms obtained during the first time period.

[0014] In some implementations of the above method, one or more components of the first echocardiogram include a biplane LVEF, and when the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold, the second daily dose of aficontan or a pharmaceutically acceptable salt thereof is lower than the first daily dose of aficontan or a pharmaceutically acceptable salt thereof. For example, the predetermined biplane LVEF threshold may be 50%.

[0015] In some implementations of the above method, one or more components of the first echocardiogram include a biplane LVEF, and when the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold, administration of aficontan or a pharmaceutically acceptable salt thereof to the patient is terminated. For example, the predetermined biplane LVEF threshold may be 50%.

[0016] In some implementations of the above method, one or more components of the first echocardiogram include a biplane LVEF, and wherein the second daily dose of aficontan or a pharmaceutically acceptable salt thereof is the same as the first daily dose of aficontan or a pharmaceutically acceptable salt thereof when the biplane LVEF of the first echocardiogram is equal to or above a predetermined biplane LVEF threshold and below a second predetermined biplane LVEF threshold. In some embodiments, the predetermined biplane LVEF threshold is 50%, and the second predetermined biplane LVEF threshold is 55%.

[0017] In some implementations of the above method, the one or more components of the first echocardiogram include biplane LVEF and post-Valsalva maneuver LVOT-G, and wherein when the biplane LVEF of the first echocardiogram is equal to or above a second predetermined biplane LVEF threshold and the post-Valsalva maneuver LVOT-G of the first echocardiogram is below a predetermined post-Valsalva maneuver LVOT-G threshold, the second daily dose of aficontan or a pharmaceutically acceptable salt thereof is the same as the first daily dose of aficontan or a pharmaceutically acceptable salt thereof. In some embodiments, the second predetermined biplane LVEF threshold is 55%, and the predetermined post-Valsalva maneuver LVOT-G threshold is 30 mmHg.

[0018] In some implementations of the above method, the one or more components of the first echocardiogram include biplane LVEF and post-Valsalva maneuver LVOT-G, and wherein the second daily dose of aficontan or a pharmaceutically acceptable salt thereof is greater than the first daily dose of aficontan or a pharmaceutically acceptable salt thereof when the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold and the post-Valsalva maneuver LVOT-G is equal to or above a predetermined post-Valsalva maneuver LVOT-G threshold. In some embodiments, the predetermined biplane LVEF threshold is 55% and the post-Valsalva maneuver LVOT-G threshold is 30 mmHg.

[0019] In some implementations of the above methods, the first daily dose of aficontan or a pharmaceutically acceptable salt thereof is about 5 mg aficontan. In some embodiments, the second daily dose of aficontan or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg aficontan. In some implementations of the above methods, the first daily dose of aficontan or a pharmaceutically acceptable salt thereof is about 5 mg aficontan and the second daily dose is about 10 mg aficontan.

[0020] In some implementations of the above method, the method further includes measuring one or more components of the first echocardiogram.

[0021] In some implementations of the above methods, the first period is about 2 weeks. In some embodiments, the second period is about 2 weeks. For example, as described herein, in some embodiments, the method provided includes:

[0022] administering to the patient a first daily dose of aficontan or a pharmaceutically acceptable salt thereof for a first period of time, wherein the first daily dose is about 5 mg aficontan and the first period of time is about 2 weeks;

[0023] assessing the patient's LVOT-G and LVEF after the first period of time (eg, using echocardiography); and

[0024] If the patient's LVOT-G after Valsalva maneuver is ≥30 mmHg and LVEF is ≥55%, a second daily dose of aficontan or a pharmaceutically acceptable salt thereof is administered to the patient, wherein the second daily dose is about 10 mg of aficontan; and if the patient's LVOT-G after Valsalva maneuver is <30 mmHg or LVEF is <55%, a second daily dose of aficontan or a pharmaceutically acceptable salt thereof is administered to the patient, wherein the second daily dose is about 5 mg of aficontan.

[0025] As described herein, in some embodiments, the second daily dose is administered for a second period (eg, about 2 weeks) prior to assessing the patient's LVOT-G and LVEF after the Valsalva maneuver.

[0026] In some implementations of the above method, a second daily dose of aficontan or a pharmaceutically acceptable salt thereof is administered to the patient for a second period of time, and the method further comprises, 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 aficontan or a pharmaceutically acceptable salt thereof, administering a third daily dose of aficontan or a pharmaceutically acceptable salt thereof to the patient for a third period of time, or terminating the administration of aficontan or a pharmaceutically acceptable salt thereof to the patient. In some embodiments, the method comprises selecting a third daily dose of aficontan 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 comprise biplane LVEF or LVOT-G after Valsalva maneuver. In some embodiments, the one or more components of the second echocardiogram comprise biplane LVEF. In some embodiments, the one or more components of the second echocardiogram comprise biplane LVEF and LVOT-G after Valsalva maneuver. In some embodiments of the methods described herein, the patient undergoes two or more echocardiograms during the second time period, and the third daily dose is selected based on combined results of the two or more echocardiograms obtained during the second time period.

[0027] In some embodiments of the above methods, one or more components of the second echocardiogram include a biplane LVEF, and when the biplane LVEF of the second echocardiogram is below a predetermined biplane LVEF threshold, the third daily dose of aficontan or a pharmaceutically acceptable salt thereof is reduced from the second daily dose of aficontan or a pharmaceutically acceptable salt thereof, or administration of aficontan or a pharmaceutically acceptable salt thereof to the patient is terminated. In some embodiments, the predetermined biplane LVEF threshold is 50%.

[0028] In some embodiments of the above methods, when the biplane LVEF of the second echocardiogram is lower than a predetermined biplane LVEF threshold and the second daily dose of aficontan or a pharmaceutically acceptable salt thereof is equal to or lower than the first daily dose of aficontan, administration of aficontan or a pharmaceutically acceptable salt thereof to the patient is terminated. In some embodiments, the predetermined biplane LVEF threshold is 50%.

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

[0030] In some embodiments of the above methods, the one or more components of the second echocardiogram include a biplane LVEF, and wherein the third daily dose of aficontan or a pharmaceutically acceptable salt thereof is the same as the second daily dose of aficontan or a pharmaceutically acceptable salt thereof when the biplane LVEF is equal to or above a predetermined biplane LVEF threshold and below a second predetermined biplane LVEF threshold. In some embodiments, the predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the second predetermined post-Valsalas LVOT-G threshold is 30 mmHg.

[0031] In some embodiments of the above methods, the one or more components of the second echocardiogram include biplane LVEF and post-Valsalva maneuver LVOT-G, and wherein when the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold and the post-Valsalva maneuver LVOT-G is below a predetermined post-Valsalva maneuver LVOT-G threshold, the third daily dose of aficontan or a pharmaceutically acceptable salt thereof is the same as the second daily dose of aficontan or a pharmaceutically acceptable salt thereof. In some embodiments, the second predetermined biplane LVEF threshold is 55%, and the predetermined post-Valsalva maneuver LVOT-G threshold is 30 mmHg.

[0032] In some embodiments of the above methods, the one or more components of the second echocardiogram include biplane LVEF and LVOT-G after Valsalva maneuver, and wherein the third daily dose of aficontan or a pharmaceutically acceptable salt thereof is greater than the second daily dose of aficontan or a pharmaceutically acceptable salt thereof when the biplane LVEF of the second echocardiogram is above a second predetermined biplane LVEF threshold and the LVOT-G after Valsalva maneuver of the second echocardiogram is equal to or above a predetermined LVOT-G threshold after Valsalva maneuver. In some embodiments, the second predetermined biplane LVEF threshold is 55%, and the predetermined LVOT-G threshold after Valsalva maneuver is 30 mmHg.

[0033] In some embodiments of the above methods, the first daily dose of aficontan or a pharmaceutically acceptable salt thereof is about 5 mg of aficontan, the second daily dose of aficontan or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg of aficontan, and the third daily dose of aficontan or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, or about 15 mg of aficontan. For example, as described herein, in some embodiments, a method is provided comprising:

[0034] administering to the patient a daily dose of aficontan or a pharmaceutically acceptable salt thereof (which may be referred to as a second daily dose) for a period of time (which may be referred to as a second period of time), wherein the daily dose is about 10 mg of aficontan and the period of time is about 2 weeks;

[0035] assessing the patient's LVOT-G and LVEF after the period of time (eg, using echocardiography); and

[0036] If the patient's LVOT-G after Valsalva maneuver is ≥30 mmHg and LVEF is ≥55%, a daily dose of aficontan or a pharmaceutically acceptable salt thereof (which may be referred to as the third daily dose) is administered to the patient, wherein the daily dose is about 15 mg of aficontan; and if the patient's LVOT-G after Valsalva maneuver is <30 mmHg or LVEF is <55%, a daily dose of aficontan or a pharmaceutically acceptable salt thereof (which may be referred to as the third daily dose) is administered to the patient, wherein the daily dose is about 10 mg of aficontan (e.g., LVEF ≥50%) or about 5 mg of aficontan (e.g., LVEF <50% but ≥40%), or if LVEF <40%, administration is discontinued for a period of time.

[0037] For example, in some embodiments, provided methods include:

[0038] administering to the patient a first daily dose of aficontan or a pharmaceutically acceptable salt thereof for a first period of time, wherein the first daily dose is about 5 mg aficontan and the first period of time is about 2 weeks;

[0039] assessing the patient's LVOT-G and LVEF after a Valsalva maneuver (e.g., using echocardiography) after the first period, wherein the patient's LVOT-G after a Valsalva maneuver is ≥30 mmHg and the LVEF is ≥55%;

[0040] administering to the patient a second daily dose of aficontan or a pharmaceutically acceptable salt thereof for a second period of time, wherein the second daily dose is about 10 mg aficontan and the second period of time is about 2 weeks;

[0041] assessing the patient's LVOT-G and LVEF after the second period of time (eg, using echocardiography); and

[0042] If the patient's LVOT-G after Valsalva maneuver is ≥30 mmHg and LVEF is ≥55%, a third daily dose of aficontan or a pharmaceutically acceptable salt thereof is administered to the patient, wherein the third daily dose is about 15 mg of aficontan; and if the patient's LVOT-G after Valsalva maneuver is <30 mmHg or LVEF is <55%, a third daily dose of aficontan or a pharmaceutically acceptable salt thereof is administered to the patient, wherein the third daily dose is about 10 mg of aficontan (e.g., LVEF ≥50%) or about 5 mg of aficontan (e.g., LVEF <50% but ≥40%), or if LVEF <40%, administration is discontinued for a period of time. As described herein, in some embodiments, the third daily dose is administered for a third period of time (e.g., about 2 weeks) prior to assessing the patient's LVOT-G and LVEF after Valsalva maneuver.

[0043] In some embodiments of the above methods, the method further comprises measuring one or more components of a second echocardiogram.

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

[0045] In some embodiments of the above methods, a third daily dose of aficontan or a pharmaceutically acceptable salt thereof is administered to the patient for a third period of time, and the method further comprises administering a fourth daily dose of aficontan or a pharmaceutically acceptable salt thereof to the patient for a fourth period of time, or terminating the administration of aficontan 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 aficontan or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises selecting a fourth daily dose of aficontan 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 comprise biplane LVEF or LVOT-G after Valsalva maneuver. In some embodiments, the one or more components of the third echocardiogram comprise biplane LVEF. In some embodiments, the one or more components of the third echocardiogram comprise biplane LVEF and LVOT-G after Valsalva maneuver. In some embodiments of the methods described herein, the patient undergoes two or more echocardiograms during the third time period, and the fourth daily dose is selected based on combined results of the two or more echocardiograms obtained during the third time period.

[0046] In some embodiments of the above methods, one or more components of the third echocardiogram include a biplane LVEF, and when the biplane LVEF of the third echocardiogram is below a predetermined biplane LVEF threshold, the fourth daily dose of aficontan or a pharmaceutically acceptable salt thereof is lower than the third daily dose of aficontan or a pharmaceutically acceptable salt thereof, or administration of aficontan or a pharmaceutically acceptable salt thereof to the patient is terminated. In some embodiments, administration of aficontan or a pharmaceutically acceptable salt thereof to the patient is terminated when the biplane LVEF of the third echocardiogram is below a predetermined biplane LVEF threshold and the third daily dose of aficontan or a pharmaceutically acceptable salt thereof is the same as the first daily dose of aficontan or a pharmaceutically acceptable salt thereof. In some embodiments, the predetermined biplane LVEF threshold is 50%.

[0047] In some embodiments of the above methods, one or more components of the third echocardiogram include a biplane LVEF, and wherein the fourth daily dose of aficontan or a pharmaceutically acceptable salt thereof is the same as the third daily dose of aficontan or a pharmaceutically acceptable salt thereof when the biplane LVEF is equal to or above a predetermined biplane LVEF threshold and below a second predetermined biplane LVEF threshold. In some embodiments, the predetermined biplane LVEF threshold is 50% and the second predetermined biplane LVEF threshold is 55%.

[0048] In some embodiments of the above methods, the one or more components of the third echocardiogram include biplane LVEF and post-Valsalva maneuver LVOT-G, and wherein the fourth daily dose of aficontan or a pharmaceutically acceptable salt thereof is the same as the third daily dose of aficontan or a pharmaceutically acceptable salt thereof when the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold and the post-Valsalva maneuver LVOT-G is below a predetermined post-Valsalva maneuver LVOT-G threshold. In some embodiments, the second predetermined biplane LVEF threshold is 55% and the second predetermined post-Valsalva maneuver LVOT-G threshold is 30 mmHg.

[0049] In some embodiments of the above methods, the one or more components of the third echocardiogram include biplane LVEF and LVOT-G after Valsalva maneuver, and wherein the fourth daily dose of aficontan or a pharmaceutically acceptable salt thereof is greater than the third daily dose of aficontan or a pharmaceutically acceptable salt thereof when the biplane LVEF of the third echocardiogram is above a second predetermined biplane LVEF threshold and the LVOT-G after Valsalva maneuver of the third echocardiogram is equal to or above a predetermined LVOT-G threshold after Valsalva maneuver. In some embodiments, the second predetermined biplane LVEF threshold is 55%, and the second predetermined LVOT-G threshold after Valsalva maneuver is 30 mmHg.

[0050] In some embodiments of the above methods, the first daily dose of aficontan or a pharmaceutically acceptable salt thereof is about 5 mg aficontan, the second daily dose of aficontan or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg aficontan, the third daily dose of aficontan or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, or about 15 mg aficontan, and the fourth daily dose of aficontan or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, about 15 mg, or about 20 mg aficontan. For example, as described herein, in some embodiments, methods are provided comprising:

[0051] administering to the patient a daily dose of aficontan or a pharmaceutically acceptable salt thereof (which may be referred to as a third daily dose) for a period of time (which may be referred to as a third period of time), wherein the daily dose is about 15 mg of aficontan and the period of time is about 2 weeks;

[0052] assessing the patient's LVOT-G and LVEF after the period of time (eg, using echocardiography); and

[0053] If the patient's LVOT-G after Valsalva maneuver is ≥30 mmHg and LVEF is ≥55%, a daily dose of aficontan or a pharmaceutically acceptable salt thereof (which may be referred to as the fourth daily dose) is administered to the patient, wherein the daily dose is about 20 mg of aficontan; and if the patient's LVOT-G after Valsalva maneuver is <30 mmHg or LVEF is <55%, a daily dose of aficontan or a pharmaceutically acceptable salt thereof (which may be referred to as the fourth daily dose) is administered to the patient, wherein the daily dose is about 15 mg of aficontan (e.g., LVEF ≥50%) or about 10 mg of aficontan (e.g., LVEF <50% but ≥40%), or if LVEF <40%, administration is discontinued for a period of time.

[0054] For example, in some embodiments, provided methods include:

[0055] administering to the patient a first daily dose of aficontan or a pharmaceutically acceptable salt thereof for a first period of time, wherein the first daily dose is about 5 mg aficontan and the first period of time is about 2 weeks;

[0056] assessing the patient's LVOT-G and LVEF after a Valsalva maneuver (e.g., using echocardiography) after the first period, wherein the patient's LVOT-G after a Valsalva maneuver is ≥30 mmHg and the LVEF is ≥55%;

[0057] administering to the patient a second daily dose of aficontan or a pharmaceutically acceptable salt thereof for a second period of time, wherein the second daily dose is about 10 mg aficontan and the second period of time is about 2 weeks;

[0058] assessing the patient's LVOT-G and LVEF after the second period of time (eg, using echocardiography); and

[0059] administering to the patient a third daily dose of aficontan or a pharmaceutically acceptable salt thereof for a third period of time, wherein the third daily dose is about 15 mg aficontan and the third period of time is about 2 weeks;

[0060] assessing the patient's LVOT-G and LVEF after the Valsalva maneuver after the third period (e.g., using echocardiography); and

[0061] If the patient's LVOT-G after Valsalva maneuver is ≥30 mmHg and LVEF is ≥55%, a fourth daily dose of aficontan or a pharmaceutically acceptable salt thereof is administered to the patient, wherein the third daily dose is about 20 mg aficontan; and if the patient's LVOT-G after Valsalva maneuver is <30 mmHg or LVEF is <55%, a fourth daily dose of aficontan or a pharmaceutically acceptable salt thereof is administered to the patient, wherein the fourth daily dose is about 15 mg aficontan (e.g., LVEF ≥50%) or about 10 mg aficontan (e.g., LVEF <50% but ≥40%), or if LVEF <40%, administration is discontinued for a period of time.

[0062] As described herein, in some embodiments, the fourth daily dose is administered for a fourth period (e.g., about 2 weeks) before assessing the patient's LVOT-G and LVEF after the Valsalva maneuver. In some embodiments, the fourth daily dose is administered for about 2 weeks or longer, for example, about 4 weeks, about 1 month, about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or longer. In some embodiments, during a fourth period, for example, a fourth period longer than about 2 weeks, the patient's cardiac structure and / or function, such as LVOT-G, LVEF, exercise capacity, etc. after the Valsalva maneuver may be assessed once or more. As described herein, the provided method can particularly improve exercise capacity.

[0063] In some embodiments of the above method, the method further comprises measuring one or more components of a third echocardiogram.

[0064] In some embodiments of the above methods, the fourth period of time is about 2 weeks.

[0065] 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-Valsa maneuver LVOT-G threshold is 30 mmHg.

[0066] In some embodiments, the daily dose is about 15 mg of aficontan. In some embodiments, the third daily dose is about 15 mg of aficontan. In some embodiments, the fourth daily dose is about 15 mg of aficontan. In some embodiments, the daily dose is about 20 mg of aficontan. In some embodiments, the fourth daily dose is about 20 mg of aficontan. In some embodiments, the daily dose is administered in the form of a tablet. In some embodiments, the amount of aficontan (which may be present in a variety of forms (e.g., free form, pharmaceutically acceptable salt form, polymorph form, etc.)) in the tablet is about the daily dose described herein. In some embodiments, the amount of aficontan in the tablet is about 5 mg. In some embodiments, the amount of aficontan in the tablet is about 10 mg. In some embodiments, the amount of aficontan in the tablet is about 15 mg. In some embodiments, the amount of aficontan in the tablet is about 20 mg. In some embodiments, the amount of aficontan in the tablet is about half of the daily dose described herein. In some embodiments, the amount of aficontan in the tablet is about 2.5 mg. In some embodiments, the amount of aficontan in the tablet is about 5 mg. In some embodiments, the amount of aficontan in the tablet is about 7.5 mg. In some embodiments, the amount of aficontan in the tablet is about 10 mg.

[0067] In some embodiments of any of the above methods, the aficontan or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, the aficontan 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 aficontan or a pharmaceutically acceptable salt thereof; (ii-1) about 10% to about 60% by weight of mannitol; (ii-2) about 5% to about 45% by weight of microcrystalline cellulose; (iii) about 0.1% to about 10% by weight of hydroxypropyl cellulose; (iv) about 1% to about 10% by weight of croscarmellose sodium; (v) about 0.1% to about 10% by weight of sodium lauryl sulfate; and vi) about 0.1% to about 10% by weight of magnesium stearate, wherein the weight % does not include the weight of the coating (if present). In some embodiments, the aficontan or a pharmaceutically acceptable salt thereof comprises one or more of polymorphic Form I, Form II, Form III, Form IV, Form V, and Form VI of aficontan. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] Figure 1An exemplary method for treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient comprising titrating the daily dose of aficontan or a pharmaceutically acceptable salt thereof is described.

[0069] Figure 2 A schematic overview of the Phase 1 clinical study of aficontan is shown. The study included a SAD cohort, a MAD cohort, a CYP2D6-PM cohort, and a food effect cohort. The MAD and CYP2D6-PM cohorts were initiated when a tolerated pharmacologically active dose (approximately 5% decrease in LVEF) was determined in the SAD cohort. The food effect cohort was initiated after the last SAD cohort was completed. The SAD 75-mg dose cohort met the criteria for stopping dose escalation, and the remaining patients in this cohort received 50 mg. Subsequently, the final SAD cohort was completed with 40 mg aficontan. CYP2D6-PM = cytochrome P450 2D6 poor metabolizer phenotype; d = day; LVEF = left ventricular ejection fraction; MAD = multiple ascending dose; qd = once daily; SAD = single ascending dose.

[0070] Figure 3A The mean (SE) maximum plasma concentrations (C ) of aficontan were shown to increase in a dose-proportional manner following single oral doses between 1 mg and 50 mg. 最大 ). Figure 3B Aficontan exposure (AUC 24 ) (B). AUC 24 = area under the plasma drug concentration-time curve from 0 to 24 h; C 最大 = maximum plasma concentration; SE = standard error.

[0071] Figure 4 The plasma concentration of aficontan over time according to multiple doses of an exemplary clinical trial is shown. The mean (SE) aficontan plasma concentration is shown. Data points are offset for clarity. Aficontan plasma concentration increases between the 5-mg dose and the 2 higher doses; however, as of day 2, there is no difference between the mean concentrations of the 7.5-mg and 10-mg doses. The clearance rates of the 5-mg and 10-mg doses are similar, and the cumulative ratios of all 3 doses are similar. For the 7th, 8th, 10th, 11th, 12th, and 13th days, only trough measurements are shown. For the 5-mg and 10-mg cohorts, the dosing period is 14 days, and the follow-up is 3 days. For the 7.5-mg cohort, dosing is extended to 17 days, and the follow-up is 3 days, and it is confirmed that steady state is reached after 10 to 12 days. SE = standard error.

[0072] Figure 5AThe SAD cohort of an exemplary aficontin clinical trial is shown and Figure 5B The MAD cohort of an exemplary afecontan clinical trial is shown. The mean (SE) change of LVEF compared to baseline is shown. Data points are offset for clarity. In the SAD and MAD cohorts, LVEF was observed to decrease within the target range (reduced by 5% to 15%). In the SAD cohort, LVEF was generally slightly reduced, and the average maximum reduction in the 50-mg group was 5.8% (1.5 h after administration). In the MAD cohort, the maximum average reduction of LVEF compared to baseline occurred in the 10-mg group (the average change was 5.0% 1.5 h after administration on day 14). LVEF = left ventricular ejection fraction; MAD = multiple ascending doses; qd, once a day; SAD = single ascending dose; SE = standard error.

[0073] Fig. 6A An analysis of the SAD cohort from an exemplary clinical trial is shown and shows that there is a trend toward a decrease in LVEF with increasing plasma concentrations of aficontan. Figure 6B An analysis of the MAD cohort of an exemplary clinical trial is shown and shows minimal suppression of LVEF for most participants at plasma aficantan concentrations ≤ 180 ng / ml. CI = confidence interval; LVEF = left ventricular ejection fraction; MAD = multiple ascending dose; SAD = single ascending dose.

[0074] Figure 7 Shown are resting LVOT-G for treatment and placebo cohorts of an exemplary clinical trial of aficontan.

[0075] Figure 8 LVOT-G after the Valsalva maneuver is shown for the treatment and placebo cohorts of an exemplary clinical trial of aficontan.

[0076] Fig. 9 Shown are changes in left atrial volume index (LAVI) for treatment and placebo cohorts of an exemplary clinical trial of aficontan.

[0077] Fig.10 Shown are changes in lateral E / e' ratios for treatment and placebo cohorts of an exemplary clinical trial of aficontan.

[0078] Fig.11 Shown are changes in mitral valve characteristics including mitral regurgitation (MR), eccentric MR, and systolic anterior motion (SAM) in the treatment and placebo cohorts of an exemplary clinical trial of aficontan.

[0079] Fig.12 Shown are changes in resting LVOT-G for treatment and placebo cohorts of an exemplary clinical trial of aficontan.

[0080] Fig.13 Shown are changes in resting LVOT-G following Valsalva maneuver for treatment and placebo cohorts of an exemplary clinical trial of aficontan.

[0081] Fig.14 Shown are changes in LVEF for treatment and placebo cohorts of an exemplary clinical trial of aficontan.

[0082] Fig.15 Shown are NYHA functional class responses for treatment and placebo cohorts from an exemplary clinical trial of aficontan.

[0083] Fig.16 Shown are the changes in mean NT-proBNP for the treatment and placebo cohorts of an exemplary clinical trial of aficontan.

[0084] Fig.17 Shown are changes in resting LVOT-G for treatment and placebo cohorts of an exemplary clinical trial of aficontan.

[0085] Fig.18 Shown are changes in resting LVOT-G following Valsalva maneuver for treatment and placebo cohorts of an exemplary clinical trial of aficontan.

[0086] Fig.19 Shown are changes in LVEF for treatment and placebo cohorts of an exemplary clinical trial of aficontan.

[0087] Fig. 20 The hemodynamic responses of the treatment and placebo cohorts according to an exemplary clinical trial of aficontan are shown.

[0088] Fig.21 Shown are NYHA functional class responses for treatment and placebo cohorts from an exemplary clinical trial of aficontan.

[0089] Fig. 22 Shown are the changes in mean NT-proBNP for the treatment and placebo cohorts of an exemplary clinical trial of aficontan.

[0090] Fig.23 Shown are hs-troponin for treatment and placebo cohorts of an exemplary clinical trial of aficontan.

[0091] Fig.24 Shown are NYHA functional class responses for treatment and placebo cohorts from an exemplary clinical trial of aficontan.

[0092] Fig.25 Shown are NYHA functional class responses for treatment and placebo cohorts from an exemplary clinical trial of aficontan.

[0093] Fig.26 The design of an open-label extension of an exemplary clinical trial of aficontan (Example 3a) is shown.

[0094] Fig. 27 Shown is the distribution of patients over time at each dose in an open-label extension of an exemplary clinical trial of aficontan (Example 3a).

[0095] Fig.28 Shown are resting LVOT-G of patients in an open-label extension of an exemplary clinical trial of aficontan (Example 3a).

[0096] Fig.29 Shown is LVOT-G after the Valsalva maneuver in patients in the open-label extension of an exemplary clinical trial of aficontan (Example 3a).

[0097] Fig.30 Shown are changes in LVEF in patients in an open-label extension of an exemplary clinical trial of aficontan (Example 3a).

[0098] Fig.31 Shown is the distribution of NYHA functional class of patients at different time points in the open-label extension of an exemplary clinical trial of aficontan (Example 3a).

[0099] Fig.32 Shown are the NYHA functional class responses of patients at different time points in an open-label extension of an exemplary clinical trial of aficontan (Example 3a).

[0100] Fig.33 Shown are mean NT-proBNP changes in patients in an open-label extension of an exemplary clinical trial of aficontan (Example 3a).

[0101] Fig.34 Shown are mean cardiac troponin I changes in patients in an open-label extension of an exemplary clinical trial of aficontan (Example 3a).

[0102] Fig.35 Shown is the change from baseline in KCCQ scores for patients in an open-label extension of an exemplary clinical trial of aficontan (Example 3a).

[0103] Fig.36 Shown are the proportions of patients with different levels of change from baseline in the patient KCCQ score in the open-label extension of an exemplary clinical trial of aficontan (Example 3a).

[0104] Fig.37Shown are the percent changes from baseline in hs-troponin I for the treatment and placebo cohorts of an exemplary clinical trial of aficontan (Example 3a).

[0105] Fig.38 The design of an exemplary Phase 3 clinical trial of aficontan is shown.

[0106] Fig.39 The change from baseline at resting LVOT-G at different time points is shown for patients in an open-label extension of an exemplary clinical trial of aficontan (Examples 3a and 3b).

[0107] Fig.40 The change from baseline in LVOT-G after the Valsalva maneuver at different time points is shown for patients in an open-label extension of an exemplary clinical trial of aficontan (Examples 3a and 3b).

[0108] Fig.41 Shown are changes in the distribution of NYHA functional classes of patients at different time points in an open-label extension of an exemplary clinical trial of aficontan (Examples 3a and 3b).

[0109] Fig.42 The changes in LVEF at different time points are shown for patients in an open-label extension of an exemplary clinical trial of aficontan (Examples 3a and 3b).

[0110] Fig.43 The design of an exemplary Phase 3 clinical trial of aficontan is shown (Example 5).

[0111] Fig.44 Baseline doses of beta blockers and calcium channel blockers are shown for 40 patients in an open-label extension of an exemplary clinical trial of aficontan (Examples 3a and 3b).

[0112] Fig.45A and Fig.45B Interim changes in NT-proBNP and hs-troponin I, respectively, are shown for patients in an open-label extension of an exemplary clinical trial of aficontan (Examples 3a and 3b).

[0113] Fig.46 An exemplary clinical trial of aficontan shows resting LVOT-G from baseline to week 12 (Example 2).

[0114] Fig.47 An exemplary clinical trial of aficontan shows LVOT-G with the Valsalva maneuver from baseline to week 12 (Example 2).

[0115] Fig.48An exemplary clinical trial of aficontan shows LVEF from baseline to week 12 (Example 2).

[0116] Fig.49 The distribution of patients demonstrating a hemodynamic response at week 10 in an exemplary clinical trial of aficontan is shown (Example 2).

[0117] Fig.50 The distribution of patients who demonstrated improvement in NYHA class at week 10 in an exemplary clinical trial of aficontan is shown (Example 2).

[0118] Fig.51 Shown are the mean proportional changes from baseline in NT-proBNP and hs-cTnI at week 10 in an exemplary clinical trial of aficontan (Example 2).

[0119] Fig.52 Shown are the doses of aficontan achieved by patients in an open-label extension of an exemplary clinical trial of aficontan (Examples 3a and 3b).

[0120] Fig.53 Core laboratory and site interpretation mean (SD) changes in resting LVOT-G from baseline at different time points are shown for patients in an open-label extension of an exemplary clinical trial of aficontan (Examples 3a and 3b). The horizontal dashed line represents the threshold for designating severe obstruction.

[0121] Fig.54 Core laboratory and site interpretation mean (SD) changes in LVOT-G by Valsalva maneuver compared to baseline for patients in an open-label extension of an exemplary clinical trial of aficontan at different time points are shown (Examples 3a and 3b). The horizontal dashed line represents the threshold for designating severe occlusion.

[0122] Fig.55 Shown are the core laboratory and site interpreted mean (SD) changes in LVEF at different time points for patients in an open-label extension of an exemplary clinical trial of aficontan (Examples 3a and 3b). The horizontal dashed line represents the low LVEF threshold at 50 mmHg.

[0123] Fig.56 The proportion of patients who demonstrated improvement in NYHA class at different weeks up to week 48 in an open-label extension of an exemplary clinical trial of aficontan are shown (Examples 3a and 3b).

[0124] Fig.57A The change in NYHA class from baseline to Weeks 36-48 is shown for 27 patients in an open-label extension of an exemplary clinical trial of aficontan (Examples 3a and 3b).

[0125] Fig.57B The change in global longitudinal strain (GLS) from baseline to Week 12 and Week 36-48 is shown in 27 patients who underwent echocardiography at Week 12 and Week 36-48 in an open-label extension of an exemplary clinical trial of aficontan (Examples 3a and 3b).

[0126] Fig.57C The change in global longitudinal strain (GLS) from baseline to Week 12 and Week 36-48 in patients who underwent echocardiography at Week 12 and Week 36-48 and had the best hemodynamic response (resting LVOT-G) in an open-label extension of an exemplary clinical trial of aficontan is shown (Examples 3a and 3b).

[0127] Fig.57D The change in global longitudinal strain (GLS) from baseline to Week 12 and Week 36-48 in patients who underwent echocardiography at Week 12 and Week 36-48 and had an optimal hemodynamic response (LVOT-G to Valsalva maneuver) is shown in an open-label extension of an exemplary clinical trial of aficontan (Examples 3a and 3b).

[0128] Fig.58 The design of an exemplary Phase 3 clinical trial of aficontan is shown.

[0129] Fig.59A An experimental X-ray powder diffraction (XRPD) pattern of polymorphic Form I of aphicontan is shown.

[0130] Fig.59B Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) graphs showing polymorphic Form I of aficontan.

[0131] Fig.59C A dynamic vapour sorption (DVS) graph of polymorph Form I of aficontan is shown.

[0132] Fig.60A The experimental XRPD pattern of polymorphic Form II of aphicontan is shown.

[0133] Fig.60B The DSC and TGA graphs of polymorphic Form II of aficontan are shown.

[0134] Fig.61A An experimental XRPD pattern showing a mixture of polymorphic forms I and III of aficontan.

[0135] Fig.61B Shown are DSC and TGA graphs of a mixture of polymorphic forms I and III of aficontan.

[0136] Fig.62AThe experimental XRPD pattern of polymorph Form IV of aphicontan is shown.

[0137] Fig.62B The DSC and TGA graphs of polymorphic Form IV of aficontan are shown.

[0138] Fig.63 The experimental XRPD pattern and two simulated patterns of polymorph Form V of aphicontan are shown (from top to bottom: simulated at 223 K; simulated at 273 K; experimental).

[0139] Fig.64A Two experimental XRPD patterns of polymorphic Form VI of aphicontan are shown: (a) top, XRPD of Form VI taken before drying; and (b) bottom, after drying (oven, vacuum, 24 hours, 25°C).

[0140] Fig.64B and Fig.64C Shown is a TGA graph of polymorphic Form VI of aficontan. Fig.64B The weight loss of an oven dried sample (oven, vacuum, overnight, 25°C) of Form VI is shown in the range of 25-300°C. Fig.64C TGA graph showing a sample of Form VI in the range of 25-300 °C which was oven dried (oven, vacuum, overnight, 25 °C) and further heated at 150 °C prior to thermogravimetric analysis.

[0141] Fig.64D and Fig.64E Shown is the DSC graph of polymorphic Form VI of aficontan. Fig.64D Shown is a DSC trace of an oven dried sample (oven, vacuum, overnight, 25°C) of Form VI in the range of 25-300°C. Fig.64E DSC plot showing a sample of Form VI in the range of 25-300°C which was oven dried (oven, vacuum, overnight, 25°C) and further heated at 150°C prior to thermogravimetric analysis. DETAILED DESCRIPTION

[0142] Described herein is the cardiac myosin inhibitor aficontan and various methods, e.g., for treating obstructive hypertrophic cardiomyopathy in a subject in need thereof using aficontan or a pharmaceutically acceptable salt thereof.

[0143] The treatment method may include adjusting the dose based on the results of one or more measured biplane left ventricular ejection fraction (LVEF) measurements and / or left ventricular outflow tract pressure gradient (LVOT-G) measurements after Valsalva maneuver, for example, to increase, decrease or maintain the dose, or to terminate administration. These measurements can be performed, for example, using echocardiography. The methods disclosed herein can be used as: 1) first-line therapy for subjects who have recently been diagnosed and / or have not received treatment; or as 2) monotherapy for participants who have previously received standard of care (SOC) medical therapy for symptomatic oHCM. It should be understood that the administration of oHCM monotherapy indicates that the patient receives only one therapy for treating oHCM (e.g., afecontan or a pharmaceutically acceptable salt thereof); however, it should be understood that the patient may also receive other therapies or therapies for treating other diseases. As described herein, "other therapies or therapies for treating other diseases" exclude SOC therapies for oHCM (e.g., one or more of β-blockers, calcium channel blockers, or disopyramide).

[0144] Aficontan is a small molecule cardiac myosin inhibitor having the structure shown below.

[0145]

[0146] Aficontan

[0147] The chemical name of aficontan 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. Small molecule inhibitors can be administered to patients, for example, orally to treat obstructive hypertrophic cardiomyopathy.

[0148] Aficontan has been described in WO 2019 / 144041, which is incorporated herein by reference. Aficontan or a pharmaceutically acceptable salt thereof can be obtained following the methods described therein. The aficontan used in the disclosed method may exist in the form of a pharmaceutically acceptable salt, a solvate, a hydrate, a polymorph, or a combination thereof, and may be formulated into any suitable pharmaceutical formulation. Aficontan may also exist in its free base form. The polymorphs of aficontan have been described in WO 2021 / 011807, which is incorporated herein by reference. The formulation of aficontan has been described in WO 2021 / 011808, which is incorporated herein by reference. Aficontan is designed to reduce the hypercontractility associated with hypertrophic cardiomyopathy (HCM). Without being limited to theory, in preclinical models, aficontan reduces myocardial contractility by directly binding to cardiac myosin at a unique and selective sex-binding site, thereby preventing myosin from entering a force-producing state. Aficontan reduces the number of active actin-myosin cross-bridges per cardiac cycle and thus reduces myocardial contractility. This mechanism of action may be therapeutically effective in conditions characterized by excessive hypercontractility, such as HCM, e.g., obstructive HCM, also known as oHCM.

[0149] definition

[0150] As used in this specification, the following words and phrases are generally intended to have the meanings as set forth below, unless otherwise indicated in the context in which they are used.

[0151] Throughout this application, unless the context indicates otherwise, reference to aphicontan includes its amorphous form or polymorphs thereof, including any of the described polymorphic forms I, II, III, IV, V or VI, or mixtures thereof.

[0152] References herein to "about" a value or parameter include (and describe) the value or parameter itself and any value or parameter that is 5% higher or 5% lower than the parameter. For example, a description of "about X" includes a description of "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.

[0153] “Recently diagnosed” patients were those with a history of oHCM of ≤ 12 months, regardless of whether they had used standard of care therapy for oHCM.

[0154] “Treatment-naive” patients were those who had not previously received standard-of-care therapy for oHCM.

[0155] “Currently untreated” patients were those who had not received standard of care therapy for oHCM within the past 12 months.

[0156] Patients with “chronic oHCM” were those with a history of oHCM >12 months who a) were currently receiving standard of care therapy for oHCM, or b) had received standard of care therapy for oHCM within the past 12 months.

[0157] "NYHA classification" or "NYHA class" refers to the New York Heart Association functional classification of heart failure symptoms. A description of each of NYHA classes I, II, III, and IV can be found in “Classes of Heart Failure”, American Heart Association, https: / / www.heart.org / en / health-topics / heart-failure / what-is-heart-failure / classes-of-heart-failure, adapted from: 1) Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart Association. Criteria Committee. “Nomenclature and criteria for diagnosis of diseases of the heart and great vessels”, 9th ed., Boston, MA: Lippincott Williams and Wilkins; March 1, 1994; and 2) Criteria Committee, New York Heart Association, Inc. Diseases of the Heartand 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 limitation in daily physical activities (e.g., shortness of breath when walking, climbing stairs). NYHA class II indicates that the patient has mild symptoms (e.g., mild shortness of breath and / or angina) and slight limitation during daily activities. NYHA class III indicates that the patient performs activities due to symptoms, even during less than normal activities (e.g., short distance walking [20-100 m]); and is comfortable only at rest. NYHA class IV indicates that the patient has severe limitation and symptoms occur even at rest; most participants are bedridden.

[0158] The term "pharmaceutically acceptable salt" refers to a salt of any compound herein that is known to be non-toxic and commonly used in the medical literature. In some embodiments, the pharmaceutically acceptable salt of the compound retains the biological effectiveness of the compound described herein and is not undesirable biologically or otherwise. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66 (1), 1-19. Inorganic acids and organic acids can be used to form pharmaceutically acceptable acid addition salts. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed using inorganic bases and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines, including naturally occurring substituted amines; cyclic amines; and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0159] If the compounds described herein are obtained in the form of acid addition salts, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the compound is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced according to conventional procedures for preparing acid addition salts from base compounds by dissolving the free base in a suitable organic solvent and treating the solution with an acid (see, e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19). Those skilled in the art will recognize various synthetic methods that can be used to prepare pharmaceutically acceptable addition salts.

[0160] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in the pharmaceutical composition is contemplated. Supplementary active ingredients may also be incorporated into the pharmaceutical composition.

[0161] The terms "patient," "individual," and "subject" refer to animals, such as mammals. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows, and humans. In some embodiments, the patient or subject is a human, such as a human who has been or will become the subject of treatment, observation, or experiment. The compounds, compositions, and methods described herein can be used for both human therapy and veterinary applications.

[0162] The term "therapeutically effective amount" or "effective amount" refers to an amount of a compound disclosed and / or described herein that is sufficient to affect the treatment as defined herein when administered to a patient in need of treatment. A therapeutically effective amount of a compound may be an amount sufficient to treat a disease responsive to modulation of cardiac myotomes. The therapeutically effective amount will vary depending, for example, on the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the specific compound, the dosing regimen to be followed, the time of administration, the mode of administration, all of which can be readily determined by one of ordinary skill in the art. A therapeutically effective amount can be determined experimentally, for example by measuring the blood concentration of the chemical entity, or theoretically, by calculating the bioavailability.

[0163] "Treatment" (and related terms, such as "treat," "treated," "treating") includes one or more of: inhibiting a disease or condition; slowing or preventing the development of clinical symptoms of a disease or condition; and / or alleviating a disease or condition (i.e., causing relief or regression of clinical symptoms). The term encompasses complete and partial reduction or prevention of a disease or condition and complete or partial reduction of clinical symptoms of a disease or condition. Thus, the compounds described and / or disclosed herein can prevent an existing disease or condition from worsening, help manage a disease or condition, or reduce or eliminate a disease or condition.

[0164] Reference to any dose of a compound described herein or a pharmaceutically acceptable salt thereof (eg, 5 mg, 10 mg, 20 mg, etc. of aphicontan) refers to the amount of the compound without any salt (ie, equivalent mass).

[0165] Treatment of obstructive hypertrophic cardiomyopathy

[0166] As further described herein, a therapeutically effective amount of aficontan may be administered to a patient to treat obstructive hypertrophic cardiomyopathy. Aficontan may be administered at a constant dose level. Aficontan may be administered at a titrated dose level. For example, the dose of aficontan may be adjusted based on the patient's response to the drug. That is, the dose of aficontan may be periodically increased, decreased, maintained, or terminated based on one or more of a measure of drug response, such as a biplane left ventricular ejection fraction (LVEF) and a LVOT-G measurement after a Valsalva maneuver.

[0167] Results from a recent clinical trial (see Example 1) show that 10 weeks of treatment with aficontan produced substantial and statistically significant reductions from baseline in mean resting left ventricular outflow tract pressure gradient (LVOT-G) (p=0.0003, p=0.0004, Cohort 1 and Cohort 2, respectively) and mean post-Valsallian maneuver LVOT-G (p=0.001, p<0.0001, Cohort 1 and Cohort 2, respectively) compared to placebo. The majority of patients treated with aficontan (78.6% in Cohort 1 and 92.9% in Cohort 2) achieved treatment goals, defined as resting gradient <30 mmHg and post-Valsallian maneuver gradient <50 mmHg at Week 10 compared to placebo (7.7%). Reductions in LVOT-G occurred within 2 weeks of starting treatment with aficontan, peaked within 2 to 6 weeks of the end of dose titration, and persisted until the end of the 10-week treatment. The observed reductions in LVOT-G were dose-dependent, and patients achieved greater reductions in LVOT-G with increasing doses of aficontan.

[0168] Treatment with aficontan was well tolerated in clinical trials. Overall, the incidence of adverse events was similar between treatment groups. Aficontan resulted in no serious adverse events and no treatment discontinuations occurred with aficontan. No new cases of atrial fibrillation were reported by the investigators. In this dose-ranging discovery trial, one patient experienced a transient decrease in left ventricular ejection fraction (LVEF), which required a dose adjustment but no dose interruption. LVEF returned to baseline within two weeks after the end of treatment in both cohorts, which confirms the reversibility of the effects with aficontan, similar to that observed in healthy participants in the Phase 1 study of aficontan.

[0169] Aficontan is administered in a therapeutically effective dose (e.g., a dose sufficient to provide treatment for a disease state). For humans, the daily dose may be between about 1 mg and about 50 mg. For example, the daily dose may be about 5 mg, about 10 mg, about 15 mg, about 20 mg, or any amount therebetween. The daily dose is the total amount administered in one day. The daily dose may be, but is not limited to, administered every day, every other day, every week, every 2 weeks, every month, or at different intervals. In some embodiments, the administration period of the daily dose is within the range of one day to a lifetime of the subject. In some embodiments, the daily dose is administered once a day. In some embodiments, the daily dose is administered in multiple divided doses, such as 2, 3, or 4 divided doses. In some embodiments, the daily dose is administered in 2 divided doses.

[0170] In one example, the patient is treated for oHCM by administering to the patient a daily dose of about 5 mg to about 20 mg of aficontan. In one example, the patient is treated for obstructive hypertrophic cardiomyopathy by administering to the patient a daily dose of about 5 mg of aficontan. In one example, the patient is treated for obstructive hypertrophic cardiomyopathy by administering to the patient a daily dose of about 10 mg of aficontan. In one example, the patient is treated for obstructive hypertrophic cardiomyopathy by administering to the patient a daily dose of about 15 mg of aficontan. In one example, the patient is treated for obstructive hypertrophic cardiomyopathy by administering to the patient a daily dose of about 20 mg of aficontan.

[0171] In some embodiments, methods for treating oHCM are provided, comprising administering aficontan or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing aficontan or a pharmaceutically acceptable salt thereof as a monotherapy, wherein the patient has recently been diagnosed with oHCM, the patient has not received treatment, or the patient has chronic oHCM. In some embodiments, methods for treating oHCM are provided, comprising administering aficontan or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing aficontan or a pharmaceutically acceptable salt thereof as a monotherapy, wherein the patient has chronic oHCM and has received SOC medical therapy for oHCM prior to the administration of aficontan or a pharmaceutically acceptable salt thereof. In some embodiments, a method for treating oHCM is provided, the method comprising administering aficontan or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing aficontan or a pharmaceutically acceptable salt thereof as a monotherapy, wherein the patient has chronic oHCM and has received SOC medical therapy for oHCM prior to the administration of aficontan or a pharmaceutically acceptable salt thereof, and the SOC medical therapy for oHCM has been discontinued prior to the administration of aficontan or a pharmaceutically acceptable salt thereof.

[0172] In some embodiments, prior to the administration of aficontan or a pharmaceutically acceptable salt thereof, the patient has a LVEF ≥ 60% and a resting LVOT-G ≥ 30 mmHg. In some embodiments, prior to the administration of aficontan, the patient has a LVEF ≥ 60% and a LVOT-G ≥ 50 mmHg after a Valsalva maneuver. In some embodiments, prior to the administration of aficontan, the patient has a LVEF ≥ 60%, a resting LVOT-G ≥ 30 mm Hg, and a LVOT-G ≥ 50 mmHg after a Valsalva maneuver. In some embodiments, prior to the administration of aficontan or a pharmaceutically acceptable salt thereof, the patient has a LVEF ≥ 60%, a resting LVOT-G ≥ 30 mmHg, and has NYHA class II or class III. In some embodiments, prior to the administration of aficontan, the patient has a LVEF ≥ 60%, a LVOT-G ≥ 50 mmHg after a Valsalva maneuver, and has NYHA class II or class III. In some embodiments, prior to administration of aficontan, the patient has a LVEF ≥ 60%, a resting LVOT-G ≥ 30 mm Hg, a LVOT-G after a Valsalva maneuver ≥ 50 mmHg, and has NYHA class II or class III.

[0173] During the course of treatment of oHCM, the dose of aficontan administered to the patient can be titrated, for example, by increasing, decreasing or maintaining the dose. Titration can be performed once during treatment, or can be repeated at intervals of time. For example, in some implementations, the dose of aficontan is titrated twice or more (e.g., 3 times, 4 times, 5 times or more) during the course of treatment. In some embodiments, before titrating the daily dose, a new daily dose is administered to the patient in a constant amount for about 1 week to about 8 weeks (or about 2 weeks to about 6 weeks, or about 4 weeks). In some embodiments, before titration, a new daily dose is administered to the patient in a constant amount for about 2 weeks. For example, the first daily dose can be administered to the patient before the first titration for about 2 weeks, wherein the daily dose is increased, decreased or maintained. Then a second titration can be performed about 2 weeks after the first titration. The titration of the dose allows the dose to be personalized for the patient's response to the drug, thereby maximizing the patient's potential therapeutic effect.

[0174] Dose titration can be based on one or more of biplane left ventricular ejection fraction (LVEF) and LVOT-G after Valsalva maneuver measured in the patient. One or more measurements can be determined, for example, using echocardiography. The echocardiogram is performed after administration of the daily dose (e.g., about 1 hour to about 3 hours after administration of the dose). In some embodiments, the echocardiogram is performed about 2 hours after administration of the daily dose.

[0175] In some embodiments, an initial daily dose of about 5 mg, about 10 mg, about 15 mg, or about 20 mg of aficontan or any amount therebetween is administered to the patient. After a period of time (e.g., about 2 weeks), the biplane LVEF and / or LVOT-G after the Valsalva maneuver are measured by echocardiography, for example, after the administration of the dose (e.g., about 1-3 hours or about 2 hours after the administration of the dose). If the biplane LVEF is lower than a predetermined biplane LVEF threshold (e.g., lower than 50%), the dose may be reduced or terminated. For example, if the biplane LVEF is lower than the biplane LVEF threshold and the current dose is not the lowest (e.g., first) dose, the dose may be reduced. If the biplane LVEF is lower than the biplane LVEF threshold and the current dose is the lowest (e.g., first) dose, the dose may be terminated. If the biplane LVEF is equal to or above a predetermined biplane LVEF threshold and is below a second predetermined biplane LVEF threshold (e.g., 50% ≤ LVEF <55%), the dose may be maintained, or if the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold (e.g., 55% or higher) and the LVOT-G after the Valsalva maneuver is below a predetermined LVOT-G threshold (e.g., less than 30%), the dose may be maintained. If the LVOT-G after the Valsalva maneuver is equal to or above a predetermined LVOT-G threshold (e.g., about 30 mmHg or greater) and the biplane LVEF is equal to or above 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 LVOT-G threshold after the Valsalva maneuver is about 30 mmHg. If the LVEF is <40% at any time, the administration of the daily dose is temporarily interrupted. In some embodiments, titration of the dose of aficontan comprises 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 terminating administration. In some embodiments, titration of the dose comprises 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.

[0176] After a period of time (e.g., about 2 weeks) of administering the first titrated dose to the patient, the dose may be titrated again (i.e., increased, decreased, or maintained) based on the patient's biplane LVEF and / or LVOT-G after Valsalva maneuver, e.g., using the same threshold parameters as discussed above. An exemplary dose titration schedule includes administering the first titrated dose for about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, about 10 weeks, or about 12 weeks, or any amount of time therebetween, followed by dose titration based on the patient's biplane LVEF and / or LVOT-G after Valsalva maneuver, e.g., using the same threshold parameters as discussed above. Additional repetitions of administration and dose titration may be implemented accordingly.

[0177] Provided herein is a method for reducing LVOT-G after Valsalva maneuver to below a specific value in a patient with symptomatic obstructive hypertrophic cardiomyopathy (oHCM), comprising administering a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof to the patient, wherein the patient has recently been diagnosed with oHCM, the patient has not received treatment, or the patient has chronic oHCM. The reduction of LVOT-G after Valsalva maneuver to less than a specific value may occur within 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 9 weeks, or 10 weeks of starting treatment with aficontan or a pharmaceutically acceptable salt thereof. The reduction of LVOT-G after Valsalva maneuver can last for at least 10 weeks of treatment. In some embodiments, the reduction of LVOT-G after Valsalva maneuver occurs within 2 to 6 weeks of the end of dose titration. In some embodiments, the reduction of LVOT-G after Valsalva maneuver reaches a peak within 2 to 6 weeks of the end of dose titration. In some embodiments, the specific LVOT-G value after the Valsalva maneuver 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.

[0178] Further provided herein is a method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient with symptoms of heart failure, wherein the patient has recently been diagnosed with oHCM, the patient has not received treatment, or the patient has chronic oHCM, the method comprising administering to the patient a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof, wherein the method reduces symptoms of heart failure as assessed by NYHA classification. In some embodiments of the foregoing, the method improves the patient's heart failure symptoms by at least one NYHA class, such as by one or two NYHA classes. In some embodiments of the foregoing, the method converts the patient from NYHA class III to class II or class I. In some embodiments of the foregoing, the method converts the patient from NYHA class III to class II. In some embodiments of the foregoing, the method converts the patient from NYHA class III to class I. In some embodiments of the foregoing, the method converts the patient from NYHA class III to class I. In some embodiments of the foregoing, the method converts the patient from NYHA class II to class I. In some embodiments of the foregoing, the reduction in symptoms of heart failure occurs within 10 weeks of initiating treatment with aficontan or a pharmaceutically acceptable salt thereof.

[0179] Figure 1 An exemplary method for treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient is described, wherein the patient has recently been diagnosed with oHCM (e.g., within the past 12 months), the patient has not received treatment for oHCM, or the patient has previously received standard of care medical therapy for oHCM and has discontinued said therapy prior to administration of aficontan, the method comprising titrating the daily dose of aficontan or a pharmaceutically acceptable salt thereof. Figure 1 The exemplary method shown provides four daily dosage levels (e.g., about 5 mg, 10 mg, 15 mg, and 20 mg), wherein the first daily dosage level is the lowest daily dosage level (e.g., about 5 mg), but can be easily modified to include additional or fewer dosage levels. Figure 1The exemplary method shown in the figure is such that the first daily dosage level is not the minimum daily dosage level. At 102, a first daily dosage level (e.g., about 5 mg) of aficontan or a pharmaceutically acceptable salt thereof is administered to the patient. After the first period of time, at 104, the daily dosage level is increased or maintained, or administration is terminated. This can be selected based on a first echocardiogram obtained from the patient after the first period of time. If the biplane LVEF of the first echocardiogram is lower than a predetermined biplane LVEF threshold (e.g., 50%), administration can be terminated 106, wherein another dose of aficontan or a pharmaceutically acceptable salt thereof is not administered to the patient. The first daily dose level (e.g., about 5 mg) may be selected to be maintained when the first echocardiogram satisfies any of the following conditions: (1) the biplane LVEF is equal to or above a predetermined biplane LVEF threshold (e.g., 50%) and below a second predetermined biplane LVEF threshold (e.g., 55%); or (2) the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold (e.g., 55%), and the post-Valsallian LVOT-G of the first echocardiogram is below a predetermined post-Valsallian LVOT-G threshold (e.g., 30 mmHg). If maintenance is selected, the first daily dose level of aficontan or a pharmaceutically acceptable salt thereof is administered to the patient at 102 for a second period of time, and optionally, the daily dose may be re-titrated at 104 after the second period of time. The daily dose level may be increased to a second daily dose level (e.g., 10 mg) when the first echocardiogram satisfies any of the following conditions: (1) the biplane LVEF is equal to or above a predetermined biplane LVEF threshold (e.g., 50%) and below a second predetermined biplane LVEF threshold (e.g., 55%); or (2) the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold (e.g., 55%), and the post-Valsallian LVOT-G of the first echocardiogram is above a predetermined post-Valsallian LVOT-G threshold (e.g., 30 mmHg). If the daily dose level is selected to be increased, the second daily dose level of aficontan or a pharmaceutically acceptable salt thereof is administered to the patient at 108 for a second period of time.

[0180] If the second daily dose level of aficontan or a pharmaceutically acceptable salt thereof (e.g., 10 mg) is administered to the patient at 108, the daily dose may be re-titrated (i.e., the daily dose may be selected to be increased, decreased, or maintained) based on the echocardiogram at 110. If the biplane LVEF of the echocardiogram is below a predetermined biplane LVEF threshold (e.g., 50%), the daily dose may be reduced to the first daily dose level (e.g., 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. The second daily dose level (e.g., about 10 mg) may be selected for maintenance when the echocardiogram satisfies any of the following conditions: (1) the biplane LVEF is equal to or above a predetermined biplane LVEF threshold (e.g., 50%) and below a second predetermined biplane LVEF threshold (e.g., 55%); or (2) the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold (e.g., 55%) and the LVOT-G after the Valsalva maneuver on the echocardiogram is below a predetermined LVOT-G threshold after the Valsalva maneuver (e.g., 30 mmHg). If maintenance is selected, the second daily dose level of aficontan or a pharmaceutically acceptable salt thereof is administered to the patient at 108 for an additional period of time, and optionally, the daily dose may be re-titrated at 110 after the period of time. When the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold (e.g., 55%) and the LVOT-G after the Valsalva maneuver on the echocardiogram is above a predetermined LVOT-G threshold after the Valsalva maneuver (e.g., 30 mmHg), the daily dose level may be increased to a third daily dose level (e.g., 15 mg). If an increase in the daily dosage level is chosen, then at 112 a second daily dosage level of aficontan or a pharmaceutically acceptable salt thereof is administered to the patient for the period.

[0181] If a third daily dose level of aficontan or a pharmaceutically acceptable salt thereof (e.g., 10 mg) is administered to the patient at 112, the daily dose may be re-titrated (i.e., the daily dose is selected to be increased, decreased, or maintained) based on the echocardiogram at 114. If the biplane LVEF on the echocardiogram is below a predetermined biplane LVEF threshold (e.g., 50%), the daily dose may be reduced to a second daily dose level (e.g., 15 mg to 10 mg). If the daily dose is reduced to the second daily dose level, the second daily dose level is administered to the patient at 108. The third daily dose level (e.g., about 15 mg) may be selected to be maintained when the echocardiogram satisfies any of the following conditions: (1) the biplane LVEF is equal to or above a predetermined biplane LVEF threshold (e.g., 50%) and below a second predetermined biplane LVEF threshold (e.g., 55%); or (2) the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold (e.g., 55%) and the post-Valsallian LVOT-G on the echocardiogram is below a predetermined post-Valsallian LVOT-G threshold (e.g., 30 mmHg). If maintenance is selected, the third daily dose level of aficontan or a pharmaceutically acceptable salt thereof is administered to the patient at 112 for another period of time, and optionally, the daily dose may be re-titrated after the period at 114. When the biplane LVEF is equal to or above a second predetermined biplane LVEF threshold (e.g., 55%) and the post-Valsallian LVOT-G of the echocardiogram is above a second predetermined post-Valsallian LVOT-G threshold (e.g., 30 mmHg), the daily dose level 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 aficontan or a pharmaceutically acceptable salt thereof is administered to the patient at 116 for a second period of time.

[0182] exist Figure 1 In the exemplary method shown, the first daily dose level is the minimum dose and therefore cannot be further reduced. However, in other embodiments, if the biplane LVEF on echocardiography is below a predetermined biplane LVEF threshold (e.g., 50%), the first daily dose level may not be the minimum dose and therefore may be reduced to a lower dose level (e.g., 10 mg to 5 mg).

[0183] exist Figure 1 In the exemplary method shown, the fourth daily dosage level is the maximum dosage, and therefore cannot be further increased. However, in other embodiments, other dosage levels can be obtained and the daily dosage can be further increased at 118. Figure 1In the method shown, at 118, a selection is made based on the echocardiogram to maintain the fourth daily dose level or to reduce the daily dose level. 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 third daily dose level (e.g., 20 mg to 15 mg). If the daily dose is reduced to the third daily dose level, a second daily dose level is administered to the patient at 112. The third daily dose level (e.g., about 15 mg) may be selected to be maintained when the echocardiogram satisfies any of the following conditions: (1) the biplane LVEF is equal to or higher than a predetermined biplane LVEF threshold (e.g., 50%) and lower than a second predetermined biplane LVEF threshold (e.g., 55%); or (2) the biplane LVEF is equal to or higher than a second predetermined biplane LVEF threshold (e.g., 55%) and the LVOT-G after the Valsalva maneuver of the echocardiogram is lower than a predetermined LVOT-G threshold after the Valsalva maneuver (e.g., 30 mmHg). If maintenance is selected, then the patient is administered a third daily dosage level of aficontan or a pharmaceutically acceptable salt thereof for another period of time at 116 , and optionally the daily dosage may be re-titrated at 118 after the period of time.

[0184] Exemplary daily dose increases include increasing from about 5 mg to about 10 mg of aficontan, increasing from about 10 mg to about 15 mg of aficontan, or increasing from about 10 mg to about 20 mg of aficontan. Other dose increases can be easily envisioned, such as increasing a given initial daily dose by about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 10 mg, or any amount therebetween. Exemplary daily dose reductions include decreasing from about 20 mg to about 10 mg, decreasing from about 15 mg to about 10 mg, or decreasing from about 10 mg to about 5 mg. Other dose reductions can be easily envisioned, such as decreasing a given initial daily dose by about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 10 mg, or any amount therebetween.

[0185] Exemplary embodiments of the methods described herein include administering a first daily dose (e.g., a first daily dose of between about 1 mg and about 20 mg (e.g., 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, or 20 mg), or any amount therebetween) of aficontan or a pharmaceutically acceptable salt thereof for a first period of time (e.g., about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 12 weeks, or any length of time therebetween), followed by maintaining the daily dose, decreasing the daily dose (e.g., decreasing the daily dose by about 1 mg to about 10 mg, e.g., decreasing the daily dose by 1 mg, 2 mg, 3 mg, 4 mg, 5 mg 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg, or any amount therebetween), increasing the daily dose (e.g., increasing the daily dose by about 1 mg to about 10 mg, e.g., increasing the daily dose by 1 mg, 2 mg, 3 mg, 4 mg, 5 mg 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg, or any amount therebetween), or increasing the daily dose (e.g., increasing the daily dose by about 1 mg to about 10 mg, e.g., increasing the daily dose by 1 mg, 2 mg, 3 mg, 4 mg, 5 mg 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg, or any amount therebetween) based on the patient's biplane LVEF and / or LVOT-G after the Valsalva maneuver. mg 6 mg, 7 mg, 8 mg, 9 mg or 10 mg, or any amount therebetween), or terminating administration to reach a second daily dose. Another exemplary embodiment of the methods described herein includes administering a first daily dose of aficontan or a pharmaceutically acceptable salt thereof for about two weeks, followed by maintaining the daily dose based on the patient's biplane LVEF and / or LVOT-G after Valsalva maneuver, reducing the daily dose by about 5 mg, increasing the daily dose by about 5 mg, or terminating administration to reach a second daily dose. Another exemplary embodiment of the methods described herein includes administering a first daily dose of aficontan or a pharmaceutically acceptable salt thereof for about three weeks, followed by maintaining the daily dose based on the patient's resting LVOT-G, biplane LVEF and / or LVOT-G after Valsalva maneuver, reducing the daily dose by about 5 mg, increasing the daily dose by about 5 mg, or terminating administration to reach a second daily dose. Another exemplary embodiment of the methods described herein comprises administering a first daily dose of aficontan 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 terminating administration based on the patient's biplane LVEF and / or LVOT-G after Valsalva maneuver, to reach a second daily dose. Another exemplary embodiment of the methods described herein comprises administering a first daily dose of aficontan 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 terminating administration based on the patient's biplane LVEF and / or LVOT-G after Valsalva maneuver, to reach a second daily dose.Another exemplary embodiment of the methods described herein comprises administering a first daily dose of aficontan or a pharmaceutically acceptable salt thereof for about 2 to about 12 weeks, followed by maintaining the daily dose, decreasing the daily dose by about 10 mg, increasing the daily dose by about 10 mg, or terminating administration to achieve a second daily dose based on the patient's biplane LVEF and / or LVOT-G after Valsalva maneuver.

[0186] Treatment of oHCM can improve exercise capacity and / or alleviate symptoms in patients with hyperdynamic ventricular contractions caused by obstructive hypertrophic cardiomyopathy. The methods disclosed herein can be used to treat patients who have been recently diagnosed, have not received treatment, or have chronic oHCM.

[0187] In some embodiments, a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy, thereby reducing the patient's LVOT-G after the Valsalva maneuver, wherein 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 been treated with standard of care medical therapy for oHCM and has discontinued the therapy prior to the administration of aficontan. In some embodiments, the patient's baseline LVOT-G after the Valsalva maneuver is 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 the administration of a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof, the LVOT-G after the Valsalva maneuver may be reduced to less than 50 mmHg, for example, to 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 aficontan or a pharmaceutically acceptable salt thereof, LVOT-G after a Valsalva maneuver is reduced by about 10 mmHg or greater, about 15 mmHg or greater, about 20 mmHg or greater, about 25 mmHg or greater, about 30 mmHg or greater, or about 35 mmHg or greater. In some embodiments, in response to administration of a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof, LVOT-G after a Valsalva maneuver is reduced by about 10 mmHg to about 40 mmHg. The reduction in LVOT-G after a Valsalva maneuver may occur after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks of daily dose administration.

[0188] In some embodiments, a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy, thereby reducing the patient's left ventricular mass index (LVMI), wherein 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 been treated with standard of care medical therapy for oHCM and has discontinued the therapy prior to the administration of aficontan. In response to administration of a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof, the LVMI may be reduced by about 1 g / m 2 or larger, about 1.5g / m 2 or larger, about 2 g / m 2 or larger, about 2.5 g / m 2 or larger, about 3 g / m 2 or larger, about 3.5 g / m 2 or greater, or about 4 g / m 2 In some embodiments, in response to administration of a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof, LVMI decreases by about 1 g / m 2 to about 10 g / m 2 , for example, a decrease of about 1 g / m 2 to about 6 g / m 2 , or about 2 g / m 2 About 5g / m 2 The reduction in LVMI can occur after about 1 week, after about 2 weeks, after about 3 weeks, after about 4 weeks, after about 5 weeks, after about 6 weeks, after about 8 weeks, or after about 10 weeks of daily dose administration.

[0189] In some embodiments, a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy, thereby reducing the patient's left atrial volume index (LAVI), wherein 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 been treated with standard of care medical therapy for oHCM and has discontinued the therapy prior to the administration of aficontan. In response to the administration of a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof, the LAVI may be reduced by about 0.5 mL / m 2 or greater, about 1 mL / m 2 or greater, about 1.5 mL / m 2 or greater, about 2 mL / m 2 or greater, or about 2.5 mL / m 2 In some embodiments, in response to administration of a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof, LAVI is reduced by about 0.5 mL / m 2to about 5 mL / m 2 mmHg, for example, a decrease of about 0.5 mL / m 2 to about 4 g / m 2 , or about 1 mL / m 2 About 3 mL / m 2 The reduction in LAVI can occur after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks of daily dose administration.

[0190] In some embodiments, a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy, thereby reducing the patient's e' value, wherein 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 been treated with standard of care medical therapy for oHCM and has discontinued the therapy prior to the administration of aficontan. In response to the administration of a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof, the e' value may be reduced by about 0.1 cm / s or greater, about 0.15 cm / s or greater, about 0.2 cm / s or greater, or about 0.25 cm / s or greater. In some embodiments, in response to the administration of a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof, the e' value is reduced by about 0.05 cm / s to about 0.3 cm / s, for example, by about 0.1 cm / s to about 0.25 cm / s, or about 0.15 cm / s to about 0.25 cm / s. The decrease in 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 of daily dose administration.

[0191] In some embodiments, a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy, thereby reducing the patient's lateral E / e' ratio, wherein the patient has recently been diagnosed with oHCM (e.g., within the past 12 months), the patient has not received oHCM treatment, or the patient has previously received standard of care medical therapy for oHCM and has discontinued the therapy prior to the administration of aficontan. In response to the administration of a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof, the lateral E / e' ratio may be reduced by about 0.5 or more, 1 or more, about 1.2 or more, about 1.5 or more, or about 1.8 or more. In some embodiments, in response to the administration of a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof, the lateral E / e' ratio is reduced by about 0.5 to about 2, for example, by about 1 to about 1.8, or by about 1.5 to about 1.8. The decrease in the lateral 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 of daily dosing.

[0192] In some embodiments, a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy to reduce the level of brain natriuretic peptide or N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in the patient, wherein 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 been treated with standard of care medical therapy for oHCM and has discontinued the therapy prior to the administration of aficontan. The reduction in the level of brain natriuretic peptide or N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in the patient may occur after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks of daily dose administration.

[0193] In some embodiments, a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy to reduce cardiac troponin I levels, wherein 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 been treated with standard of care medical therapy for oHCM and has discontinued the therapy prior to administration of aficontan. The reduction in cardiac troponin I levels in the patient may occur after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks of daily dose administration.

[0194] In some embodiments of any of the foregoing, when administration of aficontan or a pharmaceutically acceptable salt thereof is initiated, the patient with obstructive hypertrophic cardiomyopathy is classified as NYHA class III, wherein the patient has been recently diagnosed with oHCM (e.g., within the past 12 months), the patient has not been treated for oHCM, or the patient has previously been treated with standard of care medical therapy for oHCM and has discontinued the therapy prior to administration of aficontan. In some embodiments, when administration of aficontan or a pharmaceutically acceptable salt thereof is initiated, the patient with obstructive hypertrophic cardiomyopathy is classified as NYHA class II.

[0195] In some embodiments of any of the foregoing, administration of aficontan or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy improves the patient's exercise capacity, wherein 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 been treated with standard of care medical therapy for oHCM and has discontinued the therapy prior to administration of aficontan. In some embodiments of any of the foregoing, administration of aficontan or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy improves the patient's exercise capacity, e.g., as measured by changes in peak oxygen uptake (pVO2) or changes in peak oxygen uptake (pVO2) by cardiopulmonary exercise testing (CPET).

[0196] In some embodiments of any of the foregoing, administration of aficontan or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy improves total workload during CPET, wherein the patient has recently been diagnosed with oHCM (e.g., within the past 12 months), the patient has not received treatment for oHCM, or the patient has previously received standard of care medical therapy for oHCM and discontinued the therapy prior to administration of aficontan.

[0197] In some embodiments of any of the foregoing, administration of aficontan or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy improves other CPET parameters including, but not limited to, one or more of the following: (1) ventilator efficiency (VE / VCO2 slope); (2) circulatory power (VO2 x systolic BP); and (3) ventilator anaerobic threshold (VAT), wherein the patient has recently been diagnosed with oHCM (e.g., within the past 12 months), the patient has not received treatment for oHCM, or the patient has previously received standard of care medical therapy for oHCM and discontinued the therapy prior to administration of aficontan.

[0198] In some embodiments of any of the foregoing, administration of aficontan or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy improves patient health status, wherein the patient has recently been diagnosed with oHCM (e.g., within the past 12 months), the patient has not received treatment for oHCM, or the patient has previously received standard of care medical therapy for oHCM and has discontinued the therapy prior to administration of aficontan. In some embodiments of any of the foregoing, administration of aficontan or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy improves patient health status as determined by a change in the Kansas City Cardiomyopathy Questionnaire - Overall Summary Score (KCCQ-OSS). In some embodiments of any of the foregoing, administration of aficontan or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy improves patient health status as determined by a change in the Kansas City Cardiomyopathy Questionnaire - Clinical Summary Score (KCCQ-CSS). In some embodiments of any of the foregoing, administration of aficontan or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy improves patient health status as determined by a change in the Kansas City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS). In some embodiments of any of the foregoing, administration of aficontan or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy improves patient health status as determined by a change in the Kansas City Cardiomyopathy Questionnaire-Physical Limitation Score (KCCQ-PLS). In some embodiments of any of the foregoing, administration of aficontan or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy improves patient health status as determined by a change in the Kansas City Cardiomyopathy Questionnaire-Social Limitation Score (KCCQ-SLS). In some embodiments of any of the foregoing, administration of aficontan or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy improves patient health status as determined by a change in the Kansas City Cardiomyopathy Questionnaire-Quality of Life (KCCQ-QoL). In some embodiments, administration of aficontan or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy improves one or more KCCQ domain scores (e.g., KCCQ-OSS, KCCQ-CSS, KCCQ-TSS, KCCQ-PLS, KCCQ-SLS, or KCCQ-QoL) by at least about 5 points, at least about 10 points, or at least about 20 points.In some embodiments, the administration of aficontan or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy increases one or more KCCQ scores (e.g., KCCQ-OSS, KCCQ-CSS, KCCQ-TSS, KCCQ-PLS, KCCQ-SLS, or KCCQ-QoL) by about 5 points to less than 10 points, about 10 points to less than 20 points, or by at least 20 points. 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 lasts for about 6 months. In some embodiments, the administration of aficontan or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy increases KCCQ-CSS by 1 point, 2 points, 3 points, 4 points, 5 points, or more than 5 points. In some embodiments of any of the foregoing, administration of aficontan or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy improves patient health status and health-related quality of life as measured by the PRO questionnaire, as determined by changes in response to the EuroQol 5 Dimensions 5 Levels Tool (EQ-5D-5L). In some embodiments, administration with aficontan or a pharmaceutically acceptable salt thereof causes improvement in one or more HCM symptoms. In some embodiments, 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 limitation of physical activity.

[0199] Combinations of the foregoing results are also contemplated. For example, in some embodiments of any of the foregoing, administration of afifaktan or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy improves exercise capacity and functional class, wherein the patient has recently been diagnosed with oHCM (e.g., within the past 12 months), the patient has not received treatment for oHCM, or the patient has previously received standard of care medical therapy for oHCM and has discontinued the therapy prior to administration of afifaktan, e.g., as determined by: (1) a change in pVO2 from baseline of ≥1.5 mL / kg / min and an improvement in NYHA functional class of ≥1 category; or (2) a change in pVO2 from baseline of ≥3.0 mL / kg / min and no worsening of NYHA functional class. In some embodiments of any of the foregoing, administration of afifaktan or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy produces a resting LVOT-G <30 mmHg, a post-Valsalvian LVOT-G <50 mmHg, and NYHA functional class I in the patient. In some embodiments of any of the foregoing, administration of aficontan or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy produces resting LVOT-G <30 mmHg, LVOT-G after Valsalva maneuver <50 mmHg, and improvement in NYHA functional class by ≥ 1 category in the patient.

[0200] In some embodiments, the methods disclosed herein produce one or more effects selected from the group consisting of: a reduction in resting LVOT-G to less than 30 mmHg; a reduction in LVOT-G after a Valsalva maneuver to less than 50 mmHg; improved mitral regurgitation; improved cardiac relaxation; beneficial cardiac remodeling; reverse cardiac remodeling; beneficial cardiac structural remodeling; beneficial cardiac functional remodeling; reversal of adverse cardiac remodeling; reduction in mean left ventricular mass index (LVMI); improved left ventricular (LV) filling pressure; reduction in left atrial volume index (LAVI); reduction in category assessment of systolic anterior motion of the mitral leaflets; reduction in systolic anterior motion of the mitral leaflets; reduction in frequency of eccentric mitral regurgitation; reduction in mitral regurgitation; reduction in lateral E / e'; reduction in lateral 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 symptoms of heart failure, such as a reduction in NYHA classification.

[0201] Approaches to reduce background therapy in oHCM

[0202] Standard of care (SoC) drugs for the treatment of obstructive hypertrophic cardiomyopathy (oHCM) are currently recommended as first-line therapy. Standard of care drugs include one or more therapeutic agents selected from beta-blockers, calcium channel blockers, disopyramide and ranolazine. However, off-target side effects often make them unattractive to patients. Off-target side effects may include hypotension, bradycardia, fatigue, insomnia and sexual dysfunction. Background therapy reduction and / or withdrawal (BTR / W) may be beneficial to patients. For patients with heart failure with preserved ejection fraction (HFpEF) and chronotropic insufficiency, discontinuation of beta-blocker treatment has been shown to provide functional benefits and health status benefits of improving pVO2, as measured by the Minnesota Heart Failure Quality of Life Questionnaire (MLHFQ) score (Palau et al., Clin. Cardiol. 2020: 45(5):423-429).

[0203] In some aspects, a method of treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof is provided, wherein the patient is receiving one or more background therapies for oHCM. In some embodiments, a method of treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof is provided, wherein the patient is receiving background therapy for oHCM, the method comprising (1) administering a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof to the patient, and (2) reducing and / or stopping at least one background therapy. In some embodiments, the patient is receiving one, two, or three background therapies for oHCM. In some embodiments, the method comprises reducing at least one background therapy. In some embodiments, the method comprises reducing all one or more background therapies. In some embodiments, the method comprises stopping at least one background therapy. In some embodiments, the method comprises stopping all one or more background therapies. In some embodiments, at least one background therapy comprises administering at least one standard of care therapeutic agent selected from the group consisting of beta blockers, non-dihydropyridine calcium channel blockers, and disopyramide. In some embodiments, one or more of a beta-blocker, a non-dihydropyridine calcium channel blocker, and disopyramide are administered to the patient as background therapy. In some embodiments, reducing at least one background therapy comprises administering a lower dose of at least one background therapy. In some embodiments, the lower dose is 50% or less of the original dose of the background therapy. In some embodiments, (i) starting to administer a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof to the patient, and (ii) reducing and / or stopping at least one background therapy are performed simultaneously. In some embodiments, (i) starting to administer a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof to the patient, and (ii) reducing and / or stopping at least one background therapy are performed sequentially. In some embodiments, reducing and / or stopping at least one background therapy is performed after starting administration of aficontan or a pharmaceutically acceptable salt thereof. In some embodiments, the reduction and / or cessation of at least one background therapy is performed 2 weeks or more after the start of administration of aficontan 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 the start of administration of aficontan or a pharmaceutically acceptable salt thereof, or any amount therebetween. In some embodiments, the reduction and / or cessation of at least one background therapy is performed 12 weeks or more after the start of administration of aficontan or a pharmaceutically acceptable salt thereof. In some embodiments, the reduction and / or cessation of at least one background therapy is performed when the patient has been receiving a stable dose of aficontan or a pharmaceutically acceptable salt thereof for 2 weeks or more, for example 2 weeks, 3 weeks, 4 weeks, 5 weeks, 8 weeks, 10 weeks, 12 weeks, 15 weeks, 18 weeks, or 24 weeks after the start of administration of aficontan or a pharmaceutically acceptable salt thereof, or any amount therebetween.In some embodiments, reduction and / or cessation of at least one background therapy is performed when the patient has been receiving a stable dose of aficontan or a pharmaceutically acceptable salt thereof for 4 weeks or more, for example, 4 weeks, 5 weeks, 8 weeks, 10 weeks, 12 weeks, 15 weeks, 18 weeks, or 24 weeks after initiation of administration of aficontan or a pharmaceutically acceptable salt thereof, or any amount therebetween.

[0204] In another aspect, a method of treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof is provided, the method comprising: (1) administering to the patient a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof and a first dose of a standard of care treatment for oHCM for a first period of time; and (2) administering to the patient a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof and a second dose of a standard of care treatment for oHCM for a second period of time. In some embodiments, the second dose of the standard of care treatment for oHCM is lower than the first dose of the standard of care treatment. In some embodiments, the second dose of the standard of care treatment for oHCM is 50% or less of the first dose of the standard of care treatment. In some embodiments, the first period of time is at least 12 weeks. In some embodiments, prior to the start of the second period of time, aficontan or a pharmaceutically acceptable salt thereof is administered at a constant amount for at least about 4 weeks.

[0205] In another aspect, a method of treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof is provided, the method comprising: (1) administering to the patient a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof and a standard of care treatment for oHCM for a first period of time; and (2) administering to the patient a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof as a monotherapy for a second period of time. In some embodiments, the second dose of the standard of care treatment for oHCM is 50% or less of the first dose of the standard of care treatment. In some embodiments, the first period of time is at least 12 weeks. In some embodiments, prior to the start of the second period of time, aficontan or a pharmaceutically acceptable salt thereof is administered in a constant amount for at least about 4 weeks.

[0206] In another aspect, a method for treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof is provided, the method comprising: (1) administering to the patient a background therapy comprising at least one standard of care therapeutic 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 aficontan or a pharmaceutically acceptable salt thereof, and the background therapy during a first period; and (3) administering to the patient a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof, and a second dose of a standard of care therapeutic for oHCM during a second period, wherein the second dose of the standard of care therapeutic for oHCM is lower than the first dose of the standard of care therapeutic. In some embodiments, the second dose of the standard of care therapeutic for oHCM is 50% or less of the first dose of the standard of care therapeutic. In some embodiments, the first period is at least 12 weeks. In some embodiments, prior to the start of the second period, aficontan or a pharmaceutically acceptable salt thereof is administered at a constant amount for at least about 4 weeks.

[0207] In another aspect, a method of treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof is provided, the method comprising: (1) administering to the patient a background therapy comprising at least one standard of care therapeutic 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 aficontan or a pharmaceutically acceptable salt thereof, and the background therapy during a first period of time; and (3) administering to the patient a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof as a monotherapy during a second period of time. In some embodiments, the first period of time is at least 12 weeks. In some embodiments, prior to the start of the second period of time, aficontan or a pharmaceutically acceptable salt thereof is administered at a constant amount for at least about 4 weeks.

[0208] On the other hand, a method for improving myocardial mechanics in a patient in need is provided, the method comprising administering a therapeutically effective amount of aficontan 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, the method comprising administering a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof to the patient. In some embodiments, the method comprises long-term administration of aficontan or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the method comprises administering aficontan 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 aficontan for at least about 12 weeks. In some embodiments, the method comprises administering aficontan for at least about 36 weeks. In some embodiments, the method comprises administering aficontan for at least about 48 weeks. In some embodiments, the method further improves resting LVOT-G. In some embodiments, the method produces a resting LVOT-G of less than 30 mm Hg. In some embodiments, the method further improves the Valsalva LVOT-G. In some embodiments, the method produces a Valsalva LVOT-G of less than 50 mm Hg. In some embodiments, the method comprises administering aficontan or a pharmaceutically acceptable salt thereof to a patient who has an optimal hemodynamic response to treatment with aficontan or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the method comprises administering aficontan to a patient with a resting LVOT-G of less than 30 mmHg. In some embodiments, the method comprises administering aficontan 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 aficontan 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 aficontan or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has an optimal hemodynamic response to treatment with aficontan or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement in myocardial mechanics occurs after the patient has an optimal hemodynamic response to treatment with aficontan 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 responds to treatment with aficontan or a pharmaceutically acceptable salt thereof and achieves a resting LVOT-G of less than 30 mmHg and / or a Valsalva maneuver LVOT-G of less than 50 mmHg.

[0209] On the other hand, there is provided a method for improving the global longitudinal strain (GLS) of a patient in need thereof, the method comprising administering a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof to the patient. In some aspects, there is provided a method for improving the global longitudinal strain (GLS) of a patient with obstructive hypertrophic cardiomyopathy, the method comprising administering a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof to the patient. In some embodiments, the method comprises long-term administration of aficontan or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the method comprises administering aficontan 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 aficontan for at least about 12 weeks. In some embodiments, the method comprises administering aficontan for at least about 36 weeks. In some embodiments, the method comprises administering aficontan for at least about 48 weeks. In some embodiments, the method further improves resting LVOT-G. In some embodiments, the method produces a resting LVOT-G of less than 30 mm Hg. In some embodiments, the method further improves the Valsalva LVOT-G. In some embodiments, the method produces a Valsalva LVOT-G of less than 50 mm Hg. In some embodiments, the method comprises administering aficontan or a pharmaceutically acceptable salt thereof to a patient who has an optimal hemodynamic response to treatment with aficontan or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the method comprises administering aficontan to a patient with a resting LVOT-G of less than 30 mmHg. In some embodiments, the method comprises administering aficontan 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 aficontan 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 aficontan or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has an optimal hemodynamic response to treatment with aficontan or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement in GLS occurs after the patient has an optimal hemodynamic response to treatment with aficontan 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 maneuver LVOT-G of less than 50 mmHg in response to treatment with aficontan or a pharmaceutically acceptable salt thereof.

[0210] In some embodiments of any of the foregoing, the therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof is selected by titrating the daily dose of aficontan or a pharmaceutically acceptable salt thereof administered to the patient, as described herein for methods of treating oHCM.

[0211] In some embodiments, the patient suffers from a comorbidity. In some embodiments, the patient suffers from one or more of hypertension, diabetes, permanent atrial fibrillation, and paroxysmal atrial fibrillation.

[0212] The administration of the compounds and compositions disclosed and / or described herein can be via any accepted mode of administration of the therapeutic agent, including but not limited to oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal or intraocular administration. In some embodiments, the compound or composition is administered orally or intravenously. In some embodiments, the compound or composition disclosed and / or described herein is administered orally. In some embodiments, the compound or composition disclosed and / or described herein is administered by injection. In some embodiments, the compound or composition disclosed and / or described herein is administered intranasally. In some embodiments, the compound or composition disclosed and / or described herein is administered transdermally.

[0213] Pharmaceutically acceptable compositions include solid, semisolid, liquid and aerosol dosage forms, such as tablets, capsules, powders, liquids, suspensions, suppositories and aerosol forms. The compounds disclosed and / or described herein can also be administered in the following forms: sustained or controlled release dosage forms (e.g., controlled / sustained release pills, depot injections, osmotic pumps or transdermal (including electrotransport) patch forms) for extended time administration, and / or pulse administration at a predetermined rate. In some embodiments, the composition is provided in a unit dosage form suitable for single administration of precise doses.

[0214] Aficontan can be administered alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, cross-linked sodium carboxymethyl cellulose, glucose, gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical composition may also contain a small amount of non-toxic auxiliary substances, such as wetting agents, emulsifiers, solubilizers, pH buffers, etc. (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate). Typically, depending on the intended mode of administration, the pharmaceutical composition will contain about 0.005% to 95% by weight, or about 0.5% to 50% by weight of the compounds disclosed and / or described herein. The actual method of preparing such dosage forms is known or apparent to those skilled in the art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania. Suitable formulations of aficontan are disclosed in WO 2021 / 011808, which is incorporated herein by reference in its entirety.

[0215] In some embodiments, aficontan is provided in the form of a formulation comprising: (i) aficontan 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, aficontan is provided in the form of a formulation comprising: (i) aficontan; (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, dibasic calcium phosphate, dicalcium phosphate, tricalcium phosphate, compressible sugars, sugar alcohols, mannitol, sorbitol, maltitol, xylitol, lactitol, lactose, dextrose, maltose, sucrose, glucose, fructose, sucrose, raffinose, dextrates, trehalose, maltodextrin, and mixtures of any of the foregoing.

[0216] In some embodiments, the binder is selected from the group consisting of gum arabic, gum acacia, alginates, alginic acid, corn starch, copovidone, polyvinyl pyrrolidone, gelatin, glyceryl behenate, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, methyl cellulose, hydroxypropyl methyl cellulose, lactose, polyvinyl alcohol, povidone, polyethylene oxide, polyacrylate, potato starch, pregelatinized starch, sodium alginate, sodium starch, sodium carboxymethyl cellulose, starch, and a mixture of any of the foregoing.

[0217] In some embodiments, the disintegrant is selected from the group consisting of alginic acid, cross-linked sodium carboxymethylcellulose, cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, cross-linked polyvidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, polacrilin potassium, pregelatinized starch, partially hydrolyzed starch, sodium carboxymethyl starch, starch, sodium alginate, sodium carboxymethyl cellulose, and a mixture of any of the foregoing.

[0218] In some embodiments, the surfactant is selected from the group consisting of cetylpyridinium chloride, heptadecaethyleneoxycetanol, lecithin, polyoxyethylene stearate, nonoxynol 9, nonoxynol 10, octoxynol 9, sorbitan fatty acid esters, Span 20, Span 40, Span 60, Span 80, Span 85, polysorbate, polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, sodium salt of fatty alcohol sulfate, sodium lauryl sulfate, sodium salt of sulfosuccinate, sodium dioctyl sulfosuccinate, partial esters of fatty acids with alcohols, glyceryl monostearate, glyceryl monooleate, ethers of fatty alcohols with polyoxyethylene, esters of fatty acids with polyoxyethylene, copolymers of ethylene oxide and propylene oxide (Pluronic®), benzalkonium chloride, ethoxylated triglycerides, and mixtures of any of the foregoing.

[0219] In some embodiments, the lubricant is selected from the group consisting of hydrogenated castor oil, magnesium stearate, glyceryl monostearate, calcium stearate, glyceryl behenate, glyceryl distearate, glyceryl dipalmitostearate, behenyl polyoxyl-8 glyceride, sodium stearyl fumarate, stearic acid, talc, zinc stearate, mineral oil, polyethylene glycol, poloxamer, sodium lauryl sulfate, and mixtures of any of the foregoing.

[0220] In some embodiments, the formulation comprises: (i) about 1 wt % to about 80 wt % of aficontan or a pharmaceutically acceptable salt thereof; (ii) about 15 wt % to about 90 wt % of a filler; (iii) about 0.1 wt % to about 10 wt % of a binder; (iv) about 1 wt % to about 10 wt % of a disintegrant; (v) about 0.1 wt % to about 10 wt % of a surfactant; and (vi) about 0.1 wt % to about 10 wt % of a lubricant.

[0221] In some embodiments, the formulation comprises: (i) about 1 wt % to about 50 wt % of aficontan or a pharmaceutically acceptable salt thereof; (ii) about 40 wt % to about 80 wt % of a filler; (iii) about 0.5 wt % to about 5 wt % of a binder; (iv) about 2 wt % to about 8 wt % of a disintegrant; (v) about 0.5 wt % to about 5 wt % of a surfactant; and (vi) about 0.5 wt % to about 5 wt % of a lubricant.

[0222] In some embodiments, the formulation comprises: (i) about 10% to about 30% by weight of aficontan 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.

[0223] In some embodiments, the formulation comprises: (i) about 1 wt % to about 10 wt % of aficontan or a pharmaceutically acceptable salt thereof; (ii) about 70 wt % to about 90 wt % of a filler; (iii) about 1 wt % to about 3 wt % of a binder; (iv) about 4 wt % to about 6 wt % of a disintegrant; (v) about 1 wt % to about 3 wt % of a surfactant; and (vi) about 0.5 wt % to about 1.5 wt % of a lubricant.

[0224] In some embodiments, the formulation comprises: (i) about 5 weight % of aficontan or a pharmaceutically acceptable salt thereof; (ii) about 85 weight % of a filler; (iii) about 2 weight % of a binder; (iv) about 5 weight % of a disintegrant; (v) about 2 weight % of a surfactant; and (vi) about 1 weight % of a lubricant.

[0225] In some embodiments, the formulation comprises: (i) about 10 weight % of aficontan or a pharmaceutically acceptable salt thereof; (ii) about 80 weight % of a filler; (iii) about 2 weight % of a binder; (iv) about 5 weight % of a disintegrant; (v) about 2 weight % of a surfactant; and (vi) about 1 weight % of a lubricant.

[0226] In some embodiments, the formulation comprises: (i) about 1% to about 50% by weight of aficontan 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.

[0227] In some embodiments, the formulation comprises: (i) about 10% to about 30% by weight of aficontan 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.

[0228] In some embodiments, the formulation comprises: (i) about 1% to about 10% by weight of aficontan 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.

[0229] In some embodiments, the formulation comprises: (i) about 20 weight % of aficontan or a pharmaceutically acceptable salt thereof; (ii-1) about 44 weight % of mannitol; (ii-2) about 26 weight % of microcrystalline cellulose; (iii) about 2 weight % of hydroxypropyl cellulose; (iv) about 5 weight % of croscarmellose sodium; (v) about 2 weight % of sodium lauryl sulfate; and (vi) about 1 weight % of magnesium stearate.

[0230] In some embodiments, the formulation comprises: (i) about 10 weight % of aficontan or a pharmaceutically acceptable salt thereof; (ii-1) about 50 weight % of mannitol; (ii-2) about 30 weight % of microcrystalline cellulose; (iii) about 2 weight % of hydroxypropyl cellulose; (iv) about 5 weight % of croscarmellose sodium; (v) about 2 weight % of sodium lauryl sulfate; and (vi) about 1 weight % of magnesium stearate.

[0231] In some embodiments, the formulation comprises: (i) about 5 weight % of aficontan or a pharmaceutically acceptable salt thereof; (ii-1) about 54 weight % of mannitol; (ii-2) about 31 weight % of microcrystalline cellulose; (iii) about 2 weight % of hydroxypropyl cellulose; (iv) about 5 weight % of croscarmellose sodium; (v) about 2 weight % of sodium lauryl sulfate; and (vi) about 1 weight % of magnesium stearate.

[0232] In some embodiments, the aforementioned formulations are in tablet form. In some embodiments, the tablet further comprises a coating (e.g., a film coating as described elsewhere herein). In such embodiments, the weight percentages herein are provided relative to the core tablet, excluding the weight of the coating.

[0233] In some embodiments, aphicontan or a pharmaceutical composition containing aphicontan will take the form of a pill or tablet, and thus the composition may contain one or more of a diluent (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesium stearate), and / or a binder (e.g., starch, acacia gum, polyvinyl pyrrolidine, gelatin, cellulose, cellulose derivatives) and a compound disclosed and / or described herein. Other solid dosage forms include powders, pellets (marume), solutions or suspensions (e.g., in propylene carbonate, vegetable oils, or triglycerides) encapsulated in gelatin capsules.

[0234] In some embodiments, aphicontan is provided in the form of a tablet comprising: (i) a core, the total weight of which core comprises: (a) an intragranular component comprising: (ai) aphicontan 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.

[0235] In some embodiments, the intragranular filler is selected from the group consisting of powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, kaolin, corn starch, maize starch, starch derivatives, pregelatinized starch, calcium phosphate, dibasic calcium phosphate, dicalcium phosphate, tricalcium phosphate, compressible sugars, sugar alcohols, mannitol, sorbitol, maltitol, xylitol, lactitol, lactose, dextrose, maltose, sucrose, glucose, fructose, sucrose, raffinose, dextrose binders, trehalose, maltodextrin, and mixtures of any of the foregoing.

[0236] In some embodiments, the intragranular binder is selected from the group consisting of gum arabic, gum acacia, alginates, alginic acid, corn starch, copovidone, polyvinyl pyrrolidone, gelatin, glyceryl behenate, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, methyl cellulose, hypromellose, lactose, polyvinyl alcohol, povidone, polyethylene oxide, polyacrylate, potato starch, pregelatinized starch, sodium alginate, sodium starch, sodium carboxymethyl cellulose, starch, and mixtures of any of the foregoing.

[0237] In some embodiments, the intragranular disintegrant is selected from the group consisting of alginic acid, cross-linked sodium carboxymethylcellulose, cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, cross-linked polyvidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, polacrilin potassium, pregelatinized starch, partially hydrolyzed starch, sodium carboxymethyl starch, starch, sodium alginate, sodium carboxymethyl cellulose, and a mixture of any of the foregoing.

[0238] In some embodiments, the intragranular surfactant is selected from the group consisting of: cetylpyridinium chloride, heptadecaethyleneoxycetanol, lecithin, polyoxyethylene stearate, nonoxynol 9, nonoxynol 10, octoxynol 9, sorbitan fatty acid esters, Span 20, Span 40, Span 60, Span 80, Span 85, polysorbate, polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, sodium salt of fatty alcohol sulfate, sodium lauryl sulfate, sodium salt of sulfosuccinate, sodium dioctyl sulfosuccinate, partial esters of fatty acids with alcohols, glyceryl monostearate, glyceryl monooleate, ethers of fatty alcohols with polyoxyethylene, esters of fatty acids with polyoxyethylene, copolymers of ethylene oxide and propylene oxide (Pluronic®), benzalkonium chloride, ethoxylated triglycerides, and mixtures of any of the foregoing.

[0239] In some embodiments, the extragranular filler is selected from the group consisting of powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, kaolin, corn starch, maize starch, starch derivatives, pregelatinized starch, calcium phosphate, dibasic calcium phosphate, dicalcium phosphate, tricalcium phosphate, compressible sugars, sugar alcohols, mannitol, sorbitol, maltitol, xylitol, lactitol, lactose, dextrose, maltose, sucrose, glucose, fructose, sucrose, raffinose, dextrose binders, trehalose, maltodextrin, and mixtures of any of the foregoing.

[0240] In some embodiments, the extragranular disintegrant is selected from the group consisting of alginic acid, cross-linked sodium carboxymethylcellulose, cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, cross-linked polyvidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, polacrilin potassium, pregelatinized starch, partially hydrolyzed starch, sodium carboxymethyl starch, starch, sodium alginate, sodium carboxymethylcellulose, and a mixture of any of the foregoing.

[0241] In some embodiments, the extragranular lubricant is selected from the group consisting of hydrogenated castor oil, magnesium stearate, glyceryl monostearate, calcium stearate, glyceryl behenate, glyceryl distearate, glyceryl dipalmitostearate, behenyl polyoxyl-8 glyceride, sodium stearyl fumarate, stearic acid, talc, zinc stearate, mineral oil, polyethylene glycol, poloxamer, sodium lauryl sulfate, and mixtures of any of the foregoing.

[0242] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 1% to about 80% of aficontan or a pharmaceutically acceptable salt thereof, based on the total weight of the core; (a-ii) about 10% to about 80% of an intragranular filler, based on the total weight of the core; (a-iii) about 0.1% to about 10% of an intragranular binder, based on the total weight of the core; (a-iv) about 0.1% to about 5% of an intragranular disintegrant, based on the total weight of the core; and (av) about 0.1% to about 5% of an intragranular surfactant, based on the total weight of the core; and (b) an extragranular component comprising: (bi) about 5% to about 15% of an extragranular filler, based on the total weight of the core; (b-ii) about 0.1% to about 5% of an extragranular disintegrant, based on the total weight of the core; and (b-iii) about 0.1% to about 5% of an extragranular lubricant, based on the total weight of the core. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0243] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 1% to about 80% of aficontan or a pharmaceutically acceptable salt thereof, based on the total weight of the core; (a-ii) about 10% to about 80% of an intragranular filler, based on the total weight of the core; (a-iii) about 0.1% to about 10% of an intragranular binder, based on the total weight of the core; (a-iv) about 0.1% to about 5% of an intragranular disintegrant, based on the total weight of the core; and (av) about 0.1% to about 5% of an intragranular surfactant, based on the total weight of the core; and (b) an extragranular component comprising: (bi) about 5% to about 15% of an extragranular filler, based on the total weight of the core; (b-ii) about 0.1% to about 5% of an extragranular disintegrant, based on the total weight of the core; and (b-iii) about 0.1% to about 5% of an extragranular lubricant, based on the total weight of the core. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0244] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 1% to about 50% of aficontan or a pharmaceutically acceptable salt thereof, based on the total weight of the core; (a-ii) about 40% to about 80% of an intragranular filler, based on the total weight of the core; (a-iii) about 1% to about 5% of an intragranular binder, based on the total weight of the core; (a-iv) about 1% to about 5% of an intragranular disintegrant, based on the total weight of the core; and (av) about 1% to about 5% of an intragranular surfactant, based on the total weight of the core; and (b) an extragranular component comprising: (bi) about 5% to about 15% of an extragranular filler, based on the total weight of the core; (b-ii) about 1% to about 5% of an extragranular disintegrant, based on the total weight of the core; and (b-iii) about 0.1% to about 2% of an extragranular lubricant, based on the total weight of the core. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0245] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 10% to about 30% of aficontan or a pharmaceutically acceptable salt thereof, based on the total weight of the core; (a-ii) about 50% to about 70% of an intragranular filler, based on the total weight of the core; (a-iii) about 1% to about 3% of an intragranular binder, based on the total weight of the core; (a-iv) about 2% to about 4% of an intragranular disintegrant, based on the total weight of the core; and (av) about 1% to about 3% of an intragranular surfactant, based on the total weight of the core; and (b) an extragranular component comprising: (bi) about 5% to about 15% of an extragranular filler, based on the total weight of the core; (b-ii) about 1% to about 3% of an extragranular disintegrant, based on the total weight of the core; and (b-iii) about 0.1% to about 1.5% of an extragranular lubricant, based on the total weight of the core. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0246] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 1% to about 10% of aficontan or a pharmaceutically acceptable salt thereof, based on the total weight of the core; (a-ii) about 60% to about 80% of an intragranular filler, based on the total weight of the core; (a-iii) about 1% to about 3% of an intragranular binder, based on the total weight of the core; (a-iv) about 2% to about 4% of an intragranular disintegrant, based on the total weight of the core; and (av) about 1% to about 3% of an intragranular surfactant, based on the total weight of the core; and (b) an extragranular component comprising: (bi) about 5% to about 15% of an extragranular filler, based on the total weight of the core; (b-ii) about 1% to about 3% of an extragranular disintegrant, based on the total weight of the core; and (b-iii) about 0.1% to about 1.5% of an extragranular lubricant, based on the total weight of the core. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0247] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 5% of aficontan or a pharmaceutically acceptable salt thereof by weight of the core; (a-ii) about 74% of the intragranular filler by weight of the core; (a-iii) about 2% of the intragranular binder by weight of the core; (a-iv) about 3% of the intragranular disintegrant by weight of the core; and (av) about 2% of the intragranular surfactant by weight of the core; and (b) an extragranular component comprising: (bi) about 11% of the extragranular filler by weight of the core; (b-ii) about 2% of the extragranular disintegrant by weight of the core; and (b-iii) about 1% of the extragranular lubricant by weight of the core. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0248] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 10% of aficontan or a pharmaceutically acceptable salt thereof by weight of the core; (a-ii) about 69% of the total weight of the core by weight of an intragranular filler; (a-iii) about 2% of the total weight of the core by weight of an intragranular binder; (a-iv) about 3% of the total weight of the core by weight of an intragranular disintegrant; and (av) about 2% of the total weight of the core by weight of an intragranular surfactant; and (b) an extragranular component comprising: (bi) about 11% of the total weight of the core by weight of an extragranular filler; (b-ii) about 2% of the total weight of the core by weight of an extragranular disintegrant; and (b-iii) about 1% of the total weight of the core by weight of an extragranular lubricant. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0249] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 20% of aficontan or a pharmaceutically acceptable salt thereof by weight of the core; (a-ii) about 59% of the intragranular filler by weight of the core; (a-iii) about 2% of the intragranular binder by weight of the core; (a-iv) about 3% of the intragranular disintegrant by weight of the core; and (av) about 2% of the intragranular surfactant by weight of the core; and (b) an extragranular component comprising: (bi) about 11% of the extragranular filler by weight of the core; (b-ii) about 2% of the extragranular disintegrant by weight of the core; and (b-iii) about 1% of the extragranular lubricant by weight of the core. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0250] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 1% to about 50% of aficontan or a pharmaceutically acceptable salt thereof, based on the total weight of the core; (a-ii-1) about 40% to about 60% of mannitol, based on the total weight of the core; (a-ii-2) about 10% to about 30% of microcrystalline cellulose, based on the total weight of the core; (a-iii) about 1% to about 5% of hydroxypropyl cellulose, based on the total weight of the core; (a-iv) about 1% to about 5% of croscarmellose sodium, based on the total weight of the core; and (av) about 1% to about 5% of sodium lauryl sulfate, based on the total weight of the core; and (b) an extragranular component comprising: (bi) about 5% to about 15% of microcrystalline cellulose, based on the total weight of the core; (b-ii) about 1% to about 5% of croscarmellose sodium, based on the total weight of the core; and (b-iii) about 0.1% to about 2% of an extragranular lubricant, based on the total weight of the core. In some embodiments, the extragranular lubricant is magnesium stearate. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0251] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 10% to about 30% of aficontan or a pharmaceutically acceptable salt thereof, based on the total weight of the core; (a-ii-1) about 40% to about 50% of mannitol, based on the total weight of the core; (a-ii-2) about 10% to about 20% of microcrystalline cellulose, based on the total weight of the core; (a-iii) about 1% to about 3% of hydroxypropyl cellulose, based on the total weight of the core; (a-iv) about 2% to about 4% of croscarmellose sodium, based on the total weight of the core; and (av) about 1% to about 3% of sodium lauryl sulfate, based on the total weight of the core; and (b) an extragranular component comprising: (bi) about 5% to about 15% of microcrystalline cellulose, based on the total weight of the core; (b-ii) about 1% to about 3% of croscarmellose sodium, based on the total weight of the core; and (b-iii) about 0.1% to about 1.5% of an extragranular lubricant, based on the total weight of the core. In some embodiments, the extragranular lubricant is magnesium stearate. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0252] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 1% to about 10% of aficontan or a pharmaceutically acceptable salt thereof, based on the total weight of the core; (a-ii-1) about 50% to about 60% of mannitol, based on the total weight of the core; (a-ii-2) about 15% to about 25% of microcrystalline cellulose, based on the total weight of the core; (a-iii) about 1% to about 3% of hydroxypropyl cellulose, based on the total weight of the core; (a-iv) about 2% to about 4% of croscarmellose sodium, based on the total weight of the core; and (av) about 1% to about 3% of sodium lauryl sulfate, based on the total weight of the core; and (b) an extragranular component comprising: (bi) about 5% to about 15% of microcrystalline cellulose, based on the total weight of the core; (b-ii) about 1% to about 3% of croscarmellose sodium, based on the total weight of the core; and (b-iii) about 0.1% to about 1.5% of an extragranular lubricant, based on the total weight of the core. In some embodiments, the extragranular lubricant is magnesium stearate. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0253] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 20% of aficontan or a pharmaceutically acceptable salt thereof by weight of the core; (a-ii-1) about 44% of mannitol by weight of the core; (a-ii-2) about 15% of microcrystalline cellulose by weight of the core; (a-iii) about 2% of hydroxypropyl cellulose by weight of the core; (a-iv) about 3% of croscarmellose sodium by weight of the core; and (av) about 2% of sodium lauryl sulfate by weight of the core; and (b) an extragranular component comprising: (bi) about 11% of microcrystalline cellulose by weight of the core; (b-ii) about 2% of croscarmellose sodium by weight of the core; and (b-iii) about 1% of an extragranular lubricant by weight of the core. In some embodiments, the extragranular lubricant is magnesium stearate. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0254] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 10% of aficontan or a pharmaceutically acceptable salt thereof by weight of the core; (a-ii-1) about 50% of mannitol by weight of the core; (a-ii-2) about 19% of microcrystalline cellulose by weight of the core; (a-iii) about 2% of hydroxypropyl cellulose by weight of the core; (a-iv) about 3% of croscarmellose sodium by weight of the core; and (av) about 2% of sodium lauryl sulfate by weight of the core; and (b) an extragranular component comprising: (bi) about 11% of microcrystalline cellulose by weight of the core; (b-ii) about 2% of croscarmellose sodium by weight of the core; and (b-iii) about 1% of an extragranular lubricant by weight of the core. In some embodiments, the extragranular lubricant is magnesium stearate. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0255] In some embodiments, the core comprises: (a) an intragranular component comprising: (ai) about 5% by weight of aficontan or a pharmaceutically acceptable salt thereof; (a-ii-1) about 54% by weight of mannitol; (a-ii-2) about 20% by weight of microcrystalline cellulose; (a-iii) about 2% by weight of hydroxypropyl cellulose; (a-iv) about 3% by weight of cross-linked sodium carboxymethyl cellulose; and (av) about 2% by weight of sodium lauryl sulfate; and (b) an extragranular component comprising: (bi) about 11% by weight of microcrystalline cellulose; (b-ii) about 2% by weight of cross-linked sodium carboxymethyl cellulose; and (b-iii) about 1% by weight of an extragranular lubricant. In some embodiments, the extragranular lubricant is magnesium stearate. In some embodiments, the total weight of the core is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total weight of the core is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total weight of the core is about 50 mg. In some embodiments, the total weight of the core is about 70 mg. In some embodiments, the total weight of the core is about 100 mg. In some embodiments, the total weight of the core is about 150 mg. In some embodiments, the total weight of the core is about 200 mg. In some embodiments, the total weight of the core is about 400 mg.

[0256] In some embodiments, the tablet comprises a coating layer containing a coating agent. In some embodiments, the coating layer surrounds the entire core of the tablet. In some embodiments, the coating agent is selected from the group consisting of Opadry QX White 21A180025, Opadry I and Opadry II. In some embodiments, the coating agent is Opadry QX White 21A180025. In some embodiments, the tablet comprises about 0.5% to about 10% of the total weight of the core coating agent. In some embodiments, the tablet comprises about 1% to about 5% of the total weight of the core coating agent. In some embodiments, the tablet comprises about 2% to about 4% of the total weight of the core coating agent. In some embodiments, the tablet comprises about 3% of the total weight of the core coating agent. In some embodiments, the tablet comprises about 0.5% to about 10% of the total weight of the core Opadry QX White 21A180025. In some embodiments, the tablet comprises about 1% to about 5% of the total weight of the core Opadry QX White 21A180025. In some embodiments, the tablet comprises about 2% to about 4% of the total weight of the core Opadry QX White 21A180025. In some embodiments, the tablet comprises about 3% of the total weight of the core Opadry QX White 21A180025.

[0257] In some embodiments, the amount of aficontan (which may be present in various forms) in a formulation (e.g., a tablet) is about the daily dose described herein, for example, about 5 mg, about 10 mg, about 15 mg, or about 20 mg of aficontan. In some embodiments, the amount of aficontan (which may be present in various forms) in a formulation (e.g., a tablet) is about half of the daily dose described herein. In some embodiments, the amount of aficontan in a formulation (e.g., a tablet) is about 2.5 mg, about 5 mg, about 7.5 mg, or about 10 mg of aficontan.

[0258] In some embodiments, aphicontan is present in its free base form in various formulations, such as tablets. In some embodiments, methods, such as those described in the Examples, use such tablets.

[0259] Liquid pharmaceutical compositions can be prepared, for example, by dissolving, dispersing or suspending the compound disclosed and / or described herein and optional pharmaceutical additives in a carrier (e.g., water, saline, dextrose aqueous solution, glycerol, glycol, ethanol, etc.) to form a solution or suspension. Injectables can be prepared in conventional form, in a liquid solution or suspension, in an emulsion, or in a solid form suitable for dissolving or suspending in a liquid before injection. The percentage of the compound contained in such parenteral compositions depends on, for example, the physical properties of the compound, the activity of the compound, and the needs of the subject. However, an active ingredient with a percentage of 0.01% to 10% can be used in the solution, and if the composition is a solid that will be diluted to another concentration subsequently, the percentage can be higher. In some embodiments, the composition will include about 0.2 to 2% of the compound disclosed and / or described herein in the solution.

[0260] The pharmaceutical composition of the compound disclosed and / or described herein can also be used as an aerosol or solution for a nebulizer, or as a fine powder for insufflation, alone or in combination with an inert carrier such as lactose, to be applied to the respiratory tract. In this case, the particles of the pharmaceutical composition may have a diameter of less than 50 microns or less than 10 microns in some embodiments. The pharmaceutical composition of the compound disclosed and / or described herein can also be transdermally administered, for example in the form of a patch, cream, ointment, or other preparations suitable for application to the skin.

[0261] Additionally, pharmaceutical compositions may include a compound disclosed and / or described herein and one or more other pharmaceutical agents, medicaments, adjuvants, etc. Suitable pharmaceutical agents include those described herein.

[0262] Polymorph

[0263] In some embodiments, aficontan is in the form of a polymorph of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Suitable polymorphs of aficontan include those disclosed in WO 2021 / 011807 and can be prepared according to WO 2021 / 011807, which is incorporated herein by reference in its entirety. The polymorphs may have properties suitable for medical or pharmaceutical uses, such as bioavailability and stability under certain conditions. Changes in the crystal structure of a drug substance may affect the dissolution rate of the drug product (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ease of purification, ability to consistently prepare doses of known strength, etc.), and stability (e.g., thermal stability, shelf life (including resistance to degradation), etc.). Such changes may affect the preparation or formulation of pharmaceutical compositions of different doses or delivery forms (e.g., solid oral dosage forms, including tablets and capsules). Compared with other forms such as non-crystalline or amorphous forms, polymorphs can provide desired or suitable hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, reproducibility and / or process control. Therefore, polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide can provide improved manufacturing processes of active agents or stability or storage of active agent drug product forms, or have the advantages of being suitable for use as active agents. Bioavailability and / or stability. In some embodiments, the aficontan in the formulation, such as a tablet, is one of polymorphic forms I, form II, form III, form IV, form V or form VI or a combination thereof. In some embodiments, aficontan is one of polymorphic Form I, Form II, Form III, Form IV, Form V, or Form VI. In some embodiments, aficontan is polymorphic Form I or Form IV. In some embodiments, aficontan is polymorphic Form I. In some embodiments, aficontan is polymorphic Form IV.

[0264] Form I

[0265] In some embodiments, aficontan is a polymorphic Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. The 2-θ angles and relative peak intensities of Form I observable using XRPD are shown in Table P-1. In some embodiments, Form I has substantially Fig.59A XRPD pattern shown.

[0266] Table P-1

[0267]

[0268] In some embodiments, polymorph Form I has an XRPD pattern that exhibits at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks at 2-theta angles with maximum intensity in the XRPD pattern, substantially as described herein. Fig.59A As shown or as provided in Table P-1. It should be understood that relative intensities may vary according to a variety of factors, including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum. Relative peak intensities and peak attributions may vary within experimental error. In some embodiments, the peak attributions listed herein (including polymorphic form I) may vary by about ± 0.6 °, ± 0.4 °, ± 0.2 °, or ± 0.1 ° 2-θ.

[0269] In some embodiments, polymorph Form I has a molecular weight comprising 3.7±0.2, 11.2±0.2, 12.9±0.2, 13.5±0.2, 14.4±0.2, 14.9±0.2, 16.6±0.2, 17.8±0.2, 18.6±0.2, 21.6±0.2, 22.2±0.2, 22.4±0.2, 22.8±0.2, 23.2±0.2, 23.9±0. XRPD pattern of peaks at 2-θ angles of 2, 24.4±0.2, 24.7±0.2, 25.0±0.2, 25.8±0.2, 26.1±0.2, 28.6±0.2, 29.0±0.2, 29.4±0.2, 29.9±0.2, 30.6±0.2, 33.8±0.2, 36.1±0.2, 36.8±0.2, 37.8±0.2, and 39.8±0.2°. In some embodiments, polymorph Form I has an XRPD pattern comprising peaks at 2-θ angles of 3.7 ± 0.2, 11.2 ± 0.2, 12.9 ± 0.2, 13.5 ± 0.2, 14.4 ± 0.2, 18.6 ± 0.2, 22.4 ± 0.2, 24.7 ± 0.2, 25.0 ± 0.2, and 26.1 ± 0.2°. In some embodiments, polymorph Form I has an XRPD pattern comprising peaks at 2-θ angles of 3.7 ± 0.2, 11.2 ± 0.2, 12.9 ± 0.2, 14.4 ± 0.2, and 22.4 ± 0.2°. It should be understood that in addition to the XRPD pattern, peaks at 2-θ angles of 2. Fig.59A Additional peaks beyond those shown in or provided in Table P-1 may be due, for example, to the presence of impurities, solvents or other polymorphs or amorphous forms in the tested samples.

[0270] In some embodiments, Form I has substantially Fig.59BIn some embodiments, Form I is characterized by an endotherm with an onset of about 199° C., as determined by DSC. In some embodiments, Form I is characterized by an endotherm with an onset of about 199° C., as determined by DSC. In some embodiments, Form I is characterized by an endotherm with an onset of about 199° C., as determined by DSC.

[0271] In some embodiments, Form I has substantially Fig.59B TGA graph shown.

[0272] In some embodiments, Form I has substantially Fig.59C The DVS diagram shown.

[0273] 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:

[0274] (a) Form I has an XRPD pattern comprising peaks at 2-θ angles of 3.7±0.2, 11.2±0.2, 12.9±0.2, 14.4±0.2, and 22.4±0.2°; (b) Form I has an XRPD pattern comprising peaks at 2-θ angles of 3.7±0.2, 11.2±0.2, 12.9±0.2, 13.5±0.2, 14.4±0.2, 18.6±0.2, 22.4±0.2, 24.7±0.2, 25.0±0.2, and 26.1±0.2 °; or an XRPD pattern comprising a peak at a 2-θ angle of 3.7±0.2, 11.2±0.2, 12.9±0.2, 13.5±0.2, 14.4±0.2, 14.9±0.2, 16.6±0.2, 17.8±0.2, 18.6±0.2, 21.6±0.2, 22.2±0.2, 22.4±0.2, 22.8±0.2, 23.2±0.2, 23.9±0. 2, XRPD pattern of peaks at 2-θ angles of 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°;

[0275] (b) Form I has substantially Fig.59A The XRPD pattern shown in;

[0276] (c) Form I has substantially the following Fig.59B The DSC diagram shown in;

[0277] (d) Form I is characterized by an endotherm with an onset of about 199°C as determined by DSC;

[0278] (e) Form I has substantially the following Fig.59B The TGA graph shown in ; and

[0279] (f) Form I has substantially Fig.59C The DVS diagram shown in .

[0280] Form II

[0281] In some embodiments, aficontan is a polymorphic form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. The 2-θ angles and relative peak intensities of Form II observable using XRPD are shown in Table P-2. In some embodiments, Form II has substantially Fig.60A XRPD pattern shown in .

[0282] Table P-2

[0283]

[0284] In some embodiments, polymorph Form II has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks at °2-θ with maximum intensity in the XRPD pattern, substantially as Fig.60A As shown or as provided in Table P-2. It should be understood that relative intensity can vary according to a variety of factors, including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum. Relative peak intensity and peak attribution can vary within the experimental error range. In some embodiments, the peak attribution listed herein (including polymorphic form II) can vary by about ± 0.6 °, ± 0.4 °, ± 0.2 ° or ± 0.1 ° 2-θ.

[0285] In some embodiments, polymorph Form II has an XRPD pattern comprising peaks at 2-theta angles of 3.7±0.2, 7.4±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, 13.5±0.2, 14.4±0.2, 14.7±0.2, 16.1±0.2, 17.0±0.2, 18.5±0.2, 20.4±0.2, 21.6±0.2, 22.3±0.2, 23.3±0.2, 24.0±0.2, 24.3±0.2, 24.8±0.2, 25.8±0.2, 27.4±0.2, 28.8±0.2, 29.5±0.2, and 30.5±0.2°. In some embodiments, polymorph Form II has an XRPD pattern comprising peaks at 2-θ angles of 3.7 ± 0.2, 9.8 ± 0.2, 11.1 ± 0.2, 12.8 ± 0.2, 14.7 ± 0.2, 16.1 ± 0.2, 18.5 ± 0.2, 20.4 ± 0.2, 22.3 ± 0.2, and 23.3 ± 0.2°. In some embodiments, polymorph Form II has an XRPD pattern comprising peaks at 2-θ angles of 3.7 ± 0.2, 9.8 ± 0.2, 11.1 ± 0.2, 12.8 ± 0.2, and 20.4 ± 0.2°. It should be understood that in addition to the XRPD pattern, it can also be observed that Fig.60A Additional peaks beyond those shown in or provided in Table P-2 may be due, for example, to the presence of impurities, solvents or other polymorphs or amorphous forms in the tested samples.

[0286] In some embodiments, Form II has substantially Fig.60B In some embodiments, Form II is characterized by an endothermic onset at about 199°C, as determined by DSC. In some embodiments, Form II is characterized by an endothermic onset at about 199±2°C (e.g., 199±1.9°C, 199±1.8°C, 199±1.7°C, 199±1.6°C, 199±1.5°C, 199±1.4°C, 199±1.3°C, 199±1.2°C, 199±1°C, 199±0.9°C, 199±0.8°C, 199±0.7°C, 199±0.6°C, 199±0.5°C, 199±0.4°C, 199±0.3°C, 199±0.2°C, or 199±0.1°C), as determined by DSC.

[0287] In some embodiments, Form II has substantially Fig.60B TGA graph shown in .

[0288] 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:

[0289] (a) Form II has an XRPD pattern comprising peaks at 2-θ angles of 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, and 20.4±0.2°; an XRPD pattern comprising peaks at 2-θ angles of 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, 14.7±0.2, 16.1±0.2, 18.5±0.2, 20.4±0.2, 22.3±0.2, and 23.3±0.2°; or an XRPD pattern comprising peaks at 2-θ angles of 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, 14.7±0.2, 16.1±0.2, 18.5±0.2, 20.4±0.2, 22.3±0.2, and 23.3±0.2°. an XRPD pattern of peaks at 2-θ angles of 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;

[0290] (b) Form II has substantially the following Fig.60A The XRPD pattern shown in;

[0291] (c) Form II has substantially the following Fig.60B The DSC diagram shown in;

[0292] (d) Form II is characterized by a melting endotherm with an onset of about 199°C as determined by DSC; and

[0293] (e) Form II has substantially the following Fig.60B TGA graph shown in .

[0294] Form III

[0295] In some embodiments, aficontan is a polymorphic form III of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. The 2-θ angles and relative peak intensities of the mixture of forms I and III observable using XRPD are shown in Table P-3. In some embodiments, the mixture of forms I and III has substantially Fig.61A XRPD pattern shown in .

[0296] Table P-3

[0297]

[0299] In some embodiments, polymorph Form III has an XRPD pattern comprising peaks at 2-θ angles of 9.6 ± 0.2, 10.9 ± 0.2, 15.8 ± 0.2, and 18.1 ± 0.2°. In some embodiments, polymorph Form III has an XRPD pattern comprising peaks at 2-θ angles of 9.6 ± 0.2, 10.9 ± 0.2, 14.5 ± 0.2, 15.8 ± 0.2, and 18.1 ± 0.2°. In some embodiments, polymorph Form III has an XRPD pattern comprising peaks at 2-θ angles of 9.6 ± 0.2, 10.9 ± 0.2, 14.5 ± 0.2, 15.8 ± 0.2, 18.1 ± 0.2, and 20.2 ± 0.2°. It should be understood that relative intensities may vary according to a variety of factors, including sample preparation, mounting, and the instrument and analysis procedures and settings used to obtain the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein (including polymorph Form III) may vary by about ±0.6°, ±0.4°, ±0.2°, or ±0.1° 2-θ.

[0300] In some embodiments, the mixture of polymorphic forms I and III has substantially Fig.61B DSC graph shown in .

[0301] In some embodiments, the mixture of polymorphic forms I and III has substantially Fig.61B TGA graph shown in .

[0302] Form IV

[0303] In some embodiments, aficontan is a polymorphic form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. The 2-θ angles and relative peak intensities of Form IV observable using XRPD are shown in Table P-4. In some embodiments, Form IV has substantially Fig.62A XRPD pattern shown in .

[0304] Table P-4

[0305]

[0306]

[0307] In some embodiments, polymorph Form IV has an XRPD pattern that exhibits at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks at 2-theta angles with maximum intensity in the XRPD pattern, substantially as Fig.62AAs shown or as provided in Table P-4. It should be understood that relative intensities may vary according to a variety of factors, including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum. Relative peak intensities and peak attributions may vary within experimental error. In some embodiments, the peak attributions listed herein (including polymorphic form IV) may vary by about ± 0.6 °, ± 0.4 °, ± 0.2 °, or ± 0.1 ° 2-θ.

[0308] In some embodiments, polymorph Form IV has a density comprising 3.7±0.2, 7.7±0.2, 11.1±0.2, 12.4±0.2, 12.8±0.2, 13.5±0.2, 14.3±0.2, 15.5±0.2, 16.6±0.2, 17.9±0.2, 18.5±0.2, 18.6±0.2, 19.1±0.2, 19.9±0.2, 20.9±0.2, 21.5±0.2, 21.6±0.2, 21.9±0.2, 22.3±0.2, 22.4±0.2, 22.8±0.2, 23.1±0.2, 23.5±0.2, 23.9±0. 2, 24.4±0.2, 24.8±0.2, 25.0±0.2, 25.3±0.2, 25.8±0.2, 26.2±0.2, 27.1±0.2, 27.4±0.2, 28.0±0.2, 28.6±0.2, 29.0±0.2, 30.0±0.2, 30.5±0.2, 30.8±0.2, 31.0±0.2, 31.4±0.2, 33.8±0.2, 35.0±0.2, 35.7±0.2, 36.1±0.2, 36.7±0.2, 37.9±0.2, 38.1±0.2, and 39.8±0.2. In some embodiments, polymorph Form IV has an XRPD pattern comprising peaks at 2-θ angles of 3.7 ± 0.2, 11.1 ± 0.2, 12.8 ± 0.2, 13.5 ± 0.2, 21.9 ± 0.2, 22.8 ± 0.2, 23.1 ± 0.2, 23.5 ± 0.2, 24.4 ± 0.2, and 24.8 ± 0.2°. In some embodiments, polymorph Form IV has an XRPD pattern comprising peaks at 2-θ angles of 11.1 ± 0.2, 12.8 ± 0.2, 13.5 ± 0.2, 22.8 ± 0.2, and 24.4 ± 0.2°. It should be understood that in addition to the XRPD pattern, peaks at 2-θ angles of 24.4 ± 0.2° may also be observed. Fig.62A Additional peaks beyond those shown in or provided in Table P-4 may be due, for example, to the presence of impurities, solvents or other polymorphs or amorphous forms in the tested samples.

[0309] In some embodiments, Form IV has substantially Fig.62BIn some embodiments, Form IV is characterized by an onset of endothermic absorption at about 200°C, as determined by DSC. In some embodiments, Form IV is characterized by an onset of endothermic absorption 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.

[0310] In some embodiments, Form IV has substantially Fig.62B TGA graph shown in .

[0311] In some embodiments of Form IV, at least one, at least two, at least three, at least four, or all of the following (a)-(e) apply:

[0312] (a) Form IV has an XRPD pattern having peaks at 2-θ angles of 11.1±0.2, 12.8±0.2, 13.5±0.2, 22.8±0.2, and 24.4±0.2°; (b) Form IV has an XRPD pattern having peaks at 2-θ angles of 3.7±0.2, 11.1±0.2, 12.8±0.2, 13.5±0.2, 21.9±0.2, 22.8±0.2, 23.1±0.2, 23.5±0.2, 24.4±0.2, and 24.8±0.2°; or an XRPD pattern comprising a peak at a 2-θ angle of 0.2°; or a peak at a 2-θ angle of 3.7±0.2, 7.7±0.2, 11.1±0.2, 12.4±0.2, 12.8±0.2, 13.5±0.2, 14.3±0.2, 15.5±0.2, 16.6±0.2, 17.9±0.2, 18.5±0.2, 18.6±0.2, 19.1±0.2, 19.9±0.2, 20.9±0.2, 21.3±0.2, 22.4±0.2, 23.5±0.2, 24.6±0.2, 25.7±0.2, 26.8±0.2, 27.9±0.2, 28.6±0.2, 29. 1.5±0.2, 21.6±0.2, 21.9±0.2, 22.3±0.2, 22.4±0.2, 22.8±0.2, 23.1±0.2, 23.5±0.2, 23.9±0.2, 24.4±0.2, 24.8±0.2, 25.0±0.2, 25.3±0.2, 25.8±0.2, 26.2±0.2, 27.1±0.2, 27.4±0.2, 28. XRPD pattern of peaks at 2-θ angles of 0 ± 0.2, 28.6 ± 0.2, 29.0 ± 0.2, 30.0 ± 0.2, 30.5 ± 0.2, 30.8 ± 0.2, 31.0 ± 0.2, 31.4 ± 0.2, 33.8 ± 0.2, 35.0 ± 0.2, 35.7 ± 0.2, 36.1 ± 0.2, 36.7 ± 0.2, 37.9 ± 0.2, 38.1 ± 0.2, 39.8 ± 0.2°;

[0313] (b) Form IV has substantially the following Fig.62A The XRPD pattern shown in;

[0314] (c) Form IV has substantially the following Fig.62B The DSC diagram shown in;

[0315] (d) Form IV is characterized by a melting endotherm with an onset of about 200°C as determined by DSC; and

[0316] (e) Form IV has substantially the following Fig.62B TGA graph shown in .

[0317] Form V

[0318] In some embodiments, aficontan is a polymorphic Form V of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. The 2-θ angles and relative peak intensities of Form V observable using XRPD are shown in Table P-5. In some embodiments, Form V has substantially Fig.63 XRPD pattern shown in .

[0319] Table P-5

[0320]

[0321]

[0322] In some embodiments, polymorph Form V has an XRPD pattern that exhibits at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks at 2-theta angles with maximum intensity in the XRPD pattern, substantially as described herein. Fig.63 As shown or as provided in Table P-5. It should be understood that relative intensity can vary according to a variety of factors, including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum. Relative peak intensity and peak attribution can vary within the experimental error range. In some embodiments, the peak attribution listed herein (including polymorph form V) can vary by about ± 0.6 °, ± 0.4 °, ± 0.2 ° or ± 0.1 ° 2-θ.

[0323] In some embodiments, polymorph Form V has an XRPD pattern comprising peaks at the following 2-theta angles: 5.7±0.2, 8.3±0.2, 11.5±0.2, 13.8±0.2, 15.5±0.2, 15.8±0.2, 16.3±0.2, 16.6±0.2, 17.2±0.2, 17.8±0.2, 18.5±0.2, 18.9±0.2, 19.1±0.2, 19.8±0.2, 20.0±0.2, 20.2 ±0.2, 20.7±0.2, 21.2±0.2, 21.6±0.2, 23.0±0.2, 23.1±0.2, 23.3±0.2, 24.0±0.2, 24.2±0.2, 24.3±0.2, 24.6±0.2, 24.7±0.2, 25.2±0.2, 25.6±0.2, 26.7±0.2, 27.1±0.2, 27.3±0.2, 27.5±0.2, 27.9±0.2, 28.1±0.2 .2, 28.4±0.2, 28.9±0.2, 29.2±0.2, 29.7±0.2, 29.8±0.2, 29.9±0.2, 30.4±0.2, 30.6±0.2, 31.1±0.2, 31.3±0.2, 31.5±0.2, 32.0±0.2, 32.9±0.2, 33.0±0.2, 33.2±0.2, 33.5±0.2, 34.4±0.2, 34.6±0.2, 34.9±0.2 , 35.3±0.2, 35.7±0.2, 36.0±0.2, 36.2±0.2, 36.5±0.2, 36.6±0.2, 37.0±0.2, 37.1±0.2, 37.5±0.2, 37.8±0.2, 37.9±0.2, 38.3±0.2, 38.4±0.2, 38.7±0.2, 38.8±0.2, 39.3±0.2, 39.4±0.2, 39.6±0.2, and 39.9±0.2°. In some embodiments, polymorph Form V has an XRPD pattern comprising peaks at 2-theta angles of 5.7±0.2, 8.3±0.2, 11.5±0.2, 16.3±0.2, 17.2±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 20.7±0.2, 21.2±0.2, 23.3±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, 26.7±0.2, 28.1±0.2, 29.2±0.2, 29.7±0.2, 29.9±0.2, and 31.1±0.2.In some embodiments, polymorph Form V has an XRPD pattern comprising peaks at 2-θ angles of 11.5 ± 0.2, 16.3 ± 0.2, 19.1 ± 0.2, 20.0 ± 0.2, 20.2 ± 0.2, 21.2 ± 0.2, 24.0 ± 0.2, 24.7 ± 0.2, 25.6 ± 0.2, and 26.7 ± 0.2°. In some embodiments, polymorph Form V has an XRPD pattern comprising peaks at 2-θ angles of 11.5 ± 0.2, 16.3 ± 0.2, 20.0 ± 0.2, 21.2 ± 0.2, and 24.7 ± 0.2°. It should be understood that in addition to the XRPD pattern, it may also be observed. Fig.63 Additional peaks beyond those shown in or provided in Table P-5 may be due, for example, to the presence of impurities, solvents or other polymorphs or amorphous forms in the tested samples.

[0324] In some embodiments of Form V, at least one or both of the following (a)-(b) apply:

[0325] (a) Form V has an XRPD pattern comprising peaks at 2-θ angles of 11.5±0.2, 16.3±0.2, 20.0±0.2, 21.2±0.2, and 24.7±0.2°; an XRPD pattern comprising peaks at 2-θ angles of 11.5±0.2, 16.3±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 21.2±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, and 26.7±0.2°; or an XRPD pattern comprising peaks at 2-θ angles of 5.7±0.2, an XRPD pattern having peaks at 2-theta angles of 8.3±0.2, 11.5±0.2, 16.3±0.2, 17.2±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 20.7±0.2, 21.2±0.2, 23.3±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, 26.7±0.2, 28.1±0.2, 29.2±0.2, 29.7±0.2, 29.9±0.2, and 31.1±0.2 degrees; and

[0326] (b) Form V has substantially Fig.63 XRPD pattern shown in .

[0327] Form VI

[0328] In some embodiments, aficontan is a polymorphic form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. The 2-θ angles and relative peak intensities of Form VI observable using XRPD are shown in Table P-6. In some embodiments, Form VI has substantially Fig.64A XRPD pattern shown in .

[0329] Table P-6

[0330]

[0331]

[0332] In some embodiments, polymorph Form VI has an XRPD pattern that exhibits at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks at 2-θ angles with maximum intensity in the XRPD pattern, substantially as Fig.64A As shown or as provided in Table P-6. It should be understood that relative intensity can vary according to a variety of factors, including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum. Relative peak intensity and peak attribution can vary within the experimental error range. In some embodiments, the peak attribution listed herein (including polymorphic form VI) can vary by about ± 0.6 °, ± 0.4 °, ± 0.2 ° or ± 0.1 ° 2-θ.

[0333] In some embodiments, polymorph Form VI has a molecular weight comprising 3.0±0.2, 5.0±0.2, 5.4±0.2, 5.9±0.2, 7.2±0.2, 8.1±0.2, 8.9±0.2, 9.6±0.2, 9.9±0.2, 10.6±0.2, 12.1±0.2, 13.3±0.2, 14.0±0.2, 14.4 ±0.2, 14.7±0.2, 15.0±0.2, 15.4±0.2, 16.1±0.2, 16.5±0.2, 17.8±0.2, 18.9±0.2, 19.0±0.2, 19.2±0.2, 19.6±0.2, 20.0±0.2, 20.3±0.2, 20.7±0.2, 21.1±0.2, 2 1.9±0.2, 22.6±0.2, 22.9±0.2, 23.6±0.2, 23.8±0.2, 24.4±0.2, 24.8±0.2, 25.5±0.2, 26.4±0.2, 26.7±0.2, 27.3±0.2, 27.6±0.2, 28.2±0.2, 28.5±0.2, 29.0±0. In some embodiments, polymorph Form VI has an XRPD pattern comprising peaks at 2-θ angles of 5.4±0.2, 5.9±0.2, 8.1±0.2, 9.6±0.2, 10.6±0.2, 12.1±0.2, 14.0±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2°. In some embodiments, polymorph Form VI has an XRPD pattern comprising peaks at 2-θ angles of 10.6 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 16.1 ± 0.2, and 17.8 ± 0.2°. It should be understood that peaks at 2-θ angles other than 10.6 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 16.1 ± 0.2, and 17.8 ± 0.2° may also be observed in the XRPD pattern. Fig.64A Additional peaks beyond those shown in or provided in Table P-6 may be due, for example, to the presence of impurities, solvents or other polymorphs or amorphous forms in the tested samples.

[0334] In some embodiments, Form VI has substantially Fig.64B The TGA diagram shown in or substantially as Fig.64C In some embodiments, Form VI exhibits a weight loss of about 2% ± 0.5% between 25°C and 200°C as determined by TGA.

[0335] In some embodiments, Form VI has substantially Fig.64D The DSC diagram shown in or substantially as shown in Fig.64E In some embodiments, Form VI is characterized by an endothermic onset at about 200±2°C (e.g., 200±1.9°C, 200±1.8°C, 200±1.7°C, 200±1.6°C, 200±1.5°C, 200±1.4°C, 200±1.3°C, 200±1.2°C, 200±1, 200±0.9°C, 200±0.8°C, 200±0.7°C, 200±0.6°C, 200±0.5°C, 200±0.4°C, 200±0.3°C, 200±0.2°C, or 200±0.1°C) as determined by DSC. In some embodiments, Form VI is characterized by an endotherm with an 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) and a peak at about 115±2°C. (e.g., 115±1.9°C, 115±1.8°C, 115±1.7°C, 115±1.6°C, 115±1.5°C, 115±1.4°C, 115±1.3°C, 115±1.2°C, 115±1, 115±0.9°C, 115±0.8°C, 115±0.7°C, 115±0.6°C, 115±0.5°C, 115±0.4°C, 115±0.3°C, 115±0.2°C or 115±0.1°C), or at about 41±2°C. (e.g., 41±1.9°C, 41±1.8°C, 41±1.7°C, 41±1.6°C, 41±1.5°C, 41±1.4°C, 41±1.3°C, 41±1.2°C, 41±1, 41±0.9°C, 41±0.8°C, 41±0.7°C, 41±0.6°C, 41±0.5°C, 41±0.4°C, 41±0.3°C, 41±0.2°C or 41±0.1°C), or any combination thereof.

[0336] In some embodiments of Form VI, at least one, at least two, at least three, at least four, at least five, at least six, or all of the following (a)-(g) apply:

[0337] (a) Form VI has an XRPD pattern comprising peaks at 2-θ angles of 10.6±0.2, 12.1±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2°; an XRPD pattern comprising peaks at 2-θ angles of 5.4±0.2, 5.9±0.2, 8.1±0.2, 9.6±0.2, 10.6±0.2, 12.1±0.2, 14.0±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2°; or including 3.0±0.2, 5.0±0.2, 5.4±0.2, 5.9±0.2, 7.2±0.2, 8.1±0.2, 8.9±0.2, 9.6±0.2, 9.9±0.2, 10.6±0.2, 12.1±0.2, 13.3±0.2, 14.0±0.2, 14.4±0.2, 14.7±0.2, 15.0±0.2, 15.4±0.2, 16.1±0.2, 16.5±0.2, 17.8±0. .2, 18.9±0.2, 19.0±0.2, 19.2±0.2, 19.6±0.2, 20.0±0.2, 20.3±0.2, 20.7±0.2, 21.1±0.2, 21.9±0.2, 22.6±0.2, 22.9±0.2, 23.6±0.2, 23.8±0.2, 24.4±0.2, 24.8±0.2, 25.5±0.2, 26.4±0.2, 26.7±0.2, 27.3±0. XRPD pattern of peaks at 2-θ angles of .2, 27.6±0.2, 28.2±0.2, 28.5±0.2, 29.0±0.2, 29.6±0.2, 29.9±0.2, 30.4±0.2, 30.9±0.2, 31.6±0.2, 32.2±0.2, 32.6±0.2, 33.1±0.2, 33.3±0.2, 34.5±0.2, 35.0±0.2, 35.5±0.2, and 38.5±0.2;

[0338] (b) Form VI has substantially the following Fig.64A The XRPD pattern shown in;

[0339] (c) Form VI has substantially the following Fig.64B or Fig.64C TGA graph shown in .

[0340] (d) Form VI has a weight loss of about 2% ± 0.5% between 25 °C and 200 °C as determined by TGA;

[0341] (e) Form VI has substantially the following Fig.64D or Fig.64E The DSC graph shown in ; and

[0342] (f) Form IV is characterized by a melting endotherm with an onset of about 200°C as determined by DSC; and

[0343] (g) Form VI is characterized by an endotherm with an onset at about 200°C, an exotherm with an onset at about 115°C, or an endotherm with an onset at about 41°C, or any combination thereof, as determined by DSC.

[0344] Pill Box

[0345] Also provided are articles and kits containing any of the compounds or pharmaceutical compositions provided herein. The articles may include containers with labels. Suitable containers include, for example, bottles, vials, and test tubes. The containers may be formed of a variety of materials, such as glass or plastic. The containers may hold the pharmaceutical compositions provided herein. The label on the container may indicate that the pharmaceutical composition is used to prevent, treat, or inhibit a disorder described herein, and may also indicate instructions for in vivo or in vitro use.

[0346] In one aspect, provided herein are kits containing a compound or composition as described herein and instructions for use. The kit may contain instructions for treating a heart disease in an individual or subject in need thereof. The kit may additionally contain any materials or equipment that can be used to administer the compound or composition, such as vials, syringes, or IV bags. The kit may also contain sterile packaging.

[0347] In some embodiments, the present disclosure provides a method for manufacturing a medicament comprising aficontan, the method comprising:

[0348] manufacturing a first batch of tablets in which the amount of aficontan (which may be present in various forms) is about the first daily dose or about half of the first daily dose;

[0349] manufacturing a second batch of tablets wherein the amount of aficontan (which may be present in various forms) is about the second daily dose or about half of the second daily dose;

[0350] Optionally manufacturing a third batch of tablets wherein the amount of aficontan (which may be present in various forms) is about the third daily dose or about half of the third daily dose; and

[0351] Optionally, a fourth batch of tablets is manufactured in which the amount of aficontan (which may be present in various forms) is about the fourth daily dose or about half the fourth daily dose.

[0352] In some embodiments, the method comprises manufacturing a third batch of tablets, wherein the amount of aficontan (which may be present in various forms) is about the third daily dose or about half of the third daily dose. In some embodiments, the method comprises manufacturing a fourth batch of tablets, wherein the amount of aficontan (which may be present in various forms) is about the fourth daily dose or about half of the fourth daily dose.

[0353] In some embodiments, the present disclosure provides a method for manufacturing a medicament comprising aficontan, the method comprising:

[0354] manufacturing a first batch of tablets in which the amount of aficontan (which may be present in various forms) is about the first daily dose;

[0355] manufacturing a second batch of tablets in which the amount of aficontan (which may be present in various forms) is about the second daily dose;

[0356] optionally manufacturing a third batch of tablets wherein the amount of aficontan (which may be present in various forms) is about the third daily dose; and

[0357] Optionally, a fourth batch of tablets is manufactured in which the amount of aficontan (which may be present in various forms) is about the fourth daily dose.

[0358] In some embodiments, the method comprises manufacturing a third batch of tablets, wherein the amount of aficontan (which may be present in various forms) is about the third daily dose. In some embodiments, the method comprises manufacturing a fourth batch of tablets, wherein the amount of aficontan (which may be present in various forms) is about the fourth daily dose.

[0359] Various first, second, third, and fourth daily doses are described herein. In some embodiments, the daily dose is about 5 mg of aficontan. In some embodiments, the first daily dose is about 5 mg of aficontan. In some embodiments, the daily dose is about 10 mg of aficontan. In some embodiments, the daily dose is about 15 mg of aficontan. In some embodiments, the daily dose is about 20 mg of aficontan. In some embodiments, tablets with at least two different daily doses are manufactured. In some embodiments, tablets are manufactured in which the amount of aficontan (which can exist in various forms) is about 15 mg. In some embodiments, tablets are manufactured in which the amount of aficontan (which can exist in various forms) is about 2.5 mg. In some embodiments, tablets are manufactured in which the amount of aficontan (which can exist in various forms) is about 7.5 mg. It will be appreciated by those skilled in the art that in addition to aficontan, tablets may also include various other components described herein, such as fillers, binders, disintegrants, surfactants, lubricants, etc. In some embodiments, the tablets are film-coated.

[0360] Example

[0361] 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, however, they should never be construed as limiting the wide scope of the present application. Although some embodiments of the present application have been shown and described herein, it should be apparent that such embodiments are provided only by way of example. Without departing from the spirit and scope of the present invention, those skilled in the art may make many changes, modifications and substitutions. It should be understood that various alternatives to the embodiments described herein may be adopted when practicing the methods described herein.

[0362] Example 1

[0363] This first-in-human study of aficontan (also known as CK-274) was conducted to evaluate its safety, pharmacokinetics, and pharmacodynamic profile, including the effects of food or CYP2D6 poor metabolizer (CYP2D6-PM) phenotype. Aficontan is a selective cardiac myosin inhibitor that reduces preclinical measures of left ventricular contractility in vitro and in vivo, and may therefore have therapeutic potential for the management of obstructive hypertrophic cardiomyopathy. This Phase 1, double-blind, randomized, placebo-controlled study enrolled healthy adults aged 18 to 55 years to receive single ascending doses or multiple ascending doses (14 or 17 days) of aficontan or placebo. In addition to standard safety and pharmacokinetic assessments, pharmacodynamic effects were assessed by echocardiography. The study enrolled 102 participants (57 in the single-dose cohort, 24 in the multiple-dose cohort, 9 in the CYP2D6-PM cohort, and 12 in the food effect cohort). Adverse events were generally mild and no more frequent than placebo at single doses ≤50 mg and multiple doses ≤10 mg of aficontan. In the single ascending dose cohort, plasma concentrations of aficontan increased in a dose-proportional manner; the half-life of aficontan is 75 h to 85 h. Neither food nor CYP2D6-PM phenotype had a clinically meaningful effect on pharmacokinetics. With a single 50-mg dose, mean left ventricular ejection fraction (LVEF) decreased by 5.5% from baseline (p=0.0001). With multiple doses, a mean LVEF decrease of 5.0% was observed after 10 mg of aficontan once daily for 14 days. Aficontan appears to be safe and well tolerated at the doses evaluated. A pharmacodynamic effect on LVEF was demonstrated, which supports further clinical studies of aficontan.

[0364] method

[0365] Study Overview and Ethics. The study used a randomized, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) design ( Figure 2The study was not designed to determine a maximum tolerated dose, but rather to determine a pharmacologically active dose range, defined as giving an absolute decrease in left ventricular ejection fraction (LVEF) from baseline within the range of 5% to 15% (e.g., a decrease from a baseline LVEF value of 70% to between 55% and 65%). Dose escalation should be stopped when this range is reached, or when a non-tolerated dose is identified (if earlier).

[0366] Participants and Treatment. To be eligible for this study, participants were healthy adults aged 18 to 55 years with a body mass index of 18.0 to 32.0 kg / m 2 , with normal electrocardiogram (ECG) and clinical laboratory values, or only mild abnormalities that were considered clinically insignificant. Participants also had to have normal cardiac structure and function, LVEF ≥60% for the first 4 SAD cohorts, LVEF ≥65% for the subsequent SAD cohorts, all MAD cohorts, and food effect cohorts, and LVEF ≥55% for the CYP2D6-PM cohort. Participants were not allowed to use any prescription medications within 14 days, over-the-counter medications (except acetaminophen) within 7 days, or tobacco or nicotine within 3 months before the study; in addition, they were not allowed to consume alcohol, caffeine, or grapefruit within 48 hours before study enrollment.

[0367] The randomization schedule was generated centrally for each cohort and treatment period. In all cohorts, aficontan or matching placebo was administered in granular form as capsules containing approximately 240 ml of water. Study medication was administered after an overnight fast, except during the feeding period in the food-effect cohort.

[0368] Single ascending dose (SAD) cohorts. The SAD portion of the study used a randomized, double-blind, placebo-controlled, sequential, ascending dose design in which participants received single ascending oral doses of study medication. The 7 cohorts were dosed sequentially ( Figure 2 Of the 8 participants within each cohort, the first 2 were randomized (1:1) to aficontan or placebo and followed for a minimum of 2 days before dosing the remaining participants in that group. The remaining 6 participants were then randomized (5:1) to receive a single oral dose of aficontan (1 mg, 3 mg, 10 mg, 25 mg, 40 mg, 50 mg, or 75 mg) or placebo.

[0369] The initial dose of aficontan was selected using criteria based on previous animal studies and United States Food and Drug Administration guidelines with a safety margin of ≥10-fold. Dose escalation will be stopped when results determine a pharmacologically active dose range that results in a 5% to 15% decrease in LVEF or a non-tolerable dose, whichever occurs first.

[0370] Recommendations for dose escalation for the SAD cohort and the MAD cohort described below were made by the treating investigator (who was blinded to treatment group) and approved or disapproved by the unblinded Dose Level Review Committee (DLRC). Decisions were made when ≥6 participants had been treated and followed for ≥3 days, including the collection of clinical, laboratory, ECG, and telemetry data and appropriate assessment of maximum plasma drug concentrations (C 最大 ). Escalation criteria included no more than 2 participants in a dose group experiencing an LVEF <50% and no individual experiencing an LVEF <45%. Dose escalation criteria were as follows: (1) the individual did not have ongoing cardiac serious adverse events related to study drug; (2) 2 individuals did not experience similar non-cardiac serious adverse events in the same organ system that appeared to be related to study drug; (3) 2 individuals treated with afibactam did not experience a decrease in left ventricular ejection fraction (LVEF) >15% compared to the last pre-dose value (determined by the Dose Level Review Committee [DLRC]); (4) no individual experienced an LVEF <45% (unless determined by the DLRC and treating investigator to be unrelated to study drug); and (5) the treating investigator and DLRC approved the escalation and next dose level based on their clinical judgment.

[0371] Multiple ascending dose (MAD) cohorts. The MAD cohorts also used a randomized, double-blind, placebo-controlled, sequential design. Enrollment in the MAD cohorts began when the SAD cohort determined a single oral dose that was well tolerated and associated with the observed PD effects. Each of the 3 MAD cohorts included 8 participants who were randomized (6:2) to aficontan or placebo. Participants received a once-daily oral dose of study drug for 14 days (in cohorts comparing 5 or 10 mg aficontan to placebo) or 17 days (for cohorts comparing 7.5 mg aficontan to placebo).

[0372] CYP2D6 Poor Metabolizer Cohort. A separate cohort was included to evaluate the potential impact of CYP2D6 genetic variants on the PK properties of aficontan. The CYP2D6 gene encodes the cytochrome P450 2D6 enzyme, which is described as the most extensively characterized polymorphic drug-metabolizing enzyme, and previous in vitro studies have implicated CYP2D6 as a potential metabolizer of aficontan.

[0373] CYP2D6 genotype was determined at screening of all study participants; participants identified as CYP2D6-PM were excluded from the SAD and MAD cohorts but were invited to participate in the CYP2D6-PM cohort. Figure 2 Each participant received a single dose of afecontan (10 mg) or placebo. Nine participants were randomized (7:2), with the sentinel dosing group consisting of the first 2 participants treated.

[0374] Food Effect Cohort. To assess the effect of food on the PK of aficontan, a separate cohort was enrolled after completion of the last SAD cohort, with a planned enrollment of 8 to 12 participants. Participants received 2 single doses of 10 mg aficontan, separated by ≥14 days, in an open-label, 2-way crossover design. Participants were randomized in a 1:1 ratio to 1 of 2 sequences: fasted / fed or fed / fasted. During the fasting period, aficontan was administered after an overnight fast; during the fed period, aficontan was administered 30 minutes after the start of a high-fat breakfast.

[0375] Evaluate

[0376] Safety and tolerability. Safety is assessed according to the incidence of adverse events (AE) and the incidence of reduced LVEF. Treatment-emergent AE (TEAE) is defined as an AE that begins or increases after the study drug is administered. All AEs are coded using the Medical Dictionary for Regulatory Activities 21.1 version and graded using the National Cancer Institute CommonTerminology Criteria for AE (4.03 version) 5-point severity scale. Each AE is judged by the treating investigator to be related or unrelated to the study drug. Clinical laboratory tests are obtained at regular intervals in all cohorts.

[0377] For safety monitoring, participants in all cohorts undergo periodic echocardiograms assessed by cardiologists. In the SAD and MAD cohorts, echocardiograms are also reviewed by the echocardiogram core laboratory for PD assessment, as described below. In addition, Holter monitors are used to monitor participants in all cohorts with continuous 12-lead ECG recordings. For safety monitoring, single 12-lead ECGs are periodically extracted at screening, before dosing, and throughout follow-up, and interpreted by the investigator. In the SAD, MAD, and CYP2D6-PM cohorts, cardiac dynamics ECGs (triplicate 10 seconds, 12-lead ECG recordings) are obtained before the corresponding PK blood and ECG intervals quantified by qualified readers.

[0378] Pharmacokinetic Analysis. For all study groups, blood samples were obtained for PK assessments before dosing, up to 12 times daily on Day 1, and then at regular intervals throughout the study. Blood samples were collected according to the following schedule: SAD Cohort: Day 1: before and 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h, 36 h, 48 h, 72 h, 96 h, and 216 h after dosing. MAD cohort (14-day dosing): Day 1: before and 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, and 12 h after dosing; Days 2, 4, 5, 6, and 9: before (corresponding to trough samples after dosing on days 1, 3, 4, 5, and 8) and 1.5 h after dosing; Days 3, 7, 8, 10, 11, 12, and 13: before (corresponding to trough samples after dosing on days 2, 6, 7, 9, 10, 11, and 12); Day 14: before and 0.25 h, 0.5 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h after dosing h, 36 h, 48 h, 72 h and 168 h. MAD cohort (17 days of dosing): Day 1: before and 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, and 12 h after dosing; Days 2, 4, 5, 6, and 9: before (corresponding to trough samples after dosing on days 1, 3, 4, 5, and 8) and 1.5 h after dosing; Days 3, 7, 8, 10, 11, 12, 13, 14, 15, and 16: before (corresponding to trough samples after dosing on days 2, 6, 7, 9, 10, 11, and 12); Day 17: before and 0.25 h, 0.5 h, 1.5 h, 2 h, 2.5 h, 3 h, 5 h CYPD6-PM cohort: Day 1: before and 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h, 36 h, 48 h, 72 h, 96 h, 216 h, 312 h, and 552 h after dosing.Food effect cohort: Day 1: pre-dose and 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h, 36 h, 48 h, 72 h, 96 h, 144 h, and 216 h after dosing. Phoenix was used. ® WinNonlin ® Version 7.0 uses a standard non-compartmental approach to calculate PK parameters; actual sample collection times are used.

[0379] Plasma concentrations of aficontan were measured using a high performance liquid chromatography-tandem mass spectrometry method, the accuracy, precision, linearity, sensitivity and specificity of which were validated at Celerion (Lincoln, Nebraska). The analytical range (lower limit of quantitation to upper limit of quantitation) of aficontan was 1.00 ng / ml to 500 ng / ml.

[0380] Echocardiography. For PD assessment of LVEF, echocardiograms for the SAD and MAD cohorts were interpreted by an echocardiography core laboratory and used for all data analyses and dose-level review decisions, with immediate local interpretation of echocardiograms performed for safety monitoring. In the SAD cohort receiving 1 mg, 3 mg, or 10 mg of aficontan, echocardiograms were obtained on Day −1, predose on Day 1, and at 1.5 h, 4 h, and 24 h after dosing. For the SAD cohort receiving 25 mg, 40 mg, 50 mg, or 75 mg of aficontan, echocardiograms were obtained on Day −1, predose on Day 1, and at 1.5 h, 6 h, and 24 h after dosing. If the 24-h LVEF had not returned to near or above baseline, as determined by the investigator, an echocardiogram was obtained only on Day 3 (48 h after dosing). In the MAD cohort, echocardiograms were obtained on day −1, predose on day 1, and 1.5 h after dosing on days 2, 4, and 9, and 1.5 h, 24 h, and 72 h after dosing on day 14 (for the 5-mg and 10-mg cohorts) or 1.5 h, 24 h, and 72 h after dosing on day 17 (for the 7.5-mg cohort). If the participant's prior LVEF was not close to or above baseline, as determined by the investigator, an echocardiogram was obtained only 3 days after the last dose (day 17 or day 20).

[0381] Statistical Analysis. The sample size selected for this study was based on a precedent set of other first-in-human PK studies of similar nature and not on a power calculation. All participants who received ≥1 dose of study drug (aficontan or placebo) were included in the safety analysis. All participants who received ≥1 dose of study drug and had ≥1 evaluable PK plasma profile were included in the PK analysis set.

[0382] PK analyses were designed to assess single-dose kinetics, multiple-dose (steady-state) kinetics, the effects of CYP2D6 phenotype on the absorption and elimination of aficontan, and the effects of food on the absorption and elimination of aficontan. For the SAD cohort, a power model was used to assess dose proportionality of aficontan on day 1. For the MAD cohort, a power model was used to assess dose proportionality on day 1 and day 14 or 17. Several considerations were taken into account in assessing dose proportionality of the drug, such as results from statistical analysis of the power model (e.g., slope estimates and width of 2-sided 95% confidence intervals [CIs]), qualitative assessments of PK specific to the drug, and clinical relevance. For the SAD cohort, the parameter used to assess dose proportionality was the time from time 0 to the last measurable concentration (AUC 末次 ) of the plasma drug concentration-time curve (AUC), the AUC extrapolated from time 0 to infinity (AUC inf ), AUC from 0 to 24 h (AUC 24 ) and maximum plasma concentration (C 最大 ). For the MAD cohort, the parameter is AUC 24 and C on day 1 最大 , plus the AUC at the end of the dosing period (AUC tau ) and C on day 14 or 17 最大 By including the secondary (ln dose) 2 and three times (ln dose) 3 The statistical linear relationship between the ln-transformed PK parameter and the ln-transformed dose was verified by using the 5% significance level. If the quadratic and cubic effects were not statistically significant, or if the effects were statistically significant but of such small magnitude that they were not clinically relevant, a statistical linear relationship was established. SAS was used to analyze the relationship. ® Dose-proportional analysis was performed using PROC MIXED. Dose proportionality was established if a statistically linear relationship was shown and if the 2-sided 95% CI around the slope estimate parameter included a value of 1 for the dose-dependent parameter.

[0383] In the MAD cohort, Helmert contrast was used to compare ln-transformed plasma trough concentrations (C 谷) values ​​were used to perform steady-state analysis of aficontan. An analysis of variance (ANOVA) model was performed separately for each dose level; day was included as a fixed effect. Hemetic contrasts were developed so that the mean of each time point was compared to the mean of subsequent time points. Steady state was established at the time point where no statistical difference (α = 5%, 2-sided) was observed using subsequent time points.

[0384] All participants who received ≥1 dose of study drug and had ≥1 pre-dose and ≥1 post-dose echocardiogram were included in the PD analysis set. Descriptive analyses included absolute decrease in LVEF from baseline and categorical LVEF response (proportion of participants with LVEF decrease from baseline of ≥5%, ≥10%, and >15% and proportion of participants with LVEF <50% and <45%). ® Version 9.3 or higher generates descriptive statistics of echocardiographic parameters.

[0385] Dose-response analysis was performed using analysis of covariance (ANCOVA) to determine the least square mean difference (Afecontan minus placebo). To analyze the effect of drug dose on echocardiographic parameters in SAD and MAD cohorts, a linear mixed model using repeated measures analysis of covariance (ANCOVA) was used to perform inferential analysis on the PD analysis set. ANCOVA used baseline values ​​as covariates, including treatment, time point, and time point-treatment interactions as fixed effects, and changes compared to baseline as dependent variables. Unstructured variance-covariance structure was used, and the model took into account repeated measurements at time points. ANCOVA analysis was performed separately for each study section and each PD parameter. The least square mean, the difference of the least square mean (active minus placebo) and the relevant 2-side 95% CI were presented for each comparison.

[0386] Analyses of concentration 'bins' and exposure responses were also performed using ANCOVA. ®PROC MIXED performed all comparative analyses. Another inferential analysis was implemented in the SAD and MAD cohorts to evaluate the relationship between the concentration of aficontan and the LVEF of participants in the PK / PD analysis set. Concentration bin ANCOVA was implemented using a linear mixed model for repeated measures analysis, where concentration bin groups were used as fixed effects, baseline PD parameters were used as covariates, changes compared to baseline were used as dependent variables, and random intercepts were used to adjust repeated measures. An unstructured variance-covariance structure was used. The plasma concentration of aficontan was paired with consistent PD parameters. ANCOVA compared the changes in PD parameters between each bin and the pooled placebo groups. The least square mean, the difference of the least square mean (bin group minus placebo) and the relevant 2-sided 95% CI were presented for each comparison. ANCOVA analysis was performed separately for each study section. For all time points where PK data and PD measurements were available, the time points were pooled for analysis. In each part of the study, the concentration of aficontan with time-matched PD data was pooled and sorted in ascending order. The data were then divided into 5 groups of observations ('bins') from minimum to maximum, each consisting of 20% of the data points. Each bin was treated as a separate group. The concentration bins consisted of the placebo group and 5 bin groups based on the concentration pooled across all time points of aficontan treatment.

[0387] The above analysis was then repeated using concentration as a continuous variable to estimate exposure-response trends. Random intercept effects and random concentration effects were added to the ANCOVA. Estimates of the concentration slope and corresponding 2-sided 95% CI and ANCOVA analysis were presented for each study section.

[0388] For all time points for which PK data and PD measures were available, the time points were pooled for analysis. A nominal significance level of 5% was used for statistical comparisons without adjustment for multiplicity.

[0389] result

[0390] Study population. A total of 102 participants were enrolled: 57 in the SAD cohort, 24 in the MAD cohort, 9 in the CYP2D6-PM cohort, and 12 in the food effect cohort. All participants completed the study. The mean age of each cohort was between 32 and 40 years old, and most participants were male (Table 1).

[0391] Table 1: Baseline characteristics

[0392]

[0393] Values ​​are mean (range), n (%) or mean ± SD. BMI = body mass index; LVEF = left ventricular ejection fraction; MAD = multiple ascending dose; CYP2D6-PM = cytochrome P450 2D6 poor metabolizer; SAD = single ascending dose; SD = standard deviation.

[0394] For the SAD cohort, there were no safety issues that prohibited dose escalation between 1 mg and 25 mg. With the next planned dose (50 mg), 1 participant had a post-dose LVEF <50% (46.2%); however, this did not meet the dose escalation stopping rule and the 75-mg cohort was initiated. The sentinel participant in the 75-mg cohort had a post-dose LVEF <45%; therefore, the other participants were not dosed at 75 mg. Therefore, the 50-mg group was expanded, and the other 5 participants in this cohort were dosed. After expansion, 1 participant in the 50-mg dose group experienced an LVEF <45%, which also decreased by >15%. Therefore, the other participants were not dosed at ≥50 mg. The DLRC determined that the dose appropriate for the final single-dose cohort was 40 mg.

[0395] Following the results of the 1-mg to 25-mg SAD cohort, the first MAD cohort was initiated with 5 mg aficontan once daily for 14 days. There were no safety issues, and the next cohort was initiated with 10 mg once daily for 14 days. In this cohort, 2 participants met stopping criteria based on echocardiographic findings. The DLRC decided that the next treatment level should be 7.5 mg to better characterize the PK at steady state; therefore, the dosing period was expanded from 14 to 17 days to ensure that PK had reached steady state by the last day of dosing.

[0396] Safety and tolerability. There were no serious AEs, and no participant discontinued the study due to AEs. For single-dose and multiple-dose administration, the observed TEAEs were generally mild (grade 1), and aficontan was no more frequent than placebo (Tables 2 and 3). In summary, in both the SAD and MAD cohorts, the most common TEAE was headache (Tables 2 and 3).

[0397] Table 2: Treatment-emergent adverse events in the SAD cohort

[0398]

[0399] Values ​​are n (%). Most common TEAEs based on preference were reported in ≥2 participants in the total cohort. *'Bubble sensation in left chest' was consistent with gastrointestinal rather than cardiac related. † Beginning approximately 60 h after dosing. SAD = single ascending dose; TEAE = treatment-emergent adverse event.

[0400] Table 3: Treatment-emergent adverse events in the MAD cohort

[0401]

[0402] Values ​​are n (%). TEAEs based on priority were reported in ≥1 participant in the total cohort. MAD = multiple ascending dose; qd = once daily; TEAE = treatment-emergent adverse event.

[0403] Echocardiography-related AEs of decreased ejection fraction <45% based on study echocardiographer assessment were reported in 3 participants: 1 each in the SAD 40-mg cohort, 50-mg cohort, and 75-mg cohort (Table 4). All AEs were grade 1 and resolved at the time of the next echocardiographic assessment (within 2.5 h to 4.6 h). The single participant who received 75 mg of aficontan had an LVEF of 34.6% at 1.5 h postdose, a decrease in LVEF of 31.5% and concluded dose escalation in the SAD portion of the study as discussed above. At the follow-up assessment 2.5 h later, the LVEF had returned to 51.9%. No AEs of decreased ejection fraction <45% were reported in the MAD, CYP2D6-PM, or food-effect cohorts.

[0404] In all cohorts, the mean safety ECG parameters at the assessed time points were within normal limits. No clinically significant changes from baseline were observed in any parameter. The QT interval (QTcF) corrected for heart rate using Fridericia's formula did not exceed 450 ms at baseline or at any assessment during the dosing interval, except for 2 individuals with a baseline QTcF ≥ 440 ms and an increase in QTcF values ​​of 3 ms and 13 ms, respectively. In all cohorts, QTcF intervals > 30 ms did not increase, except for 1 participant in the SAD placebo group whose QTcF interval increased by 33 ms (427 ms vs. baseline value 394 ms) on Day 5. In the cardiac dynamics assessment, the class analysis of ECG parameters did not reveal cardiac safety issues, and there was no evidence of positive QT effects after a single or multiple doses of afecontan.

[0405] 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.

[0406] Table 4: Echocardiographically related AEs in patients with reduced ejection fraction <45%

[0407]

[0408] *Time after drug administration.† LVEF values ​​used for safety assessment were determined by the study cardiologist. ‡ In the SAD cohort, postdose echocardiography was performed at 1.5 h, 4 h, 6 h, 24 h, and 48 h after dosing. AE = adverse event; LVEF = left ventricular ejection fraction; SAD = single ascending dose.

[0409] Pharmacokinetics

[0410] Single-dose kinetics. The plasma profiles of aficontan were generally well characterized at all dose levels, except for the lowest dose of 1 mg (due to concentrations approaching the lower limit of quantitation) and the highest dose of 75 mg (administered to only 1 participant), as discussed above. Over the dose range of 1 mg to 50 mg, mean maximum plasma concentrations and exposures increased in a dose-proportional manner, as shown in Table 1. 最大 and the area under the plasma concentration-time curve (AUC 24 ) increased with increasing doses. Figure 3A-3B and Table 5). Mean clearance and volume of distribution were similar across doses. The median time to maximum concentration was observed between 0.5 h and 2.8 h, with a maximum of 4.0 h for all participants. Mean half-life ranged from 75 h to 85 h.

[0411] Table 5: Summary of plasma aficantan pharmacokinetics following single oral dose administration

[0412]

[0413] Multiple-dose kinetics. With once-daily dosing, mean plasma concentrations increased between the 5-mg dose and the 2 higher doses (7.5 mg and 10 mg); however, by day 2, there was little difference between the mean concentrations of the 7.5-mg and 10-mg doses ( Figure 4 ). The plasma PK parameters are shown in Table 6. By the end of the treatment period (Day 14 or Day 17), the mean plasma concentrations were between 2 and 2.5 times the plasma concentrations on Day 1. The terminal elimination half-life estimates for each dose were consistent, ranging between 77 h and 86 h. The clearance rates for the 5-mg and 10-mg doses were similar, and the accumulation ratios for the three doses were similar. Consistent with the observed terminal elimination half-life estimates, steady state was reached after 10 to 12 days ( Figure 4 ).

[0414] Table 6: Summary of plasma aficantan pharmacokinetics following multiple oral doses

[0415]

[0416] CYP2D6 poor metabolizer cohort. The mean half-life was prolonged to 110 h in CYP2D6-PM compared with 85 h in the extensive metabolizers (i.e., 10-mg SAD cohort); however, no increase in AUC was observed in this group, and the geometric mean AUC was 679 ng∙h / ml (geometric CV% 35) compared with 679 ng∙h / ml (geometric CV% 35) in the extensive metabolizers (Table 5). 24 The CYP2D6-PM did not appear to have a reduced clearance that would produce a clinically meaningful difference in exposure.

[0417] Table 7: Summary of plasma afecontan pharmacokinetics in the CYP2D6 poor metabolizer cohort

[0418]

[0419] The dose of aficontin was 10 mg. AUC and C 最大 Values ​​are presented as geometric mean and geometric CV%, T 最大 Values ​​are presented as median (range), and all other parameters are presented as arithmetic mean ± standard deviation. AUC 24 = Area under the plasma drug concentration-time curve from time 0 to 24 h; AUC inf = AUC at time 0 extrapolated to infinity; CL / F = apparent total body clearance; C 最大 = maximum plasma concentration; CV% = coefficient of variation; PK = pharmacokinetics; t ½ = half-life; T 最大 = time to reach maximum plasma concentration; Vz / F = apparent volume of distribution.

[0420] Food Effect. The PK parameters of aficontan in the food effect cohort are shown in Table 8. When taken with food, the C 最大 The increase was approximately 30% and the time to reach the maximum observed concentration was shortened (1.5 vs. 2.3 h). However, food had a minimal effect on AUC, with the geometric mean AUC in the fasting state being 24 The (geometric CV%) was 601 (33) ng∙h / ml versus 631 (25) ng∙h / ml in the fed state.

[0421] Table 8: Summary of Plasma Aficontan Pharmacokinetics in the Food Effect Cohort

[0422]

[0423] Aficontan dose was 10 mg in each cohort. *For AUC inf ,t ½, CL / F and Vz / F, n = 4. † For AUC inf ,t ½ , CL / F and Vz / F, n = 7. AUC and C 最大 Values ​​are presented as geometric mean and geometric CV%, T 最大 The median (range) is presented, and all other parameters are presented as the arithmetic mean ± standard deviation. 24 = Area under the plasma drug concentration-time curve from 0 to 24 h; AUC inf = AUC at time 0 extrapolated to infinity; CL / F = apparent total body clearance; C 最大 = maximum plasma concentration; CV% = coefficient of variation; t ½ = half-life; T 最大 = time to reach maximum plasma concentration; Vz / F = apparent volume of distribution.

[0424] Pharmacodynamics

[0425] Left ventricular ejection fraction. At baseline, the mean LVEF ranged from 61.0% to 67.5% across the cohorts (Table 1). In the SAD cohort, a mean decrease in LVEF was observed in the group receiving the highest dose of afibactam ( Figure 5A ). The maximum mean decrease from baseline was seen at 1.5 h after dosing in the 50-mg cohort (least square mean difference 5.5%, p=0.0001). LVESV and LVEDV increased statistically significantly by 8.1 mL and 6.6 mL, respectively (Table 9). There were no significant changes in other echocardiographic parameters (e.g., stroke volume, cardiac output, cardiac time intervals, and measures reflecting diastolic function) (Table 9). A single participant receiving 75 mg of aficontan exhibited a 31.5% decrease in LVEF at 1.5 h after dosing, which resolved by 2.5 h after initiation but concluded that dose escalation in the SAD portion of the study was appropriate, as discussed above. In the MAD cohort, a significant decrease in LVEF occurred with continued dosing in the 10-mg cohort ( Figure 5B The maximum mean maximum % reduction from baseline was 5.0% ( 1.5 h after dosing) seen on Day 14 in the 10-mg cohort. Figure 5B The placebo-corrected reduction (least square mean difference) of 3.2% did not reach statistical significance (p=0.21), which may be attributed to lack of statistical power in this subgroup comparison.

[0426] Table 9: Echocardiographic parameters

[0427]

[0429] The table compares placebo data with data for 50 mg aficontan (the highest well-tolerated single dose) for echocardiographic parameters at baseline and 1.5 h (the time of echocardiography closest to peak plasma concentration of aficontan). A = peak A wave velocity, bpm = beats per minute, CFB = change from baseline, CO = cardiac output, E = peak E wave velocity, EDV = end-systolic volume, ESV = end-systolic volume, ET = ejection time, e'lateral = tissue Doppler velocity of the lateral wall, IVCT = isovolumetric contraction time, IVRT = isovolumetric relaxation time, LAV = left atrial volume, LVEF = left ventricular ejection fraction, NS = not significant (p > 0.05), SD = standard deviation, SV = stroke volume

[0430] Category LVEF Response. In the SAD cohort, an absolute decrease in LVEF of ≥5% from baseline was observed in 1 of 15 participants (7%) in the placebo cohort, 1 of 6 participants (17%) in the 3-mg cohort, 2 of 6 participants (33%) in the 40-mg cohort, 7 of 11 participants (64%) in the 50-mg cohort, and 1 of 1 participant (100%) in the 75-mg cohort, whereas no participant in the 1-mg, 10-mg, or 25-mg cohort had a decrease of ≥5%. An absolute decrease in LVEF of ≥10% occurred in 1 of 6 participants (17%) in the 40-mg cohort, 2 of 11 participants (18%) in the 50-mg cohort, and 1 of 75-mg cohort (100%). A decrease in LVEF to <50% was observed in 2 of 11 participants (18%) in the 50-mg cohort (48.2% and 45.5% based on core laboratory assessment) and in 1 of 1 participant (100%) in the 75-mg cohort. Only participants in the 75-mg cohort experienced LVEF <45%.

[0431] In the MAD cohort, an absolute decrease in LVEF from baseline of ≥5% was observed in 4 participants: 1 of 6 participants (17%) who received placebo, 1 of 6 participants (17%) who received aficontan 7.5 mg once daily, and 2 of 6 participants (33%) who received aficontan 10 mg once daily. Among these participants, 2 participants in the 10-mg cohort had a decrease of ≥10%. No decrease in LVEF to <50% based on core laboratory assessment was observed in either MAD cohort.

[0432] The PK / PD relationship of aficontan was illustrated by plotting the plasma concentration of aficontan versus the change in LVEF in the SAD and MAD cohorts. Fig. 6A and Figure 6B ). In the SAD cohort, there was a trend toward decreased LVEF with increasing plasma concentrations of aficontan. The relationship between LVEF and plasma aficontan concentration was statistically significant in bin concentration analysis (122 ng / ml to 524 ng / ml, p < 0.0001) and concentration-slope analysis (p = 0.0027) in the highest plasma concentration bin. In the MAD cohort, the relationship between LVEF and plasma aficontan did not reach statistical significance in bin concentration analysis or linear regression analysis, which may be attributed to the more limited range of plasma concentrations explored and the smaller group size.

[0433] Discussion

[0434] This Phase 1, first-in-human study has established that aficontan is physiologically effective in reducing LVEF and doses (up to 50 mg as a single oral dose or up to 10 mg after multiple dosing) are well tolerated in healthy participants, thereby determining the pharmacologically active dose that will be used as the starting dose for studies in patients with HCM. In addition, a single oral dose of 10 mg was well tolerated in individuals with the CYP2D6-PM phenotype and food had no significant effect on the PK of aficontan. Together, these observations support continued development of aficontan for patients with HCM and provide a roadmap for Phase 2 studies.

[0435] Safety of Aficontan. No serious AEs were observed in the study and all participants completed the intended dosing as planned. In general, AEs were mild and of similar frequency between participants treated with Aficontan and placebo. Importantly, participants whose LVEF dropped below 50% had no adverse changes in relevant symptoms or vital signs, and the LVEF in these cases returned to baseline within 24h. This study was not intended to find the maximum tolerated dose, and therefore dose escalation was stopped immediately once a significant PD effect was observed in the SAD and MAD parts of the study; therefore, doses that were intolerant due to AEs were not determined.

[0436] Effects on LVEF. In the SAD cohort, a dose of 50 mg produced a mean LVEF reduction of 5.8%, whereas in the MAD cohort, 10 mg once daily for 14 days produced a mean absolute LVEF reduction of approximately 5%. The proportion of participants with an absolute reduction in LVEF of ≥5% from baseline increased with increasing dose; up to 64% of participants in the 50-mg SAD cohort and 33% of participants in the 10-mg MAD cohort had an absolute reduction in LVEF of ≥10% from baseline. In the SAD cohort, a statistically significant reduction in LVEF occurred with increasing plasma concentrations of aficontan when the widest exposure range of aficontan was explored. Thus, the study met its secondary objectives of identifying a pharmacologically active dose and describing its PK / PD relationship.

[0437] Three participants had a decrease in LVEF to <50%, which was rapidly reversed after study drug discontinuation. After a single dose of 50 mg, 2 (18%) participants experienced an LVEF <50% (48.2% and 45.5%). After a single dose of 75 mg, 1 participant experienced a decrease in LVEF to 34.1%. In all cases, events were noted approximately 1.5 h after dosing, and LVEF recovered to >50% by 4 h to 6 h after dosing. SAD results informed dose selection for the rest of the study, and there were no echocardiographic AEs in the MAD, CYP2D6-PM, or food effect cohorts.

[0438] Implications of PK Results. Aficontan exhibited linear kinetics over the dose range of 1 mg to 50 mg; half-life was independent of concentration, and clearance was independent of dose. Steady state was reached by the end of day 10 with the 10-mg dose and by the end of day 12 with the 5-mg and 7.5-mg doses. There were no food effects suggesting a need for a change in dosing. These findings support once-daily dosing in the fasted or fed state.

[0439] The relationship between plasma concentration and LVEF suggests a wide therapeutic index that will facilitate optimization of individual doses in patients with HCM who are expected to be titrated through an increasing range of doses until the desired PD effect is achieved. In addition, the half-life of aficontan (75 h to 85 h after a single dose; 77 h to 86 h after multiple doses) and the observed reversibility of the effect offer the potential advantage that steady state is achieved within 2 weeks and excessive effects on LVEF are easily reversed.

[0440] Conclusions. Aficontan demonstrated a favorable safety profile in healthy participants, with no serious AEs or meaningful changes in laboratory tests, ECG, or health assessments. Any decrease in LVEF to values ​​<50% was reversible within 6 h after a single dose. A pharmacologically active dose of aficontan was determined that could be used as a starting dose for studies in patients with HCM.

[0441] Example 2

[0442] A multicenter, randomized, placebo-controlled, double-blind, dose-finding Phase 2 clinical trial of aficontan was conducted in patients with symptomatic obstructive HCM (oHCM). The primary objective of the trial was to determine the safety and tolerability of aficontan. Secondary objectives were to describe the concentration-response relationship of aficontan on the left ventricular outflow tract gradient at rest and after the Valsalva maneuver as measured by echocardiography during the 10-week treatment period, to describe the dose-response relationship of aficontan, and to evaluate the plasma concentrations of aficontan in patients with oHCM. Seventeen study sites in North America and Europe screened patients for inclusion in Cohorts 1 and 2. A third cohort (Cohort 3) was also studied to evaluate the safety and efficacy of aficontan in combination with the Class IA antiarrhythmic drug disopyramide.

[0443] The first two cohorts (cohort 1 and cohort 2) did not include patients receiving disopyramide. Cohort 3 included patients receiving disopyramide. Within each of the first two cohorts, patients were randomized 2:1 to active or placebo treatment and received up to three ascending doses of aficontan or placebo based on echocardiographic guidelines. In the third cohort, all patients received up to three ascending doses of aficontan based on echocardiographic guidelines. In summary, the duration of treatment was 10 weeks, with a 4-week follow-up period after the last dose.

[0444] As patient characteristics vary substantially in this disease, individualized dose titration for pharmacodynamic (PD) response (LVOT-G reduction to <30 mmHg and maintaining LVEF >50%) was used to maximize efficacy and safety.

[0445] Patients were eligible for inclusion in the study only if all of the following criteria applied: 1. Able to understand and willing to sign the informed consent form (ICF) and willing to comply with all study procedures and restrictions for the duration specified in the activity schedule; 2. Males and females aged between 18 and 85 years at screening; 3. Weight ≥45 kg at screening; 4. Diagnosed with oHCM according to the following criteria: (a) LV hypertrophy and nondilated LV chamber in the absence of other cardiac diseases; and (b) minimum wall thickness ≥15 mm (for a positive family history of HCM or a known pathogenic gene mutation, a minimum wall thickness ≥13 mm is acceptable); 5. Adequate echocardiographic acoustic window; 6. During the screening period, LVOT-G in cohorts 1 and 2 was as follows: (a) resting gradient ≥50 mmHg; or (b) resting gradient ≥30 mmHg and <50 mmHg and LVOT-G ≥50 mmHg after Valsalva maneuver; or LVOT-G in cohort 3 was as follows: persistent resting LVOT obstruction (≥30 mmHg) or (c) LVOT-G <50 mmHg after Valsalva maneuver. mmHg) and provoked LVOT occlusion (≥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 should have been taking a stable dose for >4 weeks before randomization and are expected to continue using the same medication regimen during the study; 10. Male patients are eligible to participate in the study if they agree to the following conditions during the study and for at least 10 weeks after the last dose: (a) not donating sperm; plus (b) (i) not taking heterosexual intercourse as their preferred and usual lifestyle (long-term and persistent abstinence) and agree to maintain abstinence; or (b) (i) must agree to use male Use condoms, and if their female partner is a woman of childbearing potential, have their female partner use a highly effective contraceptive method; 11. Female patients are eligible to participate in the study if they are not pregnant or breastfeeding and at least one of the following conditions applies: (a)(i) are not women of childbearing potential, or (a)(ii) are women of childbearing potential and use highly effective contraceptive methods during the study and for at least 4 weeks after the last dose; and (b) women of childbearing potential must have a negative pregnancy test (urine or serum as required by local regulations) within 3 days before the first dose of the study intervention; 12. Be able to complete all screening procedures; and 13. Take a stable dose of disopyramide for >4 weeks before screening (cohort 3 only).

[0446] Patients were excluded from the study if any of the following criteria applied: 1. Aortic stenosis or fixed subaortic occlusion; 2. Infiltrative or storage conditions known to cause cardiac hypertrophy similar to oHCM (e.g. Noonan syndrome, Fabry disease, amyloidosis); 3. History of left ventricular (LV) systolic dysfunction (LVEF) at any time during their clinical course. <45%); 4. Documented history of current obstructive coronary artery disease (stenosis of one or more epicardial coronary arteries >70%) or documented history of myocardial infarction; 5. Treated with septal narrowing therapy (surgical myectomy or percutaneous alcohol septal ablation) during the study period or planned for either treatment; 6. Previous treatment with cardiotoxic agents (e.g., doxorubicin or similar drugs); 7. For Cohorts 1 and 2: treated with disopyramide or antiarrhythmic drugs with negative cardiotonic activity within 4 weeks prior to screening, and for Cohort 3: treated with antiarrhythmic drugs with negative cardiotonic activity other than disopyramide within 4 weeks prior to screening; 8. Any ECG abnormality that the investigator believes poses a risk to patient safety (e.g., second-degree type II atrioventricular block); 9. Documented paroxysmal atrial fibrillation during the screening period 10. Paroxysmal or permanent atrial fibrillation requiring rhythm-restoring therapy (e.g., direct current cardioplegia, ablation procedure, or antiarrhythmic therapy) ≤ 6 months before screening, but this clause does not apply if atrial fibrillation has been treated with anticoagulation and adequate heart rate control for > 6 months; 11. History of syncope or sustained ventricular tachyarrhythmia during exercise within 6 months before screening; 12. Placement of an implantable cardioverter-defibrillator (ICD) within 3 months before screening or planned placement of an ICD during the study; 13. History of receiving appropriate ICD shock for life-threatening ventricular arrhythmias within 6 months before screening; 14. Receipt of a major organ transplant (e.g., heart, lung, liver, bone marrow, kidney) or expected transplant within 12 months of randomization); 15. Liver damage, defined as total bilirubin (TBL) at screening ≥1.5 × upper limit of normal (ULN), or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 × ULN, only patients with documented Gilbert syndrome and TBL ≥1.5 × ULN due to unconjugated hyperbilirubinemia and no other liver disease are allowed; 16. Any other clinically significant condition, malignancy, active infection, other illness or disease history or evidence, in the opinion of the investigator or medical monitor, the disease will pose a risk to patient safety or interfere with study evaluation, procedures or completion; 17. Hemoglobin <10.0 g / dL at screening; 18. Estimated glomerular filtration rate (eGFR) <30 mL / min / 1.73 m at screening 2(by modified Modification of Diet in Renal Disease equation); 19. Currently participating in another investigational device or drug study or receiving an investigational device or drug <1 month (or 5 half-lives of the drug, whichever is longer) prior to screening; 20. Previously treated with aficontan or currently receiving mavacamten; 21. Known allergy to any excipient in aficontan film-coated tablets (e.g., mannitol, microcrystalline cellulose, cross-linked carboxymethyl cellulose, hydroxypropyl cellulose, sodium lauryl sulfate, magnesium stearate, Opadry QX White 21A180025).

[0447] In each cohort, patients received up to three escalating doses of afecontan, as shown in Table 11. Each patient received dose 1 once daily for 2 weeks. At week 2, patients underwent an echocardiogram 2 hours after administration of their dose. If the echocardiogram met any of the following conditions, the patient was titrated up to dose 2: (1) resting LVOT-G ≥30 mmHg and biplane LVEF ≥50%; or (2) resting LVOT-G <30 mmHg, LVOT-G ≥50 mmHg after Valsalva maneuver, and biplane LVEF ≥50%. Otherwise, the patient remained on dose 1. If LVEF was <50% at week 2, the patient was titrated down to placebo. The dose adjustment algorithm is shown in Table 10 below.

[0448] After taking the assigned dose for another 2 weeks (i.e., Week 4), each patient underwent an echocardiogram 2 hours after their dose. If the echocardiogram met any of the following criteria, the patient was escalated to the next higher dose: (1) resting LVOT-G ≥30 mmHg and biplane LVEF ≥50%; or (2) resting LVOT-G <30 mmHg, LVOT-G ≥50 mmHg after the Valsalva maneuver, and biplane LVEF ≥50%. Otherwise, the patient remained on the same dose. If LVEF <50% at Week 4, the patient was returned to the previous dose level, or if the patient was taking Dose 1, the patient was returned to placebo.

[0449] After taking the assigned dose for another 2 weeks (i.e., Week 6), each patient underwent an echocardiogram 2 hours after administration of their dose. If LVEF was <50% at Week 6, the patient was titrated down to the previous dose level or returned to placebo if the patient was taking Dose 1.

[0450] Table 10: Dose adjustment algorithm

[0451]

[0452] If at any time a patient's dose was titrated down to placebo, they remained on placebo for the duration of the study.

[0453] Table 11: Dosage regimen

[0454]

[0455] The baseline characteristics of patients in Cohort 1, Cohort 2, and Cohort 3 are shown in Tables 12 and 13.

[0456] Table 12: Baseline characteristics of patients in the Phase 2 clinical trial

[0457]

[0458] Table 13: Baseline demographic and clinical characteristics of patients in Phase 2 clinical trial cohorts 1 and 2

[0459]

[0461] * = derived from on-site echocardiographic assessment by individual investigators. BMI = body mass index; CV = coefficient of variation; LVEF = left ventricular ejection fraction; LA = left atrium; LVED = left ventricular end-diastolic dimension; LVOT = left ventricular outflow tract; NT-proBNP = N-terminal pro-B-type natriuretic peptide; NYHA FC = New York Heart Association functional class.

[0462] Echocardiograms obtained every 2 weeks and 2 weeks after the last dose were analyzed for several key structural and physiological measures as well as N-terminal pro-brain natriuretic peptide hormone (NT-proBNP).

[0463] Initial results from the clinical study include data from two sequentially administered cohorts, Cohort 1 (n = 21) and Cohort 2 (n = 20), which randomized patients 2:1 to treatment with aficontan or placebo. Patients received up to three ascending doses of aficontan (5 mg, 10 mg, 15 mg in Cohort 1 and 10 mg, 20 mg, 30 mg in Cohort 2) or placebo once daily. Patients underwent an echocardiogram after two weeks of treatment at each dose to determine potential up-titration to the next higher dose. Overall, the duration of treatment for each patient in the study was 10 weeks, with an echocardiogram performed 2 weeks after the last dose.

[0464] For patients in cohort 1 who took aficontan (n=14), mean resting LVOT-G changed from 53.8 mmHg at baseline to 13.4 mmHg at 10 weeks; for patients in cohort 2 who took aficontan (n=14), mean resting LVOT-G changed from 58.2 mmHg at baseline to 15.1 mmHg at 10 weeks; and for patients in the combined placebo group (n=13), mean resting LVOT-G changed from 52.1 mmHg at baseline to 44.0 mmHg at 10 weeks ( Figure 7 , p = 0.0003 for cohort 1 and p = 0.0004 for cohort 2 compared with placebo at 10 weeks).

[0465] For patients in cohort 1 taking aficontan (n=14), mean Valsalva LVOT-G changed from 77.4 mmHg at baseline to 38.1 mmHg at 10 weeks; for patients in cohort 2 taking aficontan (n=14), mean Valsalva LVOT-G changed from 82.3 mmHg at baseline to 29.8 mmHg at 10 weeks; and for patients in the combined placebo group (n=13), mean Valsalva LVOT-G changed from 84.6 mmHg at baseline to 76.0 mmHg at 10 weeks ( Figure 8 ; p = 0.001 for cohort 1 and p < 0.0001 for cohort 2 compared with placebo at week 10).

[0466] The mean ejection fraction increased from 72.8% at baseline to 67.3% at 10 weeks for patients taking aficontan in cohort 1 (n=14); from 75.4% at baseline to 64.1% at 10 weeks for patients taking aficontan in cohort 2 (n=14), and from 74.5% at baseline to 74.9% at 10 weeks for patients in the combination placebo group (n=13) (p=0.01 for cohort 1 and p=<0.0001 for cohort 2 versus placebo at 10 weeks).

[0467] Overall, the incidence of adverse events was similar between treatment groups. Treatment with afibactam was well tolerated in the study and adverse events were reported as mild or moderate in severity. No treatment-related serious adverse events were reported by the investigators.

[0468] No patient receiving aficontan had an LVEF <50% in cohort 1. In cohort 2, one patient with a baseline LVEF of 58% was up-titrated to 20 mg aficontan and experienced a transient LVEF decrease to <50% (remaining above 40%), requiring down-titration. No interruptions or discontinuations in treatment with aficontan occurred in any patient in either cohort.

[0469] The distribution of patients at aficontan dose in the study (cohorts 1 and 2) is shown in Table 14. The distribution of patients at aficontan dose in cohort 3 of the study is shown in Table 15.

[0470] Table 14

[0471]

[0472] Table 15

[0473]

[0474] Secondary outcomes of the clinical study included data from Cohort 3 (n=13). All patients received up to three ascending doses of aficontan (5 mg, 10 mg, 15 mg) once daily. Patients underwent echocardiography after two weeks of treatment at each dose to determine potential up-titration to the next higher dose. Overall, the treatment duration for each patient in the study was 10 weeks, and an echocardiogram was performed 2 weeks after the last dose. Efficacy endpoints included resting and provoked LVOT gradients, NYHA class, and NT-proBNP.

[0475] In cohort 3, 13 patients (age 59 ± 14 years; 54% female) with NYHA class II (n = 5) and III (n = 8) were enrolled. Patients in cohort 3 had similar demographics, LVEF, and severity of obstruction compared to cohorts 1 and 2, but were more symptomatic and had higher baseline NT-proBNP. Patients in cohort 3 had symptomatic obstructive HCM and left ventricular outflow tract gradient (LVOT-G) of ≥50 mmHg at rest or after Valsalva maneuver, and had previously been treated with disopyramide and, in most cases, beta-adrenergic blockers. All patients received up to three ascending doses of afecontan (5 mg, 10 mg, 15 mg) once daily, titrated based on echocardiographic guidelines, as discussed above. In summary, the duration of treatment was 10 weeks, with a 4-week follow-up period after the last dose. A total of 13 patients were enrolled and all completed the study while on treatment.

[0476] Results from Cohort 3 showed that substantial reductions in mean resting LVOT-G and LVOT-G after the Valsalva maneuver were achieved (defined as resting gradient <30 mmHg and gradient <50 mmHg after the Valsalva maneuver). These clinically relevant pressure gradient reductions were achieved with only modest reductions in mean left ventricular ejection fraction (LVEF); patients' LVEF did not fall below the predefined safety threshold of 50%. New York Heart Association functional class improved in the majority of patients enrolled in Cohort 3 of the trial. Pharmacokinetic data were similar to those observed in Cohorts 1 and 2. In addition, the safety and tolerability of aficontan was consistent with no treatment-induced treatment discontinuations and serious adverse events reported by investigators.

[0477] The combination of aficantan and disopyramide may provide a treatment option for patients with the most severe and refractory oHCM.

[0478] Results after 10 weeks of therapy

[0479] At baseline, there were no significant differences in key echocardiographic measures and NT-proBNP values ​​between aficontan and placebo. There was a trend toward a decrease in mean left ventricular mass index (LVMI) (-4.8 g / m 2 (±2.4) for 3.3 g / m 2 (±3.6); mean difference: 8.1 g / m 2 From baseline to week 10, indices of left ventricular (LV) filling pressures improved in the afibactam-treated group, including left atrial volume index (LAVI) (-2.9 mL / m 2 (±1.5) for 2.2mL / m 2 (±1.5), P=0.004) ( Fig. 9 ); e' (0.5 cm / s (±0.4) vs. -0.5 cm / s (±0.3), p=0.03) and lateral E / e' (-2.0 (±1.1) vs. 1.8 (±0.8), p=0.006) ( Fig.10 Similarly, differences in the systolic anterior motion of the mitral valve leaflets (SAM; -50% vs. -17.3%) were observed in afibactam vs. placebo at Week 10 ( Fig.11 ) and the frequency of eccentric mitral regurgitation (MR; -35.8% vs. +13.3%) ( Fig.11 ) decreased from baseline. At week 10, there was a significantly greater reduction in NT-proBNP with afibactam versus placebo (geometric least squares mean ratio 0.38 (0.25-0.56), p=0.0002).

[0480] Fig.12 Shown are changes in resting LVOT-G for treatment and placebo cohorts. Fig.13 Changes in resting LVOT-G with Valsalva maneuver are shown for treatment and placebo cohorts. The effects of aficontan treatment on LVOT-G were generally attenuated in patients treated with disopyramide (cohort 3) compared with patients in cohort 1 (same aficontan dose). Fig.14 Changes in LVEF are shown for the treatment and placebo cohorts. Fig.15 NYHA functional class responses for treatment and placebo cohorts are shown. Fig.16 Shown are changes in mean NT-proBNP for treatment and placebo cohorts.

[0481] The safety profiles for all three treatment cohorts are presented in Table 16. In cohort 3, 6 moderate adverse events were recorded, including pneumonia, pertussis, lung mass, back pain, shortness of breath, and orthopnea. One adverse event of asymptomatic atrial fibrillation was recorded in a patient with a known prior medical history. The remaining adverse events included gastrointestinal symptoms (a known side effect of disopyramide) and other adverse events seen in cohorts 1 and 2 (headache, dizziness). The overall safety profile in cohort 3 supports the combined use of aficontan and disopyramide.

[0482] Table 16: Safety profile of patients treated with afibactam in the Phase 2 clinical trial

[0483]

[0484] These findings indicate that aficontan treatment resulted in beneficial early cardiac remodeling associated with reductions in LVMI, LAVI, lateral E / e', SAM, eccentric mitral regurgitation, and brain natriuretic peptide, and increases in e' velocity, and further suggest that aficontan favorably affects cardiac remodeling in oHCM.

[0485] Results for cohort 1 and cohort 2

[0486] In reference cohorts 1 and 2, a complete hemodynamic response (resting LVOT gradient <30 mmHg and Valsalva gradient <50 mmHg at Week 10) was achieved in 11 of 14 patients (79%) in aficontan cohort 1 and 13 of 14 patients (93%) in aficontan cohort 2, compared with only 1 of 12 patients (8%) in the pooled placebo group ( Fig.17 , Fig.18 , Fig. 20 ).

[0487] During the treatment period, EF decreased from 73% ± 6% to 67% ± 9% in the aficontan cohort 1 (LSMean vs. placebo, p=0.007) and from 75% ± 6% to 64% ± 8% in the aficontan cohort 2 (LSMean difference vs. placebo, p<0.001), with no change in the placebo group (75% ± 6% to 75% ± 4%; p=0.5) ( Fig.19 ). Analysis of the relationship between aficontan dose and EF over time revealed a dose-dependent decrease, with a mean EF decrease of -0.6% (SE 0.084) per mg of aficontan.

[0488] In the pooled afibactam-treated groups (cohorts 1 and 2), 15 of 28 patients (53%) experienced a change in NYHA class ( Fig.21 ), including: 6 patients improved from Category III to Category II, 8 patients improved from Category II to Category I, and 1 patient improved from Category III to Category I ( Fig.24 ).

[0489] Aficontan treatment was associated with a 62% proportional reduction in NT-proBNP levels compared with placebo (p<0.001) at week 10. Importantly, 25 of 27 patients (93%) taking aficontan experienced at least some reduction in NT-proBNP levels compared with only 6 of 12 placebo-treated patients (50%).

[0490] The pooled baseline level of hs-Trop for the aphicontin groups was 17 ng / L (CV% 290), and the pooled baseline level of hs-Trop for the placebo groups was 17 ng / L (CV% 290) ( Fig.23 At week 10, patients in cohort 1 who received aficontan experienced an 18% relative reduction compared with pooled placebo (p = 0.29), and patients in cohort 2 experienced a 26% relative reduction compared with pooled placebo (p = 0.097). Changes in hs-troponin I levels in the pooled placebo group and patients in cohorts 1, 2, and 3 who received aficontan are shown in Fig.37 middle.

[0491] The early and sustained hemodynamic effects of aficontan were accompanied by significant clinical benefit in heart failure symptoms in most patients. Improvement of symptoms in one or more NYHA classes occurred in more than half of the patients treated with aficontan, including 64% in cohort 2, with most of the improvements resulting in patients transitioning from class II to being completely asymptomatic (class I). Of note, aficontan converted 7 patients from advanced heart failure symptoms (class III) to a less symptomatic state (class II or I).

[0492] This robust hemodynamic response is particularly evident as afibactam converts most obstructive HCM patients to gradient levels below the current threshold for consideration of septal narrowing therapies such as myectomy or alcohol septal ablation. This is a particularly relevant point as one advantage of septal narrowing therapies is the opportunity to convert patients with advanced restrictive symptoms (category III) to an asymptomatic or mildly symptomatic state.

[0493] Aficontan was also associated with significant reductions in NT-proBNP and hs-troponin, highlighting other potential downstream pathophysiological benefits of the compound, including reduced LV wall stress and reduced myocardial injury.

[0494] Results of Cohort 3

[0495] Patients with symptomatic (New York Heart Association [NYHA] class II / III) oHCM (resting or Valsalva maneuver LVOT gradient ≥ 50 mmHg and LVEF ≥ 60%) who were receiving standard of care medical therapy including BB and / or CBB (calcium channel blocker) plus disopyramide were enrolled in an open-label fashion. Thirteen patients were enrolled (mean age 59.4 years (SD 14.4), 53.8% female). Ten patients (77%) were taking a BB; two patients (15.4%) were taking a CCB, and one patient (7.7%) was taking both. The median (minimum, maximum) disopyramide dose was 300 mg / day (100, 600 mg / day). At baseline, mean (SD) LVEF was 74 (7.5)%; resting and Valsalva maneuver LVOT-G were 50 (25) mmHg and 78 (27) mmHg, respectively. At baseline serum NT-proBNP, 5 (38.5%) were NYHA class II and 8 (62%) were NYHA class III (geometric mean 1050 pg / mL, %CV 110). The final dose reached by 2 patients was 5 mg, 5 patients 10 mg, and 6 patients 15 mg. Resting and Valsalva maneuver LVOT gradients ( Fig.46 , Fig.47) decreased significantly during the 10-week treatment period, with mean (SD) week 10 resting LVOT-G decreasing by 27 mmHg (22) [p<0.0001] and mean Valsalva maneuver LVOT-G decreasing by 28 mmHg (32) [p=0.0002]. Mean LVEF decreased modestly from 74±7.5% to 69±7.2% [p = 0.018] ( Fig.48 ), which returned to baseline after a 2-week washout. Ten of the 13 patients (77%) showed a complete or partial response in LVOT gradient at the end of treatment ( Fig.49 Three patients (23%) achieved a transient complete or partial response during treatment, with overall improvement in gradients and symptoms at the end of treatment. Eleven patients (85%), including all eight patients with baseline NYHA class III, demonstrated ≥1 NYHA class improvement ( Fig.50 ). Two patients who did not report an improvement in NYHA class experienced a partial hemodynamic response. Changes in hemodynamics and NYHA class were reflected in reductions in cardiac biomarkers similar to those observed in cohorts 1 and 2 (patients receiving beta-blockers and / or calcium channel blockers but not disopyramide) ( Fig.51 There were no dose interruptions, treatment discontinuations, or serious adverse events. No patient had an LVEF <50%, and there were no significant changes in QTc interval or vital signs.

[0496] In this open-label study of primarily NYHA class III individuals, the addition of aficontan significantly reduced LVOT gradient in 77% of patients and improved symptoms in 85% of patients, with all baseline NYHA class III patients improving by ≥ 1 category. Importantly, aficontan was well tolerated and reversible in this cohort of patients with severe obstruction. The reduction in LVEF was similar to that observed in cohort 2 patients who did not take disopyramide. Aficontan shows efficacy as add-on therapy in patients with refractory oHCM and may offer an alternative to SRT.

[0497] Example 3a

[0498] An open-label extension clinical trial of aficontan was initiated in patients with symptomatic oHCM. The primary objective of the trial was to determine the safety and tolerability of aficontan over a 5-year period.

[0499] Patients who completed the study as described in Example 2 and did not already have atrial fibrillation were eligible for inclusion in the study. Echocardiographically guided dose titration based on live readings was controlled by the investigator and could be performed at any time during the trial, as described below.

[0500] Study Design

[0501] Each patient received dose 1 of aficontan once daily for 2 weeks. At week 2, each patient underwent a truncated echocardiogram 2 hours after administration of their dose. Patients were titrated up to dose 2 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, LVOT-G ≥50 mmHg after the Valsalva maneuver, and biplane LVEF ≥50%. Otherwise, patients remained on 5 mg of aficontan. If LVEF <50%, treatment was discontinued. If LVEF <40%, treatment was interrupted.

[0502] At Weeks 4, 6, 12, and every 12 weeks thereafter, each patient will undergo an echocardiogram or truncated echocardiogram 2 hours after administration of their dose (truncated echocardiogram at Weeks 4 and 6; and echocardiogram at Week 12 and every 12 weeks thereafter) to determine if additional dose titration is needed (see Tables 17 and 18). Ambulatory cardiac monitoring will be implemented at Weeks 48, 96, 144, 192, and 240. Cardiac magnetic resonance will be monitored at Weeks 48, 144, and 240. (See Tables 17 and 18.) Fig.26 ). The baseline characteristics of the patients enrolled in the open-label extension study are shown in Table 19.

[0503] Table 17: Dose adjustment algorithm

[0504]

[0505] Table 18: Dosage regimen

[0506]

[0507] Table 19: Baseline Characteristics of the Open-Label Extension Study

[0508]

[0509] Preliminary results

[0510] Preliminary results are shown in Figure 27-34 middle. Fig. 27 The distribution of patients at each dose over time is shown. At the time of data collection, 38 patients had been enrolled in the trial, and all 38 patients had reached at least Week 2 dosing; 37 of the 38 patients had reached at least Week 6 dosing; 30 of the 38 patients had reached at least Week 12 dosing; and 19 of the 38 patients had reached at least Week 24 dosing. The percentage of patients receiving each dose level (5 mg, 10 mg, or 15 mg) at each time point is shown in Fig. 27Based on echocardiographic data from live readings of these patients, significant decreases in resting LVOT-G and Valsalva maneuver LVOT-G over time were shown in Fig.28 and Fig.29 In the 24th week, a significant and sustained decrease in LVOT gradient was identified. In addition, a minimal and stable decrease in LVEF was noted until the 24th week, as Fig.30 as shown in the .

[0511] At baseline, 53% of patients were NYHA class III and 47% were NYHA class II.

[0512] Among patients who reached at least Week 12 of dosing: at Week 12, only 7% of patients were NYHA Class III; 52% of patients were NYHA Class II; and 41% of patients were NYHA Class I ( Fig.31 ). Relative to baseline, 72% of patients experienced an improvement of one NYHA class, and 7% experienced an improvement of two NYHA classes ( Fig.32 ).

[0513] Among patients who reached at least Week 24 of dosing: at Week 24, only 6% of patients were NYHA Class III; 39% of patients were NYHA Class II; and 56% of patients were NYHA Class I ( Fig.31 ). Relative to baseline, 61% of patients experienced an improvement of one NYHA class, and 17% experienced an improvement of two NYHA classes ( Fig.32 ).

[0514] Patients in the study showed no worsening of NYHA class from baseline.

[0515] Initial safety

[0516] Table 20

[0517]

[0518] TEAE: Treatment Emergent Adverse Event

[0519] TESAE: Treatment-emergent serious adverse event

[0520] Cardiac AEs: atrial fibrillation (2); angina (1); bradycardia (1); decreased ejection fraction (1); mitral stenosis (1); QTc prolongation (1)

[0521] One patient with LVEF < 50% and TESAE had a history of alcohol-induced atrial fibrillation prior to the study and a decrease in LVEF < 50%. Recurrent episodes of alcohol-induced atrial fibrillation had a similar decrease in LVEF to 47% while taking 15 mg aficontan; aficontan was titrated down. The patient subsequently had worsening atrial fibrillation and failed cardioreversion; aficontan was discontinued. This patient regained sinus rhythm while taking amiodarone (withdrawal from alcohol) with LVEF 60% and evidence of obstruction and has been restarted at dose 1 (5 mg) of aficontan.

[0522] One patient underwent temporary down-titration due to investigator concern about QTc prolongation in a subject with an abnormal baseline EKG. Temporary down-titration of aficontan was performed while awaiting core laboratory QTc interpretation. The QTc was confirmed to be normal, and aficontan was subsequently increased.

[0523] One subject with a severe TESAE showed altered mental status prior to planned cardiopulmonary resuscitation for worsening atrial fibrillation due to a DOAC (direct-acting oral anticoagulant), leading to hospitalization. MRI showed a presumed embolic stroke. The patient was subsequently diagnosed with a congenital heart anomaly (secundum atrial septal defect). No down-titration or interruption of afibactan was required.

[0524] Kansas City Cardiomyopathy Questionnaire (KCCQ)

[0525] The health status of participants was assessed using the KCCQ before starting afecontan in the OLE and at 12 and 24 weeks of treatment. Changes from baseline in KCCQ scores were determined, including OSS = overall summary score, CSS = clinical summary score, TSS = total symptom score, PLS = physical limitations score, SLS = social limitations score, QoL = quality of life. Relative to baseline, patients were categorized as worse (≤ -5 points), no change (-5 points to < 5 points), little improvement (5 points to < 10 points), moderate to great improvement (10 points to < 20 points), and great to great improvement (≥ 20 points).

[0526] Results showed that at week 12, OLE participants had significant improvements in KCCQ scores that were sustained through week 24. The proportion of participants with clinically important improvement (overall summary score ≥ 5 points) was 72.7% at week 12 and 72.0% at week 24. Very great clinical improvement (≥ 20 points) was seen in 36.4% at week 12 and 40.0% at week 24. Fig.35 , Fig.36 Treatment with afibactam produced significant and sustained improvements in all KCCQ domain scores for up to 6 months.

[0527] in conclusion

[0528] In this open-label extension study of patients with obstructive HCM treated with background medical therapy (including disopyramide in some cases), afibactam was associated with significant and sustained LVOT gradient reduction ( Fig.28 and Fig.29 ) and substantial improvement in heart failure symptoms (approximately 80% of patients had an improvement in one or more NYHA class) ( Fig.31 and Fig.32 ) and cardiac biomarkers (NT-proBNP and hs-cTnI) were significantly associated with ( Fig.33 and Fig.34 ). Aficontan was well tolerated, and there were no events of LVEF < 50% caused by aficontan. These data show that the treatment effect of aficontan can last up to 6 months.

[0529] Example 3b

[0530] An open-label extension clinical trial of aficontan was initiated in patients with symptomatic oHCM. The duration of treatment is expected to be several years. The primary objective of the trial is to determine the safety and tolerability of aficontan over a 5-year period.

[0531] This study can enroll up to 275 patients. After a screening period of (up to) 56 days, eligible patients are given a daily dose of aficontan. The highest maximum tolerated dose is derived from other ongoing studies of aficontan. Each patient starts at the lowest pre-specified dose and undergoes echocardiographically guided dose titration to the maximum tolerated dose (not to exceed the highest pre-specified dose). Dose adjustments may be made no more frequently than every 2 weeks. Approximately 95 study sites in the United States, Europe, and the Middle East are participating in this study.

[0532] Inclusion criteria: (1) Completion of a study investigating afecontan (i.e., according to Example 2 or Example 5); (2) Able to understand and willing to sign the ICF, and willing to comply with all study procedures and restrictions for the duration specified in the activity schedule; (3) Left ventricular ejection fraction ≥ 55%.

[0533] Exclusion Criteria. (1) Has received marvacattan. (2) Has participated in another investigational device or drug study or received an investigational device or drug <1 month (or 5 half-lives of the drug, whichever is longer) prior to screening. No other study procedures are allowed while participating in this study. (3) Has any acute or serious comorbidity (e.g., major infection or hematologic, oncologic, cardiac, renal, metabolic, gastrointestinal, or endocrine dysfunction) that, in the opinion of the site principal investigator / designee or medical monitor, would pose a risk to patient safety or interfere with study evaluations, procedures, or completion. (4) Has new-onset paroxysmal or permanent atrial fibrillation within 30 days prior to screening, requiring rhythm-restoring therapy (e.g., direct current cardioversion, ablation procedure, or antiarrhythmic therapy). Patients may be rescreened after 30 days if heart rate (HR <100 bpm) and / or rhythm are stable for >30 days. (This exclusion does not apply if atrial fibrillation has been treated with anticoagulation and adequate heart rate control for ≥14 days). (5) Have received atrial septal narrowing therapy (surgical myectomy or transcatheter alcohol ablation) since completing a previous aficontan study. (6) Currently have obstructive coronary artery disease (documented >70% stenosis in one or more arteries). (7) Have moderate or severe aortic stenosis. (8) Have a confirmed LVEF <40% with associated dose interruptions during a previous study of aficontan (i.e., according to Example 2 or Example 5). Patients may be considered for entry if data from the participant cohort have been unblinded. (9) Have a history of syncope or sustained ventricular tachyarrhythmia exercise within 30 days prior to screening. (10) History of ICD placement within 30 days prior to screening. (11) Allergy to excipients in aficontan tablets (e.g., mannitol, microcrystalline cellulose, cross-linked carboxymethyl cellulose, hydroxypropyl cellulose, sodium lauryl sulfate, magnesium stearate, Opadry QX White 21A180025).

[0534] Study Design

[0535] On day 1, each patient underwent an echocardiogram; each patient received dose 1 of aficontan once daily for 2 weeks. At week 2, each patient underwent a truncated echocardiogram after administration of their dose. If LVOT-G after the Valsalva maneuver was ≥30 mmHg and biplane LVEF was ≥55%, the patient was titrated up to dose 2. Otherwise, the patient remained on 5 mg of aficontan. If LVEF was <50%, treatment was discontinued.

[0536] At Weeks 4, 6, 12, and every 12 weeks thereafter, each patient will undergo an echocardiogram or truncated echocardiogram (truncated echocardiogram at Weeks 4 and 6; and echocardiogram at Week 12 and every 12 weeks thereafter) after administration of their dose to determine if additional dose titration is needed (see Tables 21 and 22). Patient-reported outcomes, laboratory assessments, and measurements of NT-proBNP, hs-cTnI, and other biomarkers 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. Cardiac magnetic resonance will be monitored at Weeks 48, 144, and 240. If a patient has an LVEF <40% after the Week 2 visit, a repeat echocardiogram may be performed to confirm the initial findings (preferably within 24 hours). If the echocardiogram findings are confirmed, the patient will receive a ≥2-day medication holiday. Once regional echocardiography demonstrates an LVEF ≥ 55%, patients may continue to take afibactam at a reduced previously tolerated dose.

[0537] Table 21: Dose adjustment algorithm

[0538]

[0539] Table 22: Dosage regimen

[0540]

[0541] Echocardiography

[0542] The echocardiographic parameters to be measured include at least left ventricular parameters (resting left ventricular outflow tract pressure gradient (LVOT-G), LVOT-G after Valsalva maneuver, LVEF, LVFS, left ventricular strain, left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), LV stroke volume), ventricular septum and free wall thickness, E / e', E / A, LA volume.

[0543] Cardiac MRI

[0544] The Cardiac Magnetic Resonance (CMR) Imaging substudy evaluates the effects of chronically administered aficontan doses on cardiac morphology, function, and fibrosis in patients who are eligible and elect to participate. CMR is performed at baseline at any time during the screening period and may be performed up to 8 weeks prior to the first dose of aficontan on Day 1. Patients who fail screening and are rescreened do not need to repeat the baseline CMR. If the subject has enrolled in the Example 5 CMR substudy, a baseline CMR does not need to be repeated. eGFR <30 mL / min / 1.73 m 2Patients with 4-month follow-up or gadolinium allergy could receive non-contrast CMR only. Patients could also elect to have non-contrast CMR evaluation only for any other reason. Subsequent CMR studies were 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.

[0545] NYHA functional class was recorded. If available, patients completed patient-reported outcome (PRO) questionnaires: Kansas City Cardiomyopathy Questionnaire (KCCQ), Seattle Angina Questionnaire-7 (SAQ-7), EuroQol 5 Dimensions 5 Levels Instrument (EQ-5D-5L), Patient Global Impression of Change (PGI-C) scale, Clinical Global Impression (CGI) scale, SF-36 Physical Functioning subscale (SF-36 PFS), as specified in Table 23.

[0546] Table 23: Health status and health-related quality of life planning form

[0547]

[0548] Primary End Point

[0549] The primary objective of the trial was to determine the safety and tolerability of aficontan over a 5-year period, including assessment of cardiac structure and function during long-term administration of aficontan. Safety and tolerability were evaluated by each of the following: (i) the incidence of adverse events in patients, (ii) the incidence of serious adverse events in patients, and (iii) the incidence of patients with LVEF <50%.

[0550] Secondary End Points

[0551] Secondary objectives were to assess the long-term effects of afibactam on LVOT-G in patients with oHCM as assessed by peak LVOT-G at rest and during Valsalva challenge; the proportion of patients with each of the following: a) resting LVOT-G <50 mmHg, b) resting LVOT-G <30 mmHg; c) LVOT-G <50 mmHg after Valsalva maneuver, d) LVOT-G <30 mmHg after Valsalva maneuver, or e) LVEF ≥50%, resting LVOT-G <30 mmHg, and LVOT-G <50 mmHg after Valsalva maneuver; time to first resting LVOT-G <50 mmHg; time to first LVOT-G <30 mmHg after Valsalva maneuver; time to first LVOT-G <50 mmHg after Valsalva maneuver; and time to first LVEF ≥50%, resting LVOT-G <30 mmHg mmHg and the time during which LVOT-G is <50 mmHg after the Valsalva maneuver.

[0552] Exploratory endpoints

[0553] The exploratory objectives of the study included (i) evaluating the steady-state pharmacokinetics of afecontan during long-term administration, as measured by C 谷 (ii) to assess the long-term effects of aficontan on cardiac biomarkers, as assessed by changes from baseline in NT-proBNP, hs-cTnI, Galectin-3, PINP, TIMP-1, CITP, soluble ST2, and other biomarkers at 12-week intervals until the end of participation; (iii) to assess the effects on functional outcomes, such as changes from baseline in NYHA functional class at 12-week intervals until the end of participation; and (iv) to assess the effects on symptoms of oHCM, such as by changes from baseline in EQ-5D-5L, PGI-C, CGI, Kansas City Cardiomyopathy Questionnaire (KCCQ), SAQ-7, and SF-36 physical function subscale (SF-36 ... EQ-5D =(v) To evaluate the pharmacodynamic effects of aficontan on cardiac function and structure, as assessed by the change from baseline to the end of participation in the following echocardiographic measures of cardiac function and structure at 12-week intervals: LVEF; left ventricular fractional shortening (LVFS); left ventricular stroke volume (LVSV); left ventricular end-systolic volume and end-diastolic volume (LVESV and LVEDV, respectively); ventricular septum, free wall, and maximum wall thickness; left atrial volumes; left ventricular strain (longitudinal, circumferential, radial); diastolic indices: E / e', E / A; (vi) To evaluate the effects of aficontan on electrocardiographic indices of abnormal myocardial repolarization, as assessed by the change from baseline to the end of participation in the proportion of patients with an LV strain pattern on ECG at 12-week intervals; and (vii) To evaluate the effects of aficontan on cardiac structure. , as assessed by changes from baseline to 1, 3, and 5 years and the end of participation in the following measures of cardiac morphology and structure, assessed by cardiac magnetic resonance (CMR) imaging: RV and LV mass; ventricular septum, free wall, and maximum wall thickness; left atrial volume; end-diastolic volume (EDV); end-systolic volume (ESV); (viii) to assess the effect of aficontan on cardiac function, as assessed by changes from baseline to 1, 3, and 5 years and the end of participation in the following biventricular function, assessed by CMR imaging: stroke volume (SV); ejection fraction (EF); cardiac output (CO); (ix) to assess the effect of aficontan on cardiac fibrosis, as assessed by changes from baseline to 1, 3, and 5 years and the end of participation in the following CMR parameters with late gadolinium enhancement (LGE): LGE mass (g), LGE mass % (as % of LV mass).

[0554] Interim Results of Examples 3a and 3b

[0555] Patients were administered the regimen of Example 3a or Example 3b. If treated with at least one beta-blocker (BB), non-dihydropyridine calcium channel blocker (CCB) or disopyramide, the patient was classified as receiving SoC therapy (first-line and second-line). According to the decision of the on-site investigator, and after receiving a stable dose of aficontan for ≥4 weeks and after the 12th week of the study, the patient was eligible for background therapy reduction / discontinuation (BTR / W). Successful BTR / W was defined as reducing the dose of at least one drug to ≤ 50% of the baseline. Serial metrics were collected according to the protocol, but side effects specifically related to SoC therapy were not collected.

[0556] Of the first 42 patients enrolled, 39 (93%) were taking ≥1 SoC medication, and of these, 27 (69%) were receiving BB only, 4 (10%) were receiving CCB only, 7 (18%) were receiving CCB or BB and disopyramide, and 1 patient was receiving triple therapy (3%). Among patients who received aficontan for ≥12 weeks (N=35), 20 patients (57%) attempted BTR / W, and 17 patients (85%) achieved any successful BTR / W. Ten patients completely discontinued at least one medication, and 5 patients withdrew from all SoCs (aficontan monotherapy). Three patients failed to attempt BTR / W and resumed BB due to recurrence of symptoms or increased left ventricular outflow tract gradient (LVOT-G). The baseline characteristics of all included patients and the subgroups in this analysis are shown in Table 24A. The median baseline doses of β-blockers and calcium channel blockers are shown in Fig.44 middle.

[0557] All subgroups demonstrated rapid and sustained resolution of obstruction, improvements in cardiac biomarkers, and symptoms with modest decreases in LVEF ( Figure 39-42 ). In patients with available assessments both before and after BTR / W (N = 14), BTR / W increased resting HR by 12 bpm (mean HR = 74 ± 10 bpm, p = 0.0001) and LVOT-G with Valsalva maneuver by 15 mmHg (mean Valsalva maneuver 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. The investigators considered no safety events related to afibactam therapy. NT-proBNP and hs-troponin I levels are shown in Fig.45A and Fig.45Bmiddle.

[0558] Table 24A: Baseline Characteristics

[0559]

[0560]

[0561] Second interim results up to 48 weeks

[0562] A description of the baseline characteristics of the first 45 enrolled patients is shown in Table 24B.

[0563] Table 24B: Baseline Characteristics

[0564]

[0565] *On-site reading of screening echocardiogram

[0566] The number of patients and the dose achieved at each time point are shown in Fig.52 Peak resting and Valsalva maneuver LVOT-G significantly decreased from baseline to week 48 [Δ resting mean: –32 mmHg (±28); Δ Valsalva maneuver mean: –47 mmHg (±28)] (see Table 2, respectively). Fig.53 and Fig.54 ). There was a modest decrease in LVEF from baseline to Week 48 (Δ –5±3%), and no patient experienced an afibactam-related decrease in LVEF <50% (see Fig.55 ). There was a significant improvement in NYHA class: by week 48, 88% of patients experienced an improvement of ≥1 NYHA FC, while none experienced a worsening of NYHA FC (see Fig.56 ). At baseline, 19 patients (42%) were eligible for SRT based on symptom and hemodynamic guideline criteria, despite receiving beta-blockers (78%), calcium channel blockers (18%), and disopyramide (22%). (SRT eligibility: NYHA class III or IV with LVOT gradient ≥ 50 mmHg at rest or during Valsalva maneuver or exercise exertion, or NYHA class II with syncope or near-syncope on exertion and an elevated gradient). None of these patients met these criteria as of the Week 48 visit. NT pro-BNP decreased from baseline to Week 48 (from a geometric mean [CV%] of 651.0 [160.4] to 111.1 [93.4] pg / mL), representing a 70% decrease from baseline (p<0.0001).

[0567] Mid-term global longitudinal strain (GLS) results

[0568] Patients (n = 27; baseline characteristics in Table 24C) enrolled in the open-label extension trial of afibactam (FOREST HCM) underwent echocardiography (GE E-95 ultrasound machine) at baseline, week 12, and weeks 36 to 48. GLS analyses were performed using a vendor-neutral analysis package (TOMTEC® Imaging System).

[0569] Changes in NYHA functional class are shown in Fig.57A Compared with baseline, GLS was similar at week 12 (-13.9% ± 3.2 vs. -14.3 ± 3.0, p 0.32), followed by significant improvement in GLS at weeks 36-48 (-13.9% ± 3.2 vs. -14.9% ± 2.7, p 0.012) (see Fig.57B These improvements were more pronounced in those patients with optimal hemodynamic response (resting LVOTg <30 and Valsalva maneuver LVOTg <50 mmHg; n = 21) (see Fig.57C and Fig.57D ).

[0570] Table 24C. Baseline Characteristics

[0571]

[0572] in conclusion

[0573] According to the interim results, discontinuation or reduction of SoC medical therapy following treatment with afikinase was generally effective, safe, and associated with sustained substantial improvements in clinically relevant efficacy measures.

[0574] Treatment with afibactam was associated with rapid and sustained improvement in echocardiographic hemodynamics and significant improvement in NYHA class. Afibactam eliminated SRT eligibility in all guideline-eligible patients at baseline. There were no cases of systolic dysfunction (LVEF < 50%) attributable to afibactam.

[0575] After long-term treatment, afibactam therapy produced favorable effects on myocardial mechanics (e.g., GLS), and these changes were most pronounced in patients with optimal hemodynamic responses (resting LVOTg <30 and Valsalva maneuver LVOTg <50 mmHg). Without being bound by theory, potential underlying mechanisms may include long-term afterload reduction secondary to LVOTg reduction, leading to other pathological changes, as strain improvements occur weeks after gradient reduction.

[0576] Example 4

[0577] This was a phase 3, multicenter, randomized, double-blind, active-comparison trial in participants with symptomatic oHCM and elevated LVOT-G (see Fig.38 and Fig.58 Approximately 170 eligible participants were randomized in a 1:1 ratio to receive either afecontan or metoprolol. Randomization was stratified by CPET exercise modality (treadmill / bicycle) and recent diagnosis relative to chronic oHCM. Randomization was stratified as follows: 1) participants who were treatment-naive or currently untreated (no SOC medical therapy in the past 12 months), or recently diagnosed participants (oHCM history ≤ 12 months, with or without SOC therapy); and 2) participants with chronic oHCM (>12 months) who were currently being treated or had received SOC therapy in the past 12 months. The number of participants using the bicycle CPET exercise modality was capped at approximately 50%.

[0578] The overall objectives of this active comparative trial are to evaluate the safety and efficacy of afibactam as either: 1) first-line therapy for recently diagnosed and / or treatment-naive participants; or 2) monotherapy for participants who have previously received standard of care (SOC) medical therapy for symptomatic oHCM.

[0579] The primary objective of this trial is to evaluate the effect of aficontan on exercise capacity in patients with symptomatic oHCM. The indicated endpoint is the change from baseline to week 24 in peak oxygen uptake (pVO2) based on cardiopulmonary exercise testing (CPET).

[0580] The secondary objective of this trial was to evaluate the effect of afibactam on New York Heart Association (NYHA) functional class, as determined by the proportion of patients whose NYHA functional class improved by ≥1 category from baseline to Week 12 and Week 24.

[0581] Another secondary objective of the trial was to evaluate the effect of afibactam on patients' health status, as determined by the change from baseline to weeks 12 and 24 in the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS).

[0582] Another secondary objective of this trial was to evaluate the effect of aficontan on structural remodeling, as determined by the change from baseline to week 24 in left ventricular mass index (LVMI) or left atrial volume index (LAVI).

[0583] Another secondary objective of this trial was to evaluate the effect of afibactam on N-terminal pro-brain natriuretic peptide (NT-proBNP) levels from baseline to week 24.

[0584] Another secondary objective of this trial was to evaluate the effect of aficontan on left ventricular outflow tract gradient (LVOT-G) after the Valsalva maneuver from baseline to week 24.

[0585] To evaluate the safety and tolerability profile of afecontan in patients with symptomatic oHCM, the following were recorded: (1) the incidence of reported major adverse cardiac events (cardiovascular [CV] death, cardiac arrest, non-fatal stroke, non-fatal myocardial infarction, CV hospitalization); (2) the incidence of adverse events (AEs); and (3) the incidence of left ventricular ejection fraction (LVEF) < 50%.

[0586] The exploratory objectives of this trial were to evaluate the effect of afibactam on exercise capacity and functional class, as determined by the number of patients who achieved either of the following at Week 24 compared with baseline: (1) a change in pVO2 from baseline of ≥1.5 mL / kg / min and an improvement in NYHA functional class of ≥1 category; or (2) a change in pVO2 from baseline of ≥3.0 mL / kg / min and no worsening in NYHA functional class.

[0587] Additional exploratory objectives of this trial were to evaluate the effect of afibactam on patient response over time as determined by: (1) the proportion of patients with improvement in KCCQ-CSS at Weeks 12 and 24; (2) the proportion of patients with resting LVOT-G <30 mmHg, LVOT-G <50 mmHg after Valsalva maneuver, and NYHA functional class I at Weeks 12 and 24; and (3) the proportion of patients with resting LVOT-G <30 mmHg, LVOT-G <50 mmHg after Valsalva maneuver, and an improvement in NYHA functional class of ≥ 1 category at Weeks 12 and 24.

[0588] Another exploratory objective of this trial was to evaluate the effect of aficontin on cardiac troponin levels, as determined by the change from baseline to week 24 in high-sensitivity cardiac troponin I (hs-cTnI).

[0589] Another exploratory objective of this trial was to evaluate the effect of aficontan on measures of diastolic function as determined by the change from baseline to Week 24 in the ratio of early mitral inflow velocity to early mitral annular diastolic velocity (E / e' [lateral wall]).

[0590] Another exploratory objective of this trial was to evaluate the effect of aficontan on ventricular septum thickness (IVST) remodeling as determined by the change in IVST from baseline to Week 24.

[0591] Another exploratory objective of this trial was to evaluate the effect of afibactam on other CPET parameters as determined by the change from baseline to Week 24 in each of the following: (1) ventilator efficiency / carbon dioxide production (VE / VCO2 slope); (2) circulatory power (VO2 x systolic blood pressure [SBP]); (3) ventilator anaerobic threshold (VAT); total workload (Watts); and heart rate response.

[0592] Another exploratory objective of this trial was to evaluate the effect of afibactam on health status as measured by PRO questionnaires and health-related quality of life as determined by the change from baseline to week 24 in individual responses to the EuroQol 5 Dimensions 5 Levels Instrument (EQ-5D-5L), Clinical Global Impression (CGI), Patient Global Impression of Change (PGI-C), and Seattle Angina Questionnaire-7 (SAQ-7).

[0593] Another exploratory objective of this trial was to evaluate the pharmacokinetics of aficontan and its metabolites as determined by pharmacokinetic parameters up to Week 24.

[0594] Inclusion criteria

[0595] Patients were eligible for inclusion in the trial only if all of the following criteria applied: (1) Able to understand and willing to sign the ICF and willing to comply with all trial procedures and restrictions for the duration specified in the activity schedule. (2) Males and females aged between 18 and 85 years (inclusive) at screening. (3) Body mass index <35 kg / m 2(4) Diagnosed with oHCM by cardiac magnetic resonance imaging (CMR) or echocardiography according to the following criteria: (a) left ventricular hypertrophy without left ventricular dilatation and no other cardiac disease, and (b) minimum wall thickness ≥ 15...

Claims

1. A method of treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of afecontan (Aphiconazole), or a pharmaceutically acceptable salt thereof, wherein the patient has been diagnosed with oHCM within 12 months prior to the administration of aficontan or a pharmaceutically acceptable salt thereof.

2. A method of treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of aficontan (Aphiconazole), or a pharmaceutically acceptable salt thereof, wherein the patient has not received oHCM treatment.

3. The method of claim 1 or 2, wherein the method comprises administering aficontan or a pharmaceutically acceptable salt thereof as a monotherapy for oHCM.

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

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

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

7. The method of any one of claims 1-6, wherein the patient has a resting LVOT-G of ≥ 30 mm Hg prior to administration of aficontan or a pharmaceutically acceptable salt thereof.

8. The method of any one of claims 1-7, wherein prior to administration of aficontan or a pharmaceutically acceptable salt thereof, the patient has a LVOT-G after a Valsalva maneuver of ≥ 50 mmHg.

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

10. The method of any one of claims 1-9, wherein the method improves one or more of: exercise capacity; cardiac function as measured by improvement in NYHA functional class; resting LVOT-G; LVOT-G after Valsalva maneuver; 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 pro-brain natriuretic peptide (NT-proBNP) level; high-sensitivity cardiac troponin I (hs-cTnI) level; diastolic function as measured by a reduction in lateral E / e'; ventricular septal thickness remodeling as measured by changes in ventricular septal thickness (IVST); CPET parameters selected from the group consisting of 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 a patient-reported outcome (PRO) questionnaire EuroQol Health status and health-related quality of life measured by the 5-dimensional 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. The method of claim 10, wherein the outcome is improved compared to treatment with metoprolol.

12. The method of any one of claims 10 or 11, wherein the method improves exercise capacity as measured by an increase in peak oxygen uptake (pVO2) according to cardiopulmonary exercise testing (CPET).

13. The method of any one of claims 10-12, wherein the method improves cardiac function as measured by an improvement in one or more categories of the NYHA functional classification.

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

15. The method of any one of claims 10-13, wherein the method improves exercise capacity as measured by an increase in pVO2 of at least 3.0 mL / kg / min compared to baseline and no worsening of NYHA functional class.

16. The method of any one of claims 10-13, wherein the method produces a resting LVOT-G of less than 30 mmHg, a post-Valsalas LVOT-G of less than 50 mmHg, and NYHA class I.

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

18. The method of any one of claims 10-17, wherein the method improves health status as measured by the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS).

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

20. The method of any one of claims 10-19, wherein the method reduces N-terminal pro-brain natriuretic peptide (NT-proBNP).

21. The method of any one of claims 10-20, wherein the method improves left ventricular outflow tract gradient (LVOT-G) after Valsalva maneuver.

22. The method of any one of claims 10-21, wherein the method reduces high-sensitivity cardiac troponin I (hs-cTnI).

23. The method of any one of claims 10-22, wherein the method improves diastolic function as measured by a reduction in lateral E / e'.

24. The method of any one of claims 10-23, wherein the method produces ventricular septum thickness remodeling as measured by changes in intraventricular septum thickness (IVST).

25. The method of any one of claims 10-24, wherein the method improves one or more CPET parameters selected from the group consisting of: ventilatory efficiency / carbon dioxide production (VE / VCO2 slope), cyclic power (VO2 x systolic blood pressure), ventilatory anaerobic threshold (VAT), total workload (Watts), and heart rate response.

26. The method of any one of claims 10-25, wherein the method improves health status and health-related quality of life as measured by the patient-reported outcome (PRO) questionnaire EuroQol 5 Dimensions 5 Levels Instrument (EQ-5D-5L), Clinical Global Impression (CGI), Patient Global Impression of Change (PGI-C), and Seattle Angina Questionnaire-7 (SAQ-7).

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

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

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

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

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

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. The method of any one of claims 1 to 32, comprising: administering to the patient a first daily dose of aficontan or a pharmaceutically acceptable salt thereof for a first period of time; as well as Based on one or more components of the patient's first echocardiogram obtained after the first period of time, administering a second daily dose of aficontan or a pharmaceutically acceptable salt thereof to the patient for a second period of time, or terminating the administration of aficontan or a pharmaceutically acceptable salt thereof to the patient.

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

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

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

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

38. The method of any one of claims 33-36, wherein the one or more components of the first echocardiogram comprise a biplane LVEF, and when the biplane LVEF of the first echocardiogram is equal to or above the predetermined biplane LVEF threshold and below a second predetermined biplane LVEF threshold, the second daily dose of aficontan or a pharmaceutically acceptable salt thereof is the same as the first daily dose of aficontan or a pharmaceutically acceptable salt thereof.

39. The method of any one of claims 33-36, wherein the one or more components of the first echocardiogram comprise biplane LVEF and post-Valsalva maneuver LVOT-G, and wherein the second daily dose of aficontan or a pharmaceutically acceptable salt thereof is the same as the first daily dose of aficontan or a pharmaceutically acceptable salt thereof when: (i) the biplane LVEF of the first echocardiogram is equal to or above the second predetermined biplane LVEF threshold and (ii) the post-Valsalva maneuver LVOT-G of the first echocardiogram is below a predetermined post-Valsalva maneuver LVOT-G threshold.

40. The method of any one of claims 33-36, wherein the one or more components of the first echocardiogram comprise biplane LVEF and LVOT-G after Valsalva maneuver, and wherein the second daily dose of aficontan or a pharmaceutically acceptable salt thereof is greater than the first daily dose of aficontan or a pharmaceutically acceptable salt thereof when: (i) the biplane LVEF is equal to or above the second predetermined biplane LVEF threshold and (ii) the LVOT-G after Valsalva maneuver is equal to or above the predetermined LVOT-G threshold after Valsalva maneuver.

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

42. The method of any one of claims 33 to 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. The method of any one of claims 33-35, wherein the one or more components of the first echocardiogram comprise a biplane LVEF, and wherein the administration of aficontan or a pharmaceutically acceptable salt thereof to the patient is terminated when the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold.

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

45. The method of claim 43 or 44, wherein the first period of time is about 2 weeks.

46. ​​The method of any one of claims 33-42, wherein the second daily dose of aficontan or a pharmaceutically acceptable salt thereof is administered to the patient for the second period of time, the method further comprising administering a third daily dose of aficontan or a pharmaceutically acceptable salt thereof to the patient for a third period of time, or terminating the administration of aficontan 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 aficontan or a pharmaceutically acceptable salt thereof.

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

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

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

50. The method of any one of claims 46-49, wherein the one or more components of the second echocardiogram comprise a biplane LVEF, and the third daily dose of aficontan or a pharmaceutically acceptable salt thereof is lower than the second daily dose of aficontan or a pharmaceutically acceptable salt thereof when: (i) the biplane LVEF of the second echocardiogram is lower than the predetermined biplane LVEF threshold and (ii) the second daily dose of aficontan or a pharmaceutically acceptable salt thereof is higher than the first daily dose of aficontan or a pharmaceutically acceptable salt thereof.

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

52. The method of any one of claims 46-49, wherein the one or more components of the second echocardiogram comprise a biplane LVEF, and wherein the third daily dose of aficontan or a pharmaceutically acceptable salt thereof is the same as the second daily dose of aficontan or a pharmaceutically acceptable salt thereof when the biplane LVEF of the second echocardiogram is equal to or above the predetermined biplane LVEF threshold and below the second predetermined biplane LVEF threshold.

53. The method of any one of claims 46-49, wherein the one or more components of the second echocardiogram comprise biplane LVEF and post-Valsalverhall LVOT-G, and wherein the third daily dose of aficontan or a pharmaceutically acceptable salt thereof is the same as the second daily dose of aficontan or a pharmaceutically acceptable salt thereof when: (i) the biplane LVEF of the second echocardiogram is equal to or above the second predetermined biplane LVEF threshold and (ii) the post-Valsalverhall LVOT-G of the second echocardiogram is below the predetermined post-Valsalverhall LVOT-G threshold.

54. The method of any one of claims 46-49, wherein the one or more components of the second echocardiogram comprise biplane LVEF and post-Valsdale maneuver LVOT-G, and wherein the third daily dose of aficontan or a pharmaceutically acceptable salt thereof is greater than the second daily dose of aficontan or a pharmaceutically acceptable salt thereof when: (i) the biplane LVEF is equal to or above the second predetermined biplane LVEF threshold and (ii) the post-Valsdale maneuver LVOT-G is equal to or above the predetermined post-Valsdale maneuver LVOT-G threshold.

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

56. The method of any one of claims 46-55, wherein the third period of time is about 2 weeks.

57. The method of any one of claims 46-48, wherein the one or more components of the second echocardiogram comprise a biplane LVEF, and wherein the administration of aficontan or a pharmaceutically acceptable salt thereof to the patient is terminated when: (i) the biplane LVEF of the second echocardiogram is below the predetermined biplane LVEF threshold and (ii) the second daily dose of aficontan or a pharmaceutically acceptable salt thereof is the same as the first daily dose of aficontan or a pharmaceutically acceptable salt thereof.

58. The method of any one of claims 46-56, wherein the third daily dose of aficontan or a pharmaceutically acceptable salt thereof is administered to the patient for the third period of time, the method further comprising administering a fourth daily dose of aficontan or a pharmaceutically acceptable salt thereof to the patient for the fourth period of time, or terminating the administration of aficontan 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 aficontan or a pharmaceutically acceptable salt thereof.

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

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

61. The method of claim 58, further comprising selecting the fourth daily dose of aficontan 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 58-61, wherein the one or more components of the third echocardiogram comprise a biplane LVEF, and the fourth daily dose of aficontan or a pharmaceutically acceptable salt thereof is lower than the third daily dose of aficontan or a pharmaceutically acceptable salt thereof when: (i) the biplane LVEF of the third echocardiogram is lower than the predetermined biplane LVEF threshold and (ii) the third daily dose of aficontan or a pharmaceutically acceptable salt thereof is higher than the first daily dose of aficontan or a pharmaceutically acceptable salt thereof.

63. The method of any one of claims 58-61, wherein the one or more components of the third echocardiogram comprise a biplane LVEF, and wherein the fourth daily dose of aficontan or a pharmaceutically acceptable salt thereof is the same as the third daily dose of aficontan or a pharmaceutically acceptable salt thereof when the biplane LVEF of the second echocardiogram is equal to or above the predetermined biplane LVEF threshold and below the second predetermined biplane LVEF threshold.

64. The method of any one of claims 58-61, wherein the one or more components of the third echocardiogram comprise biplane LVEF and LVOT-G after Valsalva maneuver, and wherein the fourth daily dose of aficontan or a pharmaceutically acceptable salt thereof is the same as the third daily dose of aficontan or a pharmaceutically acceptable salt thereof when: (i) the biplane LVEF of the third echocardiogram is equal to or above the second predetermined biplane LVEF threshold and (ii) the LVOT-G after Valsalva maneuver of the third echocardiogram is below the predetermined LVOT-G threshold.

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

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

67. The method of any one of claims 58-66, wherein the fourth period of time is about 2 weeks.

68. The method of any one of claims 58-60, wherein the one or more components of the third echocardiogram comprise a biplane LVEF, and wherein the administration of aficontan or a pharmaceutically acceptable salt thereof to the patient is terminated when: (i) the biplane LVEF of the second echocardiogram is below the predetermined biplane LVEF threshold and (ii) the third daily dose of aficontan or a pharmaceutically acceptable salt thereof is the same as the first daily dose of aficontan or a pharmaceutically acceptable salt thereof.

69. The method of any one of claims 37-68, wherein (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-Valsalas LVOT-G threshold is 30 mmHg; (d) the second predetermined biplane LVEF threshold is 55%, and the predetermined post-Valsalas 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-Valsalas LVOT-G threshold is 30 mmHg.

70. A method of treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, wherein the patient is receiving one or more background therapies for oHCM, the method comprising (1) administering to the patient a therapeutically effective amount of afecontan (Aphiconazole), or a pharmaceutically acceptable salt thereof, and (2) reducing and / or stopping at least one background therapy.

71. The method of claim 70, wherein the method comprises reducing at least one background therapy.

72. The method of claim 70 or 71, wherein the method comprises discontinuing at least one background therapy.

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 a beta blocker, a non-dihydropyridine calcium channel blocker, and disopyramide.

74. The method of any one of claims 70-73, wherein reducing at least one background therapy comprises administering a lower dose of at least one background therapy, wherein the lower dose is 50% or less of the original dose of the background therapy.

75. The method of any one of claims 70-74, wherein all of the one or more background therapies are discontinued.

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

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

78. The method of any one of claims 70-77, wherein reduction and / or cessation of said at least one background therapy is performed after initiation of said administration of aficontan or a pharmaceutically acceptable salt thereof.

79. The method of any one of claims 70-77, wherein reducing and / or stopping the at least one background therapy is performed 2 weeks or more after initiating the administration of aficontan or a pharmaceutically acceptable salt thereof.

80. The method of any one of claims 70-77, wherein reducing and / or stopping the at least one background therapy is performed 12 weeks or more after initiating the administration of aficontan or a pharmaceutically acceptable salt thereof.

81. The method of any one of claims 70-77, wherein reducing and / or stopping the at least one background therapy is performed when the patient has been receiving a stable dose of aficontan or a pharmaceutically acceptable salt thereof for 2 weeks or more.

82. The method of any one of claims 70-77, wherein reducing and / or stopping the at least one background therapy is performed when the patient has been receiving a stable dose of aficontan or a pharmaceutically acceptable salt thereof for 4 weeks or more.

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

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

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

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

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

88. The method of any one of claims 70-87, wherein the daily dose of aficontan or a pharmaceutically acceptable salt thereof is administered to the patient in a constant amount for about two weeks prior to titrating the daily dose.

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

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. A method of treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, the method comprising: (1) administering a therapeutically effective amount of aficontin to the patient (Aphiconazole), or a pharmaceutically acceptable salt thereof, and a first dose of a standard of care therapeutic for oHCM, for a first period of time; as well as (2) administering to the patient a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof and a second dose of the standard of care treatment for oHCM for a second period of time, wherein said second dose of said standard of care therapeutic for oHCM is lower than said first dose of said standard of care therapeutic.

92. The method of claim 91, wherein the second dose of the standard of care therapeutic for oHCM is 50% or less of the first dose of the standard of care therapeutic.

93. A method of treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, the method comprising: (1) administering a therapeutically effective amount of aficontin to the patient (Aphiconazole), or a pharmaceutically acceptable salt thereof, and a standard of care therapeutic for oHCM, for a first period; as well as (2) administering a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof as a monotherapy to the patient for a second period of time.

94. The method of any one of claims 91-93, wherein the patient in need thereof has been receiving the standard of care treatment for oHCM prior to administration of aficontan.

95. A method of treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, the method comprising: (1) administering to the patient a background therapy comprising at least one standard of care therapeutic agent selected from the group consisting of a beta blocker, a non-dihydropyridine calcium channel blocker, and disopyramide; (2) administering a therapeutically effective amount of aficontin to the patient (Aphiconazole), or a pharmaceutically acceptable salt thereof, and said background therapy, for a first period of time; as well as (3) administering to the patient a therapeutically effective amount of aficontan or a pharmaceutically acceptable salt thereof and a second dose of the standard of care treatment for oHCM for a second period of time, wherein said second dose of said standard of care therapeutic for oHCM is lower than said first dose of said standard of care therapeutic.

96. The method of claim 95, wherein the second dose of the standard of care therapeutic for oHCM is 50% or less of the first dose of the standard of care therapeutic.

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

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

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

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

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

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

103. The method of any one of claims 99-102, wherein the daily dose of aficontan or a pharmaceutically acceptable salt thereof is administered to the patient in a constant amount for about two weeks prior to titrating the daily dose.

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

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 of improving myocardial mechanics in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of aficontan (Aficontan) or a pharmaceutically acceptable salt thereof, wherein the patient suffers from obstructive hypertrophic cardiomyopathy (oHCM).

107. A method of improving global longitudinal strain (GLS) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of aphiconazole (Aphiconazole), or a pharmaceutically acceptable salt thereof, wherein the patient suffers from obstructive hypertrophic cardiomyopathy (oHCM).

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

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

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

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

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. The method of any one of claims 106-112, wherein aficontan or a pharmaceutically acceptable salt thereof is administered once daily.

114. The method of any one of claims 111-113, wherein the method comprises administering aficontan or a pharmaceutically acceptable salt thereof for at least about 12 weeks.

115. The method of any one of claims 111-113, wherein the method comprises administering aficontan or a pharmaceutically acceptable salt thereof for at least about 36 weeks.

116. The method of any one of claims 111-113, wherein the method comprises administering aficontan or a pharmaceutically acceptable salt thereof for at least about 48 weeks.

117. The method of any one of claims 111-116, wherein the method produces a resting LVOT-G of less than 30 mmHg.

118. The method of any one of claims 111-117, wherein the method produces a Valsalva maneuver LVOT-G of less than 50 mmHg.

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

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

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

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

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

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 method of claim 123, wherein the tablet comprises: (i) about 1% to about 50% by weight of said aficontan 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) from about 0.1% to about 10% by weight hydroxypropyl cellulose; (iv) from about 1% to about 10% by weight of croscarmellose sodium; (v) from about 0.1% to about 10% by weight sodium lauryl sulfate; and (vi) from about 0.1% to about 10% by weight of magnesium stearate, The weight % stated does not include the weight of any coating that may be present.

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

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