HK40122885A - Methods for treating obstructive hypertrophic cardiomyopathy - Google Patents

Description

Methods for treating obstructive hypertrophic cardiomyopathy

Cross-reference to related applications

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

Technical Field

The disclosure of this article relates to the treatment of obstructive hypertrophic cardiomyopathy and compounds and compositions that can be used to treat obstructive hypertrophic cardiomyopathy.

Background Technology

Hypertrophic cardiomyopathy (HCM) is a disease in which the heart muscle (myocardial layer) becomes abnormally thickened (hypertrophic). This thickening of the heart muscle causes the left ventricle to become smaller and stiffer, and therefore the ventricle becomes less able to relax and fill with blood. Consequently, patients with obstructive hypertrophic cardiomyopathy may suffer from diastolic abnormalities and mitral regurgitation (MR). This ultimately limits the heart's pumping function, leading to symptoms including chest pain, dizziness, shortness of breath, or syncope during physical activity. A subgroup of patients with HCM is at high risk of progressive disease, which can lead to atrial fibrillation, stroke, and death from arrhythmias. Adverse cardiac remodeling in HCM is a known risk factor for progression to arrhythmias and heart failure. Therefore, treatments to address this condition are needed.

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 properties. While 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 recently diagnosed oHCM patients and patients with chronic symptomatic oHCM require treatments that improve exercise capacity compared to beta-blockers.

Summary of the Invention

This document describes methods and compositions for treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM), including administration of the cardiac myosin inhibitor afenacin (aficamten) or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure provides methods for improving the exercise capacity of a patient, such as a patient with oHCM, including administering or delivering afenacin as described herein or a pharmaceutically acceptable salt thereof to said patient. In some embodiments, this disclosure provides methods for reducing the symptom burden, improving hemodynamics, and improving the exercise capacity of a patient, such as a patient with oHCM, including administering or delivering afenacin as described herein or a pharmaceutically acceptable salt thereof to said patient. The methods disclosed herein may be used to treat patients recently diagnosed with oHCM (diagnosed within 12 months prior to administration of afenacin or a pharmaceutically acceptable salt thereof). Patients recently diagnosed with oHCM may include treatment-naïve patients and patients who have received or are receiving standard of care (SOC) medical therapy for oHCM. The methods disclosed herein may be used to treat treatment-naïve patients (who have not yet been treated for oHCM). The methods disclosed herein may be used to treat patients with chronic oHCM. Patients with chronic oHCM include those with a history of oHCM >12 months who are currently receiving SOC therapy for oHCM, or those who received SOC therapy for oHCM within 12 months prior to administration of afecontan or a pharmaceutically acceptable salt thereof. SOC therapy includes treatment of oHCM, including administration of beta-blockers, calcium channel blockers, or disopyramide.

In some implementations of the methods disclosed herein, the methods include administering afencontan or a pharmaceutically acceptable salt thereof as monotherapy for oHCM. It should be understood that administering oHCM monotherapy indicates that the patient receives only one therapy for oHCM (e.g., afencontan or a pharmaceutically acceptable salt thereof); however, it should be understood that the patient may also receive other therapies or therapies for other conditions. As described herein, “other therapies or therapies for other conditions” excludes 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 afencontan may be titrated based on echocardiographic results.

In some embodiments of the methods disclosed herein, the patient prior to administration of afecontan or a pharmaceutically acceptable salt thereof has one or more of the following: LVEF ≥ 60%; resting LVOT-G ≥ 30 mm Hg; LVOT-G ≥ 50 mm Hg after Valsalva maneuver; NYHA Class II or 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 mm Hg, peak LVOT-G ≥ 50 mm Hg after Valsalva maneuver, is characterized as being in NYHA functional Class II or III, and _pVO2 < 80% (measured or predicted).

In some implementations of the methods disclosed herein, administration of afecontan or a pharmaceutically acceptable salt thereof improves one or more of the following: exercise capacity; cardiac function as measured by improvement in NYHA functional classification; resting LVOT-G; post-Varva action LVOT-G; health status as measured by the Kansas City Cardiomyopathy Questionnaire Clinical Pool Score (KCCQ-CSS); structural remodeling as measured by a reduction in one or more of the mean left ventricular mass index (LVMI) and left atrial volume index (LAVI); N-terminal pro-brain natriuretic peptide (NT-proBNP) levels; high-sensitivity cardiac troponin I (hs-cTnI) levels; and by Lateral E/e' reduction measures diastolic function; ventricular septal thickness remodeling measures ventricular septal thickness (IVST) remodeling; CPET parameters selected from the following: ventilation efficiency/carbon dioxide production (VE/VCO2 slope), circulatory power (VO2 × systolic blood pressure), ventilatory anaerobic threshold (VAT), total workload (watts), and heart rate response; and health status and health-related quality of life measured by the EuroQol 5-dimensional 5-level tool (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 afecontan or a pharmaceutically acceptable salt thereof improves one or more of the following: exercise capacity; cardiac function as measured by improvement in the NYHA functional classification; resting LVOT-G; post-Varva action LVOT-G; health status as measured by the Kansas City Cardiomyopathy Questionnaire Clinical Pool Score (KCCQ-CSS); structural remodeling as measured by a reduction in one or more of the mean left ventricular mass index (LVMI) and left atrial volume index (LAVI); N-terminal pro-brain natriuretic peptide (NT-proBNP) levels; high-sensitivity cardiac troponin I (hs-cTnI) levels; and lateral E/e' The reduction in diastolic function is measured by the decrease in ventricular septal thickness (IVST) remodeling; 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 are measured by the EuroQol 5-dimensional 5-level tool (EQ-5D-5L), Clinical Global Impression (CGI), Patient Global Impression (PGI-C), Seattle Angina Questionnaire-7 (SAQ-7), and Short Form Survey (SF-36). In some implementations, one or more improved outcomes are achieved compared to treatment with SOC therapy (e.g., metoprolol). In some implementations, administration with afecontan or a pharmaceutically acceptable salt thereof improves HCM symptoms, such as chest pain, dizziness, shortness of breath, syncope during physical activity, fatigue, lack of energy, and limited physical activity.

Methods of treating obstructive hypertrophic cardiomyopathy (oHCM) in patients in need may include administering a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof to the patient, wherein the therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof is selected by titrating a daily dose of afecontan 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 dose for approximately two weeks.

In some implementations of the above methods, afecontan or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 5 mg to about 20 mg. In some embodiments, the daily dose is about 5 mg. In some embodiments, the daily dose is about 10 mg. In some embodiments, the daily dose is about 15 mg. In some embodiments, the daily dose is about 20 mg. For example, as described herein, in some embodiments, the patient starts with 5 mg once daily; at approximately weeks 2, 4, and 6, the patient undergoes echocardiography to determine whether the dose should be titrated up to 10, 15, or 20 mg; if the patient's post-Valveolar action LVOT-G ≥30 mmHg and biplane left ventricular ejection fraction (LVEF) ≥55%, a 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 below 50%, a down titration may be performed. For information on increasing, maintaining, decreasing, or discontinuing the dose, see, for example, Table 26. As understood by those skilled in the art and as described herein, unless otherwise stated, the amount (e.g., in a dosage) is the amount of afecontan free base, or the corresponding amount of afecontan free base when administered in a non-free base form, such as a pharmaceutically acceptable salt.

In some implementations, the daily dose is administered as a single daily dose. In other implementations, the daily dose is administered in two divided doses.

In some embodiments, a method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need includes: administering a first-day dose of afencontan or a pharmaceutically acceptable salt thereof to the patient for a first time period; and, based on one or more portions of a first echocardiogram of the patient obtained after the first time period, administering a second-day dose of afencontan or a pharmaceutically acceptable salt thereof to the patient for a second time period, or discontinuing the administration of afencontan or a pharmaceutically acceptable salt thereof to the patient. The method may include selecting a second-day dose of afencontan or a pharmaceutically acceptable salt thereof based on one or more portions of the first echocardiogram. In some embodiments, one or more portions of the first echocardiogram include biplane LVEF, or biplane LVEF and LVOT-G after a Warburg maneuver. In some embodiments, one or more portions of the first echocardiogram include biplane LVEF. In some embodiments, one or more portions of the first echocardiogram include biplane LVEF and LVOT-G after a Warburg maneuver. In some embodiments of the method described herein, the patient undergoes two or more echocardiograms during a first time period, and the second-day dose is selected based on the combined results of the two or more echocardiograms obtained during the first time period.

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

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

In some implementations of the above method, one or more components of the first echocardiogram include biplane LVEF, and wherein when the biplane LVEF of the first echocardiogram is equal to or higher than a predetermined biplane LVEF threshold and lower than a second predetermined biplane LVEF threshold, the second-day dose of afecontan or a pharmaceutically acceptable salt thereof is the same as the first-day dose of afecontan or a pharmaceutically acceptable salt thereof. In some embodiments, the predetermined biplane LVEF threshold is 50%, and the second predetermined biplane LVEF threshold is 55%.

In some implementations of the above method, one or more components of the first echocardiogram include biplane LVEF and post-Warshall action LVOT-G, and wherein when the biplane LVEF of the first echocardiogram is equal to or higher than a second predetermined biplane LVEF threshold and the post-Warshall action LVOT-G of the first echocardiogram is lower than a predetermined post-Warshall action LVOT-G threshold, the second-day dose of afecontan or a pharmaceutically acceptable salt thereof is the same as the first-day dose of afecontan or a pharmaceutically acceptable salt thereof. In some embodiments, the second predetermined biplane LVEF threshold is 55%, and the predetermined post-Warshall action LVOT-G threshold is 30 mmHg.

In some implementations of the above method, one or more components of the first echocardiogram include biplane LVEF and post-Warshall action LVOT-G, and wherein when the biplane LVEF is equal to or higher than a second predetermined biplane LVEF threshold and the post-Warshall action LVOT-G is equal to or higher than a predetermined post-Warshall action LVOT-G threshold, the second-day dose of afecontan or a pharmaceutically acceptable salt thereof is greater than the first-day dose of afecontan or a pharmaceutically acceptable salt thereof. In some embodiments, the predetermined biplane LVEF threshold is 55%, and the post-Warshall action LVOT-G threshold is 30 mmHg.

In some implementations of the above methods, the first-day dose of afecontan or a pharmaceutically acceptable salt thereof is about 5 mg of afecontan. In some embodiments, the second-day dose of afecontan or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg of afecontan. In some implementations of the above methods, the first-day dose of afecontan or a pharmaceutically acceptable salt thereof is about 5 mg of afecontan and the second-day dose is about 10 mg of afecontan.

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

In some implementations of the above methods, the first time period is approximately two weeks. In some implementations, the second time period is approximately two weeks. For example, as described herein, in some implementations, the provided methods include:

The patient is given a first-day dose of afecontan or a pharmaceutically acceptable salt thereof for a first period of time, wherein the first-day dose is about 5 mg of afecontan and the first period of time is about 2 weeks;

After the first time period, assess the patient's LVOT-G and LVEF following the Valsalva maneuver (e.g., using echocardiography); and

If the patient's LVOT-G ≥30 mmHg and LVEF ≥55% after the Valsalva maneuver, the patient is given a second-day dose of afecontan or a pharmaceutically acceptable salt thereof, wherein the second-day dose is about 10 mg of afecontan; and if the patient's LVOT-G <30 mmHg or LVEF <55% after the Valsalva maneuver, the patient is given a second-day dose of afecontan or a pharmaceutically acceptable salt thereof, wherein the second-day dose is about 5 mg of afecontan.

As described herein, in some implementations, the second-day dose is administered for a second period (e.g., approximately 2 weeks) after assessing the patient’s Valsalva maneuver and LVOT-G and LVEF.

In some implementations of the above method, the patient is given a second-day dose of afencontan or a pharmaceutically acceptable salt thereof for a second time period, and the method further includes, based on one or more components of a second echocardiogram of the patient obtained after the second time period and the second-day dose of afencontan or a pharmaceutically acceptable salt thereof, giving the patient a third-day dose of afencontan or a pharmaceutically acceptable salt thereof for a third time period, or terminating the administration of afencontan or a pharmaceutically acceptable salt thereof to the patient. In some embodiments, the method includes selecting a third-day dose of afencontan or a pharmaceutically acceptable salt thereof based on one or more components of the second echocardiogram and the second-day dose. In some embodiments, one or more components of the second echocardiogram include biplane LVEF or LVOT-G after a Valsalva maneuver. In some embodiments, one or more components of the second echocardiogram include biplane LVEF. In some embodiments, one or more components of the second echocardiogram include biplane LVEF and LVOT-G after a Valsalva maneuver. In some embodiments of the method described herein, the patient undergoes two or more echocardiograms during a second time period, and the third-day dose is selected based on the combined results of the two or more echocardiograms obtained during the second time period.

In some embodiments of the above method, one or more components of the second echocardiogram include biplane LVEF, and when the biplane LVEF of the second echocardiogram is below a predetermined biplane LVEF threshold, the third-day dose of afencontan or a pharmaceutically acceptable salt thereof is lower than the second-day dose of afencontan or a pharmaceutically acceptable salt thereof, or administration of afencontan or a pharmaceutically acceptable salt thereof to the patient is terminated. In some embodiments, the predetermined biplane LVEF threshold is 50%.

In some embodiments of the above method, administration of afecontan or a pharmaceutically acceptable salt to the patient is terminated when the biplane LVEF of the second echocardiogram is below a predetermined biplane LVEF threshold and the second-day dose of afecontan or a pharmaceutically acceptable salt thereof is equal to or less than the first-day dose of afecontan. In some embodiments, the predetermined biplane LVEF threshold is 50%.

In some embodiments of the above method, when the second-day dose of afencontan or a pharmaceutically acceptable salt thereof is higher than the first-day dose of afencontan or a pharmaceutically acceptable salt thereof, and the biplane LVEF of the second echocardiogram is lower than a predetermined biplane LVEF threshold, the third-day dose of afencontan or a pharmaceutically acceptable salt thereof is lower than the second-day dose of afencontan or a pharmaceutically acceptable salt thereof. In some embodiments, the predetermined biplane LVEF threshold is 50%. In some embodiments, the third-day dose of afencontan or a pharmaceutically acceptable salt thereof is the same as the first-day dose of afencontan or a pharmaceutically acceptable salt thereof.

In some embodiments of the above method, one or more components of the second echocardiogram include biplane LVEF, and wherein when the biplane LVEF is equal to or higher than a predetermined biplane LVEF threshold and lower than a second predetermined biplane LVEF threshold, the third-day dose of afecontan or a pharmaceutically acceptable salt thereof is the same as the second-day dose of afecontan or a pharmaceutically acceptable salt thereof. In some embodiments, the predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the second predetermined post-Valveolar action LVOT-G threshold is 30 mmHg.

In some embodiments of the above method, one or more components of the second echocardiogram include biplane LVEF and post-Warshall action LVOT-G, and wherein when the biplane LVEF is equal to or higher than a second predetermined biplane LVEF threshold and the post-Warshall action LVOT-G is lower than a predetermined post-Warshall action LVOT-G threshold, the third-day dose of afecontan or a pharmaceutically acceptable salt thereof is the same as the second-day dose of afecontan or a pharmaceutically acceptable salt thereof. In some embodiments, the second predetermined biplane LVEF threshold is 55%, and the predetermined post-Warshall action LVOT-G threshold is 30 mmHg.

In some embodiments of the above method, one or more components of the second echocardiogram include biplane LVEF and post-Warshall action LVOT-G, and wherein when the biplane LVEF of the second echocardiogram is higher than a second predetermined biplane LVEF threshold and the post-Warshall action LVOT-G of the second echocardiogram is equal to or higher than the predetermined post-Warshall action LVOT-G threshold, the third-day dose of afecontan or a pharmaceutically acceptable salt thereof is greater than the second-day dose of afecontan or a pharmaceutically acceptable salt thereof. In some embodiments, the second predetermined biplane LVEF threshold is 55%, and the predetermined post-Warshall action LVOT-G threshold is 30 mmHg.

In some embodiments of the above method, the first-day dose of afecontan or a pharmaceutically acceptable salt thereof is about 5 mg of afecontan, the second-day dose of afecontan or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg of afecontan, and the third-day dose of afecontan or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, or about 15 mg of afecontan. For example, as described herein, in some embodiments, the provided method includes:

The patient is given a daily dose of afecontan or a pharmaceutically acceptable salt thereof (referred to as the second day dose) for a period of time (referred to as the second period), wherein the daily dose is about 10 mg of afecontan and the period is about 2 weeks;

After the stated time period, assess the patient's LVOT-G and LVEF following the Valsalva maneuver (e.g., using echocardiography); and

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

For example, in some implementations, the provided methods include:

The patient is given a first-day dose of afecontan or a pharmaceutically acceptable salt thereof for a first period of time, wherein the first-day dose is about 5 mg of afecontan and the first period of time is about 2 weeks;

After the first time period, assess the patient's post-Varva maneuver LVOT-G and LVEF (e.g., using echocardiography), wherein the patient's post-Varva maneuver LVOT-G ≥30 mmHg and LVEF ≥55%;

The patient was given a second-day dose of afecontan or a pharmaceutically acceptable salt thereof for a second period of time, wherein the second-day dose was about 10 mg of afecontan and the second period of time was about 2 weeks;

After the second time period, assess the patient's LVOT-G and LVEF following the Valsalva maneuver (e.g., using echocardiography); and

If the patient's post-Warshall maneuver LVOT-G ≥30 mmHg and LVEF ≥55%, the patient is given a third-day dose of afencontan or a pharmaceutically acceptable salt thereof, wherein the third-day dose is about 15 mg of afencontan; and if the patient's post-Warshall maneuver LVOT-G <30 mmHg or LVEF <55%, the patient is given a third-day dose of afencontan or a pharmaceutically acceptable salt thereof, wherein the third-day dose is about 10 mg of afencontan (e.g., LVEF ≥50%) or about 5 mg of afencontan (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-day dose is administered for a third period (e.g., about 2 weeks) before assessing the patient's post-Warshall maneuver LVOT-G and LVEF.

In some embodiments of the above method, the method further includes measuring one or more components of a second echocardiogram.

In some implementations of the above method, the third period is approximately two weeks.

In some embodiments of the above method, the patient is administered a third-day dose of afencontan or a pharmaceutically acceptable saline thereof for a third time period. The method further includes administering a fourth-day dose of afencontan or a pharmaceutically acceptable saline thereof for a fourth time period based on one or more portions of the patient's third echocardiogram obtained after the third time period and the third-day dose of afencontan or a pharmaceutically acceptable saline thereof, or discontinuing administration of afencontan or a pharmaceutically acceptable saline thereof to the patient. In some embodiments, the method further includes selecting a fourth-day dose of afencontan or a pharmaceutically acceptable saline thereof based on one or more portions of the third echocardiogram and the third-day dose. In some embodiments, one or more portions of the third echocardiogram include biplane LVEF or post-Valveolar LVOT-G. In some embodiments, one or more portions of the third echocardiogram include biplane LVEF. In some embodiments, one or more portions of the third echocardiogram include both biplane LVEF and post-Valveolar LVOT-G. In some embodiments of the method described herein, the patient undergoes two or more echocardiograms during a third time period, and the fourth-day dose is selected based on the combined results of the two or more echocardiograms obtained during the third time period.

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

In some embodiments of the above method, one or more components of the third echocardiogram include biplane LVEF, and wherein when the biplane LVEF is equal to or higher than a predetermined biplane LVEF threshold and lower than a second predetermined biplane LVEF threshold, the fourth-day dose of afecontan or a pharmaceutically acceptable salt thereof is the same as the third-day dose of afecontan or a pharmaceutically acceptable salt thereof. In some embodiments, the predetermined biplane LVEF threshold is 50%, and the second predetermined biplane LVEF threshold is 55%.

In some embodiments of the above method, one or more components of the third echocardiogram include biplane LVEF and post-Warshall action LVOT-G, and wherein when the biplane LVEF is equal to or higher than a second predetermined biplane LVEF threshold and the post-Warshall action LVOT-G is lower than a predetermined post-Warshall action LVOT-G threshold, the fourth-day dose of afecontan or a pharmaceutically acceptable salt thereof is the same as the third-day dose of afecontan or a pharmaceutically acceptable salt thereof. In some embodiments, the second predetermined biplane LVEF threshold is 55%, and the second predetermined post-Warshall action LVOT-G threshold is 30 mmHg.

In some embodiments of the above method, one or more components of the third echocardiogram include biplane LVEF and post-Warshall action LVOT-G, and wherein when the biplane LVEF of the third echocardiogram is higher than a second predetermined biplane LVEF threshold and the post-Warshall action LVOT-G of the third echocardiogram is equal to or higher than a predetermined post-Warshall action LVOT-G threshold, the fourth-day dose of afecontan or a pharmaceutically acceptable salt thereof is greater than the third-day dose of afecontan or a pharmaceutically acceptable salt thereof. In some embodiments, the second predetermined biplane LVEF threshold is 55%, and the second predetermined post-Warshall action LVOT-G threshold is 30 mmHg.

In some embodiments of the above method, the first-day dose of afecontan or a pharmaceutically acceptable salt thereof is about 5 mg of afecontan; the second-day dose of afecontan or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg of afecontan; the third-day dose of afecontan or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, or about 15 mg of afecontan; and the fourth-day dose of afecontan or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, about 15 mg, or about 20 mg of afecontan. For example, as described herein, in some embodiments, the provided method includes:

The patient is given a daily dose of afecontan or a pharmaceutically acceptable salt thereof (referred to as the third day dose) for a period of time (referred to as the third period), wherein the daily dose is about 15 mg of afecontan and the period is about 2 weeks;

After the stated time period, assess the patient's LVOT-G and LVEF following the Valsalva maneuver (e.g., using echocardiography); and

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

For example, in some implementations, the provided methods include:

The patient is given a first-day dose of afecontan or a pharmaceutically acceptable salt thereof for a first period of time, wherein the first-day dose is about 5 mg of afecontan and the first period of time is about 2 weeks;

After the first time period, assess the patient's post-Varva maneuver LVOT-G and LVEF (e.g., using echocardiography), wherein the patient's post-Varva maneuver LVOT-G ≥30 mmHg and LVEF ≥55%;

The patient was given a second-day dose of afecontan or a pharmaceutically acceptable salt thereof for a second period of time, wherein the second-day dose was about 10 mg of afecontan and the second period of time was about 2 weeks;

After the second time period, assess the patient's LVOT-G and LVEF following the Valsalva maneuver (e.g., using echocardiography); and

The patient was given a third-day dose of afecontan or a pharmaceutically acceptable salt thereof for a third period of time, wherein the third-day dose was about 15 mg of afecontan and the third period of time was about 2 weeks;

After the third time period, assess the patient's LVOT-G and LVEF following the Valsalva maneuver (e.g., using echocardiography); and

If the patient's LVOT-G ≥30 mmHg and LVEF ≥55% after the Valsalva maneuver, the patient is given a fourth-day dose of afecontan or a pharmaceutically acceptable salt thereof, wherein the third-day dose is about 20 mg of afecontan; and if the patient's LVOT-G <30 mmHg or LVEF <55% after the Valsalva maneuver, the patient is given a fourth-day dose of afecontan or a pharmaceutically acceptable salt thereof, wherein the fourth-day dose is about 15 mg of afecontan (e.g., LVEF ≥50%) or about 10 mg of afecontan (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 fourth-day dose is administered for a fourth period (e.g., approximately 2 weeks) before assessing the patient's post-Warshall maneuver LVO-G and LVEF. In some embodiments, the fourth-day dose is administered for approximately 2 weeks or longer, such as approximately 4 weeks, approximately 1 month, approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or longer. In some embodiments, during the fourth period, such as a fourth period longer than approximately 2 weeks, the patient's cardiac structure and/or function, such as post-Warshall maneuver LVO-G, LVEF, exercise capacity, etc., may be assessed once or multiple times. As described herein, the methods provided are particularly effective in improving exercise capacity.

In some embodiments of the above method, the method further includes measuring one or more components of a third echocardiogram.

In some implementations of the above method, the fourth period is approximately two weeks.

In some implementations of the above method, the first predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the predetermined VOT-G threshold after the Valsalva maneuver is 30 mmHg.

In some embodiments, the daily dose is about 15 mg of afecontan. In some embodiments, the third-day dose is about 15 mg of afecontan. In some embodiments, the fourth-day dose is about 15 mg of afecontan. In some embodiments, the daily dose is about 20 mg of afecontan. In some embodiments, the fourth-day dose is about 20 mg of afecontan. In some embodiments, the daily dose is administered in tablet form. In some embodiments, the amount of afecontan in the tablet (which may be present in various forms, such as free form, pharmaceutically acceptable salt form, polymorphic form, etc.) is approximately the daily dose described herein. In some embodiments, the amount of afecontan in the tablet is about 5 mg. In some embodiments, the amount of afecontan in the tablet is about 10 mg. In some embodiments, the amount of afecontan in the tablet is about 15 mg. In some embodiments, the amount of afecontan in the tablet is about 20 mg. In some embodiments, the amount of afecontan in the tablet is about half the daily dose described herein. In some embodiments, the amount of afecontan in the tablet is about 2.5 mg. In some embodiments, the amount of afecontan in the tablet is about 5 mg. In some embodiments, the amount of afecontan in the tablet is about 7.5 mg. In some embodiments, the amount of afecontan in the tablet is about 10 mg.

In some embodiments of any of the above methods, the afecontan or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, the afecontan 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 afencontan 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 dodecyl sulfate; and (vi) about 0.1% to about 10% by weight of magnesium stearate, wherein the weight percentages do not include the weight of the coating (if present). In some embodiments, the afencontan or a pharmaceutically acceptable salt thereof comprises one or more of the polymorphs of afencontan: form I, form II, form III, form IV, form V, and form VI.

Attached Figure Description

Figure 1 illustrates an exemplary method for treating obstructive hypertrophic cardiomyopathy (oHCM) in patients, which includes titrating a daily dose of afencontan or a pharmaceutically acceptable salt thereof.

Figure 2 shows a schematic overview of the Phase 1 clinical trial of afecontan. The study included the SAD cohort, MAD cohort, CYP2D6-PM cohort, and food effect cohort. The MAD and CYP2D6-PM cohorts were initiated when the tolerated pharmacologically active dose (LVEF reduction of approximately 5%) was determined in the SAD cohort. The food effect cohort was initiated after the completion of the last SAD cohort. 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 of afecontan. CYP2D6-PM = cytochrome P450 2D6 weak metabolizer phenotype; d = day; LVEF = left ventricular ejection fraction; MAD = multiple escalation doses; qd = once daily; SAD = single escalation dose.

Figure 3A shows the mean (SE) maximum plasma concentration ( _Cmax ) of afencontin increased in a dose-proportional manner after a single oral dose between 1 mg and 50 mg. Figure 3B shows the exposure (AUC ₂₄ ) of afencontin increased in a dose-proportional manner after a single oral dose between 1 mg and 50 mg (B). AUC ₂₄ = area under the plasma drug concentration-time curve from 0 to 24 h; _Cmax = maximum plasma concentration; SE = standard error.

Figure 4 shows plasma concentrations of afecontan over time at multiple doses according to an exemplary clinical trial. Mean (SE) afecontan plasma concentrations are shown. Data points are offset for clarity. Afecontan plasma concentrations increased between the 5-mg dose and two higher doses; however, there was no difference in mean concentration between the 7.5-mg and 10-mg doses up to day 2. Clearance was similar for the 5-mg and 10-mg doses, and the cumulative ratios were similar for all three doses. Only trough measurements are shown for days 7, 8, 10, 11, 12, and 13. For the 5-mg and 10-mg cohorts, the dosing period was 14 days, with a follow-up of 3 days. For the 7.5-mg cohort, the dosing period was extended to 17 days, with a follow-up of 3 days, and steady state was confirmed after 10 to 12 days. SE = Standard Error.

Figure 5A shows the SAD cohort of an exemplary afecontan clinical trial, and Figure 5B shows the MAD cohort of an exemplary afecontan clinical trial. The mean (SE) change in LVEF compared to baseline is shown. Data points are offset for clarity. In both the SAD and MAD cohorts, a decrease in LVEF was observed within the target range (5% to 15%). In the SAD cohort, LVEF generally decreased slightly, with a maximum mean decrease of 5.8% in the 50-mg group (1.5 h post-dose). In the MAD cohort, the maximum mean decrease in LVEF compared to baseline occurred in the 10-mg group (mean change of 5.0% 1.5 h post-dose on day 14). LVEF = Left ventricular ejection fraction; MAD = Multiple escalation dose; qd, once daily; SAD = Single escalation dose; SE = Standard error.

Figure 6A shows an analysis of the SAD cohort from the exemplary clinical trial and demonstrates a decreasing trend in LVEF with increasing afecontan plasma concentration. Figure 6B shows an analysis of the MAD cohort from the exemplary clinical trial and demonstrates minimal inhibition of LVEF in most participants at plasma afecontan concentrations ≤180 ng/ml. CI = confidence interval; LVEF = left ventricular ejection fraction; MAD = multiple escalation dose; SAD = single escalation dose.

Figure 7 shows the resting LVOT-G in the treatment and placebo cohorts based on an exemplary clinical trial of afencontin.

Figure 8 shows the Vault-G after the action in the treatment and placebo cohorts based on an exemplary clinical trial of afencontin.

Figure 9 shows the changes in left atrial volume index (LAVI) in the treatment and placebo cohorts based on an exemplary clinical trial of afencontin.

Figure 10 shows the variation of the lateral E/e' ratio in the treatment and placebo cohorts based on an exemplary clinical trial of afencontin.

Figure 11 shows the changes in mitral valve characteristics, including mitral regurgitation (MR), eccentric MR, and presystolic motion (SAM), in the treatment and placebo cohorts of an exemplary clinical trial of afencontin.

Figure 12 shows the changes in resting LVOT-G in the treatment and placebo cohorts based on an exemplary clinical trial of afencontin.

Figure 13 shows the changes in resting Valsalva maneuver LVOT-G in the treatment and placebo cohorts based on an exemplary clinical trial of afencontin.

Figure 14 shows the changes in LVEF in the treatment and placebo cohorts based on an exemplary clinical trial of afencontin.

Figure 15 shows the NYHA functional class responses in the treatment and placebo cohorts based on an exemplary clinical trial of afencontin.

Figure 16 shows the changes in mean NT-proBNP in the treatment and placebo cohorts based on an exemplary clinical trial of afencontin.

Figure 17 shows the changes in resting LVOT-G in the treatment and placebo cohorts based on an exemplary clinical trial of afencontin.

Figure 18 shows the changes in resting Valsalva maneuver LVOT-G in the treatment and placebo cohorts based on an exemplary clinical trial of afencontin.

Figure 19 shows the changes in LVEF in the treatment and placebo cohorts based on an exemplary clinical trial of afencontin.

Figure 20 shows the hemodynamic responses in the treatment and placebo cohorts based on an exemplary clinical trial of afencontin.

Figure 21 shows the NYHA functional class responses in the treatment and placebo cohorts based on an exemplary clinical trial of afencontin.

Figure 22 shows the changes in mean NT-proBNP in the treatment and placebo cohorts based on an exemplary clinical trial of afencontin.

Figure 23 shows hs-troponin in the treatment and placebo cohorts based on an exemplary clinical trial of afencontin.

Figure 24 shows the NYHA functional category responses in the treatment and placebo cohorts based on an exemplary clinical trial of afencontin.

Figure 25 shows the NYHA functional class responses in the treatment and placebo cohorts based on an exemplary clinical trial of afencontin.

Figure 26 shows the design of an open-label extension for an exemplary clinical trial of afencontin (Example 3a).

Figure 27 shows the distribution of patients over time at various doses in an open-label extension of an exemplary clinical trial of afencontan (Example 3a).

Figure 28 shows a patient’s resting LVOT-G in an open-label extension of an exemplary clinical trial of afencontin (Example 3a).

Figure 29 shows a patient’s VOT-G after the Valsalva maneuver in an open-label extension of an exemplary clinical trial of afencontin (Example 3a).

Figure 30 shows changes in LVEF in patients during an open-label extension of an exemplary clinical trial of afencontin (Example 3a).

Figure 31 shows the distribution of NYHA functional categories in patients at different time points in an open-label extension of an exemplary clinical trial of afencontin (Example 3a).

Figure 32 shows the NYHA functional class response of patients at different time points in an open-label extension of an exemplary clinical trial of afencontin (Example 3a).

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

Figure 34 shows the mean change in cardiac troponin I in patients during an open-label expansion of an exemplary clinical trial of afencontan (Example 3a).

Figure 35 shows the change in patients’ KCCQ scores compared to baseline in an open-label extension of an exemplary clinical trial of afencontin (Example 3a).

Figure 36 shows the proportion of patients with different levels of change in KCCQ score compared to baseline in an open-label extension of an exemplary clinical trial of afencontin (Example 3a).

Figure 37 shows the percentage change in hs-troponin I from baseline in the treatment and placebo cohorts of an exemplary clinical trial of afencontin (Example 3a).

Figure 38 shows the design of an exemplary phase 3 clinical trial for afencontin.

Figure 39 shows the changes in resting LVOT-G compared to baseline at different time points in patients in an exemplary clinical trial of afencontin in an open-label extension (Examples 3a and 3b).

Figure 40 shows the changes in LVOT-G compared to baseline in patients at different time points after the Valsalva maneuver in an exemplary clinical trial of afecontan (Examples 3a and 3b).

Figure 41 shows the changes in the distribution of NYHA functional classes in patients at different time points in an open-label extension of exemplary clinical trials of afencontan (Examples 3a and 3b).

Figure 42 shows the changes in LVEF at different time points in patients during an open-label extension of an exemplary clinical trial of afencontin (Examples 3a and 3b).

Figure 43 shows the design of an exemplary phase 3 clinical trial of afencontin (Example 5).

Figure 44 shows the baseline doses of beta-blockers and calcium channel blockers in 40 patients in an open-label extension of an exemplary clinical trial of afecontan (Examples 3a and 3b).

Figures 45A and 45B show the interim changes in NT-proBNP and hs-troponin I in patients during an open-label extension of an exemplary clinical trial of afecontan (Examples 3a and 3b).

Figure 46 shows an exemplary clinical trial of afencontin from baseline to week 12 at rest (Example 2).

Figure 47 shows the Valsalva maneuver LVOT-G from baseline to week 12 in an exemplary clinical trial of afencontin (Example 2).

Figure 48 shows the LVEF from baseline to week 12 in an exemplary clinical trial of afencontin (Example 2).

Figure 49 shows the distribution of patients who exhibited hemodynamic responses at week 10 of an exemplary clinical trial of afencontin (Example 2).

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

Figure 51 shows the mean proportional change of NT-proBNP and hs-cTnI compared to baseline at week 10 of an exemplary clinical trial of afecontan (Example 2).

Figure 52 shows the afecontan doses achieved by patients in an open-label extension of an exemplary clinical trial of afecontan (Examples 3a and 3b).

Figure 53 shows the variation of resting LVOT-G at different time points compared to baseline in patients in an open-label extension of an exemplary clinical trial of afencontin (Examples 3a and 3b). Horizontal dashed lines indicate thresholds specifying severe obstruction.

Figure 54 shows the variation of the core laboratory and field-interpreted mean (SD) of Vascular action LVOT-G at different time points in an exemplary clinical trial of afencontin compared to baseline (Examples 3a and 3b). The horizontal dashed line indicates the threshold specifying severe obstruction.

Figure 55 shows the variation of the core laboratory and field-interpreted mean (SD) LVEF in patients at different time points in an exemplary clinical trial of afencontin (Examples 3a and 3b). The horizontal dashed line represents the low LVEF threshold at 50 mmHg.

Figure 56 shows the proportion of patients who showed NYHA class improvement at different weeks up to week 48 in an open-label extension of an exemplary clinical trial of afecontan (Examples 3a and 3b).

Figure 57A shows the change in NYHA class from baseline to weeks 36–48 in an open-label extension of an exemplary clinical trial of afecontan (Examples 3a and 3b).

Figure 57B shows the variation of global longitudinal strain (GLS) from baseline to weeks 12 and 36–48 in 27 patients who underwent echocardiography at weeks 12 and 36–48 in an open-label extension of an exemplary clinical trial of afecontan (Examples 3a and 3b).

Figure 57C shows the change in global longitudinal strain (GLS) from baseline to weeks 12 and 36–48 in patients who underwent echocardiography at weeks 12 and 36–48 and had the best hemodynamic response (resting LVOT-G) in an open-label extension of an exemplary clinical trial of afecontan (Examples 3a and 3b).

Figure 57D shows the change in global longitudinal strain (GLS) from baseline to weeks 12 and 36–48 in patients who underwent echocardiography at weeks 12 and 36–48 and had the best hemodynamic response (Valveo-G) in an open-label extension of an exemplary clinical trial of afecontan (Examples 3a and 3b).

Figure 58 shows the design of an exemplary phase 3 clinical trial for afencontin.

Figure 59A shows the experimental X-ray powder diffraction (XRPD) pattern of polymorph I of afencontan.

Figure 59B shows the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) plots of afencontin polymorph I.

Figure 59C shows the dynamic vapor-phase adsorption (DVS) diagram of afencontin's polymorph I.

Figure 60A shows the experimental XRPD plot of polymorph II of afencontin.

Figure 60B shows the DSC and TGA plots of polymorph II of afencontin.

Figure 61A shows the experimental XRPD plot of a mixture of polymorphs I and III of afencontin.

Figure 61B shows the DSC and TGA plots of a mixture of polymorphs I and III of afilcontan.

Figure 62A shows the experimental XRPD plot of the polymorphic form IV of afencontin.

Figure 62B shows the DSC and TGA plots of the polymorphic form IV of afencontin.

Figure 63 shows the experimental XRPD plot and two simulation plots of the polymorphic form V of afencontan (from top to bottom: simulation at 223 K; simulation at 273 K; experimental).

Figure 64A shows two experimental XRPD plots of the polymorphic form VI of aficantane: (a) top, XRPD of form VI obtained before drying; and (b) bottom, after drying (oven, vacuum, 24 hours, 25°C).

Figures 64B and 64C show the TGA plots of polymorphic form VI of afencontin. Figure 64B shows the weight loss of dried samples of form VI (oven drying, vacuum, overnight, 25°C) in the range of 25–300°C. Figure 64C shows the TGA plots of samples of form VI in the range of 25–300°C, which underwent oven drying (oven drying, vacuum, overnight, 25°C) and further heating at 150°C prior to thermogravimetric analysis.

Figures 64D and 64E show the DSC diagrams of polymorphic form VI of afencontin. Figure 64D shows the DSC diagram of a dried sample of form VI (oven drying, vacuum, overnight, 25°C) in the range of 25–300°C. Figure 64E shows the DSC diagram of a sample of form VI in the range of 25–300°C, which underwent oven drying (oven drying, vacuum, overnight, 25°C) and further heating at 150°C prior to thermogravimetric analysis.

Detailed Implementation

This article describes the cardiac myosin inhibitor afecontan and various methods, such as for treating obstructive hypertrophic cardiomyopathy in subjects in need with afecontan or a pharmaceutically acceptable salt thereof.

Treatment 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 the Valsalva maneuver, such as increasing, decreasing, or maintaining the dose, or discontinuing administration. These measurements may be performed, for example, using echocardiography. The methods disclosed herein may be used as: 1) first-line therapy in recently diagnosed and/or previously untreated subjects; or as monotherapy in 2) participants who have previously received standard of care (SOC) medical therapy for symptomatic oHCM. It should be understood that administration of oHCM monotherapy indicates that the patient is receiving only one therapy for oHCM (e.g., afencontan or a pharmaceutically acceptable salt thereof); however, it should be understood that the patient may also receive other therapies or therapies used to treat other conditions. As described herein, “other therapies or therapies used to treat other conditions” excludes SOC therapies used for oHCM (e.g., one or more of beta-blockers, calcium channel blockers, or disopyramide).

Afencontan is a small molecule cardiac myosin inhibitor with the structure shown below.

Aficantan

Afcontan's chemical name is (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Small molecule inhibitors can be administered orally, for example, to patients to treat obstructive hypertrophic cardiomyopathy.

Afencontan is described in WO 2019/144041, which is incorporated herein by reference. Afencontan or a pharmaceutically acceptable salt thereof can be obtained by following the methods described therein. Afencontan used in the disclosed methods may be present in pharmaceutically acceptable salts, solvates, hydrates, polymorphs, or combinations thereof, and may be formulated into any suitable pharmaceutical preparation. Afencontan may also be present in its free base form. Polymorphs of afencontan are described in WO 2021/011807, which is incorporated herein by reference. Formulations of afencontan are described in WO 2021/011808, which is incorporated herein by reference. Afencontan is designed to reduce hyperconstrictivity associated with hypertrophic cardiomyopathy (HCM). Not limited to theory, in preclinical models, afencontan reduces myocardial contractility by binding directly to cardiac myosin at unique and sex-selective binding sites, thereby preventing myosin from entering a productive state. Afencontan reduces the number of active actin-myosin crossbridges in each cardiac cycle and thus reduces myocardial contractility. This mechanism of action may be effective in treating disorders characterized by excessive hyperconstriction, such as hemomyositis (HCM), for example, obstructive HCM, also known as oHCM.

definition

As used in this specification, unless otherwise specified in the context of their use, the following words and phrases are generally intended to have the meanings described below.

Throughout this application, unless the context otherwise requires, references to afencontan include its amorphous form or polymorphs thereof, including any one or a mixture of polymorphs I, II, III, IV, V or VI as described.

References to “about” values or parameters in this document include (and describe) the value or parameter itself and any value or parameter that is 5% higher or lower than said parameter. For example, a description of “about X” includes the 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 in between.

"Recently diagnosed" patients refer to those with a history of oHCM ≤ 12 months, regardless of whether they have used standard oHCM care therapy.

"Untreated" patients refer to those who have not previously received standard care for oHCM.

"Currently untreated" patients are those who have not received standard care therapy for oHCM in the past 12 months.

"Chronic oHCM" patients are defined as patients with an oHCM history of >12 months, who a) are currently receiving standard care for oHCM, or b) have received standard care for oHCM within the past 12 months.

"NYHA classification" or "NYHA category" refers to the New York Heart Association functional classification of heart failure symptoms. Descriptions of each of NYHA categories I, II, III, and IV can be found in "Classes of Heart Failure," American Heart Association, 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 a 1) “Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels”, 9th ed., Boston, MA: Lippincott Williams and Wilkins; March 1, 1994; and 2) Criteria Committee, New York Heart Association, Inc. Diseases of the Heart and Blood Vessels. Nomenclature and Criteria for Diagnosis, 6th ed., Boston, Little, Brown and Co. 1964, p. 114. In short, NYHA Class I indicates that the patient has no limitation in daily physical activity (e.g., shortness of breath when walking or climbing stairs). NYHA Class II indicates that the patient has mild symptoms (e.g., mild shortness of breath and/or angina) and slight limitations during daily activities. NYHA Category III indicates that the patient is active due to symptoms, even during periods of below-normal activity (e.g., short walks [20-100 m]); and feels comfortable only at rest. NYHA Category IV indicates that the patient has severe limitations, with symptoms present even at rest; most participants are bedridden.

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

If the compounds described herein are obtained as 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, the addition salt, particularly a pharmaceutically acceptable addition salt, can be produced, in accordance with the conventional procedure for preparing acid addition salts from base compounds, by dissolving the free base in a suitable organic solvent and treating said solution with acid (see, for example, Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19). Those skilled in the art will recognize the various synthetic methods that can be used to prepare pharmaceutically acceptable addition salts.

The terms "pharmaceutically acceptable carrier" or "pharmaceuticalally acceptable excipient" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents. The use of such media and reagents for pharmaceutical active substances is well known in the art. Unless any conventional media or reagent is incompatible with the active ingredient, its use in a pharmaceutical composition should be considered. Additional active ingredients may also be incorporated into pharmaceutical compositions.

The terms "patient," "individual," and "subject" refer to animals, such as mammals. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cattle, and humans. In some embodiments, the patient or subject is a human, such as a human who has been or will be a subject of treatment, observation, or experimentation. The compounds, compositions, and methods described herein are for both human therapeutic and veterinary applications.

The term "therapeutic effective amount" or "effective amount" means the amount of a compound disclosed and/or described herein that is sufficient to affect the treatment as defined herein when administered to a patient requiring treatment. A therapeutically effective amount of a compound may be an amount sufficient to treat a disease that responds to regulation of the cardiac myofascitis. Therapeutic effective amounts will vary depending on factors such as the subject being treated and the disease condition, the subject's weight and age, the severity of the disease condition, the specific compound, the dosing regimen to be followed, the time of administration, and the method of administration, all of which can be readily determined by those skilled in the art. Therapeutic effective amounts can be determined experimentally, for example, by determining the blood concentration of the chemical entity, or theoretically, by calculating bioavailability.

"Treatment" (and related terms such as "treat," "treated," "treating") includes one or more of the following: 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 disappearance of clinical symptoms). The term encompasses the complete and partial reduction or prevention of a disease or condition and the complete or partial reduction of clinical symptoms of a disease or condition. Therefore, the compounds described and/or disclosed herein may prevent the worsening of an existing disease or condition, help manage a disease or condition, or alleviate or eliminate a disease or condition.

Any reference to any dose of the compound described herein or a pharmaceutically acceptable salt thereof (e.g., aficanthan at doses of 5 mg, 10 mg, 20 mg, etc.) refers to the amount of the compound without any salt (i.e., equivalent mass).

Treatment of obstructive hypertrophic cardiomyopathy

As further described herein, a therapeutically effective dose of afecontan can be administered to a patient to treat obstructive hypertrophic cardiomyopathy. Afecontan can be administered at a constant dose level. Afecontan can be administered at a titrated dose level. For example, the dose of afecontan can be adjusted based on the patient's response to the drug. That is, the dose of afecontan can be periodically increased, decreased, maintained, or discontinued based on one or more of measurements of drug response, such as biplane left ventricular ejection fraction (LVEF) and post-Valveolar action LVOT-G measurements.

Results from a recent clinical trial (see Example 1) demonstrate that, compared with placebo, afencontan treatment for 10 weeks produced substantial and statistically significant reductions 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-Warshall action LVOT-G (p=0.001, p<0.0001, cohort 1 and cohort 2, respectively). The majority of patients treated with afencontan (78.6% in cohort 1 and 92.9% in cohort 2) achieved their treatment goals, defined as a resting gradient <30 mmHg and a post-Warshall action gradient <50 mmHg at week 10, compared with placebo (7.7%). The reduction in LVOT-G occurred within 2 weeks of initiation of afencontan treatment, peaked within 2 to 6 weeks after the end of dose titration, and persisted until the end of 10 weeks of treatment. The observed reduction in LVOTTAGE was dose-dependent, and patients achieved a greater reduction in LVOTTAGE with increasing afecontan dose.

Afenicone was well tolerated in clinical trials. Overall, the incidence of adverse events was similar between treatment groups. No serious adverse events occurred with afenicone, and no treatment interruptions were reported. No new cases of atrial fibrillation were reported. In this dose-range discovery trial, one patient experienced a transient decrease in left ventricular ejection fraction (LVEF), requiring dose adjustment but not interruption. LVEF returned to baseline within two weeks of treatment completion in both cohorts, confirming the reversibility of the effects of afenicone, similar to what was observed in healthy participants in a phase 1 study of afenicone.

Afencontan is administered at a therapeutically effective dose (e.g., a dose sufficient to provide treatment for a disease state). For humans, the daily dose may range from about 1 mg to 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 between these. The daily dose is the total amount administered within a day. The daily dose may be administered (but is not limited to) daily, every other day, weekly, every two weeks, monthly, or at different intervals. In some embodiments, the daily dose is administered over a period of time, from one day to a lifetime, for the subject. In some embodiments, the daily dose is administered once daily. 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.

In one instance, a patient with oHCM was treated by administering afencontan at a daily dose of approximately 5 mg to approximately 20 mg. In another instance, a patient with obstructive hypertrophic cardiomyopathy was treated by administering afencontan at a daily dose of approximately 5 mg. In another instance, a patient with obstructive hypertrophic cardiomyopathy was treated by administering afencontan at a daily dose of approximately 10 mg. In another instance, a patient with obstructive hypertrophic cardiomyopathy was treated by administering afencontan at a daily dose of approximately 15 mg. In another instance, a patient with obstructive hypertrophic cardiomyopathy was treated by administering afencontan at a daily dose of approximately 20 mg.

In some embodiments, a method for treating oHCM is provided, the method comprising administering afencontan or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing afencontan 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, a method for treating oHCM is provided, the method comprising administering afencontan or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing afencontan 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 administration of afencontan or a pharmaceutically acceptable salt thereof. In some embodiments, a method for treating oHCM is provided, the method comprising administering afencontan or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing afencontan 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 administration of afencontan or a pharmaceutically acceptable salt thereof, and has discontinued SOC medical therapy for oHCM prior to administration of afencontan or a pharmaceutically acceptable salt thereof.

In some embodiments, prior to administration of afecontan or a pharmaceutically acceptable salt thereof, the patient's LVEF ≥ 60% and resting LVOT-G ≥ 30 mmHg. In some embodiments, prior to administration of afecontan, the patient's LVEF ≥ 60% and LVOT-G ≥ 50 mmHg after the Warburg maneuver. In some embodiments, prior to administration of afecontan, the patient's LVEF ≥ 60%, resting LVOT-G ≥ 30 mmHg, and LVOT-G ≥ 50 mmHg after the Warburg maneuver. In some embodiments, prior to administration of afecontan or a pharmaceutically acceptable salt thereof, the patient's LVEF ≥ 60%, resting LVOT-G ≥ 30 mmHg, and NYHA Class II or Class III. In some embodiments, prior to administration of afecontan, the patient's LVEF ≥ 60%, LVOT-G ≥ 50 mmHg after the Warburg maneuver, and NYHA Class II or Class III. In some implementations, prior to afecontan administration, patients have LVEF ≥ 60%, resting LVOT-G ≥ 30 mm Hg, LVOT-G ≥ 50 mm Hg after Valsalva maneuver, and are NYHA Class II or Class III.

During a course of oHCM, the dose of afecontan administered to the patient can be titrated, for example, by increasing, decreasing, or maintaining the dose. Titration can be performed once during treatment or repeated at intervals. For example, in some implementations, the dose of afecontan is titrated two or more times (e.g., three, four, five, or more times) during the course of treatment. In some embodiments, a new daily dose is administered to the patient at a constant level for about one to about eight weeks (or about two to about six weeks, or about four weeks) prior to titration. In some embodiments, a new daily dose is administered to the patient at a constant level for about two weeks prior to titration. For example, a first daily dose may be administered to the patient for about two weeks prior to the first titration, during which the daily dose is increased, decreased, or maintained. A second titration may then be performed about two weeks after the first titration. Dose titration allows for individualized dosing based on the patient's response to the drug, thereby maximizing the potential therapeutic effect on the patient.

Dosage titration may be based on one or more of the biplane left ventricular ejection fraction (LVEF) and LVOT-G after the Warburg maneuver, measured in the patient. One or more measurements may be determined, for example, using echocardiography. Echocardiography is performed after administration of the daily dose (e.g., approximately 1 to approximately 3 hours after administration). In some embodiments, echocardiography is performed approximately 2 hours after administration of the daily dose.

In some implementations, an initial daily dose of about 5 mg, about 10 mg, about 15 mg, or about 20 mg of afecontan, or any amount in between, is administered to the patient. After a period of time (e.g., about 2 weeks), such as after dose administration (e.g., about 1-3 hours or about 2 hours after dose administration), biplane LVEF and/or LVOT-G after a Valsalva maneuver are measured by echocardiography. If the biplane LVEF is below a predetermined biplane LVEF threshold (e.g., below 50%), the dose may be reduced or terminated. For example, if the biplane LVEF is below the biplane LVEF threshold and the current dose is not the lowest (e.g., the first) dose, the dose may be reduced. If the biplane LVEF is below the biplane LVEF threshold and the current dose is the lowest (e.g., the first) dose, the dose may be terminated. If the biplane LVEF is equal to or higher than a predetermined biplane LVEF threshold and lower than a second predetermined biplane LVEF threshold (e.g., 50% ≤ LVEF < 55%), the dose may be maintained. Alternatively, if the biplane LVEF is equal to or higher than a second predetermined biplane LVEF threshold (e.g., 55% or higher) and the post-Warshall action LVOT-G is lower than a predetermined LVOT-G threshold (e.g., less than 30%), the dose may be maintained. If the post-Warshall action LVOT-G is equal to or higher than a predetermined LVOT-G threshold (e.g., about 30 mmHg or higher) and the biplane LVEF is equal to or higher than a second predetermined biplane LVEF threshold (e.g., about 55% or higher), the daily dose is increased. In some embodiments, the biplane LVEF threshold is about 50%, and the post-Warshall action LVOT-G threshold is about 30 mmHg. If the LVEF is < 40% at any time, the daily dose administration is temporarily interrupted. In some embodiments, titration of afecontan dose includes maintaining the dose at the current dose; increasing the dose by about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 10 mg, or any amount thereof; 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 thereof; or discontinuing administration. In some embodiments, titration of dose includes maintaining the dose at the current dose; increasing the dose by about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 10 mg, or any amount thereof; 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 thereof.

After a period of time (e.g., about 2 weeks) following administration of the first titration dose to the patient, the dose may be re-tied (i.e., increased, decreased, or maintained) based on the patient's biplane LVEF and/or VOT-G following a Warburg maneuver, for example using the same threshold parameters discussed above. Exemplary dose titration schedules include administration of the first titration dose for approximately 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks, or 12 weeks, or any time interval thereof, followed by dose titration based on the patient's biplane LVEF and/or VOT-G following a Warburg maneuver, for example using the same threshold parameters discussed above. Further repetitions of administration and dose titration may be performed accordingly.

This article provides a method for reducing LVOTT-G below a specific value after a Warburg maneuver in a patient with symptomatic obstructive hypertrophic cardiomyopathy (oHCM), comprising administering a therapeutically effective amount of afencontan or a pharmaceutically acceptable salt thereof to the patient, wherein the patient has recently been diagnosed with oHCM, the patient is untreated, or the patient has chronic oHCM. The reduction of LVOTT-G below a specific value after a Warburg maneuver can occur within 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 9 weeks, or 10 weeks after the initiation of treatment with afencontan or a pharmaceutically acceptable salt thereof. The reduction of LVOTT-G after a Warburg maneuver can persist for at least 10 weeks of treatment. In some embodiments, the reduction of LVOTT-G after a Warburg maneuver occurs within 2 to 6 weeks after the end of dose titration. In some embodiments, the reduction of LVOTT-G after a Warburg maneuver peaks within 2 to 6 weeks after the end of dose titration. In some implementations, the LVOTT-G value after a specific Warburg action 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.

This document further provides a method for treating obstructive hypertrophic cardiomyopathy (oHCM) in patients 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 afecontan or a pharmaceutically acceptable salt thereof, wherein the method reduces heart failure symptoms, as assessed by NYHA classification. In some of the foregoing embodiments, the method improves the patient's heart failure symptoms by at least one NYHA category, for example, by one or two NYHA categories. In some of the foregoing embodiments, the method converts the patient from NYHA category III to category II or category I. In some of the foregoing embodiments, the method converts the patient from NYHA category III to category II. In some of the foregoing embodiments, the method converts the patient from NYHA category III to category I. In some of the foregoing embodiments, the method converts the patient from NYHA category II to category I. In some of the foregoing embodiments, the reduction in heart failure symptoms occurs within 10 weeks of initiating treatment with afecontan or a pharmaceutically acceptable salt thereof.

Figure 1 illustrates an exemplary method for treating a patient with obstructive hypertrophic cardiomyopathy (oHCM), 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 medical care for oHCM and discontinued the treatment prior to administration of afecontan. The method includes titrating a daily dose of afecontan or a pharmaceutically acceptable salt thereof. The exemplary method shown in Figure 1 provides four daily dose levels (e.g., about 5 mg, 10 mg, 15 mg, and 20 mg), wherein the first daily dose level is the lowest daily dose level (e.g., about 5 mg), but can be readily modified to include additional or fewer dose levels. The exemplary method shown in Figure 1 can be further modified such that the first daily dose level is not the lowest daily dose level. At 102, the patient is administered the first daily dose level (e.g., about 5 mg) of afecontan or a pharmaceutically acceptable salt thereof. After the first period, at 104, the daily dose level is increased or maintained, or administration is discontinued. The choice can be based on a first echocardiogram obtained from the patient after the first time interval. If the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold (e.g., 50%), administration can be terminated at 106, wherein another dose of afecontan or a pharmaceutically acceptable salt thereof is no longer administered to the patient. The first day dose level (e.g., about 5 mg) can be maintained when either of the following conditions is met by the first echocardiogram: (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-Warshall action LVOT-G of the first echocardiogram is below a predetermined post-Warshall action LVOT-G threshold (e.g., 30 mmHg). If maintenance is chosen, the patient is administered the first day dose level of afecontan or a pharmaceutically acceptable salt thereof at 102 for a second time interval, and optionally, the daily dose can be re-tied at 104 after the second time interval. The daily dose level may be increased to the second-day dose level (e.g., 10 mg) when the first echocardiogram meets either 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 post-Warshall action LVOT-G of the first echocardiogram is higher than a predetermined post-Warshall action LVOT-G threshold (e.g., 30 mmHg). If the daily dose level is increased, the second-day dose level of afecontan or a pharmaceutically acceptable salt thereof is administered to the patient at 108 for a second duration.

If the patient is given a second-day dose level of afecontan or a pharmaceutically acceptable salt thereof (e.g., 10 mg) at point 108, the daily dose can be retied at point 110 based on echocardiography (i.e., choosing to increase, decrease, or maintain the daily dose). If the biplane LVEF on echocardiography is below a predetermined biplane LVEF threshold (e.g., 50%), the daily dose can be reduced to the first-day dose level (e.g., about 10 mg to about 5 mg). If the daily dose is reduced to the first-day dose level, the first-day dose level (e.g., about 5 mg) is administered to the patient at point 102. The second-day dose level (e.g., about 10 mg) may be maintained when either of the following conditions is met by echocardiography: (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 echocardiographic post-Warshall action LVT-G is lower than a predetermined post-Warshall action LVT-G threshold (e.g., 30 mmHg). If maintenance is chosen, the second-day dose level of afecontan 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 retied at 110 after said period of time. When the biplane LVEF is equal to or higher than a second predetermined biplane LVEF threshold (e.g., 55%) and the echocardiographic post-Warshall action LVT-G is higher than a predetermined post-Warshall action LVT-G threshold (e.g., 30 mmHg), the daily dose level may be increased to a third-day dose level (e.g., 15 mg). If an increased daily dose level is chosen, the patient is given a second-day dose of afecontan or a pharmaceutically acceptable salt thereof at 112 for the duration stated.

If the patient is given a third-day dose level of afecontan or a pharmaceutically acceptable salt thereof (e.g., 10 mg) at point 112, the daily dose can be retied at point 114 based on echocardiography (i.e., choosing to increase, decrease, or maintain the daily dose). If the biplane LVEF on echocardiography is below a predetermined biplane LVEF threshold (e.g., 50%), the daily dose can be reduced to a second-day dose level (e.g., 15 mg to 10 mg). If the daily dose is reduced to a second-day dose level, the second-day dose level is administered to the patient at point 108. The third-day dose level (e.g., about 15 mg) may be maintained when either of the following conditions is met by echocardiography: (1) 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) biplane LVEF is equal to or higher than a second predetermined biplane LVEF threshold (e.g., 55%) and echocardiographic post-Warshall action LVOT-G is lower than a predetermined post-Warshall action LVOT-G threshold (e.g., 30 mmHg). If maintenance is chosen, the third-day dose level of afecontan 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 retied at 114 after said period. When the biplane LVEF is equal to or higher than a second predetermined biplane LVEF threshold (e.g., 55%) and echocardiographic post-Warshall action LVOT-G is higher than a second predetermined post-Warshall action LVOT-G threshold (e.g., 30 mmHg), the daily dose level may be increased to a fourth-day dose level (e.g., 20 mg). If an increased daily dose level is chosen, the patient is given a fourth-day dose of afecontan or a pharmaceutically acceptable salt thereof at 116 for a second period.

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

In the exemplary method shown in Figure 1, the fourth-day dose level is the maximum dose and therefore cannot be increased further. However, in other embodiments, other dose levels are available and the daily dose can be further increased at point 118. In the method shown in Figure 1, at point 118, a selection is made based on echocardiography to maintain the fourth-day dose level or reduce the daily dose level. If the biplane LVEF on the echocardiogram is below a predetermined biplane LVEF threshold (e.g., 50%), the daily dose can be reduced to the third-day dose level (e.g., 20 mg to 15 mg). If the daily dose is reduced to the third-day dose level, the second-day dose level is administered to the patient at point 112. The third-day dose level (e.g., about 15 mg) may be maintained if either of the following conditions is met by echocardiography: (1) 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) biplane LVEF is equal to or higher than a second predetermined biplane LVEF threshold (e.g., 55%) and the echocardiographic post-Warshall action LVOT-G is lower than a predetermined post-Warshall action LVOT-G threshold (e.g., 30 mmHg). If maintenance is selected, the third-day dose level of afecontan or a pharmaceutically acceptable salt thereof is administered to the patient at 116 for another period of time, and optionally, the daily dose may be retied at 118 after said period.

Exemplary daily dose increases include increasing from about 5 mg to about 10 mg afecontan, from about 10 mg to about 15 mg afecontan, or from about 10 mg to about 20 mg afecontan. Other dose increases are readily conceivable, such as increasing the 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 between thereof. Exemplary daily dose decreases include decreasing from about 20 mg to about 10 mg, from about 15 mg to about 10 mg, or from about 10 mg to about 5 mg. Other dose decreases are readily conceivable, such as decreasing the 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 between thereof.

An exemplary implementation of the method described herein includes administering a first-day dose (e.g., a first-day dose 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 such first-day dose) of afecontan 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 such duration), followed by administration based on the patient's biplane LVEF and/or Valsalva maneuver. LVOT-G can be administered at a maintenance daily dose, a reduced daily dose (e.g., reducing the daily dose by about 1 mg to about 10 mg, such as a reduction of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg, or any amount in between), an increased daily dose (e.g., increasing the daily dose by about 1 mg to about 10 mg, such as an increase of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg, or any amount in between), or discontinued to reach the second day's dose. Another exemplary embodiment of the method described herein includes administering a first-day dose of afecontan or a pharmaceutically acceptable salt thereof for about two weeks, followed by a maintenance daily dose of LVOT-G, a reduction of about 5 mg, an increase of about 5 mg, or discontinuation of administration based on the patient's biplane LVEF and/or Valsalva maneuver, to reach the second day's dose. Another exemplary embodiment of the method described herein includes administering a first-day dose of afencontan or a pharmaceutically acceptable salt thereof for approximately three weeks, followed by a maintenance dose of LVOT-G based on the patient's resting LVOT-G, biplane LVEF and/or Warburg maneuver, reducing the daily dose by approximately 5 mg, increasing the daily dose by approximately 5 mg, or discontinuing administration to reach the second-day dose. Another exemplary embodiment of the method described herein includes administering a first-day dose of afencontan or a pharmaceutically acceptable salt thereof for approximately two weeks, followed by a maintenance dose of LVOT-G based on the patient's biplane LVEF and/or Warburg maneuver, reducing the daily dose by approximately 10 mg, increasing the daily dose by approximately 10 mg, or discontinuing administration to reach the second-day dose. Another exemplary embodiment of the method described herein includes administering a first-day dose of afencontan or a pharmaceutically acceptable salt thereof for approximately three weeks, followed by a maintenance dose of LVOT-G based on the patient's biplane LVEF and/or Warburg maneuver, reducing the daily dose by approximately 10 mg, increasing the daily dose by approximately 10 mg, or discontinuing administration to reach the second-day dose. Another exemplary implementation of the method described herein includes administering a first-day dose of afecontan or a pharmaceutically acceptable salt thereof for approximately 2 to approximately 12 weeks, followed by maintenance of the daily dose of LVOT-G based on the patient's biplane LVEF and/or Valsalva maneuver, reducing the daily dose by approximately 10 mg, increasing the daily dose by approximately 10 mg, or discontinuing administration to reach the second-day dose.

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 in this article can be used to treat patients who have recently been diagnosed, are untreated, or have chronic oHCM.

In some embodiments, a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy (oHCM) to reduce the patient's post-Warshall action LVT-G, wherein the patient has recently been diagnosed with oHCM (e.g., within the past 12 months), has not received oHCM treatment, or has previously received standard medical care for oHCM and discontinued such treatment prior to afecontan administration. In some embodiments, the patient's baseline post-Warshall action LVT-G 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 afecontan or a pharmaceutically acceptable salt thereof, the post-Warshall action LVT-G may be reduced to less than 50 mmHg, for example, reduced 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 the administration of a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof, the VLOTO-G decreases by approximately 10 mmHg or greater, approximately 15 mmHg or greater, approximately 20 mmHg or greater, approximately 25 mmHg or greater, approximately 30 mmHg or greater, or approximately 35 mmHg or greater after the Warburg maneuver. In some embodiments, in response to the administration of a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof, the VLOTO-G decreases by approximately 10 mmHg to approximately 40 mmHg after the Warburg maneuver. The decrease in VLOTO-G after the Warburg maneuver can occur approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 5 weeks, approximately 6 weeks, approximately 8 weeks, or approximately 10 weeks after the daily dose is administered.

In some implementations, a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy (oHCM) to reduce 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 received oHCM treatment, or the patient previously received standard medical care for oHCM and discontinued such treatment prior to afecontan administration. In response to administration of a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof, LVMI may be reduced by about 1 g/ ^m² or greater, about 1.5 g/ ^m² or greater, about 2 g/ ^m² or greater, about 2.5 g/ ^m² or greater, about 3 g/ ^m² or greater, about 3.5 g/ ^m² or greater, or about 4 g/ ^m² or greater. In some implementations, in response to the administration of a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof, the LVMI decreases by about 1 g/ ^m² to about 10 g/ ^m² , for example, by about 1 g/ ^m² to about 6 g/ ^m² , or by about 2 g/ ^m² to about 5 g/ ^m² . The decrease in LVMI may occur approximately 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 10 weeks after daily dose administration.

In some implementations, a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy (oHCM) to reduce 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 received oHCM treatment, or the patient previously received standard medical care for oHCM and discontinued such treatment prior to afecontan administration. In response to administration of a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof, LAVI may be reduced by about 0.5 mL/ ^m² or greater, about 1 mL/ ^m² or greater, about 1.5 mL/ ^m² or greater, about 2 mL/ ^m² or greater, or about 2.5 mL/ ^m² or greater. In some implementations, in response to the administration of a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof, LAVI is reduced by about 0.5 mL/ ^m² to about 5 mL/ ^m² mmHg, for example, by about 0.5 mL/ ^m² to about 4 g/ ^m² , or by about 1 mL/ ^m² to about 3 mL/ ^m² . The reduction in LAVI may occur about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after daily dose administration.

In some implementations, a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy (oHCM) to reduce 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 received oHCM treatment, or the patient previously received standard medical care for oHCM and discontinued such treatment prior to afecontan administration. In response to administration of a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof, the e' value may decrease 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 implementations, in response to the administration of a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof, the e' value decreases 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 by about 0.15 cm/s to about 0.25 cm/s. The decrease in the e' value may occur about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 10 weeks after the daily dose is administered.

In some embodiments, a therapeutically effective amount of afencontan or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy (oHCM) to reduce 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 previously received standard medical care for oHCM and discontinued such treatment prior to afencontan administration. In response to the administration of a therapeutically effective amount of afencontan or a pharmaceutically acceptable salt thereof, the lateral E/e' ratio may be reduced by about 0.5 or greater, 1 or greater, about 1.2 or greater, about 1.5 or greater, or about 1.8 or greater. In some embodiments, in response to the administration of a therapeutically effective amount of afencontan or a pharmaceutically acceptable salt thereof, the lateral E/e' ratio is reduced by about 0.5 to about 2, for example, reduced by about 1 to about 1.8, or about 1.5 to about 1.8. The decrease in the lateral E/e' ratio can occur approximately 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 10 weeks after daily dose administration.

In some implementations, a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy (oHCM) to reduce the level of brain natriuretic peptide (BNP) or N-terminal pro-proBNP (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 received oHCM treatment, or the patient has previously received standard medical care for oHCM and discontinued such treatment prior to administration of afecontan. The reduction in BNP or N-terminal pro-proBNP (NT-proBNP) levels in the patient may occur approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 5 weeks, approximately 6 weeks, approximately 8 weeks, or approximately 10 weeks after daily dose administration.

In some implementations, a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy (oHCM) 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 received oHCM treatment, or the patient has previously received standard medical care for oHCM and discontinued that treatment prior to afecontan administration. The reduction in cardiac troponin I levels in patients may occur approximately 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 10 weeks after daily dose administration.

In some embodiments of the foregoing, when administration of afecontan or a pharmaceutically acceptable salt thereof is initiated, patients with obstructive hypertrophic cardiomyopathy are classified as NYHA Category III, 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 medical care for oHCM and discontinued such treatment prior to administration of afecontan. In some embodiments, when administration of afecontan or a pharmaceutically acceptable salt thereof is initiated, patients with obstructive hypertrophic cardiomyopathy are classified as NYHA Category II.

In some embodiments of the foregoing, afencontan or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy (oHCM) to improve 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 received oHCM treatment, or the patient has previously received standard medical care for oHCM and discontinued such treatment prior to administration of afencontan. In some embodiments of the foregoing, afencontan or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy to improve the patient's exercise capacity, for example, as measured by changes in peak oxygen uptake ( _pVO2 ) or by changes in peak oxygen uptake ( _pVO2 ) measured by cardiopulmonary exercise testing (CPET).

In some embodiments of any of the foregoing, administering afecontan 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 oHCM treatment, or the patient has previously received standard medical care for oHCM and discontinued the treatment prior to administration of afecontan.

In some embodiments of any of the foregoing, administration of afencontan 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 oHCM treatment, or the patient has previously received standard medical care for oHCM and discontinued such treatment prior to administration of afencontan.

In some embodiments of the foregoing, afencontin or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy (oHCM) to improve the patient's health status, 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 discontinued such therapy prior to administration of afencontin. In some embodiments of the foregoing, afencontin or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy to improve the patient's health status, as determined by variations in the Kansas City Cardiomyopathy Questionnaire - Overall Summary Score (KCCQ-OSS). In some embodiments of the foregoing, afencontin or a pharmaceutically acceptable salt thereof is administered to a patient with obstructive hypertrophic cardiomyopathy to improve the patient's health status, as determined by variations in the Kansas City Cardiomyopathy Questionnaire - Clinical Summary Score (KCCQ-CSS). In some embodiments of the foregoing, administration of afencontin or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy improves the patient's health status, as determined by changes in the Kansas City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS). In some embodiments of the foregoing, administration of afencontin or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy improves the patient's health status, as determined by changes in the Kansas City Cardiomyopathy Questionnaire-Physical Restriction Score (KCCQ-PLS). In some embodiments of the foregoing, administration of afencontin or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy improves the patient's health status, as determined by changes in the Kansas City Cardiomyopathy Questionnaire-Social Restriction Score (KCCQ-SLS). In some embodiments of the foregoing, administration of afencontin or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy improves the patient's health status, as determined by changes in the Kansas City Cardiomyopathy Questionnaire-Quality of Life (KCCQ-QoL). In some embodiments, administration of afecontan or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in an improvement of at least about 5, at least about 10, or at least about 20 points in one or more KCCQ domain scores (e.g., KCCQ-OSS, KCCQ-CSS, KCCQ-TSS, KCCQ-PLS, KCCQ-SLS, or KCCQ-QoL). In some embodiments, administration of afecontan or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy results in an improvement of about 5 to less than 10, about 10 to less than 20, or at least 20 points in one or more KCCQ scores (e.g., KCCQ-OSS, KCCQ-CSS, KCCQ-TSS, KCCQ-PLS, KCCQ-SLS, or KCCQ-QoL). In some such embodiments, the improvement in one or more KCCQ domain scores is an improvement in KCCQ-OSS. In some embodiments, the improvement in one or more KCCQ domain scores lasts for about 6 months. In some embodiments, administration of afencontan or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy (HCM) improves the KCCQ-CSS score by 1, 2, 3, 4, 5, or more. In some embodiments of any of the foregoing, administration of afencontan or a pharmaceutically acceptable salt thereof to a patient with HCM 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-Dimensional 5-Level Tool (EQ-5D-5L). In some embodiments, administration in combination with afencontan 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 reduction in the severity and/or frequency of chest pain, dizziness, shortness of breath, syncope during physical activity, fatigue, lack of energy, or limitation of physical activity.

This also includes combinations of the aforementioned results. For example, in some embodiments of any of the foregoing, administration of afecontan 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 oHCM treatment, or the patient has previously received standard medical care for oHCM and discontinued such treatment prior to administration of afecontan, for example, as determined by: (1) a change _{in pVO2} from baseline ≥1.5 mL/kg/min and an improvement in NYHA functional class ≥1 class; or (2) a change in _pVO2 from baseline ≥3.0 mL/kg/min and no worsening of NYHA functional class. In some embodiments of any of the foregoing, administration of afecontan or a pharmaceutically acceptable salt thereof to a patient with obstructive hypertrophic cardiomyopathy produces resting LVOT-G <30 mmHg, LVOT-G <50 mmHg after Valsalva maneuver, and NYHA functional class I in the patient. In some implementations of any of the foregoing, administration of afecontan or a pharmaceutically acceptable salt thereof to patients with obstructive hypertrophic cardiomyopathy produces a resting LVOT-G <30 mmHg, a LVOT-G <50 mmHg after Valsalva maneuver, and an improvement of ≥1 NYHA functional category in the patients.

In some implementations, the methods disclosed herein produce one or more effects selected from the group consisting of: a decrease in resting LVOT-G to less than 30 mmHg; a decrease in LVOT-G to less than 50 mmHg after a Valsalva maneuver; improved mitral regurgitation; improved cardiac relaxation; beneficial cardiac remodeling; reversed 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 the category assessment of mitral leaflet presystolic motion; reduction in mitral leaflet presystolic motion; reduction in the 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 pro-brain natriuretic peptide hormone (NT-proBNP) levels; reduction in cardiac troponin I levels; reduction in left ventricular wall stress; reduction in myocardial injury; and reduction in symptoms of heart failure, such as a decrease in NYHA classification.

Methods to reduce oHCM background therapy

Standard of care (SoC) medications for the treatment of obstructive hypertrophic cardiomyopathy (oHCM) are currently recommended as first-line therapy. SoCs include one or more of a beta-blocker, calcium channel blocker, 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 discontinuation (BTR/W) may be beneficial to patients. For patients with heart failure with preserved ejection fraction (HFpEF) and chronotropic dysfunction, discontinuation of beta-blocker therapy has been shown to provide functional and health benefits in 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).

In some aspects, methods are provided for treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in patients in need, wherein the patients are receiving one or more background therapies for oHCM. In some embodiments, methods are provided for treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in patients in need, wherein the patients are receiving background therapies for oHCM, the methods comprising (1) administering to the patient a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof, and (2) reducing and/or discontinuing at least one background therapy. In some embodiments, the patient is receiving one, two, or three background therapies for oHCM. In some embodiments, the methods comprise reducing at least one background therapy. In some embodiments, the methods comprise reducing all or one or more background therapies. In some embodiments, the methods comprise discontinuing at least one background therapy. In some embodiments, the methods comprise discontinuing all or one or more background therapies. In some embodiments, at least one background therapy comprises administering at least one standard of care treatment selected from the group consisting of a beta-blocker, a non-dihydropyridine calcium channel blocker, 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 includes 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) initiating administration of a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof to the patient, and (ii) reducing and/or discontinuing at least one background therapy are performed simultaneously. In some embodiments, (i) initiating administration of a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof to the patient, and (ii) reducing and/or discontinuing at least one background therapy are performed sequentially. In some embodiments, reducing and/or discontinuing at least one background therapy is performed after initiation of administration of afecontan or a pharmaceutically acceptable salt thereof. In some embodiments, reduction and/or discontinuation of at least one background therapy is performed 2 weeks or longer after initiation of afencontan or a pharmaceutically acceptable salt thereof, such as at 2, 3, 4, 5, 8, 10, 12, 15, 18, or 24 weeks after initiation of afencontan or a pharmaceutically acceptable salt thereof, or any amount in between. In some embodiments, reduction and/or discontinuation of at least one background therapy is performed 12 weeks or longer after initiation of afencontan or a pharmaceutically acceptable salt thereof. In some embodiments, reduction and/or discontinuation of at least one background therapy is performed when the patient has been receiving a stable dose of afencontan or a pharmaceutically acceptable salt thereof for 2 weeks or longer, such as at 2, 3, 4, 5, 8, 10, 12, 15, 18, or 24 weeks after initiation of afencontan or a pharmaceutically acceptable salt thereof, or any amount in between. In some implementations, at least one background therapy is reduced and/or discontinued when the patient has been receiving a stable dose of afecontan or a pharmaceutically acceptable salt thereof for 4 weeks or longer, such as at 4, 5, 8, 10, 12, 15, 18 or 24 weeks after initiation of administration of afecontan or a pharmaceutically acceptable salt thereof, or at any amount in between.

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

On the other hand, a method is provided for treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in patients of need, the method comprising: (1) administering to the patient a therapeutically effective amount of afecontan or a pharmaceutically acceptable saline thereof, along with a standard of care for oHCM, for a first period; and (2) administering to the patient a therapeutically effective amount of afecontan or a pharmaceutically acceptable saline thereof as monotherapy, for a second period. In some embodiments, the second dose of the standard of care for oHCM is 50% or less of the first dose of the standard of care. In some embodiments, the first period is at least 12 weeks. In some embodiments, afecontan or a pharmaceutically acceptable saline thereof is administered at a constant amount for at least about 4 weeks prior to the start of the second period.

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

On the other hand, a method is provided for treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in patients in need, the method comprising: (1) administering a background therapy to the patient, the background therapy comprising at least one standard of care 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 afecontan or a pharmaceutically acceptable salt thereof to the patient during a first time period, along with the background therapy; and (3) administering a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof to the patient during a second time period as a single therapy. In some embodiments, the first time period is at least 12 weeks. In some embodiments, afecontan or a pharmaceutically acceptable salt thereof is administered at a constant amount for at least about 4 weeks prior to the start of the second time period.

On the other hand, methods for improving myocardial mechanics in patients in need are provided, the methods comprising administering a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof to the patient. In some aspects, methods for improving myocardial mechanics in patients with obstructive hypertrophic cardiomyopathy are provided, the methods comprising administering a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof to the patient. In some embodiments, the methods comprise long-term administration of afecontan or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the methods comprise administration of afecontan 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 methods comprise administration of afecontan for at least about 12 weeks. In some embodiments, the methods comprise administration of afecontan for at least about 36 weeks. In some embodiments, the methods comprise administration of afecontan for at least about 48 weeks. In some embodiments, the methods further improve resting LVOT-G. In some embodiments, the method produces a resting LVOT-G of less than 30 mmHg. In some embodiments, the method further improves the Valsalva maneuver LVOT-G. In some embodiments, the method produces a Valsalva maneuver LVOT-G of less than 50 mmHg. In some embodiments, the method includes administering afencontan or a pharmaceutically acceptable salt thereof to a patient who has an optimal hemodynamic response to treatment with afencontan or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the method includes administering afencontan to a patient with a resting LVOT-G of less than 30 mmHg. In some embodiments, the method includes administering afencontan to a patient with a Valsalva maneuver LVOT-G of less than 50 mmHg. In some embodiments, the patient has a resting LVOT-G of less than 30 mmHg due to treatment with afencontan or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has a Valsalva maneuver LVOT-G of less than 50 mmHg due to treatment with afencontan or a pharmaceutically acceptable salt thereof. In some implementations, the patient achieves an optimal hemodynamic response to treatment with afencontan or its pharmaceutically acceptable saline. In some implementations, the improvement in myocardial mechanics occurs after the patient has achieved an optimal hemodynamic response to treatment with afencontan or its pharmaceutically acceptable saline. In some implementations, the improvement in myocardial mechanics occurs approximately 4 weeks, 6 weeks, 8 weeks, 12 weeks, or 36 weeks (or any number of weeks in between) after the patient has responded to treatment with afencontan or its pharmaceutically acceptable saline to a resting LVT-G of less than 30 mmHg and/or a Valsalva maneuver LVT-G of less than 50 mmHg.

On the other hand, methods for improving global longitudinal strain (GLS) in patients in need are provided, the methods comprising administering a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof to the patient. In some aspects, methods for improving global longitudinal strain (GLS) in patients with obstructive hypertrophic cardiomyopathy are provided, the methods comprising administering a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof to the patient. In some embodiments, the methods comprise long-term administration of afecontan or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the methods comprise administration of afecontan 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 methods comprise administration of afecontan for at least about 12 weeks. In some embodiments, the methods comprise administration of afecontan for at least about 36 weeks. In some embodiments, the methods comprise administration of afecontan for at least about 48 weeks. In some embodiments, the methods further improve resting LVOT-G. In some embodiments, the method produces a resting LVOT-G of less than 30 mmHg. In some embodiments, the method further improves the Valsalva maneuver LVOT-G. In some embodiments, the method produces a Valsalva maneuver LVOT-G of less than 50 mmHg. In some embodiments, the method includes administering afencontan or a pharmaceutically acceptable salt thereof to a patient who has an optimal hemodynamic response to treatment with afencontan or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the method includes administering afencontan to a patient with a resting LVOT-G of less than 30 mmHg. In some embodiments, the method includes administering afencontan to a patient with a Valsalva maneuver LVOT-G of less than 50 mmHg. In some embodiments, the patient has a resting LVOT-G of less than 30 mmHg due to treatment with afencontan or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has a Valsalva maneuver LVOT-G of less than 50 mmHg due to treatment with afencontan or a pharmaceutically acceptable salt thereof. In some implementations, the patient achieves an optimal hemodynamic response to treatment with afencontan or its pharmaceutically acceptable saline. In some implementations, GLS improvement occurs after the patient has achieved an optimal hemodynamic response to treatment with afencontan or its pharmaceutically acceptable saline. In some implementations, GLS improvement occurs approximately 4 weeks, 6 weeks, 8 weeks, 12 weeks, or 36 weeks (or any number of weeks in between) after the patient has responded to treatment with afencontan or its pharmaceutically acceptable saline to a resting LVOT-G of less than 30 mmHg and/or a Valsalva maneuver LVOT-G of less than 50 mmHg.

In some embodiments of any of the foregoing, the therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof is selected by dripping a daily dose of afecontan or a pharmaceutically acceptable salt thereof onto the patient, as described herein in relation to methods for treating oHCM.

In some implementations, the patient has comorbidities. In some implementations, the patient has one or more of hypertension, diabetes, permanent atrial fibrillation, and paroxysmal atrial fibrillation.

The compounds and compositions disclosed and/or described herein may be administered via any acceptable mode of therapeutic application, including but not limited to oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. In some embodiments, the compounds or compositions are administered orally or intravenously. In some embodiments, the compounds or compositions disclosed and/or described herein are administered orally. In some embodiments, the compounds or compositions disclosed and/or described herein are administered by injection. In some embodiments, the compounds or compositions disclosed and/or described herein are administered intranasally. In some embodiments, the compounds or compositions disclosed and/or described herein are administered transdermally.

Pharmaceutically acceptable compositions include solid, semi-solid, liquid, and aerosol dosage forms, such as tablets, capsules, powders, liquids, suspensions, suppositories, and aerosols. The compounds disclosed and/or described herein may also be administered in the following forms: sustained-release or controlled-release dosage forms (e.g., controlled/sustained-release pills, accumulation injections, osmotic pumps, or transdermal (including electrotransport) patches) for extended-time administration, and/or pulsed administration at a predetermined rate. In some embodiments, the compositions are provided in unit dosage forms suitable for a precise single-dose administration.

Afencontan 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, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical composition may also contain small amounts of non-toxic excipients such as wetting agents, emulsifiers, solubilizers, pH buffers, etc. (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitol monolaurate, triethanolamine acetate, triethanolamine oleate). Typically, depending on the intended administration regimen, 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. Practical methods for preparing such dosage forms are known or obvious to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania. Suitable formulations of afecontan are disclosed in WO 2021/011808, which is incorporated herein by reference in its entirety.

In some embodiments, afecontan is provided in the form of a formulation comprising: (i) afecontan 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, 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, dicalcium phosphate, dicalcium phosphate, tricalcium phosphate, compressible sugars, sugar alcohols, mannitol, sorbitol, maltitol, xylitol, lactitol, lactose, dextrose, maltose, sucrose, glucose, fructose, sucrose, raffinose, dextrate, trehalose, maltodextrin, and mixtures of any of the foregoing substances.

In some embodiments, the adhesive is selected from the group consisting of: gum arabic, acacia gum, alginate, alginic acid, corn starch, copovidone, polyvinylpyrrolidone, gelatin, glyceryl behenate, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, 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 mixtures of any of the foregoing substances.

In some embodiments, the disintegrant is selected from the group consisting of: alginate, croscarmellose sodium, cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, croscarmellose, sodium glycolate starch, low-substituted hydroxypropyl cellulose, polacrine potassium, pregelatinized starch, partially hydrolyzed starch, sodium carboxymethyl starch, starch, sodium alginate, sodium carboxymethyl cellulose, and mixtures of any of the foregoing substances.

In some embodiments, the surfactant is selected from the group consisting of: hexadecylpyridine chloride, heptadecanoylvinyloxycetyl alcohol, lecithin, polyoxyethylene stearate, nonoxyphenyl alcohol ether 9, nonoxyphenyl alcohol ether 10, octylphenyl alcohol ether 9, dehydrated sorbitol fatty acid ester, Span 20, Span 40, Span 60, Span 80, Span 85, polysorbate, polysorbate ester 20, polysorbate ester 21, polysorbate ester 40, polysorbate... Sorbitol 60, polysorbate 61, polysorbate 65, polysorbate 80, sodium fatty alcohol sulfate, sodium dodecyl sulfate, sodium sulfosuccinate, sodium dioctyl sulfosuccinate, fatty acid and alcohol metaesters, glyceryl monostearate, glyceryl monooleate, fatty alcohol and polyoxyethylene ethers, fatty acid and polyoxyethylene esters, copolymers of ethylene oxide and propylene oxide (Pluronic®), benzalkonium chloride, ethoxylated triglycerides, and mixtures of any of the foregoing substances.

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 dipalmitoate stearate, behenyl polyoxy-8 glyceryl ester, sodium stearoyl fumarate, stearic acid, talc, zinc stearate, mineral oil, polyethylene glycol, poloxamer, sodium dodecyl sulfate, and mixtures of any of the foregoing substances.

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

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

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

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

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

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

In some embodiments, the formulation comprises: (i) about 1% to about 50% by weight of afecontan 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 dodecyl sulfate; and (vi) about 0.1% to about 10% by weight of magnesium stearate.

In some embodiments, the formulation comprises: (i) about 10% to about 30% by weight of afencontan 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 dodecyl sulfate; and (vi) about 0.5% to about 1.5% by weight of magnesium stearate.

In some embodiments, the formulation comprises: (i) about 1% to about 10% by weight of afecontan 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 dodecyl sulfate; and (vi) about 0.5% to about 1.5% by weight of magnesium stearate.

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

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

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

In some embodiments, the aforementioned formulation is in tablet form. In some embodiments, the tablet also comprises a coating (e.g., film coating as described elsewhere herein). In such embodiments, the weight percentages herein are provided relative to the core tablet and exclude the weight of the coating.

In some embodiments, afecontan or a pharmaceutical composition containing afecontan will be in the form of pills or tablets, and therefore 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, farnesian gum, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives), as well as compounds disclosed and/or described herein. Other solid dosage forms include powders encapsulated in gelatin capsules, marumes, solutions, or suspensions (e.g., in propylene carbonate, vegetable oil, or triglycerides).

In some embodiments, afecontan is provided in tablet form, the tablet comprising: (i) a core, the total weight of which comprises: (a) an in-particle component comprising: (a-i) afecontan or a pharmaceutically acceptable salt thereof; (a-ii) an in-particle filler; (a-iii) an in-particle binder; (a-iv) an in-particle disintegrant; and (a-v) an in-particle surfactant; and (b) an out-of-particle component comprising: (b-i) an out-of-particle filler; (b-ii) an out-of-particle disintegrant; and (b-iii) an out-of-particle lubricant; and optionally (ii) a coating layer comprising a coating agent.

In some embodiments, the granular 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, dicalcium 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 substances.

In some embodiments, the intragranular binder is selected from the group consisting of: gum arabic, acacia gum, alginate, alginic acid, corn starch, copovidone, polyvinylpyrrolidone, gelatin, glyceryl behenate, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, 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 mixtures of any of the foregoing substances.

In some embodiments, the intraparticle disintegrant is selected from the group consisting of: alginate, croscarmellose sodium, cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, croscarmellose, sodium glycolate starch, low-substituted hydroxypropyl cellulose, polacrine potassium, pregelatinized starch, partially hydrolyzed starch, sodium carboxymethyl starch, starch, sodium alginate, sodium carboxymethyl cellulose, and mixtures of any of the foregoing substances.

In some embodiments, the intraparticle surfactant is selected from the group consisting of: hexadecylpyridine chloride, heptadecanoyl chloride, cetyl alcohol, lecithin, polyoxyethylene stearate, nonoxyphenyl alcohol ether 9, nonoxyphenyl alcohol ether 10, octylphenyl alcohol ether 9, sorbitol fatty acid ester, Span 20, Span 40, Span 60, Span 80, Span 85, polysorbate, polysorbate ester 20, polysorbate ester 21, and polysorbate ester 40. Polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, sodium fatty alcohol sulfate, sodium dodecyl sulfate, sodium sulfosuccinate, sodium dioctyl sulfosuccinate, fatty acid and alcohol metaesters, glyceryl monostearate, glyceryl monooleate, fatty alcohol and polyoxyethylene ethers, fatty acid and polyoxyethylene esters, copolymers of ethylene oxide and propylene oxide (Pluronic®), benzalkonium chloride, ethoxylated triglycerides, and mixtures of any of the foregoing substances.

In some embodiments, the particulate excipient 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, 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 substances.

In some embodiments, the exodisintegrant is selected from the group consisting of: alginate, croscarmellose sodium, cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, croscarmellose, sodium glycolate starch, low-substituted hydroxypropyl cellulose, polacrine potassium, pregelatinized starch, partially hydrolyzed starch, sodium carboxymethyl starch, starch, sodium alginate, sodium carboxymethyl cellulose, and mixtures of any of the foregoing substances.

In some embodiments, the particulate external lubricant is selected from the group consisting of: hydrogenated castor oil, magnesium stearate, glyceryl monostearate, calcium stearate, glyceryl behenate, glyceryl distearate, glyceryl dipalmitate stearate, behenyl polyoxy-8 glyceryl ester, sodium stearoyl fumarate, stearic acid, talc, zinc stearate, mineral oil, polyethylene glycol, poloxamer, sodium dodecyl sulfate, and mixtures of any of the foregoing substances.

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

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

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

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

In some embodiments, the core comprises: (a) an in-particle component comprising: (a-i) about 1% to about 10% of afecontan or a pharmaceutically acceptable salt thereof by weight of the total core; (a-ii) about 60% to about 80% of an in-particle filler by weight of the total core; (a-iii) about 1% to about 3% of an in-particle binder by weight of the total core; (a-iv) about 2% to about 4% of an in-particle disintegrant by weight of the total core; and (a-v) about 1% to about 3% of an in-particle surfactant by weight of the total core; and (b) an out-of-particle component comprising: (b-i) about 5% to about 15% of an out-of-particle filler by weight of the total core; (b-ii) about 1% to about 3% of an out-of-particle disintegrant by weight of the total core; and (b-iii) about 0.1% to about 1.5% of an out-of-particle lubricant by weight of the total core. In some embodiments, the total core weight is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

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

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

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

In some embodiments, the core comprises: (a) an intraparticle component comprising: (a-i) about 1% to about 50% of afecontan or a pharmaceutically acceptable salt thereof by weight of the total core; (a-ii-1) about 40% to about 60% of mannitol by weight of the total core; (a-ii-2) about 10% to about 30% of microcrystalline cellulose by weight of the total core; (a-iii) about 1% to about 5% of hydroxypropyl cellulose by weight of the total core; (a-iv) about 1% to about 5% of croscarmellose sodium by weight of the total core; and (a-v) about 1% to about 5% of sodium dodecyl sulfate by weight of the total core; and (b) an extraparticle component comprising: (b-i) about 5% to about 15% of microcrystalline cellulose by weight of the total core; (b-ii) about 1% to about 5% of croscarmellose sodium by weight of the total core; and (b-iii) about 0.1% to about 2% of an extraparticle lubricant by weight of the total core. In some embodiments, the external lubricant is magnesium stearate. In some embodiments, the total core weight is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

In some embodiments, the core comprises: (a) an intraparticle component comprising: (a-i) about 10% to about 30% of afeniconazole or a pharmaceutically acceptable salt thereof by weight of the total core; (a-ii-1) about 40% to about 50% of mannitol by weight of the total core; (a-ii-2) about 10% to about 20% of microcrystalline cellulose by weight of the total core; (a-iii) about 1% to about 3% of hydroxypropyl cellulose by weight of the total core; (a-iv) about 2% to about 4% of croscarmellose sodium by weight of the total core; and (a-v) about 1% to about 3% of sodium dodecyl sulfate by weight of the total core; and (b) an extraparticle component comprising: (b-i) about 5% to about 15% of microcrystalline cellulose by weight of the total core; (b-ii) about 1% to about 3% of croscarmellose sodium by weight of the total core; and (b-iii) about 0.1% to about 1.5% of an extraparticle lubricant by weight of the total core. In some embodiments, the external lubricant is magnesium stearate. In some embodiments, the total core weight is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

In some embodiments, the core comprises: (a) an intraparticle component comprising: (a-i) about 1% to about 10% by weight of afencontan or a pharmaceutically acceptable salt thereof; (a-ii-1) about 50% to about 60% by weight of the total core weight of mannitol; (a-ii-2) about 15% to about 25% by weight of the total core weight of microcrystalline cellulose; (a-iii) about 1% to about 3% by weight of the total core weight of hydroxypropyl cellulose; (a-iv) about 2% to about 4% by weight of the total core weight of croscarmellose sodium; and (a-v) about 1% to about 3% by weight of the total core weight of sodium dodecyl sulfate; and (b) an extraparticle component comprising: (b-i) about 5% to about 15% by weight of the total core weight of microcrystalline cellulose; (b-ii) about 1% to about 3% by weight of the total core weight of croscarmellose sodium; and (b-iii) about 0.1% to about 1.5% by weight of the total core weight of an extraparticle lubricant. In some embodiments, the external lubricant is magnesium stearate. In some embodiments, the total core weight is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

In some embodiments, the core comprises: (a) an intraparticle component comprising: (a-i) about 20% by weight of afecontan or a pharmaceutically acceptable salt thereof; (a-ii-1) about 44% by weight of the core; (a-ii-2) about 15% by weight of the core; (a-iii) about 2% by weight of the core; (a-iv) about 3% by weight of the core; and (a-v) about 2% by weight of the core; and (b) an extraparticle component comprising: (b-i) about 11% by weight of the core; (b-ii) about 2% by weight of the core; and (b-iii) about 1% by weight of the core; and an extraparticle lubricant. In some embodiments, the extraparticle lubricant is magnesium stearate. In some embodiments, the total core weight is about 50 mg, about 70 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, the total core weight is about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the total core weight is about 50 mg. In some embodiments, the total core weight is about 70 mg. In some embodiments, the total core weight is about 100 mg. In some embodiments, the total core weight is about 150 mg. In some embodiments, the total core weight is about 200 mg. In some embodiments, the total core weight is about 400 mg.

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

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

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 core weight of the coating agent. In some embodiments, the tablet comprises about 1% to about 5% of the total core weight of the coating agent. In some embodiments, the tablet comprises about 2% to about 4% of the total core weight of the coating agent. In some embodiments, the tablet comprises about 3% of the total core weight of the coating agent. In some embodiments, the tablet comprises about 0.5% to about 10% of Opadry QX White 21A180025 of the total core weight. In some embodiments, the tablet contains about 1% to about 5% of Opadry QX White 21A180025 by weight of the core total weight. In some embodiments, the tablet contains about 2% to about 4% of Opadry QX White 21A180025 by weight of the core total weight. In some embodiments, the tablet contains about 3% of Opadry QX White 21A180025 by weight of the core total weight.

In some embodiments, the amount of afecontan (which may be present in various forms) in the formulation (e.g., tablets) is approximately the daily dose described herein, such as about 5 mg, about 10 mg, about 15 mg, or about 20 mg of afecontan. In some embodiments, the amount of afecontan (which may be present in various forms) in the formulation (e.g., tablets) is about half the daily dose described herein. In some embodiments, the amount of afecontan in the formulation (e.g., tablets) is about 2.5 mg, about 5 mg, about 7.5 mg, or about 10 mg of afecontan.

In some embodiments, afecontan 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.

Liquid pharmaceutically acceptable compositions may be prepared, for example, by dissolving, dispersing, or suspending the compounds disclosed and/or described herein, and optional pharmaceutical additives, in a carrier (e.g., water, saline, aqueous dextran solution, glycerol, glycol, ethanol, etc.) to form a solution or suspension. Injectable formulations may be prepared in conventional forms, as liquid solutions or suspensions, as emulsions, or as solids suitable for dissolving or suspending in a liquid prior to injection. The percentage of the compound contained in such parenteral compositions depends, for example, the physical properties of the compound, the activity of the compound, and the needs of the subject. However, a percentage of 0.01% to 10% of the active ingredient may be used in solution, and a higher percentage may be used if the composition is a solid that will subsequently be diluted to another concentration. In some embodiments, the composition will contain about 0.2% to 2% of the compounds disclosed and/or described herein in solution.

Pharmaceutical compositions of the compounds disclosed and/or described herein may also be administered to the respiratory tract as an aerosol or solution for use in a nebulizer, or as a fine powder for inhalation, alone or in combination with an inert carrier such as lactose. In this case, the particles of the pharmaceutical composition may have a diameter of less than 50 micrometers, or less than 10 micrometers in some embodiments. Pharmaceutical compositions of the compounds disclosed and/or described herein may also be administered transdermally, for example in the form of patches, creams, ointments, or other formulations suitable for application to the skin.

In addition, pharmaceutical compositions may include the compounds disclosed and/or described herein and one or more other pharmaceutical agents, medicines, adjuvants, etc. Suitable pharmaceutical agents and medicines include those described herein.

Polymorphs

In some embodiments, afencontan is a polymorphic form of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Suitable polymorphs of afencontan 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 use, such as bioavailability and stability under certain conditions. Variations in the crystal structure of a pharmaceutical substance can affect the dissolution rate of the pharmaceutical 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 in different dosage forms or delivery formats (e.g., solid oral dosage forms, including tablets and capsules). Polymorphs offer desirable or suitable hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, reproducibility, and/or process control compared to other forms such as amorphous or non-crystalline forms. Therefore, polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide may offer advantages such as improved manufacturing processes of the active agent or stability or storage of the active agent in a pharmaceutical product form, or bioavailability and/or stability suitable for use as an active agent. In some embodiments, formulations, such as afecontan in tablets, are one or a combination of polymorphs I, II, III, IV, V, or VI. In some embodiments, afencontin is one of polymorphs I, II, III, IV, V, or VI. In some embodiments, afencontin is polymorph I or IV. In some embodiments, afencontin is polymorph I. In some embodiments, afencontin is polymorph IV.

Form I

In some embodiments, afecontan is polymorphic form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. The 2-θ angle and relative peak intensity of form I, observable using XRPD, are shown in Table P-1. In some embodiments, form I has an XRPD plot substantially as shown in Figure 59A.

Table P-1

In some embodiments, polymorphic form I has an XRPD plot showing at least two, three, four, five, six, seven, eight, nine, or ten peaks with maximum intensity at a 2-θ angle in the XRPD plot, substantially as shown in Figure 59A or as provided in Table P-1. It should be understood that relative intensities can vary depending on a variety of factors, including sample preparation, setup, and the instruments and analytical procedures and settings used to obtain the spectra. Relative peak intensities and peak assignments can vary within experimental error ranges. In some embodiments, the peak assignments listed herein (including polymorphic form I) can vary by approximately ±0.6°, ±0.4°, ±0.2°, or ±0.1°2-θ.

In some embodiments, polymorphic form I has values including 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, and 23.9±0. 2. XRPD plots 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°. In some embodiments, polymorphic form I has an XRPD plot containing 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, polymorphic form I has an XRPD plot containing 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 additional peaks may also be observed in the XRPD plot besides those shown in Figure 59A or provided in Table P-1, for example, due to the presence of impurities, solvents, or other polymorphs or amorphous forms in the test sample.

In some embodiments, Form I has a differential DSC plot substantially as shown in Figure 59B. In some embodiments, Form I is characterized by initiating heat absorption at approximately 199°C, as determined by DSC. In some embodiments, Form I is characterized by initiating heat absorption at 199 ± 2°C (e.g., 199 ± 1.9°C, 199 ± 1.8°C, 199 ± 1.7°C, 199 ± 1.6°C, 199 ± 1.5°C, 199 ± 1.4°C, 199 ± 1.3°C, 192 ± 1.2°C, 199 ± 1°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.

In some implementations, Form I has a TGA diagram that is essentially as shown in Figure 59B.

In some implementations, Form I has a DVS diagram that is essentially as shown in Figure 59C.

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

(a) Form I has an XRPD plot containing peaks at 2-θ angles of 3.7±0.2, 11.2±0.2, 12.9±0.2, 14.4±0.2, and 22.4±0.2°; an XRPD plot containing 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 plot containing 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, and 14.9±0.2°. XRPD plots of peaks at 2-θ angles of 16.6±0.2, 17.8±0.2, 18.6±0.2, 21.6±0.2, 22.2±0.2, 22.4±0.2, 22.8±0.2, 23.2±0.2, 23.9±0.2, 24.4±0.2, 24.7±0.2, 25.0±0.2, 25.8±0.2, 26.1±0.2, 28.6±0.2, 29.0±0.2, 29.4±0.2, 29.9±0.2, 30.6±0.2, 33.8±0.2, 36.1±0.2, 36.8±0.2, 37.8±0.2, and 39.8±0.2°;

(b) Form I has an XRPD diagram that is essentially as shown in Figure 59A;

(c) Form I has a DSC diagram that is essentially as shown in Figure 59B;

(d) Form I is characterized by the onset of heat absorption at approximately 199°C, as determined by DSC.

(e) Form I has a TGA diagram that is essentially as shown in Figure 59B; and

(f) Form I has a DVS diagram that is essentially as shown in Figure 59C.

Form II

In some embodiments, afecontan is polymorphic form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. The 2-θ angle and relative peak intensity of form II, observable using XRPD, are shown in Table P-2. In some embodiments, form II has an XRPD plot substantially as shown in Figure 60A.

Table P-2

In some embodiments, polymorphic form II has an XRPD plot showing at least two, three, four, five, six, seven, eight, nine, or ten peaks with maximum intensity at °2-θ in the XRPD plot, substantially as shown in Figure 60A or as provided in Table P-2. It should be understood that relative intensities can vary depending on a variety of factors, including sample preparation, setup, and the instruments and analytical procedures and settings used to obtain the spectra. Relative peak intensities and peak assignments can vary within experimental error ranges. In some embodiments, the peak assignments listed herein (including polymorphic form II) can vary by approximately ±0.6°, ±0.4°, ±0.2°, or ±0.1°2-θ.

In some embodiments, polymorphic form II has an XRPD plot containing peaks at 2-θ 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 II has an XRPD plot containing 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 II has an XRPD plot containing 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 additional peaks may also be observed in the XRPD plot besides those shown in Figure 60A or provided in Table P-2, for example, due to the presence of impurities, solvents, or other polymorphs or amorphous forms in the test sample.

In some embodiments, form II has a DSC plot substantially as shown in Figure 60B. In some embodiments, form II is characterized by initiating heat absorption at approximately 199°C, as determined by DSC. In some embodiments, form II is characterized by initiating heat absorption at approximately 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.

In some implementations, Form II has a TGA diagram that is essentially as shown in Figure 60B.

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

(a) Form II has an XRPD plot containing 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 plot containing 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 plot containing peaks at 2-θ angles of 3.7±0.2, 7.4±0.2, 9.8±0.2, 12.8±0.2, and 20.4 ... and 20.4±0.2°; or an XRPD plot containing peaks at 2-θ angles of 3.7±0.2, 9.8±0.2, 12.8±0.2, and 20.4±0.2°; or an XRPD plot containing peaks at 2-θ angles of 3.7±0.2, 9.8±0.2, 12.8±0.2, and 20.4±0.2°; or an XRPD plot containing peaks at 2-θ angles of 3.7 XRPD plots of peaks at 2-θ angles of 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°;

(b) Form II has an XRPD plot that is essentially as shown in Figure 60A;

(c) Form II has a DSC diagram that is essentially as shown in Figure 60B;

(d) Form II is characterized by melting and endothermic reaction beginning at approximately 199°C, as determined by DSC; and

(e) Form II has a TGA diagram that is essentially as shown in Figure 60B.

Form III

In some embodiments, afecontan is the 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 angle 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 an XRPD plot substantially as shown in Figure 61A.

Table P-3

In some embodiments, polymorph III has an XRPD plot containing 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 III has an XRPD plot containing 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 III has an XRPD plot containing 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 can vary depending on a variety of factors, including sample preparation, setup, and the instrumentation and analytical procedures and settings used to obtain the spectra. Relative peak intensities and peak assignments can vary within the experimental error range. In some implementations, the peak assignments listed herein (including polymorphic form III) can vary by approximately ±0.6°, ±0.4°, ±0.2°, or ±0.1°2-θ.

In some embodiments, the mixture of polymorphic forms I and III has a DSC diagram that is substantially as shown in Figure 61B.

In some embodiments, the mixture of polymorphic forms I and III has a TGA diagram that is substantially as shown in Figure 61B.

Form IV

In some embodiments, afecontan is the polymorphic form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. The 2-θ angle and relative peak intensities of form IV, observable using XRPD, are shown in Table P-4. In some embodiments, form IV has an XRPD plot substantially as shown in Figure 62A.

Table P-4

In some embodiments, the polymorphic form IV has an XRPD plot showing at least two, three, four, five, six, seven, eight, nine, or ten peaks with maximum intensity at a 2-θ angle in the XRPD plot, substantially as shown in Figure 62A or as provided in Table P-4. It should be understood that relative intensities can vary depending on a variety of factors, including sample preparation, setup, and the instruments and analytical procedures and settings used to obtain the spectra. Relative peak intensities and peak assignments can vary within experimental error ranges. In some embodiments, the peak assignments listed herein (including those for polymorphic form IV) can vary by approximately ±0.6°, ±0.4°, ±0.2°, or ±0.1°2-θ.

In some embodiments, the polymorphic form IV has values including 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, and 23.9±0. 2. XRPD plots of peaks at 2-θ angles of 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, the polymorphic form IV has an XRPD plot containing 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, the polymorphic form IV has an XRPD plot containing 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 additional peaks may also be observed in the XRPD plot besides those shown in Figure 62A or provided in Table P-4, for example, due to the presence of impurities, solvents, or other polymorphs or amorphous forms in the test sample.

In some embodiments, form IV has a DSC plot substantially as shown in Figure 62B. In some embodiments, form IV is characterized by initiating heat absorption at approximately 200°C, as determined by DSC. In some embodiments, form IV is characterized by initiating heat absorption at approximately 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°C, 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 implementations, form IV has a TGA diagram that is essentially as shown in Figure 62B.

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:

(a) Form IV has an XRPD plot with peaks at 2-θ angles of 11.1±0.2, 12.8±0.2, 13.5±0.2, 22.8±0.2, and 24.4±0.2°; and peaks at 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°. XRPD plot of the peak at the 2-θ angle of 0.8±0.2°; or containing 3.7±0.2, 7.7±0.2, 11.1±0.2, 12.4±0.2, 12.8±0.2, 13.5±0.2, 14.3±0.2, 15.5±0.2, 16.6±0.2, 17.9±0.2, 18.5±0.2, 18.6±0.2, 19.1±0.2, 19.9±0.2, 20.9±0.2. 21.5±0.2, 21.6±0.2, 21.9±0.2, 22.3±0.2, 22.4±0.2, 22.8±0.2, 23.1±0.2, 23.5±0.2, 23.9±0.2, 24.4±0.2, 24.8±0.2, 25.0±0.2, 25.3±0.2, 25.8±0.2, 26.2±0.2, 27.1±0.2, 27.4±0.2, 28 XRPD plots 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, and 39.8±0.2°;

(b) Form IV has an XRPD diagram that is essentially as shown in Figure 62A;

(c) Form IV has a DSC diagram that is essentially as shown in Figure 62B;

(d) Form IV is characterized by initiating melting and endothermic activity at approximately 200°C, as determined by DSC; and

(e) Form IV has a TGA diagram that is essentially as shown in Figure 62B.

Form V

In some embodiments, afecontan is the 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 angle and relative peak intensities of form V, observable using XRPD, are shown in Table P-5. In some embodiments, form V has an XRPD plot substantially as shown in Figure 63.

Table P-5

In some embodiments, the polymorphic form V has an XRPD plot showing at least two, three, four, five, six, seven, eight, nine, or ten peaks with maximum intensity at a 2-θ angle in the XRPD plot, substantially as shown in Figure 63 or as provided in Table P-5. It should be understood that relative intensities can vary depending on a variety of factors, including sample preparation, setup, and the instruments and analytical procedures and settings used to obtain the spectra. Relative peak intensities and peak assignments can vary within experimental error ranges. In some embodiments, the peak assignments listed herein (including those for polymorphic form V) can vary by approximately ±0.6°, ±0.4°, ±0.2°, or ±0.1°2-θ.

In some embodiments, the polymorphic form V has an XRPD plot containing peaks at the following 2-θ 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, 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, the polymorphic form V has an XRPD plot containing peaks at 2-θ angles of 5.7±0.2, 8.3±0.2, 11.5±0.2, 16.3±0.2, 17.2±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 20.7±0.2, 21.2±0.2, 23.3±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, 26.7±0.2, 28.1±0.2, 29.2±0.2, 29.7±0.2, 29.9±0.2, and 31.1±0.2. In some embodiments, the polymorphic form V has an XRPD plot containing 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, the polymorphic form V has an XRPD plot containing 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 additional peaks may also be observed in the XRPD plot besides those shown in Figure 63 or provided in Table P-5, for example, due to the presence of impurities, solvents, or other polymorphs or amorphous forms in the test sample.

In some implementations of form V, at least one or both of the following (a)-(b) apply:

(a) Form V has an XRPD plot containing 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 plot containing 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 plot containing peaks at 5.7±0.2°. 2. XRPD plots of peaks at 2-θ 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°; and

(b) Form V has an XRPD plot that is essentially as shown in Figure 63.

Form VI

In some embodiments, afecontan is the 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 angle and relative peak intensities of form VI, observable using XRPD, are shown in Table P-6. In some embodiments, form VI has an XRPD plot substantially as shown in Figure 64A.

Table P-6

In some embodiments, polymorphic form VI has an XRPD plot showing at least two, three, four, five, six, seven, eight, nine, or ten peaks with maximum intensity at a 2-θ angle in the XRPD plot, substantially as shown in Figure 64A or as provided in Table P-6. It should be understood that relative intensities can vary depending on a variety of factors, including sample preparation, setup, and the instrumentation and analytical procedures and settings used to obtain the spectrum. Relative peak intensities and peak assignments can vary within experimental error ranges. In some embodiments, the peak assignments listed herein (including polymorphic form VI) can vary by approximately ±0.6°, ±0.4°, ±0.2°, or ±0.1°2-θ.

In some embodiments, the polymorphic form VI has values 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, and 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. 2. XRPD plots of peaks at 2-θ angles of 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. In some embodiments, polymorphic form VI has XRPD plots of 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, polymorphic form VI has an XRPD plot containing 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 additional peaks may also be observed in the XRPD plot besides those shown in Figure 64A or provided in Table P-6, for example, due to the presence of impurities, solvents, or other polymorphs or amorphous forms in the test sample.

In some embodiments, form VI has a TGA diagram substantially as shown in Figure 64B or substantially as shown in Figure 64C. In some embodiments, form VI exhibits a weight loss of approximately 2% ± 0.5% between 25°C and 200°C, as determined by TGA.

In some embodiments, form VI has a DSC plot substantially as shown in FIG. 64D or substantially as shown in FIG. 64E. In some embodiments, form VI is characterized by initiating heat absorption at approximately 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 °C, 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 temperatures of approximately 200±2℃ (e.g., 200±1.9℃, 200±1.8℃, 200±1.7℃, 200±1.6℃, 200±1.5℃, 200±1.4℃, 200±1.3℃, 200±1.2℃, 200±1, 200±0.9℃, 200±0.8℃, 200±0.7℃). It begins to absorb heat at temperatures of 200±0.6℃, 200±0.5℃, 200±0.4℃, 200±0.3℃, 200±0.2℃, or 200±0.1℃, and begins to absorb heat at approximately 115±2℃ (e.g., 115±1.9℃, 115±1.8℃, 115±1.7℃, 115±1.6℃, 115±1.5℃, 115±1.4℃, 115±1.3℃). It begins to absorb heat at approximately 115±1.2℃, 115±1℃, 115±0.9℃, 115±0.8℃, 115±0.7℃, 115±0.6℃, 115±0.5℃, 115±0.4℃, 115±0.3℃, 115±0.2℃, or 115±0.1℃, or at approximately 41±2℃ (e.g., 41±1.9℃, 41±1.8℃ ... Heat absorption begins at 1.7℃, 41±1.6℃, 41±1.5℃, 41±1.4℃, 41±1.3℃, 41±1.2℃, 41±1, 41±0.9℃, 41±0.8℃, 41±0.7℃, 41±0.6℃, 41±0.5℃, 41±0.4℃, 41±0.3℃, 41±0.2℃, or 41±0.1℃, or any combination thereof.

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:

(a) Form VI has an XRPD plot containing 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°; and an XRPD plot containing 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°. Figure D; or containing 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± XRPD plots of peaks at 2-θ angles of 0.2, 27.6±0.2, 28.2±0.2, 28.5±0.2, 29.0±0.2, 29.6±0.2, 29.9±0.2, 30.4±0.2, 30.9±0.2, 31.6±0.2, 32.2±0.2, 32.6±0.2, 33.1±0.2, 33.3±0.2, 34.5±0.2, 35.0±0.2, 35.5±0.2, and 38.5±0.2°;

(b) Form VI has an XRPD diagram that is essentially as shown in Figure 64A;

(c) Form VI has a TGA diagram that is essentially as shown in Figure 64B or Figure 64C.

(d) Form VI exhibits approximately 2% ± 0.5% weight loss between 25°C and 200°C, as determined by TGA;

(e) Form VI has a DSC diagram that is substantially as shown in Figure 64D or Figure 64E; and

(f) Form IV is characterized by melting and endothermic activity starting at approximately 200°C, as determined by DSC; and

(g) Form VI is characterized by the ability to begin absorbing heat at about 200°C, releasing heat at about 115°C, or absorbing heat at about 41°C, or any combination thereof, as determined by DSC.

medicine box

Articles and packaging containing any of the compounds or pharmaceutical compositions provided herein are also provided. The articles may include labeled containers. Suitable containers include, for example, bottles, vials, and test tubes. The containers may be formed from a variety of materials, such as glass or plastic. The containers may contain the pharmaceutical compositions provided herein. Labels on the containers may indicate that the pharmaceutical composition is intended for the prevention, treatment, or inhibition of the diseases described herein, and may also indicate instructions for in vivo or in vitro use.

In one aspect, this document provides a medicine box containing the compounds or compositions described herein and instructions for use. The medicine box may contain instructions for use in treating a heart condition in an individual or subject of need. The medicine box may additionally contain any materials or devices that can be used to administer the compound or composition, such as vials, syringes, or IV bags. The medicine box may also contain sterile packaging.

In some embodiments, this disclosure provides a method for manufacturing a pharmaceutical agent comprising afecontan, the method comprising:

The first batch of tablets was manufactured, in which the amount of afecontan (which may be present in various forms) was approximately the first day dose or approximately half of the first day dose;

Manufacture a second batch of tablets, wherein the amount of afencontan (which may be present in various forms) is approximately the second day dose or approximately half the second day dose;

Optionally, a third batch of tablets is manufactured, wherein the amount of afecontan (which may be present in various forms) is approximately the third-day dose or approximately half the third-day dose; and

Optionally, a fourth batch of tablets is manufactured, wherein the amount of afecontan (which may be present in various forms) is approximately the fourth day dose or approximately half the fourth day dose.

In some embodiments, the method includes manufacturing a third batch of tablets, wherein the amount of afecontan (which may be present in various forms) is approximately the third-day dose or approximately half the third-day dose. In some embodiments, the method includes manufacturing a fourth batch of tablets, wherein the amount of afecontan (which may be present in various forms) is approximately the fourth-day dose or approximately half the fourth-day dose.

In some embodiments, this disclosure provides a method for manufacturing a pharmaceutical agent comprising afecontan, the method comprising:

The first batch of tablets was manufactured, containing approximately the amount of afecontan (which may be present in various forms) for the first day's dose.

Manufacture a second batch of tablets, in which the amount of afencontan (which may be present in various forms) is approximately the second day's dose;

Optionally, a third batch of tablets is manufactured, wherein the amount of afecontan (which may be present in various forms) is approximately the third-day dose; and

Optionally, a fourth batch of tablets is manufactured, wherein the amount of afecontan (which may be present in various forms) is approximately the fourth day's dose.

In some embodiments, the method includes manufacturing a third batch of tablets, wherein the amount of afecontan (which may be present in various forms) is approximately the third-day dose. In some embodiments, the method includes manufacturing a fourth batch of tablets, wherein the amount of afecontan (which may be present in various forms) is approximately the fourth-day dose.

This document describes various first, second, third, and fourth day doses. In some embodiments, the daily dose is about 5 mg of afecontan. In some embodiments, the first day dose is about 5 mg of afecontan. In some embodiments, the daily dose is about 10 mg of afecontan. In some embodiments, the daily dose is about 15 mg of afecontan. In some embodiments, the daily dose is about 20 mg of afecontan. In some embodiments, tablets having at least two different daily doses are manufactured. In some embodiments, tablets containing about 15 mg of afecontan (which may be present in various forms) are manufactured. In some embodiments, tablets containing about 2.5 mg of afecontan (which may be present in various forms) are manufactured. In some embodiments, tablets containing about 7.5 mg of afecontan (which may be present in various forms) are manufactured. Those skilled in the art will understand that, in addition to afecontan, tablets may also contain various other components described herein, such as fillers, binders, disintegrants, surfactants, lubricants, etc. In some implementations, the tablets are coated with a film.

Example

This application can be better understood by referring to the following non-limiting embodiments, which are provided as exemplary implementations of this application. The following embodiments are presented to illustrate the embodiments more fully; however, they should not in any way be construed as limiting the broad scope of this application. Although certain embodiments of this application have been shown and described herein, it should be apparent that such embodiments are provided by way of example only. Many variations, modifications, and substitutions can be made by those skilled in the art without departing from the spirit and scope of the invention. It should be understood that various alternatives to the embodiments described herein may be employed in practicing the methods described herein.

Example 1

This first-in-human study of afecontan (also known as CK-274) was conducted to evaluate its safety, pharmacokinetics, and pharmacodynamic profile, including its effects on food or the CYP2D6 poor metabolizer (CYP2D6-PM) phenotype. Afecontan is a selective cardiac myosin inhibitor that reduces preclinical measurements of left ventricular contractility in vitro and in vivo, and therefore has the potential to manage obstructive hypertrophic cardiomyopathy. This phase 1, double-blind, randomized, placebo-controlled study enrolled healthy adults aged 18 to 55 years to receive a single-escalation or multiple-escalation (14-day or 17-day) dose of afecontan or placebo. Pharmacodynamic effects were assessed by echocardiography in addition to standard safety and pharmacokinetic assessments. 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 with placebo at single doses ≤50 mg and multiple doses ≤10 mg of afencontan. In the single-increase-dose cohort, plasma concentrations of afencontan increased proportionally to the dose; the half-life of afencontan was 75 h to 85 h. Food and CYP2D6-PM phenotype had no clinically significant effect on pharmacokinetics. With a single 50-mg dose, the mean left ventricular ejection fraction (LVEF) decreased by 5.5% compared to baseline (p=0.0001). With multiple doses, a 5.0% decrease in mean LVEF was observed after 10 mg afencontan once daily for 14 days. At the evaluated doses, afencontan appeared to be safe and well-tolerated. The pharmacodynamic effect on LVEF was demonstrated, supporting further clinical studies of afencontan.

method

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

Participants and Treatment. To be eligible for this study, participants should be healthy adults aged 18 to 55 years with a body mass index of 18.0 to 32.0 kg/ ^m² , normal electrocardiogram (ECG) and clinical laboratory values, or only minor abnormalities considered clinically insignificant. Participants must also have normal cardiac structure and function, with LVEF ≥60% for the first four SAD cohorts, LVEF ≥65% for subsequent SAD cohorts, all MAD cohorts, and the food effect cohort, and LVEF ≥55% for the CYP2D6-PM cohort. Prior to the study, participants were not permitted to use any prescription medications within 14 days, nonprescription medications (except acetaminophen) within 7 days, or tobacco or nicotine use within 3 months; additionally, they were not permitted to consume alcohol, caffeine, or grapefruit within 48 hours prior to study enrollment.

Randomization schedules were generated for each cohort and treatment period. In all cohorts, afencontan or a matched placebo was administered in granule form as capsules containing approximately 240 ml of water. The study drug was administered after overnight fasting, except during the eating period in the food effect cohort.

Single-Average-Dose (SAD) Cohort. The SAD portion of the study used a randomized, double-blind, placebo-controlled, sequential, escalating-dose design, in which participants received a single escalating oral dose of the study drug. Seven cohorts were administered sequentially (Figure 2). Of the eight participants in each cohort, the first two were randomized (1:1) to afecontan or placebo and followed for a minimum of two days, after which the remaining participants in that cohort were administered. The remaining six participants were then randomized (5:1) to receive a single oral dose of afecontan (1 mg, 3 mg, 10 mg, 25 mg, 40 mg, 50 mg, or 75 mg) or placebo.

The initial dose of afecontan is selected using guidelines from the United States Food and Drug Administration (FDA) based on prior animal studies and employing ≥10 times the safety limits. Dose escalation is stopped when the results determine a pharmacologically active dose range that reduces LVEF by 5% to 15% or an intolerable dose (whichever occurs first).

Recommendations regarding dose escalation for the SAD cohort and the MAD cohort described below are made by the treatment investigator (who is blinded in the treatment group) and approved or disapproved by the unblinded Dose Level Review Committee (DLRC). Decisions are made when ≥6 participants have been treated and followed up for ≥3 days, including the collection of clinical, laboratory, ECG, and telemetry data, as well as echocardiographic data appropriate for assessing LV function at maximum plasma drug concentration ( _Cmax ). Escalation criteria include no more than 2 participants in the dose group having LVEF <50% and no individual having LVEF <45%. The dose escalation criteria are as follows: (1) no persistent serious cardiac adverse events related to the study drug in the individual; (2) no similar non-cardiac serious adverse events in the same organ system in two individuals that appear to be related to the study drug; (3) no decrease in left ventricular ejection fraction (LVEF) of >15% in two individuals treated with afecontan compared to the value before the last dose (as determined by the Dose Level Review Committee [DLRC]); (4) no LVEF <45% in the individual (unless determined by the DLRC and the treatment investigator to be unrelated to the study drug); and (5) the treatment investigator and the DLRC approve the escalation and next dose level based on their clinical judgment.

Multiple escalation dose (MAD) cohorts. The MAD cohorts also employed a randomized, double-blind, placebo-controlled, sequential design. Enrollment in the MAD cohorts began when the SAD cohorts identified a single oral dose that was well-tolerated and associated with the observed PD effect. Each of the three MAD cohorts comprised eight participants, who were randomized (6:2) to afecontan or placebo. Participants received an oral dose of the study drug once daily for 14 days (in the cohorts comparing 5 or 10 mg afecontan versus placebo) or 17 days (in the cohort comparing 7.5 mg afecontan versus placebo).

A cohort of weak metabolizers of CYP2D6. A separate cohort was included to evaluate the potential impact of CYP2D6 genetic variants on the PK properties of afencontin. The CYP2D6 gene encodes the cytochrome P450 2D6 enzyme, described as the most widely characterized pleomorphic drug-metabolizing enzyme, and previous in vitro studies have suggested that CYP2D6 is a potential metabolic enzyme for afencontin.

CYP2D6 genotype was determined during screening of all study participants; participants identified as CYP2D6-PM were excluded from the SAD and MAD cohorts but invited to participate in the CYP2D6-PM cohort. Following the SAD 25-mg cohort, the first individual in the CYP2D6-PM cohort was administered (Figure 2). Each participant received a single dose of afencontan (10 mg) or placebo. Nine participants were randomized (7:2), with the sentinel dosing group consisting of the first two participants treated.

Food Effect Cohort. To assess the pharmacokinetic (PK) effect of food on afencontin, a separate cohort was recruited after the completion of the last SAD cohort, with a planned enrollment of 8 to 12 participants. In an open-label, 2-factor crossover design, participants received two single doses of 10 mg afencontin, ≥14 days apart. Participants were randomly assigned in a 1:1 ratio to one of two sequences: fasting/eating or eating/fasting. During the fasting period, afencontin was administered after overnight fasting; during the eating period, afencontin was administered 30 minutes after the start of a high-fat breakfast.

Evaluate

Safety and tolerability. Safety was assessed based on the incidence of adverse events (AEs) and the incidence of reduced LVEF. Treatment-emergent AEs (TEAEs) were defined as AEs that began or increased after administration of the study drug. All AEs were coded using the Medical Dictionary for Regulatory Activities, version 21.1 and graded using the National Cancer Institute Common Terminology Criteria for AEs (version 4.03) 5-point severity scale. Each AE was judged by the treatment investigator to be relevant or irrelevant to the study drug. Clinical laboratory testing was obtained at regular intervals in all cohorts.

For safety monitoring, participants in all cohorts underwent periodic echocardiography evaluated by a cardiologist. In the SAD and MAD cohorts, echocardiography was also reviewed by the echocardiography core laboratory for PD assessment, as described below. Additionally, participants in all cohorts were monitored using a Holter monitor with consecutive 12-lead ECG recordings. For safety monitoring, single 12-lead ECGs were periodically extracted at screening, before administration, and throughout follow-up, and interpreted by the investigator. In the SAD, MAD, and CYP2D6-PM cohorts, cardiac dynamic ECGs (triple 10-second, 12-lead ECG recordings) were obtained before the corresponding PK blood and ECG intervals quantified by a qualified reader.

Pharmacokinetic analysis. For all study groups, blood samples were obtained for PK assessment before administration, 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 administration 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 administration. MAD cohort (14-day administration): Day 1: Before administration 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 administration; Days 2, 4, 5, 6, and 9: Before administration (corresponding to gluten samples after administration on Days 1, 3, 4, 5, and 8) and 1.5 h after administration; Days 3, 7, 8, 10, 11, 12, and 13: Before administration (corresponding to gluten samples after administration on Days 2, 6, 7, 9, 10, 11, and 12); Day 14: Before administration 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, and 24 h after administration. h, 36 h, 48 h, 72 h and 168 h. MAD cohort (17-day administration): Day 1: Before administration 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 administration; Days 2, 4, 5, 6, and 9: Before administration (corresponding to gluten samples after administration on Days 1, 3, 4, 5, and 8) and 1.5 h after administration; Days 3, 7, 8, 10, 11, 12, 13, 14, 15, and 16: Before administration (corresponding to gluten samples after administration on Days 2, 6, 7, 9, 10, 11, and 12); Day 17: Before administration and 0.25 h, 0.5 h, 1.5 h, 2 h, 2.5 h, 3 h, 5 h, 6 h, 8 h, and 12 h after administration. h, 7 h, 9 h, 12 h, 24 h, 36 h, 48 h, 72 h, and 168 h. CYPD6-PM cohort: Day 1: Before and after administration at 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h, 36 h, 48 h, 72 h, 96 h, 216 h, 312 h, and 552 h. Food effect cohort: Day 1: Before and after administration at 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h, 36 h, 48 h, 72 h, 96 h, 144 h, and 216 h. The PK parameters were calculated using the standard non-compartmental method with ^{Phoenix® WinNonlin®} version 7.0; actual sample collection time was used.

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

Echocardiography. For PD assessment of LVEF, echocardiograms from the SAD and MAD cohorts were interpreted by the echocardiography core laboratory and used for all data analysis and dose level review decisions, while immediate local interpretation of echocardiograms was performed for safety monitoring. In the SAD cohort receiving 1 mg, 3 mg, or 10 mg afecontan, echocardiograms were obtained on day-1, before dosing on day 1, and at 1.5 h, 4 h, and 24 h after dosing. In the SAD cohort receiving 25 mg, 40 mg, 50 mg, or 75 mg afecontan, echocardiograms were obtained on day-1, before dosing on day 1, and at 1.5 h, 6 h, and 24 h after dosing. If LVEF has not returned to near or above baseline by 24 h, as determined by the investigator, echocardiograms were obtained only on day 3 (48 h after dosing). In the MAD cohort, echocardiography was performed on day -1, before dosing 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 a participant's previous LVEF was not close to or higher than baseline, as determined by the investigator, echocardiography was performed only on day 3 (day 17 or day 20) after the last dose.

Statistical analysis. The sample size selected for this study was based on a precedent set of other first-in-human PK studies with similar properties and not on power calculations. Safety analyses included all participants who received ≥1 dose of the study drug (alfenacin or placebo). The PK analysis set included all participants who received ≥1 dose of the study drug and had ≥1 evaluable PK plasma profile.

PK analysis was designed to assess single-dose kinetics, multiple-dose (steady-state) kinetics, the effect of the CYP2D6 phenotype on the absorption and elimination of afecontan, and the effect of food on the absorption and elimination of afecontan. For the SAD cohort, a power factor model was used on day 1 to evaluate afecontan dose proportion. For the MAD cohort, a power factor model was used on days 1 and 14 or 17 to evaluate dose proportion. Several factors were considered when assessing drug dose proportion, such as results from statistical analysis derived from the power factor model (e.g., slope estimates and the width of the two-sided 95% confidence interval [CI]), qualitative assessment of drug-specific PK, and clinical relevance. For the SAD cohort, the parameters used to assess dose proportion were the area under the plasma drug concentration-time curve (AUC) from time 0 to the last measurable concentration (AUC _last ), the AUC extrapolated from time 0 to infinity (AUC _inf ), the AUC from time 0 to 24 h (AUC ₂₄ ), and the maximum plasma concentration ( _Cmax ). For the MAD cohort, the parameters with _{the largest} C values were AUC ₂₄ and day 1, plus the AUC (AUC _tau ) at the _end of the dosing period and day 14 or 17. A statistically linear relationship between the ln-converting PK parameter and the ln-converting dose was validated by including ^secondary (ln-dose) and ^tertiary (ln-dose) effects. A statistically linear relationship was established if the secondary and tertiary effects were not statistically significant at the 5% significance level, or if the effects were statistically significant but had small values that were not clinically relevant. Dose-proportioning analyses were performed using ^SAS® PROC MIXED. Dose proportioning was established if a statistically linear relationship was shown and if the 95% CI around the slope estimate parameter included a value of 1 for the dose-dependent parameter.

In the MAD cohort, steady-state analysis of afencontan was performed using Helmert contrast to assess ln-converted plasma trough concentration (C _-trough ). Analysis of variance (ANOVA) models were performed individually for each dose level; the number of days included was used as a fixed effect. A Helmert contrast was developed to compare the mean at each time point with subsequent time points. Steady-state was established at time points where no statistically significant differences were observed at subsequent time points (α = 5%, 2-sided).

The PD analysis set included all participants who received ≥1 dose of the study drug and had ≥1 pre-dose and ≥1 post-dose echocardiographic measurements. Descriptive analyses included absolute reduction in LVEF compared to baseline and categorical LVEF response (proportion of participants with LVEF reductions of ≥5%, ≥10%, and >15% compared to baseline, and proportion of participants with LVEF reductions of <50% and <45%). Descriptive statistics for echocardiographic parameters were generated using ^SAS® version 9.3 or later.

Dose-response analysis was performed using analysis of covariance (ANCOVA) to determine the least squares mean difference (afenacan minus placebo). To analyze the effect of drug dosage on echocardiographic parameters in the SAD and MAD cohorts, inferential analyses were performed on the PD analysis set using linear mixed models of repeated measures analysis of covariance (ANCOVA). ANCOVA used baseline values as covariates, treatment, time points, and time point-treatment interactions as fixed effects, and change from baseline as the dependent variable. An unstructured variance-covariance structure was used, and the model accounted for repeated measures at time points. ANCOVA analyses were performed separately for each study portion and each PD parameter. The least squares mean, the difference of the least squares mean (active minus placebo), and the relevant two-sided 95% CI are presented for each comparison.

ANCOVA was also used to perform concentration 'bin' and exposure-response analyses. All comparative analyses were performed using ^SAS® PROC MIXED. An additional inferential analysis was performed in the SAD and MAD cohorts to evaluate the relationship between afencontin concentrations and LVEF in participants in the PK/PD analysis pool. Concentration bin ANCOVA was performed using a linear mixed model of repeated measures analysis, where the bin group was used as a fixed effect, baseline PD parameters as covariates, change from baseline as the dependent variable, and a random intercept was used to adjust for repeated measures. An unstructured variance-covariance structure was used. Plasma concentrations of afencontin were paired with consistent PD parameters. ANCOVA compared changes in PD parameters between each bin and the pooled placebo groups. Least squared means, differences of least squared means (bin group minus placebo), and related 2-sided 95% CIs were presented for each comparison. ANCOVA analyses were performed separately for each study segment. For all time points where PK data and PD measures were available, the time points were pooled for analysis. Within each segment of the study, afencontin concentrations with time-matched PD data were pooled and sorted in ascending order. The data were then divided into 5 observation groups ('bins') from smallest to largest, 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 the five bin groups comprised of the pooled concentrations at all time points based on afencontan treatment.

The above analysis was then repeated using concentration as a continuous variable to estimate the exposure-response trend. The random intercept effect and random concentration effect were added to ANCOVA. Estimates of the concentration slope and corresponding two-sided 95% CIs, along with ANCOVA analysis, are presented for each study portion.

For all time points where PK data and PD measures were available, these time points were pooled for analysis. A 5% nominal significance level was used for statistical comparisons, without adjusting for multiplicity.

result

Study Group. A total of 102 participants were recruited: 57 in the SAD cohort, 24 in the MAD cohort, 9 in the CYP2D6-PM cohort, and 12 in the food effects cohort. All participants completed the study. The mean age of each cohort ranged from 32 to 40 years, and the majority of participants were male (Table 1).

Table 1: Baseline Characteristics

Values are the mean (range), n (%), or mean ± SD. BMI = Body Mass Index; LVEF = Left Ventricular Ejection Fraction; MAD = Multiple Increment Dose; CYP2D6-PM = Cytochrome P450 2D6 Weak Metabolizer; SAD = Single Increment Dose; SD = Standard Deviation.

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

Following the results of the 1-mg to 25-mg SAD cohort, the first MAD cohort was started with 5 mg afecontan once daily for 14 days. No safety issues were identified, and the next cohort was started with 10 mg once daily for 14 days. In this cohort, based on echocardiographic results, two participants met the discontinuation criteria. The DLRC determined that the next treatment level should be 7.5 mg to better characterize PK at steady state; therefore, the dosing period was extended from 14 days to 17 days to ensure that PK had reached steady state by the last day of dosing.

Safety and tolerability. No serious adverse events (AEs) were observed, and no participants discontinued the study due to AEs. For both single-dose and multiple-dose administration, observed TEAEs were generally mild (Grade 1), and afecontan was not more frequent with afecontan than with placebo (Tables 2 and 3). In summary, headache was the most common TEAE in both the SAD and MAD cohorts (Tables 2 and 3).

Table 2: Treatment-urgent adverse events in the SAD cohort

Values are n (%). The most common TEAEs were reported in ≥2 participants in the overall cohort based on priority. *'Left chest blistering' is consistent with gastrointestinal rather than cardiac related symptoms. ^† Initiated approximately 60 h after administration. SAD = Single escalation dose; TEAE = Treatment-emergent adverse event.

Table 3: Treatment-urgent adverse events in the MAD cohort

The value is n (%). TEAEs based on priority are reported in ≥1 participant in the total cohort. MAD = multiple escalation dose; qd = once daily; TEAE = treatment-emergent adverse event.

Echocardiographically related adverse events (AEs) of <45% reduction in ejection fraction were reported in 3 participants based on study echocardiographic expert assessment: one in each of the SAD 40-mg, 50-mg, and 75-mg cohorts (Table 4). All AEs were Grade 1 and resolved at the next echocardiographic assessment (within 2.5 h to 4.6 h). The single participant receiving 75 mg afecontan had 34.6% LVEF at 1.5 h post-dose, a 31.5% reduction in LVEF, and the conclusion was drawn regarding the dose escalation of the SAD portion of the study as discussed above. At the subsequent assessment 2.5 h later, LVEF had returned to 51.9%. No AEs of <45% reduction in ejection fraction were reported in the MAD, CYP2D6-PM, or food effect cohorts.

In all cohorts, the mean safety ECG parameters at the assessed time points were within the normal limits. No clinically significant changes compared to baseline were observed in any parameter. The QT interval (QTcF), adjusted for heart rate using Fridericia's formula, did not exceed 450 ms at baseline or at any assessment during the dosing interval, except for two individuals with a baseline QTcF ≥ 440 ms and QTcF values increasing by 3 ms and 13 ms, respectively. In all cohorts, QTcF intervals > 30 ms did not increase, except for one participant in the SAD placebo group whose QTcF interval increased by 33 ms on day 5 (427 ms vs. 394 ms at baseline). Categorical analysis of ECG parameters in cardiac dynamic assessments did not reveal any cardiac safety issues, and there was no evidence of a positive QT effect following single or multiple doses of afencontan.

At the time points following drug administration, all vital signs were within normal limits. No clinically significant serum chemistry, hematology, or urinalysis findings were observed during the study period.

Table 4: Echocardiographic-related adverse events (AEs) with a reduction in ejection fraction <45%

*Time following drug administration. ^† LVEF values used for safety assessment were determined by a research cardiologist. ^‡ In the SAD cohort, post-dose echocardiography was performed at 1.5 h, 4 h, 6 h, 24 h, and 48 h post-dose. AE = Adverse events; LVEF = Left ventricular ejection fraction; SAD = Single escalation dose.

Pharmacokinetics

Single-dose kinetics. Plasma afecontan profiles at all dose levels were generally well characterized, except for the lowest dose of 1 mg (due to concentrations close to the lower limit of quantitation) and the highest dose of 75 mg (administered to only one participant), as discussed above. Within the dose range of 1 mg to 50 mg, mean maximum plasma concentrations and exposures increased in a dose-proportional manner, as illustrated by the increase in the area under the plasma concentration-time curve (AUC ₂₄ ) from _Cmax to time 0 to 24 h with increasing dose (Figures 3A-3B and Table 5). Mean clearance and volume of distribution were similar at each dose. The median time to maximum concentration was observed between 0.5 h and 2.8 h, with the maximum time for all participants being 4.0 h. The mean half-life ranged from 75 h to 85 h.

Table 5: Summary of plasma pharmacokinetics of afecontan after a single oral dose

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

Table 6: Summary of plasma pharmacokinetics of afecontan after multiple oral doses

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

Table 7: Summary of plasma afecontan pharmacokinetics in a CYP2D6 weak metabolizer cohort

Afencontan was administered at a dose of 10 mg. AUC and _Cmax are presented as geometric mean and geometric CV%, respectively, while _Tmax is presented as median (range), and all other parameters are presented as arithmetic mean ± standard deviation. AUC ₂₄ = area under the plasma drug concentration-time curve from time 0 to 24 h; AUC _inf = AUC extrapolated from time 0 to infinity; CL/F = apparent total body clearance; _Cmax = maximum plasma concentration; CV% = coefficient of variation; PK = pharmacokinetics; t _½ = half-life; _Tmax = time to reach maximum plasma concentration; Vz/F = apparent volume of distribution.

Effects of food. The p-PK parameters of afecontan in the food effect cohort are shown in Table 8. When administered with food, afecontan showed _{a maximum} C increase of approximately 30% and a shortened time to reach the observed maximum concentration (1.5 vs. 2.3 h). However, food had a minimal effect on AUC, with the geometric mean _AUC24 (geometric CV%) at fasting being 601 (33) ng∙h/ml compared to 631 (25) ng∙h/ml at fed conditions.

Table 8: Summary of plasma afecontan pharmacokinetics in the food effect cohort

Afencontan dose was 10 mg in each cohort. * For AUC _inf , _t½ , CL/F, and Vz/F, n = 4. ^† For AUC _inf , _t½ , CL/F, and Vz/F, n = 7. AUC and _Cmax are presented as geometric mean and geometric CV%, _Tmax as median (range), and all other parameters are presented as arithmetic mean ± standard deviation. _AUC24 = area under the plasma drug concentration-time curve from 0 to 24 h; AUC _inf = AUC extrapolated to infinity from time 0; CL/F = apparent total body clearance; _Cmax = maximum plasma concentration; CV% = coefficient of variation; _t½ = half-life; _Tmax = time to reach maximum plasma concentration; Vz/F = apparent volume of distribution.

Pharmacodynamics

Left ventricular ejection fraction (LVEF). At baseline, the mean LVEF for each cohort ranged from 61.0% to 67.5% (Table 1). In the SAD cohort, a mean decrease in LVEF was observed in the group receiving the highest dose of afecontan (Figure 5A). In the 50-mg cohort, the maximum mean decrease from baseline was observed at 1.5 h post-dose (mean difference of least squares 5.5%, p = 0.0001). LVESV and LVEDV increased statistically significantly by 8.1 mL and 6.6 mL, respectively (Table 9). Other echocardiographic parameters (e.g., stroke volume, cardiac output, cardiac time interval, and measures reflecting diastolic function) showed no significant changes (Table 9). A single participant receiving 75 mg afecontan showed a 31.5% decrease in LVEF at 1.5 h post-dose, which resolved at 2.5 h post-dose, but the dose escalation in the SAD portion of the study was discussed above. In the MAD cohort, a significant decrease in LVEF was observed with continued dosing in the 10-mg cohort (Figure 5B). In the 10-mg cohort, the maximum mean decrease from baseline was 5.0% at 1.5 h post-dose on day 14 (Figure 5B). The 3.2% placebo-corrected decrease (least squared mean difference) did not reach statistical significance (p=0.21), which may be attributed to a lack of statistical power in this subgroup comparison.

Table 9: Echocardiographic parameters

The table compares placebo data for echocardiographic parameters at baseline and 1.5 h (the time closest to peak plasma concentration of afecontan) with data from 50 mg afecontan (the highest well-tolerated single dose). A = peak A-wave velocity, bpm = heartbeats 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.

Category of 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 100% in the 75-mg cohort, while no participants in the 1-mg, 10-mg, or 25-mg cohorts experienced 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 participants (100%). A decrease in LVEF to <50% was observed in 2 out of 11 participants (18%) in the 50-mg cohort (48.2% and 45.5% according to core laboratory assessment) and in 1 out of 100% of participants in the 75-mg cohort. Only participants in the 75-mg cohort experienced LVEF <45%.

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

Relationship between plasma concentration and LVEF. The p-p-p-d-p ...

Discussion

This Phase 1, first-in-human study established afencontan at a physiologically effective dose for reducing LVEF and well-tolerated in healthy participants (up to 50 mg as a single oral dose or up to 10 mg after multiple dosings), thus determining the pharmacologically active dose to be used as the starting dose in studies in patients with HCM. Furthermore, 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 pharmacokinetic activity of afencontan. These observations collectively support the continued development of afencontan for patients with HCM and provide a roadmap for Phase 2 studies.

Safety of afencontan. No serious adverse events (AEs) were observed in the study and all participants completed their scheduled dosing. Generally, AEs were mild and similar in frequency between participants treated with afencontan and placebo. Importantly, participants whose LVEF dropped below 50% experienced no adverse changes in related symptoms or vital signs, and their LVEF returned to baseline within 24 hours. This study was not intended to determine the maximum tolerated dose, and therefore dose escalation was immediately stopped once a significant PD effect was observed in the SAD and MAD portions of the study; therefore, doses intolerable due to AEs were not determined.

Effects on LVEF. In the SAD cohort, a 50 mg dose produced a 5.8% mean LVEF reduction, while in the MAD cohort, a 10 mg dose once daily for 14 days produced approximately a 5% mean absolute LVEF reduction. The proportion of participants with an absolute LVEF reduction ≥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 LVEF reduction ≥10% from baseline. In the SAD cohort, when exploring the widest range of afecontan exposure, LVEF decreased statistically significantly with increasing afecontan plasma concentration. Therefore, the study achieved its secondary objective of determining the pharmacologically active dose and describing its pharmacokinetic/pharmacokinetic relationship.

Three participants experienced a decrease in LVEF to <50%, which rapidly reversed after study drug discontinuation. Following a single dose of 50 mg, two (18%) participants experienced LVEF <50% (48.2% and 45.5%). Following a single dose of 75 mg, one participant experienced a decrease in LVEF to 34.1%. In all cases, events were observed approximately 1.5 h post-dose, and LVEF recovered to >50% by 4 to 6 h post-dose. SAD results inform dose selection for other parts of the study, and no echocardiographic AEs were observed in the MAD, CYP2D6-PM, or food effect cohorts.

Implications of the PK results: Afencontan exhibited linear kinetics across a dose range of 1 mg to 50 mg; the half-life was concentration-independent, and clearance was dose-independent. Steady state was reached at the end of day 10 with a 10-mg dose and at the end of day 12 with 5-mg and 7.5-mg doses. No effects indicated a need to change the diet used for administration. These findings support once-daily administration, whether fasting or with food.

The relationship between plasma concentration and LVEF indicates a broad therapeutic index, which will facilitate individual dose optimization in patients with HCM, expected to be achieved through dose titration in an escalating range until the desired PD effect is reached. Furthermore, the potential advantage offered by afencontan's half-life (75 h to 85 h after single dosing; 77 h to 86 h after multiple dosing) and the observed reversibility of the effect lies in reaching steady state within 2 weeks and easily reversing excessive effects on LVEF.

Conclusion. Afencontan demonstrated a favorable safety profile in healthy participants, with no serious adverse events or significant changes in laboratory tests, ECG, or health assessments. Any decrease in LVEF to <50% within 6 hours after single-dose administration was reversible. Determine the pharmacologically active dose of afencontan that can be used as the starting dose for studies in patients with HCM.

Example 2

A multicenter, randomized, placebo-controlled, double-blind, dose-finding phase 2 clinical trial of afencontin was conducted in patients with symptomatic obstructive hemorrhage (oHCM). The primary objective was to determine the safety and tolerability of afencontin. Secondary objectives included elucidating the concentration-response relationship of afencontin along the left ventricular outflow tract gradient at rest and after Warburg maneuvers, as measured by echocardiography, during a 10-week treatment period; elucidating the dose-response relationship of afencontin; and evaluating plasma concentrations of afencontin in patients with oHCM. Patients were screened at 17 study sites in North America and Europe for inclusion in cohorts 1 and 2. A third cohort (cohort 3) was also investigated to evaluate the safety and efficacy of afencontin in combination with the class IA antiarrhythmic drug disopyramide.

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 receive either active or placebo treatment and received up to three escalating doses of afencontan or placebo based on echocardiographic guidelines. In the third cohort, all patients received up to three escalating doses of afencontan based on echocardiographic guidelines. In summary, the treatment duration was 10 weeks, with a 4-week follow-up period after the last dose.

Because patient characteristics change substantially in this disease, individualized dose titration based on pharmacodynamic (PD) response (LVOT-G reduced to <30 mmHg while maintaining LVEF >50%) is employed to maximize efficacy and safety.

Patients are eligible for inclusion in the study only if all of the following criteria apply: 1. They are able to understand and are willing to sign an informed consent form (ICF) and to comply with all study procedures and restrictions for the duration specified in the activity schedule; 2. They are males or females aged between 18 and 85 years at screening; 3. They weigh ≥45 kg at screening; 4. They are diagnosed with oHCM according to the following criteria: (a) hypertrophic and non-dilated LV chambers in the absence of other heart diseases; and (b) minimum wall thickness ≥15 mm (minimum wall thickness ≥13 mm is acceptable for a positive family history of HCM or a known pathogenic gene mutation); 5. Sufficient 6. During screening, the LVOT-G of cohorts 1 and 2 are 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 the LVOT-G of cohort 3 are as follows: sustained resting LVOT occlusion (≥30 mmHg) and provocative 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. Taking β-blockers, verapamil ( Patients receiving verapamil, diltiazem, or ranolazine should have been on a stable dose for >4 weeks prior to randomization and are expected to continue using the same medication regimen during the study period; 10. Male patients are eligible to participate in the study if they agree to the following conditions at least 10 weeks after the last dose during the study period and: (a) not donating sperm; plus (b)(i) not having heterosexual intercourse as their preferred and usual lifestyle (long-term and persistent abstinence) and agreeing to remain abstinent; or (b)(i) must agree to use male condoms if their female partner is a woman of fertility potential. 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) they are not women of reproductive potential, or (a)(ii) they are women of reproductive potential and have used highly effective contraception during the study period and for at least 4 weeks after the last dose; and (b) women of reproductive potential must have a negative pregnancy test (urine or serum as required by local regulations) within 3 days prior to the first dose of the study intervention; 12. They are able to complete all screening procedures; and 13. They have taken a stable dose of disopyramide for >4 weeks prior to screening (cohort 3 only).

Patients were excluded from the study if any of the following criteria applied: 1. Aortic stenosis or fixed subaortic occlusion; 2. A known infiltrative or reservoir-like condition causing cardiac hypertrophy similar to oHCM (e.g., Noonan syndrome, Fabry disease, amyloidosis); 3. A history of left ventricular (LV) systolic dysfunction (LVEF) at any time during their clinical course. 4. A documented history of current obstructive coronary artery disease (one or more epicardial coronary artery stenosis >70%) or a documented history of myocardial infarction; 5. Treatment with ventricular septal reduction therapy (surgical myotomy or percutaneous alcohol ventricular septal ablation) or planned for either treatment during the study period; 6. Previous treatment with cardiotoxic agents (e.g., doxorubicin or similar drugs); 7. For cohorts 1 and 2: treatment with disopyramide or an antiarrhythmic drug with negative cardiotonic activity within 4 weeks prior to screening, and for cohort 3: treatment with an antiarrhythmic drug with negative cardiotonic activity other than disopyramide within 4 weeks prior to screening; 8. Any ECG abnormality that the investigator considers to pose a risk to patient safety (e.g., second-degree type II atrioventricular block); 9. A documented history of paroxysmal atrial fibrillation during the screening period. 10. Paroxysmal or permanent atrial fibrillation requiring rhythm restoration therapy (e.g., direct current cardiopulmonary resuscitation, ablation procedure, or antiarrhythmic therapy) within ≤6 months prior to screening, but this clause does not apply if atrial fibrillation has been treated with anticoagulation and the heart rate has been adequately controlled for >6 months; 11. History of syncope or persistent ventricular tachyarrhythmic movement within 6 months prior to screening; 12. Placement of an implantable cardioverter defibrillator (ICD) within 3 months prior to screening or planned placement of an ICD during the study; 13. History of receiving appropriate ICD shock due to life-threatening ventricular arrhythmia within 6 months prior to screening; 14. Receiving a major organ transplant (e.g., heart, lung, liver, bone marrow, kidney) or expected to receive one within 12 months of randomization; 15. Liver impairment, defined as total bilirubin (TBL) at screening. 16. ≥1.5 × Upper Limit of Normal (ULN), or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 × ULN, except for patients with documented Gilbert syndrome and TBL ≥1.5 × ULN due to unconjugated hyperbilirubinemia and without other liver disease; 17. Any other clinically significant condition, malignancy, active infection, other illness or history or evidence of disease that, in the opinion of the investigator or medical monitor, would pose a risk to patient safety or interfere with the evaluation, procedure or completion of the study; 18. Heme <10.0 g/dL at screening; 19. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 ^m2 at screening (through Modification of Diet in Renal Disease). 19. Currently participating in another research device or drug study or receiving a research device or drug less than 1 month prior to screening (or 5 half-lives of the drug, whichever is longer); 20. Previously treated with afecontan or currently treated with mavacamten; 21. Known hypersensitivity to any excipients in afecontan film-coated tablets (e.g., mannitol, microcrystalline cellulose, croscarmellose, hydroxypropyl cellulose, sodium lauryl sulfate, magnesium stearate, Opadry QX White 21A180025).

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. In week 2, patients underwent echocardiography 2 hours after administration. 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 Warburg maneuver, and biplane LVEF ≥50%. Otherwise, patients continued to receive dose 1. If LVEF was <50% in week 2, patients were titrated down to placebo. The dose adjustment algorithm is shown in Table 10 below.

Two weeks after the administration of the allocated dose (i.e., week 4), each patient underwent echocardiography 2 hours after administration of 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 already on dose 1, the patient was returned to placebo.

Two weeks after the allocated dose (i.e., week 6), each patient underwent echocardiography 2 hours after administration. If LVEF <50% at week 6, the patient was titrated down to the previous dose level, or if the patient was taking dose 1, the patient was returned to placebo.

Table 10: Dosage Adjustment Algorithm

If at any point a patient’s dose is titrated down to placebo, the patient will continue to take placebo for the duration of the study.

Table 11: Dosing Regimen

Baseline characteristics of patients in cohorts 1, 2 and 3 are shown in Tables 12 and 13.

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

Table 13: Baseline demographics and clinical characteristics of patients in cohorts 1 and 2 of the Phase 2 clinical trial

* = Derived from individual researchers' on-site echocardiographic assessment. BMI = Body Mass Index; CV = Coefficient of Variation; LVEF = Left Ventricular Ejection Fraction; LA = Left Atrium; LVED = Left Ventricular End-Diastolic Size; LVOT = Left Ventricular Outflow Tract; NT-proBNP = N-terminal Pro-B-type Natriuretic Peptide; NYHA FC = New York Heart Association Functional Class.

We analyzed several key structural and physiological measures from echocardiograms obtained every 2 weeks and 2 weeks after the last dose, as well as N-terminal pro-brain natriuretic peptide (NT-proBNP).

Initial results from the clinical study included data from two sequentially administered cohorts, Cohort 1 (n = 21) and Cohort 2 (n = 20), in which patients were randomly assigned 2:1 to afecontan or placebo. Patients received up to three escalating doses of afecontan (5 mg, 10 mg, 15 mg in Cohort 1 and 10 mg, 20 mg, 30 mg in Cohort 2) or placebo once daily. Echocardiography was performed two weeks after each dose to determine potential uptiing to the next higher dose. In summary, the duration of treatment for each patient in the study was 10 weeks, with echocardiography performed two weeks after the last dose.

For patients taking afecontan in cohort 1 (n=14), the mean resting LVOT-G decreased from 53.8 mmHg at baseline to 13.4 mmHg at 10 weeks; for patients taking afecontan in cohort 2 (n=14), the mean resting LVOT-G decreased from 58.2 mmHg at baseline to 15.1 mmHg at 10 weeks; and for patients in the placebo combination group (n=13), the mean resting LVOT-G decreased 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 to placebo at 10 weeks).

For patients taking afecontan in cohort 1 (n=14), the mean Valsalva maneuver LVOT-G decreased from 77.4 mmHg at baseline to 38.1 mmHg at 10 weeks; for patients taking afecontan in cohort 2 (n=14), the mean Valsalva maneuver LVOT-G decreased from 82.3 mmHg at baseline to 29.8 mmHg at 10 weeks; and for patients in the combination placebo group (n=13), the mean Valsalva maneuver LVOT-G decreased 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 to placebo at 10 weeks).

In cohort 1, the mean ejection fraction of patients taking afecontan (n=14) decreased from 72.8% at baseline to 67.3% at 10 weeks; in cohort 2, the mean ejection fraction of patients taking afecontan (n=14) decreased from 75.4% at baseline to 64.1% at 10 weeks; and in the placebo combination group (n=13), the mean ejection fraction of patients decreased from 74.5% at baseline to 74.9% at 10 weeks (p = 0.01 for cohort 1 and <0.0001 for cohort 2 compared to placebo at 10 weeks).

In summary, the incidence of adverse events was similar between the treatment groups. Afencontan was well tolerated in the study, and the severity of adverse events was reported as mild or moderate. No treatment-related serious adverse events were reported by the investigators.

In Cohort 1, none of the patients receiving afecontan had a lower LVEF of <50%. In Cohort 2, one patient with a baseline LVEF of 58% was titrated up to 20 mg afecontan and experienced a transient decrease in LVEF to <50% (maintaining above 40%), requiring downtiing. No interruption or discontinuation of afecontan treatment occurred in any patient in either cohort.

The patient distribution at afecontan doses in studies (cohorts 1 and 2) is shown in Table 14. The patient distribution at afecontan doses in cohort 3 of studies is shown in Table 15.

Table 14

Table 15

Secondary outcomes of the clinical study included data from cohort 3 (n=13). All patients received up to three escalating doses of afecontan once daily (5 mg, 10 mg, 15 mg). Echocardiography was performed two weeks after each dose to determine potential uptiing to the next higher dose. In summary, the duration of treatment for each patient in the study was 10 weeks, with echocardiography performed 2 weeks after the last dose. Efficacy endpoints included resting and activated LVOT gradients, NYHA class, and NT-proBNP.

In cohort 3, 13 patients (aged 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 obstruction severity 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 a resting or Warburg maneuver-related left ventricular outflow tract gradient (LVOT-G) ≥50 mmHg, and had previously been treated with disopyramide and, in most cases, with a beta-adrenergic blockade. All patients received up to three escalating doses of afecontan (5 mg, 10 mg, 15 mg) once daily, titrated according to 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 at the time of treatment.

Results from cohort 3 showed a substantial reduction in mean resting LVOTT-G and post-Varvato maneuver LVOTT-G (defined as a resting gradient <30 mmHg and a post-Varvato maneuver gradient <50 mmHg). These clinically relevant pressure gradient reductions were achieved, and mean left ventricular ejection fraction (LVEF) decreased only modestly; patients' LVEF did not fall below 50% of the predetermined safety threshold. New York Heart Association functional class improved in most patients participating in cohort 3. Pharmacokinetic data were similar to those observed in cohorts 1 and 2. Furthermore, the safety and tolerability of afencontan were consistent with investigator-reported treatment interruptions and serious adverse events.

The combination of afecontan and disopyramide provides a treatment option for patients with the most severe and refractory oHCM.

Results after 10 weeks of treatment

At baseline, there were no significant differences in key echocardiographic measures and NT-proBNP values between afecontan and placebo. Patients taking afecontan tended to have a smaller mean left ventricular mass index (LVMI) compared to placebo (-4.8 g/ ^m² (±2.4) vs. 3.3 g/ ^m² (±3.6); mean difference: 8.1 g/ ^m² , p = 0.063). From baseline to week 10, left ventricular (LV) filling pressure indices improved in the afecontan treatment group, including left atrial volume index (LAVI) (-2.9 mL/ ^m² (±1.5) vs. 2.2 mL/ ^m² (±1.5), P=0.004) (Figure 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) (Figure 10). Similarly, at week 10, in afencontan versus placebo, a decrease was observed in the class assessment of presystolic motion of the mitral leaflets (SAM; -50% vs -17.3%) (Figure 11) and the frequency of eccentric mitral regurgitation (MR; -35.8% vs +13.3%) (Figure 11) relative to baseline. At week 10, a significantly larger reduction in NT-proBNP was observed with afencontan versus placebo (geometric least squares mean ratio 0.38 (0.25–0.56), p = 0.0002).

Figure 12 shows the changes in resting LVOT-G in the treatment and placebo cohorts. Figure 13 shows the changes in resting Warburg maneuver LVOT-G in the treatment and placebo cohorts. In patients treated with disopyramide (cohort 3), the effect of afecontan treatment on LVOT-G was generally weakened compared to patients in cohort 1 (same afecontan dose). Figure 14 shows the changes in LVEF in the treatment and placebo cohorts. Figure 15 shows the NYHA functional class response in the treatment and placebo cohorts. Figure 16 shows the changes in mean NT-proBNP in the treatment and placebo cohorts.

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

Table 16: Safety profile of patients treated with afecontan in Phase 2 clinical trials

These findings indicate that afecontan treatment leads to beneficial early cardiac remodeling, which is associated with a reduction in LVMI, LAVI, lateral E/e', SAM, eccentric mitral regurgitation, and brain natriuretic peptide, as well as an increase in e' velocity, and further indicate that afecontan favorably affects cardiac remodeling in oHCM.

Results of Queue 1 and Queue 2

In reference cohorts 1 and 2, compared to only 1 of 12 patients (8%) in the pooled placebo group, 11 of 14 patients (79%) in afecontan cohort 1 and 13 of 14 patients (93%) in afecontan cohort 2 achieved complete hemodynamic response (resting LVOT gradient <30 mmHg and Valverde action gradient <50 mmHg at week 10) (Figures 17, 18, and 20).

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

In the pooled afecontan treatment groups (cohorts 1 and 2), 15 out of 28 patients (53%) experienced one or more NYHA category changes (Figure 21), including: 6 patients moving from category III to category II, 8 patients moving from category II to category I, and 1 patient moving from category III to category I (Figure 24).

At week 10, afecontan treatment was associated with a 62% reduction in NT-proBNP levels compared to placebo (p<0.001). Importantly, 25 out of 27 patients (93%) receiving afecontan experienced at least a reduction in NT-proBNP levels, compared to only 6 out of 12 patients (50%) receiving placebo.

The baseline hs-Trop level in the pooled afecontan group was 17 ng/L (CV% 290), and the baseline hs-Trop level in the pooled placebo group was 17 ng/L (CV% 290) (Figure 23). At week 10, patients receiving afecontan in cohort 1 experienced an 18% relative decrease compared to the pooled placebo group (p = 0.29), and patients in cohort 2 experienced a 26% relative decrease compared to the pooled placebo group (p = 0.097). Changes in hs-troponin I levels in the pooled placebo groups and in patients receiving afecontan in cohorts 1, 2, and 3 are shown in Figure 37.

Afencontan's early and sustained hemodynamic effects are accompanied by significant clinical benefit in most patients with heart failure symptoms. Improvement in one or more NYHA categories occurred in more than half of patients treated with afencontan, including 64% in cohort 2, with most of these improvements leading to a transition from Category II to completely asymptomatic (Category I). It should be noted that afencontan caused 7 patients to transition from late-stage heart failure symptoms (Category III) to a less symptomatic state (Category II or I).

This robust hemodynamic response is particularly evident because afencontan converts most patients with obstructive HCM to gradient levels below the current threshold for considering septal reduction therapies (such as myotomy or alcohol septal ablation). This is especially relevant because one advantage of septal reduction therapies is the opportunity to convert patients with late restrictive symptoms (Category III) to an asymptomatic or mildly symptomatic state.

Afencontan was also associated with a significant reduction in NT-proBNP and hs-troponin, highlighting the compound's potential to generate other downstream pathophysiological benefits, including reduced LV wall stress and myocardial injury.

Results of Queue 3

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

In this open-label study primarily targeting NYHA class III individuals, the addition of afecontan significantly reduced the LVOT gradient in 77% of patients and improved symptoms in 85% of patients, with all baseline NYHA class III patients showing improvement of ≥ 1 class. Importantly, afecontan was well tolerated and demonstrated reversibility in this cohort of patients with severe obstruction. The reduction in LVEF was similar to that observed in cohort 2 patients not receiving disopyramide. Afecontan has shown efficacy as adjunctive therapy in patients with refractory oHCM and can provide an alternative to SRT.

Example 3a

An open-label, extended clinical trial of afencontin was initiated in patients with symptomatic oHCM. The primary objective of the trial was to determine the safety and tolerability of afencontin over a 5-year period.

Patients who have completed the study as described in Example 2 and do not yet have atrial fibrillation are eligible for enrollment in the study. Echocardiographic-guided dose titration based on on-site readings is investigator-controlled and can be performed at any time during the trial, as described below.

Research Design

Each patient received afecontan once daily for 2 weeks. In week 2, each patient underwent a truncated echocardiogram 2 hours after administration. The patient was 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, the patient continued to receive 5 mg of afecontan. Treatment was discontinued if LVEF <50%. Treatment was interrupted if LVEF <40%.

Echocardiography or truncated echocardiography was performed on each patient 2 hours after administration at weeks 4, 6, 12, and every 12 weeks thereafter (truncated echocardiography at weeks 4 and 6; and echocardiography at week 12 and every 12 weeks thereafter) to determine if additional dose titration was required (see Tables 17 and 18). Ambulatory cardiac monitoring was performed at weeks 48, 96, 144, 192, and 240. Cardiac magnetic resonance imaging was performed at weeks 48, 144, and 240 (see Figure 26). Baseline characteristics of patients enrolled in the open-label extended study are shown in Table 19.

Table 17: Dosage Adjustment Algorithm

Table 18: Dosing Regimen

Table 19: Baseline characteristics of open-label extension studies

Preliminary results

Preliminary results are shown in Figures 27-34. Figure 27 shows the distribution of patients over time at each dose. At data collection, 38 patients were enrolled in the trial, and all 38 patients had reached at least week 2 of dosing; 37 of the 38 patients had reached at least week 6 of dosing; 30 of the 38 patients had reached at least week 12 of dosing; and 19 of the 38 patients had reached at least week 24 of dosing. The percentage of patients receiving each dose level (5 mg, 10 mg, or 15 mg) at each time point is shown in Figure 27. Based on echocardiographic data from field readings of these patients, significant reductions in resting LVOT-G and Warburg maneuver LVOT-G over time are shown in Figures 28 and 29; significant and sustained reductions in the LVOT gradient were identified between weeks 2 and 24. Additionally, a minimal and stable decrease in LVEF was observed up to week 24, as shown in Figure 30.

At baseline, 53% of patients were NYHA Class III and 47% were NYHA Class II.

Among patients who had reached at least week 12 of dosing: at week 12, only 7% of patients were NYHA class III; 52% were NYHA class II; and 41% were NYHA class I (Figure 31). Relative to baseline, 72% of patients had experienced an improvement of one NYHA class, and 7% had improved by two NYHA classes (Figure 32).

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

No patients in the study showed a worsening of their NYHA class from baseline.

Preliminary safety

Table 20

TEAE: Treatment of acute adverse events

TESAE: Treatment of acute and serious adverse events

Cardiac adverse events (AEs): atrial fibrillation (2); angina pectoris (1); bradycardia (1); decreased ejection fraction (1); mitral stenosis (1); QTc prolongation (1)

A patient with LVEF < 50% and TESAE had a prior history of alcohol-induced atrial fibrillation with a LVEF decrease of < 50%. Upon administration of 15 mg afecontan, recurrent episodes of alcohol-induced atrial fibrillation with a similar LVEF decrease to 47% were observed; afecontan was down-titrated. The patient subsequently developed worsening atrial fibrillation and failed cardiac remission; afecontan was discontinued. This patient regained sinus rhythm with LVEF 60% and evidence of obstruction upon administration of amiodarone (alcohol withdrawal) and has since restarted a 1 mg dose (5 mg) of afecontan.

Because researchers were concerned about QTc prolongation in subjects with abnormal baseline EKG, one patient underwent a temporary downtitration. A temporary afencontan downtitration was performed while awaiting interpretation of the QTc from the core laboratory. QTc was confirmed to be normal, and afencontan was subsequently increased.

A subject with severe TESAE was hospitalized due to worsening atrial fibrillation caused by DOAC (direct-acting oral anticoagulant) and altered mental status prior to planned cardiac resuscitation. MRI revealed a suspected embolic stroke. The patient was subsequently diagnosed with a congenital cardiac abnormality (secretory atrial septal defect). Down-titration or discontinuation of afencontan was not required.

Kansas City Cardiomyopathy Questionnaire (KCCQ)

In OLE, participants' health status was assessed using the KCCQ before initiation of afencontin and at weeks 12 and 24 of treatment. Changes in KCCQ scores relative to baseline were measured, including OSS (Overall Pooled Score), CSS (Clinical Pooled Score), TSS (Total Symptom Score), PLS (Physical Limitation Score), SLS (Social Limitation Score), and QoL (Quality of Life). Relative to baseline, patients were categorized as worsening (≤ -5 points), no change (-5 to < 5 points), minor improvement (5 to < 10 points), moderate to significant improvement (10 to < 20 points), and significant to extremely significant improvement (≥ 20 points).

Results showed that OLE participants exhibited significant improvements in their KCCQ scores at week 12, which persisted up to week 24. The proportion of participants with clinically significant improvements (overall pooled score ≥5) was 72.7% at week 12 and 72.0% at week 24. Magnitude clinical improvements (≥20 points) were observed in 36.4% of participants at week 12 and in 40.0% at week 24 (Figures 35 and 36). Afencontan treatment resulted in significant and sustained improvements in all KCCQ domains for up to 6 months.

in conclusion

In this open-label extended study of patients with obstructive HCM treated with background medical therapies (including disopyramide in some cases): afecontan was associated with significant and sustained reductions in LVOT gradients (Figures 28 and 29) and substantial improvements in heart failure symptoms (approximately 80% of patients had improvements in one or more NYHA categories) (Figures 31 and 32), as well as significant reductions in cardiac biomarkers (NT-proBNP and hs-cTnI) (Figures 33 and 34). Afecontan was well tolerated, and there were no afecontan-induced LVEF < 50% events. These data demonstrate that the therapeutic effects of afecontan can last up to 6 months.

Example 3b

An open-label, extended clinical trial of afecontan will be 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 afecontan over a 5-year period.

This study may include up to 275 patients. After a screening period of up to 56 days, eligible patients will be administered afecontan daily doses. The maximum tolerated dose was determined through other ongoing afecontan studies. Each patient will start with the lowest pre-specified dose and undergo echocardiographic-guided dose titration to the maximum tolerated dose (not exceeding the highest pre-specified dose). Dose adjustments will not be made more than once every 2 weeks. Approximately 95 study sites in the United States, Europe, and the Middle East participated in this study.

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

Exclusion criteria. (1) Having received mavacartan treatment. (2) Having participated in another study device or drug study or having received a study device or drug within 1 month prior to screening (or 5 half-lives of the drug, whichever is longer). Other study procedures are not permitted during participation in this study. (3) Having any acute or serious comorbidity (e.g., major infection or hematological, oncological, cardiac, renal, metabolic, gastrointestinal, or endocrine dysfunction) that, according to the field principal investigator/designated person or medical monitor, would pose a risk to patient safety or interfere with study evaluation, procedures, or completion. (4) Having a new onset of paroxysmal or permanent atrial fibrillation within 30 days prior to screening that requires rhythm restoration therapy (e.g., direct current cardioversion, ablation, or antiarrhythmic therapy). Patients may be rescreened after 30 days if their heart rate (HR <100 bpm) and/or rhythm has been stable for >30 days. (This exclusion does not apply if atrial fibrillation has been treated with anticoagulation and the heart rate has been adequately controlled for ≥14 days). (5) Has received atrial septal reduction therapy (surgical myocardiography or transcatheter alcohol ablation) since completing a previous afencontan study. (6) Currently has obstructive coronary artery disease (recorded stenosis >70% in one or more arteries). (7) Has moderate or severe aortic stenosis. (8) Has a confirmed LVEF <40% during a previous afencontan study with a related dose interruption (i.e., according to Example 2 or Example 5). Patients may be considered for inclusion if data from the participant cohort has been unblinded. (9) History of syncope or sustained ventricular tachyarrhythmia within 30 days prior to screening. (10) History of ICD placement within 30 days prior to screening. (11) Hypersensitivity to excipients in afencontan tablets (e.g., mannitol, microcrystalline cellulose, croscarmellose, hydroxypropyl cellulose, sodium lauryl sulfate, magnesium stearate, Opadry QX White 21A180025).

Research Design

On day 1, each patient underwent echocardiography; each patient received afecontan at dose 1 once daily for 2 weeks. In week 2, each patient underwent truncated echocardiography after their dose. If LVOT-G ≥30 mmHg and biplane LVEF ≥55% after the Valsalva maneuver, the patient was titrated up to dose 2. Otherwise, the patient continued to receive 5 mg of afecontan. Treatment was discontinued if LVEF <50%.

Echocardiography or truncated echocardiography (truncation at weeks 4, 6, 12, and every 12 weeks thereafter) was performed on each patient after dose administration to determine if additional dose titration was required (see Tables 21 and 22). Patient-reported outcomes, laboratory assessments, and measurements of NT-proBNP, hs-cTnI, and other biomarkers were performed at week 12 and every 12 weeks thereafter. Ambulatory cardiac monitoring was performed at weeks 48, 96, 144, 192, and 240. Cardiac magnetic resonance imaging was performed at weeks 48, 144, and 240. If the patient's LVEF was <40% after the week 2 visit, repeat echocardiography was performed to confirm the initial finding (preferably within 24 hours). If the echocardiographic findings were confirmed, the patient would receive a pharmacological holiday of ≥2 days. Once a local echocardiogram shows LVEF ≥ 55%, the patient can continue taking afecontan at a reduced previously tolerated dose.

Table 21: Dosage Adjustment Algorithm

Table 22: Dosing Regimen

Echocardiography

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

Cardiac MRI

The cardiac magnetic resonance (CMR) imaging substudy evaluates the effects of long-term afecontan dose administration on cardiac morphology, function, and fibrosis in eligible and selected patients. CMR is performed at baseline at any time during the screening period and may be performed within 8 weeks prior to the first dose of afecontan on day 1. Patients who fail screening and are re-screened do not need to repeat the baseline CMR. If a subject has already enrolled in the Example 5 CMR substudy, a repeat baseline CMR is not required. Patients with eGFR <30 mL/min/1.73 ^m² or who are hypersensitive to gadolinium may receive only non-contrast CMR. Patients may also choose non-contrast CMR evaluation only for any other reason. Subsequent CMR studies are 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.

Record the NYHA functional classification. If available, the patient will complete the Patient Reported Outcomes (PRO) questionnaires: Kansas City Cardiomyopathy Questionnaire (KCCQ), Seattle Angina Questionnaire-7 (SAQ-7), EuroQol 5-Dimensional 5-Level Tool (EQ-5D-5L), Patient Global Impression of Change (PGI-C) scale, Clinical Global Impression (CGI) scale, and SF-36 Physical Function Subscale (SF-36 PFS), as specified in Table 23.

Table 23: Health Status and Health-Related Quality of Life Plan

Primary endpoint

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

Secondary endpoint

The secondary objective was to assess the long-term effect of afecontan on LVOTG in patients with oHCM, as evaluated by LVOTG peak values at rest and during Valsalva maneuver; the proportion of patients meeting each of the following criteria: a) resting LVOTG <50 mmHg, b) resting LVOTG <30 mmHg; c) LVOTG <50 mmHg after Valsalva maneuver, d) LVOTG <30 mmHg after Valsalva maneuver, or e) LVEF ≥50%, resting LVOTG <30 mmHg and LVOT-G <50 mmHg after Valsalva maneuver; time to first resting LVOT-G <50 mmHg; time to first resting LVOT-G <30 mmHg; time to first Valsalva maneuver followed by LVOT-G <50 mmHg; time to first Valsalva maneuver followed by LVOT-G <30 mmHg; and time to first LVEF ≥50%, resting LVOT-G <30 mmHg, and Valsalva maneuver followed by LVOT-G <50 mmHg.

Exploratory endpoint

The exploratory objectives of this study include (i) assessing steady-state pharmacokinetics during long-term afecontan use, such as through monitoring at 1-year intervals until the _end of participation; (ii) assessing the long-term effects of afecontan on cardiac biomarkers, such as changes in NT-proBNP, hs-cTnI, Galectin-3, PINP, TIMP-1, CITP, soluble ST2, and other biomarkers compared to baseline at 12-week intervals until the end of participation; (iii) assessing the impact on functional outcomes, such as changes in NYHA functional categories compared to baseline at 12-week intervals until the end of participation; and (iv) assessing the impact on symptoms of oHCM, such as through EQ-5D-5L, PGI-C, CGI, Kansas City Cardiomyopathy Questionnaire (KCCQ), SAQ-7, and SF-36 Physical Functional Subscales (SF-36) at 12-week intervals. (v) Assess the pharmacodynamic effects of afecontan on cardiac function and structure, as assessed by changes in the following echocardiographic cardiac function and structure measures from baseline to the end of participation 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); interventricular septum, free wall, and maximum wall thickness; left atrial volume; left ventricular strain (longitudinal, circumferential, radial); diastolic index: E/e', E/A; (vi) Assess the effects of afecontan on abnormal myocardial repolarization electrocardiographic indices, as assessed by changes in the proportion of patients exhibiting LV strain patterns on ECG at 12-week intervals from baseline to the end of participation; (vii) Assess the effects of afecontan on cardiac structure. The effects of afencontan on cardiac function were assessed by changes in the following cardiac morphological and structural measures from baseline to 1, 3, and 5 years and at the end of the period, as evaluated by cardiac magnetic resonance (CMR) imaging: RV and LV mass; interventricular septum, free wall, and maximum wall thickness; left atrial volume; end-diastolic volume (EDV); end-systolic volume (ESV); (viii) the effects of afencontan on cardiac function were assessed by changes in the following biventricular function measures from baseline to 1, 3, and 5 years and at the end of the period, as evaluated by CMR imaging: stroke volume (SV); ejection fraction (EF); cardiac output (CO); (ix) the effects of afencontan on cardiac fibrosis were assessed by changes in the following CMR parameters with late gadolinium enhancement (LGE) from baseline to 1, 3, and 5 years and at the end of the period: LGE mass (g), LGE mass % (in LV mass %).

Interim results of Examples 3a and 3b

Patients were administered according to the protocol of Example 3a or Example 3b. Patients were classified as receiving SoC therapy (first-line and second-line) if treated with at least one β-blocker (BB), non-dihydropyridine calcium channel blocker (CCB), or disopyramide. Patients were eligible for background therapy reduction/discontinuation (BTR/W) based on the decision of the field investigator and after ≥4 weeks of stable-dose afecontan and after week 12 of the study. A successful BTR/W was defined as a reduction of at least one drug dose to ≤ 50% of baseline. Serial measures were collected according to the protocol, but side effects specifically related to SoC therapy were not collected.

Of the first 42 patients included, 39 (93%) were taking ≥1 SoC drug, and of these, 27 (69%) were receiving only BB, 4 (10%) only CCB, 7 (18%) received CCB or BB and disopyramide, and 1 patient was receiving triple therapy (3%). Among patients treated with afecontan 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 drug, and 5 patients withdrew from all SoCs (afecontan monotherapy). Three patients failed to attempt BTR/W and resumed BB due to symptom recurrence or increased left ventricular outflow tract gradient (LVOT-G). Baseline characteristics of all included patients and subgroups in this analysis are shown in Table 24A. Baseline median doses of β-blockers and calcium channel blockers are shown in Figure 44.

All subgroups showed rapid and sustained relief of obstruction, improvement in cardiac biomarkers, and symptoms with a moderate decrease in LVEF (Figures 39–42). In patients who underwent available assessment before and after BTR/W (N = 14), BTR/W increased resting HR by 12 bpm (mean HR = 74 ± 10 bpm, p = 0.0001) and increased Valsalva maneuver LVOT-G 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 researchers considered no safety events associated with afecontan therapy. NT-proBNP and hs-troponin I levels are shown in Figures 45A and 45B.

Table 24A: Baseline Characteristics

Second interim results at up to 48 weeks

The baseline characteristics of the first 45 included patients are described in Table 24B.

Table 24B: Baseline Characteristics

* Screening of echocardiograms for on-site reading

The number of patients and the dose achieved at each time point are shown in Figure 52. From baseline to week 48, peak resting and Warburg maneuver LVOTS-G decreased significantly [Δresting mean: –32 mmHg (±28); ΔWarburg maneuver mean: –47 mmHg (±28)] (see Figures 53 and 54, respectively). LVEF decreased modestly from baseline to week 48 (Δ –5±3%), and no patients experienced afecontan-related decrease in LVEF <50% (see Figure 55). NYHA class showed significant improvement: by week 48, 88% of patients experienced an improvement of ≥1 NYHA FC, and none experienced a deterioration in NYHA FC (see Figure 56). At baseline, despite receiving β-blockers (78%), calcium channel blockers (18%), and disopyramide (22%), 19 patients (42%) still met the criteria for SRT based on symptom and hemodynamic guidelines. (SRT eligibility: NYHA Class III or IV with an LVOT gradient ≥ 50 mmHg at rest or during Valsalva maneuvers or exertion, or NYHA Class II with exertional symptoms of syncope or near-syncope and an increasing gradient). These patients did not meet these criteria by 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% reduction from baseline (p < 0.0001).

Intermediate Global Longitudinal Strain (GLS) Results

Patients enrolled in the afecontan open-label extended trial (FOREST HCM) (n=27; baseline characteristics in Table 24C) underwent echocardiography (GE E-95 ultrasound machine) at baseline, week 12, and weeks 36–48. GLS analysis was performed using a vendor-neutral analysis package (TOMTEC® imaging system).

Changes in NYHA functional categories are shown in Figure 57A. Compared to 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 between weeks 36 and 48 (-13.9% ± 3.2 vs. -14.9% ± 2.7, p 0.012) (see Figure 57B). These improvements were more pronounced in patients with the best hemodynamic response (resting LVT<30 and Valsalva maneuver LVT<50 mmHg; n=21) (see Figures 57C and 57D).

Table 24C. Baseline Characteristics

in conclusion

Based on interim results, discontinuing or reducing SoC medical therapy after treatment with afecontan is generally effective and safe, and is associated with sustained substantial improvement in clinically relevant efficacy indicators.

Afencontan treatment was associated with rapid and sustained improvement in echocardiographic hemodynamics and significant improvement in NYHA class. Afencontan disqualified patients from SRT in all patients who were eligible at baseline. There were no cases of systolic dysfunction (LVEF <50%) caused by afencontan.

Following long-term treatment, afencontan therapy has a beneficial effect on myocardial mechanics (e.g., GLS), and these changes are most pronounced in patients with optimal hemodynamic response (resting LVOTg <30 and Valsalva maneuver LVOTg <50 mmHg). Without being bound by theory, potential underlying mechanisms may include a long-term reduction in afterload secondary to the decrease in LVOTg, leading to other pathological changes, as strain improvement occurs several weeks after the gradient reduction.

Example 4

This is a phase 3, multicenter, randomized, double-blind, active comparative trial in participants with symptomatic oHCM and elevated LVOTTY (see Figures 38 and 58). Approximately 170 eligible participants were randomized in a 1:1 ratio to receive afencontin or metoprolol. Randomization was stratified based on CPET exercise mode (treadmill/cycling) and recent diagnosis relative to chronic oHCM. The randomization stratification was as follows: 1) participants who were untreated 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 treated or had received SOC therapy in the past 12 months. The number of participants using the cycling CPET exercise mode was capped at approximately 50%.

The overall objective of this active comparative trial is to evaluate the safety and efficacy of afecontan as each of the following: 1) as first-line therapy in recently diagnosed and/or treatment-naïve participants; or 2) as monotherapy in participants who have previously received standard of care (SOC) medical therapy for symptomatic oHCM.

The primary objective of this trial was to evaluate the effect of afencontin on exercise capacity in patients with symptomatic oHCM. The indicated endpoint was the change in peak oxygen uptake ( _pVO2 ) from baseline to week 24, as measured by cardiopulmonary exercise testing (CPET).

A secondary objective of this trial was to evaluate the effect of afecontan on New York Heart Association (NYHA) functional classification, as determined by the proportion of patients whose NYHA functional classification improved by ≥1 class from baseline to week 12 and week 24.

Another secondary objective of this trial was to evaluate the effects of afecontan on patient health, as determined by changes in the Kansas City Cardiomyopathy Questionnaire-Clinical Roundup Score (KCCQ-CSS) from baseline to week 12 and week 24.

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

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

Another secondary objective of this trial was to evaluate the effect of afencontin on the left ventricular outflow tract gradient (LVOT-G) following Valsalva maneuvers from baseline to week 24.

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, nonfatal stroke, nonfatal myocardial infarction, CV hospitalization); (2) the incidence of adverse events (AEs); and (3) the incidence of left ventricular ejection fraction (LVEF) < 50%.

The exploratory objective of this trial is to evaluate the effects of afecontan on motor function and functional class, as determined by the number of patients at week 24 who achieved either of the following: (1) a change in _pVO2 from baseline ≥1.5 mL/kg/min and an improvement in NYHA functional class ≥1 class; or (2) a change in _pVO2 from baseline ≥3.0 mL/kg/min and no deterioration in NYHA functional class.

Another exploratory objective of this trial was to evaluate the effect of afecontan 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 NYHA functional class I improvement by ≥ 1 at weeks 12 and 24.

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

Another exploratory objective of this trial was to evaluate the effect of afencontan on measures of diastolic function, such as the change in the ratio between early mitral inflow velocity and early diastolic velocity of the mitral annulus (E/e' [lateral wall]) from baseline to week 24.

Another exploratory objective of this trial is to evaluate the effect of afencontan on ventricular septal thickness (IVST) remodeling, as determined by changes in IVST from baseline to week 24.

Another exploratory objective of this trial was to evaluate the effects of afencontin on other CPET parameters, as determined by the changes in each of the following from baseline to week 24: (1) ventilator efficiency/carbon dioxide production (VE/ _VCO2 slope); (2) cycle power ( _VO2 x systolic blood pressure [SBP]); (3) ventilator anaerobic threshold (VAT); total workload (watts); and heart rate response.

Another exploratory objective of this trial was to evaluate the effects of afencontin on health status and health-related quality of life as measured by the PRO questionnaire, such as changes in individual responses to the EuroQol 5-Dimensional 5-Level Tool (EQ-5D-5L), Clinical Global Impression (CGI), Patient Global Impression (PGI-C), and Seattle Angina Questionnaire-7 (SAQ-7) from baseline to week 24.

Another exploratory objective of this trial is to evaluate the pharmacokinetics of afecontan and its metabolites, as determined based on pharmacokinetic parameters up to week 24.

Inclusion criteria

Patients are eligible for inclusion in the trial only if all of the following criteria apply: (1) They are able to understand and are willing to sign the ICF and to comply with all trial procedures and restrictions for the duration specified in the activity schedule. (2) They are males and females aged between 18 and 85 years of age (inclusive) at the time of screening. (3) Their body mass index is <35 kg/ ^m² . (4) They are diagnosed with oHCM by cardiac magnetic resonance imaging (CMR) or echocardiography according to the following criteria: (a) left ventricular hypertrophy without left ventricular dilation and without other cardiac disease, and (b) minimum ventricular wall thickness ≥15 mm (minimum wall thickness ≥13 mm is acceptable for known pathogenic genetic variants or a positive family history of HCM). (5) They have a resting LVOT-G ≥30 mmHg and/or a LVOT-G ≥50 mmHg after a Valsalva maneuver during the screening period, as determined by an echocardiography core laboratory. (6) Their LVEF is ≥60% at the time of screening, as determined by an echocardiography core laboratory. (7) New York Heart Association (NYHA) functional class II or III at screening visit 2. (8) Hemoglobin ≥10 g/dL at screening. (9) Respiratory exchange ratio (RER) ≥1.05 and pVO2 <100% predicted at screening CPET according to core laboratory at screening visit 2. (10) Adequate echocardiographic acoustic window. (11) Male patients are eligible to participate in the trial if they agree to the following conditions at least 4 weeks after the last dose of afecontan during the trial period and after the last dose: (a) not donating sperm, plus (b) (i) not having heterosexual intercourse as their preferred and usual lifestyle (long-term and persistent abstinence) and agreeing to remain abstinent, or (ii) must agree to use male condoms and, if their female partner is a woman of fertility potential, have their female partner use a highly effective method of contraception. (12) Female patients are eligible to participate in the study if they are not pregnant, breastfeeding, or planning to donate oocytes and meet at least one of the following criteria: (a) they are not women of reproductive potential (WOCBP), or they are WOCBP and have used highly effective contraception for at least 4 weeks during the trial and after the last dose of afecontan, and their male partner consents to condom use; and (b) WOCBP patients must have a negative pregnancy test (urine or serum as required by local regulations) on day 1 before the first dose of afecontan in the study. (13) They must be able to complete all screening procedures. (14) Their KCCQ-CSS score is ≥35 and ≤90 at screening. (15) Patients who have previously been exposed to mavacartan are allowed to participate, but must have discontinued mavacartan for at least 8 weeks before signing the informed consent form and must obtain approval from the medical monitor before enrollment. Approximately 10% of oHCM patients who have previously received mavacartan may participate in the study with the approval of the medical monitor.

Exclusion criteria

Patients will be excluded from the trial if any of the following criteria are met: (1) Medical indications for discontinuation of beta-blockers or calcium channel blockers (except for oHCM). (2) History of intolerance or medical contraindications to beta-blocker therapy. (3) Resting SBP > 160 mmHg at screening. (4) Resting heart rate > 100 bpm at screening. (5) Significant valvular heart disease (as determined by the investigator), including moderate to severe valvular aortic stenosis or fixed subaortic obstruction, and/or mitral regurgitation not due to anterior systolic displacement of the mitral valve. (6) Known or suspected infiltrative, hereditary, or reservoir conditions similar to oHCM that cause cardiac hypertrophy (e.g., Noonan syndrome, Fabry disease, amyloidosis). (7) History of left ventricular systolic dysfunction (LVEF < 45%) or stress-induced cardiomyopathy at any time during the clinical course of the disease. (8) Inability to exercise on a treadmill or bicycle (e.g., orthopedic limitations). (9) Has received septal reduction therapy (surgical myotomy or percutaneous alcohol septal ablation) within 6 months of screening (Note: Patients who have received septal reduction therapy > 6 months prior to screening are allowed up to approximately 10% of the total), or have any treatment plan that cannot be postponed during the trial. (10) Has a history of paroxysmal or persistent atrial fibrillation or atrial flutter (patients who have received radiofrequency ablation for atrial flutter within 6 months prior to screening without recurrence are allowed). (11) Is currently or recently (< 4 weeks) using disopyramide. (12) Has a history of syncope, symptomatic ventricular arrhythmia, or persistent ventricular tachyarrhythmia within 6 months prior to screening. (13) Has had an ICD placed within 3 months prior to screening or plans to have an ICD placed during the trial. (14) Estimated glomerular filtration rate (eGFR) at screening < 30 mL/min/1.73 ^m² (according to the improved renal diet formula). (15) Previous treatment with afecontan or previous intolerance to mavacartan (low LVEF, requiring permanent drug discontinuation).

Overall design.

The screening period begins upon informed consent and will include pre-clearance (screening visit 1) and post-clearance (screening visit 2) clinical assessments. Patients not currently receiving oHCM medical therapy do not require a clearance period and will only participate in screening visit 2. Upon meeting eligibility criteria, participants will be randomly assigned to receive either afencontin and metoprolol placebo or metoprolol and afencontin placebo.

Participants enrolled in this trial must have an LVEF ≥ 60% prior to randomization. Randomization was based on CPET exercise mode (treadmill/cycling) and recent diagnosis relative to chronic oHCM as follows: (1) untreated or currently untreated participants (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 currently receiving treatment or who have received SOC therapy in the past 12 months with chronic oHCM (> 12 months). All randomized participants may receive up to 4 escalating doses of IP within the first 6 weeks of the trial, as shown in Table 27 below.

Participants will be assigned IP in a double-blind manner at each trial visit. During the first 6 weeks of treatment, the IP dose will be individually titrated at weeks 2, 4, and 6 according to echocardiographic and vital sign criteria (see Figure 26). At these visits, a non-blinded echocardiography specialist will review echocardiographic (LVEF and LVOT-G) and vital sign (SBP and resting heart rate) data, and a non-blinded echocardiography specialist or a non-blinded designated person will input the data into the Interactive Network Response System (IWRS) and perform dose adjustments in a blinded manner according to a pre-specified algorithm.

Participants receiving afecontan will start with a dose of 5 mg once daily (dose 1), which may be increased to 10 mg, 15 mg, and 20 mg once daily as they continue to meet two echocardiographic escalation criteria, or their current dose will be maintained if the escalation criteria are not met. If LVEF is <50% at any time, the dose of afecontan will be titrated down, and if LVEF is <40% at any time, afecontan will be temporarily discontinued.

Participants receiving metoprolol will start with a dose of 50 mg once daily (dose 1), which may be increased to 100 mg, 150 mg and 200 mg once daily as they continue to meet two echocardiographic escalation criteria and two vital signs criteria, or their current dose will be maintained if they do not meet the escalation criteria.

If, at any time during the trial, a participant experiences an intolerable adverse event (AE), which, in the investigator's judgment, is drug-related and compels the participant to request discontinuation of the IP, the IP dose may be reduced to the previous dose level. For participants receiving dose 1, the IP was discontinued.

Treatment lasted for 24 weeks, with a 4-week follow-up period after the last dose (weeks 24 to 28). The primary endpoint of _pVO2 was measured by CPET at randomization and week 24.

Table 25: Vital Signs and Echocardiographic Criteria for IP Dosage Adjustment

bpm = heart rate per minute; IP = research product; LVEF = left ventricular ejection fraction; LVOT-G = left ventricular outflow tract gradient; NA = not applicable; SBP = systolic blood pressure

Table 26: Dosage Titration Standards

^Once the patient's afecontan dose is titrated down, further increases are not permitted.

Table 27: Dosing Regimen

Following randomization, each patient received dose 1 (5 mg afecontan, 50 mg metoprolol) once daily for two weeks. At the second-week visit, patients underwent echocardiography 2 hours after dose administration. Patients were titrated up to dose 2 (10 mg afecontan, 100 mg metoprolol) if the echocardiogram met the following criteria: LVOT-G ≥30 mmHg after the Valsalva maneuver and biplane LVEF ≥55%. Otherwise, patients continued with dose 1 unless IWRS assigned them to placebo if their LVEF at week 2 was <50%.

Two weeks after the assigned dose, at the week 4 visit, each patient underwent echocardiography 2 hours after their dose was administered. If the echocardiogram met the following criteria, the patient was titrated up to the next higher dose: LVOT-G ≥30 mmHg after the Warburg maneuver and biplane LVEF ≥55%. Otherwise, the patient continued to receive the same dose unless the IWRS reassigned the patient to the previous dose level if the LVEF at week 4 was <50%, or to placebo if the patient was already on dose 1.

Two weeks after the assigned dose, at the week 6 visit, each patient underwent echocardiography 2 hours after their dose administration. If the echocardiogram met the following criteria, the patient was titrated up to the next higher dose: LVOT-G ≥30 mmHg after the Warburg maneuver and biplane LVEF ≥55%. Otherwise, the patient continued to receive the same dose unless the IWRS reassigned the patient to the previous dose level if the LVEF at week 6 was <50%, or to placebo if the patient was already on dose 1.

At the week visits of 8, 12, 16, 20, and 24, each patient underwent echocardiography 2 hours after administration of their afecontan dose to ensure LVEF ≥50%. If LVEF <50% at week 8, the IWRS assigned the patient to the next lower dose, or, if the patient was taking dose 1, to placebo.

Dose escalation must meet all criteria, but down titration or IP discontinuation only requires meeting one criterion. If down titration occurs, further up titration is not permitted. Up titration of IP is not permitted after week 6, but down titration to the next lowest dose is allowed. (Dose escalation for each participant will be based on the criteria described in Tables 25-27). Importantly, the lower limit of LVEF used for dose escalation is increased from 50% to 55% to provide a safe limit compared to the LVEF threshold (<50%), which will trigger a dose reduction. If LVEF is <50% at any time, afenicone is down titrated, and if LVEF is <40% at any time, afenicone is temporarily discontinued.

LVEF safety threshold

If a nonblinded ultrasound cardiologist observes that the LVEF has exceeded the defined safety threshold of <40% or believes that a participant requires urgent medical care, the nonblinded ultrasound cardiologist or nonblinded designee will enter the LVEF value into the IWRS and discuss the results with the blinded investigator or qualified designee. These situations will be communicated to the medical monitor.

If a participant's LVEF is < 40% at any time, the following steps should be taken after consulting with a medical monitor: IP should be stopped and maintained for at least 7 days. Echocardiography should be repeated as determined by the investigator until a normal LVEF (≥ 55%) is recorded, at which point the participant may restart IP after downtiing. The dose interruption should be recorded in the eCRF, including the reason for the interruption, the date of the last dose, and the date of restart.

If a temporary IP interruption occurs due to reaching a safety threshold, blinded treatment is resumed after at least 7 days. If the participant is taking 5 mg afecontan or 50 mg metoprolol (as determined by IWRS), a lower dose may be used or a placebo may be permanently switched.

The plan is to titrate the metoprolol dose downwards in week 24.

The last dose of afencontan and afencontan placebo will be administered at week 24 (or at the delayed week 24 visit). Dosing of afencontan and afencontan placebo will be discontinued. To maintain blinding, all participants will receive a down titration of metoprolol or metoprolol placebo at home the day after the week 24 visit.

Cardiopulmonary exercise testing (CPET). All patients underwent CPET and gas exchange analysis, and the methods were standardized at all participating sites as described in the CPET manual. The test involved continuous ECG monitoring by trained personnel and was conducted in an area equipped with cardiopulmonary resuscitation equipment. A treadmill is the preferred mode of exercise testing. For CPET laboratories that do not perform treadmill testing, a stationary bike is an acceptable alternative. Exercise protocols for both modes are provided in the CPET manual. Patients must use the same testing mode for all exercise tests during the trial period. Whenever possible, CPET was administered by the same trial personnel using the same equipment and after other trial procedures (including echocardiography, KCCQ, EQ-5D-5L, CGI, PGI-C, NYHA Class, SAQ-7, vital signs, ECG, blood sampling, and IP administration) on the day of the visit. Patients who did not undergo an exercise protocol will be familiarized with the technique during screening.

All CPET tests are symptom-limited, and patients are strongly encouraged to achieve maximal effort and a response rate (RER) ≥1.05. Record the reason for terminating the submaximal motor test. If the RER ≥1.05, the test is identified as maximal effort.

Week 24 CPET should be performed at screening at approximately the same time of day as baseline CPET (e.g., morning, noon, afternoon), consistent with the timing of the last dose of beta-blocker and IP. Whenever possible, patients should undergo exercise testing between 3 and 10 hours after taking the beta-blocker.

If investigators identify a life-threatening arrhythmia, early ischemia, severe hypotension, or other serious findings during CPET, the patient is asked to stop the exercise test and notify his/her physician of the results. If the patient is undergoing a screening test, he/she will not be randomized to the trial. Enrolled patients with non-life-threatening events or findings that necessitate stopping the test may resume testing when it is safe and after appropriate treatment, depending on the investigator's assessment.

Echocardiography. Echocardiography was performed during screening and before day 1 of administration. Comprehensive or focused echocardiography was performed at weeks 2, 4, 6, 8, 12, 16, 20, and 24, 2 hours (±60 min) after outpatient administration. Comprehensive echocardiography was also performed at week 28.

Certified ultrasound technicians will perform echocardiography using standard, high-quality, high-fidelity equipment. Whenever possible, the same ultrasound technician will perform all studies on a single patient. Echocardiography is performed according to the echocardiography manual after the patient has been supine and resting for at least 10 minutes. The echocardiography manual will also include instructions for performing the Valsalva maneuver and for LVOT-G imaging.

When echocardiography is scheduled concurrently with blood tests, vital signs, and/or ECG, the evaluation order should be: vital signs, ECG, blood test, and echocardiography. Blood tests should be performed at the scheduled time, followed by echocardiography.

In addition to the right ventricular function measurements detailed in the echocardiography protocol, the echocardiographic parameters to be measured include at least the left ventricular parameters (resting left ventricular outflow tract pressure gradient (LVOT-G), LVOT-G after Warburg action, LVEF, LVFS, global longitudinal strain (GLS), left ventricular end-diastolic diameter (LVEDD), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic diameter (LVESD), left ventricular end-systolic volume (LVESV), left ventricular cardiac output (LVCO), LV stroke volume, LVOT velocity interval (VTI), interventricular septal thickness (IVST), isovolumetric contraction time (IVCT), IVRT, E/E ratio (interventricular septum and lateral), and left atrial volume (LAV)).

Unscheduled echocardiography may be obtained when clinically indicated, for example, to assess adverse events (AEs) or to follow up on clinically significant changes in previous echocardiography, as determined by the investigator. Results are interpreted by an unblinded echocardiography cardiologist at the study site.

All echocardiograms (including those not scheduled) were sent to the core laboratory for interpretation. Field interpretation of LVEF and LVOT-G was used for dose escalation and reduction decisions via IWRS. Core laboratory quantification of echocardiograms was used for all statistical analyses.

Optional HCM Participant Experience Substudy. Participants who agree to participate in the optional HCM participant experience substudy will undergo two semi-structured, qualitative (entry and exit) interviews conducted remotely by trained personnel from an independent vendor (see Table 28). The entry interview can be conducted anytime after signing the informed consent form and before Day 1. The exit interview can be conducted anytime after the week 20 visit but before the last IP dose at week 24. The interviews will be conducted remotely. The entry interview will collect verbal information from participants regarding their own perceptions of baseline function, symptom load, activities of daily living, and expectations for the study. The exit interview will collect verbal information from participants regarding their experiences with oHCM function and effects, symptom load, activities of daily living, and overall treatment experience. In addition, all participants will complete surveys remotely on Day 1, at weeks 2, 4, 6, 8, 12, 16, 20, and 24. These surveys will track self-selected personal goals to capture the aspects of oHCM that were most meaningful or troublesome to them throughout the trial. These goals will be achieved using the SMART framework: Specific, Measurable, Achievable, Relevant, and Time-bound.

Table 28: HCM Patient Experience Questionnaire

Example 5

The following examples illustrate a phase 3, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of afecontan in adults with symptomatic hypertrophic cardiomyopathy (oHCM) and left ventricular outflow tract obstruction (LVOT-G). This trial evaluated the effects of afecontan treatment on cardiopulmonary exercise capacity and overall health in patients with symptomatic oHCM over a 24-week period. The aim of this trial was to establish the efficacy and safety of afecontan in improving exercise capacity and patient symptoms in patients with oHCM, as well as reducing the left ventricular outflow tract gradient (LVOT-G).

This is a phase 3 randomized, placebo-controlled, double-blind, multicenter trial in patients with symptomatic oHCM. Approximately 270 eligible patients were randomized in a 1:1 ratio to receive afencontan or placebo. Echocardiographic-guided dose titration was used to administer 5 mg, 10 mg, 15 mg, or 20 mg doses or matched placebo in escalation. Randomization was stratified using a beta-blocker and CPET exercise mode.

The trial consisted of three phases. The screening phase lasted up to 6 weeks. The double-blind, placebo-controlled treatment phase lasted 24 weeks. A 4-week safety follow-up period followed the last dose of afecontan. Afecontan was administered orally once daily. During the initial six weeks of treatment, the afecontan dose was individually titrated by echocardiography at weeks 2, 4, and 6. Dose escalation occurred only at the week 2, 4, and 6 visits if the patient had a LVOT-G ≥30 mmHg after a Valsalva maneuver and ≥55% biplane LVEF. Echocardiography was performed at each subsequent visit during the trial, and dose was titrated down as necessary. The primary endpoint of _pVO2 was measured by CPET at screening and at the end of treatment (week 24). Patients continued to take background HCM medications consistent with regional clinical practice guidelines during the trial, if applicable.

The CMR imaging sub-study was opened to approximately 40 patients who consented to participate.

Genetic sub-studies: Consenting patients undergo DNA analysis using whole-genome sequencing, whole-exome sequencing, next-generation sequencing, and/or other methods to identify genetic variants.

The primary mitigation strategy is facilitated through individualized dosing titration protocols based on each patient’s response to afencontin and applying predetermined echocardiographic criteria, including LVEF thresholds for dose escalation, down-tipping, and drug discontinuation.

Patients enrolled in this trial were required to have ≥60% LVEF prior to randomization, as confirmed by a central echocardiography laboratory. A low starting dose of 5 mg and a maximum dose of 20 mg were chosen because these doses were found to be well tolerated in a phase 2 study (CY 6021) in patients with oHCM and to effectively reduce LVOT-G without adversely affecting overall LVEF. Individualized dose escalation was only performed if the following criteria were met: LVOT-G ≥30 mmHg after the Warburg maneuver and biplane LVEF ≥55%. Importantly, the lower limit of LVEF for dose escalation was increased from 50% to 55% compared to CY 6021 to provide a safe limit compared to the LVEF threshold (<50%), which would trigger dose reduction. If LVEF was <50% at any time, the dose of afecontan was titrated down, and if LVEF was <40% at any time, afecontan was temporarily discontinued.

The primary objective of this trial was to evaluate the effect of afencontin on exercise capacity in patients with symptomatic oHCM. The indicated endpoint was the change in peak oxygen uptake ( _pVO2 ) from baseline to week 24, as measured by cardiopulmonary exercise testing (CPET).

The secondary objective of this trial was to evaluate the effects of afecontan on patient health, as determined by changes in the Kansas City Cardiomyopathy Questionnaire-Clinical Roundup Score (KCCQ-CSS) from baseline to week 12 and week 24.

Another secondary objective of this trial was to evaluate the effect of afecontan on New York Heart Association (NYHA) functional classification, as determined by the proportion of patients whose NYHA functional classification improved by ≥1 class from baseline to week 12 and week 24.

Another secondary objective was to evaluate the effect of afencontin on the left ventricular outflow tract gradient (LVOT-G) after the Valsalva maneuver, as determined by changes in LVOT-G from baseline to week 12 and week 24 after the Valsalva maneuver and the proportion of patients with LVOT-G <30 mmHg after the Valsalva maneuver at week 12 and week 24.

Another secondary objective was to evaluate the effect of afencontin on motor performance, as determined by the change in total workload from baseline to week 24 during CPET.

To evaluate the safety and tolerability characteristics 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, nonfatal stroke, nonfatal myocardial infarction, CV hospitalization); (2) the incidence of new-onset persistent atrial fibrillation; (3) the incidence of appropriate implantable cardioverter defibrillator (ICD) discharge and abortive sudden cardiac death; (4) the incidence of left ventricular ejection fraction (LVEF) < 50%; and (5) the incidence of treatment-emergent adverse events.

The exploratory objective of this trial was to evaluate the effects of afecontan on motor function and functional class, as determined by the number of patients at week 24 who achieved the following from baseline: (1) a change _{in pVO2} from baseline ≥1.5 mL/kg/min and an improvement in NYHA functional class ≥1 class; or (2) a change in _pVO2 from baseline ≥3.0 mL/kg/min and no deterioration in NYHA functional class.

Another exploratory objective of this trial was to evaluate the effect of afecontan on patient response over time, as determined by: (1) the proportion of patients with a KCCQ-CSS improvement of >5 points at weeks 12 and 24; (2) the proportion of patients with resting LVOT-G <30 mmHg, LVOT-G <50 mmHg after the 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 the Valsalva maneuver, and NYHA functional class I improvement of ≥1 class at weeks 12 and 24.

Another exploratory objective of this trial was to evaluate the effects of afencontin on other CPET parameters, as determined by the following changes from baseline to week 24: (1) ventilator efficiency (VE/ _VCO2 slope); (2) cyclic power ( _VO2 x systolic BP); and (3) ventilator anaerobic threshold (VAT).

Another exploratory objective of this trial was to evaluate the effects of afencontin on health status and health-related quality of life as measured by the PRO questionnaire, as determined by changes in individual responses to the EuroQol 5-Dimensional 5-Level Tool (EQ-5D-5L) from baseline to week 24.

Another exploratory objective of this trial is to evaluate the effects of afecontan on cardiac function and structure, as determined by echocardiographic measurements of changes in cardiac structure and systolic function from baseline to week 24, including: LVEF, left ventricular end-systolic and end-diastolic volumes (LVESV and LVEDV, respectively), and left atrial volume.

Another exploratory objective of this trial is to evaluate the effect of afecontan on biomarker levels, such as changes in NT-pro-BNP, hs-cardiac-TnI, and other biomarkers from baseline up to week 24.

Another exploratory objective of this trial is to evaluate the effects of afencontan on left ventricular mass, function, and structure using cardiac magnetic resonance (CMR) imaging, as determined by changes in CMR measurements of left ventricular (LV) mass index, LVEF, interventricular septum and free wall thickness, left atrial volume index, LVESV, and LVEDV from baseline to week 24.

Another exploratory objective of this trial is to evaluate the pharmacokinetics of afecontan and its metabolites, as determined based on pharmacokinetic parameters up to week 24.

Overall Design. This is a phase 3 randomized, placebo-controlled, double-blind, multicenter trial in patients with symptomatic oHCM. Approximately 270 eligible patients were randomized in a 1:1 ratio to receive afecontan or placebo. Randomization was stratified by using beta-blocker (yes or no) and CPET exercise mode (treadmill or bicycle) and was conducted in an Interactive Web Response System (IWRS). The number of patients receiving beta-blocker was capped and would not exceed approximately 70% of total enrollment. The number of patients with persistent atrial fibrillation at screening was also capped at approximately 15%, and the number of patients using the bicycle CPET exercise mode was also capped at approximately 50%.

Afencontan is administered orally once daily with or without food. During the initial six weeks of treatment, the afencontan dose is individually titrated by echocardiography at weeks 2, 4, and 6. Dose escalation at weeks 2, 4, and 6 occurs only if the patient has a LVOT-G after a Valsalva maneuver ≥30 mmHg and a biplane LVEF ≥55%. Echocardiography is performed at each subsequent visit during the trial, and the dose is titrated down as necessary. The primary endpoint of _pVO2 is measured by CPET at screening and at the end of treatment (week 24). If applicable, patients continue to take background HCM medications consistent with regional clinical practice guidelines during the trial.

All patients were followed up from randomization to their final visit date according to the Schedule of Activities (SoA) (see Trial Design, Figure 43), regardless of whether they continued receiving afecontan, unless they had prematurely discontinued the trial or withdrawn their consent. Early discontinuation visits were conducted for patients who discontinued the trial early.

This trial was designed to provide data supporting the clinical efficacy and safety of afenicone in patients with symptomatic oHCM and a VLOT-G >50 mmHg after the Warburg maneuver. A reduction in VLOT-G was expected to be associated with improvements in patient symptoms, health status, and motor function. Because patient characteristics are substantially altered in this disease, individualized dose titration for PD response (a reduction in VLOT-G to <30 mmHg after the Warburg maneuver while maintaining LVEF ≥55%) was employed to maximize efficacy and safety. Eligibility criteria were designed to include a patient population representative of the general population with oHCM while ensuring patient safety in this trial. A placebo-controlled and double-blind approach was used in this trial to avoid bias in data collection, including safety assessments and PD measurements that included both primary and secondary endpoints.

Patients are eligible for inclusion in the trial only if all of the following criteria apply: (1) They understand and are willing to sign the ICF and adhere to all trial procedures and restrictions for the duration specified in the activity schedule. (2) They are males and females aged between 18 and 85 years (inclusive) at the time of screening. (3) Their body mass index is <35 kg/ ^m² . (4) They are diagnosed with HCM according to the following criteria: (a) they have hypertrophic and non-dilated LV chambers in the absence of other heart diseases, and (b) they have the following end-diastolic LV wall thicknesses as measured by echocardiography core laboratory: ≥15 mm for one or more myocardial segments, or ≥13 mm for one or more wall segments, and a known pathogenic gene mutation or a positive family history of HCM. (5) They have a resting LVOT-G ≥30 mmHg and a post-Varva action LVOT-G ≥50 mmHg at the time of screening, as measured by echocardiography core laboratory. (6) Their LVEF is ≥60% at the time of screening, as measured by echocardiography core laboratory. (7) New York Heart Association (NYHA) functional class II or III at screening. (8) Hemoglobin ≥10 g/dL at screening. (9) Predicted respiratory exchange ratio (RER) ≥1.05 and pVO2 <80% at screening CPET according to core laboratory. (10) Patients taking beta-blockers, verapamil, or diltiazem should have been on a stable regimen for >6 weeks prior to randomization and are expected to continue using the same regimen during the trial. (11) Male patients are eligible to participate in the trial if they agree to the following conditions at least 4 weeks after the last dose of afecontan during the trial: (a) not donate sperm, plus (b) (i) not having heterosexual intercourse as their preferred and usual lifestyle (long-term and persistent abstinence) and agreeing to remain abstinent, or (ii) must agree to use male condoms and, if their female partner is a woman of fertility potential, have their female partner use a highly effective method of contraception. (12) Female patients are eligible to participate in the study if they are not pregnant, breastfeeding, or planning to donate eggs and at least one of the following conditions applies: (a) they are not women of reproductive potential (WOCBP), or they are WOCBP and have used highly effective contraception during the trial and for at least 4 weeks after the last dose of afecontan and their male partner consents to the use of condoms, and (b) WOCBPs must have a negative pregnancy test (urine or serum as required by local regulations) on day 1 before the first dose of afecontan in the study. (13) They are able to complete all screening procedures.

Patients will be excluded from the trial if any of the following criteria apply: (1) Significant valvular heart disease (in investigator's judgment), including moderate to severe valvular aortic stenosis and/or regurgitation, or moderate to severe mitral regurgitation not caused by presystolic motion of the mitral valve. (2) A documented history of current obstructive coronary artery disease (one or more epicardial coronary artery stenosis >70%) or a documented history of myocardial infarction. (3) A known or suspected infiltrative, hereditary, or reservoir condition similar to oHCM that causes cardiac hypertrophy (e.g., Noonan syndrome, Fabry disease, amyloidosis). (4) Previous treatment with cardiotoxic agents (e.g., doxorubicin or similar drugs). (5) A history of LV systolic dysfunction (LVEF <45%) or stress-induced cardiomyopathy at any time during its clinical course. (6) Any ECG abnormality that the investigator considers to pose a risk to patient safety (e.g., second-degree type II atrioventricular block). (7) Paroxysmal atrial fibrillation documented during the screening period. (8) Paroxysmal or permanent atrial fibrillation requiring rhythm restoration therapy (e.g., direct current heart rate restoration, atrial fibrillation ablation procedure, or antiarrhythmic therapy) within ≤6 months prior to screening. (This exclusion does not apply if atrial fibrillation has been treated with anticoagulation and the heart rate has been adequately controlled for >6 months.) (9) History of syncope or persistent ventricular tachyarrhythmia exercise within 6 months prior to screening. (10) Placement of an ICD within 3 months prior to screening or planned placement of an ICD during the trial. (11) History of receiving appropriate ICD discharge for life-threatening ventricular arrhythmia within 6 months prior to screening. (12) Treatment with ventricular septal reduction therapy (surgical myotomy or percutaneous alcohol ventricular septal ablation) or planned for either treatment during the trial period. (13) Inability to exercise on a treadmill or bicycle (e.g., orthotic restriction). (14) Indoor air oxygen saturation reading recorded at screening <90%. (15) Liver impairment, defined as total bilirubin (TBL) ≥1.5 × upper limit of normal (ULN) at screening, or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 × ULN. Patients with documented Gilbert's syndrome and TBL ≥1.5 × ULN due to unconjugated hyperbilirubinemia and without other liver impairment are permitted. (16) Receiving a major organ transplant (e.g., heart, lung, liver, bone marrow, kidney) or expected to receive a transplant within 12 months of randomization. (17) Any other clinically significant condition, malignancy, active infection, other illness or history or evidence of disease that, in the opinion of the investigator or medical monitor, would pose a risk to patient safety or interfere with trial evaluation, procedure or completion; (18) Estimated glomerular filtration rate (eGFR) at screening <30 mL/min/1.73 m2 (by modified renal diet improvement equation). (19) Currently participating in another investigational device or drug trial or having received an investigational device or drug less than 1 month prior to screening (or 5 half-lives of the drug, whichever is longer); other investigational procedures are not permitted while participating in this trial. (20) Previously treated with afecontan or mavacartan. (21) Any known hypersensitivity to excipients in the investigational drug tablets (e.g., mannitol, microcrystalline cellulose, croscarmellose, hydroxypropyl cellulose, sodium lauryl sulfate, magnesium stearate, Opadry QX White 21A180025).

Exclusion criteria for the CMR sub-study included (1) intolerance to CMR, (2) having an ICD, or (3) having a pacemaker.

Dosage modification and scheduled dose titration. Patients randomly assigned to receive afecontan may receive up to four escalating doses of afecontan during the first 6 weeks of the trial, as shown in Table 29 and Figure 43. The starting dose for patients receiving afecontan is 5 mg once daily (dose 1), and may be escalated to 10 mg, 15 mg, and 20 mg once daily as escalation criteria are met, or the current dose will be discontinued if escalation criteria are not met.

Table 29: Echocardiographic standards for predetermined dose titration

^Once the patient's afecontan dose is titrated down, no further increases are permitted. If the LVEF is < 50% at 5 mg, the patient will receive a placebo.

Following randomization, each patient received dose 1 (5 mg) once daily for two weeks. At the week 2 visit, patients underwent echocardiography 2 hours after administration of their afecontan dose. Patients were titrated up to dose 2 (10 mg) if the echocardiogram met the following criteria: LVOT-G ≥30 mmHg after the Warburg maneuver and biplane LVEF ≥55%. Otherwise, patients continued with dose 1 unless IWRS assigned them to placebo if their LVEF at week 2 was <50%.

Two weeks after the assigned dose, at the week 4 visit, each patient underwent echocardiography 2 hours after administration of their afecontan dose. If the echocardiogram met the following criteria, the patient was titrated up to the next higher dose: LVOT-G ≥30 mmHg after the Warburg maneuver and biplane LVEF ≥55%. Otherwise, the patient continued to receive the same dose unless the IWRS reassigned the patient to the previous dose level if the LVEF at week 4 was <50%, or to placebo if the patient was already on dose 1.

Two weeks after the assigned dose, at the week 6 visit, each patient underwent echocardiography 2 hours after administration of their afecontan dose. If the echocardiogram met the following criteria, the patient was titrated up to the next higher dose: LVOT-G ≥30 mmHg after the Warburg maneuver and biplane LVEF ≥55%. Otherwise, the patient continued to receive the same dose unless the IWRS reassigned the patient to the previous dose level if the LVEF at week 6 was <50%, or to placebo if the patient was already on dose 1.

Two weeks after the assigned dose, at the week 8 visit, each patient underwent echocardiography 2 hours after administration of their afecontan dose to ensure LVEF ≥50%. If LVEF <50% at week 8, the IWRS will assign the patient to the next lower dose, or, if the patient is taking dose 1, to placebo.

No further dose escalations are permitted after week 6. During the study, dose reductions may be made at scheduled or unscheduled visits for safety reasons. Dose reductions are determined using the IWRS system based on echocardiographic results. After week 8, dose reductions are based on echocardiographic results from the initial scheduled or unscheduled visit. If LVEF <50%, the IWRS will assign the patient to the next lower dose, or placebo if the patient is already taking dose 1. The IWRS will not further reduce the dose for at least 7 days after a previous reduction.

Cardiopulmonary exercise testing (CPET). All patients undergo CPET and gas exchange analysis, and the methodology will be standardized at all participating sites as described in the CPET manual. The test involves continuous ECG monitoring by trained personnel and is conducted in an area equipped with cardiopulmonary resuscitation equipment. A treadmill is the preferred mode of exercise testing. For CPET laboratories that do not perform treadmill testing, a stationary bike is an acceptable alternative. Exercise protocols for both modes are provided in the CPET manual. Patients must use the same testing mode for all exercise tests during the trial period. Whenever possible, CPET is administered by the same trial personnel using the same equipment and is performed after other trial procedures (including echocardiography, KCCQ, EQ-5D-5L, CGI, PGI-C, NYHA Class, SAQ-7, vital signs, ECG, blood sampling, and IP administration) on the day of the visit. Patients who have not undergone an exercise protocol during screening will become familiar with the technique.

All CPET tests are symptom-limited and patients will be strongly encouraged to achieve maximal effort and a response rate (RER) ≥1.05. The reason for terminating submaximal motor tests will be documented. If the RER ≥1.05, the test will be identified as maximal effort.

Week 24 CPET should be performed at screening at approximately the same time of day as baseline CPET (e.g., morning, noon, afternoon), consistent with the timing of the last dose of beta-blocker and IP. Whenever possible, patients should undergo exercise testing between 3 and 10 hours after taking the beta-blocker.

If investigators identify a life-threatening arrhythmia, early ischemia, severe hypotension, or other serious findings during CPET, the patient will be asked to stop the exercise test and their physician will be notified of the results. If the patient is undergoing a screening test, they will not be randomized to the trial. Enrolled patients with non-life-threatening events or findings that necessitate stopping the test may resume testing when it is safe and after appropriate treatment, depending on the investigator's assessment.

Echocardiography. Echocardiography was performed during screening and before day 1 of administration. Echocardiography was also performed at weeks 2, 4, 6, 8, 12, 16, 20, 24, and 28, and 2 hours after outpatient administration.

Certified ultrasound technicians will perform echocardiography using standard, high-quality, high-fidelity equipment. Whenever possible, the same ultrasound technician will perform all studies on a single patient. Echocardiography will be performed according to the echocardiography manual after the patient has been supine and resting for at least 10 minutes. The echocardiography manual will also include instructions for performing the Valsalva maneuver and for LVOT-G imaging.

When echocardiography is scheduled concurrently with blood tests, vital signs, and/or ECG, the evaluation order will be: vital signs, ECG, blood test, and echocardiography. Blood tests should be performed at the scheduled time, followed by echocardiography.

In addition to the right ventricular function measurements detailed in the echocardiography protocol, the echocardiographic parameters to be measured include at least the left ventricular parameters (resting left ventricular outflow tract pressure gradient (LVOT-G), LVOT-G after Warburg action, LVEF, LVFS, global longitudinal strain (GLS), left ventricular end-diastolic diameter (LVEDD), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic diameter (LVESD), left ventricular end-systolic volume (LVESV), left ventricular cardiac output (LVCO), LV stroke volume, LVOT velocity interval (VTI), interventricular septal thickness (IVST), isovolumetric contraction time (IVCT), IVRT, E/E ratio (interventricular septum and lateral), and left atrial volume (LAV)).

Unscheduled echocardiograms may be obtained when clinically indicated, for example, to assess adverse events (AEs) or to follow up on clinically significant changes in previous echocardiograms, as determined by the investigator. Results will be interpreted by an unblinded ultrasound cardiologist at the study site.

All echocardiograms (including unscheduled ones) will be sent to the core laboratory for interpretation. Field interpretation of LVEF and LVOT-G will be used for dose escalation and reduction decisions via IWRS. Core laboratory quantification of echocardiograms will be used for all statistical analyses.

Cardiac magnetic resonance imaging (CMR). The CMR imaging sub-study will evaluate the effects of afencontan doses on cardiac morphology, function, and fibrosis in approximately 40 eligible and consenting oHCM patients. CMR will be performed during the screening period and week 24. Non-contrast CMR may be performed in patients with eGFR <30 mL/min/1.73 m2 or those hypersensitive to gadolinium.

Baseline characteristics: 282 patients were included. Patient baseline characteristics are shown in Table 30. The mean (SD) age was 59.1 (12.94) years, 40.1% were female, and 22% were non-white. Baseline New York Heart Association functional categories were: Category II, 203 patients (72%); Category III, 67 patients (23.8%); and Category IV, 1 patient (0.4%). More than half of the patients (172; 68%) were taking beta-blockers. The mean baseline pVO2 was 18.5 (SD 4.5) mL/kg/min or 57.1% of the predicted maximum, and the mean Kansas City Cardiomyopathy Questionnaire clinical symptom score was 74.7 (SD 18.1). The geometric mean high-sensitivity troponin I was 16.9 (7.7, 27.2) ng/L. Left ventricular ejection fraction, LVOT-G, and N-terminal pro-brain natriuretic peptide were all blinded.

Table 30: Baseline Characteristics

Example 6

The polymorphs of afencontin, forms I, II, III, IV, V, and VI, were characterized by various analytical techniques, including XRPD, DSC, TGA, and DVS, as described in WO 2021/011807.

Claims (126)

1. A method for treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need, the method comprising administering a therapeutically effective amount of afecontan to the patient. (Aficanthan) Or a pharmaceutically acceptable salt thereof, wherein the patient has been diagnosed with oHCM within 12 months prior to administration of afencontan or a pharmaceutically acceptable salt thereof. 2. A method for treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need, the method comprising administering a therapeutically effective amount of afecontan to the patient. (Aficanthan) 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 afencontan or a pharmaceutically acceptable salt thereof as a monotherapy for oHCM. 4. A method for treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need, the method comprising administering a therapeutically effective amount of afecontan to the patient. (Aficanthan) Or a pharmaceutically acceptable salt thereof as a monotherapy for oHCM, wherein the patient has chronic oHCM and has previously received standard medical care for oHCM and has discontinued said therapy prior to administration of afencontin or a pharmaceutically acceptable salt thereof. 5. The method of claim 4, wherein the standard medical therapy of care comprises treatment with one or more therapeutic agents selected from beta-blockers, calcium channel blockers, and disopyramide. 6. The method of any one of claims 1-5, wherein the patient has ≥ 60% LVEF prior to administration of afecontan 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 afecontan or a pharmaceutically acceptable salt thereof. 8. The method of any one of claims 1-7, wherein the patient has a Valsalva maneuver of ≥50 mmHg before administration of afencontin or a pharmaceutically acceptable salt thereof. 9. The method of any one of claims 1-8, wherein the patient is characterized as NYHA class II or III prior to administration of afecontan or a pharmaceutically acceptable salt thereof. 10. The method of any one of claims 1-9, wherein the method improves one or more of the following: exercise capacity; cardiac function as measured by improvement in NYHA functional classification; resting LVOT-G; post-Varva maneuver LVOT-G; health status as measured by the Kansas City Cardiomyopathy Questionnaire Clinical Roundup Score (KCCQ-CSS); structural remodeling as measured by 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; and lateral E /e's reduced diastolic function; ventricular septal thickness remodeling as measured by changes in ventricular septal thickness (IVST); CPET parameters selected from the following: ventilation efficiency/carbon dioxide production (VE/VCO2 slope), circulatory power (VO2 × systolic blood pressure), ventilatory anaerobic threshold (VAT), total workload (watts), and heart rate response; and health status and health-related quality of life as measured by the EuroQol 5-dimensional 5-level tool (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 results are improved compared to treatment with metoprolol. 12. The method of any one of claims 10 or 11, wherein the method improves exercise capacity, such as by increasing the peak oxygen uptake (pVO2) measured according to a cardiopulmonary exercise test (CPET). 13. The method of any one of claims 10-12, wherein the method improves cardiac function, as measured by 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 athletic performance, as measured by an increase of at least 1.5 mL/kg/min in pVO2 compared to baseline and an improvement in at least one NYHA functional category. 15. The method of any one of claims 10-13, wherein the method improves athletic performance, as measured by an increase of at least 3.0 mL/kg/min in pVO2 compared to baseline and no deterioration in 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 Valsalva maneuver-followed LVOT-G of less than 50 mmHg, and NYHA category I. 17. The method of any one of claims 10-13, wherein the method produces an improvement in resting LVOT-G of less than 30 mmHg, post-Valveolar LVOT-G of less than 50 mmHg, and at least one NYHA functional category. 18. The method of any one of claims 10-17, wherein the method improves health conditions, as measured by the Kansas City Cardiomyopathy Questionnaire Clinical Roundup 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 the 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 the 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 septal thickness remodeling, as measured by changes in ventricular septal thickness (IVST). 25. The method of any one of claims 10-24, wherein the method improves one or more CPET parameters selected from the following: ventilation efficiency/carbon dioxide production (VE/VCO2 slope), cycle power (VO2 × systolic blood pressure), ventilation 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 EuroQol 5-dimensional 5-level tool (EQ-5D-5L), Clinical Global Impression (CGI), Patient Global Impression (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 afecontan or a pharmaceutically acceptable salt thereof is selected by instilling a daily dose of afecontan or a pharmaceutically acceptable salt thereof onto 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 the course of treatment. 30. The method of any one of claims 27-29, wherein the daily dose is administered to the patient at a constant amount for about two weeks prior to titration of the daily dose. 31. The method of any one of claims 1-30, wherein afencontan or a pharmaceutically acceptable salt thereof is administered at 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 1-32, wherein the method comprises: The patient was administered a first-day dose of afencontan or a pharmaceutically acceptable salt thereof, for the first time period; and Based on one or more components of the first echocardiogram of the patient obtained after the first time period, the patient is given a second-day dose of afecontan or a pharmaceutically acceptable salt thereof for the second time period, or the administration of afecontan or a pharmaceutically acceptable salt thereof to the patient is terminated. 34. The method of claim 33, further comprising measuring 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 post-Varva action LVOT-G. 36. The method of any one of claims 33-35, further comprising selecting a second daily dose of afencontan or a pharmaceutically acceptable salt thereof based on 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 biplane LVEF, and when the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold, the second day dose of afencontan or a pharmaceutically acceptable salt thereof is lower than the first day dose of afencontan 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 biplane LVEF, and when the biplane LVEF of the first echocardiogram is equal to or higher than the predetermined biplane LVEF threshold and lower than the second predetermined biplane LVEF threshold, the second day dose of afecontan or a pharmaceutically acceptable salt thereof is the same as the first day dose of afecontan 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-Warshall action LVOT-G, and wherein the second day dose of afecontan or a pharmaceutically acceptable salt thereof is the same as the first day dose of afecontan or a pharmaceutically acceptable salt thereof when: (i) the biplane LVEF of the first echocardiogram is equal to or higher than a second predetermined biplane LVEF threshold and (ii) the post-Warshall action LVOT-G of the first echocardiogram is lower than a predetermined post-Warshall action 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 post-Warshall action LVOT-G, and wherein the second day dose of afecontan or a pharmaceutically acceptable salt thereof is greater than the first day dose of afecontan or a pharmaceutically acceptable salt thereof when: (i) the biplane LVEF is equal to or greater than the second predetermined biplane LVEF threshold and (ii) the post-Warshall action LVOT-G is equal to or greater than the predetermined post-Warshall action LVOT-G threshold. 41. The method of any one of claims 33-40, wherein the first day dose of afecontan or a pharmaceutically acceptable salt thereof is about 5 mg of afecontan, and the second day dose of afecontan or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg of afecontan. 42. The method of any one of claims 33-41, wherein: (i) the first time period is about 2 weeks, (ii) the second time period is about 2 weeks, or (iii) the first time period is about 2 weeks and the second time period 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 biplane LVEF, and when the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold, the administration of afecontan or a pharmaceutically acceptable salt thereof to the patient is terminated. 44. The method of claim 43, wherein the first daily dose of afecontan or a pharmaceutically acceptable salt thereof is about 5 mg of afecontan. 45. The method of claim 43 or 44, wherein the first period is approximately 2 weeks. 46. The method of any one of claims 33-42, wherein the administration of the second day dose of afecontan or a pharmaceutically acceptable salt thereof to the patient continues for the second time period, the method further comprising administering a third day dose of afecontan or a pharmaceutically acceptable salt thereof to the patient for the third time period, or terminating the administration of afecontan or a pharmaceutically acceptable salt thereof to the patient based on: (i) one or more portions of a second echocardiogram of the patient obtained after the second time period, and (ii) the second day dose of afecontan or a pharmaceutically acceptable salt thereof. 47. The method of claim 46, further comprising measuring 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 the Valsalva maneuver. 49. The method of any one of claims 46-48, further comprising the third day dose based on (i) the one or more components of the second echocardiogram and (ii) the second day dose selection of afecontan or a pharmaceutically acceptable salt thereof. 50. The method of any one of claims 46-49, wherein the one or more components of the second echocardiogram comprise biplane LVEF, and the third day dose of afecontan or a pharmaceutically acceptable salt of afecontan is lower than the second day dose of afecontan or a pharmaceutically acceptable salt of afecontan when: (i) the biplane LVEF of the second echocardiogram is below the predetermined biplane LVEF threshold and (ii) the second day dose of afecontan or a pharmaceutically acceptable salt of afecontan is higher than the first day dose of afecontan or a pharmaceutically acceptable salt of afecontan. 51. The method of claim 50, wherein the third-day dose of afecontan or a pharmaceutically acceptable salt thereof is the same as the first-day dose of afecontan 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 biplane LVEF, and wherein when the biplane LVEF of the second echocardiogram is equal to or higher than the predetermined biplane LVEF threshold and lower than the second predetermined biplane LVEF threshold, the third-day dose of afecontan or a pharmaceutically acceptable salt thereof is the same as the second-day dose of afecontan or a pharmaceutically acceptable salt thereof. 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-Warshall action LVOT-G, and wherein the third-day dose of afecontan or a pharmaceutically acceptable salt thereof is the same as the second-day dose of afecontan or a pharmaceutically acceptable salt thereof when: (i) the biplane LVEF of the second echocardiogram is equal to or higher than the second predetermined biplane LVEF threshold and (ii) the post-Warshall action LVOT-G of the second echocardiogram is lower than the predetermined post-Warshall action 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-Warshall action LVOT-G, and wherein the third-day dose of afecontan or a pharmaceutically acceptable salt thereof is greater than the second-day dose of afecontan or a pharmaceutically acceptable salt thereof when: (i) the biplane LVEF is equal to or greater than the second predetermined biplane LVEF threshold and (ii) the post-Warshall action LVOT-G is equal to or greater than the predetermined post-Warshall action LVOT-G threshold. 55. The method of any one of claims 46-54, wherein the first day dose of afecontan or a pharmaceutically acceptable salt thereof is about 5 mg of afecontan, the second day dose of afecontan or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg of afecontan, and the third day dose of afecontan or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, or about 15 mg of afecontan. 56. The method of any one of claims 46-55, wherein the third time period is approximately 2 weeks. 57. The method of any one of claims 46-48, wherein the one or more components of the second echocardiogram comprise biplane LVEF, and the administration of afecontan or a pharmaceutically acceptable salt 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 day dose of afecontan or a pharmaceutically acceptable salt thereof is the same as the first day dose of afecontan or a pharmaceutically acceptable salt thereof. 58. The method of any one of claims 46-56, wherein the administration of the third-day dose of afecontan or a pharmaceutically acceptable salt thereof to the patient continues for the third time period, the method further comprising administering a fourth-day dose of afecontan or a pharmaceutically acceptable salt thereof to the patient for the fourth time period, or terminating the administration of afecontan or a pharmaceutically acceptable salt thereof to the patient based on: (i) one or more portions of a third echocardiogram of the patient obtained after the third time period, and (ii) the third-day dose of afecontan or a pharmaceutically acceptable salt thereof. 59. The method of claim 58, further comprising measuring 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 the Valsalva maneuver. 61. The method of claim 58, further comprising selecting a fourth-day dose of afencontan or a pharmaceutically acceptable salt thereof based on (i) the one or more components of the third echocardiogram and (ii) the third-day dose. 62. The method of any one of claims 58-61, wherein the one or more components of the third echocardiogram comprise biplane LVEF, and the fourth day dose of afecontan or a pharmaceutically acceptable salt of afecontan is lower than the third day dose of afecontan or a pharmaceutically acceptable salt of afecontan when: (i) the biplane LVEF of the third echocardiogram is below the predetermined biplane LVEF threshold and (ii) the third day dose of afecontan or a pharmaceutically acceptable salt of afecontan is higher than the first day dose of afecontan or a pharmaceutically acceptable salt of afecontan. 63. The method of any one of claims 58-61, wherein the one or more components of the third echocardiogram comprise biplane LVEF, and wherein when the biplane LVEF of the second echocardiogram is equal to or higher than the predetermined biplane LVEF threshold and lower than the second predetermined biplane LVEF threshold, the fourth-day dose of afecontan or a pharmaceutically acceptable salt thereof is the same as the third-day dose of afecontan or a pharmaceutically acceptable salt thereof. 64. The method of any one of claims 58-61, wherein the one or more components of the third echocardiogram comprise biplane LVEF and post-Valveolar action LVOT-G, and wherein the fourth-day dose of afecontan or a pharmaceutically acceptable salt thereof is the same as the third-day dose of afecontan or a pharmaceutically acceptable salt thereof when: (i) the biplane LVEF of the third echocardiogram is equal to or higher than the second predetermined biplane LVEF threshold and (ii) the post-Valveolar action LVOT-G of the third echocardiogram is lower than 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-Warshall action LVOT-G, and wherein the fourth-day dose of afecontan or a pharmaceutically acceptable salt thereof is greater than the third-day dose of afecontan or a pharmaceutically acceptable salt thereof when: (i) the biplane LVEF of the third echocardiogram is equal to or greater than the second predetermined biplane LVEF threshold and (ii) the post-Warshall action LVOT-G of the third echocardiogram is equal to or greater than the predetermined post-Warshall action LVOT-G threshold. 66. The method of any one of claims 58-65, wherein the first day dose of afecontan or a pharmaceutically acceptable salt thereof is about 5 mg of afecontan, the second day dose of afecontan or a pharmaceutically acceptable salt thereof is about 5 mg or about 10 mg of afecontan, the third day dose of afecontan or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg or about 15 mg of afecontan, and the fourth day dose of afecontan or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, about 15 mg or about 20 mg of afecontan. 67. The method of any one of claims 58-66, wherein the fourth period is approximately 2 weeks. 68. The method of any one of claims 58-60, wherein the one or more components of the third echocardiogram comprise biplane LVEF, and the administration of afecontan or a pharmaceutically acceptable salt 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-day dose of afecontan or a pharmaceutically acceptable salt thereof is the same as the first-day dose of afecontan 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 dual-plane LVEF threshold is 50%, and the predetermined LVOT-G threshold after the Valsalva maneuver is 30 mmHg; (d) The second predetermined biplane LVEF threshold is 55%, and the predetermined LVOT-G threshold after the Valsalva maneuver is 30 mmHg; or (c) The predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the predetermined LVOT-G threshold after the Valsalva maneuver is 30 mmHg. 70. A method for treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need, wherein the patient is receiving one or more background therapies for oHCM, the method comprising (1) administering a therapeutically effective amount of afecontan to the patient. (Aficanthan) (2) or a pharmaceutically acceptable salt thereof, and (3) reduce and/or discontinue at least one background therapy. 71. The method of claim 70, wherein the method includes reducing at least one background therapy. 72. The method of claim 70 or 71, wherein the method includes stopping 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 β-blockers, non-dihydropyridine calcium channel blockers, 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 stopped. 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 the at least one background therapy is reduced and/or discontinued after the administration of afencontan or a pharmaceutically acceptable salt thereof is initiated. 79. The method of any one of claims 70-77, wherein the at least one background therapy is reduced and/or discontinued two weeks or more after the initiation of administration of afencontan or a pharmaceutically acceptable salt thereof. 80. The method of any one of claims 70-77, wherein the at least one background therapy is reduced and/or discontinued 12 weeks or longer after the initiation of afencontan or a pharmaceutically acceptable salt thereof. 81. The method of any one of claims 70-77, wherein the at least one background therapy is reduced and/or discontinued when the patient has been receiving a stable dose of afencontan or a pharmaceutically acceptable salt thereof for 2 weeks or longer. 82. The method of any one of claims 70-77, wherein the at least one background therapy is reduced and/or discontinued when the patient has been receiving a stable dose of afencontan or a pharmaceutically acceptable salt thereof for 4 weeks or longer. 83. The method of any one of claims 70-82, wherein one, two, or three background therapies for oHCM are administered to the patient. 84. The method of any one of claims 70-83, wherein administration of one or more of a β-blocker, a non-dihydropyridine calcium channel blocker, and disopyramide to the patient is a background therapy. 85. The method of any one of claims 70-84, wherein the therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof is selected by instilling a daily dose of afecontan or a pharmaceutically acceptable salt thereof onto the patient. 86. The method of claim 85, wherein the dose is titrated once during the course of treatment. 87. The method of claim 85, wherein the dose is titrated two or more times during the course of treatment. 88. The method of any one of claims 70-87, wherein, prior to titrating the daily dose, the daily dose of afencontan or a pharmaceutically acceptable salt thereof is administered to the patient at a constant amount for about two weeks. 89. The method of any one of claims 70-88, wherein afecontan or a pharmaceutically acceptable salt thereof is administered at 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 for treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in patients of need, the method comprising: (1) Administer a therapeutically effective dose of afecontan to the patient. (Aficanthan) Or a pharmaceutically acceptable saline and a first dose of oHCM standard of care, continued for the first period of time; and (2) Administer to the patient a therapeutically effective dose of afencontan or a pharmaceutically acceptable saline thereof, along with a second dose of oHCM, as part of the standard of care regimen, for a second period of time. The second dose of the standard care treatment agent for oHCM is lower than the first dose of the standard care treatment agent. 92. The method of claim 91, wherein the second dose of the standard care agent of oHCM is 50% or less of the first dose of the standard care agent. 93. A method for treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in patients of need, the method comprising: (1) Administer a therapeutically effective dose of afecontan to the patient. (Aficanthan) Or a pharmaceutically acceptable saline and standard of care for oHCM, continued for the first period; and (2) Administer a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof to the patient as a single therapy for a second period. 94. The method of any one of claims 91-93, wherein the patient in need has received the standard treatment of oHCM prior to administration of afecontan. 95. A method for treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in patients of need, the method comprising: (1) Background therapy administered to the patient consisting of at least one group of a beta-blocker, a non-dihydropyridine calcium channel blocker and disopyramide; (2) Administer a therapeutically effective dose of afecontan to the patient. (Aficanthan) Or a pharmaceutically acceptable salt thereof, along with the aforementioned background therapy, continued for the first period; and (3) Administer to the patient a therapeutically effective dose of afencontan or a pharmaceutically acceptable saline thereof, along with a second dose of oHCM, as part of the standard of care regimen, for a second period of time. The second dose of the standard care treatment agent for oHCM is lower than the first dose of the standard care treatment agent. 96. The method of claim 95, wherein the second dose of the standard care agent of oHCM is 50% or less of the first dose of the standard care agent. 97. A method for treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in patients of need, the method comprising: (1) Background therapy administered to the patient consisting of at least one group of a beta-blocker, a non-dihydropyridine calcium channel blocker and disopyramide; (2) Administer a therapeutically effective dose of afecontan to the patient. (Aficanthan) Or a pharmaceutically acceptable salt thereof, along with the aforementioned background therapy, continued for the first period; and (3) Administer a therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof to the patient as a single therapy for a second period. 98. The method of any one of claims 91-97, wherein the first time period is at least 12 weeks. 99. The method of any one of claims 91-98, wherein the therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof is selected by instilling a daily dose of afecontan or a pharmaceutically acceptable salt thereof onto the patient. 100. The method of any one of claims 91-99, wherein afencontan or a pharmaceutically acceptable salt thereof is administered at a constant amount for at least 4 weeks prior to the start of the second time period. 101. The method of claim 100, wherein the dose is titrated once during the course of treatment. 102. The method of claim 100, wherein the dose is titrated two or more times during the course of treatment. 103. The method of any one of claims 99-102, wherein, prior to titrating the daily dose, the daily dose of afencontan or a pharmaceutically acceptable salt thereof is administered to the patient at a constant amount for about two weeks. 104. The method of any one of claims 91-103, wherein afecontan or a pharmaceutically acceptable salt thereof is administered at 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 for improving myocardial mechanics in a patient in need, the method comprising administering a therapeutically effective amount of afecontan to the patient. (Afencontan) or a pharmaceutically acceptable salt thereof, wherein the patient has obstructive hypertrophic cardiomyopathy (oHCM). 107. A method for improving global longitudinal strain (GLS) in a patient in need, the method comprising administering a therapeutically effective amount of afencontan to the patient. (Aficanthan) Or a pharmaceutically acceptable salt thereof, wherein the patient has obstructive hypertrophic cardiomyopathy (oHCM). 108. The method of claim 106 or 107, wherein the therapeutically effective amount of afecontan or a pharmaceutically acceptable salt thereof is selected by instilling a daily dose of afecontan or a pharmaceutically acceptable salt thereof onto the patient. 109. The method of claim 108, wherein the dose is titrated once during the course of treatment. 110. The method of claim 108, wherein the dose is titrated two or more times during the course of treatment. 111. The method of any one of claims 106-110, wherein afecontan or a pharmaceutically acceptable salt thereof is administered at 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 afecontan 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 afecontan 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 afecontan 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 afecontan 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 Valverde motion 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 due to treatment with afencontan 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 of less than 50 mmHg due to treatment with afencontin 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 afencontan or a pharmaceutically acceptable salt thereof. 122. The method of any one of claims 1-121, wherein the afecontan or a pharmaceutically acceptable salt thereof is administered orally. 123. The method of claim 122, wherein the afecontan 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% by weight to about 50% by weight of the afecontan or a pharmaceutically acceptable salt thereof; (ii-1) Mannitol, about 10% by weight to about 60% by weight; (ii-2) Approximately 5% to approximately 45% by weight of microcrystalline cellulose; (iii) About 0.1% by weight to about 10% by weight of hydroxypropyl cellulose; (iv) about 1% to about 10% by weight of croscarmellose sodium; (v) Sodium dodecyl sulfate, about 0.1% by weight to about 10% by weight; and (vi) Magnesium stearate, about 0.1% by weight to about 10% by weight, The weight percentage mentioned above does not include the weight of any coating that may be present. 126. The method of any one of claims 1-125, wherein the afecontan or a pharmaceutically acceptable salt thereof comprises one or more of the polymorphic forms I, II, III, IV, V and VI of afecontan.