Treatment of Cushing's syndrome without significant impact on cardiac rhythm

Abstract

Applicants disclose methods, uses, and compositions for treating patients suffering from Cushing Syndrome or Cushing Disease (collectively referred to as' CS ') without causing a significant QT interval extension (e.g., the difference of the QT interval after administration from the baseline QT interval by no more than about 10 milliseconds). The therapeutic amount of the heteroaryl ketone fused aza-naphthane compound may be from about 50 mg / day (mg / day) to up to about 500 mg / day, in embodiments, up to about 800 mg / day. The methods, uses, and compositions can shorten QT intervals, and can be used to treat QT prolongation in patients, including CS patients. The treatment may be a treatment administered orally to a fasting patient or an eating patient. The heteroaryl ketone fused aza-naphthane compounds can be administered with meals. The heteroaryl ketone fused aza-naphthane compound may be reracolan, which is (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl) sulfonyl)-4, 4a, 5, 6, 7, 8-hexahydro-1H-pyrazolo [3, 4-g] isoquinolin-4a-yl) (4-(trifluoromethyl) pyridin-2-yl) methanone having the following structure (I) # imgabs 0 #

Description

Background Art

[0001] A healthy heart and healthy heart rhythm are crucial for an individual's health. The electronic measurement of the heart rhythm is called an electrocardiogram (ECG). The ECG measurement of heart activity includes measuring the time intervals between significant ECG features detected by the ECG. The significant features of the ECG include the P wave, QRS complex, and T wave. The time interval between the start of the "QRS" complex and the end of the "T" wave is called the "QT" interval. In healthy individuals, the "QT interval" is approximately 400 milliseconds (ms) (usually between about 350 ms and 450 ms). A QT interval greater than about 450 ms in men or greater than about 460 ms in women is considered a prolonged QT interval, which may indicate an increased risk of arrhythmia, including the potentially fatal torsades de pointes ventricular tachycardia.

[0002] Patients with a prolonged QT interval are at a greater risk of syncope, seizures, atrial fibrillation, ventricular tachycardia, stroke, and even sudden death (A1-Khatib et al., JAMA 289(16):2120-2127(2003); Soliman et al., Journal of the American College of Cardiology 59(16):1460-1467(2012)). Drug-induced QT interval prolongation is a risk factor for cardiovascular complications, including torsades de pointes ventricular tachycardia, ventricular tachycardia, stroke, and cardiac arrest (van Noord et al., Br J Clin Pharmacol. 2010;70(1):16-23; Roden DM. N Engl J Med. 2004;350(10):1013-1022; Raj et al., Circulation. 2009;120(12):1123-1132.). Therefore, regulatory agencies recommend a comprehensive assessment of the QT interval prolongation and proarrhythmic potential of all new candidate drugs.

[0003] Cortisol is a steroid hormone secreted by the adrenal gland under the action of adrenocorticotropic hormone (ACTH). Cortisol action requires cortisol to bind to the glucocorticoid receptor (GR). Cushing's syndrome and Cushing's disease (collectively referred to as "CS") are conditions caused by cortisol excess. Such cortisol excess can be caused by any of a variety of possible causes, including excessive ACTH release by the pituitary gland, excessive cortisol secretion by the adrenal gland, or cortisol or ACTH secretion by a tumor. Long-term or excessive administration of glucocorticoids, such as dexamethasone, prednisone, etc. (which act similarly to cortisol) can also lead to CS.

[0004] Compounds that modulate or affect the binding of cortisol to GR are called GR modulators (GRMs); GRMs that selectively modulate GR are called selective GRMs (SGRMs). Pharmaceutical treatments for CS include GRMs and SGRMs (e.g., mifepristone); drugs that affect cortisol production (e.g., ketoconazole, levoketoconazole, and osilodrostat); and drugs that affect adrenocorticotropic hormone (ACTH) levels (e.g., pasireotide). However, to date, most drugs approved or widely used to treat CS are associated with QT interval prolongation, including pasireotide (Colao et al., N Engl J Med. 2012;366(10):914 - 924), osilodrostat (Fleseriu et al., Pituitary. 2016;19(2):138 - 148), levoketoconazole (Fleseriu et al., Lancet Diabetes Endocrinol. 2019;7(11):855 - 865), and other drugs. Such QT interval prolongation can have very serious adverse effects on patients.

[0005] Studies have found that the QT interval in male CS patients is greater than that in the matched control group of healthy male subjects (this difference is statistically significant; see Giraldi et al., Exp Clin Endocrinol Diabetes 2011, 119(4):221 - 224). There is no difference between female CS patients and the matched control group of healthy female subjects (Giraldi et al.). Thus, while both male and female CS patients receiving any of the above CS drug treatments may be at risk of QT interval changes due to the drug treatment, male CS patients who are already at risk of abnormal QT intervals may be at a greater risk of arrhythmia than female CS patients receiving these drug treatments. Currently, the need for safe CS drugs that do not have an adverse effect on the heart rhythm, including drugs that do not cause QT prolongation (which can lead to fatal arrhythmias), is unmet. Therefore, to reduce the risk of arrhythmia and its associated adverse reactions, improved treatment methods and compositions for CS patients are needed that do not affect the QT interval. Summary of the Invention

[0006] QT interval prolongation is a serious side effect of previous CS drug treatments; QT interval prolongation increases the risk of serious arrhythmias in patients, leading to an increased risk of heart attack, stroke, and sudden death, which is one of the many potentially harmful side effects of QT interval prolongation.

[0007] The present disclosure relates to a novel method for treating Cushing's syndrome and Cushing's disease (collectively referred to as "CS") without causing significant QT interval prolongation and arrhythmia. The method includes administering to a subject an effective amount of a heteroaryl ketone-fused naphthyridine compound that modulates GR. The heteroaryl ketone-fused naphthyridine compound is disclosed in U.S. Patent 8,859,774, the entire content of which is incorporated herein by reference.

[0008] In an embodiment, the applicant discloses a method for treating a patient with CS without significantly prolonging the QT interval or QTc interval, which includes:

[0009] administering an effective amount of a heteroaryl ketone-fused naphthyridine compound,

[0010] wherein the treatment does not significantly prolong QT or QTc measured by electrocardiogram (ECG), where QT is the duration of the time interval between the start of the QRS complex of the ECG and the end of the T wave of the ECG, and where QTc is the QT interval corrected for heart rate,

[0011] thereby treating Cushing's syndrome or Cushing's disease without significantly prolonging the QT interval. In an embodiment, the heteroaryl ketone-fused naphthyridine compound is GRM, and in a further embodiment, the heteroaryl ketone-fused naphthyridine compound is SGRM, such as relacorilant. Relacorilant is ((R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, which has the following structure:

[0012]

[0013] In an embodiment, GRM (e.g., SGRM, such as relacorilant) is administered orally. In an embodiment, GRM or SGRM can be administered by injection, infusion, transdermal administration, or other means or routes of administration. In an embodiment, GRM or SGRM (e.g., relacorilant) can be administered with food, or with water, or with both food and water. In other embodiments, GRM or SGRM (e.g., relacorilant) can be administered in the absence of food.

[0014] Currently, the need for safe CS drugs that do not cause QT prolongation and potentially fatal arrhythmias remains unmet. Based on current clinical study results in healthy volunteers and CS patients, ranucicliban is not associated with QT interval prolongation. Heteroaryl ketone-fused phenanthridine compounds (such as ranucicliban) are considered to meet this need. In addition to not causing QT interval prolongation, safe CS drugs are also needed to shorten the QT interval in patients in need (including CS patients with QT interval prolongation). Heteroaryl ketone-fused phenanthridine compounds (such as ranucicliban) are also considered to meet this need.

[0015] Accordingly, the present method provides an improved method for treating and reducing QT interval prolongation in patients in need thereof. Accordingly, the present method provides an improved method for treating CS patients, which, unlike existing treatment methods, does not significantly prolong the cardiac QT interval and does not significantly increase the risk of arrhythmia, torsades de pointes, sudden death, stroke, and other cardiovascular diseases in CS patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 A schematic diagram of the study protocol is shown.

[0017] Figure 2A Shows the predicted changes in geometric mean QTc in subjects receiving 50 milligrams (mg), 150 mg, 250 mg, and 500 mg doses of ranucicliban in a single ascending dose (SAD) study. The dots with bars show the mean QTc values at C 最大 (time of highest ranucicliban plasma concentration) for each dose ± 90% confidence intervals (CI) of these points; the line connecting these geometric means represents the predicted mean ΔΔQTcF, and the band around the line represents the 90% CI of this predicted value. For doses of 50, 150, 250, and 500 mg, the placebo-corrected predicted change in QTc is less than 5 milliseconds (ms). Colored markers and error bars: Predicted mean (90% CI) ΔΔQTcF at the observed geometric mean highest concentration of ranucicliban (C 最大 ). Dashed line: 10-ms ΔΔQTcF action threshold. Solid line and gray shaded area: Predicted mean ΔΔQTcF and its 90% CI. CI, confidence interval. SAD formula: ΔΔQTcF = -0.005 (milliseconds) - 0.588 (milliseconds / ng / mL) × ranucicliban concentration (ng / mL). Abbreviations (throughout this application): ΔΔQTcF = change in placebo-corrected baseline QTcF; CI = confidence interval; C 最大 = maximum concentration; LS = least squares; MAD = multiple ascending doses; SAD = single ascending dose; QTcF = QT interval corrected for heart rate using the Fridericia formula.

[0018] Figure 2B Shows the predicted changes in geometric mean QTc in a multiple ascending dose (MAD) study in subjects receiving 50 milligrams (mg), 150 mg, 250 mg, and 500 mg doses of raloxaclam. The dots with bars show the mean QTc values at C 最大 (time of maximum raloxaclam plasma concentration) for each dose ± 90% confidence intervals (CIs) of these points; the line connecting these geometric means represents the predicted mean ΔΔQTcF, and the band around the line represents the 90% CI of this predicted value. For doses of 50, 150, 250, and 500 mg, the placebo-corrected predicted changes in QTc were less than 10 milliseconds (ms). Colored markers and error bars: Predicted mean (90% CI) ΔΔQTcF at the observed maximum geometric concentration of raloxaclam (C 最大 ). Dashed line: 10-ms ΔΔQTcF effect threshold. Solid line and gray shaded area: Predicted mean ΔΔQTcF and its 90% CI. CI, confidence interval. MAD formula: ΔΔQTcF = -1.804 (milliseconds) - 2.341 (milliseconds / ng / mL) × raloxaclam concentration (ng / mL).

[0019] Figures 3A - 3E Shows the changes in QTc within 8 hours after administration of raloxaclam. At 2 hours (C 最大 time), QTc decreased slightly. Data were from 103 healthy volunteers who received single or multiple ascending doses (SAD / MAD) of raloxaclam (up to 500 mg QD) for up to 14 days; 24 healthy volunteers received placebo. Abbreviations: ΔΔQTcF = change in placebo-corrected baseline QTcF; CI = confidence interval; LS = least squares; MAD = multiple ascending dose; SAD = single ascending dose; QTcF = QT interval corrected for heart rate using the Fridericia formula.

[0020] Figure 3A Shows the changes in QTc within 8 hours after administration of single doses of 5 mg, 15 mg, or 50 mg of raloxaclam. The doses were 5 mg (circles), 15 mg (squares), and 50 mg (triangles), respectively.

[0021] Figure 3B Shows the changes in QTc within 8 hours after administration of single doses of 150 mg, 300 mg, or 500 mg of raloxaclam. The doses were 150 mg (circles), 300 mg (squares), and 500 mg (triangles), respectively.

[0022] Figure 3CShows the change in QTc within 8 hours after the first administration of ralacorlan in a daily multi-dose regimen. The doses were 50 mg / day (circles); 150 mg / day (squares); 250 mg / day (upward triangles); and 500 mg / day (downward triangles).

[0023] Figure 3D Shows the change in QTc within 8 hours after 7 days of daily multi-dose administration of ralacorlan. The doses were 50 mg / day (circles); 150 mg / day (squares); 250 mg / day (upward triangles); and 500 mg / day (downward triangles).

[0024] Figure 3E Shows the change in QTc within 8 hours after 14 days of daily multi-dose administration of ralacorlan. The doses were 50 mg / day (circles); 150 mg / day (squares); 250 mg / day (upward triangles); and 500 mg / day (downward triangles).

[0025] Figure 4A Shows the results of the TQT study on day 1 and day 5 after administration of ralacorlan (400 mg (squares) or 800 mg (triangles)) or moxiflaxin (positive control; diamonds). Notably, after ralacorlan administration, ΔΔQTcF seems to decline over time. These results rule out an adverse effect of ralacorlan on ΔΔQTcF within 24 hours on day 1 or day 5 after ralacorlan administration. The dashed line represents the 10-millisecond ΔΔQTcF action threshold.

[0026] Figure 4B Shows as Figure 4A shown, where Figure 4B only the results of day 5 after administration of ralacorlan (400 mg (solid circles) or 800 mg (triangles)) or moxiflaxin (positive control; circles) are shown. These results rule out an adverse effect of ralacorlan on ΔΔQTcF within 24 hours on day 5 after ralacorlan administration. Baseline QTcF is the mean of data extracted from ECG recordings taken 45, 30, and 15 minutes before dosing. In Figure 4A and 4B , both the LS mean and 90% CI values are based on a linear mixed effects model, where ΔQTcF is the dependent variable, period, sequence, time, treatment, and the interaction of time and treatment are fixed effects, and baseline QTcF is a covariate. The unstructured covariance matrix failed to converge, and an autoregressive structure was used to specify the repeated measurements of each participant at post-dose time points during treatment. The dashed line represents the 10-millisecond ΔΔQTcF action threshold.

[0027] Figure 5Shows the results of the TQT study and the theoretical model, the results of which rule out the adverse effect of relacorilant on ΔΔQTcF at concentrations up to approximately 4500 ng / mL. Markers and error bars: Mean (90% CI) ΔΔQTcF estimated at the observed geometric mean maximum relacorilant concentration at the therapeutic dose (400 mg dose; square symbols) and supra-therapeutic dose (800 mg dose; triangular symbols). Dashed line: 10-ms ΔΔQTcF action threshold. Solid line and shaded area: Predicted mean ΔΔQTcF and its 90% CI, calculated from ΔΔQTcF = -1.2501 (milliseconds) - 0.97 (×10 -3 milliseconds / ng / mL) × relacorilant concentration (ng / mL). The black solid line and grey shaded area represent the model-predicted mean ΔΔQTcF and 90% CI, which are calculated from the formula ΔΔQTcF = -1.2501 (milliseconds) - 0.97 (×10 -3 milliseconds / ng / mL) × relacorilant concentration (ng / mL). The square and triangular data points and error bars represent the mean (90% CI) ΔΔQTcF estimated at the geometric mean relacorilant C 最大 at the therapeutic dose (400 mg) and supra-therapeutic dose (800 mg), respectively. The dashed line represents the 10-ms ΔΔQTcF action threshold.

[0028] Figure 6A Shows the median QTcF of CS patients treated with low-dose relacorilant (100 to 200 mg / day relacorilant). No significant change in the median QTcF was observed in the low-dose group. Data are based on the baseline median QTcF and the median QTcF at weeks 2 - 16 (95% CI) of 13 - 17 patients in the low-dose group. Baseline was defined as the mean of three readings at the last follow-up before the first dose. Low-dose relacorilant included 100 mg / day for 4 weeks; then 150 mg / day for 4 weeks; then 200 mg / day for 4 weeks. Abbreviations (throughout this application): BL = baseline; CS = Cushing's syndrome.

[0029] Figure 6B Shows the median QTcF of CS patients treated with high-dose relacorilant (250 to 400 mg / day relacorilant). No significant change in the median QTcF was observed in the high-dose group. Data are based on the baseline median QTcF and the median QTcF at weeks 2 - 16 (95% CI) of 9 - 17 patients in the high-dose group. Baseline was defined as the mean of three readings at the last follow-up before the first dose. High-dose relacorilant included 250 mg / day for 4 weeks; then 300 mg / day for 4 weeks; then 350 mg / day for 4 weeks, then 400 mg / day for 4 weeks. Abbreviations (throughout this application): BL = baseline; CS = Cushing's syndrome. Detailed implementation mode Background art

[0031] Prolongation of the QT interval is an important problem in patients with CS. Approximately one-quarter of men experience QT prolongation (Giraldi et al., Exp Clin Endocrinol Diabetes 2011; 119(4): 221-224). The greater the degree of QT interval prolongation, the greater the risk of arrhythmia events (including potentially fatal torsades de pointes ventricular tachycardia). Arrhythmia also increases the risk of heart attack, stroke, and sudden death, as well as other serious and potentially fatal cardiac and cardiovascular diseases. Compounds previously used to treat CS include levoketoconazole, ketoconazole, osilodrostat, pasireotide, and mifepristone. All approved CS drug treatments are associated with QT interval prolongation (see, for example, levoketoconazole and osilodrostat ).

[0032] Therefore, the need for safe CS drugs that do not cause QT prolongation and do not lead to potentially fatal arrhythmias or other serious cardiac and cardiovascular diseases has not been met. As disclosed herein, heteroaryl ketone-fused naphthyridine compounds (including the heteroaryl ketone-fused naphthyridine compound relacorilant) can meet such needs. The administration of relacorilant does not cause QT interval prolongation.

[0033] There is also an unmet need for methods of reducing the QT interval and methods of treatment, as well as for the treatment of QT prolongation in patients in need thereof. There is also an unmet need for safe CS drugs that can reduce the QT interval in patients in need thereof (including CS patients with QT interval prolongation). Heteroaryl ketone-fused naphthyridine compounds (such as relacorilant) can be used to provide improved treatment and methods of reducing QT interval prolongation for patients in need thereof (including CS patients). The methods, uses, and compositions disclosed herein can reduce the QT interval, including, for example, doses of about 400 mg / day, 500 mg / day, or up to 800 mg / day, and can be used to treat QT prolongation in patients (including CS patients).

[0034] This application demonstrates that no QT prolongation was present following the administration of relacorilant in healthy subjects (NCT03508635, "Phase 1 Study"), thorough QT studies in healthy volunteers (NCT04795479, "TQT Study"), and CS patients (Phase 2 Study from CS patients, (NCT02804750, "CS Study")). Thus, the heteroaryl ketone fused phenanthridine compound relacorilant can be safely used in patients at risk of QT interval prolongation, including CS patients, and can also be safely used in patients with QT interval prolongation, including CS patients (e.g., male CS patients with QT interval prolongation). As described below, a trend towards decreased ΔΔQTcF was observed at higher relacorilant concentrations ( Figure 2A and 2B ). At the time with the highest concentration (2 hours), a decrease in ΔΔQTcF was observed ( Figures 3A - 3E ). Figure 4A and 4B show that relacorilant (at doses of 400 mg and 800 mg) had no adverse effect on the QT interval, while moxifloxacin did have such an adverse effect (as expected for a positive control compound). Figure 5 shows the QT clinical outcomes and related theoretical models in healthy volunteers treated with relacorilant, excluding the adverse effect of relacorilant on ΔΔQTcF in the concentration range up to approximately 4500 ng / mL. Figure 6A and 6B In, the study results of CS patients (receiving low-dose or high-dose relacorilant) showed that no significant change in median QTcF was observed in either dose group.

[0035] Therefore, this study shows that following the administration of relacorilant at a dose exceeding 400 mg / day (e.g., 800 mg / day), its maximum plasma concentration (C 最大 ) does not result in significant QT interval prolongation. (The relacorilant doses used in previous studies of relacorilant were 500 mg / day or less). Thus, heteroaryl ketone fused phenanthridine compounds (such as relacorilant) can be administered to CS patients at a dose exceeding 400 mg / day without significantly increasing the risk of arrhythmia, and thus without significantly increasing the risk of heart attack, stroke, or sudden death, as well as various potentially harmful side effects of QT interval prolongation.

[0036] In an embodiment, the methods and uses are applicable to CS patients at high risk of QT interval prolongation, including CS patients with prolonged QT interval or QTc interval. Administration of the heteroarylketone-fused naphthyridine compound ranolazine does not increase the QT interval. Thus, it is not considered that administration to CS patients with prolonged QT interval increases the risk of arrhythmia and other cardiovascular diseases in such CS patients. Since administration of the heteroarylketone-fused naphthyridine compound ranolazine does not increase the QT interval, it is not considered that administration to CS patients taking drugs that prolong the QT interval further increases the risk of arrhythmia and other cardiovascular diseases in such CS patients. Although co-administration of ranolazine with food increases its bioavailability, and since administration of the heteroarylketone-fused naphthyridine compound ranolazine does not increase the QT interval, it is not considered that co-administration of up to or more than 400 mg of ranolazine with food increases the risk of arrhythmia and other cardiac and cardiovascular diseases (as disclosed herein, administration of amounts of 500 mg / day and 800 mg / day to a subject is safe).

[0037] In an embodiment of the methods and uses disclosed herein, the difference between the patient's QT interval measured after administration of the heteroarylketone-fused naphthyridine compound and the patient's baseline QT interval measured before administration of the heteroarylketone-fused naphthyridine compound is no more than 10 milliseconds (ms or msec). In an embodiment, the effective amount of the heteroarylketone-fused naphthyridine compound is from about 50 milligrams per day (mg / day) to about 400 mg / day, or about 500 mg / day. In a further embodiment, the effective amount of the heteroarylketone-fused naphthyridine compound is from about 50 milligrams per day (mg / day) to about 800 mg / day. In an embodiment, the heteroarylketone-fused naphthyridine compound is administered orally. In an embodiment, the heteroarylketone-fused naphthyridine compound is administered to a fasting patient (i.e., a patient who has not eaten a meal for at least 4 hours prior to administration of the heteroarylketone-fused naphthyridine compound). In an embodiment, the heteroarylketone-fused naphthyridine compound is administered to a fed patient (i.e., a patient who has eaten a meal within less than one hour prior to administration of the heteroarylketone-fused naphthyridine compound). In an embodiment, the heteroarylketone-fused naphthyridine compound is administered to a patient with a meal. In an embodiment, the heteroarylketone-fused naphthyridine compound is ranolazine.

[0038] In the studies disclosed herein, administration of raloxazine to healthy subjects resulted in a slight decrease in the QT interval (measured as the QTc interval corrected for heart rate) compared to placebo. For example, a trend towards a decrease in the placebo-corrected QTc interval change (ΔΔQTcF) was observed at higher raloxazine concentrations (a decrease in ΔΔQTcF was observed 2 hours after administration of raloxazine, when the plasma concentration of raloxazine was at its maximum). Accordingly, we believe that raloxazine may be useful in shortening or normalizing the QTc interval in patients with prolonged QTc intervals.

[0039] Accordingly, the applicant discloses a method for treating patients with CS and prolonged QT intervals, which comprises: identifying a patient with CS as having a prolonged QT interval, wherein the QT interval refers to the duration of the time interval between the start of the QRS complex of an electrocardiogram (ECG) and the end of the T wave of the ECG; and administering an effective amount of a heteroaryl ketone-fused naphthyridine compound (such as raloxazine), the effective amount being about 400 mg / day to about 800 mg / day of the heteroaryl ketone-fused naphthyridine compound, thereby treating the patient's CS and prolonged QT interval. In an embodiment, the effective amount of the heteroaryl ketone-fused naphthyridine compound is from about 500 mg to about 800 mg. In an embodiment, the patient is male.

[0040] The applicant hereby discloses a method for shortening the QT interval in patients with prolonged QT intervals, wherein the QT interval is the duration of the time interval between the start of the QRS complex of an electrocardiogram (ECG) and the end of the T wave of the ECG, the method comprising administering to the patient an effective amount of a heteroaryl ketone-fused naphthyridine compound, such as an effective amount of raloxazine, thereby shortening the QT interval of the patient. In an embodiment, the method for shortening the QT interval in patients with prolonged QT intervals comprises the step of determining whether the patient has a prolonged QT interval. In an embodiment of the method for shortening the QT interval in patients with prolonged QT intervals, the patient is male.

[0041] The applicant hereby discloses the use of a heteroaryl ketone-fused naphthyridine compound (such as raloxazine) in the treatment of patients with CS without significantly prolonging the QT interval of the patient. The applicant hereby discloses the use of a heteroaryl ketone-fused naphthyridine compound (such as raloxazine) in the preparation of a medicament for treating patients with CS without significantly prolonging the QT interval of the patient. The applicant hereby discloses a pharmaceutical composition comprising a GRM heteroaryl ketone-fused naphthyridine compound (such as SGRM raloxazine) without significantly prolonging the QT interval of the patient, for use in treating patients with CS. The applicant hereby discloses the use of a heteroaryl ketone-fused naphthyridine compound (such as raloxazine) in shortening the QT interval in patients in need thereof, including patients with CS and prolonged QT intervals. Such uses include the use of a heteroaryl ketone-fused naphthyridine compound (such as raloxazine) in the manufacture of a medicament for treating male patients.

[0042] New Methods and Uses of Heteroaryl Ketone-Fused Naphthalenes

[0043] Disclosed herein are new methods for treating CS and uses of the disclosed compounds. The methods and uses can treat patients with CS without significantly affecting heart rhythm. For example, the methods and uses can treat patients with CS without significantly affecting the QT interval. The methods include administering to a subject an effective amount of a heteroaryl ketone-fused naphthalene compound. Preferably, the heteroaryl ketone-fused naphthalene compound is GRM, which is a compound capable of modulating GR. In an embodiment, the heteroaryl ketone-fused naphthalene compound is a selective GRM (SGRM) compound that has little or no modulating effect on other steroid hormone receptors (such as the progesterone receptor, aldosterone receptor, or androgen receptor).

[0044] In embodiments of the methods and uses disclosed herein (including methods and uses for treating CS and methods and uses for reducing the QT interval), they include administering to a subject an effective amount of a heteroaryl ketone-fused naphthalene compound, wherein the heteroaryl ketone compound is a compound described in US 8,859,774 (the entire content of which is incorporated herein by reference) and has the following structure:

[0045]

[0046] wherein

[0047] R 1 is a heteroaryl ring having 5 to 6 ring atoms and 1 to 4 heteroatoms each independently selected from: N, O, and S, optionally substituted with 1 to 4 groups each independently selected from R 1a ;

[0048] Each R 1a is independently selected from: hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -CN, N-oxide, C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl;

[0049] Ring J is selected from the group consisting of: a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring, and a heteroaryl ring, wherein the heterocycloalkyl and heteroaryl rings have 5 to 6 ring atoms and 1 to 4 heteroatoms each independently selected from N, O, and S;

[0050] Each R 2 is independently selected from: hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl-C 1-6 alkoxy, -CN, -OH, -NR 2a R 2b , -C(O)R 2a , -C(O)OR 2a , -C(O)NR 2a R 2b , -SR 2a , -S(O)R 2a , -S(O)2R 2a , C 3-8 cycloalkyl and C 3-8 heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with 1 to 4 R 2c groups;

[0051] Alternatively, two R 2 groups attached to the same carbon combine to form an oxo group (=O);

[0052] Alternatively, two R 2 groups combine to form a heterocycloalkyl ring having 5 to 6 ring atoms and 1 to 3 heteroatoms each independently selected from N, O, and S, and said heterocycloalkyl ring is optionally substituted with 1 to 3 R 2d groups;

[0053] R 2a and R 2b are each independently selected from: hydrogen and C 1-6 alkyl;

[0054] Each R 2c is independently selected from the group consisting of: hydrogen, halogen, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, -CN, and - NR 2a R 2b :

[0055] Each R 2d is independently selected from: hydrogen and C 1-6 alkyl, or two R 2d groups attached to the same ring atom combine to form (=O);

[0056] R 3 is selected from the group consisting of: phenyl and pyridyl, each of which is optionally substituted with 1 - 4 R 3a groups;

[0057] Each R 3a is independently selected from: hydrogen, halogen, and C 1-6 haloalkyl; and

[0058] The subscript n is an integer from 0 to 3;

[0059] or a salt or isomer thereof.

[0060] In an embodiment, the methods for treating CS and shortening the QT interval disclosed herein include administering to a subject an effective amount of the SGRM heteroaryl ketone-fused naphthyridine compound ryalcolein. Ryalcolein (also known as "CORT125134") is (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, which has the following structure:

[0061] Ryalcolein is disclosed in Example 18 of U.S. Patent 8,859,774, the entire content of which is incorporated herein by reference.

[0062] In an embodiment, the methods disclosed herein can be used to treat a patient suffering from CS by administering an effective amount of a heteroaryl ketone-fused naphthyridine GRM or SGRM, and another CS treatment, to effectively treat CS without causing significant QT prolongation.

[0063] In an embodiment of the methods disclosed herein, a patient suffering from CS is administered an effective amount of a heteroaryl ketone-fused phenanthridine GRM or SGRM (e.g., riluzole) to effectively treat the patient. Such administration can be daily (e.g., once a day, twice a day, or three times a day), or at other intervals (e.g., once every other day, once every three days, or other intervals). In an embodiment, an effective amount of GRM or SGRM (such as riluzole) administered to treat CS can be, for example, 50 milligrams (mg), or 75 mg, or 100 mg, or 150 mg, or 200 mg, or 225 mg, or 250 mg, or 300 mg, or 325 mg, or 350 mg, or 375 mg, or 400 mg, or 425 mg, or 450 mg, or 475 mg, or 500 mg, or 525 mg, or 550 mg, or 575 mg, or 600 mg, or 625 mg, or 650 mg, or 675 mg, or 700 mg, or 725 mg, or 750 mg, or 775 mg, or 800 mg, or other amounts. In an embodiment, the heteroaryl ketone-fused phenanthridine GRM or SGRM (e.g., riluzole) can be administered orally and can be administered with food, or with water, or with both food and water. Generally, the administration of GRM (e.g., SGRM, such as riluzole) is a once-daily administration; however, in an embodiment, the administration can be twice a day, or three times a day, or can be every other day, or every three days, or every four days, or at other intervals as needed or convenient. The administration of the heteroaryl ketone-fused phenanthridine GRM or SGRM (e.g., riluzole) can continue for weeks, months, or years as needed; for example, the administration of riluzole can continue for weeks, months, or years as needed.

[0064] An effective amount of riluzole or other GRM or SGRM can be administered to the patient by oral means, e.g., via the oral cavity, in the form of a capsule, pill, tablet, liquid, emulsion, or other composition suitable for oral administration. Riluzole can be administered with food, or with water, or with both food and water. In other embodiments, GRM (e.g., riluzole) can be administered in the absence of food, or to a fasting subject or patient in the absence of food.

[0065] Definitions

[0066] As used herein, the term "AE" is an abbreviation for "adverse event".

[0067] As used herein, the term "AR" refers to the accumulation ratio (the ratio between the steady-state plasma exposure and the plasma exposure on the first day of dosing).

[0068] As used herein, the term "AUC" refers to the area under the plasma concentration-time curve calculated using the linear up / logarithmic down trapezoidal method.

[0069] As used herein, the term "AUC 0-24 " refers to the AUC from time zero to 24 hours after dosing.

[0070] As used herein, the term "AUC 0-τ " refers to the AUC from time zero to the end of the dosing interval.

[0071] As used herein, the term "AUC inf " refers to the AUC extrapolated from time zero to infinity.

[0072] As used herein, the term "AUC 最终 " refers to the AUC from time zero to the time of the final measurable concentration (Cfinal).

[0073] As used herein, the terms "pulse" and "heartbeat" refer to a single heartbeat, including the T wave, QRS complex, and P wave. The T wave, QRS complex, PR interval, QT interval, P wave, and other features of the electrocardiogram are defined according to the generally accepted definitions in the art (e.g., see Figure 2-25 and the text on pages 40-41 in Cardiovascular Physiology Cardiovascular Physiology ), Berne and Levy, 3rd edition, 1977).

[0074] As used herein, the term "C avg " refers to the average concentration during the dosing interval.

[0075] As used herein, the term "C 最大 " refers to the maximum plasma concentration observed.

[0076] As used herein, the term "C 最小 " refers to the minimum plasma concentration observed during the dosing interval.

[0077] As used herein, the term "Δ" refers to the change relative to the baseline.

[0078] As used herein, the term "ΔΔ" refers to the placebo-corrected change from the baseline.

[0079] As used herein, the term "ECG" is the abbreviation for electrocardiogram.

[0080] As used herein, the "Fridericia formula" is QTcF = (QT) / (RR 1 / 3 ).

[0081] As used herein, the term "FI" refers to the fluctuation index (an assessment of the change in plasma peak concentration and plasma trough concentration observed during the dosing interval).

[0082] As used herein, the term "HR" refers to heart rate.

[0083] As used herein, the term "ΔHR" refers to the change in heart rate relative to baseline.

[0084] As used herein, the term "ΔΔHR" refers to the placebo-corrected baseline change in heart rate.

[0085] As used herein, the term "mean (SD)" refers to the mean of a set of data points ± the standard deviation of that set of data points.

[0086] Moxifloxacin is a fluoroquinolone compound sold under as a trade name, which is the monohydrochloride salt of 1-cyclopropyl-7-[(S,S)-2,8-diazabicyclo[4.3.0]non-8-yl]-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, and its clinical use is as an antibiotic. Moxifloxacin has been shown to prolong the QT interval of the electrocardiogram in some patients. Its chemical structure is

[0087]

[0088] As used herein, the phrase "multiple ascending doses" and its acronym "MAD" refer to administering a test drug (e.g., ralclonolam) to each of a group of subjects more than once and obtaining results from those subjects after administration. Each subject receives an initial low dose, followed by increasing doses of the test drug.

[0089] As used herein, the term "PR" refers to the PR interval of the ECG.

[0090] As used herein, the term "ΔPR" refers to the change in the PR interval relative to baseline.

[0091] As used herein, the term "ΔΔPR" refers to the placebo-corrected change in the PR interval relative to baseline.

[0092] As used herein, the term "QD" refers to once-daily drug administration.

[0093] As used herein, the term "QRS" refers to the QRS interval of the ECG.

[0094] As used herein, the term "ΔQRS" refers to the change in the QRS interval relative to baseline.

[0095] As used herein, the term "ΔΔQRS" refers to the change in the placebo-corrected QRS interval relative to baseline.

[0096] As used herein, the term "QT interval" refers to the QT interval of an electrocardiogram, which is the interval from the start of ventricular depolarization to the end of ventricular repolarization (the time interval between the start of the "QRS" complex and the end of the "T" wave of the ECG). In healthy individuals, the "QT interval" is approximately 400 milliseconds (ms) (usually between about 350 ms and 450 ms). As used herein, the term "QT interval" refers to the interval between the start of the QRS complex and the end of the T wave; thus, the term QT interval includes the uncorrected interval and the heart rate-corrected QT interval "QTc", calculated in any way, including QTcF, which is the QTc calculated according to the Fredericia formula.

[0097] As used herein, the term "QTc" refers to the ECG-corrected QT interval corrected for heart rate. One method of calculating QTc is to divide the measured QT interval by the square root of the RR interval (the interval between consecutive R peaks in consecutive QRS complexes) (other rules divide by the cube root of the RR interval, or use a linear regression method; see, for example, A1-Khatib et al., JAMA 289(16):2120-2127 (2003)).

[0098] As used herein, the term "QTcF" refers to the ECG QT interval corrected for heart rate using the Fridericia formula. QTcF is calculated by using the Fridericia formula to divide the measured QT interval by the cube root of the RR interval: QTcF = (QT) / (RR 1 / 3 )

[0099] As used herein, the term "ΔΔQTcF" refers to the placebo-corrected change in baseline QTcF.

[0100] As used herein, when the term "adverse reaction" is used for placebo-corrected ΔQTcF values (ΔΔQTcF), it means an increase in the ΔΔQTcF value (referring to a prolonged QT interval). "Adverse reaction" is usually expressed numerically, for example, "adverse reaction > 10 milliseconds" means that any increase in the ΔΔQTcF value is less than 10 milliseconds.

[0101] As used herein, the terms "prolonged QT interval", "significant QT interval prolongation", etc. all refer to an increase in the QT interval or QTc interval by more than 10 milliseconds compared to the patient's baseline QT interval or baseline QTc interval. If the patient's baseline QT interval is unknown, a QT interval greater than about 450 milliseconds in males or greater than about 470 milliseconds in females will be considered a prolonged QT interval. For patients with a wide QRS interval, if the QTcF interval is greater than about 500 milliseconds, it is considered a high QTcF interval (a wide QRS interval if the QRS interval is greater than about 120 ms).

[0102] As used herein, the term "RR" refers to the RR interval of an ECG.

[0103] As used herein, the phrase "single ascending dose" and its acronym "SAD" refer to administering a single dose of a test drug (e.g., relacorilant) to a group of subjects (usually healthy volunteer subjects) and obtaining results from these subjects after administration. Typically, a low dose is administered to a first group of subjects; then a larger dose is administered to another group of subjects; even larger doses can be administered to other different groups of subjects to provide data on the dose range of the test drug.

[0104] As used herein, the term "SAE" is an abbreviation for serious adverse event.

[0105] As used herein, the term "t 1 / 2 " refers to the apparent terminal elimination half-life.

[0106] As used herein, the term "T 最大 " refers to the time to reach the maximum plasma concentration (C 最大 ) after administration.

[0107] As used herein, the term "TEAE" is an abbreviation for treatment-emergent adverse event.

[0108] As used herein, the term "TQT" is an abbreviation for "Thorough QT / QTc", i.e., a study designed to evaluate the effect of a drug (such as moxifloxacin or relacorilant) on cardiac repolarization. As used herein, the effect on cardiac repolarization is evaluated by the effect (or lack thereof) of the drug on the corrected QT (QTc) interval.

[0109] As used herein, the term "patient" refers to a person who is receiving or will receive or has received medical care for a disease or condition (such as, CS).

[0110] As used herein, the term "effective amount" or "therapeutic amount" refers to the amount of a pharmaceutical agent that effectively treats, eliminates or alleviates at least one symptom of the disease being treated. In some cases, a "therapeutically effective amount" or "effective amount" may refer to the amount of a functional agent or pharmaceutical composition that can be used to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any test method known in the art.

[0111] As used herein, the terms "significant" and "significantly" are used to describe a change in a value or effect, meaning that the change in the value or effect is expected to produce a clinical effect. For example, a significant change in the QT interval or QTc interval refers to a change greater than 10 milliseconds (ms) compared to the baseline QT interval or QTc interval.

[0112] As used herein, the terms "substantial" and "substantially" are used to describe a change in a value or effect, meaning that the change in the value or effect is expected to produce a clinical effect. For example, a substantial change in the QT interval or QTc interval refers to a change greater than 10 milliseconds (ms) compared to the baseline QT interval or QTc interval.

[0113] As used herein, the terms "administering / administering", "dosing", "administered" or "administered" refer to providing a compound or composition (e.g., those described herein) to a subject or patient. For example, the compound or composition can be administered orally to a patient (i.e., the subject receives the compound or composition through the mouth in the form of a pill, capsule, liquid, or other form suitable for administration through the mouth. Oral administration can be buccal (wherein the compound or composition is contained in the mouth, such as under the tongue, and absorbed therein). Based on the fact that the compound or composition can be delivered by injection, that is, by a needle, microneedle, pressure syringe or other means of piercing the skin or forcing the compound or composition through the subject's skin. The injection can be intravenous (i.e., into a vein), intraarterial (i.e., into an artery), intraperitoneal (i.e., into the peritoneum), intramuscular (i.e., into a muscle) or by other injection routes. The administration route can also include rectal, vaginal, transdermal, pulmonary (e.g., by inhalation), subcutaneous (e.g., by absorption into the skin from an implant containing the compound or composition) or by other routes.

[0114] As used herein, the term "combination therapy" refers to administering at least two agents to a subject to treat a disease. The two agents may be administered simultaneously or sequentially in any order over the entire treatment period or a portion of the treatment period. The at least two agents may be administered according to the same or different dosing regimens.

[0115] As used herein, the term "glucocorticoid receptor" ("GR") refers to the type II GR, which is an intracellular receptor family that specifically binds to glucocorticoids such as cortisol and / or cortisol analogs (such as dexamethasone) (see, e.g., Turner and Muller, J. Mol. Endocrinol. Oct. 1, 2005 35283-292). (The term "glucocorticoid" may be abbreviated as "GC".) The type II glucocorticoid receptor is also referred to as the cortisol receptor. The term includes isoforms of GR, recombinant GR, and mutant GR.

[0116] The term "glucocorticoid receptor modulator" ("GRM") refers to any compound that modulates the binding of glucocorticoids to GR or modulates any biological response associated with the binding of GR to an agonist. For example, a GRM that is an agonist (such as dexamethasone) is capable of increasing the activity of tyrosine aminotransferase ("TAT") in HepG2 cells (human hepatocellular carcinoma cell line; ECACC, UK). A GRM that is an antagonist (such as mifepristone) is capable of decreasing the activity of tyrosine aminotransferase ("TAT") in HepG2 cells. TAT activity can be measured as described in the literature: A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452.

[0117] As used herein, the term "selective glucocorticoid receptor modulator" ("SGRM") refers to a selective GRM, i.e., any composition or compound that selectively modulates the glucocorticoids that bind to GR or selectively modulates any biological response associated with the binding of GR to an agonist. By "selective", the drug preferentially binds to GR rather than other nuclear receptors, such as the progesterone receptor ("PR"), the mineralocorticoid receptor ("MR"), or the androgen receptor ("AR"). Preferably, the affinity of the selective glucocorticoid receptor modulator for GR is 10 times the affinity of its binding to the MR, AR, or PR, both the MR and PR, both the MR and AR, both the AR and PR, or the MR, AR, and PR (K d value of 1 / 10). Relacorilant is an SGRM.

[0118] As used herein, the term "compound" is used to denote a molecular moiety having a unique, recognizable chemical structure. The molecular moiety ("compound") can exist in free form, in which it is not associated with other molecules. The compound can also exist as part of a larger aggregate, in which it is associated with one or more other molecules but still retains its chemical identity. A solvate is an example of such an associated form, in which a molecular moiety having a defined chemical structure ("compound") is associated with solvent molecules. A hydrate is a solvate in which the associated solvent is water. Reference to a "compound" refers to the molecular moiety itself (having the structure described), whether it exists in free form or in an associated form.

[0119] As used herein, the term "composition" is intended to encompass a product containing specific ingredients, such as the compound, its tautomeric forms, its derivatives, its analogs, its stereoisomers, its polymorphs, its deuterated species, its pharmaceutically acceptable salts, esters, ethers, metabolites, mixtures of isomers, its pharmaceutically acceptable solvates, and a specific amount of a pharmaceutically acceptable composition, as well as any product directly or indirectly produced by the combination of a specific amount of specific ingredients. For a pharmaceutical composition, the term is intended to encompass a product comprising an active ingredient and an inert ingredient constituting a carrier, as well as any product directly or indirectly formed from the combination, compounding, or aggregation of any two or more ingredients, or the decomposition of one or more ingredients, or other types of reactions or interactions of one or more ingredients. Accordingly, the pharmaceutical compositions of the present invention are intended to encompass any composition prepared by mixing a compound of the present invention with its pharmaceutically acceptable carrier.

[0120] As used herein, the terms "pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that assist in the administration of an active agent to and its absorption by a subject, and can be included in the compositions of the present invention without causing significant adverse toxicological effects to the patient. These terms are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption delaying agents, etc. that are compatible with the administration of a drug. The use of such media and agents for pharmaceutically active substances is well known in the art. These media or agents should be considered for use in the compositions unless any conventional medium or agent is incompatible with the active compound. Supplementary active compounds can also be incorporated into the compositions. Those of ordinary skill in the art will understand that other pharmaceutical excipients can be used in the present invention.

[0121] "Salt" refers to the acid or base salts of the compounds used in the methods disclosed herein. Illustrative examples of pharmaceutically acceptable salts are: salts of inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), salts of organic acids (acetic acid, propionic acid, glutamic acid, citric acid, etc.), and quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts. It is understood that pharmaceutically acceptable salts are non-toxic. Other information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pennsylvania, 1985, which is incorporated herein by reference.

[0122] Pharmaceutical Compositions and Administration

[0123] In an embodiment, the present invention provides a pharmaceutical composition for treating CS, the pharmaceutical composition comprising a pharmaceutically acceptable excipient and a GRM (such as, for example, rilaclan). In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient and an SGRM. In a preferred embodiment, the pharmaceutical composition comprises rilaclan and one or more pharmaceutically acceptable excipients.

[0124] Suitable formulations can be prepared and administered in a variety of oral, parenteral, and topical dosage forms. GRMs and SGRMs can be administered orally. For example, a GRM can be administered as a pill, capsule, or liquid formulation as described herein. Oral formulations include tablets, pills, powders, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, etc. suitable for ingestion by a patient. Alternatively, GRMs and SGRMs can also be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally.

[0125] For preparing pharmaceutical compositions from GRMs and SGRMs, the pharmaceutically acceptable carrier can be solid or liquid. Solid form formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. Details on formulations and administration techniques are widely described in the scientific and patent literature, see, for example, the latest edition of Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania ("Remington").

[0126] In a powder, the carrier is a finely divided solid which is mixed with the finely divided active ingredient, the heteroarylketone-fused phenanthridine GRM or SGRM (e.g., rilaclan). In a tablet, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compressed into the desired shape and size.

[0127] The powders and tablets preferably contain 5% or 10% to 70% of the active compound (e.g., rilaclan). Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting waxes, cocoa butter, etc. The term "formulation" is intended to include formulations in which the active compound is accompanied by an encapsulating material as the carrier, the carrier providing a capsule in which the active ingredient, with or without other carriers, is surrounded by the carrier and thereby associated therewith. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0128] Suitable solid excipients are carbohydrate or protein fillers, including but not limited to: sugars, including lactose, sucrose, mannitol or sorbitol; starches from corn, wheat, rice, potato or other plants; celluloses, such as methylcellulose, hydroxypropylmethylcellulose or sodium carboxymethylcellulose; gums, including gum arabic and tragacanth; and proteins, such as gelatin and collagen. If necessary, disintegrants or solubilizers can be added, such as cross-linked polyvinylpyrrolidone, agar, alginic acid, or its salts, such as sodium alginate.

[0129] The sugar-coated core has a suitable coating agent, such as a concentrated sugar solution, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbomer gel, polyethylene glycol and / or titanium dioxide, lacquer solution and a suitable organic solvent or solvent mixture. Dyes or pigments can be added to the tablet or sugar-coated tablet coating for product labeling or characterizing the amount (i.e., dose) of the active compound. The pharmaceutical formulations of the present invention can also be in the form of oral administration: for example, push-fit capsules made of gelatin, and sealed soft capsules made of gelatin and a coating agent (such as glycerol or sorbitol). The push-fit capsules can contain a GR regulator mixed with a filler or binder (such as lactose or starch), a lubricant (such as talc or magnesium stearate), and optionally a stabilizer. In the soft capsules, the GR regulator compound can be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin or liquid polyethylene glycol with or without a stabilizer.

[0130] Formulations in liquid form include solutions, suspensions and emulsions, such as water or water / propylene glycol solutions. The liquid formulations can include salts, such as sodium chloride, or sugars (e.g., such as sucrose). For parenteral injection, the liquid formulations can be formulated as solutions in aqueous polyethylene glycol solutions.

[0131] The pharmaceutical compositions disclosed herein can be provided in salt form and can be formed with many acids, including but not limited to hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, etc. The salts tend to be more soluble in aqueous or other protic solvents in the corresponding free base form. In other cases, the formulation can be a lyophilized powder in 1 mM - 50 mM histidine, 0.1% - 2% sucrose, 2% - 7% mannitol in the pH range of 4.5 to 5.5, which is combined with a buffer before use.

[0132] Also included are solid form formulations for conversion to a liquid form formulation for oral administration immediately before use. Such liquid forms include solutions, suspensions and emulsions. In addition to the active ingredient, the formulations can also contain colorants, flavorants, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0133] An oily suspension can be formulated by suspending SGRM in a vegetable oil (such as peanut oil, olive oil, sesame oil or coconut oil), or a mineral oil (such as liquid paraffin), or a mixture thereof. The oily suspension may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. A sweetening agent can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These preparations can be preserved by adding an antioxidant (such as ascorbic acid). For examples of injectable oily carriers, see Minto, J Pharmacol. Exp. Ther. 281: 93-102, 1997. The pharmaceutical preparation of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil or a mineral oil as described above, or a mixture thereof. Suitable emulsifiers include: natural gums, such as gum arabic and tragacanth, natural phospholipids, such as soy lecithin, esters or partial esters of fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening agents and flavoring agents, as in the case of syrups and elixirs. Such preparations may also contain a demulcent, a preservative or a coloring agent.

[0134] The pharmaceutical preparation is preferably in the form of a unit dosage form. In this form, the preparation is subdivided into unit doses containing an appropriate amount of the active component GRM or SGRM (such as, for example, rilakuran). The unit dosage form can be a kit preparation, the kit containing discrete, quantified preparations, such as prepackaged tablets, capsules and powders in vials or ampoules. Additionally, the unit dosage form itself can be a capsule, a tablet, a cachet or a lozenge, or a kit form of an appropriate amount of any of these dosage forms.

[0135] The amount of the active component in the unit dose preparation can vary, or can be adjusted within the following ranges: 1 mg to 10,000 mg, or 10 mg to 800 mg, or for example, 50 mg to 500 mg. Depending on the specific application and the potency of the active component, suitable doses also include approximately 10 mg, 20, 30, 40, 50, 60, 70, 75, 80, 90, 100, 150, 200, 250, 300, 400, 500, 600 mg, 700 mg or 800 mg. If necessary, the composition may also contain other compatible therapeutic agents.

[0136] The preparation should provide a sufficient amount of the active agent to effectively treat CS. Thus, in one embodiment, the daily dosage of a pharmaceutical preparation for oral administration of GRM (such as rilakuran) is about 1 to about 20 milligrams per kilogram of body weight per day (mg / kg / day), or the daily dosage is about 1.5 to 15 mg / kg / day, or about 2 to 10 mg / kg / day.

[0137] In some embodiments, the GRM is administered in a single dose. For example, the GRM can be administered as a single dose once daily. In other embodiments, the GRM is administered in more than one dose, such as 2, 3, 4, 5, 6, 7 or more doses. In some cases, the doses are equal. In other cases, the doses are unequal. The dose can be increased or gradually decreased during administration. The dose will vary depending on, for example, patient characteristics.

[0138] Any suitable GRM dose can be used in the methods disclosed herein. A suitable GRM dose can be a daily dose or a dose at other dosing intervals (e.g., twice daily, every other day, every three days or other intervals). The administered dose of GRM (e.g., rilaclan) can be at least about 50 milligrams (mg) or about 75 mg, such as about 100 mg, about 150 mg, about 200 mg, about 225 mg, about 250 mg, about 300 mg, about 350 mg, about 375 mg, about 400 mg, about 450 mg, about 500 mg, about 525 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg or more. In an embodiment, the GRM is administered orally. In some embodiments, the GRM is administered in at least one dose. In other words, the GRM can be administered in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses. In an embodiment, the GRM is administered orally in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses.

[0139] The duration of treatment with GRM or SGRM for treating CS can vary depending on the severity of the subject's disease and the subject's response to GRM or SGRM. In an embodiment, the treatment can continue until needed. In an embodiment, the treatment can continue until the patient is able to receive oral medications. In some embodiments, rilaclan can be administered for up to about 2 years or longer. In an embodiment, the administration of a heteroaryl ketone-fused naphthyridine GRM or SGRM (such as rilaclan) can continue for 1, 2, 3, 4, 5, 10, 15, 20, 24, 30, 36, 48, 50, 52, 100, 104, 156 or 208 weeks or longer, as needed to treat the patient. In an embodiment, the GRM (such as rilaclan) can be continuously administered as long as the patient needs such administration or as long as the patient is still able to receive such GRM administration.

[0140] In some embodiments, the administration of GRM or SGRM is not continuous and can be discontinued for one or more periods and then resumed for one or more periods. Suitable periods of discontinuation include 1 to 10 weeks, 2 to 8 weeks, 3 to 6 weeks, and 4 to 5 weeks.

[0141] GRM and SGRM can be used in combination with other active agents known to modulate the glucocorticoid receptor, or with adjuvants that may be ineffective alone but that may contribute to the efficacy of the active agent.

[0142] After preparing a pharmaceutical composition containing a GR modulator of the present invention in an acceptable carrier, it can be placed in a suitable container and labeled for the treatment of the indicated disorders. For administration of GRM or SGRM, such labeling should include, for example, relevant instructions on the amount, frequency, and method of administration.

[0143] Examples

[0144] The following examples are provided for illustration only and not limitation. Those skilled in the art will readily recognize that there are multiple non-critical parameters that can be varied or modified and that will yield substantially similar results.

[0145] Example: Evaluation of the effect of relacorilant on heart rhythm

[0146] The studies disclosed herein evaluated the cardiac effects of the heteroaryl ketone-fused naphthyridine compound relacorilant by determining the effects of relacorilant therapeutic and supratherapeutic plasma concentrations on the heart rate-corrected QT interval (QTc) in healthy subjects and patients with Cushing's syndrome (CS). These studies showed that relacorilant did not increase the QT interval, and there was a trend for the QT interval to shorten with increasing relacorilant dose. Other observations and results included evaluating the effects of relacorilant on other electrocardiogram (ECG) parameters, including heart rate (HR), PR and QRS intervals, and T-wave morphology; and evaluating the safety and tolerability of relacorilant therapeutic and supratherapeutic oral doses in healthy subjects.

[0147] The results of three relacorilant studies were incorporated into this application: a Phase 1 placebo-controlled single- and multiple-ascending-dose (SAD / MAD) study in healthy volunteers (relacorilant doses up to 500 mg for up to 14 days) (NCT03508635); a Phase 1 placebo- and positive-control thorough QT study of therapeutic (400 mg) and supratherapeutic (800 mg) doses of relacorilant in healthy volunteers, which followed the regulatory guidelines of the International Council for Harmonization (ICH) (NCT04795479); and a Phase 2 open-label study in patients with endogenous CS that administered low (200 mg) and high (400 mg) doses of relacorilant daily for up to 16 weeks (NCT02804750). All subjects had normal QTc at the start of each study. Serial ECG recordings were made at baseline / before dosing, and the change in QTc relative to baseline was calculated at multiple time points after dosing. A linear mixed-effects model approach was used to evaluate the association between plasma relacorilant concentration and the effect on the QTc interval.

[0148] In one aspect, these studies evaluated the safety and tolerability of treatment and supra-therapeutic doses of rilakuran following oral administration in healthy subjects. The therapeutic dose of rilakuran was set at 400 mg / day, which is consistent with the daily therapeutic dose range of rilakuran (100 mg to 400 mg) in studies for the treatment of CS and oncology indications. Data on the effect of food on rilakuran showed that, compared to the fasting state, administration of rilakuran with a high-fat or moderate-fat breakfast increased the maximum plasma concentration (C 最大 ) by only approximately 34% and 41%, respectively. In addition, clinical data on rilakuran showed that in patients receiving the highest clinical dose of 400 mg / day, drug-drug interactions and food effects only led to a slight and transient increase in the plasma concentration of rilakuran. Furthermore, the FDA has set the exposure limit of rilakuran at 40,000 ng*h / mL and recommended that in the presence of a separate positive control, it is not necessary to achieve multiples of the highest exposure. Therefore, these studies used 400 mg of moxifloxacin as a positive control and conservatively set the supra-therapeutic dose of rilakuran at 800 mg / day (twice the therapeutic dose of rilakuran). At the supra-therapeutic dose (800 mg) once daily for 5 consecutive days, the plasma concentrations of rilakuran and its metabolites were expected to exceed the concentrations achieved by patients at the highest therapeutic dose (400 mg / day).

[0149] These studies included a randomized, partially double-blind, placebo- and active-controlled, multi-dose, four-way crossover, thorough QT / QTc (TQT) study to investigate the effect of rilakuran on cardiac repolarization. These studies measured the change in placebo-corrected QTcF relative to baseline (ΔΔQTcF); the changes in QTcF, HR, PR, and QRS intervals relative to baseline (ΔQTcF, ΔHR, ΔPR, and ΔQRS); the placebo-corrected changes in HR, PR, and QRS intervals relative to baseline (ΔΔHR, ΔΔPR, and ΔΔQRS); the categorical outliers of QTcF, HR, PR, and QRS intervals; the changes in T-wave morphology and the frequency of U-wave appearance during treatment; the PK parameters of rilakuran and its metabolites (CORT125337, CORT125336, and CORT125295) and moxifloxacin; and the safety profile, including AE / SAE, physical examination, clinical chemistry, hematology, urine analysis, ECG, and vital signs.

[0150] These studies included a "first-in-human" study in healthy volunteers, a "thorough QT" (TQT) study in healthy volunteers, and a study in patients with Cushing's syndrome (CS study). These studies are briefly summarized as follows:

[0151] First-in-human study

[0152] A Phase 1, 3-part, single-center, first-in-human study (NCT03508635) enrolled 103 healthy volunteers who received single or multiple escalating doses (SAD / MAD) of relacorilant (up to 500 mg QB) for up to 14 days; 24 volunteers received placebo.

[0153] TQT study

[0154] A Phase 1, randomized, partially double-blind, crossover, thorough QT study (NCT04795479) was conducted to evaluate the effect of multiple doses of relacorilant on cardiac repolarization in healthy volunteers. Participants were randomly assigned to receive either a therapeutic dose of relacorilant (400 mg QD, n = 25), a supratherapeutic dose (800 mg QD, n = 28), or placebo (n = 29) for 5 days. Moxifloxacin (400 mg, single dose, n = 28) was used as a positive control.

[0155] CS study

[0156] A single-arm, open-label Phase 2 study (NCT02804750) was conducted in patients with CS. Seventeen patients received low-dose relacorilant (100 - 200 mg QD) for 12 weeks; 18 patients received high-dose relacorilant (250 - 400 mg QD) for 16 weeks.

[0157] In all studies, ECG data were collected and the Fridericia formula was used to calculate the heart rate-corrected QT interval (QTcF). Participants with a family history or risk factors for torsades de pointes, or those with a prolonged QT interval at screening, were ineligible. An exposure-response analysis of the effect of relacorilant on the heart rate-corrected QT interval (QTc) was performed using a linear model with an intercept.

[0158] Relacorilant 100 mg soft capsules were administered orally to the subjects. The study included administration of relacorilant to 103 healthy volunteers (single or escalating doses up to 500 mg once daily (mg QD) of relacorilant). The study also included administration of multiple doses of relacorilant to healthy volunteers at 400 mg QD (n = 25, "therapeutic dose") and 800 mg QD (n = 28, "supratherapeutic dose"). Additionally, the study further included administration of relacorilant to patients with CS (100 - 200 mg QD (n = 17, low dose) or 250 - 400 mg QD (n = 18, high dose)). No significant QT interval prolongation was observed in the study associated with the administration of relacorilant.

[0159] Figure 1 A schematic diagram of the study protocol is shown.

[0160] Main inclusion criteria

[0161] Healthy male and female subjects aged 18 - 55 years, with body mass index (BMI) ≥ 18.0 kg / m 2 and ≤ 30.0 kg / m 2 , with electrocardiogram (ECG) showing sufficient cardiac conduction and no clinically significant abnormalities. Subjects with significantly prolonged baseline ECG intervals, including QTcF > 450 milliseconds (msec), PR > 200 msec or QRS > 120 msec, or subjects with resting heart rate < 45 bpm or > 100 bpm, are not included in this study. Part of this study analyzed the incidence of adverse events / serious adverse events (AE / SAE) in the enrolled subjects, as well as the results of physical examinations, clinical serum chemistry, hematology, urine analysis, ECG, and vital signs.

[0162] Safety assessment included monitoring of adverse events (AE) or serious adverse events (SAE) throughout the study period, as well as physical examinations, clinical chemistry, hematology, urine analysis, safety ECG assessment, and vital signs examinations conducted during each dosing period. When ECG acquisition was performed simultaneously with safety ECG, vital signs assessment, and blood sampling, it was carried out in the above order. Throughout the study period, including the screening procedure and 4 dosing periods, the total blood sampling volume for each subject was approximately 470 mL.

[0163] Measurements

[0164] ECG measurement: During each dosing period, at 3 time points before dosing on Day 1 ( - 45, - 30, and - 15 minutes before administration), once before dosing on Day 5 (approximately simultaneously with blood sample collection from the subject), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours after dosing on Day 1 and Day 5, repeated ECGs of cardiac dynamics were collected and extracted from continuous (Holter) recordings.

[0165] Pharmacokinetic (PK) parameters

[0166] Non - compartmental methods were used for PK analysis to obtain estimates of the following parameters as much as possible:

[0167] For relacorilant and its metabolites (CORT125337, CORT125336, and CORT125295):

[0168] On Day 1: C 最大 、T 最大 、AUC 最终 and AUC0 - 24 ;

[0169] On Day 5: C 最大 、T 最大 、AUC最终 、AUC 0-τ 、C avg 、FI and AR.

[0170] For moxifloxacin: C 最大 、T 最大 、AUC 最终 and AUC 0-24 .

[0171] On the 1st and 5th days of each dosing period, blood samples were collected before dosing and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours after dosing. The PK blood samples on the 1st day were collected before dosing on the 2nd day. Plasma concentration data of relacorilant and its metabolites (CORT125337, CORT125336, and CORT125295) or moxifloxacin were determined using validated liquid chromatography tandem mass spectrometry (LC-MS / MS).

[0172] Evaluation criteria

[0173] ECG parameters: The primary endpoint was the placebo-corrected change in baseline QTcF (ΔΔQTcF). Secondary endpoints included:

[0174] Changes in QTcF, HR, PR, and QRS intervals relative to baseline (ΔQTcF, ΔHR, ΔPR, and ΔQRS);

[0175] Placebo-corrected changes in baseline HR, PR, and QRS (ΔΔHR, ΔΔPR, and ΔΔQRS);

[0176] QTcF, HR, PR, and QRS categorical outliers;

[0177] The frequency of changes in T-wave morphology and the presence of U-waves during treatment.

[0178] Study treatment

[0179] Each subject received 4 treatments in random order during the study. Each dosing consisted of 8 capsules (except for moxifloxacin on the 5th day), which included:

[0180] - Treatment T: 400 mg of relacorilant (4 capsules) + relacorilant placebo (4 capsules) were administered orally multiple times once a day for 5 days;

[0181] - Treatment ST: 800 mg of relacorilant (8 capsules) were administered orally multiple times once a day for 5 days;

[0182] - Treatment P: Relacorilant placebo (8 capsules) were administered orally multiple times once a day for 5 days;

[0183] - Treatment M: Once daily, multiple oral administrations of raloxazine placebo (8 capsules) for 4 days, followed by a final single oral administration of 400 mg moxifloxacin (one tablet) on Day 5.

[0184] After confirming subject eligibility, on the first day of Phase 1, the subject was randomly assigned to one of 12 dosing sequences. Randomization was performed by the contracted contract research organization (CRO) in accordance with the relevant SOP. The randomization scheme and code were generated using software.

[0185] Fasting / Meals during Confinement

[0186] The subject checked into the clinical center in the morning on the first day of each dosing period (the day before dosing, the day of enrollment). After check-in, the subject remained at the clinical center until the morning of Day 6 of each dosing period. Meals were provided on the first day of each dosing period, and then at least 10 hours of overnight fasting was required before dosing on the morning of the second day of each dosing period (Day 1). During the study confinement period, free drinking water was allowed except for 1 hour before and after dosing. During this confinement period, standardized meals and beverages were provided. Standardized meals were defined as low-fat meals in which ≤20% of the calorie intake was from fat.

[0187] Some of the study subjects in this study were healthy subjects. On the last day of their respective treatment periods, a single dose of moxifloxacin (400 mg; Treatment M) was included as a positive control to determine the sensitivity of the study to detect small QTc changes. Raloxazine doses included a therapeutic dose level (400 mg; Treatment T) and a supratherapeutic dose level (800 mg; Treatment ST). This study was blinded to the subjects, investigators, study personnel, and the sponsor, where the doses in the raloxazine groups (Treatment T and Treatment ST) were blinded, while the raloxazine placebo group (Treatment P) was blinded; the moxifloxacin group (Treatment M) was open-label. Enrolled subjects were randomly assigned to one of twelve (12) dosing sequences and received 4 different treatments according to the dosing sequences shown below:

[0188] Dosing Sequence

[0189] Sequence 1 2 3 4 5 6 7 8 9 10 11 12 Phase 1 Processing T ST P M ST P T M P T ST M Phase 2 Processing ST M T P P M ST T T M P ST Phase 3 Processing P T M ST T ST M P ST P M T Phase 4 Processing M P ST T M T P ST M ST T P

[0190] Where: M: 400 mg moxifloxacin; P: raloxazine placebo; T: raloxazine therapeutic dose (400 mg); ST: raloxazine supratherapeutic dose (800 mg).

[0191] In each period, subjects were admitted to the clinical center on the morning of Day 1 and remained until the morning of Day 6. During the study period when subjects were randomized to treatment T, ST, or P, the applicable study product (400 mg or 800 mg of relaquer, or relaquer placebo) was taken once daily in the morning for 5 consecutive days. During the period of administration of the active control (treatment M), relaquer placebo was administered on Days 1 to 4 to be consistent with the dosing schedule of the other three treatments, and a single dose of moxifloxacin was administered in an open-label manner on the morning of Day 5. Therefore, treatments on Days 1 to 4 were double-blind; it was not known until the morning of Day 5 whether the subject was assigned to receive moxifloxacin. Each dosing period (from Period 2 to Period 4) was separated from the previous period by a washout period of at least 10 days, from Day 6 of the previous period to Day 1 (first dose) of the next period, to prevent carryover effects. The last visit was conducted on Day 6 of Period 4. Safety telephone follow-up was scheduled 7 days (± 2 days) after the last visit / early termination (ET) visit.

[0192] During each dosing period, a 12-lead ECG was performed and data were extracted from the continuous recording (Holt) at predetermined time points for measurement of heart rate and QTcF (QT interval corrected using Fridericia's formula) and other ECG intervals (PR interval and QRS interval), and for assessment of T wave morphology. Plasma concentrations of relaquintin, relaquintin metabolites, and moxifloxacin were analyzed using blood samples collected at predetermined time points matched to the ECG time to assess potential cardiodynamic effects of relaquintin.

[0193] ECG assessment of cardiac dynamics

[0194] Methods: Cardiodynamic ECG data were obtained using 12-lead Holter equipment and evaluated by a blinded central ECG laboratory, and safety ECGs were evaluated by blinded investigators. All Holter ECG data were acquired using the M12R ECG continuous 12-lead digital recorder from Global Instrumentation (Manlius, NY, USA). Continuous 12-lead Holter digital ECG data were stored on secure digital memory cards. At pre-specified time points, extracted Holter ECG data were selected for analysis and read centrally by a blinded central laboratory (ERT).

[0195] The ECG blinded central laboratory (“ERT”) uses the following analysis principles: the ECG reader is blinded to the subject, visit, and treatment assignment; only a limited number of readers are used in the study; the ECGs of a specific subject during the baseline and treatment periods are repeatedly read on the same lead and analyzed by the same reader. The main analysis lead is lead II. If lead II cannot be analyzed, the main analysis lead for the entire subject dataset is changed to another lead.

[0196] The following is a brief description of the ECG analysis method used by ERT.

[0197] TQT Plus electrocardiogram extraction technology

[0198] Ten 14-second digital 12-lead ECG tracings are extracted from the continuous Holter recordings using the “TQT Plus method” (a computer-aided statistical method used by ERT). This method is capable of extracting the ECG with the lowest HR variability and noise within the extraction time window specified by the protocol (e.g., the change in HR and QT interval from one heartbeat to another is within a <10% range). At each protocol-specified time point, ten ECG repeats are extracted from a 5-minute “ECG window” (usually the last 5 minutes of a 15-minute period during which the subject maintains a supine or semi-supine quiet position).

[0199] QT analysis with expert-level precision

[0200] QT analysis with expert-level precision was performed on all analyzable (non-artifact) heartbeats among the ten ECG repeats. A statistical quality control procedure was used to review and evaluate all heartbeats, and “high” and “low” confidence heartbeats were identified based on multiple criteria, including: QT or QTc values exceeding or falling below certain thresholds (biologically unlikely); RR values exceeding or falling below certain thresholds (biologically unlikely); rapid changes in QT, QTc, or RR values between different heartbeats.

[0201] The main electrocardiogram parameters (QT, QTc, RR) of all heartbeats of all repeatedly recorded “high-confidence” records were measured using iCOMPAS software (ER Company (eResearchTechnology, Inc.), Philadelphia, Pennsylvania, USA). All low-confidence heartbeats were manually reviewed and adjudicated according to the pass-fail criteria. The final QC assessment was performed by a cardiologist. Heartbeats considered acceptable after manual review were included in the analysis. The median QT, QTc, and RR of each extracted repeated record were calculated, and then the mean of all available medians from a certain nominal time point was used as the reportable value for the subject at that time point.

[0202] At each time point, T-wave morphology classification analysis was performed on 3 out of 10 ECG replicates, and the PR and QRS intervals were measured manually. Each fiducial point (P-wave onset, Q-wave onset, S-wave end, and T-wave end) was electronically marked. For T-wave morphology and the presence of U waves, the changes that occurred during the process were evaluated, i.e., changes that were not present at baseline. For each T-wave morphology and U-wave category, if the category was observed in any replicate at that time point, it was considered present. For baseline, if the category was observed in any replicate at all time points that constituted the baseline, it was considered present. The T-wave morphology categories are described below.

[0203] Table: T-wave morphology and U-wave presence categories (manual assessment)

[0204] Category description

[0205]

[0206] Statistical analysis of cardiac dynamics ECG: ECG readings were performed in a blinded manner. The preliminary analysis was based on the concentration-QTc model, which studied the relationship between the plasma concentration of raloxifene (and its related metabolites) and the change in QTcF from baseline (ΔQTcF), aiming to exclude adverse reactions with a placebo-corrected ΔQTcF value (ΔΔQTcF) > 10 ms (clinically relevant plasma concentration). In addition, the effects of raloxifene on placebo-corrected ΔQTcF, ΔHR, ΔPR, and ΔQRS (ΔΔQTcF, ΔΔHR, ΔΔPR, and ΔΔQRS) were evaluated at each post-dose time point ("analysis by time point"). Classification outlier analysis was performed on the changes in QTcF, HR, PR, QRS, T-wave morphology, and the presence of U waves. A model similar to the preliminary analysis was used to evaluate the detection sensitivity by analyzing the effect of moxifloxacin on ΔΔQTcF through concentration-QTc. The detection sensitivity was considered to have been achieved when the slope of the concentration-QTc relationship reached a 10% significance level in a two-sided test and the predicted QT effect (i.e., the lower limit of the 90% confidence interval for ΔΔQTcF bilaterally) was greater than 5 ms at the geometric mean observed for 400 mg of moxifloxacin. 最大 When the slope of the concentration-QTc relationship reached a 10% significance level in a two-sided test and the predicted QT effect (i.e., the lower limit of the 90% confidence interval for ΔΔQTcF bilaterally) was greater than 5 ms at the geometric mean observed for 400 mg of moxifloxacin, the detection sensitivity was considered to have been achieved.

[0207] Safety ECG

[0208] Safety ECG assessments were conducted according to the standard practice at the study sites. Subjects were supine for at least 15 minutes prior to each time point of the ECG assessment. Safety ECGs were performed and evaluated by the investigator at screening, on the first day of each dosing period, on days 1 to 5 of each dosing period, at 2, 6, and 8 hours after dosing on day 1, at 2 hours after dosing on days 2 to 5, and prior to discharge on day 6. The allowable time window for post-dose time points was ±15 minutes. The results of the 12-lead ECG, including heart rate, PR interval, RR interval, QRS duration, QT and QTcF intervals, were reviewed by the investigator or a designated person trained in ECG reading, and the safety ECG assessment results were interpreted overall (normal, clinically significant abnormality, or non-clinically significant abnormality) at each time point. All clinically significant abnormal changes were recorded as AEs. Any clinically significant abnormal changes relative to baseline were followed until the abnormality was resolved or adequately explained.

[0209] Results in healthy volunteers

[0210] Prolongation of the QT interval is an important issue in patients with CS. Approximately 26% of male CS patients have QT interval prolongation, and the risk of arrhythmic events is related to the degree of QT interval prolongation. All currently approved drug therapies are associated with QT interval prolongation, which poses a major challenge to the treatment of CS. The results of this article show that no QT interval prolongation occurred after the use of the investigational selective glucocorticoid receptor modulator relacorilant in healthy volunteers and CS patients.

[0211] In a 3-part, single-center, first-in-human study (NCT03508635, "Phase 1 study"), 103 healthy volunteers received single or multiple escalating doses (SAD / MAD) of relacorilant (up to 500 mg QB) for up to 14 days; 24 volunteers received placebo. In a randomized, partially double-blind, crossover thorough QT study (NCT04795479, "TQT study"), the effects of multiple treatment doses (400 mg QD, n = 25) and supratherapeutic doses (800 mg QD, n = 28) of relacorilant on cardiac repolarization in healthy volunteers were investigated. Single-dose moxifloxacin (400 mg, n = 28) was used as a positive control; 29 volunteers received placebo. In a single-group open-label Phase 2 study (NCT02804750, "CS study"), 17 CS patients were treated with low-dose relacorilant (100 - 200 mg QD) for 12 weeks, and 18 patients were treated with high-dose relacorilant (250 - 400 mg QD) for 16 weeks. In all studies, ECG data were collected, and the heart rate-corrected QT interval (QTcF) was evaluated using the Fridericia formula.

[0212] The baseline electrocardiogram parameters of each treatment group were consistent with the expectations of the healthy population. The average heart rate (HR) ranged from 58.7 to 60.7 beats per minute (bpm), the average QTcF ranged from 405.6 to 407.2 milliseconds, the average PR ranged from 132.6 to 137.9 milliseconds, and the average QRS ranged from 104.4 to 105.0 milliseconds.

[0213] The investigational doses of relacorilant at 400 mg and 800 mg QD had no clinically relevant effect on HR. The least squares (LS) mean of the change in HR from baseline (ΔHR) in the relacorilant group was consistent with the pattern observed in the placebo group. The LS mean placebo-corrected ΔHR (ΔΔHR) at each time point after dosing ranged from -3.2 bpm (800 mg treatment, 12 hours after dosing on Day 1) to 2.4 bpm (800 mg treatment, 2 hours after dosing on Day 5).

[0214] First-in-human trial of relacorilant

[0215] In the single ascending dose (SAD) phase, 42 and 12 participants were randomly assigned to receive relacorilant or placebo, respectively, to obtain ECG data. In the multiple ascending dose (MAD) phase, 34 and 12 participants were randomly assigned to receive relacorilant or placebo, respectively, to obtain ECG data. The baseline mean (SD) QTcF values were within the expected range for healthy subjects (range 378.9 (11.7) milliseconds to 403.5 (9.4) milliseconds), and the SD QTcF values were similar in the relacorilant and placebo groups during the SAD and MAD study phases (see Table 1) (values in parentheses represent standard deviation).

[0216] Table 1.

[0217] ECG parameters in healthy volunteers randomized to receive relacorilant or placebo during the SAD and MAD phases of a Phase 1 first-in-human study.

[0218]

[0219] Abbreviations: ΔQTcF = change in QTcF relative to baseline; ΔΔQTcF = placebo-corrected change in QTcF relative to baseline; CI = confidence interval; ECG = electrocardiogram; LS = least squares; MAD = multiple ascending dose; QTcF = QT interval corrected for heart rate using the Fridericia formula; SAD = single ascending dose.

[0220] a Data represent the mean (SD) QTcF or LS mean (90% CI) ranges in healthy volunteers who received a single dose of 5 mg, 15 mg, 50 mg, 150 mg, 300 mg, or 500 mg relacorilant during the SAD phase.

[0221] The b data represent the mean (SD) QTcF baseline or LS mean (90% CI) ranges for healthy volunteers who received raloxifene at 50 mg / day, 150 mg / day, 250 mg / day, or 500 mg / day for 14 days during the MAD phase.

[0222] The c data represent the LS mean (90% CI) ΔQTcF value ranges for healthy volunteers who received placebo for 14 days during the MAD phase.

[0223] During the SAD or MAD study phases, raloxifene did not produce clinically relevant adverse effects on QTcF. At all SAD and MAD post-dose time points and for all doses of raloxifene, the LS mean ΔQTcF of raloxifene was similar to placebo. In both groups, the LS mean placebo-corrected ΔQTcF (ΔΔQTcF) after raloxifene administration was small and mostly negative (Table 1). During the SAD and MAD study phases, there were no significant differences in ΔΔQTcF among different raloxifene doses, and the mean ΔΔQTcF at any time point did not exceed 5 milliseconds ( Figures 3A - 3E ).

[0224] The raloxifene plasma concentration and QTcF data during the SAD and MAD phases were best fit by a linear model with treatment-specific intercepts. For both phases, the slope (90% CI) estimated by the model was slightly negative (SAD: -0.59 [-2.14, 0.97] × 10 -3 milliseconds / ng / mL; MAD: -2.34 [-3.16 to -1.52] × 10 -3 milliseconds / ng / mL). Therefore, no concentration-dependent effect of raloxifene on QTc prolongation was found. The exposure-response model predictions of the mean ΔΔQTcF at the raloxifene plasma peak concentration during the SAD and MAD phases also indicated that increasing the raloxifene dose was not associated with QTc interval prolongation ( Figure 2A and 2B ). Based on the modeled SAD and MAD results, within the observed plasma concentration range up to approximately 4000 ng / mL, an effect of raloxifene on ΔΔQTcF prolongation beyond a 10-millisecond threshold was excluded (and Figure 2A and 5 the data and modeling presented do not indicate an effect beyond the 10-millisecond threshold).

[0225] In the Phase I study (first-in-human study), rilakuran doses up to 500 mg daily did not have clinically relevant adverse effects on ECG parameters. Adverse effects with a placebo-corrected baseline QTcF change (ΔΔQTcF) of more than 10 ms were excluded. In the TQT study, moxifloxacin control showed the expected QT interval prolongation, confirming the sensitivity of the assay. Rilakuran had no clinically relevant effects on ECG parameters and showed a similar effect to placebo. Based on concentration-QTc analysis, adverse effects with a ΔΔQTcF of more than 10 ms were excluded across the observed range of rilakuran plasma concentrations (there was a trend towards QT interval shortening at higher doses). The CS study confirmed that these favorable results also applied to CS patients: no significant change in median QTcF was observed in either dose group throughout the CS study. In addition, no cases of hypokalemia were reported in the CS study. Based on the TQT study and supported by additional data in healthy volunteers and CS patients, rilakuran was not associated with QT prolongation.

[0226] Thus, no significant changes in ECG parameters relative to baseline or between different dose levels were observed. At any time point in any treatment group, the mean placebo-corrected ΔQTcF (ΔΔQTcF) did not exceed 3 ms. A trend towards QTc shortening (ΔΔQTcF tended to decrease) was observed at higher rilakuran concentrations ( Figure 2A and 2B ). At the time with the highest concentration (2 hours), a decrease in ΔΔQTcF was observed ( Figures 3A - 3E ). Based on exposure-response analysis, adverse reactions with a placebo-corrected baseline QTcF change greater than approximately 10 ms could be excluded (see Figure 2A and 2B ).

[0227] Comprehensive QT / QTc study (“TQT study”)

[0228] ECG data were obtained from 25 participants receiving the therapeutic dose (400 mg) of ralaxanide, 28 participants receiving the supratherapeutic dose (800 mg) of ralaxanide, 29 participants receiving only placebo, and 28 participants receiving moxifloxacin as a positive control. The baseline mean (SD) QTcF values for all participants were within the expected range for healthy subjects (range: 405.6 (15.33) msec to 407.2 (17.49) msec). The LS mean ΔQTcF values were generally slightly negative (range: -11.7 msec to 2.0 msec) over two days and at all time points after receiving the therapeutic and supratherapeutic doses of ralaxanide and placebo. In contrast, when treated with 400 mg of moxifloxacin as a positive control on Day 5, the LS mean (90% CI) of QTcF before dosing (5.7 (3.3, 8.2) msec) increased rapidly to a maximum observed value of 9.7 (7.2, 12.2) msec at 16 hours after dosing starting from 1 hour after dosing.

[0229] Figure 4A Shows the results of the TQT study on Day 1 and Day 5 after administration of ralaxanide (400 mg (squares) or 800 mg (triangles)) or moxiflaxin (positive control; diamonds). Notably, after administration of ralaxanide, ΔΔQTcF appears to decline over time. These results rule out an adverse effect of ralaxanide on ΔΔQTcF within 24 hours on Day 1 or Day 5 after administration of ralaxanide. The dashed line indicates the 10-msec ΔΔQTcF action threshold.

[0230] Figure 4B Shows the results of the TQT study on Day 5 after administration of ralaxanide (400 mg (solid circles) or 800 mg (solid triangles)) or moxiflaxin (positive control; open circles). These results rule out an adverse effect of ralaxanide on ΔΔQTcF within 24 hours 5 days after administration of ralaxanide.

[0231] As Figure 4BAs shown, on Day 5, the least-squares (LS) mean (90% confidence interval [CI]) of ΔΔQTcF for both doses of ralaclan was negative at all time points after dosing, ranging from -8.0 (11.5, -4.6) milliseconds to -3.9 (-7.3, -0.5) milliseconds. At all time points after dosing of both doses of ralaclan, the upper limit of the 90% CI around the LS mean of ΔΔQTcF was below the ICH E14 threshold of 10 milliseconds. On Day 5, the LS mean (90% CI) of ΔΔQTcF for 400 mg of moxifloxacin increased to a peak of 10.7 (7.3, 14.1) milliseconds at 1.5 hours after dosing. Consistent with the regulatory expectations for the positive control, the lower limit of the 90% CI around the LS mean of ΔΔQTcF for moxifloxacin exceeded 5 milliseconds at 4 of the 12 time points after dosing.

[0232] Consistent with the results of the first-in-human trial, a linear model with a treatment effect-specific intercept provided the best fit to the ralaclan concentration and ΔΔQTcF data. The estimated slope (90% CI) of the ralaclan plasma concentration in the concentration-QTc relationship was shallow and slightly negative (-0.97 (-1.68, -0.25) × 10 -3 milliseconds / ng / mL), and the treatment effect-specific intercept (90% CI) was small, at -1.25 milliseconds (-2.00, -0.51). At the geometric mean peak concentration of ralaclan, the predicted effects on QTcF for the 400 mg dose (C 最大 1831.6 ng / mL) and the 800 mg dose (C 最大 2705.5 ng / mL) were -3.02 milliseconds (90% CI: -4.16 to -1.88) and -3.87 milliseconds (90% CI: -5.56 to -2.17), respectively ( Figure 5 ).

[0233] Table 2

[0234] Predicted ΔΔQTcF Intervals at the Geometric Mean Peak Concentrations of Ralaclan and Moxifloxacin (PK / QTc Population)

[0235]

[0236] CI = confidence interval; msec = milliseconds; n = number of subjects used in the calculation.

[0237] 1 Based on a linear mixed-effects model, with ΔQTcF as the dependent variable, the time-matched ralaclan plasma concentration as the explanatory variable, the central baseline QTcF as an additional covariate, treatment (ralaclan = 1 or placebo = 0) and time as fixed effects, and a random intercept and slope for each subject.

[0238] 2Based on the linear mixed-effects model, with ΔQTcF as the dependent variable, the time-matched moxifloxacin plasma concentration as the explanatory variable, the central baseline QTcF as an additional covariate, treatment (moxifloxacin = 1 or placebo = 0) and time as fixed effects, and a random intercept and slope for each subject.

[0239] Based on the concentration-QTc modeling results, an effect on ΔΔQTcF exceeding the 10-millisecond threshold can be excluded within the observed ranolazine plasma concentration range (up to approximately 4500 ng / mL at supratherapeutic doses).

[0240] Figure 5 Shows the results of the TQT study (squares and error bars (400 mg dose) and triangles and error bars (800 mg dose)) and the theoretical model (solid line and shaded area), the results of which exclude an adverse effect of ranolazine on ΔΔQTcF (change greater than 10 milliseconds) within the concentration range up to approximately 4500 ng / mL. Markers and error bars: mean (90% CI) ΔΔQTcF estimated at the observed geometric mean maximum ranolazine concentration, at therapeutic (squares) and supratherapeutic (triangles) doses. Dashed line: 10-ms ΔΔQTcF effect threshold. Solid line and shaded area: predicted mean ΔΔQTcF and its 90% CI, calculated from ΔΔQTcF = -1.2501 (milliseconds) - 0.97 (×10 -3 milliseconds / ng / mL) × ranolazine concentration (ng / mL). As described in the ICH E14 clinical guideline document (Guidance for Industry: E14 Clinical Evaluation of QT / QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs, US Department of Health and Human Services, 2005), this constitutes a negative TQT study.

[0241] Phase 2 study of ranolazine in patients with Cushing's syndrome ("CS study")

[0242] The low-dose and high-dose ranolazine groups included 17 and 18 patients, respectively. At baseline, the mean (SD) QTcF range in the low-dose group was 393.6 (16.5) milliseconds to 394.2 (16.2) milliseconds, and in the high-dose group was 403.4 (36.3) milliseconds to 409.9 (27.2) milliseconds, confirming no QTc interval prolongation at baseline. During the entire study period, the median QTcF did not change significantly in both groups ( Figure 6A and6B )。In both groups and across all doses of ryalcolein, the mean (SD) ΔQTcF values were small and not statistically significant (range: -2.2 (13.5) ms to 1.8 (24.4) ms; all P values > 0.3). In both groups, abnormal sinus tachycardia was the most common ECG finding after baseline, observed in 3 patients (17.6%) in the low-dose group and 2 patients (11.1%) in the high-dose group.

[0243] Figure 6A and 6B respectively show the median QTcF values of CS patients receiving low-dose ryalcolein (6A) and the QTcF values of CS patients receiving high-dose ryalcolein (6B). No significant changes in the median QTcF were observed between the two groups. SUMMARY OF THE INVENTION

[0245] In the first-in-human study, ryalcolein at doses up to 500 mg (QD) did not show significant mean changes compared to baseline for any measured ECG parameter. No significant differences were observed between the dose levels or between ryalcolein and placebo. Cases of QTcF interval > 450 ms or an increase in QTcF interval > 30 ms after dosing were not reported. Throughout the study and in each dose group, the QTcF changes (ΔQTcF) compared to baseline were similarly small and mostly negative; no dose-dependence was observed. For ryalcolein at daily doses up to 400 mg, adverse effects with placebo-corrected ΔQTcF (ΔΔQTcF) exceeding 10 ms were excluded. Exposure-response analysis showed a slightly negative correlation between ryalcolein plasma levels and ΔΔQTcF, but positive concentration-dependent effects were excluded. Thus, ryalcolein did not have an adverse effect on ECG parameters in the first-in-human study.

[0246] In the TQT study, ryalcolein at therapeutic and supratherapeutic doses did not have an adverse effect on ECG parameters. The QTc values of the moxifloxacin positive control increased rapidly as expected, confirming the detection sensitivity. The ΔQTcF values of ryalcolein at therapeutic and supratherapeutic doses were essentially similar to placebo. Based on concentration-QTc analysis, adverse effects with ΔΔQTcF exceeding 10 ms were excluded within the observed ryalcolein plasma concentration range (up to approximately 4500 ng / mL). Similar to the Phase 1 study, the estimated slope of the ryalcolein concentration-QTc curve was shallow and negative, and the treatment effect-specific intercept was statistically significant. In the TQT study, ryalcolein does not have an adverse effect on ECG parameters; these results constitute a negative TQT study.

[0247] In the CS study, ranolazine had no adverse effect on electrocardiogram parameters. During the entire study, no significant changes were observed in the median QTcF in either of the two dose groups. Therefore, the favorable QT results in the study conducted in healthy volunteers were confirmed in CS patients.

[0248] In all 3 studies (first-in-human study, TQT, and CS study), ranolazine was well tolerated. In the Phase 1 study, Holter ECG data were collected from 44 study participants. Ranolazine up to 500 mg had no adverse effect on ECG parameters. Adverse effects with placebo-corrected baseline QTcF change (ΔΔQTcF) exceeding 10 ms were excluded. In the TQT study, the results with moxifloxacin treatment confirmed the assay sensitivity. Ranolazine had no adverse effect on ECG parameters and showed an effect similar to placebo. Based on concentration-QTc analysis, adverse effects with ΔΔQTcF exceeding 10 ms were excluded within the observed plasma concentration range of ranolazine. The CS study confirmed that these results also apply to CS patients. During the entire study, no significant changes were observed in the median QTcF in either group.

[0249] We herein describe the ECG results of three studies of the investigational drug ranolazine for the treatment of CS: a first-in-human study in healthy volunteers, a thorough QT / QTc study in healthy volunteers according to regulatory guidelines, and a 16-week Phase 2 study in CS patients. All participants in the ranolazine studies had normal QTc intervals at screening and remained within the normal range during treatment. Overall, the results presented here indicate that ranolazine administration (including up to supratherapeutic doses) had no effect on QTc interval prolongation in healthy volunteers or in patients with endogenous CS. In the first-in-human study in healthy volunteers, ranolazine had no meaningful clinical effect on QTcF within the dose range administered during the SAD and MAD periods. No obvious dose-dependence was observed during the SAD and MAD study phases, and the LS mean ΔΔQTcF did not exceed 5 milliseconds at any time point. The results of the concentration-QTc model further indicated that an effect with ΔΔQTcF exceeding 10 milliseconds could be excluded within the observed plasma concentration range of ranolazine (up to approximately 4000 ng / mL).

[0250] These results were confirmed in a comprehensive QT / QTc study with positive controls of relacorilant at dedicated placebo and therapeutic and supratherapeutic doses. As shown in the first-in-human trial, at all post-dose time points, the effect of relacorilant at therapeutic and supratherapeutic doses on ΔQTcF was similar to that of placebo. In addition, for both doses, ΔΔQTcF was consistently small and generally slightly negative. Importantly, at all post-dose time points, the upper limit of the two-sided 90% confidence interval of the LS mean ΔΔQTc of relacorilant at both doses was below 10 milliseconds. In addition, the results of the concentration-QTc model excluded an effect on ΔΔQTcF of more than 10 milliseconds within the observed plasma concentration range of relacorilant (up to approximately 4500 ng / mL at supratherapeutic doses). The comprehensive QT / QTc study was able to detect a slight increase in QTcF, which was confirmed by the lower limit of the maximum LS mean ΔΔQTcF observed in the moxifloxacin positive control being >5 milliseconds. Collectively, these results constitute a negative QT / QTc study outcome, in line with the provisions of the ICH E14 clinical regulatory guideline (U.S. Food and Drug Administration, E14 Clinical evaluation of QT / QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs - Questions and answers (R3) (E14 Clinical evaluation of QT / QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs - Questions and answers), U.S. Department of Health and Human Services; 2017).

[0251] In the first-in-human trial and the comprehensive QT / QTc study, the administration of relacorilant was accompanied by a slight downward trend in placebo-corrected ΔQTc. The QTc interval of 390 - 450 milliseconds in men and 390 - 460 milliseconds in women is considered the normal range. Notably, all participants in the relacorilant study had a normal QTc interval at screening and remained within the normal range during the treatment period.

[0252] The results and conclusions of two relacorilant studies in healthy volunteers were further confirmed by the ECG results of a 16-week relacorilant Phase 2 study in patients with endogenous CS. At all time points and all relacorilant doses, the mean ΔQTcF values of relacorilant were small and not statistically significant.

[0253] The absence of QTc prolongation with relacorilant here is in contrast to most currently approved or widely used CS therapies (e.g., pasireotide, ketoconazole, and other drugs used to treat Cushing's syndrome).

[0254] Compared with existing CS therapies, at all doses studied to date (including supra-therapeutic doses), relacorilant has consistently shown no QTc prolongation in healthy volunteers and CS patients. These results suggest that relacorilant does not carry a risk of triggering ventricular arrhythmias and their associated sequelae, including cardiac arrest. Thus, based on the data disclosed herein, relacorilant is not associated with QT interval prolongation, thereby fulfilling an unmet need for a safe CS drug that does not cause QT interval prolongation and potentially fatal arrhythmias.

[0255] In addition to the patients discussed in this example, no clinically significant QT prolongation was observed in another study in which at least 12 Cushing's syndrome patients were treated with relacorilant while also receiving another drug that is known to cause QT prolongation (these drugs are fluoroquinolones, imidazole derivatives, macrolides, or protease inhibitors).

[0256] The results of this study showed that ΔΔQTcF trended downward with treatment at higher concentrations of relacorilant, and ΔΔQTcF decreased at the highest concentration reached (2 hours). These results suggest that relacorilant administration may help shorten the QT interval. Thus, these results suggest that relacorilant administration may help treat patients with QT interval prolongation, such as CS patients and other patients.

[0257] All patents, patent publications, publications, and patent applications cited in this specification are hereby incorporated by reference in their entirety as if each publication or patent application was specifically and individually incorporated by reference herein. In addition, while the invention has been described in detail for purposes of illustration and example, it will be apparent to those of ordinary skill in the art from the teachings of the invention that certain changes and modifications can be made without departing from the spirit or scope of the appended claims.

Claims

1. A method for treating a patient suffering from Cushing's syndrome or Cushing's disease (collectively referred to as "CS") without significantly prolonging the QT interval of the patient, wherein the QT interval is the duration of the time interval between the start of the QRS complex of an electrocardiogram (ECG) and the end of the T wave of the ECG, wherein, If the QT interval increases by more than 10 milliseconds (ms) relative to the patient's baseline QT interval, the patient's QT interval is significantly prolonged. The method comprises: administering an effective amount of a heteroaryl ketone-fused naphthyridine compound, wherein the treatment does not significantly prolong the patient's QT interval, whereby the patient's CS is treated without significantly prolonging the patient's QT interval.

2. The method according to claim 1, wherein the heteroaryl ketone-fused naphthyridine compound is ryalcolein, which is (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone and has the following structure:

3. The method according to claim 1, wherein the effective amount of the heteroaryl ketone-fused naphthyridine compound is an amount selected from the group consisting of: about 50 mg / day to about 800 mg / day, about 50 mg / day to about 500 mg / day, and about 400 mg / day to about 800 mg / day.

4. The method according to claim 1, wherein administering the effective amount of the heteroaryl ketone-fused naphthyridine compound does not significantly increase the risk of arrhythmia in the patient.

5. The method according to claim 1, wherein administering the effective amount of the heteroaryl ketone-fused naphthyridine compound does not significantly increase the risk of heart attack in the patient.

6. The method according to claim 1, wherein the patient has been administered a QT-prolonging drug, and wherein administering the effective amount of the heteroaryl ketone-fused naphthyridine compound does not significantly increase the risk of stroke in the patient.

7. The method according to claim 1, wherein administering the effective amount of the heteroaryl ketone-fused naphthyridine compound does not significantly increase the risk of sudden death in the patient.

8. The method according to claim 1, wherein the heteroaryl ketone-fused naphthyridine compound is administered orally.

9. The method according to claim 1, wherein the heteroaryl ketone-fused naphthyridine compound is administered to a fasting patient, where a fasting patient is a patient who has not eaten a meal for at least 4 hours prior to administration of the heteroaryl ketone-fused naphthyridine compound.

10. The method according to claim 1, wherein 50 mg / day to 400 mg / day of the heteroaryl ketone-fused naphthyridine compound is administered to the patient with food or to a fed patient, where a fed patient is a patient who has eaten a meal within less than one hour prior to administration of the heteroaryl ketone-fused naphthyridine compound.

11. The method according to claim 1, wherein the patient is male.

12. A method for treating a patient suffering from Cushing's syndrome or Cushing's disease (collectively referred to as "CS") and having a prolonged QT interval, wherein the QT interval is the duration of the time interval between the start of the QRS complex of an electrocardiogram (ECG) and the end of the T wave of the ECG, and wherein a prolonged QT interval means a QT interval greater than about 450 ms in males or greater than about 460 ms in females, The method comprises: Determining that a patient with CS has a prolonged QT interval, Administering an effective amount of a heteroaryl ketone-fused naphthyridine compound, the effective amount being from about 400 milligrams (mg) to about 800 mg of the heteroaryl ketone-fused naphthyridine compound, Thereby treating the patient's CS and prolonged QT interval.

13. The method according to claim 12, wherein the heteroaryl ketone-fused naphthyridine compound is relacorilant, which is (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone and has the following structure:

14. The method according to claim 12, wherein the effective amount of the heteroaryl ketone-fused naphthyridine compound is about 800 mg.

15. A method for reducing the QT interval in a patient having a prolonged QT interval, wherein the QT interval is the duration of the time interval between the start of the QRS complex of an electrocardiogram (ECG) and the end of the T wave of the ECG, and wherein a prolonged QT interval means a QT interval greater than about 450 ms in males or greater than about 460 ms in females, The method comprises: Administering to the patient an effective amount of a heteroaryl ketone-fused naphthyridine compound, Thereby shortening the patient's QT interval.

16. The method according to claim 15, wherein the heteroaryl ketone-fused naphthyridine compound is relacorilant, which is (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone and has the following structure:

17. The method according to claim 15, wherein the effective amount of the heteroaryl ketone-fused naphthyridine compound is from about 400 milligrams (mg) to about 800 mg of the heteroaryl ketone-fused naphthyridine compound.

18. The method according to claim 15, wherein the effective amount of the heteroaryl ketone-fused naphthyridine compound is about 800 mg.

19. A method for reducing the QT interval effect in patients receiving a drug known to prolong the QT interval of the electrocardiogram (ECG) in some patients, wherein the QT interval is the duration of the time interval between the start of the QRS complex of the ECG and the end of the T wave of the ECG, and wherein a prolonged QT interval means a QT interval in males greater than about 450 ms or a QT interval in females greater than about 460 ms, The method comprises: administering to the patient receiving the drug known to prolong the QT interval of the electrocardiogram (ECG) in some patients an effective amount of a heteroaryl ketone-fused naphthyridine compound, thereby reducing the effect of the drug on the QT interval of the patient.

20. The method according to claim 19, wherein the heteroaryl ketone-fused naphthyridine compound is relacorilant, which is (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone and has the following structure:

21. The method according to claim 19, wherein the effective amount of the heteroaryl ketone-fused naphthyridine compound is from about 400 milligrams (mg) to about 800 mg of the heteroaryl ketone-fused naphthyridine compound.

22. The method according to claim 19, wherein the effective amount of the heteroaryl ketone-fused naphthyridine compound is about 800 mg.

23. Use of a heteroaryl ketone-fused naphthyridine compound in the treatment of Cushing's syndrome or Cushing's disease (collectively "CS") which does not cause significant QT interval prolongation, wherein the QT interval is the duration of the time interval between the start of the QRS complex of the electrocardiogram (ECG) and the end of the T wave of the ECG, and wherein a prolonged QT interval means a QT interval in males greater than about 450 ms or a QT interval in females greater than about 460 ms.

24. The use according to claim 23, wherein the heteroaryl ketone-fused naphthyridine compound is relacorilant, which is (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone and has the following structure:

25. The use according to claim 23, wherein the CS patient has a prolonged QT interval.

26. Use of a heteroaryl ketone-fused naphthyridine compound in the manufacture of a drug for the treatment of Cushing's syndrome or Cushing's disease (collectively "CS"), which drug does not cause significant QT interval prolongation, wherein the QT interval is the duration of the time interval between the start of the QRS complex of the electrocardiogram (ECG) and the end of the T wave of the ECG, and wherein a prolonged QT interval means a QT interval in males greater than about 450 ms or a QT interval in females greater than about 460 ms.

27. Use according to claim 26, wherein the heteroaryl ketone-fused naphthyridine compound is relacorilant, which is (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, and has the following structure: For manufacturing a medicament for treating Cushing's syndrome or Cushing's disease (collectively "CS"), said medicament not causing significant QT interval prolongation, wherein the QT interval is the duration of the time interval between the start of the QRS complex of an electrocardiogram (ECG) and the end of the T wave of the ECG, and wherein a prolonged QT interval means a QT interval greater than about 450 ms for males or greater than about 460 ms for females.

28. Use according to claim 26, wherein the CS patient has a prolonged QT interval.

29. A pharmaceutical composition for treating a patient with Cushing's syndrome or Cushing's disease (collectively "CS") that does not cause significant QT interval prolongation, wherein the QT interval is the duration of the time interval between the start of the QRS complex of an electrocardiogram (ECG) and the end of the T wave of the ECG, and wherein a prolonged QT interval means a QT interval of greater than about 450 ms in males or greater than about 460 ms in females, and the pharmaceutical composition comprises a pharmaceutically acceptable excipient and the heteroaryl ketone-fused naphthyridine compound relacorilant, which is (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, and has the following structure:

30. Use according to claim 29, wherein the CS patient has a prolonged QT interval.

31. Use of a heteroaryl ketone-fused naphthyridine compound for reducing the QT interval in a patient with a prolonged QT interval, wherein the QT interval is the duration of the time interval between the start of the QRS complex of an electrocardiogram (ECG) and the end of the T wave of the ECG, and wherein a prolonged QT interval means a QT interval of greater than about 450 ms in males or greater than about 460 ms in females.

32. Use according to claim 31, wherein the heteroaryl ketone-fused naphthyridine compound is relacorilant, which is (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, and has the following structure:

33. Use of a heteroaryl ketone-fused naphthyridine compound in the manufacture of a medicament for reducing the QT interval in a patient with a prolonged QT interval, wherein the QT interval is the duration of the time interval between the start of the QRS complex of an electrocardiogram (ECG) and the end of the T wave of the ECG, and wherein a prolonged QT interval means a QT interval of greater than about 450 ms in males or greater than about 460 ms in females.

34. The use according to claim 33, wherein the heteroaryl ketone-fused naphthyridine compound is ryalcolein, which is (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone and has the following structure:

35. A method for reducing the QT interval effect in a patient receiving a drug known to prolong the QT interval of the electrocardiogram (ECG) of some patients, wherein the QT interval is the duration of the time interval between the start of the QRS complex of the ECG and the end of the T wave of the ECG, and wherein a prolonged QT interval means that the QT interval in males is greater than about 450 ms or the QT interval in females is greater than about 460 ms.

36. The use according to claim 35, wherein the heteroaryl ketone-fused naphthyridine compound is ryalcolein, which is (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone and has the following structure:

37. The use of a heteroaryl ketone-fused naphthyridine compound in the manufacture of a medicament for reducing the QT interval effect in a patient receiving a drug known to prolong the QT interval of the electrocardiogram (ECG) of some patients, wherein the QT interval is the duration of the time interval between the start of the QRS complex of the ECG and the end of the T wave of the ECG, and wherein a prolonged QT interval means that the QT interval in males is greater than about 450 ms or the QT interval in females is greater than about 460 ms.

38. The use according to claim 37, wherein the heteroaryl ketone-fused naphthyridine compound is ryalcolein, which is (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone and has the following structure:

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