Treatment of Cushing's syndrome without significantly affecting cardiac rhythm

Abstract

Applicant discloses methods, uses, and compositions of heteroaryl ketone-fused azadecalin compounds for treating patients suffering from Cushing's syndrome or Cushing's disease (collectively, "CS") without causing significant QT interval prolongation (e.g., a QT interval after administration that differs from the baseline QT interval by more than about 10 milliseconds). The therapeutic dose of the heteroaryl ketone-fused azadecalin compound can be from about 50 to up to about 500 mg / day, and in some embodiments, up to about 800 mg / day. The methods, uses, and compositions can reduce the QT interval and can be useful for treating QT prolongation in patients, including those with CS. The treatment can be administered to fasting or fed patients. The heteroaryl ketone-fused azadecalin compound can be administered with a meal. The heteroaryl ketone-fused azadecalin compound can be a relacolinant 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: JPEG2025540132000021.jpg7486

Description

[Technical Field]

[0001] A healthy heart with a healthy heart rhythm is important to a person's well-being. Electronic measurement of heart rhythm is called an electrocardiogram (ECG). ECG measurement of cardiac activity includes the time intervals measured between prominent ECG features detected by the ECG. Prominent ECG features include the P wave, QRS complex, and T wave. The time interval between the onset 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) (typically approximately 350 ms to 450 ms). A QT interval greater than approximately 450 ms in men and approximately 460 ms in women is considered a prolonged QT interval and may indicate an increased risk of cardiac arrhythmias, including potentially fatal torsades de pointes. [Background technology]

[0002] Patients with a prolonged QT interval may be at increased risk of syncope, seizures, atrial fibrillation, ventricular tachycardia, stroke, and even sudden death (Al-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 prolonged QT interval is a risk factor for cardiovascular comorbidities, including torsades de pointes, ventricular tachycardia, stroke, and sudden 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 have recommended thorough evaluation of all new drug candidates for QT interval prolongation and proarrhythmic effects.

[0003] Cortisol is a steroid hormone secreted by the adrenal glands through the action of adrenocorticotropin hormone (ACTH). Cortisol action requires that cortisol bind to the glucocorticoid receptor (GR). Cushing's syndrome and Cushing's disease (collectively "CS") are disorders of cortisol excess. Such cortisol excess can result from any of several possible causes, including excessive ACTH release from the pituitary gland, excessive cortisol secretion from the adrenal glands, or secretion of cortisol or ACTH from tumors. Prolonged or excessive administration of glucocorticoids, such as dexamethasone, prednisone, and others (which mimic cortisol action), can also cause CS.

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

[0005] The QT intervals of male CS patients were found to be larger than those of healthy male subjects in matched controls (this difference was statistically significant; see Giraldi et al., Exp Clin Endocrinol Diabetes 2011, 119(4):221-224). No differences were observed between female CS patients and healthy female subjects in matched controls (Giraldi et al.). Thus, although both male and female CS patients treated with any of the CS drugs discussed above may be at risk for changes in QT interval due to the drug treatment, male CS patients who are already at risk for abnormal QT intervals may be at greater risk for abnormal heart rhythms than female CS patients treated with these drugs.

[0006] There is an unmet need for safe CS drugs that do not adversely alter heart rhythm, including drugs that do not cause QT prolongation (which can potentially lead to fatal arrhythmias). Thus, there is a need for improved methods and compositions used to treat patients with CS that do not affect the QT interval in order to reduce the risk of abnormal heart rhythms and associated adverse effects. Summary of the Invention

[0007] A prolonged QT interval is a serious side effect of previous CS drug treatment; QT prolongation increases the patient's risk of serious cardiac arrhythmias, which can lead to an increased risk of heart attack, stroke, and sudden death, among other potential adverse side effects of QT prolongation.

[0008] Disclosed herein is a novel method for treating Cushing's syndrome and Cushing's disease (collectively "CS") without causing significant QT prolongation and without causing significant changes in cardiac rhythm. The method comprises administering to a subject an effective amount of a heteroaryl ketone-fused azadecalin compound that modulates GR. Heteroaryl ketone-fused azadecalin compounds are disclosed in U.S. Patent No. 8,859,774, the entire contents of which are incorporated herein by reference in their entirety.

[0009] In embodiments, Applicant provides a method of treating a patient suffering from CS without significantly prolonging the QT interval or QTc interval, comprising: administering an effective amount of a heteroaryl ketone-fused azadecalin compound; wherein the therapeutic treatment does not significantly prolong QT or QTc as measured by electrocardiogram (ECG), where QT is the length 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 QTc is the QT interval corrected for heart rate; This discloses the method, wherein the Cushing's syndrome or Cushing's disease is treated without significantly prolonging the QT interval. In an embodiment, the heteroaryl ketone-fused azadecalin compound is a GRM, and in a further embodiment, the heteroaryl ketone-fused azadecalin compound is an 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), having the following structure: [ka]

[0010] In embodiments, the GRM (e.g., an SGRM such as relacorilant) is administered orally. In embodiments, the GRM or SGRM may be administered by injection, infusion, transdermal application, or other administration means or route. In embodiments, the GRM or SGRM (e.g., relacorilant) may be administered with food, with water, or with both food and water. In other embodiments, the GRM or SGRM (e.g., relacorilant) may be administered in the absence of food.

[0011] There is an unmet need for safe CS agents that do not cause QT prolongation and potentially fatal arrhythmias. Based on present results from clinical trials in healthy volunteers and patients with CS, relacorilant is not associated with QT prolongation. Heteroaryl ketone-fused azadecalin compounds, such as relacorilant, are believed to be able to meet this need. There is also an unmet need for safe CS agents that, in addition to not causing QT prolongation, can reduce the QT interval in patients in need, including in CS patients with prolonged QT intervals. Heteroaryl ketone-fused azadecalin compounds, such as relacorilant, are believed to be able to meet this need well.

[0012] Thus, the present method provides an improved method for treating and reducing a prolonged QT interval in patients in need thereof. As such, the present method provides an improved method for treating CS patients that, unlike previous treatments, does not significantly prolong the cardiac QT interval and does not significantly increase the risk of cardiac arrhythmias, torsades de pointes, sudden death, stroke, and other cardiac and cardiovascular disorders in CS patients. [Brief explanation of the drawings]

[0013] [Figure 1] Figure 1 shows a schematic diagram of the study protocol. [Figure 2A]Figure 2A shows the predicted change in geometric mean QTc for subjects receiving 50 milligrams (mg), 150 mg, 250 mg, and 500 mg of relacorilant in a single ascending dose (SAD) study. The barred points indicate the mean QTc values ​​at Cmax (time of maximum relacorilant plasma concentration) for each dose ± 90% confidence interval (CI) for such points; the line connecting these geometric means indicates the predicted mean ΔΔQTcF, and the band around the line provides the 90% CI for the prediction. The placebo-corrected predicted change in QTc is less than 5 milliseconds (ms) for the 50 mg, 150 mg, 250 mg, and 500 mg doses. Colored markers and error bars: predicted mean (90% CI) ΔΔQTcF at the observed geometric mean relacorilant maximum concentration (Cmax). Dashed line: 10-ms ΔΔQTcF effect threshold. Solid line and gray shaded area: predicted mean ΔΔQTcF with 90% CI. CI, confidence interval. SAD formula: ΔΔQTcF = -0.005 (msec) - 0.588 (msec / ng / mL) x relaxorilant concentration (ng / mL). Abbreviations (throughout this application): ΔΔQTcF = placebo-corrected baseline QTcF change; CI = confidence interval; Cmax = maximum concentration; LS = least squares; MAD = multiple ascending dose; SAD = single ascending dose; QTcF = QT interval corrected for heart rate using the Fridericia formula. [Figure 2B]Figure 2B shows the predicted change in geometric mean QTc for subjects in a multiple ascending dose (MAD) study receiving relacorilant doses of 50 milligrams (mg), 150 mg, 250 mg, and 500 mg. Points with bars indicate the mean QTc value at Cmax (time of maximum relacorilant plasma concentration) for each dose ± 90% confidence interval (CI) for such points; the line connecting these geometric means indicates the predicted mean ΔΔQTcF, and the band around the line provides the 90% CI for the prediction. The placebo-corrected predicted change in QTc is less than 10 milliseconds (ms) for doses of 50 mg, 150 mg, 250 mg, and 500 mg. Colored markers and error bars: predicted mean (90% CI) ΔΔQTcF at the observed geometric mean relacorilant maximum concentration (Cmax). Dashed line: 10-ms ΔΔQTcF effect threshold. Solid line and grey shaded area: predicted mean ΔΔQTcF with 90% CI. CI, confidence interval. MAD formula: ΔΔQTcF = -1.804 (msec) - 2.341 (msec / ng / mL) × relaxorilant concentration (ng / mL). [Figure 3A] Figures 3A-3E show the change in QTc over an 8-hour period after administration of relacorilant. At 2 hours (time of Cmax), there was a slight decrease in QTc. Data were obtained from 103 healthy volunteers who received single or multiple ascending doses (SAD / MAD) of relacorilant (up to 500 mg QD) for up to 14 days; 24 healthy volunteers who received placebo. Abbreviations: ΔΔQTcF = placebo-corrected baseline QTcF change; 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. Figure 3A shows the change in QTc over an 8-hour period after administration of a single dose of 5 mg, 15 mg, or 50 mg of relacorilant. The doses were 5 mg (circles); 15 mg (squares); and 50 mg (triangles). [Figure 3B]Figures 3A-3E show the change in QTc over an 8-hour period after administration of relacorilant. At 2 hours (time of Cmax), there was a slight decrease in QTc. Data were obtained from 103 healthy volunteers who received single or multiple ascending doses (SAD / MAD) of relacorilant (up to 500 mg QD) for up to 14 days; 24 healthy volunteers who received placebo. Abbreviations: ΔΔQTcF = placebo-corrected baseline QTcF change; 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. Figure 3B shows the change in QTc over an 8-hour period after administration of a single dose of 150 mg, 300 mg, or 500 mg of relacorilant. The doses were 150 mg (circle); 300 mg (square); and 500 mg (triangle). [Figure 3C] Figures 3A-3E show the change in QTc over an 8-hour period after administration of relacorilant. At 2 hours (time of Cmax), there was a slight decrease in QTc. Data were obtained from 103 healthy volunteers who received single or multiple ascending doses (SAD / MAD) of relacorilant (up to 500 mg QD) for up to 14 days; 24 healthy volunteers who received placebo. Abbreviations: ΔΔQTcF = placebo-corrected baseline QTcF change; 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. Figure 3C shows the change in QTc over an 8-hour period after the first daily multiple dose of relacorilant was administered. The doses were 50 mg / day (circles); 150 mg / day (squares); 250 mg / day (triangles pointing up); and 500 mg / day (triangles pointing down). [Figure 3D]Figures 3A-3E show the change in QTc over an 8-hour period after administration of relacorilant. At 2 hours (time of Cmax), there was a slight decrease in QTc. Data were obtained from 103 healthy volunteers who received single or multiple ascending doses (SAD / MAD) of relacorilant (up to 500 mg QD) for up to 14 days; 24 healthy volunteers who received placebo. Abbreviations: ΔΔQTcF = placebo-corrected baseline QTcF change; 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. Figure 3D shows the change in QTc over an 8-hour period after administration of multiple daily doses of relacorilant for 7 days. The doses were 50 mg / day (circles); 150 mg / day (squares); 250 mg / day (triangles pointing up); and 500 mg / day (triangles pointing down). [Figure 3E] Figures 3A-3E show the change in QTc over an 8-hour period after administration of relacorilant. At 2 hours (time of Cmax), there was a slight decrease in QTc. Data were obtained from 103 healthy volunteers who received single or multiple ascending doses (SAD / MAD) of relacorilant (up to 500 mg QD) for up to 14 days; 24 healthy volunteers who received placebo. Abbreviations: ΔΔQTcF = placebo-corrected baseline QTcF change; 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. Figure 3E shows the change in QTc over an 8-hour period after administration of multiple daily doses of relacorilant for 14 days. The doses were 50 mg / day (circles); 150 mg / day (squares); 250 mg / day (triangles pointing up); and 500 mg / day (triangles pointing down). [Figure 4A]Figure 4A shows the results of the TQT study on days 1 and 5 of administration of relacorilant (400 mg (squares) or 800 mg (triangles)) or moxifloxacin (positive control; diamonds). Note that ΔΔQTcF appears to decrease with time after relacorilant administration. These results rule out an adverse effect of relacorilant on ΔΔQTcF over the 24-hour period on days 1 or 5 of relacorilant administration. The dashed line indicates the 10-msec ΔΔQTcF effect threshold. [Figure 4B] Figure 4B shows similar TQT study results to those shown in Figure 4A, but for only the 5th day after administration of relacorilant (400 mg (filled circles) or 800 mg (filled triangles)) or moxifloxacin (positive control; circles). These results rule out an adverse effect of relacorilant on ΔΔQTcF over 24 hours on the 5th day of relacorilant administration. Baseline QTcF was calculated using data extracted from ECG recordings taken 45, 30, and 15 minutes before administration. The mean of the QTcF data is shown in Figures 4A and 4B. In both Figures 4A and 4B, the LS means and 90% CI values ​​are based on a linear mixed-effects model with ΔQTcF as the independent variable, period, sequence, time, treatment, and time by treatment interactions as fixed effects, and baseline QTcF as the covariate. The unstructured covariance matrix was unable to converge, so an autoregressive structure was used to specify repeated measurements at post-dose time points for each participant during treatment. The dashed line indicates the 10-msec ΔΔQTcF effect threshold. [Figure 5]Figure 5 shows the results and theoretical modeling of the TQT study, which eliminate an adverse effect of relacorilant on ΔΔQTcF over a range of relacorilant concentrations up to approximately 4500 ng / mL. Markers and error bars: estimated mean (90% CI) ΔΔQTcF at the geometric mean maximum relacorilant concentration observed with therapeutic (400 mg dose; square symbols) and supratherapeutic (800 mg dose; triangle symbols) dosing. Dashed line: 10-ms ΔΔQTcF effect threshold. Solid line and shaded area: predicted mean ΔΔQTcF with 90% CI, calculated from ΔΔQTcF = -1.2501 (msec) - 0.97 (× 10 msec / ng / mL) × relacorilant concentration (ng / mL). The solid black line and gray shaded area represent the model-predicted mean ΔΔQTcF and 90% CI, calculated from the formula ΔΔQTcF = -1.2501 (msec) - 0.97 (× 10 msec / ng / mL) × relacorilant concentration (ng / mL). The square and triangle data points and error bars represent the estimated mean (90% CI) ΔΔQTcF at the geometric mean relacorilant Cmax from therapeutic (400 mg) and supratherapeutic (800 mg) dosing, respectively. The dashed line indicates the 10-ms ΔΔQTcF effect threshold. [Figure 6A] Figure 6A shows median QTcF values ​​in CS patients receiving low-dose relacorilant (100 mg / day to 200 mg / day relacorilant). No significant changes in median QTcF were observed in the low-dose group. Data are median QTcF at baseline and median (95% CI) QTcF at weeks 2 to 16, based on 13 to 17 patients in the low-dose group. Baseline is defined as the mean of three readings at the final visit before the first dose of study drug. Low-dose relacorilant included 100 mg / day for 4 weeks, followed by 150 mg / day for 4 weeks, and then 200 mg / day for 4 weeks. Abbreviations (throughout this application): BL = baseline; CS = Cushing's syndrome. [Figure 6B]Figure 6B shows median QTcF values ​​in CS patients receiving high-dose relacorilant (250 mg / day to 400 mg / day relacorilant). No significant changes in median QTcF were observed in the high-dose group. Data are median QTcF at baseline and median (95% CI) QTcF at weeks 2 to 16, based on 9 to 17 patients in the high-dose group. Baseline is defined as the mean of three readings at the final visit before the first dose of study drug. High-dose relacorilant included 250 mg / day for 4 weeks, followed by 300 mg / day for 4 weeks, then 350 mg / day for 4 weeks, and then 400 mg / day for 4 weeks. Abbreviations (throughout this application): BL = baseline; CS = Cushing's syndrome. DETAILED DESCRIPTION OF THE INVENTION

[0014] Introduction QT prolongation is a significant concern for patients with CS. Approximately one-quarter of men have been reported to have QT prolongation (Giraldi et al. Exp Clin Endocrinol Diabetes 2011;119(4):221-224). A higher degree of QT prolongation correlates with a greater risk of cardiac arrhythmic events, including potentially fatal torsades de pointes. Cardiac arrhythmias are also associated with an increased risk of heart attack, stroke, and sudden death, among other serious, potentially fatal, cardiac and cardiovascular disorders. Compounds previously used to treat CS include levocetoconazole, ketoconazole, osilodrostat, pasireotide, and mifepristone. All approved medical treatments for CS have been associated with QT prolongation (e.g., levocetoconazole (RECORLEV)). (登録商標) ) and osilodrostat (ISTURISA (登録商標) ) for more information.

[0015] Therefore, there is an unmet need for safe CS agents that do not cause QT prolongation and potentially fatal arrhythmias or other serious cardiac and cardiovascular disorders. As disclosed herein, heteroaryl ketone-fused azadecalin compounds, including the heteroaryl ketone-fused azadecalin compound, relacorilant, may meet this need. Administration of relacorilant does not cause QT prolongation.

[0016] There is a further unmet need for methods and treatments for reducing the QT interval and for treatments for QT prolongation in patients in need. There is a further unmet need for safe CS agents that can reduce the QT interval in patients in need, including in CS patients with a prolonged QT interval. The use of heteroaryl ketone-fused azadecalin compounds, such as relacorilant, may provide improved methods for treating and reducing a prolonged QT interval in patients in need, including CS patients. The methods, uses, and compositions disclosed herein may reduce the QT interval, including doses of, for example, about 400 mg / day, 500 mg / day, or up to 800 mg / day, and may be useful for treating QT prolongation in patients, including CS patients.

[0017] This application demonstrates the absence of QT prolongation with administration of relacorilant in healthy subjects (NCT03508635, "Phase 1 Study"); in a thorough QT study in healthy volunteers (NCT04795479, "TQT Study"); and in patients with CS (from a Phase 2 study in patients with CS (NCT02804750, "CS Study"). Thus, the heteroaryl ketone-fused azadecalin compound, relacorilant, can be safely administered to patients at risk for QT prolongation, including patients with CS, and to patients with QT prolongation, including patients with CS (e.g., male CS patients without QT prolongation). As discussed below, a trend toward decreased ΔΔQTcF was observed at higher relacorilant concentrations (Figures 2A and 2B), with the highest concentrations A reduction in ΔΔQTcF was observed at 2 h (Figures 3A-3E). Figures 4A and 4B show that relacorilant (at doses of 400 mg and 800 mg) had no adverse effect on the QT interval, whereas moxifloxacin did (as expected for a positive control compound). Figure 5 shows clinical QT outcomes in healthy volunteer subjects administered relacorilant, and associated theoretical modeling, which eliminates the adverse effect of relacorilant on ΔΔQTcF over a range of relacorilant concentrations up to approximately 4500 ng / mL. In Figures 6A and 6B, results from a study in CS patients (receiving either low or high doses of relacorilant) show that no significant changes in median QTcF were observed in either dose group.

[0018] Therefore, this study aims to assess the maximum plasma concentration (C) of relacorilant after administration of doses greater than 400 mg / day, e.g., 800 mg / day. max) have shown that this does not result in a significant prolongation of the QT interval. (Previous studies of relacorilant used relacorilant doses of 500 mg / day or less.) Therefore, heteroaryl ketone-fused azadecalin compounds, such as relacorilant, can be administered to CS patients at doses greater than 400 mg / day without significantly increasing the risk of cardiac arrhythmias and, therefore, without significantly increasing the risk of heart attack, stroke, or sudden death, among the multiple potential adverse side effects of QT prolongation.

[0019] In embodiments, the methods and uses may be applied to CS patients at high risk for QT prolongation, including CS patients with a prolonged QT interval or a prolonged QTc interval. Administering the heteroaryl ketone-fused azadecalin compound, relacorilant, does not increase the QT interval, and therefore, administration to CS patients with a prolonged QT interval is not believed to increase the risk of arrhythmias and other cardiac and cardiovascular disorders in such CS patients. Administering the heteroaryl ketone-fused azadecalin compound, relacorilant, does not increase the QT interval, and therefore, administration to CS patients receiving drugs that prolong the QT interval is not believed to further increase the risk of arrhythmias and other cardiac and cardiovascular disorders in CS patients. Although administering relacorilant with food increases its bioavailability, because the heteroaryl ketone-fused azadecalin compound, relacorilant, does not increase the QT interval, administration of relacorilant at doses up to and above 400 mg with food has not been shown to increase the risk of arrhythmias and other cardiac and cardiovascular disorders (as disclosed herein, doses of 500 mg / day and 800 mg / day have been safely administered to subjects).

[0020] In embodiments of the methods and uses disclosed herein, the patient's QT interval measured after administration of the heteroaryl ketone-fused azadecalin compound does not differ by more than 10 milliseconds (ms or msec) from the patient's baseline QT interval measured before administration of the heteroaryl ketone-fused azadecalin compound. In embodiments, the effective amount of the heteroaryl ketone-fused azadecalin compound is about 50 milligrams per day (mg / day) to about 400 mg / day, or about 500 mg / day. In further embodiments, the effective amount of the heteroaryl ketone-fused azadecalin compound is about 50 milligrams per day (mg / day) to about 800 mg / day. In embodiments, the heteroaryl ketone-fused azadecalin compound is administered orally. In embodiments, the heteroaryl ketone-fused azadecalin compound is administered to a fasting patient (i.e., a patient who has not eaten for at least 4 hours prior to administration of the heteroaryl ketone-fused azadecalin compound). In embodiments, the heteroaryl ketone-fused azadecalin compound is administered to a fed patient (i.e., a patient who has eaten a meal less than one hour prior to administration of the heteroaryl ketone-fused azadecalin compound). In embodiments, the heteroaryl ketone-fused azadecalin compound is administered to the patient with a meal. In embodiments, the heteroaryl ketone-fused azadecalin compound is a relaxolant.

[0021] In the studies disclosed herein, administration of relacorilant to healthy subjects resulted in a modest decrease in the QT interval (measured by the heart rate-corrected QTc interval) compared to placebo. For example, a trend toward a reduction in the placebo-corrected change in the QTc interval (ΔΔQTcF) was observed at higher relacorilant concentrations (a reduction in ΔΔQTcF was observed 2 hours after relacorilant administration, the time at which the maximum plasma concentration of relacorilant was observed). Therefore, it is believed that relacorilant may be useful for reducing or normalizing the QTc interval in patients with QTc interval prolongation.

[0022] Accordingly, Applicant discloses a method of treating a patient suffering from CS and a prolonged QT interval, comprising: identifying the patient as suffering from CS with a prolonged QT interval, the QT interval being the length of the time interval between the onset of the QRS complex of the ECG and the end of the T wave of the ECG; and administering an effective amount of a heteroaryl ketone-fused azadecalin compound, such as relacolinant, wherein the effective amount is about 400 milligrams per day (mg / day) to about 800 mg / day of the heteroaryl ketone-fused azadecalin compound, thereby treating the patient's CS and prolonged QT interval. In an embodiment, the effective amount of the heteroaryl ketone-fused azadecalin compound is about 500 mg to about 800 mg. In an embodiment, the patient is male.

[0023] Applicant discloses a method for reducing a QT interval in a patient with a prolonged QT interval, the QT interval being the length of the time interval between the onset of the QRS complex of an electrocardiogram (ECG) and the end of the T wave of the ECG, comprising administering to the patient an effective amount of a heteroaryl ketone-fused azadecalin compound, e.g., an effective amount of relacorilant, thereby reducing the QT interval in the patient. In an embodiment, the method for reducing a QT interval in a patient with a prolonged QT interval comprises determining that the patient is suffering from a prolonged QT interval. In an embodiment of the method for reducing a QT interval in a patient with a prolonged QT interval, the patient is male.

[0024] Applicants disclose herein the use of heteroaryl ketone-fused azadecalin compounds, such as relacorilant, to treat a patient suffering from CS without significantly prolonging the patient's QT interval. Applicants disclose herein the use of heteroaryl ketone-fused azadecalin compounds, such as relacorilant, in the manufacture of a medicament for treating a patient suffering from CS without significantly prolonging the patient's QT interval. Applicants disclose herein a pharmaceutical composition comprising a GRM heteroaryl ketone-fused azadecalin compound, such as SGRM relacorilant, for treating a patient suffering from CS without significantly prolonging the patient's QT interval. Applicants disclose herein the use of heteroaryl ketone-fused azadecalin compounds, such as relacorilant, to reduce the QT interval in patients in need thereof, including CS patients suffering from a prolonged QT interval. Such uses include the use of heteroaryl ketone-fused azadecalin compounds, such as relacolinant, in the manufacture of a medicament for treating a male patient.

[0025] Novel methods and uses of heteroaryl ketone-fused azadecalins Disclosed herein are novel methods and uses of the disclosed compounds for treating CS. The methods and uses provide treatment for patients suffering from CS without significantly affecting cardiac rhythm. For example, the methods and uses provide treatment for patients suffering from CS without significantly affecting the QT interval. The methods include administering to a subject an effective amount of a heteroaryl ketone-fused azadecalin compound. Preferably, the heteroaryl ketone-fused azadecalin compound is a GRM:GR modulating compound. In embodiments, the heteroaryl ketone-fused azadecalin compound is a selective GRM (SGRM) compound that has little or no modulating effect on other steroid hormone receptors (e.g., progesterone receptor, aldosterone receptor, or androgen receptor).

[0026] 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), the method comprises administering to a subject an effective amount of a heteroaryl ketone-fused azadecalin compound, wherein the heteroaryl ketone compound is a compound described in U.S. Pat. No. 8,859,774 (which is incorporated herein by reference in its entirety) having the following structure, or salts and isomers thereof: [ka] During the ceremony R 1 has a 5- to 6-membered ring and 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S; R 1a is a heteroaryl ring optionally substituted by 1 to 4 groups independently selected from Each R 1a is 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 independently selected from the group consisting of heterocycloalkyl; Ring J is selected from the group consisting of a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring, and a heteroaryl ring, and the heterocycloalkyl and heteroaryl rings have 5- to 6-membered rings and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; Each R 2 is hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 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 the heterocycloalkyl group is independently selected from the group consisting of 1 to 4 R 2c optionally substituted by groups; Alternatively, two R's attached to the same carbon 2 groups taken together form an oxo group (=O); Alternatively, two R 2 groups taken together form a 5- to 6-membered ring and a heterocycloalkyl ring having 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S, and the heterocycloalkyl ring is 2d optionally substituted by groups; R 2a and R 2b is hydrogen and C 1-6 are each independently selected from the group consisting of alkyl; Each R 2c is hydrogen, halogen, hydroxy, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -CN, and -NR 2a R 2b independently selected from the group consisting of: Each R 2d is hydrogen and C 1-6 alkyl, or two R attached to the same ring atom 2d The groups together form (=O); R 3 is 1 to 4 R 3a selected from the group consisting of phenyl and pyridyl, each of which may be substituted by a group; Each R 3a is hydrogen, halogen, and C 1-6 independently selected from the group consisting of haloalkyl; The subscript n is an integer from 0 to 3.

[0027] In embodiments, the methods disclosed herein for treating CS and reducing the QT interval comprise administering to a subject an effective amount of the SGRM heteroaryl ketone-fused azadecalin compound, relacorilant. Relacorilant (also referred to as "CORT125134") has the following structure: ((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). [ka] Relacorilant is disclosed in Example 18 of US Pat. No. 8,859,774, which is incorporated herein by reference in its entirety.

[0028] In embodiments, the methods disclosed herein may be used to treat patients suffering from CS by administering an effective amount of a heteroaryl ketone-fused azadecalin GRM or SGRM that is effective in treating CS without causing significant QT prolongation, in combination with another CS treatment.

[0029] In embodiments of the methods disclosed herein, an effective amount of a heteroaryl ketone-fused azadecalin GRM or SGRM (e.g., relacolinant) is administered to a patient suffering from CS effective to treat the patient. Such administration can be daily (e.g., once daily, or twice daily, or three times daily) or at other intervals (e.g., every other day, or once every three days, or other intervals). In embodiments, an effective amount for treating CS by administration of a GRM or SGRM, such as relacorilant, 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 amount effective to treat CS. In embodiments, the heteroaryl ketone-fused azadecalin GRM or SGRM (e.g., relacorilant) can be administered orally, with food, with water, or with both food and water. Typically, the GRM (e.g., an SGRM such as relacorilant) is administered once daily; however, in embodiments, administration can be twice daily, or three times daily, or every other day, or every third day, or every fourth day, or at other intervals as needed or convenient. Administration of the heteroaryl ketone-fused azadecalin GRM or SGRM (e.g., relacorilant) can continue for weeks, months, or years as needed; for example, relacorilant administration can continue for weeks, months, or years as needed.

[0030] An effective amount of relacorilant, or other GRM or SGRM, can be administered to a patient orally, for example, by mouth, in the form of a capsule, pill, tablet, fluid, emulsion, or other composition suitable for oral administration. Relacorilant can be administered with food, with water, or with both food and water. In other embodiments, the GRM (e.g., relacorilant) can be administered in the absence of food, and can be administered to a fasting subject or patient in the absence of food.

[0031] definition As used herein, the term "AE(s)" is an acronym for adverse event(s).

[0032] As used herein, the term "AR" refers to the accumulation ratio (the ratio between plasma exposure at steady state and plasma exposure on the first day of dosing).

[0033] As used herein, the term "AUC" refers to the area under the plasma concentration-time curve calculated using the linear-increase / log-decrease trapezoidal method.

[0034] As used herein, the term "AUC 0-24 " refers to the AUC from time zero to 24 hours after administration.

[0035] As used herein, the term "AUC 0-tau " refers to the AUC from time zero to the end of the dosing interval.

[0036] As used herein, the term "AUC inf " refers to the AUC extrapolated from time 0 to infinity.

[0037] As used herein, the term "AUC last ” is the time from time 0 to the last measurable concentration (C last ) refers to the AUC up to

[0038] As used herein, the terms "beat" and "heartbeat" refer to a single heartbeat, including the T wave, QRS complex, and P wave. Such T waves, QRS complexes, PR intervals, QT intervals, P waves, and other features of the ECG are defined as recognized in the art (e.g., Berne and Levy, 2003). rd (See Figures 2-25 and text on pages 40-41 of Cardiovascular Physiology, Volume 1, Issue 1, 1977.)

[0039] As used herein, the term "C avg " refers to the average concentration over the dosing interval.

[0040] As used herein, the term "C max " refers to the maximum observed plasma concentration.

[0041] As used herein, the term "C min " refers to the minimum observed plasma concentration over the dosing interval.

[0042] As used herein, the term "Δ" refers to change from baseline.

[0043] As used herein, the term "ΔΔ" refers to the placebo-corrected change from baseline.

[0044] As used herein, the term "ECG" is an acronym for electrocardiogram.

[0045] As used herein, the "Fridericia formula" refers to the QTcF = (QT) / (RR 1 / 3 )

[0046] As used herein, the term "FI" refers to the fluctuation index (an assessment of the fluctuation observed from peak to trough plasma concentrations during the dosing interval).

[0047] As used herein, the term "HR" refers to heart rate.

[0048] As used herein, the term "ΔHR" refers to the change in heart rate from baseline.

[0049] As used herein, the term "ΔΔHR" refers to the placebo-corrected change from baseline in heart rate.

[0050] 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.

[0051] Moxifloxacin is marketed as Avelox® as 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 for clinical use as an antibiotic. (登録商標) Moxifloxacin is a fluoroquinolone compound sold as a fluoroquinolone. Moxifloxacin has been shown to prolong the QT interval on the electrocardiogram in some patients. Its chemical structure is: [ka]

[0052] As used herein, the phrase "multiple ascending doses" and its acronym "MAD" refer to the administration of more than one dose of a test drug (e.g., relacorilant) to each of a group of subjects, and the results obtained from such subjects after such administration. Each subject receives an initial low dose, followed by increasing doses of the test drug.

[0053] As used herein, the term "PR" refers to the PR interval of an ECG.

[0054] As used herein, the term "ΔPR" refers to the change in PR interval from baseline.

[0055] As used herein, the term "ΔΔPR" refers to the placebo-corrected change from baseline in the PR interval.

[0056] As used herein, the term "QD" refers to once-daily drug administration.

[0057] As used herein, the term "QRS" refers to the QRS interval of an ECG.

[0058] As used herein, the term "ΔQRS" refers to the change in QRS interval from baseline.

[0059] As used herein, the term "ΔΔQRS" refers to the placebo-corrected change from baseline in QRS interval.

[0060] As used herein, the term "QT interval" refers to the QT interval of an ECG, which is the interval from the onset of ventricular depolarization to the end of ventricular repolarization (the time interval between the onset of the "QRS" complex and the end of the "T" wave of an ECG). In healthy individuals, the "QT interval" is approximately 400 milliseconds (ms) (typically about 350 ms to 450 ms). As used herein, the term "QT interval" refers to the interval between the onset of the QRS complex and the end of the T wave; therefore, the term QT ​​interval refers to both the uncorrected interval and any calculated interval, including QTcF, but also includes the heart rate corrected QT interval "QTc," where QTc is calculated according to the Fridericia formula.

[0061] As used herein, the term "QTc" refers to the corrected QT interval of an ECG 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 successive R peaks of successive QRS complexes). (Other methods are to divide by the cube root of the RR interval or use linear regression; see, e.g., Al-Khatib et al., JAMA 289(16):2120-2127(2003)).

[0062] As used herein, the term "QTcF" refers to the QT interval of an ECG corrected for heart rate using the Fridericia formula. QTcF is calculated using the Fridericia formula by dividing the measured QT interval by the cube root of the RR interval: QTcF = (QT) / (RR 1 / 3 ) is used to calculate it.

[0063] As used herein, the term "ΔΔQTcF" refers to the placebo-corrected change from baseline in QTcF.

[0064] As used herein, the term "adverse effect" as applied to placebo-corrected ΔQTcF (ΔΔQTcF) refers to an increase in ΔΔQTcF (indicating a prolonged QT interval). Numerical values ​​are typically applied in reference to an "adverse effect," e.g., "adverse effect >10 msec" means that the increase in ΔΔQTcF is less than 10 msec.

[0065] As used herein, the terms "prolonged QT interval," "significant QT prolongation," and the like refer to an increase in the QT interval or QTc interval of more than 10 msec compared to a patient's baseline QT interval or baseline QTc interval. When a patient's baseline QT interval is not known, a QT interval of more than about 450 ms in men or more than about 470 ms in women is considered to be a prolonged QT interval. A QTcF interval of more than about 500 ms in patients with a wide QRS interval (a QRS interval of more than about 120 ms is considered a wide QRS interval) is considered to be a high QTcF interval.

[0066] As used herein, the term "RR" refers to the RR interval of an ECG.

[0067] As used herein, the phrase "single ascending dose" and its acronym "SAD" refer to the administration of a single dose of a test drug (e.g., relacorilant) to a group of subjects (typically healthy volunteer subjects) and the results obtained from those subjects after such administration. Typically, a low dose is administered to a first group of subjects; higher doses are then administered to a different group of subjects; and even higher doses are given to yet another group of subjects to provide data on a dose range of the test drug.

[0068] As used herein, the term "SAE(s)" is an acronym for serious adverse event(s).

[0069] As used herein, the term "t 1 / 2 " refers to the apparent terminal elimination half-life.

[0070] As used herein, the term "T max " is the maximum plasma concentration (C max ) after administration.

[0071] As used herein, the term "TEAE(s)" is an acronym for treatment-emergent adverse event(s).

[0072] As used herein, the term "TQT" is an acronym for thorough QT / QTc, a controlled study assessing the effect of drugs such as moxifloxacin or relacorilant on cardiac repolarization. As used herein, the effect on cardiac repolarization was assessed by the drug effect (or lack thereof) on the corrected QT (QTc) interval.

[0073] As used herein, the term "patient" refers to a human who is receiving, will be receiving, or has received medical treatment for a disease or condition, such as, for example, CS.

[0074] As used herein, the term "effective amount" or "therapeutic amount" refers to an amount of a pharmacologically active agent effective to treat, eliminate, or alleviate at least one symptom of the disease being treated. In some cases, a "therapeutically effective amount" or "effective amount" may refer to an amount of a functional agent or pharmaceutical composition useful to exhibit a detectable therapeutic or inhibitory effect. Such an effect may be detected by any assay method known in the art.

[0075] As used herein, the terms "significant" and "significantly," when used to characterize a change in value or effect, refer to a change in value or effect that is expected to have a clinical effect. For example, a significant change in QT or QTc interval is a change of more than 10 milliseconds (ms) compared to the baseline QT or QTc interval.

[0076] As used herein, the terms "substantial" and "substantially," when used to characterize a change in value or effect, refer to a change in value or effect that is expected to have a clinical effect. For example, a substantial change in QT or QTc interval is a change of more than 10 milliseconds (ms) compared to the baseline QT or QTc interval.

[0077] As used herein, the terms "administer," "administering," "administered," or "administration" refer to giving a compound or composition (e.g., those described herein) to a subject or patient. For example, a compound or composition may be orally administered to a patient (i.e., the subject receives the compound or composition via the mouth as a pill, capsule, liquid, or other form suitable for administration via the mouth. Oral administration may be buccal (the compound or composition is held in the mouth, e.g., under the tongue, where it is absorbed). Administration may be injection, i.e., delivery, of the compound or composition via a needle, microneedle, douche, or other means of piercing the skin of the subject or forcing the compound or composition through the skin. Injection may 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. Routes of administration may also include rectal, intravaginal, transdermal, via the lungs (e.g., by inhalation), subcutaneous (e.g., by absorption into the skin from an implant containing the compound or composition), or by other routes.

[0078] As used herein, the term "combination therapy" refers to the administration of at least two pharmaceutical agents to a subject to treat a disease. The two agents may be administered simultaneously or in any order during all or part of the treatment period. The at least two agents may be administered following the same or different dosing regimens.

[0079] As used herein, the term "glucocorticoid receptor" ("GR") refers to type II GR, a family of intracellular receptors that specifically bind glucocorticoids, such as cortisol, and / or cortisol analogs, such as dexamethasone (see, e.g., Turner & Muller, J. Mol. Endocrinol. October 1, 2005, 35, 283-292). (The term "glucocorticoid" is sometimes abbreviated as "GC"). The type II glucocorticoid receptor is also referred to as the cortisol receptor. The term includes GR isomers, recombinant GRs, and mutant GRs.

[0080] The term "glucocorticoid receptor modulator" (GRM) refers to any compound that modulates glucocorticoid binding to GR or modulates any biological response associated with GR binding to an agonist. For example, GRMs acting as agonists, such as dexamethasone, increase the activity of tyrosine aminotransferase (TAT) in HepG2 cells (human hepatocellular carcinoma cell line; ECACC, UK). GRMs acting as antagonists, such as mifepristone, decrease the activity of tyrosine aminotransferase (TAT) in HepG2 cells. TAT activity can be measured as outlined in A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452.

[0081] As used herein, the term "selective glucocorticoid receptor modulator" (SGRM) refers to a composition or compound, a selective GRM, that selectively modulates glucocorticoid binding to GR or any biological response associated with GR binding to an agonist. By "selective," it is meant that the drug binds preferentially to GR rather than other nuclear receptors, such as the progesterone receptor (PR), the corticoid receptor (MR), or the androgen receptor (AR). A selective glucocorticoid receptor modulator has a K >10× greater affinity for MR, AR, or PR, both MR and PR, both MR and AR, both AR and PR, or MR, AR, and PR. d Preferably, the receptor binds to GR with an affinity that is 1 / 10 of the value of the receptor.

[0082] As used herein, the term "compound" is used to refer to a molecular moiety of a unique, identifiable chemical structure. A molecular moiety ("compound") can exist in the form of a free species, not associated with other molecules. A compound can also exist as part of a larger aggregate that is not associated with other molecule(s), but nevertheless retains its chemical identity. A solvate, in which a molecular moiety of a defined chemical structure ("compound") is associated with a molecule(s) of solvent, is an example of such an associated form. A hydrate is a solvate in which the associated solvent is water. A description of a "compound" refers to the molecular moiety itself (of the described structure), whether it exists in free or associated form.

[0083] As used herein, the term "composition" is intended to encompass products containing specific components, such as the above-mentioned compounds, their tautomeric forms, their derivatives, their analogs, their stereoisomers, their polymorphs, their deuterated species, their pharmaceutically acceptable salts, esters, ethers, metabolites, isomeric mixtures, their pharmaceutically acceptable solvates, and pharmaceutically acceptable compositions, in specific amounts, as well as any product obtained directly or indirectly from combining the above-mentioned specific components in the above-mentioned specific amounts. Such terms, relating to pharmaceutical compositions, are intended to encompass products containing active ingredient(s) and inactive ingredient(s) constituting the carrier, as well as any product obtained directly or indirectly from the combination, grouping, or aggregation of any two or more of the above-mentioned components, or from the dissociation of one or more of the components, or from other types of reaction or interaction of one or more of the components. Thus, the pharmaceutical compositions of the present invention are intended to encompass any composition made by combining a compound of the present invention with a pharmaceutically acceptable carrier.

[0084] As used herein, the terms "pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to a substance that aids in the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing significant negative toxicological effects to the patient. These terms are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active agents is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, its use in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0085] "Salt" refers to an acid or base salt of a compound used in the methods disclosed herein. Illustrative examples of pharmaceutically acceptable salts are mineral acid salts (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), organic acid salts (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.), and quaternary ammonium salts (such as methyl iodide, ethyl iodide, etc.). It is understood that pharmaceutically acceptable salts are non-toxic. Further information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0086] Pharmaceutical Compositions and Administration In embodiments, the present invention provides pharmaceutical compositions for treating CS, the pharmaceutical compositions comprising a pharmaceutically acceptable formulation excipient and a GRM, such as relacorilant. In some embodiments, the pharmaceutical compositions comprise a pharmaceutically acceptable formulation excipient and an SGRM. In preferred embodiments, the pharmaceutical composition comprises relacorilant and pharmaceutically acceptable formulation excipient(s).

[0087] Suitable formulations can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms. GRMs and SGRMs can be administered orally. For example, the GRMs can be administered as pills, capsules, or liquid formulations as described herein. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, and the like, suitable for ingestion by patients. Alternatively, GRMs and SGRMs can also be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally.

[0088] For preparing pharmaceutical compositions from GRMs and SGRMs, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A 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 regarding formulation and administration techniques are well documented in the scientific and patent literature; see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton PA ("Remington's"), most recent publications.

[0089] In powders, the carrier is a finely divided solid in admixture with the finely divided active ingredient, a heteroaryl ketone-fused azadecalin GRM or SGRM, such as relacolinant. In tablets, the active ingredient is mixed with a carrier having the required binding properties in suitable proportions and compacted into the desired shape and size.

[0090] The powders and tablets preferably contain 5% or 10% to 70% of the active compound (e.g., relacolinant). Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting waxes, cocoa butter, and the like. The term "preparation" is intended to include formulations of the active compound combined with an encapsulating material as a carrier to provide a capsule in which the active ingredient is surrounded by the carrier, with or without other carriers. Cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0091] Suitable solid formulation excipients are carbohydrate or protein fillers, which may include, but are 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; and gums including acacia and tragacanth; and proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as cross-linked polyvinylpyrrolidone, agar, alginic acid, or a salt thereof, for example, sodium alginate.

[0092] Dragee cores are coated with suitable coatings such as gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and concentrated sugar solutions that may also contain suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings for product identification or to characterize the amount of active compound (i.e., dosage). The pharmaceutical preparations of the present invention can also be used orally using push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules may contain the GR modulator mixed with a filler or binder such as lactose or starch, a lubricant such as talc or magnesium stearate, and, optionally, a stabilizer. In soft capsules, the GR modulator compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol, with or without stabilizers.

[0093] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. Liquid preparations may contain a salt, for example, sodium chloride, or a sugar, for example, sucrose. For parenteral injection, liquid preparations may be formulated in solution in aqueous polyethylene glycol solution.

[0094] The pharmaceutical compositions disclosed herein may be provided as salts, which may be formed with a number of acids, including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. The corresponding free base salts tend to be more soluble in aqueous or other protic solvents. In other cases, the preparations may be lyophilized powders in 1 mM to 50 mM histidine, 0.1% to 2% sucrose, 2% to 7% mannitol, at a pH range of 4.5 to 5.5, which are combined with a buffer prior to use.

[0095] Also included are solid form preparations that are intended to be converted shortly before use into liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredients, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0096] Oil suspensions can be formulated by suspending the SGRM in vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, or in mineral oils such as liquid paraffin; or in mixtures thereof. The oil suspensions can contain thickening agents such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners such as glycerol, sorbitol, or sucrose can be used to provide a palatable oral preparation. These preparations can be preserved by adding an antioxidant such as ascorbic acid. For examples of injectable oil vehicles, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical formulations of the present invention can also be in the form of oil-in-water emulsions. The oil phase can be the above-mentioned vegetable oils or mineral oils, or mixtures thereof. Suitable emulsifying agents include naturally occurring gums such as acacia and tragacanth, naturally occurring phosphatides such as soybean lecithin, esters or partial esters derived from 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 emulsions may also contain sweeteners and flavoring agents, as in the preparation of syrups and elixirs. Such preparations may also contain a demulcent, preservative, or coloring agent.

[0097] The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing an appropriate amount of the active ingredient, for example, a GRM or GRMS, such as relacolinant. The unit dosage form may be a packaged preparation, such as a package containing discrete amounts of the preparation, such as packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form may also be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

[0098] The amount of active ingredient in a unit dose preparation may be varied or adjusted from 1 mg to 1000 mg, or from 10 mg to 800 mg, or, for example, from 50 mg to 500 mg. Suitable dosages also include about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg, depending on the specific use and efficacy of the active ingredient. The compositions may also contain other compatible therapeutic agents, if desired.

[0099] The formulation may provide a sufficient amount of active agent to effectively treat CS. Thus, in one embodiment, a pharmaceutical formulation for administration of a GRM, such as oral relacorilant, is administered in a daily dose of about 1 mg / kg body weight / day to about 20 mg / kg body weight / day (mg / kg / day), about 1.5 mg / kg / day to 15 mg / kg / day, or about 2 mg / kg / day to 10 mg / kg / day.

[0100] In some embodiments, the GRM is administered in one dose. For example, the GRM may be administered in a single dose given once per day. In other embodiments, the GRM is administered in more than one dose, for example, two, three, four, five, six, seven, or more doses. In some cases, the doses are of equal amounts. In other cases, the doses are of different amounts. The dose may increase or decrease over the length of administration. The amount may vary, for example, according to patient characteristics.

[0101] Any suitable GRM dose may be used in the methods disclosed herein. A suitable GRM dose may be a daily dose or may be a dose administered at other times (e.g., twice daily, every other day, once every three days, or other intervals). The administered dose of the GRM, e.g., relacorilant, may be at least about 50 milligrams (mg), or about 75 mg, e.g., 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 embodiments, the GRM is administered orally. In some embodiments, the GRM is administered in at least one dose. In other words, the GRM may be administered in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses. In embodiments, the GRM is administered orally in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses.

[0102] The length of treatment with a GRM or SGRM to treat CS can vary depending on the severity of the condition in a subject and the subject's response to the GRM or SGRM. In embodiments, the treatment may continue as long as needed. In embodiments, the treatment may continue as long as the patient is able to receive oral medication. In some embodiments, relacorilant may be administered for a period of up to about 2 years or more. In embodiments, administration of a heteroaryl ketone-fused azadecalin GRM or SGRM, such as relacorilant, may continue for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 10 weeks, 15 weeks, 20 weeks, 24 weeks, 30 weeks, 36 weeks, 48 ​​weeks, 50 weeks, 52 weeks, 100 weeks, 104 weeks, 156 weeks, or 208 weeks, or longer, as needed to treat the patient. In embodiments, administration of a GRM, such as relacorilant, may continue as long as the patient requires such administration or as long as the patient remains able to receive such GRM administration.

[0103] In some embodiments, administration of a GRM or SGRM is not continuous and can be stopped for one or more periods, after which administration begins again for one or more periods. Suitable periods for which administration can be stopped include 1 to 10 weeks, 2 to 8 weeks, 3 to 6 weeks, and 4 to 5 weeks.

[0104] GRMs and SGRMs may be used in combination with other active agents known to be useful in modulating the glucocorticoid receptor, or with adjuvants that may not be effective alone but may contribute to the efficacy of the active agents.

[0105] After being formulated in an acceptable carrier, pharmaceutical compositions containing a GR modulator of the invention can be placed in an appropriate container and labeled for treatment of an indicated condition. For administration of a GRM or SGRM, such labeling can include, for example, instructions regarding the amount, frequency, and method of administration. [Example]

[0106] The following examples are offered by way of illustration and not by way of limitation. Those of skill in the art will readily recognize a wide variety of non-critical parameters that could be changed or modified to give essentially similar results.

[0107] Example Evaluation of the effects of relacorilant on cardiac rhythm The studies disclosed herein evaluated the cardiac effects of relacorilant, a heteroaryl ketone-fused azadecalin compound, by determining the effects of therapeutic and supratherapeutic plasma concentrations of relacorilant 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 that higher doses of relacorilant tended to lower the QT interval. 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 therapeutic and supratherapeutic oral doses of relacorilant in healthy subjects.

[0108] This application includes results from three studies of relacorilant: a Phase 1, placebo-controlled, single- and multiple-ascending-dose (SAD / MAD) study (up to 500 mg of relacorilant over a maximum of 14 days) in healthy volunteers (NCT03508635); a Phase 1, placebo- and positive-controlled, thorough QTc study of therapeutic (400 mg) and supratherapeutic (800 mg) doses of relacorilant in healthy volunteers conducted in accordance with International Council for Harmonisation (ICH) regulatory guidelines (NCT04795479); and a Phase 2, open-label study of low-dose (200 mg) and high-dose (400 mg) relacorilant administered daily for up to 16 weeks in patients with endogenous CS (NCT02804750). All study participants had normal QTc intervals at the start of each study. Serial ECG recordings were obtained at baseline / pre-dose, and changes in QTc from baseline at multiple post-dose time points were calculated. The relationship between plasma relaxant concentrations and effects on the QTc interval was assessed using linear mixed-effects modeling.

[0109] In one aspect, these studies evaluated the safety and tolerability of therapeutic and supratherapeutic oral doses of relacorilant in healthy subjects. The therapeutic dose of relacorilant was set at 400 mg / day, in accordance with the daily therapeutic dose range of relacorilant of 100 mg to 400 mg in studies for the treatment of CS and for oncological applications. Data on the effect of food on relacorilant were obtained by measuring the maximum plasma concentration (C max ) demonstrated that plasma concentrations of relacorilant increased by approximately 34% and 41% when administered with a high-fat and a moderate-fat breakfast, respectively, compared to fasted conditions. Clinical data on relacorilant also indicated that drug-drug interactions and food effects resulted in only small, transient increases in relacorilant plasma concentrations in patients receiving the highest clinical dose of 400 mg / day. In addition, the FDA has set a relacorilant exposure limit of 40,000 ng*h / mL and advises that achieving multiple times the maximum exposure scenario in the presence of a separate positive control is not necessary. Therefore, these studies included 400 mg of moxifloxacin as a positive control, and the supratherapeutic dose of relacorilant was conservatively set at 800 mg / day (twice the therapeutic dose of relacorilant). A supratherapeutic dose of 800 mg once daily for 5 days was expected to result in plasma concentrations of relacorilant and its metabolites that exceeded those achieved in patients with the highest therapeutic dose of 400 mg / day.

[0110] These studies included a randomized, partially double-blind, placebo- and positive-controlled, multiple-dose, 4-way crossover, thorough QT / QTc (TQT) study investigating the effects of relacorilant on cardiac repolarization. These studies measured the following: placebo-corrected change from baseline in QTcF (ΔΔQTcF); change from baseline in QTcF, HR, and PR and QRS intervals (ΔQTcF, ΔHR, ΔPR, and ΔQRS); placebo-corrected change from baseline in HR, and PR and QRS intervals (ΔΔHR, ΔΔPR, and ΔΔQRS); categorical outliers for QTcF, HR, and PR and QRS intervals; treatment frequency-occurring changes in T-wave morphology and the presence of U waves; PK parameters of relaxorilant and its metabolites (CORT125337, CORT125336, and CORT125295) and moxifloxacin; and safety profile including AEs / SAEs, physical examination, clinical chemistry, hematology, urinalysis, ECG, and vital signs.

[0111] 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: First-in-Human Trials The Phase 1, three-stage, single-center, first-in-human trial (NCT03508635) included 103 healthy volunteers who received single or multiple ascending doses (SAD / MAD) of relacorilant (up to 500 mg QD) for up to 14 days; 24 received placebo. TQT Test A Phase 1, randomized, partially double-blind, crossover, thorough-quantity trial (NCT04795479) assessed the effects of multiple doses of relacorilant on cardiac repolarization in healthy volunteers. Participants were randomized to a dosing sequence to receive relacorilant at therapeutic (400 mg QD, n=25) or supratherapeutic (800 mg QD, n=28) doses or placebo (n=29) for 5 days. Moxifloxacin (400 mg single dose, n=28) was used as a positive control. CS exam A single-arm, open-label, phase 2 study (NCT02804750) in patients with CS. Seventeen patients received low-dose relacorilant (100 mg to 200 mg QD) for 12 weeks; 18 patients received high-dose relacorilant (250 mg to 400 mg QD) for 16 weeks.

[0112] In all studies, ECG data were collected and the heart rate-corrected QT interval was calculated using the Fridericia formula (QTcF). Participants with a family history or risk of torsades de pointes or a prolonged QT interval at screening were ineligible to participate. An exposure-response analysis of the effect of relaxant on the heart rate-corrected QT interval (QTc) was performed using a linear model with an intercept.

[0113] Relacorilant was administered orally to subjects via 100 mg soft gel capsules. The study involved administration of relacorilant to 103 healthy volunteers (receiving single or ascending doses of relacorilant up to 500 mg once daily (mg QD)). The study also involved multiple doses of relacorilant at 400 mg QD (n=25, "therapeutic dose") and 800 mg QD (n=28, "supratherapeutic dose") to healthy volunteers. The study also involved administration of relacorilant to patients with CS at 100-200 mg QD (n=17, low dose) or 250-400 mg QD (n=18, high dose). No significant QT prolongation associated with relacorilant administration was observed in the study.

[0114] A schematic diagram of the study protocol is presented in Figure 1.

[0115] Main study patient criteria Healthy male and female subjects were 18 to 55 years of age, had a body mass index (BMI) of ≥ 18.0 kg / m² and ≤ 30.0 kg / m², without any clinically significant abnormalities, and adequate cardiac conduction by electrocardiogram (ECG). Subjects with significant baseline prolongation of ECG intervals, including QTcF > 450 milliseconds (msec), PR > 200 msec, or QRS > 120 msec, or a resting heart rate < 45 bpm or > 100 bpm, were not enrolled in this study. The incidence of AEs / SAEs, as well as the results of physical examination, clinical blood chemistry, hematology, urinalysis, ECG, and vital signs, were analyzed in enrolled subjects as part of the study.

[0116] Safety assessments included adverse event (AE) or serious adverse event (SAE) monitoring throughout the entire study period, as well as physical examination, clinical chemistry, hematology, urinalysis, safety ECG assessment, and vital signs performed during each dosing period. If the ECG draw was consistent with the safety ECG, vital sign assessment and blood draw were performed, and procedures were performed in that order. The total volume of blood collected from each subject was approximately 470 mL during the entire study period, including screening procedures and the four dosing periods.

[0117] measurement ECG Measurements: During each dosing period, cardiac dynamic repeat ECGs were collected and extracted from continuous (Holter) recordings at approximately the same time as the collection of blood samples from the subjects, at three time points prior to dosing on Day 1 (-45, -30, and -15 minutes pre-dose) and once pre-dose on Day 5, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dose on Days 1 and 5.

[0118] Pharmacokinetic (PK) parameters PK analyses were performed using non-compartmental methods to obtain estimates of the following parameters, where possible: For Relacorilant and its metabolites (CORT125337, CORT125336, and CORT125295): Day 1:C max , T max , AUC last , and AUC 0-24 ; Day 5:C max , T max , C min , AUC last , AUC 0-tau , C avg , FI, and AR. About moxifloxacin: C max , T max , AUC last , and AUC 0-24 .

[0119] During each period, blood samples were collected pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dose on Days 1 and 5 of each dosing period. PK blood sampling on Day 1 was completed prior to dosing on Day 2. Plasma concentration data for relacorilant and its metabolites (CORT125337, CORT125336, and CORT125295) or moxifloxacin were determined using validated liquid chromatography tandem mass spectrometry (LC-MS / MS).

[0120] Evaluation criteria ECG parameters: The primary endpoint was placebo-corrected change from baseline in QTcF (ΔΔQTcF). Secondary endpoints included: Changes from baseline in QTcF, HR, PR, and QRS interval (ΔQTcF, ΔHR, ΔPR, and ΔQRS); placebo-corrected changes from baseline in HR, PR, and QRS (ΔΔHR, ΔΔPR, and ΔΔQRS); categorical outliers for QTcF, HR, PR, and QRS; Frequency of treatment - Appearance changes in T wave morphology and presence of U waves.

[0121] Test Procedures Each subject received four treatments in a randomized sequence over the course of the study. Each dose consisted of eight capsules (except for moxifloxacin on Day 5), containing: Treatment T: Multiple oral doses of 400 mg relacorilant (4 capsules) plus relacorilant placebo (4 capsules) once daily for 5 days; -Treatment ST: Multiple oral doses of 800 mg relacorilant (8 capsules) once daily for 5 days; Treatment P: Multiple oral doses of relacorilant placebo (8 capsules) once daily for 5 days; Treatment M: Multiple oral doses of relaxorilant placebo (8 capsules) once daily for 4 days, and a final single oral dose of 400 mg moxifloxacin (1 tablet) on the 5th day.

[0122] Subjects were randomized to one of 12 dosing sequences on Day -1 of Period 1 after confirmation of subject eligibility. Randomization was performed by a contracted contract research organization (CRO) adhering to relevant SOPs. The randomization scheme and code were generated using SAS® software.

[0123] Fasting / Diet during Confinement Subjects were admitted to the clinical site in the morning of Day -1 (one day prior to dosing, check-in day) of each dosing period. After check-in, subjects remained at the clinical site until the morning of Day 6 during each dosing period. A meal was provided on Day -1 of each period prior to an overnight fast of at least 10 hours prior to dosing the following morning (Day 1) of each dosing period. Water was allowed ad libitum during the confinement period of the study, except for one hour before and after dosing. Standard food and beverages were provided during this confinement period. A standard diet is defined as a low-fat diet with ≦20% of caloric intake from fat.

[0124] In the portion of the study conducted in healthy subjects, a single dose of moxifloxacin (400 mg; Treatment M) on the last day of each treatment period was included as a positive control to determine the sensitivity of the study to detect small QTc changes. Relacorilant doses included both a therapeutic dose level (400 mg; Treatment T) and a supratherapeutic dose level (800 mg; Treatment ST). The study was blinded to subjects, investigators, study staff, and sponsor to relacorilant (Treatment T and ST) and to relacorilant placebo (Treatment P); and open-label to moxifloxacin (Treatment M). Enrolled subjects were randomized to one of twelve (12) dosing sequences and received four different treatments according to the assigned dosing sequence shown below: [Table 1] M: 400 mg moxifloxacin; P: placebo for relacorilant; T: therapeutic dose (400 mg) of relacorilant; ST: supratherapeutic dose (800 mg) of relacorilant.

[0125] During each period, subjects were admitted to the clinical site in the morning of Day -1 and remained at the site until the morning of Day 6. Once subjects were randomized to Treatment T, ST, or P during the study period, they received the applicable study product (400 mg or 800 mg relacorilant or relacorilant placebo) once daily in the morning for 5 consecutive days. During the positive control (Treatment M) dosing period, relacorilant placebo was administered on Days 1-4 in conjunction with the dosing schedules of the other three treatments, and moxifloxacin was administered open-label as a single dose in the morning of Day 5. Therefore, the treatments on Days 1-4 were double-blind; prior to the morning of Day 5, subjects did not know whether they were assigned to receive moxifloxacin. Each dosing period (Periods 2–4) 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 subsequent period, to prevent carryover effects. The final visit was Day 6 of Period 4. A safety telephone follow-up was scheduled 7 days (±2 days) after the final / early termination (ET) visit.

[0126] During each dosing period, a 12-lead ECG was performed, and data were extracted from continuous recordings (Holter) at scheduled time points for measurement of heart rate and QTcF (QT interval corrected using the Fridericia formula) and other ECG intervals (PR and QRS intervals), as well as assessment of T-wave morphology. Plasma concentrations of relacorilant, its metabolites, and moxifloxacin were analyzed using blood samples collected at scheduled time points that were time-matched to the ECG to assess the potential cardiodynamic effects of relacorilant.

[0127] Cardiac Dynamic ECG Assessment In this study, a 12-lead Holter device was used to obtain cardiac dynamic ECG data assessed by a blinded central ECG laboratory, and safety ECGs were evaluated by a blinded investigator. All Holter ECG data were collected using a Global Instrumentation (Manlius, NY, USA) M12R ECG continuous 12-lead digital recorder. Continuous 12-lead Holter digital ECG data were stored on an SD memory card. Extracted Holter ECGs were selected for use in pre-determined analysis and centrally read by a blinded central laboratory (ERT).

[0128] The following principles were used for blinded central laboratory ("ERT") analysis of ECGs: ECG readers were blinded to subject, visit, and treatment assignment; a limited number of readers were employed in the study; baseline and on-treatment ECGs for a particular subject were overread in the same lead and analyzed by the same reader. The primary analyzed lead was Lead II. When Lead II was not analyzable, the primary lead for subsequent analysis was changed to another lead for the entire subject data set.

[0129] Below is a brief description of the ECG analysis method utilized by ERT.

[0130] TQT+ECG extraction technology Ten 14-second digital 12-lead ECG tracings were extracted from consecutive Holter recordings using the "TQT Plus method," a computer-assisted statistical process utilized by ERT. This method allowed extraction of ECGs with the lowest HR variability and noise (e.g., beat-to-beat HR and QT variations within a <10% range) within the protocol-specific extraction time window. At each protocol-specific time point, 10 ECG repeats were extracted from a 5-minute "ECG window" (typically the last 5 minutes of a 15-minute period maintained in a supine or semi-recumbent quiet position).

[0131] Precision QT analysis by experts A thorough QT analysis by an expert was performed on all analyzable (non-artifactual) beats in the 10 ECG repeats. Statistical quality control methods were used to review and assess all beats to identify "high" and "low" confidence beats using several criteria, including: QT or QTc values ​​above or below a certain threshold (biologically unlikely); RR values ​​above or below a certain threshold (biologically unlikely); and rapid changes in QT, QTc, or RR from beat to beat.

[0132] Measurements of all primary ECG parameters (QT, QTc, RR) for all recorded beats of all replicates deemed "high confidence" were performed using iCOMPAS software (eResearch Technology, Inc., Philadelphia, PA, USA). All low confidence beats were manually reviewed and judged using pass / fail criteria. Final QC assessment was performed by a cardiologist. Beats found acceptable by manual review were included in the analysis. Median QT, QTc, and RR values ​​from each extracted replicate were calculated, and then the average of all available medians from the nominal time point was used as the reportable value for the subject at that time point.

[0133] Categorical T-wave morphology analysis and PR and QRS interval measurements were performed manually on 3 of 10 ECG repeats at each time point. Each fiducial point (onset of P wave, onset of Q wave, disappearance of S wave, and disappearance of T wave) was electronically marked. For T-wave morphology and the presence of U waves, treatment-emergent changes, i.e., changes not present at baseline, were assessed. For each category of T-wave morphology and U wave, the category was considered present if any repeat was observed at that time point. For baseline, the category was considered present if any repeat was observed from all time points comprising the baseline. The T-wave morphology categories are described below. [Table 2]

[0134] Cardiac Dynamics ECG Statistical Analysis: ECG readings were performed blinded. The primary analysis was based on concentration-QTc modeling of the relationship between plasma concentrations of relacorilant (and applicable metabolite(s)) and change in QTcF (ΔQTcF) from baseline, with the intention of excluding adverse effects of placebo-corrected ΔQTcF (ΔΔQTcF) >10 ms at clinically relevant plasma levels. The effects of relacorilant on placebo-corrected ΔQTcF, ΔHR, ΔPR, and ΔQRS (ΔΔQTcF, ΔΔHR, ΔΔPR, and ΔΔQRS) were also assessed at each post-dose time point ("by-time point" analysis). Categorical outlier analysis was performed for changes in QTcF, HR, PR, QRS, T-wave morphology, and the presence of U waves. Assay sensitivity was assessed by concentration-QTc analysis of the effect of moxifloxacin on ΔΔQTcF using a model similar to that used in the primary analysis above. Assay sensitivity is defined as the slope of the concentration-QTc relationship that is statistically significant at the 10% level of significance in a two-sided test and the predicted QT effect (i.e., the lower limit of the two-sided 90% confidence interval for ΔΔQTcF) is greater than the observed geometric mean C of 400 mg moxifloxacin. max was considered to be met when the time it took to complete the test exceeded 5 ms.

[0135] safety ecg Safety ECG assessments were performed according to local standard practice. Subjects rested in the supine position for at least 15 minutes before each ECG assessment. Safety ECGs were performed and evaluated by the investigator at screening on Day -1 of each dosing period, and during each dosing period (Days 1-5), at 2, 6, and 8 hours post-dose on Day 1, and at 2 hours post-dose on Days 2-5, and before discharge on Day 6. The accepted time window for post-dose time points was ±15 minutes. The investigator or a designee trained in ECG reading reviewed the 12-lead ECG results, including heart rate, PR interval, RR interval, QRS length, QT, and QTcF intervals, and provided an overall interpretation of the safety ECG assessment at each time point (normal, clinically significant abnormal, or clinically insignificant abnormal). All clinically significant abnormal changes were reported as AEs. Any clinically significant abnormal change from baseline was followed until the abnormality resolved or was adequately explained.

[0136] Results in healthy volunteers QT prolongation is a significant concern for patients with CS. Approximately 26% of men with CS have been reported to have QT prolongation, and the risk of cardiac arrhythmia events correlates with the degree of QT prolongation. All currently approved medical treatments are associated with QT prolongation, posing significant challenges in the management of CS. The results presented herein demonstrate the absence of QT prolongation with relaxant, an investigational selective glucocorticoid receptor modulator, in healthy volunteers and patients with CS.

[0137] In a three-phase, single-center, first-in-human study (NCT03508635, "Phase 1 Study"), 103 healthy volunteers received single or multiple ascending doses of relacorilant (up to 500 mg QD) for up to 14 days; 24 received placebo. In a randomized, partially double-blind, crossover, thorough QT study (NCT04795479, "TQT Study"), the effects of multiple therapeutic doses (400 mg QD, n=25) and supratherapeutic doses (800 mg QD, n=28) of relacorilant on cardiac repolarization were tested in healthy volunteers. A single dose of moxifloxacin (400 mg, n=28) served as the positive control; 29 participants received placebo. In a single-arm, open-label Phase 2 study (NCT02804750, "CS Study"), 17 patients with CS received low-dose relacorilant (100 mg to 200 mg QD) for 12 weeks, and 18 patients received high-dose relacorilant (250 mg to 400 mg QD) for 16 weeks. In all studies, ECG data were collected and heart rate-corrected QT intervals were assessed using the Fridericia formula (QTcF).

[0138] Baseline ECG parameters were within the expected ranges in a healthy population for the procedure, with a mean heart rate (HR) ranging from 58.7 to 60.7 beats per minute (bpm), a mean QTcF of 405.6 msec to 407.2 msec, a mean PR of 132.6 msec to 137.9 msec, and a mean QRS of 104.4 msec to 105.0 msec. Relacorilant at the test doses of 400 mg QD and 800 mg QD had no clinically relevant effects on HR. The least-squares (LS) mean change from baseline in HR (ΔHR) for relacorilant followed the pattern observed for placebo. The LS mean placebo-corrected ΔHR (ΔΔHR) for post-dose time points ranged from -3.2 bpm (12 hours post-dose on Day 1 for 800 mg treatment) to 2.4 bpm (12 hours post-dose on Day 5 for 800 mg treatment).

[0139] First-in-human trials of Relacorilant ECG data were available from 42 and 12 participants randomized to relacorilant or placebo, respectively, during the single ascending dose (SAD) phase, and from 34 and 12 participants randomized to relacorilant or placebo, respectively, during the multiple ascending dose (MAD) phase. Baseline mean (SD) QTcF values ​​were within the expected range in a healthy population (range, 378.9.1 (11.7) msec to 403.5 (9.4) msec) and similar to those in the relacorilant and placebo cohorts during the SAD and MAD study phases, respectively (see Table 1). (Values ​​in parentheses indicate standard deviation.) [Table 3] Abbreviations: ΔQTcF = QTcF change from baseline; ΔΔQTcF = placebo-corrected QTcF change from 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. a Data represent the range of mean (SD) QTcF or LS mean (90% CI) values ​​for healthy volunteers who received a single dose of 5 mg, 15 mg, 50 mg, 150 mg, 300 mg, or 500 mg of relacorilant during the SAD phase. b Data represent the range of mean (SD) QTcF baseline or LS mean (90% CI) values ​​for healthy volunteers receiving relacorilant at 50 mg / day, 150 mg / day, 250 mg / day, or 500 mg / day for 14 days during the MAD phase. c Data show the range of LS mean (90% CI) ΔQTcF values ​​for healthy volunteers who received placebo for 14 days during the MAD phase.

[0140] Relacorilant had no clinically relevant adverse effects on QTcF during the SAD or MAD test phases. At all SAD and MAD post-dose time points and for all relacorilant doses, the LS mean ΔQTcF for relacorilant was similar to that for placebo. In both groups, the post-dose LS mean placebo-corrected ΔQTcF (ΔΔQTcF) for relacorilant was small and mostly negative (Table 1). No clear differences in ΔΔQTcF were observed for different relacorilant doses in the SAD and MAD test phases, and the mean ΔΔQTcF did not exceed 5 msec at any time point (Figures 3A-3E).

[0141] Relacorilant plasma concentration and QTcF data in the SAD and MAD phases were best fit to a linear model with treatment-specific intercepts. For both phases, the model-estimated slope (90% CI) was slightly negative (SAD: -0.59 [-2.14, 0.97] x 10 -3 msec / ng / mL;MAD:-2.34[-3.16~-1.52]×10 -3 msec / ng / mL). Therefore, no concentration-dependent effect of relacorilant on QTc prolongation was confirmed. Exposure-response model-predicted results for mean ΔΔQTcF at peak relacorilant plasma concentrations during the SAD and MAD phases also indicated that increasing relacorilant doses were not associated with QT interval prolongation (Figures 2A and 2B). Based on the modeled SAD and MAD results, the prolonging effect of relacorilant on ΔΔQTcF above the 10 msec threshold was eliminated within the observed range of plasma concentrations up to approximately 4000 ng / mL (no effect above the 10 msec threshold was suggested by the data and modeling shown in Figures 2A and 5).

[0142] In a phase 1 (first-in-human) study, relacorilant at doses up to 500 mg daily had no clinically relevant adverse effects on ECG parameters. Adverse effects on placebo-corrected changes from baseline QTcF (ΔΔQTcF) of greater than 10 ms were eliminated. In a total QT study, the moxifloxacin control demonstrated the expected QT interval prolongation, confirming assay sensitivity. relacorilant had no clinically relevant effects on ECG parameters, demonstrating placebo-like efficacy. Based on concentration-QTc analysis, adverse effects on ΔΔQTcF greater than 10 ms were eliminated across the entire observed range of relacorilant plasma concentrations (a trend toward QT interval reduction was observed at higher doses). The CS study confirmed that these favorable findings also apply to patients with CS: no significant changes in median QTcF were observed in any treatment group throughout the CS study. Furthermore, no cases of hypokalemia were reported in the CS study. Based on the TQT study, and supported by further data in healthy volunteers and patients with CS, relacorilant was not associated with QT prolongation.

[0143] Therefore, no notable changes in ECG parameters were observed from baseline or between dose levels. The mean placebo-corrected ΔQTcF (ΔΔQTcF) did not exceed 3 ms at any time point in either dose group. A trend toward a shorter QTc (toward a reduction in ΔΔQTcF) was observed at higher relaxilant concentrations (Figures 2A and 2B), with a reduction in ΔΔQTcF observed at the highest concentration (2 hours) (Figures 3A-3E). Based on exposure-response analysis, adverse effects on placebo-corrected changes from baseline QTcF of more than approximately 10 ms could be excluded (see Figures 2A and 2B).

[0144] Thorough QT / QTc study ("TQT study") ECG data were available for 25 participants receiving therapeutic (400 mg) relacorilant, 28 participants receiving supratherapeutic (800 mg) relacorilant, 29 participants receiving placebo only, and 28 participants receiving the moxifloxacin positive control. For all participants, mean (SD) QTcF values ​​at baseline were within the expected range for a healthy population (range: 405.6 (15.33) msec to 407.2 (17.49) msec). LS mean delta QTcF was slightly negative (range: -11.7 msec to 2.0 msec) for both therapeutic and supratherapeutic doses of relacorilant, as well as for placebo, on both days and at all post-dose time points. In contrast, treatment with 400 mg of moxifloxacin positive control on day 5 resulted in a rapid increase from the LS mean (90% CI) of predose QTcF, starting at 1 hour postdose (5.7 (3.3, 8.2) msec) to a maximum observed value of 9.7 (7.2, 12.2) msec at 16 hours postdose.

[0145] Figure 4A shows the results of the TQT study on days 1 and 5 of administration of relacorilant (400 mg (squares) or 800 mg (triangles)) or moxifloxacin (positive control; diamonds). Note that ΔΔQTcF appears to decrease with time after relacorilant administration. These results rule out an adverse effect of relacorilant on ΔΔQTcF over the 24-hour period on days 1 or 5 of relacorilant administration. The dashed line indicates the 10 msec ΔΔQTcF effect threshold.

[0146] Figure 4B shows the results of the TQT study on day 5 of administration of relacorilant (400 mg (filled circles) or 800 mg (filled triangles) or moxifloxacin (positive control; open circles). These results exclude an adverse effect of relacorilant on ΔΔQTcF over 24 hours after 5 days of relacorilant administration.

[0147] As shown in Figure 4B, on Day 5, the LS mean (90% CI) ΔΔQTcF for both doses of relacorilant was negative at all post-dose time points, ranging from -8.0 (-11.5, -4.6) msec to -3.9 (-7.3, -0.5) msec. At all post-dose time points and for both doses of relacorilant, the upper limit of the 90% CI around the LS mean ΔΔQTcF was below the 10 msec ICH E14 threshold. On Day 5, the LS mean (90% CI) ΔΔQTcF for 400 mg of moxifloxacin increased to a peak value of 10.7 (7.3, 14.1) msec at 1.5 hours post-dose. Consistent with regulatory expectations for the positive control, the lower limit of the 90% CI around the LS mean ΔΔQTcF for moxifloxacin exceeded 5 msec at four of the 12 post-dose time points.

[0148] As in the first-in-human study, a linear model with a treatment effect-specific intercept gave the best fit to the relacorilant concentration and ΔΔQTcF data. The estimated slope (90% CI) of the relacorilant plasma concentration in the concentration-QTc relationship was shallow and slightly negative (-0.97 (-1.68, -0.25) × 10 -3 At the geometric mean peak relacorilant concentrations, the predicted effect on QTcF was 0.25 msec / ng / mL, and the small treatment effect-specific intercept (90% CI), -1.25 msec (-2.00, -0.51). max 1831.6ng / mL) and 800mg dose (C max For the serotonin-dependent vasoconstriction (SDS) and vasoconstriction (P < 0.05), the mean vasoconstriction was -3.02 msec (90% CI: -4.16 to -1.88) and -3.87 msec (90% CI: -5.56 to -2.17) respectively (Figure 5). [Table 4] CI = confidence interval; msec = milliseconds; n = number of subjects used in the calculation. 1Based on a linear mixed-effects model with ΔQTcF as the independent variable, time-matched relacorilant plasma concentrations as the explanatory variable, median baseline QTcF as an additional covariate, treatment (relacorilant = 1 or placebo = 0) and time as fixed effects, and a random intercept and slope per subject. 2 Based on a linear mixed-effects model with ΔQTcF as the independent variable, time-matched moxifloxacin plasma concentrations as the explanatory variable, median baseline QTcF as an additional covariate, treatment (moxifloxacin = 1 or placebo = 0) and time as fixed effects, and a random intercept and slope per subject.

[0149] Based on the concentration-QTc modeling results, an effect on ΔΔQTcF above the 10 msec threshold could be excluded within the observed range of relacorilant plasma concentrations (up to approximately 4500 ng / mL at supratherapeutic dosing).

[0150] 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 theoretical modeling (solid line and shaded area), which eliminate adverse effects of relacorilant on ΔΔQTcF (changes >10 msec) over a range of relacorilant concentrations up to approximately 4500 ng / mL. Markers and error bars: Estimated mean (90% CI) ΔΔQTcF at the observed geometric mean maximum relacorilant concentration with therapeutic (squares) and supratherapeutic (triangle) dosing. Dashed line: 10 ms ΔΔQTcF effect threshold. Solid line and shaded area: Predicted mean ΔΔQTcF with 90% CI calculated from ΔΔQTcF = -1.2501 (msec) - 0.97 (× 10-3 msec / ng / mL) × relacorilant concentration (ng / mL). This is in agreement with the ICH This constitutes a negative TQT study as described in the E14 clinical guidance document (Industry Guidance: E14 Clinical Evaluation of QT / QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs, US Dept. HHS, 2005).

[0151] A Phase 2 Study of Relacorilant in Patients with Cushing's Syndrome (the "CS Study") The low-dose and high-dose relacorilant groups included 17 and 18 patients, respectively. At baseline, mean (SD) QTcF ranged from 393.6 (16.5) msec to 394.2 (16.2) msec in the low-dose group and from 403.4 (36.3) msec to 409.9 (27.2) msec in the high-dose group, confirming the absence of baseline QT prolongation. Median QTcF did not change significantly in either group throughout the study (Figures 6A and 6B). In both groups and for all doses of relacorilant, mean (SD) ΔQTcF values ​​were small and not statistically significant (range, −2.2 (13.5) msec to 1.8 (24.4) msec; all P > .3). In both groups, abnormal sinus tachycardia was the most common post-baseline ECG finding, observed in three patients (17.6%) in the low-dose group and two patients (11.1%) in the high-dose group.

[0152] Figures 6A and 6B show the median QTcF values ​​for CS patients receiving low-dose relacorilant (6A) and high-dose relacorilant (6B). No significant changes in median QTcF were observed in either group.

[0153] summary In first-in-human studies, relacorilant did not produce any notable mean changes from baseline in any measured ECG parameters at doses up to 500 mg QD. No notable differences were observed between relacorilant and placebo. No cases of post-dose QTcF intervals >450 ms or QTcF interval increases >30 ms were reported. Changes in QTcF from baseline (ΔQTcF) were similarly small and mostly negative throughout the study and across crossover groups; no dose-dependence was observed. Adverse effects of relacorilant on placebo-corrected ΔQTcF (ΔΔQTcF) of >10 ms were eliminated for doses up to 400 mg / day. Exposure-response analysis demonstrated a slight negative relationship between relacorilant plasma levels and ΔΔQTcF, excluding a positive concentration-dependent effect. Therefore, relacorilant did not negatively affect ECG parameters in first-in-human studies.

[0154] In the TQT study, therapeutic and supratherapeutic doses of relacorilant had no adverse effects on ECG parameters. The moxifloxacin positive control demonstrated the expected rapid increase in QTc, confirming assay sensitivity. ΔQTcF values ​​for therapeutic and supratherapeutic relacorilant were generally similar to those for placebo. Based on concentration-QTc analysis, adverse effects on ΔΔQTcF of greater than 10 ms were excluded within the entire observed range of relacorilant plasma concentrations (up to approximately 4500 ng / mL). As in the Phase 1 study, the estimated slope of the relacorilant concentration-QTc curve was shallow and negative, with a statistically significant treatment effect-specific intercept. Lelacorilant did not negatively affect ECG parameters in the TQT study; these results constitute a negative TQT study.

[0155] In the CS study, relacorilant had no adverse effects on ECG parameters. No significant changes in median QTcF were observed in any treatment group throughout the study. Therefore, the favorable QT findings in healthy volunteers were confirmed in patients with CS.

[0156] Across all three studies (first-in-human, total quality test, and clinical study), relacorilant was well tolerated. In the Phase 1 study, Holter ECG data were collected in 44 study participants. Relacorilant had no adverse effects on ECG parameters at doses up to 500 mg. Adverse effects on placebo-corrected changes from baseline QTcF (ΔΔQTcF) of greater than 10 ms were eliminated. In the total quality test study, results from moxifloxacin treatment confirmed assay sensitivity. Relacorilant had no adverse effects on ECG parameters and demonstrated placebo-like efficacy. Based on concentration-QTc analysis, adverse effects on ΔΔQTcF greater than 10 ms were eliminated across the entire observed range of relacorilant plasma concentrations. The clinical study confirmed these findings in patients with CS. No significant changes in median QTcF were observed in either group throughout the study.

[0157] We describe here the ECG results for the investigational drug for CS, relacorilant, from three studies: a first-in-human study in healthy volunteers, a thorough QT / QTc study in healthy volunteers conducted according to regulatory guidelines, and a phase 2 study in patients with CS lasting up to 16 weeks. All participants in the relacorilant study had normal QTc intervals at screening and remained within the normal range throughout treatment. Overall, the results presented here demonstrate that relacorilant administration, including up to supratherapeutic doses, does not affect QTc interval prolongation in healthy volunteers or in patients with endogenous CS. In the first-in-human study in healthy volunteers, there was no meaningful clinical effect of relacorilant on QTcF across the dose range administered during the SAD and MAD phases. There was no discernible dose-dependent effect, and the LS mean ΔΔQTcF did not exceed 5 msec at any point during the SAD and MAD study phases. Concentration-QTc modeling results further indicated that effects on ΔΔQTcF of greater than 10 ms could be eliminated for the observed plasma concentration range of relaxorilant up to approximately 4000 ng / mL. These results were confirmed in specialized placebo- and positive-controlled thorough QT / QTc studies of relacorilant at therapeutic and supratherapeutic doses. As seen in the first-in-human study, the effects of both therapeutic and supratherapeutic relacorilant on ΔQTcF at all post-dose time points were similar to those of placebo. Furthermore, for both doses, ΔΔQTcF was consistently small and generally slightly negative. Importantly, the upper limits of the two-sided 90% CIs around the LS mean ΔΔQTcF for both doses of relacorilant were less than 10 msec at all post-dose time points. Furthermore, concentration-QTc modeling results excluded effects on ΔΔQTcF greater than 10 msec within the observed relacorilant plasma concentration range of approximately 4500 ng / mL seen with supratherapeutic dosing. The ability of the thorough QT / QTc study to detect small increases in QTcF was confirmed by a lower limit of >5 msec near the maximum LS mean ΔΔQTcF observed for the moxifloxacin positive control. Together, these results constitute a negative QT / QTc study as described by the ICH E14 clinical regulatory guideline (US Food and Drug Administration. E14 Clinical evaluation of QT / QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs—Questions and answers (R3). US Department of Health and Human Services; 2017).

[0158] In both the first-in-human and thorough QT / QTc studies, relacorilant administration was associated with a slight trend toward a decrease in placebo-corrected ΔQTc. A QTc interval of 390 msec to 450 msec in men and 390 msec to 460 msec in women is suggested as the normal range, and it is noted that all participants in the relacorilant study had normal QTc intervals at screening and remained within the normal range during treatment.

[0159] The findings and conclusions from the two studies of relacorilant in healthy volunteers were further confirmed by ECG results from a 16-week Phase 2 study of relacorilant in patients with endogenous CS. At all time points and for all doses of relacorilant, the mean ΔQTcF values ​​for relacorilant were small and not statistically significant.

[0160] The absence of QTc prolongation with relacorilant presented here contrasts with currently approved or widely prescribed therapies for CS (e.g., pasoleotide, levocetconazole, and other drugs used to treat Cushing's syndrome).

[0161] In contrast to existing therapies for CS, relacorilant has consistently demonstrated a lack of QTc prolongation in healthy volunteers and patients with CS at all doses tested to date, including supratherapeutic doses. These results suggest that relacorilant should not pose a risk of ventricular arrhythmias and related sequelae, including sudden cardiac arrest. Therefore, based on the data disclosed herein, relacorilant is not associated with QT prolongation and therefore fulfills a previously unmet need for a safe CS agent that does not cause QT prolongation and potentially fatal arrhythmias.

[0162] In addition to the patients discussed in this example, no clinically significant QT prolongation was observed in another study in which at least 12 patients with Cushing's syndrome received relacorilant while also receiving other medications known to cause QT prolongation (these were fluoroquinolines, imidazole derivatives, macrolides, or protease inhibitor drugs).

[0163] The results show a trend toward a decrease in ΔΔQTcF at higher relacorilant concentrations, with a decrease in ΔΔQTcF observed at the highest concentration (2 hours). These results indicate that relacorilant administration may be useful in reducing the QT interval. These results therefore indicate that relacorilant administration may be useful in treating patients, such as those with CS and other patients suffering from QT interval prolongation.

[0164] All patents, patent publications, publications, and patent applications recited herein are hereby incorporated by reference in their entirety as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. Also, while the foregoing invention has been described somewhat generally by way of example and for purposes of clarity of understanding, it will be readily apparent to those skilled in the art that certain changes and modifications can be made therein without departing from the spirit or scope of the appended claims.

Claims

1. 1. A method of treating a patient suffering from Cushing's syndrome or Cushing's disease (collectively "CS") without significantly prolonging the patient's QT interval, comprising: the QT interval is the length of the time interval between the onset of the QRS complex of an electrocardiogram (ECG) and the end of the T wave of the ECG, and the patient's QT interval is significantly prolonged if the QT interval increases by more than 10 milliseconds (ms) from the patient's baseline QT interval; The method comprising: administering an effective amount of a heteroaryl ketone-fused azadecalin compound; wherein said treatment does not significantly prolong said patient's QT interval; This treats the patient's CS without significantly prolonging the patient's QT interval.

2. 2. The method of claim 1, wherein the heteroaryl ketone-fused azadecalin compound is a 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, having the following structure: 【Chemistry 1】

3. 10. The method of claim 1, wherein the effective amount of the heteroaryl ketone-fused azadecalin compound is an amount selected from the group consisting of about 50 milligrams per day (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. 10. The method of claim 1, wherein said administration of an effective amount of said heteroaryl ketone-fused azadecalin compound does not significantly increase said patient's risk of cardiac arrhythmia.

5. 10. The method of claim 1, wherein said administration of an effective amount of said heteroaryl ketone-fused azadecalin compound does not significantly increase said patient's risk of heart attack.

6. 2. The method of claim 1, wherein the patient is receiving a drug that prolongs QT, and the administration of an effective amount of the heteroaryl ketone-fused azadecalin compound does not significantly increase the patient's risk of stroke.

7. 10. The method of claim 1, wherein said administration of an effective amount of said heteroaryl ketone-fused azadecalin compound does not significantly increase the patient's risk of sudden death.

8. 10. The method of claim 1, wherein the heteroaryl ketone-fused azadecalin compound is administered orally.

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

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

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

12. 1. A method of treating a patient suffering from Cushing's syndrome or Cushing's disease (collectively "CS") and suffering from a prolonged QT interval, wherein the QT interval is the length 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, wherein a prolonged QT interval is a QT interval greater than about 450 ms in males or greater than about 460 ms in females; The method comprising: identifying the CS patient as suffering from a prolonged QT interval; administering an effective amount of a heteroaryl ketone-fused azadecalin compound, wherein said effective amount is from about 400 milligrams (mg) to about 800 mg of said heteroaryl ketone-fused azadecalin compound; thereby treating CS and prolonged QT interval in the patient.

13. 13. The method of claim 12, wherein the heteroaryl ketone-fused azadecalin compound is a 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, having the following structure: 【Chemistry 2】

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

15. 1. A method for reducing a prolonged QT interval in a patient having a prolonged QT interval, wherein the QT interval is the length 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 a prolonged QT interval is a QT interval greater than about 450 ms in males or greater than about 460 ms in females; The method comprising: administering to said patient an effective amount of a heteroaryl ketone-fused azadecalin compound. thereby decreasing the QT interval in the patient.

16. 16. The method of claim 15, wherein the heteroaryl ketone-fused azadecalin compound is a 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, having the following structure: 【Transformation 3】

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

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

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

20. 20. The method of claim 19, wherein the heteroaryl ketone-fused azadecalin compound is a 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, having the following structure: 【Chemistry 4】

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

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

23. Use of a heteroaryl ketone-fused azadecalin compound to treat Cushing's syndrome or Cushing's disease (collectively "CS") without resulting in significant QT interval prolongation, wherein the QT interval is the length of the time interval between the onset of the QRS complex of the electrocardiogram (ECG) and the end of the T wave of the ECG, and a prolonged QT interval is a QT interval of greater than about 450 ms in men or greater than about 460 ms in women.

24. 24. The use of claim 23, wherein the heteroaryl ketone-fused azadecalin compound is a 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, having the following structure: 【Transformation 5】

25. 24. The use of claim 23, wherein the CS patient suffers from QT interval prolongation.

26. Use of a heteroaryl ketone-fused azadecalin compound in the manufacture of a medicament for the treatment of Cushing's syndrome or Cushing's disease (collectively "CS") without significant QT interval prolongation, wherein the QT interval is the length of the time interval between the onset of the QRS complex of an electrocardiogram (ECG) and the end of the T wave of the ECG, and a prolonged QT interval is a QT interval of greater than about 450 ms in men or greater than about 460 ms in women.

27. The heteroaryl ketone-fused azadecalin compound is a 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, having the following structure: 【Transformation 6】 27. The use of claim 26, in the manufacture of a medicament for the treatment of Cushing's syndrome or Cushing's disease (collectively "CS") without significant QT interval prolongation, wherein the QT interval is the length 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 a prolonged QT interval is a QT interval of greater than about 450 ms in men or greater than about 460 ms in women.

28. 27. The use of claim 26, wherein the CS patient is suffering from QT interval prolongation.

29. 1. A pharmaceutical composition for use in treating a patient suffering from Cushing's syndrome or Cushing's disease (collectively "CS") without significant QT interval prolongation, wherein the QT interval is the length of the time interval between the onset of the QRS complex of an electrocardiogram (ECG) and the end of the T wave of the ECG, and a prolonged QT interval is a QT interval of greater than about 450 ms in males or greater than about 460 ms in females; The pharmaceutical composition comprises a pharmaceutically acceptable formulation excipient and a heteroaryl ketone-fused azadecalin 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, having the following structure: 【Transformation 7】

30. 30. The use of claim 29, wherein the CS patient is suffering from QT interval prolongation.

31. Use of a heteroaryl ketone-fused azadecalin compound to reduce a prolonged QT interval in a patient with the QT interval, wherein the QT interval is the length 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 a prolonged QT interval is a QT interval of greater than about 450 ms in men or greater than about 460 ms in women.

32. 32. The use of claim 31, wherein the heteroaryl ketone-fused azadecalin compound is a 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, having the following structure: 【Transformation 8】

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

34. 34. The use of claim 33, wherein the heteroaryl ketone-fused azadecalin compound is a 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, having the following structure: 【Chemistry 9】

35. 1. Use of a heteroaryl ketone-fused azadecalin compound to reduce the effect on the electrocardiogram (ECG) QT interval in a patient receiving a drug known to prolong the QT interval in some patients, wherein the QT interval is the length 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 a prolonged QT interval is a QT interval of greater than about 450 ms in men or greater than about 460 ms in women.

36. 36. The use of claim 35, wherein the heteroaryl ketone-fused azadecalin compound is a 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, having the following structure: 【Chemistry 10】

37. Use of a heteroaryl ketone-fused azadecalin compound in the manufacture of a medicament for reducing the effect on the electrocardiogram (ECG) QT interval in a patient receiving a drug known to prolong the QT interval in some patients, wherein the QT interval is the length 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 a prolonged QT interval is a QT interval of greater than about 450 ms in men or greater than about 460 ms in women.

38. 38. The use of claim 37, wherein the heteroaryl ketone-fused azadecalin compound is a 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, having the following structure: 【Chemistry 11】

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