Methods of treating hypertension with a combination of an aldosterone synthase inhibitor and a diuretic

Abstract

The present invention provides a method for treating hypertension in a hypertensive subject, comprising administering to the subject an amount of a diuretic and an amount of a CYP 11β2 beta-hydroxylase inhibitor once or twice daily, the combined amount being sufficient to treat hypertension in the hypertensive subject when taken in combination with other antihypertensive agents. In particular, the method is sufficient to induce a safe and robust reduction in hypertension (a reduction in systolic blood pressure of greater than 10 mmHg) in the hypertensive subject.

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Application No. 63 / 425,803, filed November 16, 2022, and U.S. Provisional Application No. 63 / 400,312, filed August 23, 2022, the contents of each of which are incorporated by reference in their entirety.

[0002] Throughout this application, various publications are referenced, including those referenced within parentheses. The entire disclosures of all publications identified in this application are incorporated herein by reference in their entirety to provide further description of the technology to which the present invention pertains and features of the art that may be used in conjunction with the present invention.

[0003] The present invention relates to a method for treating hypertension by inhibiting aldosterone synthase (CYP11β2 beta-hydroxylase). [Background technology]

[0004] Aldosterone is the primary mineralocorticoid in humans, produced in the zona glomerulosa of the adrenal cortex by aldosterone synthase (CYP11β2 beta-hydroxylase). Aldosterone is a key component of the renin-angiotensin-aldosterone system (RAAS), which primarily acts as a regulator of electrolyte and fluid homeostasis.

[0005] Mineralocorticoid receptor-blocking agents (mineralocorticoid receptor antagonists, MRAs), such as spironolactone and eplerenone, prevent aldosterone from binding to the mineralocorticoid receptor. Several clinical trials have demonstrated their benefits for the treatment of hypertension. Given the role of aldosterone in the RAAS, inhibition of aldosterone synthase is a possible alternative to mineralocorticoid receptor-blocking agents for treating hypertension. However, previous studies have suggested that some of the effects of aldosterone may occur independently through stimulation of the mineralocorticoid receptor / classical steroid-receptor complex (Grossmann, C., & Gekle, M., 2009; Good, DW, 2007; Mihailidou, A.S., & Funder, JW, 2005). Furthermore, the mineralocorticoid receptor is not selective for aldosterone, rather it has similar affinity for the glucocorticoids cortisol and corticosterone.

[0006] Diuretics are medications designed to increase the amount of water and salt excreted from the body in urine. Thiazide diuretics are the most commonly prescribed diuretics, often used to treat high blood pressure. Thiazide diuretics not only reduce fluid volume but also cause vascular relaxation. Thiazide diuretics reduce blood potassium levels. This reduction in potassium occurs through two indirect mechanisms: (1) inhibition of the sodium-chloride symporter in the distal tubule of the nephron and (2) stimulation of aldosterone, which activates Na+ / K+-ATPase in the collecting duct. Inhibition of the sodium-chloride symporter increases the availability of chloride and sodium in the urine. Once urine reaches the collecting duct, the increased availability of chloride and sodium activates Na+ / K+-ATPase, which, in turn, increases sodium absorption and potassium excretion in the urine. Chronic administration of thiazide diuretics reduces the total blood volume of the body. This activates the renin-angiotensin system and stimulates aldosterone secretion, which in turn activates Na+ / K+-ATPase and increases urinary potassium excretion. Therefore, the use of a combination of an ACE inhibitor and a thiazide prevents hypokalemia.

[0007] Administering two drugs to treat a given condition, such as the combination of an aldosterone synthase inhibitor and a thiazide to treat hypertension, poses several potential problems. In vivo interactions between the two drugs are complex. The effects of either single drug are related to its absorption, distribution, and excretion. When two drugs are introduced into the body, each drug may affect the absorption, distribution, and excretion of the other drug, thus altering the effects of the other. For example, one drug may inhibit, activate, or induce the production of enzymes involved in the metabolic pathway of the other drug's excretion (Food and Drug Administration, 2020). Therefore, when two drugs are administered to treat the same condition in human subjects, it is impossible to predict whether each drug will complement, have no effect on, or interfere with the therapeutic activity of the other drug. The interaction between the two drugs may enhance or mitigate the side effects of each drug. Therefore, when two drugs are administered to treat a disease, it is impossible to predict the changes that will occur in the negative side effect profile of each drug. Summary of the Invention [Problem to be solved by the invention]

[0008] The renin-angiotensin-aldosterone system (RAAS) is a complex, multifaceted system in which numerous different pathways, enzymes, and hormones interact in positive and negative feedback loops. Given the complexity of the renin-angiotensin-aldosterone system, there are many uncertainties surrounding the use of aldosterone synthase inhibitors in combination with other antihypertensive therapies to treat hypertension. In particular, the effects of combining aldosterone synthase inhibitors with diuretics, such as thiazides, on hypertension have not been studied to date. Furthermore, identifying specific patient populations that will derive the greatest benefit from aldosterone synthase inhibition remains an important goal in the field of cardiovascular health. [Means for solving the problem]

[0009] The present invention provides a method for treating hypertension in a hypertensive subject, comprising administering to the subject an amount of a diuretic and an amount of a CYP 11β2 beta-hydroxylase inhibitor once or twice daily, the combined amount being sufficient to treat hypertension in the hypertensive subject, preferably when taken in combination with other antihypertensive agents. In particular, the method is sufficient to induce a safe and robust reduction in hypertension (a reduction in systolic blood pressure of more than 10 mmHg) in the hypertensive subject.

[0010] The present invention also provides a method for treating hypertension in a hypertensive subject taking at least one diuretic, comprising administering to the subject once or twice daily a CYP 11β2 beta-hydroxylase inhibitor in an amount sufficient to thereby treat hypertension in the hypertensive subject.

[0011] The present invention also provides a method of identifying a subject for treatment of hypertension with a CYP 11β2 beta-hydroxylase inhibitor, comprising the steps of: (a) (i) a systolic blood pressure greater than 130 mmHg in said subject; and (ii) a diastolic BP of greater than 80 mmHg in said subject measuring the (b) selecting a subject taking at least one diuretic thereby identifying said subject for treatment of hypertension with a CYP 11β2 beta-hydroxylase inhibitor.

[0012] The invention also provides pharmaceutical compositions, packages, and unit dosage forms for use in any one of the methods described herein. [Brief explanation of the drawings]

[0013] [Figure 1]Figure 1: Study outline for Compound A HBr. ABPM = ambulatory blood pressure monitoring; BP = blood pressure; BID = twice daily; EOT = end of treatment; FU = follow-up; PRA = plasma renin activity; QD = once daily. a = If screening results were available, an inclusion / exclusion assessment was performed. If subjects were ineligible based on screening results, they did not continue until Visit 4. If screening results were not available, subjects proceeded to Visit 4. If screening results were not available at Visit 4, subjects should attend Visit 5 to determine final eligibility. If eligible based on screening results, ABPM assessment will begin at Visit 5. b = ABPM procedures began at home approximately 24 hours prior to randomization (Study Day 1). Alternatively, sites were allowed to schedule a site visit on Study Day 0 (Visit 5) to begin ABPM procedures. Training on ABPM procedures was provided either at the site visit or by telephone. [Figure 2] Figure 2: Waterfall plot showing change in systolic blood pressure (AOBP) at week 8. This figure shows the waterfall plots for the full analysis and safety population (FAS) analyses for the placebo, 50 mg QD, and 100 mg QD groups, and the protocol-per-protocol (PP) analysis for the 100 mg group. The model mean and observed mean of protocol-per-protocol are also shown for each group. [Figure 3] Figure 3: Waterfall plot showing AOBP change in systolic blood pressure at week 8. The figure shows the waterfall plot of the FAS analysis of 12.5 mg QD, 12.5 mg BID, and 25 mg BID using all subjects with measurements at week 8. Model means and observed adherence to protocol means are also shown for each group. [Figure 4]Figure 4: Bar graph showing mean change in systolic blood pressure from baseline. Figure presents the final analysis including both the full analysis set (FAS, all evaluable subjects who received at least one dose of Compound A HBr) and protocol adherence (PP, only subjects who received ≥75% of study drug through the week 8 visit). Part 2 data show the median mean values ​​from week 5 to the final visit at week 6. [Figure 5] Figure 5: Graph of the mean automated office blood pressure change from baseline observed at week 8 for the QD dosing regimen, showing the dose response to Compound A HBr. The BID protocol adherence cohort is shown on the far right of the graph. [Figure 6] Figure 6: Graph showing change in systolic blood pressure from baseline at week 8 for the pooled cohorts of 50 mg QD, 100 mg QD, 12.5 mg BID and 25 mg BID. [Figure 7] Figure 7: Waterfall plot showing change in systolic blood pressure from the placebo and 100 mg QD groups pooled from both Part 1 and Part 2. Part 2 data from the interim snapshot, including all randomized subjects and the mean values ​​from the last visit at weeks 5-6, with a minimum of week 2. [Figure 8] Figure 8: Graph showing change in estimated glomerular filtration rate (eGFR) in various dosing cohorts. [Figure 9] Figure 9: Graph showing an example of ambulatory 24-hour blood pressure monitoring. The graph shows 24-hour ambulatory blood pressure (systolic) of subjects receiving 100 mg QD of Compound A HBr relative to baseline, demonstrating the mean 24-hour blood pressure reduction and restoration of the normal nocturnal blood pressure reduction pattern. [Figure 10] Figure 10: Graph showing change in systolic blood pressure at week 8 relative to baseline as measured using the ABPM full analysis set. [Figure 11]Figure 11: Waterfall plot showing 24-hour mean and nighttime mean ABPM change at week 8 relative to baseline. The 100 mg QD dose level provides superior 24-hour blood pressure reduction. The nighttime blood pressure reduction from the 100 mg QD dose level appears to be superior to 25 mg BID. [Figure 12] Figure 12: Model (MMRM) least squares mean (standard error) change from baseline at week 8 in seated automated, laboratory-measured systolic blood pressure (mmHg) for Part 1 (full analysis set). Error bars represent standard error. Numbers inside the bars represent the number of subjects with no missing data. P values ​​represent statistically significant differences compared to placebo. *p=0.0114. **p=0.042. Abbreviations: BID, twice daily; mg, milligrams; mmHg, millimeters of mercury; QD, once daily; SBP, systolic blood pressure; SEM, standard error of the mean. [Figure 13] Figure 13: Model (MMRM) least squares mean (standard error) change from baseline at week 8 in seated automated, laboratory-measured systolic blood pressure (mmHg) for Parts 1 and 2 (full analysis set). Error bars represent standard error. Numbers inside the bars represent the number of subjects with no missing data. Abbreviations: mg, milligrams; mmHg, millimeters of mercury; MMRM, repeated measures mixed-effects model; QD, once daily; SBP, systolic blood pressure; SEM, standard error of the mean. [Figure 14] Figure 14: Boxplot of measured change from baseline at week 8 in seated automated, laboratory-measured systolic blood pressure (mmHg) in Part 1 (full analysis set). ◇, mean; -, median; ·, outlier. The upper and lower boundaries of each box represent the first and third quartiles. Abbreviations: BID, twice daily; mg, milligrams; mmHg, millimeters of mercury; QD, once daily; SBP, systolic blood pressure. [Figure 15]Figure 15: Boxplot of measured change from baseline at week 8 in seated automated, laboratory-measured systolic blood pressure (mmHg) for subjects randomized to 100 mg QD in Parts 1 and 2 (full analysis set). ◇, mean; -, median; l, ·, outlier. The upper and lower boundaries of each box represent the first and third quartiles. Abbreviations: mg, milligrams; mmHg, millimeters of mercury; QD, once daily; SBP, systolic blood pressure. [Figure 16] Figure 16: Percentage of subjects with seated automated office-measured BP / DBP ≦130 / 80 mmHg at week 8 in Part 1 (full analysis set). Subjects who did not undergo assessment at week 8 or received rescue medication by week 8 were considered failures. The number inside the bar represents the number of subjects who achieved AOBP ≦130 / 80 mmHg. [Figure 17] Figure 17: Percentage of subjects with seated automated office-measured BP / DBP ≦130 / 80 mmHg at study week 8 among subjects randomized to 100 mg QD in Parts 1 and 2 (full analysis set). Subjects not assessed at week 8 or who received rescue medication by week 8 were considered failures. The number inside the bar represents the number of subjects who achieved AOBP ≦130 / 80 mmHg. [Figure 18] Figure 18: Time (in weeks) to first occurrence of seated automated office-measured BP / DBP ≦130 / 80 mmHg in Part 1 (full analysis set). Subjects who failed to achieve BP ≦130 / 80 mmHg before Week 8 / EoT were censored at the date of Week 8 / EoT. Subjects who did not have follow-up before Week 8 / EoT were censored at the date of their last known BP assessment. Subjects who took rescue medication were censored at the date rescue medication was initiated. Missed events represent subjects who did not have a post-baseline assessment of BP. For subject 146-040, the study duration (>27 weeks) and treatment duration (>18 weeks) were longer than planned due to AEs leading to temporary discontinuation. [Figure 19]Figure 19: Time (in weeks) to first occurrence of seated automated office-measured BP / DBP ≦130 / 80 mmHg in subjects randomized to 100 mg QD in Parts 1 and 2 (full analysis set). Subjects who failed to achieve BP ≦130 / 80 mmHg before Week 8 / EoT were censored at the date of Week 8 / EoT. Subjects who did not have follow-up before Week 8 / EoT were censored at the date of the last known BP assessment. Subjects who took rescue medication were censored at the date of initiation of rescue medication. Missed events represent subjects who did not have a post-baseline assessment of BP. [Figure 20] Figure 20: Mean (standard error) change in serum potassium from baseline over time in QD dose cohorts in Part 1 (safety population). [Figure 21] Figure 21: Mean (standard error) change in serum potassium from baseline over time in the BID dose cohorts in Part 1 (safety population). [Figure 22] Figure 22: Mean (standard error) change from baseline in serum potassium over time in Part 2 (safety population). [Figure 23] Figure 23: Mean (standard error) change in serum sodium from baseline over time in QD dose cohorts in Part 1 (safety population). [Figure 24] Figure 24: Mean (standard error) change in serum sodium over time from baseline in BID dose cohorts in Part 1 (safety population). [Figure 25] Figure 25: Mean (standard error) change from baseline in serum sodium over time in Part 2 (safety population). [Figure 26]Figure 26: Relationship between median baseline body mass index (BMI, kg / m2) and serum leptin (ng / dl). Data are derived from pooled data from low-renin subjects (part 1) from the lorundrostat 25 mg BID, 50 mg QD, and 100 mg QD cohorts. Each of these cohorts demonstrated a significant reduction in median serum aldosterone at week 4 compared to baseline (9.6%, 65.2%, and 70.0%, respectively). [Figure 27] Figure 27: Relationship between baseline BMI and mean change in systolic BP (mmHg) measured by AOBP compared to baseline at week 8. Data derived from pooled data from low-renin subjects (part 1) from the lorundrostat 25 mg BID, 50 mg QD, and 100 mg QD cohorts. DETAILED DESCRIPTION OF THE INVENTION

[0014] How to Treat High Blood Pressure The present invention provides a method for treating hypertension in a hypertensive subject, comprising administering to the subject an amount of a diuretic and an amount of a CYP 11β2 beta-hydroxylase inhibitor once or twice daily, the combined amount being sufficient to treat hypertension in the hypertensive subject, preferably when taken in combination with other antihypertensive agents. In particular, the method is sufficient to induce a safe and robust reduction in hypertension (a reduction in systolic blood pressure of more than 10 mmHg) in the hypertensive subject.

[0015] In an embodiment of the invention, the diuretic and the CYP 11β2 beta-hydroxylase inhibitor are administered in a combined pharmaceutical composition.

[0016] In an embodiment of the invention, the diuretic and the CYP 11β2 beta-hydroxylase inhibitor are administered simultaneously.

[0017] In an embodiment of the invention, the combined amounts are effective to produce a greater than additive therapeutic result in treating a subject.

[0018] In an embodiment of the invention, the amount of CYP 11β2 beta-hydroxylase inhibitor and the amount of diuretic when administered together are more effective to treat a subject than the same amount of each agent when administered alone.

[0019] The present invention also provides a method for treating hypertension in a hypertensive subject taking at least one diuretic, comprising administering to the subject once or twice daily a CYP 11β2 beta-hydroxylase inhibitor in an amount sufficient to thereby treat hypertension in the hypertensive subject.

[0020] In an embodiment of the invention, the diuretic is a thiazide diuretic.

[0021] In one embodiment, the hypertensive subject has a body mass index of at least 30, preferably greater than 30, preferably 30-50, more preferably 30-40.

[0022] In certain embodiments, the hypertensive subject is a male hypertensive subject with a waist-to-hip ratio greater than 0.90 or a female hypertensive subject with a waist-to-hip ratio greater than 0.85.

[0023] In one embodiment, the hypertensive subject has a serum leptin concentration of at least 30 ng / dL, preferably at least 35 ng / dL, more preferably at least 40 ng / dL, or more preferably 30-50 ng / dL, 30-45 ng / dL, or 35-50 ng / dL.

[0024] In embodiments, the hypertensive subject is (a) a plasma aldosterone concentration of 6 ng / dL or greater in said subject by immunoassay; and / or (b) a plasma aldosterone concentration of 1 ng / dL or greater by LC-MS in the subject; It has.

[0025] Plasma aldosterone concentrations can be measured by standard commercially available tests known in the art. Such measurements can be performed by FDA-approved laboratories. See, for example, Stowasser et al., Clin Biochem Rev, 31(2):39-56 (2010), citing Schirpenbach et al., Clinical Chemistry 52, No. 9 (2006):1749-1755. Notably, the assay for measuring aldosterone reported in Schirpenbach is an immunoassay. As reported in Guo et al., The Journal of Clinical Endocrinology & Metabolism 103, No. 11 (2018):3965-3973, LC-MS assays have been shown to have higher specificity. In some embodiments, a plasma aldosterone concentration of 6 ng / dL or greater measured by an immunoassay, e.g., ELISA, corresponds to a plasma aldosterone concentration of about 1 ng / dL or greater measured by LC-MS.

[0026] The present invention provides a method of treating hypertension in a hypertensive subject in need thereof, comprising: (a) (i) a systolic blood pressure greater than 130 mmHg in said subject; (ii) a diastolic BP of greater than 80 mmHg in said subject measuring the (b) selecting a subject taking at least one diuretic; and (c) administering to the subject an effective amount of a CYP 11β2 beta-hydroxylase inhibitor. The present invention provides a method comprising:

[0027] The present invention provides a method of treating hypertension in a hypertensive subject in need thereof, comprising: (a) Subjects with hypertension (i) have a systolic blood pressure greater than 130 mmHg; (ii) have a diastolic BP greater than 80 mmHg, and (iii) taking at least one diuretic receiving an identification that administering to the subject an effective amount of a CYP 11β2 beta-hydroxylase inhibitor. The present invention provides a method comprising:

[0028] In certain embodiments, the diuretic is a thiazide diuretic.

[0029] In one embodiment, step (a) further comprises determining in the subject a body mass index (BMI) of at least 30, preferably greater than 30, preferably between 30 and 50, more preferably between 30 and 40, or a waist-to-hip ratio greater than 0.90 if the hypertensive subject is male, or greater than 0.85 if the hypertensive subject is female, or receiving identification that the subject has that body mass index (BMI) or that waist-to-hip ratio.

[0030] In one embodiment, step a) further comprises determining that the subject has a serum leptin concentration of at least 30 ng / dL, preferably at least 35 ng / dL, more preferably at least 40 ng / dL, or more preferably 30-50 ng / dL, 30-45 ng / dL, or 35-50 ng / dL, or receiving identification that the subject has such a serum leptin concentration.

[0031] In an embodiment of the present invention, step (a) comprises: (a) measuring a plasma aldosterone concentration of 6 ng / dL or greater in said subject by immunoassay; or (b) measuring a plasma aldosterone concentration of 1 ng / dL or greater in said subject by LC-MS Further includes:

[0032] In an embodiment of the present invention, the hypertensive subject is taking or has taken a hypertensive medication selected from an ACE inhibitor, an angiotensin receptor blocker, a calcium channel blocker, or a combination of two or more thereof. In an embodiment of the present invention, the hypertensive subject is taking or has taken at least two of the above hypertensive medications.

[0033] In an embodiment of the invention, 50% or more of CYP11β2 beta-hydroxylase activity is inhibited for 40-60% of a 24-hour period.

[0034] In an embodiment of the invention, 50% or more of the activity of CYP11β2 beta-hydroxylase is inhibited for 10 to 14 hours out of a 24 hour period.

[0035] In an embodiment of the invention, the CYP11β2 beta-hydroxylase inhibitor reduces the subject's serum aldosterone level by 50-90% for a period of 8 hours or more and 16 hours or less compared to the subject's pre-dosing serum aldosterone level.

[0036] In an embodiment of the invention, the CYP11β2 beta-hydroxylase inhibitor reduces the subject's serum aldosterone level by 60-80% for a period of 8 hours or more and 16 hours or less compared to the subject's pre-dosing serum aldosterone level.

[0037] In an embodiment of the invention, a CYP11β2 beta-hydroxylase inhibitor enables a subject's serum aldosterone to be restored to or above the subject's pre-dosing serum aldosterone level for 16 to 24 hours after administration of the dose.

[0038] In an embodiment of the invention, 50% or more of the activity of CYP11β2 beta-hydroxylase is inhibited for 1 to 16 hours, or preferably for 3 to 8 hours, in a 24 hour period.

[0039] In embodiments, the CYP11β2 beta-hydroxylase inhibitor is: (a) inhibiting CYP11β2β-hydroxylase activity by 50% or more for 1 to 16 hours, preferably 3 to 8 hours; (b) inhibiting CYP11β2β-hydroxylase activity by 60% or more for 1 to 13 hours, preferably 2 to 6 hours; (c) inhibiting 70% or more of the activity of CYP11β2 beta-hydroxylase for 1 to 9 hours, preferably 2 to 5 hours; (d) inhibiting 80% or more of the activity of CYP11β2 beta-hydroxylase for a period of 1 to 6 hours, preferably 1 to 3 hours; and / or (e) inhibiting 90% or more of the activity of CYP11β2 beta-hydroxylase for 0 to 3 hours, preferably 0 to 1 hour; It is administered once daily in an amount sufficient to This treats hypertension in a hypertensive subject.

[0040] In embodiments, the CYP11β2 beta-hydroxylase inhibitor is: (a) inhibiting CYP11β2 beta-hydroxylase activity by 50% or more for 1 to 20 hours, preferably 4 to 11 hours; (b) inhibiting CYP11β2 beta-hydroxylase activity by 60% or more for 1 to 17 hours, preferably 3 to 9 hours; (c) inhibiting 70% or more of the activity of CYP11β2β-hydroxylase for 1 to 15 hours, preferably 2.5 to 7 hours; (d) inhibiting 80% or more of the activity of CYP11β2 beta-hydroxylase for a period of 1 to 10 hours, preferably 2 to 5 hours; and / or (e) inhibiting 90% or more of the activity of CYP11β2β-hydroxylase for 1 to 5 hours, preferably for 0.5 to 2.5 hours; It is administered once daily in an amount sufficient to This treats hypertension in a hypertensive subject.

[0041] In an embodiment of the invention, a CYP11β2 beta-hydroxylase inhibitor is administered to a subject once daily. In an embodiment of the invention, a CYP11β2 beta-hydroxylase inhibitor is administered in the morning. In an embodiment of the invention, a CYP11β2 beta-hydroxylase inhibitor is administered to a subject twice daily. In a preferred embodiment of the invention, a CYP11β2 beta-hydroxylase inhibitor is administered to a subject once daily in the morning.

[0042] In an embodiment of the invention, the CYP11β2 beta-hydroxylase inhibitor is (a) administered daily for at least one week; (b) administered daily for at least 2 weeks; (c) administered daily for at least 4 weeks; or (d) administered daily for at least 8 weeks.

[0043] In embodiments of the invention, the ambulatory systolic blood pressure of the hypertensive subject is reduced by at least 10 mmHg, 10 to 55 mmHg, 10 to 50 mmHg, 10 to 45 mmHg, 10 to 40 mmHg, 10 to 35 mmHg, 10 to 30 mmHg, 10 to 25 mmHg, 10 to 20 mmHg, or 10 to 15 mmHg compared to the ambulatory systolic blood pressure of the hypertensive subject before administration of the CYP11β2 beta-hydroxylase inhibitor, preferably by at least 10 mmHg, 10 to 55 mmHg, 10 to 50 mmHg, 10 to 45 mmHg, 10 to 40 mmHg, 10 to 35 mmHg, 10 to 30 mmHg, 10 to 25 mmHg, 10 to 20 mmHg, or 10 to 15 mmHg compared to the ambulatory systolic blood pressure of the hypertensive subject before administration of the CYP11β2 beta-hydroxylase inhibitor, for at least 8 weeks.

[0044] In embodiments of the invention, the ambulatory diastolic blood pressure of the hypertensive subject is reduced by at least 5 mmHg, 5 to 25 mmHg, 5 to 20 mmHg, or 5 to 15 mmHg compared to the ambulatory diastolic blood pressure of the hypertensive subject before administration of the CYP11β2 beta-hydroxylase inhibitor, preferably by at least 5 mmHg, 5 to 25 mmHg, 5 to 20 mmHg, or 5 to 15 mmHg compared to the ambulatory diastolic blood pressure of the hypertensive subject before administration of the CYP11β2 beta-hydroxylase inhibitor, for at least 8 weeks.

[0045] In the embodiments of the present invention (a) the subject's office-measured systolic blood pressure is lower than the subject's office-measured systolic blood pressure before administration of the CYP11β2 beta-hydroxylase inhibitor; and / or (b) the subject's 24-hour ambulatory systolic blood pressure is lower than the subject's ambulatory systolic blood pressure before administration of the CYP11β 2 beta-hydroxylase inhibitor.

[0046] In the embodiments of the present invention (a) the subject's office-measured systolic blood pressure is at least 10 mmHg lower than the subject's office-measured systolic blood pressure before administration of the CYP11β 2 beta-hydroxylase inhibitor; and / or (b) the subject's ambulatory systolic blood pressure is at least 10 mmHg lower than the subject's ambulatory systolic blood pressure prior to administration of the CYP11β 2 beta-hydroxylase inhibitor.

[0047] In the embodiments of the present invention (a) the subject's office-measured diastolic blood pressure is lower than the subject's office-measured diastolic blood pressure before administration of the CYP11β2 beta-hydroxylase inhibitor; (b) the subject's office-measured systolic blood pressure and diastolic blood pressure are lower than the subject's office-measured systolic blood pressure and diastolic blood pressure before administration of the CYP11β2 beta-hydroxylase inhibitor; (c) the subject's ambulatory systolic blood pressure and diastolic blood pressure are lower than the subject's ambulatory systolic blood pressure and diastolic blood pressure before administration of the CYP11β 2 beta-hydroxylase inhibitor; and / or (d) the subject's systolic blood pressure is reduced to less than 130 mmHg, and / or the subject's diastolic blood pressure is reduced to less than 80 mmHg.

[0048] In the embodiments of the present invention (a) the subject's ambulatory systolic blood pressure is at least 10 mmHg lower and the subject's ambulatory diastolic blood pressure is at least 5 mmHg lower, respectively, compared to the subject's ambulatory systolic blood pressure and diastolic blood pressure, respectively, prior to administration of the CYP11β 2 beta-hydroxylase inhibitor. (b) the subject's office-measured systolic blood pressure is at least 10 mmHg lower and the subject's office-measured diastolic blood pressure is at least 5 mmHg lower, compared to the subject's office-measured systolic blood pressure and diastolic blood pressure, respectively, before administration of the CYP11β2 beta-hydroxylase inhibitor; and / or (c) the subject's systolic blood pressure is reduced to less than 130 mmHg, and / or the subject's diastolic blood pressure is reduced to less than 80 mmHg.

[0049] In an embodiment of the invention, the duration of inhibition of CYP11β2 beta-hydroxylase activity is sufficient to maintain sodium status and volume reduction in a hypertensive subject.

[0050] In an embodiment of the invention, the method does not result in a persistent state of hyperkalemia or mild non-ion gap metabolic acidosis in hypertensive subjects.

[0051] In embodiments of the present invention, the CYP11β2 beta-hydroxylase inhibitor does not substantially accumulate in the hypertensive subject, and preferably, the lack of significant accumulation of the CYP11β2 beta-hydroxylase inhibitor in the hypertensive subject allows the aldosterone levels in the hypertensive subject to return to pre-administration baseline within 24 to 48 hours of administration of the CYP11β2 beta-hydroxylase inhibitor, more preferably within 16 to 24 hours of administration of the CYP11β2 beta-hydroxylase inhibitor.

[0052] In embodiments of the invention, the potassium level of the hypertensive subject is generally maintained within a clinically normal range, preferably the potassium level of the hypertensive subject is only mildly improved compared to the hypertensive subject's potassium level prior to administration of the CYP11β2 beta-hydroxylase inhibitor, more preferably the hypertensive subject's potassium level is improved by no more than 0.35 mmol / L, more preferably the hypertensive subject's potassium level is maintained below a level of 5.5 mmol / L, and more preferably the hypertensive subject's potassium level is maintained between 3.5 mEq / L and 5.1 mEq / L.

[0053] In an embodiment of the invention, a CYP11β2 beta-hydroxylase inhibitor is administered to a hypertensive subject: (a) suppressing aldosterone production in a subject; (b) improving serum and / or plasma potassium levels in a subject; and / or (c) improving plasma renin activity (PRA) in a subject; Administered in the following amounts:

[0054] In the embodiments of the present invention (a) the AUC-24 of serum and / or plasma aldosterone is reduced in the subject by at least 25% compared to the aldosterone level in the subject prior to administration of the CYP11β 2 beta-hydroxylase inhibitor; (b) the serum and / or plasma potassium level in the subject is improved by at least 0.2 mMol / L compared to the serum and / or plasma potassium level in the subject prior to administration of the CYP11β 2 beta-hydroxylase inhibitor; and / or (c) the PRA in the subject is improved by at least 5 ng / mL / hr compared to the PRA in the subject prior to administration of the CYP11β 2 beta-hydroxylase inhibitor.

[0055] In an embodiment of the invention, the aldosterone levels in a hypertensive subject follow a substantially normal circadian rhythm.

[0056] In an embodiment of the invention, the hypertensive subject's mean sleep systolic blood pressure is reduced (a) compared to the hypertensive subject's mean sleep systolic blood pressure before receiving a CYP11β2 beta-hydroxylase inhibitor, and / or (b) compared to the hypertensive subject's mean daytime systolic blood pressure. In an embodiment, the hypertensive subject's mean sleep systolic blood pressure is reduced by: (a) a change of at least 10%, between 10% and 40%, between 10% and 30%, or between 10% and 20% compared to the mean daytime systolic blood pressure of hypertensive subjects; and / or (b) at least 8 mmHg, at least 10 mmHg, between 8 and 55 mmHg, between 10 and 45 mmHg, or between 10 and 25 mmHg compared to the hypertensive subject's mean systolic blood pressure during sleep before receiving the CYP11β2 beta-hydroxylase inhibitor Decreases.

[0057] In an embodiment of the invention, the CYP11β2 beta-hydroxylase inhibitor is selective for inhibiting CYP11β2 beta-hydroxylase activity compared to inhibiting CYP11β1 beta-hydroxylase activity, and preferably the inhibition constant (Ki) for CYP11β1 beta-hydroxylase divided by the Ki for CYP11β2 beta-hydroxylase is greater than 100.

[0058] In an embodiment of the invention, a CYP11β2 beta-hydroxylase inhibitor is administered to a hypertensive subject in an amount less than that which would cause the subject's serum and / or plasma 11-deoxycortisterone (11-DOC) level to exceed 600 pmol / L, preferably less than that which would cause the subject's serum and / or plasma 11-DOC level to exceed 400 pmol / L.

[0059] In an embodiment of the invention, a CYP11β2 beta-hydroxylase inhibitor is administered to a subject in an amount less than that which causes an accumulation of 11-DOC greater than 0.1 ng / ml in a hypertensive subject.

[0060] In an embodiment of the invention, a CYP11β2 beta-hydroxylase inhibitor is administered to a hypertensive subject in an amount that does not cause clinically significant upregulation of adrenocortical hormone synthesis in the subject.

[0061] In an embodiment of the invention, a CYP11β2 beta-hydroxylase inhibitor is administered to a hypertensive subject to: (a) does not cause a clinically significant decrease in the subject's serum and / or plasma cortisol levels compared to the subject's serum and / or plasma cortisol levels prior to administration of the CYP11β2 beta-hydroxylase inhibitor; (b) does not result in a clinically significant increase in the subject's serum and / or plasma 11-DOC levels compared to the subject's serum and / or plasma 11-DOC levels prior to administration of the CYP11β 2 beta-hydroxylase inhibitor; and / or (c) does not cause a clinically significant increase in the subject's serum and / or plasma 11-deoxycortisol levels compared to the subject's serum and / or plasma 11-deoxycortisol levels prior to administration of the CYP11β 2 beta-hydroxylase inhibitor; It is administered in doses.

[0062] In an embodiment of the invention, a CYP11β2 beta-hydroxylase inhibitor is administered to a hypertensive subject to: (a) does not cause a decrease in the subject's serum and / or plasma cortisol levels by more than 20% compared to the subject's serum and / or plasma cortisol levels prior to administration of the CYP11β2 beta-hydroxylase inhibitor, preferably does not cause a decrease in the subject's serum and / or plasma cortisol levels by more than 10% compared to the subject's serum and / or plasma cortisol levels prior to administration of the CYP11β2 beta-hydroxylase inhibitor; (b) does not result in an increase in the subject's serum and / or plasma 11-DOC level by more than 20% compared to the subject's serum and / or plasma 11-DOC level prior to administration of the CYP11β2 beta-hydroxylase inhibitor, preferably does not result in an increase in the subject's serum and / or plasma 11-DOC level by more than 10% compared to the subject's serum and / or plasma 11-DOC level prior to administration of the CYP11β2 beta-hydroxylase inhibitor; and / or (c) does not cause an increase in the subject's serum and / or plasma 11-deoxycortisol levels by more than 20% compared to the subject's serum and / or plasma 11-deoxycortisol levels prior to administration of the CYP11β2 beta-hydroxylase inhibitor, preferably does not cause an increase in the subject's serum and / or plasma 11-deoxycortisol levels by more than 10% compared to the subject's serum and / or plasma 11-deoxycortisol levels prior to administration of the CYP11β2 beta-hydroxylase inhibitor; It is administered in doses.

[0063] In an embodiment of the present invention, the CYP11β2 beta-hydroxylase inhibitor is a compound described in U.S. Patent No. 10,029,993, the disclosure of which is incorporated herein by reference. In an embodiment, the CYP11β2 beta-hydroxylase inhibitor is a compound described in U.S. Patent No. 10,329,263, the disclosure of which is incorporated herein by reference. In an embodiment, the CYP11B2 beta-hydroxylase inhibitor is a 1,2,4-triazine compound or a pharmaceutically acceptable salt thereof.

[0064] In embodiments, the CYP11β2 beta-hydroxylase inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0065] [ka] (I) [In the formula, 1) X and Y are the following (i) to (iii): (i) X is N and Y is CH or C-RY; (ii) X is CH and Y is N, or (iii) X is CH and Y is CH; represents one of the following: 2)R Y represents an alkyl group, 3) R Arepresents an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group, or an optionally partially hydrogenated and optionally substituted 6- to 10-membered monocyclic or bicyclic heteroaryl group, 4) R 1 represents a hydrogen atom or an alkyl group, 5)R 2 represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aliphatic heterocyclic group, or an optionally partially hydrogenated and optionally substituted heteroaryl group; 6)R 3 represents a hydrogen atom or an alkyl group. or a pharmaceutically acceptable salt thereof.

[0066] In embodiments, the CYP11β2 beta-hydroxylase inhibitor is a compound of formula (A) (also referred to herein as “Compound A”) or a pharmaceutically acceptable salt thereof:

[0067] [ka] (A) is.

[0068] In an embodiment, the CYP11β2 beta-hydroxylase inhibitor is a pharmaceutically acceptable salt of a compound of formula (A).

[0069] In embodiments, the CYP11β2 beta-hydroxylase inhibitor is the monohydrobromide salt of the compound of formula (A), i.e., Compound A HBr.

[0070] In an embodiment, the CYP11β2 beta-hydroxylase inhibitor is the free base form of the compound of formula (A).

[0071] In an embodiment, preferably when the CYP11β2 beta-hydroxylase inhibitor is Compound A, more preferably Compound A HBr: (a) Between 5 mg and 100 mg of a CYP11β2 beta-hydroxylase inhibitor is administered orally twice daily, 12 hours apart; (b) 10 mg to 50 mg of a CYP11β2 beta-hydroxylase inhibitor administered orally twice daily, 12 hours apart; (c) between 5 mg and 100 mg of a CYP11β2 beta-hydroxylase inhibitor administered orally once daily; or (d) Between 10 mg and 50 mg of a CYP11β2 beta-hydroxylase inhibitor is administered orally once daily.

[0072] In an embodiment, preferably when the CYP11β2 beta-hydroxylase inhibitor is Compound A, more preferably Compound A HBr: (a) 12.5 mg of a CYP11β2 beta-hydroxylase inhibitor is administered orally twice daily, 12 hours apart; (b) 25 mg of a CYP11β2 beta-hydroxylase inhibitor administered orally twice daily, 12 hours apart; (c) 12.5 mg of a CYP11β2 beta-hydroxylase inhibitor administered orally once daily; (d) 50 mg of a CYP11β2 beta-hydroxylase inhibitor administered orally once daily; or (e) 100 mg of a CYP11β2 beta-hydroxylase inhibitor is administered orally once daily.

[0073] In one embodiment, when the CYP11β2 beta-hydroxylase inhibitor is Compound A and the diuretic is a thiazide diuretic: (a) 12.5 mg of a CYP11β 2 beta-hydroxylase inhibitor is administered orally once daily, and hypertensive subjects experience a placebo-adjusted reduction in systolic blood pressure of at least 5 mmHg, preferably between 5 and 10 mmHg; (b) 50 mg of a CYP11β2 beta-hydroxylase inhibitor is administered orally once daily, and the hypertensive subject experiences a placebo-adjusted reduction in systolic blood pressure of at least 10 mmHg, preferably between 10 and 15 mmHg; or (c) 100 mg of a CYP11β2 beta-hydroxylase inhibitor is administered orally once daily, and the hypertensive subject experiences a placebo-adjusted reduction in systolic blood pressure of at least 9 mmHg, preferably between 9 and 15 mmHg.

[0074] In certain embodiments, the CYP11β2 beta-hydroxylase inhibitor is a compound having the following structure: or a pharmaceutically acceptable salt thereof:

[0075] [ka] is.

[0076] In one embodiment, the CYP11β2 beta-hydroxylase inhibitor is a compound having the following structure:

[0077] [ka] or a pharmaceutically acceptable salt thereof, wherein: (a)R 1 is C1-C7-alkyl, (b)R 2、 R 3 , R 4 and R 5 is H, (c)R 6 is H, halogen or C1-C7-alkyl, (d)R 7、 R 8、 R 9、 R 10 and R 11 is H, (e)R 12 is H or a halogen, (f)A 1 is CR13 and (g)A 2 is NR 14 or CR 15 R 16 and (h)A 3 is CR 17 and (i)R 13 is H or a halogen, (j)R 14 is -(CR 20 R 21 ) q -(CR 22 R 23 ) r -(CR 24 R 25 ) p -NR 26 R 27 and the sum of q, r, and p is at least 2; (k)R 15 is -(CR 20 R 21 ) q -(CR 22 R 23 ) r -(CR 24 R 25 ) p -NR 26 R 27 and (l)R 16 is H, (m) or R 6 and R 16 together with the carbon atoms to which they are attached form a double bond, (n)R 17、 R 20、 R 21、 R 22、 R 23、 R 24、 R 25 and R 26 is H, (o)R 27 is H, -S(O)R 31 , -C(O)R 31 or -C(O)OR 31 and R 26 is H and R27 is H, then the sum of q, r, and p is at least 1, (p)R 31 is C1-C7-alkyl, chloropyridinyl, hydroxyl-C1-C7-alkyl or C3-C8-cycloalkyl, (q) n is zero or one; (r) p is zero or one; (s) q is zero or one, (t)r is zero or one.

[0078] The synthesis of these compounds is described in U.S. Patent No. 9,353,081(B2), the entire contents of which are incorporated herein by reference. In one embodiment, the CYP11β2 beta-hydroxylase inhibitor is a compound described in U.S. Patent No. 9,353,081(B2), preferably a compound that is selective for inhibiting CYP11β2 beta-hydroxylase activity relative to inhibiting CYP11β1 beta-hydroxylase activity, and preferably has an inhibition constant (Ki) for CYP11β1 beta-hydroxylase divided by Ki for CYP11β2 beta-hydroxylase greater than 100.

[0079] In one embodiment, the CYP11β2 beta-hydroxylase inhibitor is a compound having the following structure:

[0080] [ka] or a pharmaceutically acceptable salt thereof, wherein: (a) A is N, (b) W is CR6; (c) X is CR6; (d) Y is CR6; (e) Z is CR6; (f) R1 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NRaRb, NHS02Rc, (CH2)nNRaRb, (CH2)nNHS02Rd, (CH2)nNHC02Rd, CO2Re, CORf, (CH2)nORf, or CReRfOH; (g) R2 is hydrogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NHSORc, CHNRaRb, CHNHSO2Rd, CO2Re, CORf, CH2ORf, or CReRfOH; (h) R3 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NRaRb, NHS02Rc, (CH2)nNRaRb, (CH2)nNHS02Rd, CO2Re, CORf, (CH2)nORf, or CReRfOH; (i) each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; (j) R4 is alkyl, cycloalkyl, haloalkyl, or heteroalkyl; (k) R6 at each occurrence is independently hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, or carboxyl; (l) Ra, Rb, Rc, Rd, Re, and Rf, in each occurrence, are independently hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyalkyl, C(O)OCi-6alkyl, C(O)Ci-6alkyl, if attached to a nitrogen atom, a nitrogen protecting group, or if attached to an oxygen atom, an oxygen protecting group; or Ra and Rb, together with the atoms to which they are attached, form a heterocycloalkyl ring; or Re and Rf, together with the atoms to which they are attached, form a cycloalkyl ring.

[0081] The synthesis of this compound is described in U.S. Patent No. 10,538,511, the entire contents of which are incorporated herein by reference. In one embodiment, the CYP11β2 beta-hydroxylase inhibitor is a compound described in U.S. Patent No. 10,538,511, preferably a compound that is selective for inhibiting CYP11β2 beta-hydroxylase activity relative to inhibiting CYP11β1 beta-hydroxylase activity, and preferably has an inhibition constant (Ki) for CYP11β1 beta-hydroxylase divided by Ki for CYP11β2 beta-hydroxylase greater than 100.

[0082] In one embodiment, the CYP11β2 beta-hydroxylase inhibitor is a compound having the following structure:

[0083] [ka] or a salt or enantiomer thereof, wherein: (a)R 1 are one, two or three independently halogen, haloalkyl, NO2, CN, COOR 5 , SO2R 5 ,CONR 5 R 6 , SO2NR 5 R 6 , N.R. 5 R 6 , OR5 , alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, or aryl; (b)R 2 is one or more independently halogen, haloalkyl, NO2, CN, COOR 5 , SO2R 5 ,CONR 5 R 6 , SO2NR 5 R 6 , N.R. 5 R 6 , OR 5 , alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, or aryl; (c)R 3 is alkyl, alkenyl, or alkynyl, any of which may be joined by one or more R 7 is further substituted by (d)R 4 is NR 5 R 6 , S.R. 5 OR 5 and (e)R 5 and R 6 are independently hydrogen, alkyl, aryl, or haloalkyl; (f)R 7 H, halogen, alkyl, haloalkyl, NO2, CN, COOR 8 , SO2R 8 ,CONR 8 R 9 , SO2NR 8 R 9 , N.R. 8 R 9 OR 8 and (g)R 8 and R 9 are independently hydrogen, alkyl, or haloalkyl; (h) and the compound is not benzo[d]thiazol-2-yl(pyridin-3-yl)methanol.

[0084] The synthesis of this compound is described in U.S. Patent No. 10,287,282, the entire contents of which are incorporated herein by reference. In one embodiment, the CYP11β2 beta-hydroxylase inhibitor is a compound described in U.S. Patent No. 10,287,282, preferably a compound that is selective for inhibiting CYP11β2 beta-hydroxylase activity relative to inhibiting CYP11β1 beta-hydroxylase activity, and preferably has an inhibition constant (Ki) for CYP11β1 beta-hydroxylase divided by Ki for CYP11β2 beta-hydroxylase greater than 100.

[0085] In an embodiment of the invention, the hypertensive subject has a plasma renin activity of 1 ng / mL / hr or less.

[0086] In an embodiment of the invention, the hypertensive subject has a plasma renin activity of 0.6 ng / mL / hr or less.

[0087] In an embodiment of the invention, the hypertensive subject has a plasma renin activity of 4 ng / mL / hr or less.

[0088] In an embodiment of the invention, the hypertensive subject has a plasma renin activity of 3 ng / mL / hr or less.

[0089] In an embodiment of the invention, the hypertensive subject has a plasma renin activity of 2 ng / mL / hr or less.

[0090] In an embodiment of the invention, the hypertensive subject has a plasma aldosterone concentration of 6 ng / dL or greater, as measured by immunoassay.

[0091] In an embodiment of the invention, the hypertensive subject has a plasma aldosterone concentration of 1 ng / dL or greater as measured by LC-MS.

[0092] In a preferred embodiment of the present invention, the hypertensive subject has a plasma renin activity of 1 ng / mL / h or less and a plasma aldosterone concentration of 6 ng / dL or more, as measured by immunoassay. In a preferred embodiment of the present invention, the hypertensive subject has a plasma renin activity of 1 ng / mL / h or less and a plasma aldosterone concentration of 1 ng / dL or more, as measured by LC-MS. In a further preferred embodiment, the hypertensive subject is taking or has taken a hypertensive medication selected from a diuretic, an ACE inhibitor, an angiotensin receptor blocker, a calcium channel blocker, or a combination of two or more thereof.

[0093] Alternatively, in embodiments in which the hypertensive subject is not taking a hypertensive medication selected from a diuretic, an ACE inhibitor, an angiotensin receptor blocker, or a calcium channel blocker, in one embodiment the hypertensive subject has a plasma renin activity of 0.6 ng / mL / hr or less and a plasma aldosterone concentration of 6 ng / dL or greater as measured by immunoassay or 1 ng / dL or greater as measured by LC-MS.

[0094] In an embodiment of the invention, the hypertensive subject has secondary hypertension, preferably primary aldosteronism. In another embodiment of the invention, the hypertensive subject does not have primary aldosteronism, preferably the hypertensive subject has primary hypertension.

[0095] The present invention also provides a method for identifying a subject for treatment of hypertension with a CYP11β2 beta-hydroxylase inhibitor, comprising: (a) (i) a systolic blood pressure greater than 130 mmHg in said subject; and (ii) a diastolic BP of greater than 80 mmHg in said subject and measuring (b) Selecting subjects taking at least one diuretic thereby identifying said subject for treatment of hypertension with a CYP11β2 beta-hydroxylase inhibitor.

[0096] In an embodiment of the invention, the diuretic is a thiazide diuretic.

[0097] In an embodiment of the invention, step (a) further comprises measuring in said subject a body mass index (BMI) of at least 30, preferably greater than 30, preferably between 30 and 50, more preferably between 30 and 40, or if said subject is male, measuring in said subject a waist-to-hip ratio of greater than 0.90, or if said subject is female, measuring in said subject a waist-to-hip ratio of greater than 0.85.

[0098] In an embodiment of the invention, step (a) further comprises measuring in said subject a serum leptin concentration of at least 30 ng / dL, preferably at least 35 ng / dL, or more preferably at least 40 ng / dL.

[0099] In an embodiment of the invention, step a) comprises: (a) measuring a plasma aldosterone concentration of 6 ng / dL or greater in the subject by immunoassay; or (b) measuring a plasma aldosterone concentration of 1 ng / dL or greater by LC-MS in said subject; Further includes:

[0100] In preferred embodiments of the present invention, subjects identified for treatment with a CYP11β2 beta-hydroxylase inhibitor experience a mean reduction in systolic blood pressure of at least 10 mmHg, 10 to 55 mmHg, 10 to 50 mmHg, 10 to 45 mmHg, 10 to 40 mmHg, 10 to 35 mmHg, 10 to 30 mmHg, 10 to 25 mmHg, 10 to 20 mmHg, or 10 to 15 mmHg when treated with the CYP11β2 beta-hydroxylase inhibitor, compared to the mean systolic blood pressure of the hypertensive subjects prior to treatment with the CYP11β2 beta-hydroxylase inhibitor. In particularly preferred embodiments, the ambulatory systolic blood pressure of a subject identified for treatment with a CYP11β2 beta-hydroxylase inhibitor is reduced to less than 130 mmHg when treated with a CYP11β2 beta-hydroxylase inhibitor, and / or the mean ambulatory diastolic blood pressure of a subject identified for treatment with a CYP11β2 beta-hydroxylase inhibitor is reduced to less than 80 mmHg when treated with a CYP11β2 beta-hydroxylase inhibitor.

[0101] composition The invention also provides pharmaceutical compositions, packages and unit dosage forms for use in any one of the methods described herein.

[0102] Therefore, the present invention provides (a) an amount of a compound of Formula (A) or a pharmaceutically acceptable salt thereof:

[0103] [ka] (A) and a pharmaceutically acceptable carrier; (b) a second pharmaceutical composition comprising an amount of a thiazide diuretic and a pharmaceutically acceptable carrier; and (c) instructions for using the first and second pharmaceutical compositions together to treat a subject suffering from hypertension. Provide a package including:

[0104] The present invention also provides a compound of formula (A) or a pharmaceutically acceptable salt thereof for use as add-on therapy or in combination with a thiazide diuretic in the treatment of a subject suffering from hypertension:

[0105] [ka] (A) to provide.

[0106] The present invention also provides (a) an amount of a compound of Formula (A) or a pharmaceutically acceptable salt thereof:

[0107] [ka] (A) (b) and an amount of a thiazide diuretic for use in treating a subject suffering from hypertension. wherein the compound of formula (A) and the thiazide diuretic are administered simultaneously, contemporaneously or concomitantly.

[0108] The present invention also provides (a) an amount of a compound of Formula (A) or a pharmaceutically acceptable salt thereof:

[0109] [ka] (A) (b) and an amount of a thiazide diuretic A pharmaceutical composition comprising: A pharmaceutical composition is provided in which a compound of formula (A) and a thiazide diuretic are combined and each is present in an amount effective to treat hypertension in a hypertensive subject.

[0110] The present invention also provides an amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof, for use in the treatment of a subject suffering from hypertension, as add-on therapy or in combination with a thiazide diuretic:

[0111] [ka] (A) The present invention provides a pharmaceutical composition comprising:

[0112] The present invention also provides a therapeutic package for dispensing or for use in dispensing to a subject suffering from hypertension, comprising: (a) one or more unit doses, each such unit dose comprising: (i) an amount of a compound of Formula (A) or a pharmaceutically acceptable salt thereof:

[0113] [ka] (A) and (ii) an amount of a thiazide diuretic Including, one or more unit doses, wherein, upon simultaneous administration to the subject, the individual amounts of the compound of Formula (A) and the thiazide diuretic in the unit dose are effective to treat the subject; and (b) a finished pharmaceutical container therefor, containing said unit dose(s) and further containing or comprising a label directing use of said package in treating said subject. A treatment package is provided, including:

[0114] The present invention also provides a method for treating a subject suffering from hypertension, comprising administering to said subject a compound in a unit dosage form. (a) an amount of a compound of Formula (A) or a pharmaceutically acceptable salt thereof:

[0115] [ka] (A) and (b) a dose of a thiazide diuretic 1. A pharmaceutical composition comprising: Provided is a pharmaceutical composition wherein, upon simultaneous administration to the subject of one or more of the unit dosage forms of the composition, the individual amounts of the compound of Formula (A) and the thiazide diuretic in the composition are effective to treat the subject.

[0116] definition Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used to practice or test embodiments of the present invention, exemplary methods and / or materials are described below. In case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are merely illustrative and are not necessarily intended to be limiting.

[0117] In the discussion, unless otherwise specified, adjectives such as "substantially" and "about" modifying a condition or relationship characteristic of a feature or features of embodiments of the present invention are understood to mean defining that condition or feature as being within acceptable tolerances for operation of the embodiment for its intended use. In embodiments, about means within a standard deviation using measurements generally accepted in the art. In embodiments, about means a range extending up to + / - 10% of the specified value. In embodiments, about includes the specified value. Unless otherwise indicated, the word "or" in this specification and claims is considered to be an inclusive "or" rather than an exclusive "or," indicating at least one of the items it conjugates, and any combination thereof.

[0118] The terms "a" and "an," as used above and elsewhere in this specification, should be understood to refer to "one or more" of the listed components. It will be apparent to one of ordinary skill in the art that the use of the singular includes the plural unless specifically stated otherwise. Thus, the terms "a," "an," and "at least one" are used interchangeably in this application.

[0119] For the purpose of better understanding the present teachings, and without in any way limiting the scope of the present teachings, unless otherwise indicated, all numerals expressing numbers, percentages or proportions, and other numerical values ​​used in the specification and claims should be understood to be modified in all instances by the term "about." Accordingly, unless specifically stated to the contrary, the numerical parameters set forth in the following specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, each numerical parameter should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0120] In the description and claims of this application, the verbs "comprise," "include," and "have," and each of their conjugations, are used to indicate that the object(s) of the verb are not necessarily an exhaustive list of components, elements, or parts of the object(s) of the verb. Other terms, as used herein, are intended to be defined by their well-known meanings in the art.

[0121] "Hypertension," also known as high blood pressure, is blood pressure that is higher than normal. In 2017, the American College of Cardiology and the American Heart Association published guidelines for the management of hypertension, defining it as a systolic blood pressure of 130 mmHg and a diastolic blood pressure of 80 mmHg or higher. Stage 1 hypertension is defined as a systolic blood pressure of 130-139 mmHg and a diastolic blood pressure of 80-89 mmHg, while stage 2 hypertension is defined as a systolic blood pressure greater than 140 mmHg and a diastolic blood pressure greater than 90 mmHg. As used herein, "hypertension" includes both stage 1 and stage 2 hypertension unless otherwise indicated. In one embodiment, a hypertensive subject has stage 1 hypertension. In another embodiment, a hypertensive subject has stage 2 hypertension. Hypertension includes multifactorial hypertension, including hypertension without a single clear cause (primary hypertension) and hypertension with a direct cause (secondary hypertension). As used herein, "hypertension" includes both primary and secondary hypertension, unless indicated to the contrary. In embodiments, a hypertensive subject has primary hypertension. In other embodiments, a hypertensive subject has secondary hypertension. Primary aldosteronism (hyperaldosteronism), the most common form of secondary hypertension, is a condition that occurs when the adrenal glands produce too much aldosterone. In embodiments in which a hypertensive subject has secondary hypertension, the subject has primary aldosteronism.

[0122] "CYP11β2," "Cyp11B2," or "CYP11β2 beta-hydroxylase" is a cytochrome P450 enzyme encoded by the CYP11B2 gene in humans, which catalyzes a series of reactions that produce aldosterone from 11-deoxycorticosterone (i.e., aldosterone precursor). Therefore, it is referred to in the art as "aldosterone synthase." Cyp11B2 is primarily expressed in the adrenal cortex zona glomerulosa, and plasma aldosterone levels are regulated by the enzymatic activity of Cyp11B2 present in the adrenal gland. Aldosterone is expressed in other tissues, such as the cardiovascular system, kidney, adipose tissue, and brain.

[0123] "CYP11β1," "Cyp11B1," or "CYP11β1 beta-hydroxylase" is a cytochrome P450 enzyme involved in the biosynthesis of adrenal corticosteroids, encoded in humans by the CYP11B1 gene. It is also referred to in the art as "steroid 11β-hydroxylase."

[0124] An "inhibitor" refers to a compound (e.g., a compound described herein) that reduces activity when compared to a control, such as the absence of the compound or a compound with known inactivity. Inhibitors can be small molecule inhibitors, antibody inhibitors, protein inhibitors, biomolecule inhibitors, natural ligands, etc. An "inhibitor" can exist, for example, in the form of a pharmaceutically acceptable salt of a compound described herein.

[0125] As used herein, "compound A" refers to a compound of formula (A):

[0126] [ka] (A) 3-[4-[[trans-4-(acetamino)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine It refers to a disubstituted 1,2,4-triazine compound represented by the formula:

[0127] "Compound A HBr" refers to the hydrobromic acid (HBr) salt of Compound A. The weight and / or strength of "Compound A HBr" and the "compounds" of the invention refer to the weight of the free base of the HBr salt, and not the weight of the HBr salt.

[0128] Compound A and pharmaceutically acceptable salts thereof can be made by the methods described, for example, in U.S. Pat. No. 10,029,993 and European Publication No. 3549935, the disclosures of which are incorporated herein by reference in their entireties.

[0129] "Treating" or "treatment," as used herein (and as is well understood in the art), also broadly includes any approach to achieving beneficial or desired results in a subject's condition, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether partial or complete, and whether detectable or undetectable, reduction in the extent of disease, stabilization of the disease state (i.e., not worsening), prevention of the spread or spread of disease, delay or slowing of disease progression, improvement or alleviation of the disease state, reduction in recurrence of disease, and remission. In other words, "treatment," as used herein, includes any cure, amelioration, or prevention of disease. Treatment can prevent the onset of disease, arrest the spread of disease, alleviate the symptoms of disease, completely or partially eliminate the underlying cause of disease, shorten the duration of disease, or a combination of these.

[0130] As used herein, "treating" and "treatment" include prophylactic treatment. Treatment involves administering a therapeutically effective amount of an active agent to a subject. The administration step may be a single administration or may include a series of administrations. The length of the treatment period depends on various factors, such as the severity of the condition, the age of the patient, the concentration of the active agent, the activity of the composition used for treatment, or a combination thereof. It is also understood that the effective dosage of an agent used for treatment or prevention may increase or decrease over the course of a specific treatment or prevention regimen. Dosage amounts may vary and may be determined by standard diagnostic assays known in the art. In embodiments, long-term administration may be required. For example, the composition is administered to a subject in an amount and for a period sufficient to treat the patient. In embodiments, the treating or treatment is not prophylactic treatment.

[0131] "Diuretic" refers to a hypertension medication that increases urine production, thereby increasing the amount of water and salt excreted from the body. The diuretic can be a carbonic anhydrase inhibitor, a loop diuretic, a potassium-sparing diuretic, a thiazide diuretic, or any other diuretic known in the art. Exemplary carbonic anhydrase inhibitors include acetazolamide, brinzolamide, dorzolamide, dichlorphenamide, ethoxaolamide, zoniamide, indisulam, and methazolamide. Exemplary loop diuretics include bumatenide, ethacrynic acid, torasemide, and furosemide. Exemplary potassium-sparing diuretics include epelerenone, triamterene, spironolactone, and amiloride. Exemplary thiazide diuretics include indapamide, hydrochlorothiazide, chlorthalidone, metolazone, methyclothiazide, chlorothiazide, methylclothiazide, metolazone, bendroflumethiazide, polythiazide, and hydroflumethiazide. Other diuretics include pamabrom and mannitol.

[0132] "Angiotensin-converting enzyme inhibitors" or "ACE inhibitors" refer to high blood pressure medications that block the conversion of angiotensin I to angiotensin II, thereby dilating blood vessels and lowering blood pressure. Exemplary ACE inhibitors include benazepril, zofenopril, perindopril, trandolapril, captopril, enalapril, lisinopril, and ramipril.

[0133] "Angiotensin receptor blockers" or "angiotensin II inhibitors" refer to high blood pressure medications that block the receptor binding of angiotensin II, thereby dilating blood vessels and lowering blood pressure. Exemplary angiotensin receptor blockers include eprosartan, olmesartan, valsartan, candesartan, losartan, telmisartan, irbesartan, valsartan, and azilsartan medoxomil.

[0134] "Calcium channel blockers" refer to hypertension medications that block calcium from entering cardiac and arterial cells through calcium channels, thereby lowering blood pressure. Calcium channel blockers can be dihydropyridine calcium channel blockers, phenylalkylamine calcium channel blockers, benzothiazepine calcium channel blockers, non-selective calcium channel blockers, or any other calcium channel blockers known in the art. Dihydropyridine calcium channel blockers include amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, and pranidipine. Phenylalkylamine calcium channel blockers include fendiline, gallipamil, and verapamil. Benzothiazepine calcium channel blockers include diltiazem. Nonselective calcium channel blockers include mibefradil, bepridil, flunarizine, fluspirilene, and fendiline. Other calcium channel blockers include gabapentin, pregabalin, and ziconotide.

[0135] The "normal circadian rhythm" of aldosterone levels follows a diurnal pattern, with lows occurring late at night and peaks after early morning awakening. In one embodiment, the aldosterone levels of a hypertensive subject follow a substantially normal circadian rhythm. In one such embodiment, a CYP11β2 beta-hydroxylase inhibitor of the present invention, when administered once daily in the morning after walking, suppresses the abnormally elevated production of aldosterone during walking hours. In the evening, the suppression of aldosterone production begins to wane, and by dawn, the normal increase in serum aldosterone returns to its normal direction, as it would under normal circumstances. The circadian rhythm of aldosterone in normal subjects and subjects with primary aldosteronism is described in Kem, David C., et al., "Circadian rhythm of plasma aldosterone concentration in patients with primary aldosteronism," The Journal of Clinical Investigation 52.9 (1973): 2272-2277, the contents of which are specifically incorporated herein by reference.

[0136] The present invention provides a method for reducing systolic blood pressure in a hypertensive subject "during sleep." In this context, "during sleep" refers to the sleep period in the hypertensive subject's normal sleep / wake cycle. In other words, "during sleep" refers to the approximately 7-9 hours of sleep (usually at night) that a hypertensive subject experiences each day during the approximately 15-17 hours of wakefulness, and does not refer to any short periods of sleep (i.e., naps) that may occur outside of the sleep phase of the subject's normal sleep / wake cycle. The blood pressure of non-hypertensive individuals typically decreases during sleep, with blood pressure being approximately 10%-15% lower during sleep than during wakefulness. In contrast, hypertensive subjects may experience a smaller decrease in blood pressure during sleep, or may not experience any decrease in blood pressure at all. Thus, the method of the present invention helps hypertensive subjects recover the decrease in blood pressure that typical non-hypertensive subjects experience during sleep.

[0137] A subject's "pre-dose level" of serum aldosterone refers to the subject's serum aldosterone level at the same time without treatment with a CYP11β2 beta-hydroxylase inhibitor.As discussed above, aldosterone levels follow a circadian pattern, with lows occurring late at night and peaks occurring after waking up early in the morning.Therefore, in embodiments in which a CYP11β2 beta-hydroxylase inhibitor dose reduces a subject's serum aldosterone level by a certain percentage compared to its "pre-dose level," the reduction in serum aldosterone is measured by comparing it to the serum aldosterone level of the same subject at the same time without the administration of a CYP11β2 beta-hydroxylase inhibitor.For example, a subject's serum aldosterone level at 11 AM is measured after the administration of a CYP11β2 beta-hydroxylase inhibitor, compared to the serum aldosterone level of the same subject at 11 AM before any administration of a CYP11β2 beta-hydroxylase inhibitor.

[0138] general In the case of the above-described embodiments, it is contemplated that each embodiment disclosed herein is applicable to each of the other disclosed embodiments.

[0139] As used herein, all headings are for organizational purposes only and are not intended to limit the disclosure in any way. The content of any individual section may be equally applicable to all sections. All combinations of the various elements disclosed herein are within the scope of the invention.

[0140] Additional objects, advantages, and novel features of the present invention will become apparent to those skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, all of the various embodiments and aspects of the present invention as described hereinabove and as claimed in the claims section below will find experimental support in the following examples.

[0141] It is understood that certain features of the invention that are described, for clarity, in the context of individual embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the invention that are described in the context of a single embodiment may also be provided individually or in any suitable subcombination, or as preferred in any other described embodiment of the invention. Certain features that are described in the context of various embodiments are not considered essential features of those embodiments unless the embodiment cannot function without those elements.

[0142] Examples are presented below to facilitate a more complete understanding of the present invention. The following examples illustrate exemplary modes of making and practicing the invention. However, the scope of the present invention is not limited to the specific embodiments disclosed in these examples, which are for illustrative purposes only. [Example]

[0143] [Example 1]

[0144] A randomized, double-blind, placebo-controlled, dose-ranging, multi-center study was conducted to evaluate the effects of orally administered Compound A HBr on blood pressure for the treatment of hypertension in male and female subjects aged 18 years and older.

[0145] Test Design The study consists of two parts. To enroll in Part 1 of the study, subjects must have a plasma renin activity (PRA) value of 1 ng / mL / h or less on a morning basis. If the PRA value is greater than 1 ng / mL / h on a morning basis, the subject may be eligible to participate in Part 2 of the study.

[0146] For Part 1, 163 enrolled subjects aged 18 years or older were randomized into six equal treatment groups (1:1:1:1:1:1)—12.5 mg BID, 25 mg BID, 12.5 mg QD, 50 mg QD, 100 mg QD, or placebo. After review of interim clinical data, further randomization was stopped for the two lowest dose levels (12.5 mg QD and 12.5 mg BID) due to a lack of significant consistent reductions in blood pressure; however, patients randomized up to that point remained in the study until completion. Therefore, after review of interim clinical data, subjects were randomized into four equal treatment groups (1:1:1:1)—25 mg BID, 50 mg QD, 100 mg QD, or placebo.

[0147] For Part 2, 36 enrolled subjects aged 18 years or older were randomized (5:1) to either 100 mg QD (Compound A HBr) or placebo, such that the Compound A HBr treatment group consisted of approximately 30 subjects and the placebo treatment group consisted of approximately 6 subjects.

[0148] Subjects received their assigned study medication (Compound A HBr or placebo) orally according to their assigned dosing regimen for 8 weeks, beginning on Study Day 1. All subjects in Part 1 (regardless of treatment group) received treatment BID to ensure complete blinding. All subjects in the QD dose group received the active medication as a morning dose. Upon returning to the study site or at the end of Study Weeks 1, 2, 3, 4, 5, 6, 7, and 8 (± 2 days), subjects were observed by the clinical investigator or a qualified family health professional for protocol-specified efficacy and safety assessments and procedures, adverse event (AE) evaluation, and compliance verification associated with study medication use. Subjects also completed telephone visits and blood pressure (BP) checks at home for approximately 3 days after their last dose of study medication. Subjects participated in up to a total of 14 clinic visits, including a pre-screening visit, a screening / placebo run-in visit, a second visit during placebo run-in, a clinic visit to initiate ABPM procedures, a randomization visit, visits every 8 weeks during double-blind treatment, and an end-of-study visit scheduled 4 weeks after the last study treatment for final efficacy and safety assessments.

[0149] A schematic diagram of this study design is shown in Figure 1.

[0150] Automated Office Blood Pressure (AOBP) Procedure Using an automated oscillometric sphygmomanometer device, subjects' systolic and diastolic blood pressure was measured in the examination room after approximately 5 minutes of rest in a seated position.

[0151] 24-hour ambulatory blood pressure monitoring (ABPM) procedure Ambulatory blood pressure monitoring was performed using an ambulatory blood pressure monitoring device consisting of a blood pressure cuff worn on the subject's arm attached to a small recording device that is typically attached to the subject's belt or waistband.

[0152] The ABPM device is worn for 24 hours. Throughout that period, the device periodically records the subject's blood pressure during the subject's daily routine and while they sleep. Thus, ABPM provides a complete record of the subject's blood pressure over a 24-hour period.

[0153] Twenty-four-hour ABPM was measured at the clinic at baseline and at study week 7. If, for any reason, the ABPM procedure was deemed unsuccessful at the end of study week 7, it may be repeated at study week 8, but without imputation, regardless of the use of rescue medication. In addition, ABPM was collected at the end of study week 4 in Part 2. If a repeat test was performed, it supersedes the original test results for that visit.

[0154] Specific derived variables based on ABPM measurements include 24-hour, daytime, and nighttime averages of SBP, DBP, and heart rate.

[0155] Changes from baseline to week 7 in 24-hour mean SBP (and DBP) based on ABPM will be analyzed using ANCOVA, with treatment group period and 24-hour mean baseline values ​​as covariates.

[0156] Nocturnal blood pressure drop is defined as follows: 100% × (average daytime SBP - average nighttime SBP) / average daytime SBP

[0157] Nocturnal blood pressure declines will be expressed as percentages and summarized by treatment group and visit using descriptive statistics. Additionally, the number and percentage of subjects with nocturnal blood pressure declines in each of the blood pressure decline classifications (Bloomfield & Park, 2015) will be presented by treatment group and visit. The classifications are as follows: (a)<10% (b) 10 to 20% (including these) (c)>20%

[0158] Eligibility Criteria Selection Criteria The study was conducted using subjects who met the following inclusion criteria: (a) Male subjects aged 18 years or older and female subjects who are not pregnant or breastfeeding (b) automated office blood pressure (AOBP) with systolic blood pressure (SBP) ≥ 130 mmHg (c) Basal antihypertensive treatment with two or more drugs (d) serum cortisol ≥ 18 mcg / dL

[0159] Exclusion criteria Subjects will be excluded from this study if they meet any of the following exclusion criteria: (a) Concurrent use of epithelial sodium channel blockers or mineralocorticoid receptor antagonists (b) Subjects with hypokalemia (c) Subjects with hyperkalemia (d) Subjects with serum cortisol <3 mcg / dL (e) Subjects with serum sodium <135 mEq / L (f) Subjects with an estimated glomerular filtration rate <60 mL / min / 1.73 m2 (g) Subjects with type 1 or uncontrolled type 2 diabetes (hemoglobin A1c ≥ 9%) (h) Body mass index >40 kg / m 2 Subject to (i) Subjects with unstable angina (j) Subjects with SBP ≥ 175 mmHg or diastolic blood pressure (DBP) ≥ 100 mmHg for Part 1, and subjects with SBP ≥ 160 mmHg or DBP ≥ 100 mmHg for Part 2, before screening, at the start of screening / placebo run-in, or at randomization. (k) Subjects who have a decrease in SBP ≥ 20mmHg or DBP ≥ 10mmHg from sitting to standing at the time of screening (l) Subjects suspected of non-compliance with antihypertensive drug treatment in the opinion of the investigator (m) Subjects who, in the opinion of the investigator, have any major medical illness or condition. (n) Subjects who, in the opinion of the investigator, have any acute or chronic medical or neuropathological condition. (o) Subjects receiving treatment with any of the following medications: (i) Topical corticosteroids (ii) sympathomimetic vasoconstrictors (iii) theophylline (iv) phosphodiesterase type 5 inhibitors (v) NSAIDs (vi) Intramuscular steroids (vii) estrogen (viii) cytochrome (ix) strong CYP3A and CYP3A4 inducers (p) Subjects with known hypersensitivity to Compound A HBr or any of the excipients (q) Subjects who are night shift workers.

[0160] Treatment Groups and Interventions The study included the following treatment groups and corresponding interventions:

[0161] [Table 1]

[0162] Study endpoints Primary endpoint The primary endpoint was the change in systolic blood pressure (SBP) measured in the office (mean of the last two of five unattended measurements using an automated oscillometric sphygmomanometer device after approximately five minutes of rest in a seated position) from baseline to the end of the eighth week of the study.

[0163] Secondary endpoints Secondary endpoints of this study were: (a) Changes in 24-hour ambulatory blood pressure monitoring (ABPM) parameters (systolic and diastolic) from baseline to the end of week 7 of the study. (b) Change in office-measured SBP from baseline to the end of weeks 1, 2, 3, 4, 5, 6, and 7 of the study. (c) Change in office-measured diastolic blood pressure (DBP) from baseline to the end of weeks 1, 2, 3, 4, 5, 6, 7, and 8 of the study. (d) Percentage of subjects achieving a clinic-measured BP of ≤130 / 80 mmHg by the end of week 8 of the study

[0164] Pharmacodynamic endpoints The pharmacodynamic endpoints of this study were: (a) Changes in plasma 11-deoxycortisol and PRA from baseline to the end of study week 4 and to the end of follow-up (i.e., for Part 1, end of study week 12, and for Part 2, end of study week 10). (b) Changes in serum aldosterone, cortisol, and 11-deoxycorticosterone concentrations from baseline to the end of week 4 of the study and to the end of follow-up.

[0165] Pharmacokinetic endpoints The pharmacokinetic endpoints of this study were the area under the plasma concentration versus time curve (AUC), maximum plasma concentration (Cmax), time to maximum concentration (Tmax), and half-life (t 1 / 2 ) will be summarized descriptively for randomization (baseline) and study weeks 1, 4, and 8.

[0166] Safety Endpoints The safety endpoints of this study were: (a) Incidence and severity of all concurrently reported adverse events (AEs) (b) changes in vital signs (orthostatic SBP, orthostatic DBP, temperature, heart rate, and respiratory rate); (c) Changes in electrocardiogram parameters (heart beat intervals: PR, QRS, QT, and corrected QT interval using Fridericia's formula) (d) Changes in clinical laboratory assessments (hematology, chemistry, coagulation, and urinalysis) (e) Change in office-measured SBP from study week 8 (end of treatment period) to the end of follow-up (i.e., for part 1, end of study week 12, and for part 2, end of study week 10).

[0167] Analysis methodology The following analysis populations will be defined in this study:

[0168] Full Analysis Set (FAS) The FAS includes all randomized subjects who received at least one dose of randomized study treatment (MLS-101 or placebo). The FAS will be the primary population for efficacy analyses. In analyses performed on the FAS, subjects will be analyzed according to their randomized study treatment group unless otherwise specified.

[0169] Protocol-Persistent Population (PPS or PP) The per-protocol population includes all subjects in the FAS who completed the study week 8 visit without any major protocol violations that could affect the reliability of the data for the primary efficacy assessment. In the analysis based on the PPS, subjects are analyzed according to their randomized study treatment group. All criteria for excluding subjects from the PPS will be based on blinded data review prior to unblinding of the study.

[0170] Subjects may be excluded from the per-protocol analysis population if they meet any of the following criteria: (a) Not meeting the inclusion / exclusion criteria (b) Use of Prohibited Medications. Subjects using rescue medications will not be excluded from the PPS unless the subject meets other criteria for exclusion from the PPS. (c) Non-compliance with investigational drug (d) Outside the efficacy assessment window at the study week 8 visit

[0171] Alternative criteria for exclusion from the per-protocol analysis population were also applied to accommodate unanticipated events occurring during the conduct of the study.

[0172] Analyses on the per-protocol analysis population will be ancillary and limited to the primary endpoint (i.e., "product evaluand").

[0173] Safety Analysis Set (SAF) The safety analysis set includes all enrolled subjects who received at least one dose of study treatment (MLS-101 or placebo). In analyses performed on the safety analysis set, subjects are analyzed according to the treatment they actually received.

[0174] PK / PD analysis set (PKPD) The PK / PD analysis population includes all subjects in the SAF with sufficient data available for analysis of pharmacokinetic and pharmacodynamic measurements. In the PKPD-based analysis, subjects are analyzed according to the treatment they actually received.

[0175] Defining a baseline Baseline is defined as the last available observation of the parameter of interest before the first dose of investigational medicinal product (IMP) in the double-blind treatment period.

[0176] For AOBP measurements and any other clinical or laboratory variables for repeat assessment at screening and baseline visits, baseline is defined as the mean of the last two non-missing values ​​before the first dose of IMP during the double-blind treatment period.

[0177] Change from baseline is calculated as follows: Post-Baseline Result - Baseline Result

[0178] Percent change from baseline is calculated as follows: (change from baseline / baseline result) x 100%.

[0179] Summary of Results A dose-response relationship existed across the QD dose range, with the 50 mg and 100 mg QD doses associated with a mean reduction in AOBP-measured systolic BP of -11 to -13 mmHg (Part 1 adherence-to-protocol, placebo-adjusted analysis: 100 mg cohort = -10.3 mmHg, Part 1 and Part 2 combined full analysis population (intermediate) = -9.9 mmHg, N = 58 actives).

[0180] Once-daily dosing was as effective as twice-daily dosing, and the results of the two BID cohorts were not as good as those of the 50 mg and 100 mg QD cohorts.

[0181] In a pooled analysis of the 50 mg QD, 100 mg QD, 12.5 mg BID, and 25 mg BID cohorts (N=103), 25% of subjects demonstrated a change in BPsys >-25 mmHg and 41% a change >-15 mmHg.

[0182] Using automated office blood pressure (AOBP), there was little difference in treatment response between individuals in part 1 and in the results available from part 2, suggesting that PRA does not appear to be a strong determinant of response (serum and urinary aldosterone were also unhelpful).

[0183] Twenty-four hour ambulatory BP measurements demonstrated a nocturnal reduction in systolic BP of -11.5 + / - 2.9 mmHg in the 100 mg QD cohort, with the associated increase in nocturnal "BP lowering" consistent with a sustained nocturnal benefit after AM dosing.

[0184] The pooled (Part 1 and Part 2) 100 mg QD safety analysis population (n=60) demonstrated good safety and tolerability, with no effect on serum cortisol, few episodes of mild or moderate hyperkalemia, and no episodes of severe hyperkalemia.

[0185] Automated office blood pressure results Full analysis and safety population (FAS) analyses were performed using all subjects with a week 8 measurement. A adherence-to-protocol (PP) analysis was also performed using all subjects who completed treatment through the week 8 visit. Waterfall plots showing the AOBP change in systolic blood pressure at week 8 from the FAS analysis for the placebo, 50 mg QD, and 100 mg QD groups and the PP analysis for the 100 mg group are presented in Figure 2. Waterfall plots showing the AOBP change in systolic blood pressure at week 8 from the 12.5 mg QD, 12.5 mg BID, and 25 mg BID groups are presented in Figure 3. Model means and observed adherence-to-protocol means are also shown for each group.

[0186] The mean change in systolic blood pressure from baseline is shown in Figure 4. The figure presents the final analysis, including both the full analysis set (FAS, all evaluable subjects who received at least one dose of Compound A HBr) and protocol adherence (PP, only subjects who received 75% or more of the study drug through the week 8 visit). Data for Part 2 represent the median mean values ​​for the last visit between weeks 5 and 6.

[0187] The dose-response of Compound A HBr was observed based on the analysis of the change in systolic AOBP from baseline in the QD regimen. Figure 5 shows the mean change in automated office blood pressure from baseline observed at week 8 for the QD dosing regimen. The BID protocol adherence cohort is shown on the far right side of this graph.

[0188] A pooled analysis of the change in systolic blood pressure from baseline at week 8 for the 50 mg QD, 100 mg QD, 12.5 mg BID, and 25 mg BID cohorts was performed and then separated into quartiles based on the degree of systolic blood pressure response. Figure 6 is a graph showing the change in systolic blood pressure from baseline at week 8 for the pooled cohort, lowest response quartile, highest response quartile, and placebo. Twenty-five percent of subjects achieved a reduction in systolic blood pressure of greater than -23 mmHg, with a mean reduction of -33.4 + / - 1.5 mmHg. Forty-one percent of subjects achieved a reduction in systolic blood pressure of 15 mmHg or greater.

[0189] Figure 7 is a waterfall plot showing the change in systolic blood pressure from the placebo and 100 mg QD groups pooled from both Part 1 and Part 2. Part 2 data from the interim snapshot for all randomized subjects and for the last visit at a mean of 5–6 weeks and a minimum of 2 weeks.

[0190] Analysis of factors affecting blood pressure changes An analysis was conducted to identify factors that influence the degree of blood pressure reduction in hypertensive subjects. As summarized in the table below, Compound A HBr was found to be particularly effective in reducing blood pressure in individuals with a body mass index (BMI) greater than 30. This effect was observed across the entire treatment cohort. A BMI greater than 30 is considered to be in the obese range. Similarly, a waist-to-hip ratio greater than 0.90 for men and 0.85 for women is considered to be in the obese range. Therefore, it is inferred that Compound A HBr is particularly effective in reducing blood pressure in men with a waist-to-hip ratio greater than 0.90 and in women with a waist-to-hip ratio greater than 0.85.

[0191] Additionally, as summarized in the table below, Compound A HBr was found to be particularly effective in lowering blood pressure in individuals who were taking a thiazide diuretic as one of their baseline hypertension medications, and this effect was observed across all treatment cohorts.

[0192] [Table 2]

[0193] All values ​​were determined using least squares analysis of model means using all available information. ** Difference in effect between 2 and 3+ backgrounds due to imbalance in placebo response

[0194] Ambulatory blood pressure (ABPM) results A graph showing an example of ambulatory 24-hour blood pressure monitoring is presented in Figure 9. The graph shows 24-hour ambulatory blood pressure (systolic) for subjects receiving 100 mg QD of Compound A HBr relative to baseline, demonstrating the mean 24-hour blood pressure reduction and restoration of the normal nocturnal blood pressure reduction pattern.

[0195] A graph showing the change in systolic blood pressure at week 8 relative to baseline, as measured using the ABPM full analysis set, is presented in Figure 10. Waterfall plots showing the change in 24-hour mean and nighttime mean ABPM relative to baseline at week 8 are presented in Figure 11. The 100 mg QD dose level provides superior 24-hour blood pressure reduction. The nighttime blood pressure reduction from the 100 mg QD dose level appears to be superior to 25 mg BID.

[0196] The most consistent benefit across all measures was observed in the 100mg QD cohort, as shown in the summary table below.

[0197] [Table 3]

[0198] Nocturnal hypotension, defined as 100% × (24-hour ambulatory daytime SBP - 24-hour ambulatory monitoring nighttime SBP) / 24-hour ambulatory monitoring daytime

[0199] safety No serious adverse events (SAEs) related to study medication were observed in this study. Adverse events requiring drug discontinuation or dose reduction, showing incidence in Part 1 versus incidence in Part 2, are presented in Table 4 below.

[0200] [Table 4]

[0201] Serum potassium The mean serum potassium (K+) changes for the groups are shown in the table below.

[0202] [Table 5]

[0203] The number of individuals in the 100 mg QD cohort who experienced confirmed or multiple increases in serum potassium above the normal range during treatment is shown in the table below.

[0204] [Table 6] * Measurements were rare events that were not verified by repeat measurements, which resulted in discontinuation of study drug (protocol deviation).

[0205] Change in estimated glomerular filtration rate (eGFR) A dose-dependent and reversible decrease in eGFR was observed. This phenomenon has been reported with ACE / ARBs and more recently SGLT2 inhibition due to a reduction in intraglomerular pressure, which is thought to attenuate the progression of hypertensive nephropathy. A graph showing the change in estimated glomerular filtration rate (eGFR) in various treatment cohorts is presented in Figure 8. [Example 2]

[0206] A full analysis was performed of the study described in Example 1. This full analysis confirmed the findings described above in Example 1, as follows:

[0207] Summary of Results Lorundrostat was effective in lowering BP in individuals with inadequately treated or treatment-resistant hypertension.

[0208] There were dose-response and exposure-response relationships, with mean placebo-adjusted reductions in SBP of 9.58 mmHg and 7.81 mmHg at the 50 mg QD and 100 mg QD doses, respectively.

[0209] 24-hour ABPM, central BP, and nocturnal SBP values ​​confirmed that a reduction in SBP was observed in AOBP, most notably in the 100 mg QD dose cohort.

[0210] The safety dataset for lorundrostat showed it to be safe and well tolerated, with no effect on serum cortisol, the expected small increases in serum potassium, and relatively few episodes of clinically significant hyperkalemia.

[0211] The results demonstrate clinically and statistically significant placebo-adjusted reductions in AOBP SBP of 9.58 mmHg (p=0.0114) and 7.81 mmHg (p=0.0422) in the 50 mg and 100 mg QD cohorts, respectively, in Part 1. In Part 2, the reduction in AOBP SBP observed in the 100 mg QD cohort was similar to that observed with the same dose in Part 1 (-11.5 mmHg, p=0.8426).

[0212] The reduction in AOBP SBP was verified and confirmed by a comparable reduction in 24-hour ABPM SBP. ABPM data further demonstrated the benefit of lorundrostat in reducing both central and nocturnal SBP.

[0213] Subgroup analysis showed that BMI > 30 kg / m 2There was a statistically and clinically significant reduction in AOBP SBP in subjects with AOBP SBP, in subjects in the upper tertile of baseline AOBP SBP, and in subjects taking thiazide diuretics.

[0214] Pharmacodynamic responses demonstrated a dose-dependent decrease in serum aldosterone levels and a comparable increase in plasma renin activity. 11-deoxycorticosterone levels were unaffected. Morning serum cortisol levels were moderately improved. Adrenocorticism did not occur during the study. Due to supply chain disruptions, the ability to perform ACTH stimulation tests was limited during the first part of the study. However, the majority of subjects in Part 2, who received 100 mg QD, the highest dose tested, underwent ACTH stimulation tests at baseline and after 8 weeks of treatment. No individuals had abnormal ACTH stimulation results.

[0215] A decline in eGFR was observed in all treatment groups, with the greatest decline evident in the lorundrostat treatment group compared with placebo.

[0216] Primary efficacy endpoint: Change from baseline in seated automated laboratory-measured systolic blood pressure at week 8 The results of the repeated measures mixed effects model (MMRM) analysis of the primary efficacy endpoint, change in seated AOBP SBP from baseline to week 8, are presented in Figure 12 and Table 7 for Part 1 and in Figure 13 and Table 8 for the 100 mg QD dose cohorts from Parts 1 and 2.

[0217] In Part 1, statistically significant reductions from baseline in model AOBP SBP were detected in the 50 mg QD cohort (least squares mean [LSM] difference: -9.58 mmHg; p=0.0114) and 100 mg QD cohort (LSM difference: -7.81 mmHg; p=0.0422) at week 8 (Figure 12 and Table 7). The 12.5 mg BID, 25 mg BID, and 12.5 mg QD cohorts demonstrated greater BP reductions than placebo (placebo-adjusted reductions of -7.2 mmHg, -6.97 mmHg, and -1.53 ​​mmHg, respectively), although none of these demonstrated statistical significance. The above results were similar in sensitivity analyses using the FAS, analyses using the PPS, and analyses using additional estimands.

[0218] The change in SBP from baseline to week 8 was similar for the 100 mg QD cohort in Parts 1 and 2 (LSM difference: 0.74 mmHg; p=0.8426) (Figure 13 and Table 8). Furthermore, no statistically significant discernible difference in AOBP SBP from baseline was observed between subjects receiving lorundrostat 100 mg QD with a baseline PRA <1 ng / mL / h and those with a baseline PRA ≥1 ng / mL / h in Parts 1 and 2 combined (Table 9).

[0219] Boxplots of the mean change in measured AOBP SBP from baseline to week 8 are presented in Figure 14 for Part 1 and Figure 15 for Part 2.

[0220] [Table 7]

[0221] Analyses used an MMRM approach with fixed effects for categorical terms of treatment, week number, and treatment-by-week interaction, and baseline SBP as a fixed continuous covariate. No adjustment for multiplicity was performed.

[0222] Abbreviations: BID, twice daily; CI, confidence interval; Δ, difference; LSM, least squares mean; mg, milligram; mmHg, millimeter of mercury; MMRM, repeated measures mixed effects model; QD, once daily; SBP, systolic blood pressure; SEM, standard error of the mean.

[0223] [Table 8]

[0224] Analyses used an MMRM approach with fixed effects for categorical terms of treatment, week number, and treatment-by-week interaction, and baseline SBP as a fixed continuous covariate. No adjustment for multiplicity was performed.

[0225] Abbreviations: CI, confidence interval; Δ, difference; LSM, least squares mean; mg, milligram; mmHg, millimeter of mercury; MMRM, repeated measures mixed effects model; QD, once daily; SBP, systolic blood pressure; SEM, standard error of the mean.

[0226] [Table 9]

[0227] Analyses were performed using ANCOVA modeled with the two baseline PRA variables (<1 ng / mL / h vs. ≥1 ng / mL / h) as factors and baseline SBP as a covariate in the subset of subjects randomized to receive 100 mg QD. Two ANCOVA models (weeks 4 and 8) were performed separately.

[0228] Abbreviations: ANCOVA, analysis of covariance; CI, confidence interval; Δ, difference; FAS, maximum analysis set; h, time; LSM, least squares mean; mg, milligram; mL, milliliter; mmHg, millimeter of mercury; ng, nanogram; PRA, plasma renin activity; QD, once daily; SBP, systolic blood pressure; SEM, standard error of the mean.

[0229] Secondary Efficacy Endpoints Change from baseline in seated automated laboratory-measured diastolic blood pressure at week 8 At week 4, a statistically significant decrease from baseline in the AOBP DBP model was detected across all cohorts except for the 12.5 mg QD in part 1. At week 8, a statistically significant decrease from baseline in model AOBP DBP was detected only in the 50 mg QD cohort (LSM difference: -5.46 mmHg; p=0.0224), although all lorundrostat dose groups demonstrated a greater numerical decrease than placebo (Table 10). The change in DBP from baseline to week 8 was not statistically different between the 100 mg QD cohort in parts 1 and 2 (LSM difference: 0.98 mmHg; p=0.6406) (Table 11).

[0230] [Table 10]

[0231] Analyses used MMRM procedures with fixed effects for categorical terms of treatment, week number, and treatment-by-week interaction, and baseline DBP as a fixed continuous covariate. P values ​​≤ 0.05 are in bold. Abbreviations: BID, twice daily; CI, confidence interval; Δ, difference; DBP, diastolic blood pressure; LSM, least squares mean; mmHg, millimeters of mercury; QD, once daily; SEM, standard error of the mean.

[0232] [Table 11]

[0233] Analyses used the MMRM approach with fixed effects for categorical terms of treatment, week, and treatment-by-week interaction, and baseline DBP as a fixed continuous covariate. Abbreviations: CI, confidence interval; Δ, difference; DBP, diastolic blood pressure; FAS, full analysis set; LSM, least squares mean; mg, milligram; mmHg, millimeters of mercury; MMRM, repeated measures mixed-effects model; QD, once daily; SEM, standard error of the mean.

[0234] Changes in seated automated office-measured blood pressure parameters from baseline to week 8 Mean SBP decreased over the first 4 to 5 weeks of treatment, including in the placebo group (Tables 12 and 13). The reduction in mean DBP (Tables 14 and 15) was smaller than that observed for SBP, with only small changes from baseline in the placebo group. In general, BP reductions reached a plateau at approximately 4 weeks of treatment.

[0235] [Table 12]

[0236] Baseline was defined as the mean of the last two nonmissing values ​​before the first dose of study treatment, including scheduled outpatient visits. Abbreviations: BID, twice daily; BL, baseline; CFB, change from baseline; mmHg, millimeters of mercury; QD, once daily; SD, standard deviation.

[0237] [Table 13]

[0238] Baseline was defined as the mean of the last two nonmissing values ​​before the first dose of study treatment, including scheduled outpatient visits. Abbreviations: CFB, change from baseline; mmHg, millimeters of mercury; QD, once daily; SD, standard deviation.

[0239] [Table 14]

[0240] Baseline was defined as the mean of the last two nonmissing values ​​before the first dose of study treatment, including scheduled outpatient visits. Abbreviations: BID, twice daily; CFB, change from baseline; mmHg, millimeters of mercury; QD, once daily; SD, standard deviation.

[0241] [Table 15]

[0242] Baseline was defined as the mean of the last two nonmissing values ​​before the first dose of study treatment, including scheduled outpatient visits. Abbreviations: CFB, change from baseline; mmHg, millimeters of mercury; QD, once daily; SD, standard deviation.

[0243] Proportion of subjects with seated automated office-measured diastolic blood pressure ≤ 130 / 80mmHg Overall, six subjects in Part 1 and three subjects in Part 2 had an AOBP at or below the AHA cutpoint for hypertension (130 / 80 mmHg) at baseline (Tables 16 and 17). By week 8, the proportion of subjects with an AOBP ≦130 / 80 mmHg across all doses in Part 1 ranged from 23.3% in the placebo cohort to 43.3% in the 25 mg BID cohort (Figure 16). In Part 2, 54.8% of the 100 mg QD cohort achieved this treatment goal compared to 30% of the 100 mg QD cohort in Part 1 (Figure 17).

[0244] [Table 16]

[0245] Baseline was defined as the mean of the last two nonmissing values ​​before the first dose of study treatment, including scheduled outpatient visits. Abbreviations: BID, twice daily; DBP, diastolic blood pressure; mmHg, millimeters of mercury; QD, once daily; SBP, systolic blood pressure.

[0246] [Table 17]

[0247] Baseline was defined as the mean of the last two nonmissing values ​​before the first dose of study treatment, including scheduled outpatient visits. Abbreviations: DBP, diastolic blood pressure; mmHg, millimeters of mercury; QD, once daily; SBP, systolic blood pressure.

[0248] Time to first occurrence of seated automated examination room BP / DBP ≦130 / 80mmHg Excluding subjects assigned to the placebo group, the majority of subjects who achieved an SBP / DBP of 130 / 80 mmHg did so between weeks 2 and 4 of treatment in both Part 1 and Part 2 (Figures 18 and 19).

[0249] Changes from baseline at the end of treatment in 24-hour ambulatory blood pressure monitoring parameters Model changes in ABPM parameters (24-hour SBP, DBP, MAP, central SBP, central DBP, and central MAP; daytime SBP, DBP, and MAP; nighttime SBP and DBP) demonstrated consistent AHT effects (Tables 18 and 19). Results are comparable to those reported for ABPM parameters (SBP and DBP).

[0250] The changes from baseline to EoT in the measured 24-hour, daytime, and nighttime mean ABPM SBP, DBP, and MAP are summarized in Table 20. The changes from baseline in 24-hour mean ABPM SBP and DBP at EoT were numerically smaller than those reported for AOBP, an expected finding with the different measurement modalities.

[0251] [Table 18]

[0252] P values ​​in bold indicate p<0.05.

[0253] [Table 19]

[0254] P values ​​in bold indicate p<0.05.

[0255] [Table 20]

[0256] [Table 21]

[0257] In many of the treatment cohorts, the proportion of subjects achieving a 10% or greater nocturnal reduction in ABPM SBP increased from baseline to the last post-baseline assessment (Tables 22 and 23).

[0258] [Table 22]

[0259] Nocturnal blood pressure decline was defined as 100% × (24-hour ABPM mean daytime SBP − 24-hour ABPM mean nighttime SBP) / 24-hour ABPM mean daytime SBP.

[0260] [Table 23]

[0261] Nocturnal blood pressure decline was defined as 100% × (24-hour ABPM mean daytime SBP − 24-hour ABPM mean nighttime SBP) / 24-hour ABPM mean daytime SBP.

[0262] Analysis of factors affecting blood pressure changes Analyses were conducted to identify factors that influence the degree of blood pressure reduction in hypertensive subjects. As shown in the table below, lorundrostat is particularly effective at reducing blood pressure in individuals with a body mass index (BMI) greater than 30. This effect was observed across all treatment cohorts.

[0263] Additionally, as shown in the table below, lorundrostat was found to be particularly effective at lowering blood pressure in individuals taking a thiazide diuretic as one of their baseline hypertension medications, and this effect was observed across all treatment cohorts.

[0264] There were no apparent consistent differences between the mean change from baseline in AOBP SBP at week 8 when summarized by sex (male, female), age (<65, 65–79, ≥80 years), race (Black or African American, other), number of AHT medications at baseline (≥2, ≥3), or concurrent use of angiotensin-converting enzyme inhibitors (ACEi) or ARBs in Part 1 (Table 24) or Part 2 (Table 25).

[0265] Pooled data from low-renin subjects (Part 1) from the lorundrostat 25 mg BID, 50 mg QD, and 100 mg QD cohorts were used to analyze the relationship between median baseline body mass index (BMI) and serum leptin (ng / dl), as well as the relationship between baseline BMI and mean change in systolic BP (mmHg) measured by AOBP at week 8 compared to baseline (Figures 26 and 27). Each of these cohorts demonstrated a significant decrease in median serum aldosterone at week 4 compared to baseline. When treated as a continuous variable, there was a robust relationship between increasing BMI and increasing serum leptin. When treated as a continuous variable, there was a robust relationship between decreasing BMI and BP. These two associations support the hypothesis that increasing serum leptin is associated with greater decreases in BP. These data are consistent with the hypothesis that increased leptin production in the setting of visceral obesity contributes to increased aldosterone-mediated hypertension. They further support the hypothesis that inhibition of aldosterone synthesis abolishes the stimulatory effect of leptin on aldosterone production.

[0266] [Table 24]

[0267] Abbreviations: AA, African American; ARB, angiotensin receptor blocker; ACEi, angiotensin-converting enzyme inhibitor; AHT, antihypertensive; BID, twice daily; BL, baseline; CFB, change from baseline; mg, milligram; QD, once daily; SD, standard deviation; Wk8, week 8; yr, age.

[0268] [Table 25]

[0269] Abbreviations: AA, African American; ARB, angiotensin receptor blocker; ACEi, angiotensin-converting enzyme inhibitor; AHT, antihypertensive; BL, baseline; CFB, change from baseline; mg, milligram; NE, not evaluable; QD, once daily; SD, standard deviation; Wk8, week 8; yr, age.

[0270] In Part 1 (Table 26) and Part 2 (Table 27), there was a clear augmentation of the AHT effect of lorundrostat, with the most pronounced BMI improvement in the 100 mg QD dose cohort (Table 26). Exploratory analysis using MMRM revealed a placebo-adjusted reduction in AOBP SBP of -16.7 mmHg (p=0.0023) in the 50 mg QD cohort in Part 1 and -12.3 mmHg (p=0.0297) in the 100 mg QD cohort in Part 1 (data not shown).

[0271] [Table 26]

[0272] Abbreviations: BID, twice daily; BL, baseline; CFB, change from baseline; NE, not evaluable; QD, once daily; SD, standard deviation; Wk8, week 8.

[0273] [Table 27]

[0274] Abbreviations: BL, baseline; CFB, change from baseline; NE, not evaluable; QD, once daily; SD, standard deviation; Wk8, week 8.

[0275] In Part 1 and Part 2 (Table 28 and Table 29, respectively), there was a clear increasing effect of lorundrostat on AHT with improvement in baseline AOBP SBP. It should be noted that a greater AHT effect with improvement in baseline AOBP SBP was also observable in the placebo cohort in Part 1, with only the 50 mg QD cohort in Part 1 demonstrating a statistically significant placebo-adjusted reduction in AOBP SBP from baseline at Week 8 (-19.9 mmHg, p=0.0113).

[0276] [Table 28]

[0277] Abbreviations: BID, twice daily; BL, baseline; CFB, change from baseline; QD, once daily; SD, standard deviation; Wk8, week 8.

[0278] [Table 29]

[0279] Abbreviations: BL, baseline; CFB, change from baseline; NE, not evaluable; QD, once daily; SD, standard deviation; Wk8, week 8.

[0280] There also appeared to be a greater reduction in AOBP SBP from baseline in subjects concomitantly using thiazide diuretics in Part 1 (Table 30), but this was less evident in Part 2 (Table 31). In Part 1, statistically significant placebo-adjusted reductions in AOBP SBP at week 8 were achieved in the 12.5 mg BID and 50 mg QD cohorts, with mean changes of -10.7 mmHg (p=0.047) and -12.9 mmHg (p=0.0108), respectively.

[0281] [Table 30]

[0282] Abbreviations: BID, twice daily; BL, baseline; CFB, change from baseline; QD, once daily; Wk8, week 8.

[0283] [Table 31]

[0284] Abbreviations: BL, baseline; CFB, change from baseline; NE, not evaluable; QD, once daily; Wk8, week 8.

[0285] In Part 1 (Table 32) or Part 2 (Table 33), sex (male, female), age (<65, 65-79, ≥80), race (Black or African American, other), BMI (<25, 25-30, ≥30 kg / m 2 Summarizing by baseline seated AOBP DBP, number of AHT medications at baseline (≥2, ≥3), or concurrent use of ACEi or ARB, there were no apparent consistent differences between the mean change from baseline in AOBP DBP at week 8.

[0286] [Table 32]

[0287] Abbreviations: AA, African American; ARB, angiotensin receptor blocker; ACEi, angiotensin-converting enzyme inhibitor; AHT, antihypertensive; BID, twice daily; BL, baseline; BMI, body mass index; CFB, change from baseline; kg, kilogram; m, meter; QD, once daily; SBP, systolic blood pressure; SD, standard deviation; Wk8, week 8; yr, age.

[0288] [Table 33] TIFF2025527695000049.tif90163

[0289] Abbreviations: AA, African American; ARB, angiotensin receptor blocker; ACEi, angiotensin-converting enzyme inhibitor; AHT, antihypertensive; BL, baseline; BMI, body mass index; CFB, change from baseline; hr, hour; kg, kilogram; m, meter; mL, milliliter; ng, nanogram; PRA, plasma renin activity; QD, once daily; SBP, systolic blood pressure; SD, standard deviation; Wk8, week 8; yr, age.

[0290] In Part 1, a small increase in the AHT effect of lorundrostat was evident when used concomitantly with a thiazide diuretic (Table 34), but this was not the case in Part 2 (Table 35). In Part 1, a statistically significant placebo-adjusted reduction in AOBP DBP was achieved at week 8 in patients using a thiazide diuretic at baseline in the 50 mg QD cohort (-7.7 mmHg, p=0.0291), but not in patients not taking a thiazide diuretic at baseline in either dose cohort.

[0291] [Table 34]

[0292] [Table 35]

[0293] Pharmacokinetic response C max Systemic exposure to lorundrostat, expressed as CI or AUC, increased with increasing dose, but there was moderately high inter-subject variability. For the 100 mg QD dose in Cohort 1 and Cohort 2, the steady-state (Day 28) C max were 1620 ng / mL and 1360 ng / mL, respectively (mean values ​​were approximately 1490 ng / mL), and AUC 0-24 are 14900ng, respectively. *h / mL and 7480ng * h / mL (mean value is approximately 11190 ng * Other important parameters are summarized in Table 36. Trough plasma concentration values ​​are shown in Table 37.

[0294] [Table 36]

[0295] Abbreviations: AUC, area under the curve; BID, twice daily; CV, coefficient of variation; geo, geometric; hr, time; mg, milligram; mL, milliliter; N, number of subjects; n, number of observations; ng, nanogram; QD, once daily.

[0296] [Table 37]

[0297] Concentrations are in ng / mL. Abbreviations: BID, twice daily; CV, coefficient of variation; geo, geometric; mg, milligram; mL, milliliter; N, number of subjects; n, number of observations; ng, nanogram; QD, once daily.

[0298] Pharmacodynamic response At baseline in Part 1, mean serum cortisol levels in the active treatment groups ranged between 9.443 μg / dL and 11.272 μg / dL, compared with 10.507 μg / dL for placebo (Table 38). No consistently significant changes in serum cortisol levels relative to baseline were observed over the course of treatment and follow-up, with percent changes from baseline ranging from 3.8% to 19.2% (active treatment) vs. -0.8% (placebo) at week 4, 20.6% to 51.4% (active treatment) vs. 37.7% (placebo) at week 8, and -1.2% (active treatment) to 22.7% (active treatment) vs. 17.1% (placebo) at week 12. A similar pattern was observed in Part 2, with baseline serum cortisol levels in the active treatment group being 11.118 μg / dL in the 100 mg QD dose group, with no significant changes observed over the course of treatment and follow-up. The percent changes from baseline were 20.1% at Week 4, 153.4% ​​at Week 8, and 1.5% at Week 12 (Table 39).

[0299] Although there was wide variability within each individual dose cohort, transient increases in 11-deoxycorticosterone and 11-deoxycortisol were seen in the active treatment group in Part 1 compared to placebo at Week 4. Values ​​returned to a range similar to placebo at Week 12 (Table 38). In Part 2, 11-deoxycorticosterone and 11-deoxycortisol were similar to baseline in subjects treated with lorundrostat 100 mg QD at Weeks 4 and 10 (Table 39).

[0300] In Part 1, aldosterone levels generally decreased relative to baseline in lorundrostat-treated subjects at week 4 (-40.1% to 7.4%) compared with subjects receiving placebo (3.6%) and remained lower relative to placebo at week 12 (-26.6% to 15.9% vs. 38.1%, respectively; Table 38). In lorundrostat-treated subjects in Part 2, aldosterone levels remained stable but were lower than baseline by weeks 4 and 10 (Table 39).

[0301] Renin activity, expressed as percent change from baseline, improved in all lorundrostat-treated subjects, regardless of dose and baseline PRA value, reaching peak levels at week 4 and remaining elevated compared to baseline at weeks 12 (part 1) and 10 (part 2) (Tables 38 and 39, respectively). Placebo values ​​in part 1 remained relatively consistent with baseline.

[0302] [Table 38]

[0303] [Table 39]

[0304] In Part 1, subjects treated with lorundrostat, regardless of dose, showed a greater decline in eGFR compared to placebo as early as 1 week of treatment, and the decline remained stable through week 8 (Table 40). The greatest decline from baseline was seen in the 100 mg QD dose group, with a decline of 10.91 mL / min / 1.73 m at week 2. 2 A mean maximum reduction of -6.80 mL / min / 1.73 m was achieved over 8 weeks of treatment. 2 to -10.91 mL / min / 1.73 m 2 In contrast, the mean eGFR in the placebo group remained relatively stable throughout treatment, reaching −2.80 mL / min / 1.73 m at week 2. 2 The mean maximum decrease (range: -0.83 mL / min / 1.73 m 2 ~-2.80mL / min / 1.73m 2 ) was reached. Estimated glomerular filtration rate was estimated using the CKD-EPI equation.

[0305] In Part 2, a similar trend was seen for mean eGFR in the 100 mg QD treatment group, with an initial sharp decline followed by a less significant decline through week 8 (Table 41).

[0306] [Table 40]

[0307] [Table 41]

[0308] safety At least one treatment-emergent TEAE was reported by 83 subjects (73 [54.9%] lorundrostat-treated and 10 [33.3%] placebo-treated) in Part 1 and 20 subjects (19 [61.3%] lorundrostat-treated and 1 [16.7%] placebo-treated) in Part 2. Of these subjects, 30 from Part 1 (27 [20.3%] active-treated and 3 [10%] placebo-treated) and 9 from Part 2 (29.0% for lorundrostat alone) experienced a TEAE considered at least likely related to the study drug.

[0309] Two (1.5%) subjects in Part 1 and one (3.2%) subject in Part 2 reported SAEs, one of which (worsening of pre-existing hyponatremia) was considered likely related to the study drug. All events occurred in lorundrostat-treated subjects.

[0310] Thirty-six subjects in part 1 (35 [26.3%] lorundrostat-treated and 1 (3.3) placebo-treated) and 4 (12.9%) subjects receiving active treatment in part 2 reported at least one AESI.

[0311] Across all active treatment cohorts, 10 subjects in part 1 and 2 subjects in part 2 experienced TEAEs leading to permanent discontinuation of study drug, and 24 subjects in part 1 and 7 subjects in part 2 experienced TEAEs leading to dose modification.

[0312] No deaths were reported in either Part 1 or Part 2.

[0313] The most frequently reported events by PTs were hyperkalemia (1 subject [3.3%] in the placebo cohort in Part 1, 31 subjects [23.3%] in the active-treatment cohort in Part 1, and 8 subjects [25.8%] in the 100 mg QD cohort in Part 2), decline in eGFR (1 subject [3.3%] in the placebo cohort in Part 1 and 9 subjects [6.8%] in the active-treatment cohort in Part 1), and urinary tract infection (7 subjects [5.3%] in the active-treatment cohort in Part 1 and 2 subjects [6.5%] in the 100 mg QD cohort in Part 2). Muscle cramps were reported by 3 (9.7%) subjects in the 100 mg QD cohort in Part 2.

[0314] There was no apparent relationship between study drug dose and the frequency of treatment-emergent TEAEs, treatment-emergent TEAEs of at least moderate severity, or treatment-emergent TEAEs considered by the investigator to be at least possibly related to the study drug.

[0315] Serum potassium and creatinine levels improved, while serum sodium levels decreased, in the active treatment cohort compared with placebo in both Part 1 and Part 2. These changes are consistent with lorundrostat's mechanism of action.

[0316] Seven subjects experienced transient improvements in serum potassium (>6.0 mmol / L); none of these were considered SAEs, and all resolved promptly after intervention (study drug discontinuation or dose adjustment).

[0317] There were no notable findings regarding vital signs, physical examination, or ECG parameters.

[0318] Treatment-emergent adverse events (TEAEs) Overall, 28 subjects in Part 1 experienced a moderate-intensity treatment-emergent TEAE (3 [10.0%] subjects in the placebo cohort and 25 [18.8%] subjects in the active-treatment cohort), and 1 subject (0.8%) in the 12.5 mg QD cohort experienced a severe treatment-emergent TEAE (Table 42). The only moderate-severity treatment-emergent TEAEs reported by PTs in two or more subjects in all dose groups were hyperkalemia (4 [3.0%] subjects) and hypertension (3 [2.3%] subjects), all of which were reported in subjects in the active-treatment cohort. The one severe treatment-emergent TEAE was a case of hyperkalemia.

[0319] In Part 2, there were 12 subjects (38.7%) who experienced one or more moderate treatment-emergent TEAEs, and one subject (3.2%) who experienced one or more severe treatment-emergent TEAEs, all of which were in the 100 mg QD cohort (Table 43). The only moderately severe treatment-emergent TEAEs reported in two or more subjects were hyperkalemia (five [16.1%] subjects) and muscle cramps (two [6.5%] subjects). One severe treatment-emergent TEAE was a case of hyponatremia.

[0320] [Table 42]

[0321] Adverse events occurring in at least two subjects per SOC and / or PT and / or severity are shown for every dose group. SOCs without PT and / or severity for at least two subjects are shown by SOC only. PTs without severity for at least two subjects are shown by SOC and PT only.

[0322] [Table 43]

[0323] Adverse events occurring in at least two subjects per SOC and / or PT and / or severity are shown for every dose group. SOCs without PT and / or severity for at least two subjects are shown by SOC only. PTs without severity for at least two subjects are shown by SOC and PT only.

[0324] Ten (7.5%) subjects in all Part 1 of the active treatment cohort experienced a treatment-emergent TEAE leading to permanent discontinuation of study drug (Table 44); hyperkalemia (5 [3.8%] subjects) was the only such event reported in more than one subject.

[0325] In Part 2, two subjects (6.5%) experienced treatment-emergent TEAEs that led to permanent discontinuation of study drug; both of these subjects were in the 100 mg QD cohort. Such events did not occur in both subjects.

[0326] [Table 44]

[0327] [Table 45]

[0328] Change in estimated glomerular filtration rate (eGFR) A dose-dependent and reversible decrease in eGFR was observed. This phenomenon has been reported with ACE / ARBs and more recently SGLT2 inhibition due to a reduction in intraglomerular pressure, which is thought to attenuate the progression of hypertensive nephropathy. A graph showing the change in estimated glomerular filtration rate (eGFR) in various treatment cohorts is presented in Figure 8.

[0329] Clinical laboratory evaluation There were no significant changes in bicarbonate, calcium, glucose, magnesium, phosphate, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), alanine phosphatase (ALP), total or indirect bilirubin, albumin, protein, urate, or urea nitrogen from baseline to week 8 in parts 1 or 2. There were no significant changes in hematology and coagulation parameters, or in urinalysis and spot / 24-hour urine parameters, from baseline to week 8 in parts 1 or 2.

[0330] Serum potassium In both Part 1 and Part 2, serum potassium levels improved in the active treatment cohorts compared to the placebo cohorts, with the highest improvements seen in the 100 mg QD cohort in Part 1 and Part 2 and the two BID cohorts in Part 1 (Figure 20, Figure 21, and Figure 22).

[0331] The mean serum potassium (K+) changes for the groups are summarized in the table below.

[0332] [Table 46]

[0333] The number of individuals who experienced confirmed or multiple increases in serum potassium above the normal range during treatment is shown in the table below.

[0334] [Table 47]

[0335] serum K + Six of 163 subjects (3.6%) had one or more episodes of >6.0 mmol / L, five of which were considered unrelated to the study medication.

[0336] * Measurements in one subject were rare events that were not verified by repeat measurements with discontinuation of study drug (protocol deviation).

[0337] Serum sodium Serum sodium concentrations decreased in the active treatment groups (Figures 23, 24 and 25).

[0338] Discussion This example describes a multicenter, randomized, placebo-controlled, double-blind, dose-ranging study among adults with uncontrolled hypertension despite treatment with at least two baseline AHT medications. The results of this study demonstrate that aldosterone synthase inhibition with lorundrostat was well tolerated as add-on therapy to a stable regimen of AHT medications and induced both clinically and statistically significant reductions in AOBP after 8 weeks of treatment.

[0339] Overall, 42 clinical trial sites across the United States participated in this study. 163 subjects were randomized to Part 1 (141 [86.5%] completed the study), and 37 subjects were randomized to Part 2 (33 [89.2%] completed the study). Across all doses and study parts, baseline demographic, lifestyle, and cardiovascular history characteristics were similar and relatively evenly distributed by gender and relevant racial and ethnic minority groups. As expected, the study population was primarily elderly and overweight / obese, and a significant proportion, if not half, of the subjects were being treated for type 2 diabetes. Nearly 36% of participants were Black or African American. Furthermore, nearly half of the enrolled subjects were prescribed a two-drug AHT regimen, with the majority (>77%) being treated with an ACEi or ARB, and the majority (58%) being treated with a thiazide diuretic.

[0340] Analysis of the primary efficacy endpoint demonstrated that the majority of BP reductions were achieved within 4 weeks of treatment initiation and were generally well maintained throughout the remainder of the 8-week treatment period. Clinically significant, placebo-adjusted reductions in AOBP (SBP) were observed across all doses tested, with statistically significant reductions of 9.58 mmHg (p = 0.0114) and 7.81 mmHg (p = 0.0422) in the 50 mg and 100 mg QD cohorts in Part 1, respectively. Such reductions in SBP are important for the effective treatment of subjects with uncontrolled hypertension. A recent meta-analysis of 147 randomized trials demonstrated that a 10 mmHg reduction in SBP was associated with a 41% reduction in the risk of stroke and a 22% reduction in the risk of coronary heart disease (CHD) (Law, Morris, and Wald 2009). Furthermore, the reduction in AOBP SBP was substantiated by a comparable reduction in 24-h ABPM SBP, with lorundrostat confirmed by its associated benefit of reducing both central and nocturnal ABPM SBP, two indicators of increased risk of cardiovascular events (Hermida et al. 2014; Mousa et al. 2004).

[0341] Despite the non-standard basic therapy, the beneficial results were observed, supporting the generalizability of the effect to all subjects with uncontrolled hypertension. Furthermore, the AOBP SBP (i.e., 30 kg / m 2 The identification of subgroups with statistically significant and clinically meaningful changes in baseline (subjects with a BMI above 8 weeks and subjects using concomitant thiazide diuretics) suggests that the full efficacy of lorundrostat after 8 weeks of treatment may still be underestimated. Further studies exploring this prescribing paradigm using standardized basal regimens and / or add-on lorundrostat therapy, or within specific subpopulations, are warranted.

[0342] Renin suppression is common among patients with hypertension, and in theory, these patients should benefit most from drugs that reduce aldosterone production. Interestingly, lorundrostat-treated subjects enrolled in Part 2 (i.e., subjects with unsuppressed renin levels) demonstrated similar BP-lowering efficacy as subjects with suppressed plasma renin levels (i.e., subjects enrolled in Part 1). While Pathway 2 trials demonstrated that other MRAs (e.g., spironolactone) are effective in lowering BP across a wide range of plasma renin levels, further testing of lorundrostat in populations not selective for baseline PRA will be important to confirm the effects observed here.

[0343] Pharmacodynamic responses demonstrated a dose-dependent decrease in serum aldosterone levels and a comparable increase in plasma renin activity, consistent with lorundrostat's mechanism of action. No significant decreases in serum cortisol levels were observed over the course of treatment and follow-up compared with placebo, with percent changes from baseline ranging from 20.6% to 51.4% (active drug) vs. 37.7% (placebo) at week 8 and from -1.2% to 22.6% (active drug) vs. 17.1% (placebo) at week 12. A similar pattern was observed in Part 2, with baseline serum cortisol levels of 11.1 μg / dL in the active drug group at the 100 mg QD dose, with no significant changes observed over the course of treatment and follow-up. Most importantly, no adrenocortical hypofunction occurred during the study.

[0344] Overall, lorundrostat was safe and well tolerated. Two (1.5%) subjects in Part 1 and one (3.2%) subject in Part 2 reported treatment-emergent SAEs, of which a worsening of pre-existing hyponatremia was considered likely related to the study drug. No treatment-emergent SAEs occurred in placebo-treated subjects. No deaths were reported in either Part 1 or Part 2.

[0345] At least one treatment-emergent TEAE was reported by 83 subjects in Part 1 (73 [54.9%] lorundrostat-treated vs. 10 [33.3%] placebo-treated) and 20 subjects in Part 2 (19 [61.3%] lorundrostat-treated vs. 1 [16.7%] placebo-treated). Among lorundrostat-treated subjects, 27 (20.3%) and 9 (29.0%) from Part 1 and Part 2, respectively, experienced a TEAE considered at least likely related to the study drug. The most commonly reported AEs by PTs were hyperkalemia and decreased eGFR. All active doses experienced modest improvements in potassium levels at Week 8 relative to baseline, ranging from 0.208 mmol / L (100 mg QD, Part 2) to 0.341 mmol / L (25 mg BID, Part 1). Seven subjects experienced transient serum potassium improvements (>6.0 mmol / L), none of which were considered SAEs, and all resolved rapidly after discontinuation or dose adjustment, consistent with lorundrostat's short half-life. It should be noted that one of these events was assessed as an error due to incorrect sample processing. In a manner similar to ACE inhibitors and ARBs, the BP-lowering effect of lorundrostat resulted in a beneficial, reversible, dose-dependent decrease in eGFR.

[0346] Treatment-related hypotension occurred in three subjects and was reversible upon cessation of treatment, as expected based on lorundrostat's mechanism of action. Two of these subjects were randomized to the 100 mg QD cohort (one in both Part 1 and Part 2) and one to the 12.5 mg BID cohort. Additionally, three subjects developed orthostatic hypotension, defined as a decrease in SBP of 20 mmHg or DBP of 10 mmHg upon moving from a sitting to standing position. In each case, the episode resolved and did not recur for the remainder of the treatment period. Continued observation for symptoms of hypotension, even if minimal and reversible, is warranted in future clinical trials.

[0347] In conclusion, the primary objective of this study was to characterize the safety and efficacy of lorundrostat on blood pressure at five dose levels and two dosing regimens versus placebo when administered orally as add-on therapy to stable background therapy for the treatment of uncontrolled hypertension. The results of this study are shown below: (a) Lorundrostat was effective in lowering BP in individuals with inadequately treated or treatment-resistant hypertension. (b) There were dose-response and exposure-response relationships, with mean placebo-adjusted reductions in SBP of 9.58 mmHg and 7.81 mmHg at the 50 mg QD and 100 mg QD doses, respectively. (c) 24-hour ABPM, central BP, and nocturnal SBP values ​​confirmed that the reduction in SBP was observed in ABPM, most notably in the 100 mg QD dose cohort; and (d) The safety dataset for lorundrostat showed that it was safe and well tolerated, with no effect on serum cortisol, the expected small increases in serum potassium, and relatively few episodes of clinically significant hyperkalemia.

[0348] Future studies evaluating the long-term efficacy and safety of lorundrostat in patients with uncontrolled hypertension are needed.

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Claims

1. A method for treating hypertension in a hypertensive subject, comprising administering to the subject an amount of a diuretic and an amount of a CYP 11β2 beta-hydroxylase inhibitor once or twice daily, the combined amounts being sufficient to treat hypertension in the hypertensive subject.

2. 10. The method of claim 1, wherein the diuretic and the CYP 11β2 beta-hydroxylase inhibitor are administered in a combined pharmaceutical composition.

3. 10. The method of claim 1, wherein the diuretic and the CYP 11β2 beta-hydroxylase inhibitor are administered simultaneously.

4. 4. The method of any one of claims 1 to 3, wherein the combined amounts are effective to achieve a greater than additive therapeutic result in treating the subject.

5. 5. The method of any one of claims 1-4, wherein the amount of the CYP 11β2 beta-hydroxylase inhibitor and the amount of the diuretic when administered together are more effective to treat the subject than the same amount of each agent when administered alone.

6. A method for treating hypertension in a hypertensive subject taking at least one diuretic, comprising administering to the subject once or twice daily a CYP 11β2 beta-hydroxylase inhibitor in an amount sufficient to thereby treat hypertension in the hypertensive subject.

7. The method of any one of claims 1 to 6, wherein the diuretic is a thiazide diuretic.

8. The method of any one of claims 1 to 7, wherein the hypertensive subject has a body mass index of at least 30, preferably higher than 30, preferably between 30 and 50, more preferably between 30 and 40.

9. 9. The method of any one of claims 1 to 8, wherein the hypertensive subject is a male hypertensive subject with a waist-to-hip ratio greater than 0.90 or a female hypertensive subject with a waist-to-hip ratio greater than 0.

85.

10. 10. The method of any one of claims 1 to 9, wherein the hypertensive subject has a serum leptin concentration of at least 30 ng / dL, preferably at least 35 ng / dL, more preferably at least 40 ng / dL, or more preferably 30-50 ng / dL, 30-45 ng / dL, or 35-50 ng / dL.

11. The subjects with hypertension are a) a plasma aldosterone concentration of 6 ng / dL or greater in said subject by immunoassay, and / or b) a plasma aldosterone concentration of 1 ng / dL or greater by LC-MS in said subject; The method according to any one of claims 1 to 10, comprising:

12. 1. A method of treating hypertension in a hypertensive subject in need thereof, comprising: a) i) a systolic blood pressure greater than 130 mmHg in said subject; ii) a diastolic BP greater than 80 mmHg in said subject measuring the b) selecting a subject taking at least one diuretic; and c) administering to said subject an effective amount of a CYP 11β2 beta-hydroxylase inhibitor. A method comprising:

13. 1. A method of treating hypertension in a hypertensive subject in need thereof, comprising: a) the hypertensive subject i) have a systolic blood pressure greater than 130 mmHg; ii) have a diastolic BP greater than 80 mmHg, and iii) taking at least one diuretic receiving an identification that b) administering to said subject an effective amount of a CYP 11β2 beta-hydroxylase inhibitor. A method comprising:

14. 14. The method of claim 12 or 13, wherein the diuretic is a thiazide diuretic.

15. 14. The method of any one of claims 12 to 13, wherein step a) further comprises determining in said subject a body mass index (BMI) of at least 30, preferably higher than 30, preferably between 30 and 50, more preferably between 30 and 40, or a waist-to-hip ratio of greater than 0.90 if the hypertensive subject is male, or greater than 0.85 if the hypertensive subject is female, or receiving an identification that said subject has said body mass index (BMI) or said waist-to-hip ratio.

16. 16. The method of any one of claims 12 to 15, wherein step a) further comprises determining in the subject or receiving identification that the subject has a serum leptin concentration of at least 30 ng / dL, preferably at least 35 ng / dL, more preferably at least 40 ng / dL, or more preferably 30-50 ng / dL, 30-45 ng / dL, or 35-50 ng / dL.

17. Step a) a) measuring a plasma aldosterone concentration of 6 ng / dL or greater in said subject by immunoassay; or b) measuring a plasma aldosterone concentration of 1 ng / dL or greater in said subject by LC-MS The method of any one of claims 12 to 16, further comprising:

18. The method according to any one of claims 1 to 16, wherein the subject with hypertension is taking or has taken a hypertension medication selected from an ACE inhibitor, an angiotensin receptor blocker, a calcium channel blocker, or a combination of two or more thereof.

19. 20. The method of claim 18, wherein the hypertensive subject is taking or has taken at least two of said hypertension medications.

20. 20. The method of any one of claims 1 to 19, wherein the CYP11β2 beta hydroxylase inhibitor is administered to the subject once daily.

21. 21. The method of any one of claims 1 to 20, wherein the CYP11β2 beta-hydroxylase inhibitor is administered in the morning.

22. 20. The method of any one of claims 1 to 19, wherein the CYP11β2 beta hydroxylase inhibitor is administered to the subject twice daily.

23. CYP11β2 beta-hydroxylase inhibitors a) administered daily for at least one week; b) administered daily for at least two weeks; c) administered daily for at least 4 weeks; or d) administered daily for at least 8 weeks; 23. The method according to any one of claims 1 to 22.

24. 24. The method of any one of claims 1 to 23, wherein the ambulatory systolic blood pressure of the hypertensive subject is reduced by at least 10 mmHg, 10 to 55 mmHg, 10 to 50 mmHg, 10 to 45 mmHg, 10 to 40 mmHg, 10 to 35 mmHg, 10 to 30 mmHg, 10 to 25 mmHg, 10 to 20 mmHg, or 10 to 15 mmHg for at least 8 weeks compared to the ambulatory systolic blood pressure of the hypertensive subject prior to administration of the CYP11β 2 beta hydroxylase inhibitor.

25. 25. The method of any one of claims 1 to 24, wherein the ambulatory diastolic blood pressure of the hypertensive subject is reduced by at least 5 mmHg, 5 to 25 mmHg, 5 to 20 mmHg, or 5 to 15 mmHg for at least 8 weeks compared to the ambulatory diastolic blood pressure of the hypertensive subject prior to administration of the CYP11β 2 beta hydroxylase inhibitor.

26. 26. The method of any one of claims 1 to 25, wherein the aldosterone levels in the hypertensive subject follow a substantially normal circadian rhythm.

27. 27. The method of any one of claims 1 to 26, wherein the hypertensive subject's mean systolic blood pressure during sleep is reduced (a) compared to the hypertensive subject's mean systolic blood pressure during sleep before receiving the CYP11β 2 beta-hydroxylase inhibitor, and / or (b) compared to the hypertensive subject's mean daytime systolic blood pressure.

28. The mean systolic blood pressure during sleep in hypertensive subjects was a) at least 10%, between 10% and 40%, between 10% and 30%, or between 10% and 20% compared to the mean daytime systolic blood pressure in hypertensive subjects; and / or b) at least 8 mmHg, at least 10 mmHg, between 8 and 55 mmHg, between 10 and 45 mmHg, or between 10 and 25 mmHg compared to the mean systolic blood pressure during sleep in hypertensive subjects prior to receiving a CYP11β 2 beta-hydroxylase inhibitor; The method of any one of claims 1 to 27, wherein the amount of hydroxybenzoates in the blood is reduced.

29. 29. The method of any one of claims 1 to 28, wherein the CYP11β2 beta hydroxylase inhibitor is selective for inhibiting CYP11β2 beta hydroxylase activity compared to inhibiting CYP11β1 beta hydroxylase activity, preferably having an inhibition constant (Ki) for CYP11β1 beta hydroxylase divided by the Ki for CYP11β2 beta hydroxylase greater than 100.

30. The CYP11β2 beta-hydroxylase inhibitor is a compound of formula (A) or a pharmaceutically acceptable salt thereof: 【Chemical 1】 (A) The method according to any one of claims 1 to 29, wherein

31. 31. The method of claim 30, wherein the compound is in the form of the HBr salt of the compound of formula (A).

32. a) Between 5 mg and 50 mg of a CYP11β2 beta-hydroxylase inhibitor is administered orally twice daily, 12 hours apart; b) Between 10 mg and 30 mg of a CYP11β2 beta-hydroxylase inhibitor is administered orally twice daily, 12 hours apart; c) between 30 mg and 120 mg of a CYP11β2 beta-hydroxylase inhibitor administered orally once daily; or d) Between 40 mg and 110 mg of a CYP11β2 beta-hydroxylase inhibitor is administered orally once daily. The compound according to any one of claims 30 to 31.

33. The diuretic is a thiazide diuretic, a) 12.5 mg of a CYP11β2 beta-hydroxylase inhibitor is administered orally once daily and hypertensive subjects experience a placebo-adjusted reduction in systolic blood pressure of at least 5 mmHg, preferably between 5 and 10 mmHg; b) 50 mg of a CYP11β2 beta-hydroxylase inhibitor is administered orally once daily and the hypertensive subject experiences a placebo-adjusted reduction in systolic blood pressure of at least 10 mmHg, preferably between 10 and 15 mmHg; or c) 100 mg of a CYP11β2 beta-hydroxylase inhibitor is administered orally once daily, and hypertensive subjects experience a placebo-adjusted reduction in systolic blood pressure of at least 9 mmHg, preferably between 9 and 15 mmHg.

32. The method according to any one of claims 30 to 31.

34. 34. The method of any one of claims 1 to 33, wherein the hypertensive subject does not have primary aldosteronism, preferably the hypertensive subject has primary hypertension.

35. 1. A method of identifying a subject for treatment of hypertension with a CYP11β2 beta-hydroxylase inhibitor, comprising: a) i) a systolic blood pressure greater than 130 mmHg in said subject, and ii) a diastolic BP greater than 80 mmHg in said subject and measuring b) Selecting subjects taking at least one diuretic thereby identifying said subject for treatment of hypertension with a CYP11β2 beta-hydroxylase inhibitor.

36. 36. The method of claim 35, wherein the diuretic is a thiazide diuretic.

37. 37. The method of any one of claims 35 to 36, wherein step a) further comprises measuring in said subject a body mass index (BMI) of at least 30, preferably greater than 30, preferably between 30 and 50, more preferably between 30 and 40, or measuring in said subject a waist-to-hip ratio of greater than 0.90 if said subject is male, or measuring in said subject a waist-to-hip ratio of greater than 0.85 if said subject is female.

38. 38. The method of any one of claims 35 to 37, wherein step a) further comprises measuring in said subject a serum leptin concentration of at least 30 ng / dL, preferably at least 35 ng / dL, more preferably at least 40 ng / dL, or more preferably 30-50 ng / dL, 30-45 ng / dL, or 35-50 ng / dL.

39. Step a) a) measuring a plasma aldosterone concentration of 6 ng / dL or greater in said subject by immunoassay; or b) measuring a plasma aldosterone concentration of 1 ng / dL or greater by LC-MS in said subject; The method of any one of claims 35 to 38, further comprising:

40. a) an amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof: 【Chemistry 2】 (A) and a pharmaceutically acceptable carrier. b) a second pharmaceutical composition comprising an amount of a thiazide diuretic and a pharmaceutically acceptable carrier; and c) instructions for using the first and second pharmaceutical compositions together to treat a subject suffering from hypertension. Including the package.

41. 1. A compound of formula (A) or a pharmaceutically acceptable salt thereof for use as add-on therapy or in combination with a thiazide diuretic in the treatment of a subject suffering from hypertension: 【Chemistry 3】 (A)

42. a) an amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof: 【Chemistry 4】 (A) b) and an amount of a thiazide diuretic for use in treating a subject suffering from hypertension. wherein the compound of formula (A) and the thiazide diuretic are administered simultaneously, contemporaneously or concomitantly.

43. a) an amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof: 【Chemistry 5】 (A) b) and an amount of a thiazide diuretic A pharmaceutical composition comprising: A pharmaceutical composition wherein a compound of formula (A) and a thiazide diuretic, together, are each present in an amount effective to treat hypertension in a hypertensive subject.

44. 1. For use in the treatment of a subject suffering from hypertension, as add-on therapy or in combination with a thiazide diuretic, comprising an amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof: 【Chemistry 6】 (A) 10. A pharmaceutical composition comprising:

45. 1. A therapeutic package for dispensing or for use in dispensing to a subject suffering from hypertension, comprising: a) one or more unit doses, each such unit dose comprising: i) an amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof: 【Chemistry 7】 (A) and ii) an amount of a thiazide diuretic Including, one or more unit doses, wherein, upon simultaneous administration to the subject, the individual amounts of the compound of Formula (A) and the thiazide diuretic in the unit dose are effective to treat the subject; and b) a finished pharmaceutical container therefor, containing said unit dose(s) and further containing or comprising a label directing use of said package in treating said subject; Treatment package including:

46. A unit dosage form useful for treating subjects suffering from hypertension. a) an amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof: 【Chemistry 8】 (A) and b) an amount of a thiazide diuretic 1. A pharmaceutical composition comprising: A pharmaceutical composition wherein, upon simultaneous administration to said subject of one or more of said unit dosage forms of said composition, the individual amounts of said compound of Formula (A) and said thiazide diuretic in said composition are effective to treat the subject.

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