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

Abstract

The present invention provides a method of treating hypertension in a hypertensive subject by administering to the subject an amount of a diuretic agent and an amount of a CYP 11 [beta] 2 [beta] hydroxylase inhibitor once or twice per day, where when taken in combination with other antihypertensive agents, the amount of the CYP 11 [beta] 2 [beta] hydroxylase inhibitor is less than the amount of the diuretic agent and the amount of the CYP 11 [beta] 2 [beta] hydroxylase inhibitor. The co-administration amount is sufficient to treat hypertension in the hypertensive subject. In particular, the methods are sufficient to safely and reliably reduce hypertension in the hypertensive subject (systolic pressure reduction > 10 mmHg).

Description

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

[0002] Throughout this application, various publications are cited, including publications cited in parentheses. The disclosures of all publications mentioned in this application are hereby incorporated by reference in their entirety into this application to provide additional description of the field to which the invention pertains and features in the art that may be employed with the present invention. Technical Field

[0003] The present invention relates to a method for treating hypertension by inhibiting aldosterone synthase (CYP 11β2β hydroxylase). Background Art

[0004] Aldosterone is the major mineralocorticoid hormone in humans, produced in the zona glomerulosa of the adrenal cortex by aldosterone synthase (CYP 11β2β hydroxylase). Aldosterone is a key component of the renin-angiotensin-aldosterone system (RAAS), which primarily functions as a regulator of electrolyte and fluid homeostasis.

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

[0006] Diuretics are drugs designed to increase the amount of water and salt excreted from the body in the form of urine. Thiazide diuretics are the most commonly prescribed diuretics and are often used to treat high blood pressure. Thiazide diuretics not only reduce fluid but also cause vasodilation. Thiazide diuretics reduce the potassium concentration in the blood. This decrease in potassium occurs through two indirect mechanisms: (1) inhibition of the sodium-chloride symporter in the distal convoluted tubule of the nephron and (2) stimulation of aldosterone, which activates the sodium chloride transporter in the collecting duct. + / K +-ATPase. Inhibition of the sodium-chloride symporter increases the availability of chloride and sodium in urine. When urine reaches the collecting duct, the increased availability of chloride and sodium activates the Na + / K + -ATPase, which in turn increases sodium absorption and potassium excretion into urine. Long-term use of thiazide diuretics reduces total blood volume. This activates the renin-angiotensin system, which stimulates aldosterone secretion, thereby activating Na + / K + -ATPase and increased urinary potassium excretion. Therefore, a combination of ACE inhibitors and thiazides is used to prevent hypokalemia.

[0007] Administering two drugs to treat a given condition, such as administering a combination of an aldosterone synthase inhibitor and a thiazide to treat hypertension, raises many potential concerns. The interactions between two drugs in the body are complex. The effects of any single drug are related to its absorption, distribution, and elimination. When two drugs are introduced into the body, each drug may affect the absorption, distribution, and elimination of the other, thereby altering the effects of the other. For example, one drug may inhibit, activate, or induce the production of an enzyme involved in the metabolic pathways that eliminate the other drug (U.S. Food and Drug Administration, 2020). Therefore, when two drugs are administered to treat the same condition, it is impossible to predict whether each drug will complement the therapeutic activity of the other, have no effect on the therapeutic activity of the other, or interfere with the therapeutic activity of the other in human subjects. The interaction between the two drugs may also enhance or mitigate the side effects of each drug. Therefore, it is impossible to predict how the negative profile of each drug will change after administering two drugs to treat a condition.

[0008] The renin-angiotensin-aldosterone system (RAAS) is a complex and multifaceted system in which many different pathways, enzymes, and hormones interact in positive and negative feedback loops. Given the complexity of the renin-angiotensin-aldosterone system, the use of aldosterone synthase inhibitors in combination with other antihypertensive therapies to treat hypertension has many uncertainties. In particular, the effects of aldosterone synthase inhibitors and diuretics such as thiazides on hypertension have not been previously studied. In addition, identifying the specific patient populations that benefit most from aldosterone synthase inhibition remains an important goal in the field of cardiovascular health. Summary of the Invention

[0009] The present invention provides a method for treating hypertension in a hypertensive subject, wherein the method comprises administering to the subject once or twice daily an amount of a diuretic and an amount of a CYP 11β2β hydroxylase inhibitor, wherein the amounts co-administered are sufficient to treat the hypertension in the hypertensive subject, preferably when taken in combination with other antihypertensive agents. In particular, the method is sufficient to safely and reliably reduce hypertension in the hypertensive subject (reduction in systolic blood pressure >10 mmHg).

[0010] The present invention also provides a method for treating hypertension in a hypertensive subject taking at least one diuretic, the method comprising administering a CYP 11β2β hydroxylase inhibitor to the subject once or twice daily in an amount sufficient to treat the hypertension in the hypertensive subject.

[0011] The present invention also provides a method for identifying a subject for treatment of hypertension with a CYP 11β2β hydroxylase inhibitor, the method comprising:

[0012] (a) Measured:

[0013] (i) the subject's systolic blood pressure is greater than 130 mmHg; and

[0014] (ii) the subject's diastolic blood pressure is greater than 80 mmHg; and

[0015] (b) subjects who were taking at least one diuretic were selected;

[0016] The subject is thereby identified for treatment of hypertension with a CYP 11β2β hydroxylase inhibitor.

[0017] The invention also provides pharmaceutical compositions, packaging, and unit dosage forms for use in any of the methods described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 : Compound A HBr study mode. 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 are available, perform an inclusion / exclusion assessment. If the subject is ineligible based on the screening results, they do not proceed to Visit 4. If screening results are unavailable, the subject proceeds to Visit 4. If screening results are unavailable at Visit 4, the subject should attend Visit 5 to determine final eligibility. If eligible based on the screening results, begin ABPM assessment at Visit 5. b= Initiate the ABPM procedure at home approximately 24 hours prior to randomization (Study Day 1). Alternatively, sites were permitted to schedule an office visit on Study Day 0 (Visit 5) to initiate the ABPM procedure. Training on the ABPM procedure was conducted during the office visit or by telephone.

[0019] Figure 2 : Waterfall plot showing the change in systolic AOBP at Week 8. This figure shows waterfall plots for the full analysis and safety set (FAS) analysis for the placebo, 50 mg QD, and 100 mg QD groups, as well as the per-protocol (PP) analysis for the 100 mg group. Also shown are the modeled mean and per-protocol observed mean for each group.

[0020] Figure 3 : Waterfall plot showing the change in systolic AOBP at Week 8. This figure shows a waterfall plot of the FAS analysis using 12.5 mg QD, 12.5 mg BID, and 25 mg BID for all subjects with measurements at Week 8. The modeled mean and per-protocol observed mean are also shown for each group.

[0021] Figure 4 :Show the bar graph of the mean change of systolic blood pressure relative to baseline.This figure provides the final analysis, including the full analysis set (FAS, all evaluable subjects who received at least one dose of Compound A HBr) and the per protocol (PP, only those who received ≥75% of the study drug at the 8th week visit).Part 2 data shows the interim mean value of the last visit from Week 5 to Week 6.

[0022] Figure 5 : Graph of the change from baseline in mean observed automated office blood pressure at Week 8 for the QD dosing regimen, showing the dose response for Compound A HBr. The far right side of the graph shows the BID per-protocol cohort.

[0023] Figure 6 : Graph showing the change from baseline in systolic blood pressure at Week 8 for the 50 mg QD, 100 mg QD, 12.5 mg BID, and 25 mg BID combined cohorts, the lowest responder quartile for the combined cohort, the highest responder quartile for the combined cohort, and placebo.

[0024] Figure 7 : Waterfall plot showing the change in systolic blood pressure for the placebo and 100 mg QD groups combined for Parts 1 and 2. Part 2 data are from an interim snapshot and the average Week 5-6 last visit for all randomized subjects, with a minimum of Week 2.

[0025] Figure 8: Graph showing changes in estimated glomerular filtration rate (eGFR) in different dosing cohorts.

[0026] Figure 9 : A graph showing an example of ambulatory 24-hour blood pressure monitoring. The graph shows 24-hour ambulatory blood pressure (systolic) for subjects receiving Compound A HBr 100 mg QD relative to baseline, showing a reduction in mean 24-hour blood pressure and restoration of the normal nocturnal decline pattern.

[0027] Figure 10 : Graph showing the change from baseline in systolic blood pressure at week 8 measured using the full analysis set of ABPM.

[0028] Figure 11 Waterfall plot showing the change from baseline in 24-hour and nighttime average ABPM at 8 weeks. The 100 mg QD dose level provided superior 24-hour blood pressure reduction. Nighttime blood pressure reduction relative to the 100 mg QD dose level appeared superior to that of the 25 mg BID dose.

[0029] Figure 12 : Modeled (MMRM) least squares mean (SEM) change from baseline in seated automated office-measured systolic blood pressure (mmHg) at Week 8, Part 1 (full analysis set). Error bars represent the SEM. Numbers within bars represent the number of subjects with nonmissing data. P value represents a statistically significant difference compared with placebo. *p=0.0114. **p=0.042. Abbreviations: BID, twice daily; mg, milligram; mmHg, millimeter of mercury; QD, once daily; SBP, systolic blood pressure; SEM, standard error mean.

[0030] Figure 13 Figure : Modeled (MMRM) least-squares mean (SEM) change from baseline in seated automated office-measured systolic blood pressure (mmHg) at week 8, Parts 1 and 2 (full analysis set). Error bars represent the SEM. Numbers within bars represent the number of subjects with nonmissing data. Abbreviations: mg, milligram; mmHg, millimeter of mercury; MMRM, mixed-model repeated measures; QD, once daily; SBP, systolic blood pressure; SEM, standard error mean.

[0031] Figure 14 Figure 3: Box plots of change from baseline in seated automated office-measured systolic blood pressure (mmHg) at week 8, part 1 (full analysis set). ◇, mean; –, median; · outliers. The upper and lower boundaries of each box represent the first and third quartiles. Abbreviations: BID, twice daily; mg, milligram; mmHg, millimeter of mercury; QD, once daily; SBP, systolic blood pressure.

[0032] Figure 15 Figure 3: Box plots of change from baseline in seated automated office-measured systolic blood pressure (mmHg) at week 8 in subjects randomized to 100 mg QD, Parts 1 and 2 (full analysis set). ◇, mean; –, median; 1, outlier. The upper and lower boundaries of each box represent the first and third quartiles. Abbreviations: mg, milligram; mmHg, millimeter of mercury; QD, once daily; SBP, systolic blood pressure.

[0033] Figure 16 : Proportion of subjects with seated automated office SBP / DBP ≤ 130 / 80 mmHg at Week 8, Part 1 (Full Analysis Set). Subjects who missed the assessment at Week 8 or received rescue medication before Week 8 were considered failures. Numbers within bars represent the number of subjects who achieved AOBP ≤ 130 / 80 mmHg.

[0034] Figure 17 : Proportion of subjects randomized to 100 mg QD with a seated automated office SBP / DBP ≤ 130 / 80 mmHg at Study Week 8, Parts 1 and 2 (Full Analysis Set). Subjects who missed the assessment at Week 8 or received rescue medication before Week 8 were considered failures. Numbers within bars represent the number of subjects who achieved AOBP ≤ 130 / 80 mmHg.

[0035] Figure 18 : Time to first occurrence (weeks) of seated automated office-based SBP / DBP ≤ 130 / 80 mmHg, Part 1 (full analysis set). Subjects who were unable to achieve BP ≤ 130 / 80 mmHg before Week 8 / EoT were censored on Week 8 / EoT. Subjects lost to follow-up before Week 8 / EoT were censored on the day of the last known BP assessment. Subjects taking rescue medication were censored on the day of rescue medication initiation. Missing events correspond to subjects who did not have a post-baseline BP assessment. For subject 146-040, the study duration (> 27 weeks) and treatment duration (> 18 weeks) were longer than planned due to a temporary discontinuation due to an AE.

[0036] Figure 19: Time (week) to first occurrence of seated automated office-measured SBP / DBP ≤ 130 / 80 mmHg in subjects randomized to 100 mg QD, Parts 1 and 2 (full analysis set). Subjects who were unable to achieve BP ≤ 130 / 80 mmHg before Week 8 / EoT were censored on Week 8 / EoT. Subjects lost to follow-up before Week 8 / EoT were censored on the day of the last known BP assessment. Subjects taking rescue medication were censored on the rescue medication initiation day. Missing events correspond to subjects who did not have a post-baseline BP assessment.

[0037] Figure 20 : Mean (SEM) change from baseline in serum potassium over time in the QD dose cohort, Part 1 (Safety Analysis Set).

[0038] Figure 21 : Mean (SEM) change from baseline in serum potassium over time in the BID dose cohort, Part 1 (Safety Analysis Set).

[0039] Figure 22 : Mean (SEM) change from baseline in serum potassium over time, Part 2 (Safety Analysis Set).

[0040] Figure 23 : Mean (SEM) Change from Baseline in Serum Sodium Over Time in the QD Dosing Cohort, Part 1 (Safety Analysis Set)

[0041] Figure 24 : Mean (SEM) Change from Baseline in Serum Sodium Over Time in the BID Dose Cohort, Part 1 (Safety Analysis Set)

[0042] Figure 25 : Mean (SEM) Change from Baseline in Serum Sodium over Time, Part 2 (Safety Analysis Set)

[0043] Figure 26 : Median baseline body mass index (BMI, kg / m 2 ) and serum leptin (ng / dL). Data were pooled from the lorenstat 25 mg BID, 50 mg QD, and 100 mg QD cohorts in low-renin subjects (Part 1). 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).

[0044] Figure 27: Relationship between baseline BMI and mean change from baseline in systolic blood pressure (mmHg) as measured by AOBP at Week 8. Data were pooled from the lorenstat 25 mg BID, 50 mg QD, and 100 mg QD cohorts for low-renin subjects (Part 1). DETAILED DESCRIPTION

[0045] Methods for treating high blood pressure

[0046] The present invention provides a method for treating hypertension in a hypertensive subject, wherein the method comprises administering to the subject once or twice daily an amount of a diuretic and an amount of a CYP 11β2β hydroxylase inhibitor, wherein the amounts co-administered are sufficient to treat the hypertension in the hypertensive subject, preferably when taken in combination with other antihypertensive agents. In particular, the method is sufficient to safely and reliably reduce hypertension in the hypertensive subject (reduction in systolic blood pressure >10 mmHg).

[0047] In an embodiment of the invention, said diuretic and said CYP 11β2β hydroxylase inhibitor are administered as a combined pharmaceutical composition.

[0048] In an embodiment of the invention, said diuretic and said CYP 11β2β hydroxylase inhibitor are administered concomitantly. In an embodiment of the invention, the dosages used in combination result in a greater than additive therapeutic outcome when treating a subject.

[0049] In an embodiment of the invention, said CYP 11β2β hydroxylase inhibitor and said diuretic are more effective in treating said subject when co-administered than when each agent is administered alone in the same amount.

[0050] The present invention also provides a method for treating hypertension in a hypertensive subject taking at least one diuretic, the method comprising administering a CYP 11β2β hydroxylase inhibitor to the subject once or twice daily in an amount sufficient to treat the hypertension in the hypertensive subject.

[0051] In an embodiment of the invention, the diuretic is a thiazide diuretic.

[0052] 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.

[0053] In one embodiment, 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.

[0054] 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.

[0055] In embodiments, the hypertensive subject has:

[0056] (a) a plasma aldosterone concentration greater than or equal to 6 ng / dL as determined by an immunoassay performed in the subject; and / or

[0057] (b) a plasma aldosterone concentration greater than or equal to 1 ng / dL according to LC-MS performed in the subject.

[0058] Plasma aldosterone concentration can be measured by commercially available tests of standards 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. It is noteworthy that the assay for measuring aldosterone reported by Schirpenbach et al. 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 one embodiment, a plasma aldosterone concentration greater than or equal to 6 ng / dL measured by an immunoassay such as ELISA corresponds to a plasma aldosterone concentration greater than or equal to about 1 ng / dL measured by LC-MS.

[0059] The present invention provides a method for treating hypertension in a hypertensive subject in need thereof, the method comprising

[0060] (a) Measured

[0061] (i) the subject's systolic blood pressure is greater than 130 mmHg;

[0062] (ii) the subject's diastolic blood pressure is greater than 80 mmHg; and

[0063] (b) selecting subjects who are taking at least one diuretic; and

[0064] (c) administering to the subject an effective amount of a CYP 11β2β hydroxylase inhibitor.

[0065] The present invention provides a method for treating hypertension in a hypertensive subject in need thereof, the method comprising

[0066] (a) receiving a diagnosis of hypertensive subject

[0067] (i) systolic blood pressure greater than 130 mmHg;

[0068] (ii) diastolic blood pressure greater than 80 mmHg; and

[0069] (iii) taking at least one diuretic; and

[0070] An effective amount of a CYP 11β2β hydroxylase inhibitor is administered to the subject.

[0071] In one embodiment, the diuretic is a thiazide diuretic.

[0072] In one embodiment, step (a) further comprises measuring or receiving identification of the subject as having a body mass index (BMI) of at least 30, preferably greater than 30, preferably 30-50, more preferably 30-40, or a waist-to-hip ratio above 0.90 if the hypertensive subject is a male or above 0.85 if the hypertensive subject is a female.

[0073] In one embodiment, step a) further comprises measuring or receiving a diagnosis identifying the subject as having 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.

[0074] In an embodiment of the present invention, step (a) further comprises:

[0075] (a) the subject's plasma aldosterone concentration is greater than or equal to 6 ng / dL as measured by an immunoassay; or

[0076] (b) the subject's plasma aldosterone concentration is greater than or equal to 1 ng / dL as measured by LC-MS.

[0077] In an embodiment of the present invention, the hypertensive subject is taking or has taken a hypertensive drug 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 hypertensive drugs.

[0078] In an embodiment of the invention, 50% or more of the activity of CYP 11β2β hydroxylase is inhibited for 40%-60% of a 24 hour period.

[0079] In an embodiment of the invention, 50% or more of the activity of CYP 11β2β hydroxylase is inhibited for between 10 hours and 14 hours of a 24 hour period.

[0080] In an embodiment of the present invention, the CYP 11β2β hydroxylase inhibitor reduces the serum aldosterone level of the subject by 50%-90% relative to the serum aldosterone level of the subject before administration, for a period of not less than 8 hours and not more than 16 hours.

[0081] In an embodiment of the present invention, the CYP 11β2β hydroxylase inhibitor reduces the subject's serum aldosterone level by 60%-80% relative to the subject's serum aldosterone level before administration, for a period of not less than 8 hours and not more than 16 hours.

[0082] In an embodiment of the invention, the CYP 11β2β hydroxylase inhibitor returns the subject's serum aldosterone to the subject's pre-dose serum aldosterone level or higher during the period between 16 hours and 24 hours after administration of the dose.

[0083] In an embodiment of the invention, 50% or more of the activity of CYP 11β2β hydroxylase is inhibited for between 1 hour and 16 hours or preferably between 3 hours and 8 hours of a 24 hour period.

[0084] In an embodiment, the CYP 11β2β hydroxylase inhibitor is administered once daily in an amount sufficient to:

[0085] (a) inhibiting the activity of CYP 11β2β hydroxylase by 50% or more for between 1 hour and 16 hours, preferably between 3 hours and 8 hours;

[0086] (b) inhibiting the activity of CYP 11β2β hydroxylase by 60% or more for between 1 hour and 13 hours, preferably between 2 hours and 6 hours;

[0087] (c) inhibiting the activity of CYP 11β2β hydroxylase by 70% or more for between 1 hour and 9 hours, preferably between 2 hours and 5 hours;

[0088] (d) inhibiting the activity of CYP 11β2β hydroxylase by 80% or more for between 1 hour and 6 hours, preferably between 1 hour and 3 hours; and / or

[0089] (e) inhibiting the activity of CYP 11β2β hydroxylase by 90% or more for between 0 and 3 hours, preferably between 0 and 1 hour;

[0090] Thereby treating hypertension in the hypertensive subject.

[0091] In an embodiment, the CYP 11β2β hydroxylase inhibitor is administered once daily in an amount sufficient to:

[0092] (a) inhibiting the activity of CYP 11β2β hydroxylase by 50% or more for between 1 hour and 20 hours, preferably between 4 hours and 11 hours;

[0093] (b) inhibiting the activity of CYP 11β2β hydroxylase by 60% or more for between 1 hour and 17 hours, preferably between 3 hours and 9 hours;

[0094] (c) inhibiting the activity of CYP 11β2β hydroxylase by 70% or more for between 1 hour and 15 hours, preferably between 2.5 hours and 7 hours;

[0095] (d) inhibiting the activity of CYP 11β2β hydroxylase by 80% or more for between 1 hour and 10 hours, preferably between 2 hours and 5 hours; and / or

[0096] (e) inhibiting the activity of CYP 11β2β hydroxylase by 90% or more for between 1 hour and 5 hours, preferably between 0.5 hours and 2.5 hours;

[0097] Thereby treating hypertension in the hypertensive subject.

[0098] In an embodiment of the present invention, the CYP 11β2β hydroxylase inhibitor is administered to the subject once a day. In an embodiment of the present invention, the CYP 11β2β hydroxylase inhibitor is administered in the morning. In an embodiment of the present invention, the CYP 11β2β hydroxylase inhibitor is administered to the subject twice a day. In a preferred embodiment of the present invention, the CYP 11β2β hydroxylase inhibitor is administered to the subject once a day in the morning.

[0099] In an embodiment of the present invention, the CYP 11β2β hydroxylase inhibitor:

[0100] (a) is administered daily for at least one week;

[0101] (b) is administered daily for at least two weeks;

[0102] (c) is administered daily for at least four weeks; or

[0103] (d) is administered daily for at least eight weeks.

[0104] In an embodiment of the invention, the ambulatory systolic blood pressure of the hypertensive subject is reduced by at least 10 mmHg, by 10-55 mmHg, by 10-50 mmHg, by 10-45 mmHg, by 10-40 mmHg, by 10-35 mmHg, by 10-30 mmHg, by 10-25 mmHg, by 10-20 mmHg, or by 10-15 mmHg relative to the ambulatory systolic blood pressure of the hypertensive subject before administration of the CYP11β2β hydroxylase inhibitor, preferably relative to the ambulatory systolic blood pressure of the hypertensive subject before administration of the CYP11β2β hydroxylase inhibitor for a period of at least eight weeks.

[0105] In an embodiment of the invention, the ambulatory diastolic blood pressure of the hypertensive subject is reduced by at least 5 mmHg, reduced by 5-25 mmHg, reduced by 5-20 mmHg, or reduced by 5-15 mmHg relative to the ambulatory diastolic blood pressure of the hypertensive subject before administration of the CYP11β2β hydroxylase inhibitor, preferably relative to the ambulatory diastolic blood pressure of the hypertensive subject before administration of the CYP11β2β hydroxylase inhibitor for a period of at least eight weeks.

[0106] In an embodiment of the present invention:

[0107] (a) the subject's office-measured systolic blood pressure is reduced relative to the subject's office-measured systolic blood pressure prior to administration of the CYP 11β2β hydroxylase inhibitor; and / or

[0108] (b) the subject's 24-hour ambulatory systolic blood pressure is reduced relative to the subject's ambulatory systolic blood pressure before administration of the CYP 11β2β hydroxylase inhibitor.

[0109] In an embodiment of the present invention:

[0110] (a) the subject's office-measured systolic blood pressure is reduced by at least 10 mmHg relative to the subject's office-measured systolic blood pressure prior to administration of the CYP 11β2β hydroxylase inhibitor; and / or

[0111] (b) the subject's ambulatory systolic blood pressure is reduced by at least 10 mmHg relative to the subject's ambulatory systolic blood pressure before administration of the CYP 11β2β hydroxylase inhibitor.

[0112] In an embodiment of the present invention:

[0113] (a) the subject's office-measured diastolic blood pressure is reduced relative to the subject's office-measured diastolic blood pressure prior to administration of the CYP 11β2β hydroxylase inhibitor;

[0114] (b) the subject's office-measured systolic and diastolic blood pressure is reduced relative to the subject's office-measured systolic and diastolic blood pressure prior to administration of the CYP 11β2β hydroxylase inhibitor;

[0115] (c) the subject's ambulatory systolic and diastolic blood pressure is reduced relative to the subject's ambulatory systolic and diastolic blood pressure prior to administration of the CYP 11β2β hydroxylase inhibitor; and / or

[0116] (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.

[0117] In an embodiment of the present invention:

[0118] (a) the subject's ambulatory systolic blood pressure is reduced by at least 10 mmHg, and the subject's ambulatory diastolic blood pressure is reduced by at least 5 mmHg, each relative to the subject's ambulatory systolic blood pressure and diastolic blood pressure, respectively, prior to administration of the CYP 11β2β hydroxylase inhibitor;

[0119] (b) the subject's office-measured systolic blood pressure is reduced by at least 10 mmHg, and the subject's office-measured diastolic blood pressure is reduced by at least 5 mmHg, each relative to the subject's office-measured systolic blood pressure and diastolic blood pressure, respectively, prior to administration of the CYP 11β2β hydroxylase inhibitor; and / or

[0120] (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.

[0121] In an embodiment of the invention, the duration of inhibition of CYP 11β2β hydroxylase activity is sufficient to maintain the sodium and volume depleted state of said hypertensive subject.

[0122] In embodiments of the invention, the method does not produce sustained hyperkalemia or a mild non-anion gap metabolic acidosis state in the hypertensive subject.

[0123] In an embodiment of the invention, the CYP 11β2β hydroxylase inhibitor does not substantially accumulate in the hypertensive subject, preferably wherein the absence of substantial accumulation of the CYP 11β2β hydroxylase inhibitor in the hypertensive subject causes the aldosterone level of the hypertensive subject to return to pre-drug baseline within 24-48 hours of administration of the CYP 11β2β hydroxylase inhibitor, more preferably within 16-24 hours of administration of the CYP 11β2β hydroxylase inhibitor.

[0124] In an embodiment of the invention, the potassium level of the hypertensive subject is generally maintained within the clinical normal range, preferably wherein the potassium level of the hypertensive subject is slightly elevated relative to the potassium level of the hypertensive subject before administration of the CYP 11β2β hydroxylase inhibitor, more preferably wherein the potassium level of the hypertensive subject is elevated by 0.35 mmol / L or less, more preferably wherein the potassium level of the hypertensive subject is maintained below a level of 5.5 mmol / L, more preferably wherein the potassium level of the hypertensive subject is maintained between 3.5 mEq / l and 5.1 mEq / l.

[0125] In an embodiment of the present invention, the CYP 11β2β hydroxylase inhibitor is administered to the hypertensive subject in an amount of:

[0126] (a) inhibiting the production of aldosterone in the subject;

[0127] (b) increasing serum and / or plasma potassium levels in the subject; and / or

[0128] (c) increasing plasma renin activity (PRA) in the subject.

[0129] In an embodiment of the present invention:

[0130] (a) the subject's serum and / or plasma aldosterone AUC-24 is reduced by at least 25% relative to the subject's aldosterone level prior to administration of the CYP 11β2β hydroxylase inhibitor;

[0131] (b) the subject's serum and / or plasma potassium level is increased by at least 0.2 mMol / L relative to the subject's serum and / or plasma potassium level before administration of the CYP 11β2β hydroxylase inhibitor; and / or

[0132] (c) the subject's PRA is increased by at least 5 ng / ml / hr relative to the subject's PRA prior to administration of the CYP 11β2β hydroxylase inhibitor.

[0133] In an embodiment of the present invention, the aldosterone level of the hypertensive subject follows a substantially normal circadian rhythm.

[0134] In an embodiment of the invention, the mean systolic blood pressure during sleep of the hypertensive subject is reduced (a) relative to the mean systolic blood pressure during sleep of the hypertensive subject before receiving the CYP 11β2β hydroxylase inhibitor and / or (b) relative to the mean daytime systolic blood pressure of the hypertensive subject. In an embodiment, the mean systolic blood pressure during sleep of the hypertensive subject is:

[0135] (a) a decrease of at least 10%, a decrease of between 10% and 40%, a decrease of between 10% and 30%, or a decrease of between 10% and 20% relative to the mean daytime systolic blood pressure of the hypertensive subject; and / or

[0136] (b) a decrease of at least 8 mmHg, a decrease of at least 10 mmHg, a decrease of between 8 mmHg and 55 mmHg, a decrease of between 10 mmHg and 45 mmHg, or a decrease of between 10 mmHg and 25 mmHg relative to the hypertensive subject's mean systolic blood pressure during sleep prior to receiving the CYP 11β2β hydroxylase inhibitor.

[0137] In an embodiment of the invention, the CYP 11β2β hydroxylase inhibitor is selectively useful for inhibiting CYP 11β1β hydroxylase activity relative to inhibiting CYP 11β1β hydroxylase activity, preferably wherein the ratio of the inhibition constant (Ki) for CYP 11β1β hydroxylase to the Ki for CYP 11β2β hydroxylase is greater than 100.

[0138] In an embodiment of the present invention, the CYP 11β2β hydroxylase inhibitor is administered to the hypertensive subject in an amount below that which causes the serum and / or plasma 11-deoxycorticosterone (11-DOC) level of the subject to exceed 600 pmol / L, preferably below that which causes the serum and / or plasma 11-DOC level of the subject to exceed 400 pmol / L.

[0139] In an embodiment of the present invention, the CYP 11β2β hydroxylase inhibitor is administered to the hypertensive subject in an amount less than that causing accumulation of 11-DOC in the subject exceeding 0.1 ng / ml.

[0140] In an embodiment of the present invention, the CYP 11β2β hydroxylase inhibitor is administered to the hypertensive subject in an amount that does not cause a clinically meaningful upregulation of adrenocortical hormone synthesis in the subject.

[0141] In an embodiment of the present invention, the CYP 11β2β hydroxylase inhibitor is administered to the hypertensive subject in an amount of:

[0142] (a) does not result in a clinically meaningful decrease in the subject's serum and / or plasma Cortisol levels relative to the subject's serum and / or plasma Cortisol levels prior to administration of the CYP 11β2β hydroxylase inhibitor;

[0143] (b) does not cause a clinically meaningful increase in the subject's serum and / or plasma 11-DOC levels relative to the subject's serum and / or plasma 11-DOC levels prior to administration of the CYP 11β2β hydroxylase inhibitor; and / or

[0144] (c) does not cause a clinically meaningful increase in the subject's serum and / or plasma 11-deoxycortisol levels relative to the subject's serum and / or plasma 11-deoxycortisol levels prior to administration of the CYP 11β2β hydroxylase inhibitor.

[0145] In an embodiment of the present invention, the CYP 11β2β hydroxylase inhibitor is administered to the hypertensive subject in an amount of:

[0146] (a) does not reduce the serum and / or plasma Cortisol level of the subject by more than 20% relative to the serum and / or plasma Cortisol level of the subject before administration of the CYP 11β2β hydroxylase inhibitor, preferably does not reduce the serum and / or plasma Cortisol level of the subject by more than 10% relative to the serum and / or plasma Cortisol level of the subject before administration of the CYP 11β2β hydroxylase inhibitor;

[0147] (b) does not increase the serum and / or plasma 11-DOC level of the subject by more than 20% relative to the serum and / or plasma 11-DOC level of the subject before administration of the CYP 11β2β hydroxylase inhibitor, preferably does not increase the serum and / or plasma 11-DOC level of the subject by more than 10% relative to the serum and / or plasma 11-DOC level of the subject before administration of the CYP 11β2β hydroxylase inhibitor; and / or

[0148] (c) does not increase the serum and / or plasma 11-deoxycortisol level of the subject by more than 20% relative to the serum and / or plasma 11-deoxycortisol level of the subject before administration of the CYP 11β2β hydroxylase inhibitor, preferably does not increase the serum and / or plasma 11-deoxycortisol level of the subject by more than 10% relative to the serum and / or plasma 11-deoxycortisol level of the subject before administration of the CYP 11β2β hydroxylase inhibitor.

[0149] In an embodiment of the present invention, the CYP 11β2β 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 CYP11β2β 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 CYP11B2β hydroxylase inhibitor is a 1,2,4-triazine compound or a pharmaceutically acceptable salt thereof.

[0150] In an embodiment, the CYP 11β2β hydroxylase inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0151]

[0152] 1) wherein X and Y represent any one of the following (i) to (iii):

[0153] (i) X is N, and Y is CH or C—RY,

[0154] (ii) X is CH, and Y is N, or

[0155] (iii) X is CH, and Y is CH;

[0156] 2) R Y represents an alkyl group;

[0157] 3) R A represents a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an aryl group which may be substituted, or a 6- to 10-membered monocyclic or bicyclic heteroaryl group which may be partially hydrogenated and substituted;

[0158] 4) R 1 represents a hydrogen atom or an alkyl group;

[0159] 5)R 2 represents an alkyl group which may be substituted, a cycloalkyl group which may be substituted, an aliphatic heterocyclic group which may be substituted, or a heteroaryl group which may be partially hydrogenated and substituted; and

[0160] 6)R3 represents a hydrogen atom, or an alkyl group, or a pharmaceutically acceptable salt thereof.

[0161] In an embodiment, the CYP 11β2β hydroxylase inhibitor is a compound of formula (A) (also referred to herein as "Compound A") or a pharmaceutically acceptable salt thereof:

[0162]

[0163] In an embodiment, the CYP 11β2β hydroxylase inhibitor is a pharmaceutically acceptable salt of a compound of formula (A).

[0164] In an embodiment, the CYP 11β2β hydroxylase inhibitor is the monohydrobromide salt of the compound of formula (A), ie, Compound A HBr.

[0165] In an embodiment, the CYP 11β2β hydroxylase inhibitor is the free base form of the compound of formula (A).

[0166] In an embodiment, preferably wherein the CYP 11β2β hydroxylase inhibitor is Compound A, more preferably Compound A HBr:

[0167] (a) orally administering between 5 mg and 100 mg of the CYP 11β2β hydroxylase inhibitor twice a day at 12-hour intervals;

[0168] (b) orally administering between 10 mg and 50 mg of the CYP 11β2β hydroxylase inhibitor twice a day, 12 hours apart;

[0169] (c) oral administration of between 5 mg and 100 mg of the CYP 11β2β hydroxylase inhibitor once a day; or

[0170] (d) oral administration of between 10 mg and 50 mg of said CYP 11β2β hydroxylase inhibitor once a day.

[0171] In an embodiment, preferably wherein the CYP 11β2β hydroxylase inhibitor is Compound A, more preferably Compound A HBr:

[0172] (a) orally administering 12.5 mg of the CYP 11β2β hydroxylase inhibitor twice a day at 12-hour intervals;

[0173] (b) orally administering 25 mg of the CYP 11β2β hydroxylase inhibitor twice a day at 12-hour intervals;

[0174] (c) orally administering 12.5 mg of the CYP 11β2β hydroxylase inhibitor once a day;

[0175] (d) orally administering 50 mg of the CYP 11β2β hydroxylase inhibitor once a day; or

[0176] (e) Orally administering 100 mg of the CYP 11β2β hydroxylase inhibitor once a day.

[0177] In one embodiment, wherein the CYP 11β2β hydroxylase inhibitor is Compound A and the diuretic is a thiazide diuretic:

[0178] (a) orally administering 12.5 mg of the CYP 11β2β hydroxylase inhibitor once a day, and the systolic blood pressure of the hypertensive subject is reduced by at least 5 mmHg, preferably by between 5 mmHg and 10 mmHg after placebo adjustment;

[0179] (b) orally administering 50 mg of the CYP 11β2β hydroxylase inhibitor once a day, and the systolic blood pressure of the hypertensive subject is reduced by at least 10 mmHg, preferably by between 10 mmHg and 15 mmHg after placebo adjustment; or

[0180] (c) orally administering 100 mg of the CYP 11β2β hydroxylase inhibitor once a day, and the systolic blood pressure of the hypertensive subject is reduced by at least 9 mmHg, preferably by between 9 mmHg and 15 mmHg after placebo adjustment.

[0181] In one embodiment, the CYP 11β2β hydroxylase inhibitor is a compound having the following structure or a pharmaceutically acceptable salt thereof.

[0182]

[0183] In one embodiment, the CYP 11β2β hydroxylase inhibitor is a compound having the following structure:

[0184]

[0185] or a pharmaceutically acceptable salt thereof, wherein:

[0186] (a)R 1 is C1-C7-alkyl;

[0187] (b)R 2 、R 3 、R 4 , and R 5 It is H;

[0188] (c)R 6 is H, halogen, or C1-C7-alkyl;

[0189] (d)R 7 、R 8 、R 9 、R 10 , and R 11 It is H;

[0190] (e)R 12 is H or halogen;

[0191] (f)A 1 It's CR 13 ;

[0192] (g)A 2 It is NR 14 or CR 15 R 16 ;

[0193] (h)A 3 It's CR 17 ;

[0194] (i)R 13 is H or halogen;

[0195] (j)R 14 Yes—(CR 20 R 21 ) q —(CR 22 R 23 ) r —(CR 24 R 25 ) p —NR 26 R 27 , where the sum of q, r, and p is at least 2;

[0196] (k)R 15 Yes—(CR 20 R 21 ) q —(CR 22 R 23 ) r —(CR 24 R 25 ) p —NR 26 R 27 ;

[0197] (l)R 16 It is H;

[0198] (m) or R 6 and R 16 Together with the carbon atoms to which they are attached, they form double bonds;

[0199] (n)R17 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 , and R 26 It is H;

[0200] (o)R 27 Is H, —S(O)2R 31 ,—C(O)R 31 , or—C(O)OR 31 , where R 26 is H and R 27 In the case of H, the sum of q, r, and p is at least 1;

[0201] (p)R 31 is C1-C7-alkyl, chloropyridyl, hydroxy-C1-C7-alkyl, or C3-C8-cycloalkyl;

[0202] (q)n is zero or 1;

[0203] (r) p is zero or 1;

[0204] (s)q is zero or 1; and

[0205] (t)r is zero or 1.

[0206] 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 CYP 11β2β hydroxylase inhibitor is a compound described in U.S. Patent No. 9,353,081 B2, preferably a compound selective for inhibiting CYP 11β1β hydroxylase activity relative to inhibiting CYP 11β1β hydroxylase activity, more preferably wherein the ratio of the inhibition constant (Ki) for CYP 11β1β hydroxylase to the Ki for CYP 11β2β hydroxylase is greater than 100.

[0207] In one embodiment, the CYP 11β2β hydroxylase inhibitor is a compound having the following structure:

[0208]

[0209] or a pharmaceutically acceptable salt thereof, wherein:

[0210] (a) A is N;

[0211] (b) W is CR6;

[0212] (c) X is CR6;

[0213] (d) Y is CR6;

[0214] (e) Z is CR6;

[0215] (f) R1 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl, NRRb, NHSO2Rc, (CH2)nNRRRb, (CH2)nNHSO2Rd, (CH2)nNHCO2Rd, CO2Re, CORf, (CH2)nORf, or CReRfOH;

[0216] (g) R2 is hydrogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl, NHSO2Rc, CH2NRaRb, CH2NHSO2Rd, CO2Re, CORf, CH2ORf, or CReRfOH;

[0217] (h) R3 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl, NRRb, NHSO2Rc, (CH2)nNRaRb, (CH2)nNHSO2Rd, CO2Re, CORf, (CH2)nORf, or CReRfOH;

[0218] (i) each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0219] (j) R4 is alkyl, cycloalkyl, haloalkyl, or heteroalkyl;

[0220] (k) R6, at each occurrence, is independently hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, or carboxyl; and

[0221] (1) Ra, Rb, Rc, Rd, Re, and Rf, at each occurrence, are independently hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyalkyl, C(O)OC1-6alkyl, C(O)C1-6alkyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom; 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.

[0222] 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 CYP 11β2β hydroxylase inhibitor is a compound described in U.S. Patent No. 10,538,511, preferably a compound selective for inhibiting CYP 11β1β hydroxylase activity relative to inhibiting CYP 11β1β hydroxylase activity, more preferably wherein the ratio of the inhibition constant (Ki) for CYP 11β1β hydroxylase to the Ki for CYP 11β2β hydroxylase is greater than 100.

[0223] In one embodiment, the CYP 11β2β hydroxylase inhibitor is a compound having the following structure:

[0224]

[0225] or a salt or enantiomer thereof, wherein:

[0226] (a)R 1 is one, two, or three independent halogens, halogenated alkyls, NO2, CN, COOR 5 、SO2R 5 、CONR 5 R 6 、SO2NR 5 R 6 NR 5 R 6 , OR 5 , alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, or aryl;

[0227] (b)R 2 is one or more independent halogen, haloalkyl, NO2, CN, COOR 5 、SO2R 5 、CONR 5 R 6 、SO2NR 5 R 6 NR 5 R 6 , OR 5 , alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, or aryl;

[0228] (c)R 3 is alkyl, alkenyl, or alkynyl, any of which is further substituted by one or more R 7 replace;

[0229] (d)R 4 It is NR 5 R 6 SR5 , or OR 5 ;

[0230] (e)R 5 and R 6 are independently hydrogen, alkyl, aryl, or haloalkyl;

[0231] (f)R 7 H, halogen, alkyl, haloalkyl, NO2, CN, COOR 8 、SO2R 8 、CONR 8 R 9 、SO2NR 8 R 9 NR 8 R 9 , or OR 8 ;as well as

[0232] (g)R 8 and R 9 are independently hydrogen, alkyl, or haloalkyl,

[0233] (h) and wherein the compound is not benzo[d]thiazol-2-yl(pyridin-3-yl)methanol.

[0234] 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 CYP 11β2β hydroxylase inhibitor is a compound described in U.S. Patent No. 10,287,282, preferably a compound selective for inhibiting CYP 11β1β hydroxylase activity relative to inhibiting CYP 11β1β hydroxylase activity, more preferably wherein the ratio of the inhibition constant (Ki) for CYP 11β1β hydroxylase to the Ki for CYP 11β2β hydroxylase is greater than 100.

[0235] In an embodiment of the present invention, the plasma renin activity of the hypertensive subject is less than or equal to 1 ng / ml / hour.

[0236] In an embodiment of the present invention, the plasma renin activity of the hypertensive subject is less than or equal to 0.6 ng / ml / hour.

[0237] In an embodiment of the present invention, the plasma renin activity of the hypertensive subject is less than or equal to 4 ng / ml / hour.

[0238] In an embodiment of the present invention, the plasma renin activity of the hypertensive subject is less than or equal to 3 ng / ml / hour.

[0239] In an embodiment of the present invention, the plasma renin activity of the hypertensive subject is less than or equal to 2 ng / ml / hour.

[0240] In an embodiment of the invention, the hypertensive subject has a plasma aldosterone concentration greater than or equal to 6 ng / dL as measured by immunoassay.

[0241] In an embodiment of the invention, the hypertensive subject has a plasma aldosterone concentration greater than or equal to 1 ng / dL as measured by LC-MS.

[0242] In a preferred embodiment of the present invention, the plasma renin activity of the hypertensive subject is less than or equal to 1 ng / ml / hour and the plasma aldosterone concentration is greater than or equal to 6 ng / dL as measured by immunoassay. In a preferred embodiment of the present invention, the plasma renin activity of the hypertensive subject is less than or equal to 1 ng / ml / hour and the plasma aldosterone concentration is greater than or equal to 1 ng / dL as measured by LC-MS. In another preferred embodiment, the hypertensive subject is taking or has taken a hypertension medication selected from a diuretic, an ACE inhibitor, an angiotensin receptor blocker, a calcium channel blocker, or a combination of two or more thereof.

[0243] Alternatively, in embodiments wherein the hypertensive subject is not taking a hypertensive medication selected from a diuretic, an ACE inhibitor, an angiotensin receptor blocker, a calcium channel blocker, in one embodiment, the hypertensive subject has a plasma renin activity less than or equal to 0.6 ng / ml / hour and a plasma aldosterone concentration greater than or equal to 6 ng / dL as measured by immunoassay, or a plasma aldosterone concentration greater than or equal to 1 ng / dL as measured by LC-MS.

[0244] In an embodiment of the present invention, the hypertensive subject suffers from secondary hypertension, preferably primary aldosteronism. In other embodiments of the present invention, the hypertensive subject does not suffer from primary aldosteronism, preferably wherein the hypertensive subject suffers from essential hypertension.

[0245] The present invention also provides a method for identifying a subject for treatment of hypertension with a CYP 11β2β hydroxylase inhibitor, the method comprising:

[0246] (a) Measured:

[0247] (i) the subject's systolic blood pressure is greater than 130 mmHg; and

[0248] (ii) the subject's diastolic blood pressure is greater than 80 mmHg; and

[0249] (b) subjects who were taking at least one diuretic were selected;

[0250] This allows identification of subjects for treatment of hypertension with CYP 11β2β hydroxylase inhibitors.

[0251] In an embodiment of the invention, the diuretic is a thiazide diuretic.

[0252] In an embodiment of the present invention, step (a) further comprises measuring the subject's body mass index (BMI) to be at least 30, preferably greater than 30, preferably 30-50, more preferably 30-40, or measuring the subject's waist-to-hip ratio to be higher than 0.90 if the subject is a male, or measuring the subject's waist-to-hip ratio to be higher than 0.85 if the subject is a female.

[0253] In an embodiment of the present invention, step (a) further comprises measuring the subject's serum leptin concentration to be at least 30 ng / dL, preferably at least 35 ng / dL, or more preferably at least 40 ng / dL.

[0254] In an embodiment of the present invention, step a) further comprises:

[0255] (a) a plasma aldosterone concentration greater than or equal to 6 ng / dL as measured by an immunoassay performed in the subject; or

[0256] (b) a plasma aldosterone concentration greater than or equal to 1 ng / dL as measured by LC-MS performed in the subject.

[0257] In preferred embodiments of the invention, subjects identified for treatment with a CYP 11β2β hydroxylase inhibitor experience a decrease in mean systolic blood pressure of at least 10 mmHg, 10-55 mmHg, 10-50 mmHg, 10-45 mmHg, 10-40 mmHg, 10-35 mmHg, 10-30 mmHg, 10-25 mmHg, 10-20 mmHg, or 10-15 mmHg while being treated with the CYP 11β2β hydroxylase inhibitor, relative to the mean systolic blood pressure of the hypertensive subjects prior to treatment with the CYP 11β2β hydroxylase inhibitor. In a particularly preferred embodiment, the subject identified for treatment with a CYP 11β2β hydroxylase inhibitor has an ambulatory systolic blood pressure reduced to less than 130 mmHg while being treated with the CYP 11β2β hydroxylase inhibitor, and / or the subject identified for treatment with a CYP 11β2β hydroxylase inhibitor has an average ambulatory diastolic blood pressure reduced to less than 80 mmHg while being treated with the CYP 11β2β hydroxylase inhibitor.

[0258] Composition

[0259] The invention also provides pharmaceutical compositions, packaging, and unit dosage forms for use in any of the methods described herein.

[0260] The present invention therefore provides a package comprising:

[0261] (a) a first pharmaceutical composition comprising a certain amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof:

[0262]

[0263] and a pharmaceutically acceptable carrier;

[0264] (b) a second pharmaceutical composition comprising an amount of a thiazide diuretic and a pharmaceutically acceptable carrier; and

[0265] (c) instructions for using the first pharmaceutical composition and the second pharmaceutical composition together to treat a subject suffering from hypertension.

[0266] The present invention also provides a compound of formula (A) or a pharmaceutically acceptable salt thereof:

[0267]

[0268] The compound of formula (A) or a pharmaceutically acceptable salt thereof is used as an add-on therapy or in combination with a thiazide diuretic to treat a subject suffering from hypertension.

[0269] The present invention also provides a pharmaceutical composition, comprising:

[0270] (a) an amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof:

[0271]

[0272] (b) an amount of a thiazide diuretic, the pharmaceutical composition is for treating a subject suffering from hypertension, wherein the compound of formula (A) and the thiazide diuretic are administered simultaneously, concurrently or concomitantly.

[0273] The present invention also provides a pharmaceutical composition, comprising:

[0274] (a) an amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof:

[0275]

[0276] as well as

[0277] (b) a certain amount of thiazide diuretics,

[0278] wherein said compound of formula (A) and said thiazide diuretic are each present in an amount that is jointly effective to treat hypertension in a hypertensive subject.

[0279] The present invention also provides a pharmaceutical composition comprising a certain amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof:

[0280]

[0281] The pharmaceutical composition is used as add-on therapy or in combination with a thiazide diuretic to treat a subject suffering from hypertension.

[0282] The present invention also provides a therapeutic package for distribution to or use in a subject suffering from hypertension, the therapeutic package comprising:

[0283] (a) one or more unit doses, each such unit dose comprising:

[0284] (i) a certain amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof:

[0285]

[0286] as well as

[0287] (ii) a certain amount of thiazide diuretic,

[0288] wherein said respective amounts of said compound of formula (A) and said thiazide diuretic in said unit dose are effective to treat said subject upon concomitant administration to said subject, and

[0289] (b) a finished pharmaceutical container for the therapeutic package, the container containing the one or more unit doses, the container further containing or comprising a label directing use of the package for treating the subject.

[0290] The present invention also provides a pharmaceutical composition in unit dosage form for treating a subject suffering from hypertension, comprising:

[0291] (a) an amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof:

[0292]

[0293] as well as

[0294] (b) a certain amount of thiazide diuretics,

[0295] wherein the respective amounts of the compound of formula (A) and the thiazide diuretic in the composition are effective to treat the subject upon concomitant administration of one or more of the unit dosage forms of the pharmaceutical compositions to the subject.

[0296] definition

[0297] Unless otherwise defined, all technical terms and / or scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the present invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or test of embodiments of the present invention, exemplary methods and / or materials are described below. In the case of conflict, patent specification (including definition) is used as the criterion. In addition, described materials, methods and examples are only illustrative, and it is expected that they may not be restrictive.

[0298] In the discussion, unless otherwise stated, adjectives such as "substantially" and "about" that modify the conditions or relationship characteristics of one or more features of the embodiments of the present invention should be understood to mean that the conditions or features are defined as being within an acceptable tolerance for the operation of the embodiment for its intended application. In the embodiments, approximately means within the standard deviation using measurements generally acceptable in the art. In the embodiments, approximately means a range extending to + / - 10% of the specified value. In the embodiments, approximately includes the specified value. Unless otherwise indicated, the word "or" in the specification and claims is considered to be inclusive "or" rather than exclusive "or", and indicates at least one and any combination of the items it combines.

[0299] It should be understood that the terms "a" and "an" as used above and elsewhere herein refer to "one or more" of the listed components. It will be clear to one of ordinary skill in the art that, unless specifically stated otherwise, the use of the singular includes the plural. Thus, the terms "a" and "an" and "at least one" are used interchangeably in this application.

[0300] For the purpose of better understanding this teaching and in no way limiting the scope of teaching, unless otherwise indicated, all numerals and other numerical values ​​expressing amounts, percentages, or ratios used in the specification and claims should be understood to be modified by the term "about" in all cases. Therefore, unless otherwise indicated, the numerical parameters set forth in the following specification and the appended claims are approximate values, which may vary depending on the desired properties attempted to be obtained. At a minimum, each numerical parameter should at least be interpreted in light of the number of reported significant figures and by applying ordinary rounding techniques.

[0301] In the specification and claims of this application, each of the verbs "comprise," "include," and "have," and their variations, is used to indicate that one or more objects of the verb are not necessarily a complete list of components, elements, or parts of the subject or subjects of the verb. Other terms as used herein are intended to be defined by their well-known meanings in the art.

[0302] " Hypertension (hypertension) " is also referred to as high blood pressure (high blood pressure), is a blood pressure higher than normal. In 2017, the American College of Cardiology and the American Heart Association issued a guide to the management of hypertension, and defined hypertension as a blood pressure equal to or higher than 130mmHg systolic pressure, 80mmHg diastolic pressure. Phase 1 hypertension is defined as a blood pressure of 130-139mmHg systolic pressure, 80-89mmHg diastolic pressure, and phase 2 hypertension is defined as a blood pressure greater than 140mmHg systolic pressure, 90mmHg diastolic pressure. Unless otherwise indicated, " hypertension " as used herein includes both phase 1 and phase 2 of hypertension. In one embodiment, a hypertensive subject suffers from phase 1 hypertension. In another embodiment, a hypertensive subject suffers from phase 2 hypertension. Hypertension includes multifactorial and non-existent hypertension (essential hypertension) and hypertension (secondary hypertension) with a direct cause. Unless otherwise indicated, " hypertension " as used herein includes both essential hypertension and secondary hypertension. In an embodiment, a hypertensive subject suffers from essential hypertension. In other embodiments, the hypertensive subject suffers from secondary hypertension. Primary aldosteronism (hyperaldosteronism) is the most common form of secondary hypertension and is a condition that occurs when the adrenal glands produce too much aldosterone. In embodiments where the hypertensive subject suffers from secondary hypertension, the subject suffers from primary aldosteronism.

[0303] "CYP11β2", "Cyp11B2", or "CYP11β2β-hydroxylase" is a cytochrome P450 enzyme that is encoded by the CYP11B2 gene in humans and catalyzes a series of reactions from 11-deoxycorticosterone (i.e., a precursor of aldosterone) to aldosterone. Therefore, it is known in the art as "aldosterone synthase". Cyp11B2 is primarily expressed in the glomerular layer of the adrenal cortex, and plasma aldosterone levels are regulated by the enzymatic activity of Cyp11B2 present in the adrenal glands. Aldosterone is expressed in other tissues such as the cardiovascular system, kidneys, fat, and brain.

[0304] "CYP11β1", "Cyp11B1", or "CYP11β1βhydroxylase" is a cytochrome P450 enzyme that is encoded by the CYP11B1 gene in humans and is involved in the biosynthesis of adrenal cortical steroids. It is known in the art as "steroid 11β-hydroxylase".

[0305] 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 known to be inactive. An inhibitor can be a small molecule inhibitor, an antibody inhibitor, a protein inhibitor, a biomolecule inhibitor, a natural ligand, or the like. An "inhibitor" can be in the form of a pharmaceutically acceptable salt of a compound described herein, for example.

[0306] As used herein, "Compound A" refers to a disubstituted 1,2,4-triazine compound represented by formula (A):

[0307]

[0308] "Compound A HBr" refers to the hydrobromic acid (HBr) salt of Compound A. The weight and / or concentration of "Compound A HBr" and "the compound" herein refers to the weight of the free base (ie, Compound A) in the HBr salt, not the weight of the HBr salt.

[0309] Compound A and pharmaceutically acceptable salts thereof can be made by the methods described, for example, in US Pat. No. 10,029,993 and European Publication No. 3549935, the disclosures of which are incorporated herein by reference in their entireties.

[0310] "Treating" or "treatment" as used herein (and as well understood in the art) also broadly includes any method for obtaining a beneficial or desired result (including a clinical result) in a subject's condition. Beneficial or desired clinical results may include, but are not limited to, alleviation or improvement of one or more symptoms or conditions, alleviation of the extent of the disease, stabilization of the disease state (i.e., not worsening), prevention of disease transmission or spread, delay or slowing of disease progression, improvement or alleviation of the disease state, reduction of disease recurrence, and remission, whether partial or complete and detectable or undetectable. In other words, "treatment" as used herein includes any cure, improvement, or prevention of a disease. Treatment can prevent the occurrence of a disease; inhibit the spread of a disease; alleviate the symptoms of a disease, completely or partially eliminate the underlying cause of the disease, shorten the duration of the disease, or a combination of these things.

[0311] As used herein, "treating" includes preventive and prophylactic treatment. Treatment methods include 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 duration of the treatment period depends on a variety of 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 in the treatment, or a combination thereof. It will also be understood that the effective dose of the agent used to treat or prevent the disease can be increased or decreased over the course of a specific treatment or prevention regimen. Dosage variations can be produced and become apparent by standard diagnostic assays known in the art. In embodiments, long-term administration may be required. For example, the composition is administered to the subject in an amount sufficient to treat the patient and for a period of time sufficient to treat the patient. In embodiments, treatment is not a preventive treatment.

[0312] "Diuretic" refers to a high blood pressure medication that increases urine production, thereby increasing the amount of water and salt excreted from the body. A 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, dichloraniline, ethoxazolamide, zonisamide, indisulam, and methazolamide. Exemplary loop diuretics include bumetanide, ethacrynic acid, torsemide, and furosemide. Exemplary potassium-sparing diuretics include eplerenone, triamterene, spironolactone, and amiloride. Exemplary thiazide diuretics include indapamide, hydrochlorothiazide, chlorthalidone, metolazone, methylchlorothiazide, chlorothiazide, methylchlorothiazide, metolazone, bendroflumethiazide, polythiazide, and hydroflumethiazide. Other diuretics include pamabrom and mannitol.

[0313] "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.

[0314] "Angiotensin receptor blockers" or "angiotensin II inhibitors" refer to high blood pressure medications that block the binding of angiotensin II to receptors, thereby dilating blood vessels and lowering blood pressure. Exemplary angiotensin receptor blockers include eprosartan, olmesartan, valsartan, candesartan, losartan, telmisartan, irbesartan, valsartan, and azilsartan medoxomil.

[0315] "Calcium channel blocker" refers to a drug that blocks calcium from entering the heart and arterial cells via calcium channels, thereby reducing blood pressure. The calcium channel blocker can be a dihydropyridine calcium channel blocker, a phenylalkylamine calcium channel blocker, a benzothiazepine calcium channel blocker, a non-selective calcium channel blocker, or any other calcium channel blocker 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, gallopamil, and verapamil. Benzthiazepine calcium channel blockers include diltiazem. Nonselective calcium channel blockers include mibefradil, bepridil, flunarizine, fluspirine, and fendiline. Other calcium channel blockers include gabapentin, pregabalin, and ziconotide.

[0316] The "normal circadian rhythm" of aldosterone levels follows a diurnal pattern, with the lowest point being late at night and the highest point being early in the morning, i.e., before waking up. In one embodiment, the aldosterone levels of hypertensive subjects follow a substantially normal circadian rhythm. In one example of such an embodiment, when administered once daily after waking up in the morning, the CYP 11β2β hydroxylase inhibitor of the present invention inhibits the abnormal increase in aldosterone production during wakefulness. In the evening, the inhibition of aldosterone production begins to weaken, and the normal increase in serum aldosterone returns to normal before dawn, just as under normal circumstances. 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 describe the circadian rhythm of aldosterone in normal subjects and subjects suffering from primary aldosteronism, the contents of which are specifically incorporated herein by reference.

[0317] The present invention provides a method for reducing systolic blood pressure "during sleep" in a hypertensive subject. In this context, "during sleep" refers to the sleep period in the normal sleep / wake cycle of a hypertensive subject. In other words, "during sleep" refers to the approximately seven to nine hours of sleep (usually at night) that occur each day in a hypertensive subject between their approximately 15 to 17 hours of wakefulness, and does not refer to any short periods of sleep (i.e., naps) that may occur outside the sleep stages of the subject's normal sleep / wake cycle. Non-hypertensive individuals typically experience a drop in blood pressure during sleep, with blood pressure values ​​during sleep being approximately 10% to 15% lower than during wakefulness. In contrast, hypertensive subjects may experience a smaller drop in blood pressure during sleep or may not experience any drop in blood pressure at all. Therefore, the method of the present invention helps hypertensive subjects restore the drop in blood pressure that normal non-hypertensive subjects experience during sleep.

[0318] The "pre-dose level" of serum aldosterone in a subject refers to the serum aldosterone level of the subject at the same time of day when the subject is not being treated with a CYP 11β2β hydroxylase inhibitor. As discussed above, aldosterone levels follow a diurnal pattern, with a minimum late at night and a maximum in the early morning, i.e., before awakening. Therefore, in embodiments where a dose of a CYP 11β2β hydroxylase inhibitor reduces a subject's serum aldosterone level by a certain percentage relative to its "pre-dose level," the extent of the reduction in serum aldosterone is measured relative to the serum aldosterone level of the same subject at the same time of day when the CYP 11β2β hydroxylase inhibitor is not being administered. For example, a subject's serum aldosterone level at 11 a.m. after administration of a CYP 11β2β hydroxylase inhibitor will be measured relative to the serum aldosterone level of the same subject at 11 a.m. before any administration of the CYP 11β2β hydroxylase inhibitor.

[0319] Overview

[0320] With respect to the foregoing embodiments, each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments.

[0321] As used herein, all headings are for organizational purposes only and are not intended to limit the present disclosure in any way. The contents of any individual section are equally applicable to all sections. All combinations of the various elements disclosed herein are within the scope of the present invention.

[0322] 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, each of the various embodiments and aspects of the present invention as explained above and as claimed in the claims section below finds experimental support in the following examples.

[0323] It should be understood that certain features of the invention described in the context of separate embodiments for the sake of clarity may also be provided in combination in a single embodiment. Conversely, various features of the invention described in the context of a single embodiment for the sake of brevity may also be provided individually or in any suitable subcombination or as appropriate in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments unless the embodiment is inoperative without those elements.

[0324] The following examples are provided to facilitate a more complete understanding of the present invention. The following examples illustrate exemplary modes of making and practicing the present 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.

[0325] Example

[0326] Example 1

[0327] A randomized, double-blind, placebo-controlled, dose-ranging, multicenter 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 ≥18 years of age.

[0328] Study Design

[0329] The study consists of two parts. To participate in Part 1 of the study, subjects must have a plasma renin activity (PRA) value of ≤1 ng / mL / h based on morning measurements. If the PRA value is >1 ng / mL / h based on morning measurements, subjects may be eligible to enter Part 2 of the study.

[0330] For Part 1, 163 enrolled subjects aged ≥18 years were randomized into 6 equal treatment groups (1:1:1:1:1:1) to receive 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, the two lowest dose levels (12.5 mg QD and 12.5 mg BID) were discontinued in future randomizations due to lack of consistent meaningful blood pressure reductions, but patients who had been randomized to these two groups remained in the study until completion. Therefore, after review of interim clinical data, subjects were randomized into 4 equal treatment groups (1:1:1:1) to receive 25 mg BID, 50 mg QD, 100 mg QD, or placebo.

[0331] For Part 2, 36 enrolled subjects ≥18 years of age were randomized (5:1) to 100 mg QD Compound A HBr or placebo so that the Compound A HBr treatment group would consist of approximately 30 subjects, while the placebo treatment group would consist of approximately 6 subjects.

[0332] According to the specified dosing regimen, the subjects were orally administered the specified study drug (Compound A HBr or placebo) starting from the first day of the study for 8 weeks. All subjects in Part 1 (regardless of the dose group) received BID dosing to maintain the integrity of the blind group; for all QD dose groups, the active drug was administered as a morning dose. At the end of the study 1, 2, 3, 4, 5, 6, 7, and 8 weeks (± 2 days), the subjects returned to the research institution or were reviewed by a clinical researcher or approved home health care professional to conduct efficacy and safety assessments and procedures determined by the scheme, adverse events (AE) assessments, and study drug compliance confirmation. The subjects also completed telephone visits and blood pressure (BP) checks at home approximately 3 days after the last dose of study drug. The subjects participated in up to 14 complete clinical visits, including pre-screening visits, screening / starting placebo introduction visits, second visits during placebo introduction, clinical visits to start ABPM procedures, randomized visits, 8 weekly visits during double-blind treatment, and a study end visit arranged 4 weeks after the last study treatment to conduct final efficacy and safety assessments.

[0333] The study design is shown schematically in Figure 1 middle.

[0334] Automated Office Blood Pressure (AOBP) Program

[0335] Systolic and diastolic blood pressure were measured in the clinic using an automated oscillometric sphygmomanometer device after the subjects rested in a seated position for approximately 5 minutes.

[0336] 24-hour ambulatory blood pressure monitoring (ABPM) program

[0337] Ambulatory blood pressure monitoring is accomplished using an ambulatory blood pressure monitoring device, which consists of a blood pressure cuff worn on the subject's arm connected to a small recording device, which is usually attached to the subject's belt or waistband.

[0338] The ABPM device is worn for 24 hours. Throughout this period, the device records the subject's blood pressure at regular intervals during their normal daily activities and while they sleep. Thus, ABPM provides a complete record of the subject's blood pressure over a 24-hour period.

[0339] 24-hour ABPM was measured in the clinic at baseline and at Study Week 7. If, for any reason, the ABPM procedure was deemed failed at the end of Study Week 7, it could be repeated at Study Week 8, without imputation, regardless of rescue medication use. ABPM was also collected at the end of Study Week 4 in Part 2. If a repeat test was performed, it superseded the original test result for that visit.

[0340] Specific derived variables based on ABPM measurements included 24-hour mean, daytime mean, and nighttime mean of SBP, DBP, and heart rate.

[0341] The change from baseline to week 7 in the 24-hour mean ABPM-based SBP (and DBP) will be analyzed using ANCOVA with treatment group as a factor and the baseline 24-hour mean as a covariate.

[0342] A nighttime decline is defined as:

[0343] 100% × (daytime average SBP - nighttime average SBP) / daytime average SBP

[0344] It is expressed as a percentage and summarized by treatment group and visit using descriptive statistics. In addition, the number and percentage of subjects with nocturnal decline in each decline category are presented by treatment group and visit (Bloomfield & Park, 2015). The categories are:

[0345] (a)<10%

[0346] (b) 10%-20% (inclusive)

[0347] (c)>20%

[0348] Eligibility Criteria

[0349] Inclusion criteria

[0350] The study was conducted using subjects who met the following inclusion criteria:

[0351] (a) Male and non-pregnant or non-lactating female subjects aged ≥18 years.

[0352] (b) Automated office blood pressure (AOBP) with systolic blood pressure (SBP) ≥130 mm Hg

[0353] (c) Background antihypertensive therapy with ≥2 drugs

[0354] (d) Serum cortisol ≥ 18 mcg / dL

[0355] Exclusion criteria

[0356] Subjects were excluded from the study if they met any of the following exclusion criteria:

[0357] (a) Concomitant use of epithelial sodium channel inhibitors or mineralocorticoid receptor antagonists

[0358] (b) Subjects with hypokalemia

[0359] (c) Subjects with hyperkalemia

[0360] (d) Subjects with serum cortisol < 3 mcg / dL

[0361] (e) Subjects with serum sodium <135 mEq / L

[0362] (f) Subjects with estimated glomerular filtration rate <60 mL / min / 1.73 m2

[0363] (g) Subjects with type 1 or uncontrolled (hemoglobin A1c ≥ 9%) type 2 diabetes

[0364] (h) Body mass index > 40 kg / m 2 of subjects

[0365] (i) Subjects with unstable angina

[0366] (j) Subjects with SBP ≥ 175 mm Hg or diastolic blood pressure (DBP) ≥ 100 mm Hg in Part 1 and SBP ≥ 160 mm Hg or DBP ≥ 100 mm Hg in Part 2 before screening, screening / placebo run-in, or randomization

[0367] (k) Subjects with a decrease in SBP ≥20 mm Hg or a decrease in DBP ≥10 mm Hg from sitting to standing at screening

[0368] (l) Subjects suspected of non-compliance with antihypertensive treatment in the opinion of the investigator

[0369] (m) Subjects who, in the opinion of the researcher, have any significant medical illness or condition

[0370] (n) Subjects who, in the opinion of the investigator, have any acute or chronic medical or psychiatric condition

[0371] (o) Subjects undergoing treatment with any of the following drugs:

[0372] (i) Topical corticosteroids

[0373] (ii) Sympathomimetic decongestants

[0374] (iii) Theophylline

[0375] (iv) Phosphodiesterase type 5 inhibitors

[0376] (v)NSAID

[0377] (vi) Intramuscular steroid injection

[0378] (vii) Estrogen

[0379] (viii) Cytochrome

[0380] (ix) Strong CYP3A and CYP3A4 inducers

[0381] (p) Subjects with known hypersensitivity to Compound A HBr or any excipients

[0382] (q) Subjects who work night shifts

[0383] Grouping and intervention

[0384] The study contained the following groups and corresponding interventions:

[0385] Table 1

[0386]

[0387]

[0388] Study endpoints

[0389] Primary End Point

[0390] The primary endpoint was the change in systolic blood pressure (SBP) from baseline to the end of study week 8, measured in the office (the average of the last two of five unattended measurements performed using an automated oscillometric sphygmomanometer device after approximately 5 minutes of rest in a seated position).

[0391] Secondary End Points

[0392] Secondary endpoints of this study are:

[0393] (a) Changes in 24-hour ambulatory blood pressure monitoring (ABPM) parameters (systolic and diastolic) from baseline to the end of study week 7.

[0394] (b) Changes in office-measured SBP from baseline to the end of study weeks 1, 2, 3, 4, 5, 6, and 7.

[0395] (c) Change in office-measured diastolic blood pressure (DBP) from baseline to the end of study weeks 1, 2, 3, 4, 5, 6, 7, and 8.

[0396] (d) Proportion of subjects achieving office BP ≤ 130 / 80 mm Hg at the end of study week 8.

[0397] Pharmacodynamic endpoints

[0398] The pharmacodynamic endpoints of this study are:

[0399] (a) Changes in plasma 11-deoxycortisol and PRA from baseline to the end of study week 4 and to the end of follow-up (ie, end of study week 12 for Part 1 and end of study week 10 for Part 2).

[0400] (b) Changes in serum aldosterone, cortisol, and 11-deoxycorticosterone concentrations from baseline to the end of study week 4 and to the end of follow-up.

[0401] Pharmacokinetic endpoints

[0402] The pharmacokinetic endpoints of this study were PK parameters including 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 at randomization (baseline) and study weeks 1, 4, and 8.

[0403] Safety endpoints

[0404] The safety endpoints of this study are:

[0405] (a) The incidence and severity of all spontaneously reported adverse events (AEs)

[0406] (b) Changes in vital signs (standing SBP, standing DBP, body temperature, heart rate, and respiratory rate)

[0407] (c) Changes in electrocardiographic parameters (including cardiac intervals: PR, QRS, QT, and QT interval corrected using the Fridericia formula)

[0408] (d) Changes in clinical laboratory evaluation (hematology, chemistry, coagulation, and urinalysis)

[0409] (e) Change in office-measured SBP relative to study week 8 (end of treatment period to end of follow-up (i.e., end of study week 12 for Part 1 and end of study week 10 for Part 2)).

[0410] Analytical methods

[0411] The following analysis sets were defined in this study:

[0412] Full Analysis Set (FAS)

[0413] The FAS includes all randomized subjects who have received at least one dose of randomized study treatment (MLS-101 or placebo). The FAS will be the primary efficacy analysis set. In analyses performed on the FAS, subjects will be analyzed according to their randomized study treatment group unless otherwise specified.

[0414] Per protocol set (PPS or PP)

[0415] The per-protocol set includes all subjects in the FAS who have completed the Week 8 study visit and have no major protocol violations that could affect the validity of the primary efficacy assessment data. In PPS-based analyses, subjects will be analyzed according to their randomized study treatment group. All criteria for excluding subjects from the PPS will be based on the blinded data review before study unblinding.

[0416] Subjects were excluded from the per-protocol analysis set if any of the following criteria were met:

[0417] (a) Not meeting inclusion / exclusion criteria

[0418] (b) Use of Illegal Drugs. Subjects who use rescue medications will not be excluded from the PPS unless they already meet other criteria for exclusion from the PPS.

[0419] (c) Non-compliance with study medication

[0420] (d) Out-of-window efficacy assessment at the study week 8 visit

[0421] Alternative criteria for exclusion from the per-protocol analysis set were also applied to accommodate unforeseen events occurring during study conduct.

[0422] Analyses of the per-protocol analysis set will have supportive objectives and be limited to the primary endpoint (ie, “product estimate”).

[0423] Security Analysis Suite (SAF)

[0424] 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 will be analyzed based on the actual treatment they received. PK / PD Analysis Set (PKPD)

[0425] The PK / PD analysis set includes all subjects in the SAF with sufficient data for analysis of pharmacokinetic and pharmacodynamic measurements. In a PKPD-based analysis, subjects will be analyzed based on the actual treatment they received.

[0426] Baseline definition

[0427] Baseline was defined as the last available observation for the parameter of interest before the first administration of the investigational medicinal product (IMP) during the double-blind treatment period.

[0428] For AOBP measurements and any other clinical or laboratory variables for which repeated assessments were available at the Screening and Baseline visits, baseline was defined as the mean of the last two nonmissing values ​​before the first administration of IMP during the double-blind treatment period.

[0429] Change from baseline was calculated as: post-baseline result - baseline result.

[0430] The percent change from baseline was calculated as: (change from baseline / baseline result) x 100%.

[0431] Summary of results

[0432] There was a dose-response relationship across the QD dose range, with the 50 mg and 100 mg QD doses associated with mean reductions in systolic blood pressure measured by AOBP of -11 mmHg to -13 mmHg (per-protocol, placebo-adjusted, Part 1 100 mg cohort analysis = -10.3 mmHg, full analysis set combining Parts 1 and 2 (interim) = -9.9 mmHg, N = 58 active).

[0433] Once-daily dosing was as effective as twice-daily dosing, with results in the two BID cohorts not superior to those in the 50mg and 100mg QD cohorts.

[0434] 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 systolic BP change >-25 mmHg, while 41% demonstrated a systolic BP change >-15 mmHg.

[0435] Using automated office blood pressure (AOBP), there were few differences in treatment response between individuals in part 1 and with available results in part 2, suggesting that PRA does not appear to be a strong determinant of response (serum and urine aldosterone were also less informative).

[0436] 24-hour ambulatory blood pressure measurements demonstrated a nocturnal reduction in systolic blood pressure of -11.5 + / - 2.9 mmHg in the 100 mg QD cohort, with a corresponding increase in nocturnal "BP dips," consistent with a persistent nocturnal benefit after morning dosing.

[0437] The combined (Part 1 and Part 2) 100 mg QD safety set (n=60) showed good safety and tolerability, with no effect on serum cortisol, few episodes of mild or moderate hyperkalemia, and no episodes of severe hyperkalemia.

[0438] Automated clinic blood pressure results

[0439] All subjects with week 8 measurements were used for full analysis and safety set (FAS) analysis. All subjects who completed treatment during the eighth week visit were also used for per-protocol (PP) analysis. Waterfall plots showing changes in systolic AOBP at week 8 from the FAS analysis of the placebo, 50 mg QD, and 100 mg QD groups and the PP analysis of the 100 mg group are provided in Figure 2 Waterfall plots showing changes in systolic AOBP at week 8 from FAS analysis of the 12.5 mg QD, 12.5 mg BID, and 25 mg BID groups are provided in Figure 3 Also shown for each group are the modeled mean and the per-protocol observed mean.

[0440] The mean change in systolic blood pressure from baseline is shown in Figure 4 This figure provides the final analysis, which includes the full analysis set (FAS, all evaluable subjects who received at least one dose of Compound A HBr) and the per-protocol (PP, only those subjects who received ≥ 75% of study drug at the Week 8 visit). Part 2 data shows the interim averages from Week 5 to the last visit of Week 6.

[0441] Based on analysis of changes in systolic AOBP from baseline in the QD regimen, a Compound A HBr dose response was observed. Figure 5 Shown are the changes from baseline in mean observed automated office blood pressure for the QD dosing regimen at Week 8. The far right side of this figure shows the BID per-protocol cohort.

[0442] An analysis was performed in which the change from baseline in systolic BP at week 8 was combined for the 50 mg QD, 100 mg QD, 12.5 mg BID, and 25 mg BID cohorts and then stratified into quartiles based on the degree of systolic BP response. Figure 6 Figure 2 shows the change from baseline in systolic blood pressure at week 8 for the combined cohort, lowest responder quartile, highest responder quartile, and placebo. Twenty-five percent of subjects achieved a systolic blood pressure reduction of >-23 mmHg, with a mean reduction of -33.4 ± 1.5 mmHg. Forty-one percent of subjects achieved a systolic blood pressure reduction of ≥15 mmHg.

[0443] Figure 7 is a waterfall plot showing the change in systolic blood pressure for the placebo and 100 mg QD groups combined for Parts 1 and 2. Part 2 data are from an interim snapshot and the average Week 5-6 last visit for all randomized subjects, with a minimum of Week 2.

[0444] Analysis of factors affecting blood pressure changes

[0445] An analysis was conducted to identify factors that affect the extent 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 in the dosing cohort. BMIs above 30 were considered to be within the obese range. Similarly, male waist-to-hip ratios greater than 0.90 and female waist-to-hip ratios greater than 0.85 were considered to be within the obese range. Therefore, it was inferred that Compound A HBr was particularly effective in reducing blood pressure in men with waist-to-hip ratios greater than 0.90 and women with waist-to-hip ratios greater than 0.85.

[0446] Furthermore, as summarized in the table below, Compound A HBr was found to be particularly effective in lowering blood pressure in subjects who were receiving a thiazide diuretic as part of their background hypertension medication. This effect was observed in the dosing cohort.

[0447] Table 2

[0448]

[0449] All values ​​were determined using least squares analysis of modeled means using all available information. **Due to imbalanced placebo response, effects differ between 2 and 3+ settings.

[0450] Ambulatory blood pressure (ABPM) results

[0451] A diagram showing an example of ambulatory 24-hour blood pressure monitoring is provided in Figure 9The graph shows 24-hour ambulatory blood pressure (systolic) for subjects receiving Compound AHBr 100 mg QD relative to baseline, showing a reduction in mean 24-hour blood pressure and restoration of the normal nocturnal decline pattern.

[0452] A graph showing the change from baseline in systolic blood pressure at week 8 measured using the full analysis set of ABPM is provided in Figure 10 Waterfall plots showing the change from baseline in 24-hour average and nighttime average ABPM at 8 weeks are provided in Figure 11 The 100 mg QD dose level provided excellent 24-hour BP reduction. Nocturnal BP reduction at the 100 mg QD dose level appeared superior to that at the 25 mg BID dose level.

[0453] As summarized in the table below, the most consistent benefits across all measures were observed in the 100 mg QD cohort.

[0454] Table 3

[0455]

[0456] The nighttime decrease was defined as 100% × (24-hour ambulatory daytime SBP - 24-hour ambulatory monitoring nighttime SBP) / 24-hour ambulatory monitoring daytime.

[0457] Security

[0458] No serious adverse events (SAEs) related to study drug were observed in the trial. Adverse events requiring drug discontinuation or dose reduction showing the incidence in Part 1 relative to the incidence in Part 2 are provided in Table 4 below.

[0459] Table 4

[0460]

[0461] serum potassium

[0462] The group mean serum potassium (K+) changes are shown in the table below.

[0463] Table 5

[0464] Part 1 Part 2 merge Average value (mMol / L) +0.50 +0.23 +0.35 SD 0.96 0.51 0.75 N 26* 31 57 SEM 0.19 0.09 0.10

[0465] The number of subjects in the 100 mg QD cohort whose serum potassium was verified or increased multiple times above the normal range during treatment is shown in the table below.

[0466] Table 6

[0467] Serum K+ 5.2-5.5mMol / L 5.6-6.0mMol / L 6.1-6.5mMol / L >6.5mMol / L Part 1 5(18.5％) 3(10.7％) 0 1* Part 2 1(4％) 0 0 0 merge 6(10.3％) 3(5.2％) 0 0

[0468] *Measures are isolated events (protocol deviations) not verified by repeated measurements with study drug discontinuation.

[0469] Changes in estimated glomerular filtration rate (eGFR)

[0470] A dose-dependent and reversible reduction in eGFR was observed. This phenomenon has been reported in the setting of ACE / ARBs and more recently SGLT2 inhibition due to a reduction in intraglomerular pressure and is felt to attenuate the development of hypertensive nephropathy. Graphs showing changes in estimated glomerular filtration rate (eGFR) in the different dosing cohorts are provided in Figure 8 middle.

[0471] Example 2

[0472] A complete analysis was performed for the study described in Example 1. This complete analysis confirmed the findings described above in Example 1 as follows.

[0473] Summary of results

[0474] Lorenzostat is effective in lowering BP in individuals with inadequately treated or resistant hypertension.

[0475] There was a dose-response and exposure-response relationship, with placebo-adjusted mean reductions in SBP of 9.58 mmHg and 7.81 mmHg seen at the 50 mg QD and 100 mg QD doses, respectively.

[0476] 24-hour ABPM, central BP, and nocturnal SBP values ​​confirmed the SBP reduction seen in the setting of AOBP, which was most pronounced in the 100 mg QD dose cohort.

[0477] Safety Data Set Lorenzostat was safe and well tolerated, with no effect on serum cortisol and the expected modest increase in serum potassium, with relatively few episodes of clinically significant hyperkalemia.

[0478] The results demonstrated clinically meaningful 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. The reductions in AOBP SBP observed in the 100 mg QD cohort in Part 2 were similar to those observed in Part 1 for the same dose (-11.5 mmHg, p=0.8426).

[0479] The reduction in AOBP SBP was verified and confirmed by a comparable reduction in 24-hour ABPM SBP. ABPM data also confirmed the benefits of lorenzostat in reducing central SBP and nighttime SBP.

[0480] Subgroup analysis highlighted the importance of BMI > 30 kg / m 2 Statistically and clinically significant reductions in AOBP SBP were achieved in subjects with ≥50% AOBP, subjects in the upper tertile of baseline AOBP SBP, and subjects taking thiazide diuretics.

[0481] The pharmacodynamic response confirmed a dose-dependent decrease in serum aldosterone levels and a commensurate increase in plasma renin activity. 11-deoxycorticosterone levels were unaffected. Morning serum cortisol levels increased moderately. No adrenal insufficiency occurred during the trial. Due to supply chain disruptions, the ability to perform ACTH stimulation testing during the first part of the trial was limited. However, most subjects who were administered 100 mg QD (maximum test dose) in Part 2 performed ACTH stimulation testing at baseline and after 8 weeks of treatment. There were no individuals with abnormal ACTH stimulation results.

[0482] Reductions in eGFR were observed in all treatment groups, with significantly greater reductions in the lorenlustat-treated group compared with placebo.

[0483] Primary efficacy endpoint: Change from baseline in seated automated office-measured systolic blood pressure at week 8

[0484] The results of the mixed model repeated measures (MMRM) analysis of the primary efficacy endpoint of Part 1 (change from baseline to Week 8 in sitting AOBP and SBP) are presented in Figure 12 and Table 7, and the 100 mg QD dose cohorts for Parts 1 and 2 are presented in Figure 13 and Table 8.

[0485] At Week 8, statistically significant reductions in modeled AOBP SBP from baseline were detected in the 50 mg QD cohort (least squares mean [LSM] difference: -9.58 mmHg; p = 0.0114) and the 100 mg QD cohort (LSM difference: -7.81 mmHg; p = 0.0422) in Part 1. Figure 12 (See Table 7 for details). Although 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), none of these achieved statistical significance. Results from sensitivity analyses using the FAS, analyses using the PPS, and analyses using additional estimates were similar.

[0486] The change in SBP from baseline to Week 8 was similar in the 100 mg QD cohorts in Part 1 and Part 2 (LSM difference: 0.74 mmHg; p=0.8426) ( Figure 13 and Table 8). In addition, no statistically significant differences in the change from baseline in AOBP or SBP were seen between subjects with a baseline PRA of <1 ng / mL / h who received lorenstat 100 mg QD in Parts 1 and 2 combined, compared to subjects with a baseline PRA of ≥1 ng / mL / h (Table 9).

[0487] The box plots of the mean changes in AOBP and SBP from baseline to week 8 are presented in Figure 14 and Part 2 is presented in Figure 15 middle.

[0488] Table 7: Modeled (MMRM) Least Squares Mean (SEM) Change from Baseline in Seated Automated Office Systolic Blood Pressure (mmHg) at Week 8, Part 1 (Full Analysis Set)

[0489]

[0490] Analyses used the MMRM approach with fixed effects for categorical terms for treatment, week, and treatment-by-week interaction, and baseline SBP as a fixed continuous covariate. No adjustment for multiplicity was performed.

[0491] Abbreviations: BID, twice daily; CI, confidence interval; Δ, difference; LSM, least-squares mean; mg, milligram; mmHg, millimeter of mercury; MMRM, mixed-model repeated measures; QD, once daily; SBP, systolic blood pressure; SEM, standard error of the mean.

[0492] Table 8: Modeled (MMRM) Least Squares Mean (SEM) Change from Baseline in Seated Automated Office Systolic Blood Pressure (mmHg) at Week 8, Parts 1 and 2 (Full Analysis Set)

[0493]

[0494] Analyses used the MMRM approach with fixed effects for categorical terms for treatment, week, and treatment-by-week interaction, and baseline SBP as a fixed continuous covariate. No adjustment for multiplicity was performed.

[0495] Abbreviations: CI, confidence interval; Δ, difference; LSM, least-squares mean; mg, milligram; mmHg, millimeter of mercury; MMRM, mixed-model repeated measures; QD, once daily; SBP, systolic blood pressure; SEM, standard error of the mean.

[0496] Table 9: Modeled (ANCOVA) Least Squares Mean (SEM) Change from Baseline in Seated Automated Office Systolic Blood Pressure (mmHg) at Weeks 4 and 8 in Subjects Randomized to 100 mg QD Based on PRA Level at Baseline in Parts 1 and 2 (Full Analysis Set)

[0497]

[0498] In the subgroup of subjects randomized to receive 100 mg QD, analysis used an ANCOVA model with binary baseline PRA (<1 ng / mL / h vs. ≥1 ng / mL / h) as a factor and baseline SBP as a covariate. Two ANCOVA models (week 4 and week 8) were run separately.

[0499] Abbreviations: ANCOVA, analysis of covariance; CI, confidence interval; Δ, difference; FAS, full analysis set; h, hour; 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.

[0500] Secondary efficacy endpoints

[0501] Change from baseline in seated automated clinic-measured diastolic blood pressure at week 8

[0502] At week 4, statistically significant reductions in modeled AOBP DBP relative to baseline were detected in all cohorts except 12.5 mg QD in Part 1. At week 8, statistically significant reductions in modeled AOBP DBP relative to baseline were detected only in the 50 mg QD cohort (LSM difference: -5.46 mmHg; p=0.0224), but all lorenzastat dose groups demonstrated greater numerical reductions than placebo (Table 10). The change in DBP from baseline to week 8 between the 100 mg QD cohorts in Part 1 and Part 2 was not statistically different (LSM difference: 0.98 mmHg; p=0.6406) (Table 11).

[0503] Table 10: Seated Automated Office Diastolic Blood Pressure (mmHg) at Weeks 4 and 8 Relative to Baseline by Dose Modeled (MMRM) least squares mean (SEM) change, part 1 (full analysis set)

[0504]

[0505] Analyses used the MMRM approach with fixed effects for categorical terms for treatment, week, and treatment-by-week interaction, and baseline DBP as a fixed continuous covariate. P values ​​≤ 0.05 are indicated in bold. Abbreviations: BID, twice daily; CI, confidence interval; Δ, difference; DBP, diastolic blood pressure; LSM, least squares mean; mmHg, millimeter mercury; QD, once daily; SEM, standard error mean.

[0506] Table 11: Sit-down Automated Clinic Results at Weeks 4 and 8 by Dose for Subjects Randomized to 100 mg QD The modeled (MMRM) least square mean (SEM) change in diastolic blood pressure (mmHg) from baseline was measured in Part 1 and Part 2. Part (full analysis set)

[0507]

[0508] Analyses used the MMRM approach with fixed effects for categorical terms for 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, millimeter of mercury; MMRM, mixed-model repeated measures; QD, once daily; SEM, standard error mean.

[0509] Changes from baseline in seated automated office blood pressure parameters at week 8

[0510] Mean SBP decreased within the first 4 to 5 weeks of treatment, including the placebo group (Tables 12 and 13). Mean DBP reductions (Tables 14 and 15) were less than the observed SBP reductions, and the placebo group had minimal changes relative to baseline. Generally speaking, BP reductions reached a plateau at approximately 4 weeks of treatment.

[0511] Table 12: Mean (SD) Change from Baseline in Seated Automated Office Systolic Blood Pressure (mmHg) by Study Visit Summary of the 2016 Global Economic Outlook, Part 1 (Full Analysis)

[0512]

[0513] Baseline was defined as the mean of the last two nonmissing values ​​before the first dose of study treatment (including unscheduled visits). Abbreviations: BID, twice daily; BL, baseline; CFB, change from baseline; mmHg, millimeters of mercury; QD, once daily; SD, standard deviation.

[0514] Table 13: Mean (SD) Change from Baseline in Seated Automated Office Systolic Blood Pressure (mmHg) by Study Visit Summary of the 2016 Global Economic Outlook, Part 2 (Full Analysis)

[0515]

[0516] Baseline was defined as the mean of the last two nonmissing values ​​before the first dose of study treatment (including unscheduled visits). Abbreviations: CFB, change from baseline; mmHg, millimeters of mercury; QD, once daily; SD, standard deviation.

[0517] Table 14: Mean (SD) Change from Baseline in Seated Automated Office Diastolic Blood Pressure (mmHg) by Study Visit Summary of the 2016 Global Economic Outlook, Part 1 (Full Analysis)

[0518]

[0519] Baseline was defined as the mean of the last two nonmissing values ​​before the first dose of study treatment (including unscheduled visits). Abbreviations: BID, twice daily; CFB, change from baseline; mmHg, millimeters of mercury; QD, once daily; SD, standard deviation.

[0520] Table 15: Mean (SD) Change from Baseline in Seated Automated Office Diastolic Blood Pressure (mmHg) by Study Visit Summary of the 2016 Global Economic Outlook, Part 2 (Full Analysis)

[0521]

[0522] Baseline was defined as the mean of the last two nonmissing values ​​before the first dose of study treatment (including unscheduled visits). Abbreviations: CFB, change from baseline; mmHg, millimeters of mercury; QD, once daily; SD, standard deviation. Proportion of subjects with a seated automated office diastolic blood pressure ≤130 / 80 mmHg

[0523] Overall, six subjects in Part 1 and three subjects in Part 2 had AOBP at or below the AHA hypertension cutoff (130 / 80 mmHg) at baseline (Tables 16 and 17). By Week 8, the proportion of subjects with 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 ). 54.8% of the 100 mg QD cohort in Part 2 achieved this treatment goal compared to 30% of the 100 mg QD cohort in Part 1 ( Figure 17 ).

[0524] Table 16: Proportion of Subjects with Seated Automated Clinic SBP / DBP ≤ 130 / 80 mmHg at Week 8, Part 1 Points (full analysis set)

[0525]

[0526] Baseline was defined as the mean of the last two nonmissing values ​​before the first dose of study treatment (including unscheduled visits). Abbreviations: BID, twice daily; DBP, diastolic blood pressure; mmHg, millimeter of mercury; QD, once daily; SBP, systolic blood pressure.

[0527] Table 17: Proportion of Subjects with Seated Automated Clinic SBP / DBP ≤ 130 / 80 mmHg at Week 8, Part 2 Points (full analysis set)

[0528]

[0529] Baseline was defined as the mean of the last two nonmissing values ​​before the first dose of study treatment (including unscheduled visits). Abbreviations: DBP, diastolic blood pressure; mmHg, millimeters of mercury; QD, once daily; SBP, systolic blood pressure.

[0530] Time of first occurrence of SBP / DBP ≤ 130 / 80 mmHg during automated sitting-down clinic measurement

[0531] With the exception of subjects assigned to placebo, the majority of subjects who achieved an SBP / DBP of 130 / 80 mmHg in both Parts 1 and 2 did so between Weeks 2 and 4 of treatment ( Figure 18 and Figure 19 ). Changes in 24-hour ambulatory blood pressure monitoring parameters relative to baseline at the end of treatment

[0532] Modeled 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) showed consistent AHT effects (Tables 18 and 19). The results were consistent with the reported results of AOBP parameters (SBP and DBP).

[0533] The changes from baseline to EoT in mean 24-hour, daytime, and nighttime ABPM SBP, DBP, and MAP are summarized in Table 20. The changes from baseline in mean 24-hour ABPM SBP and DBP at EoT were numerically smaller than the reported changes in AOBP, which is an expected finding given the different measurement modalities.

[0534] Table 18: Modeled (ANCOVA) Least Squares Means of 24-Hour ABPM Parameters at End of Treatment Relative to Baseline Value changes, part 1 (full analysis set; post hoc analysis)

[0535]

[0536] Bold p-values ​​indicate p<0.05.

[0537] Table 19: 24-hour ABPM parameters at end of treatment relative to baseline for subjects randomized to 100 mg QD Modeled (ANCOVA) least squares mean change, Parts 1 and 2 (full analysis set; post hoc analysis)

[0538]

[0539] Bold p-values ​​indicate p<0.05.

[0540] Table 20: Mean (SD) Changes in 24-Hour Ambulatory Blood Pressure Monitoring Parameters from Baseline to End of Treatment, Part 1 Points (full analysis set)

[0541]

[0542] Table 21: Mean (SD) Changes in 24-Hour Ambulatory Blood Pressure Monitoring Parameters from Baseline to End of Treatment, Part 2 Points (full analysis set)

[0543]

[0544] The proportion of subjects with a ≥10% decrease in nocturnal ABPM SBP increased from baseline to the last post-baseline assessment (Tables 22 and 23) in many treatment cohorts.

[0545] Table 22: Proportion of Subjects with Nocturnal Decline in 24-Hour Ambulatory Systolic Blood Pressure, Part 1 (Full Analysis Set)

[0546]

[0547] The nighttime decrease was defined as 100% × (24-hour ABPM average daytime SBP - 24-hour ABPM average nighttime SBP) / 24-hour ABPM average daytime SBP.

[0548] Table 23: Proportion of Subjects with a Nocturnal Decline in 24-Hour Ambulatory Systolic Blood Pressure, Part 2 (Full Analysis Set)

[0549]

[0550] The nighttime decrease was defined as 100% × (24-hour ABPM average daytime SBP - 24-hour ABPM average nighttime SBP) / 24-hour ABPM average daytime SBP.

[0551] Analysis of factors affecting blood pressure changes

[0552] An analysis was conducted to identify factors that influence the extent of blood pressure reduction in hypertensive subjects. As shown in the table below, lorenzostat 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 in the dosing cohort.

[0553] Furthermore, as shown in the table below, lorenzostat was found to be particularly effective in lowering blood pressure in individuals who were receiving a thiazide diuretic as part of their background hypertension medication. This effect was observed in the dosing cohort.

[0554] There were no clear consistent differences in the mean change from baseline in AOBP or SBP at Week 8 when summarized by sex (male, female), age (<65 years, 65-79 years, ≥80 years), race (Black or African American, Other), number of AHT medications at baseline (2, ≥3), or concomitant use of angiotensin-converting enzyme inhibitors (ACEi) or ARBs in Part 1 (Table 24) or Part 2 (Table 25).

[0555] Using pooled data from the low-renin subjects in the lorenstat 25 mg BID, 50 mg QD, and 100 mg QD cohorts (Part 1), we analyzed the relationship between median baseline body mass index (BMI) and serum leptin (ng / dl), and the relationship between baseline BMI and mean change from baseline in systolic blood pressure (mmHg) as measured by AOBP at Week 8 ( Figure 26 and Figure 27 ). Each of these cohorts demonstrated a significant reduction in median serum aldosterone at week 4 compared to baseline. Treated as a continuous variable, there was a strong relationship between increased BMI and increased serum leptin. Treated as a continuous variable, there was a strong relationship between BMI and decreased BP. Both of these associations support the hypothesis that elevated serum leptin is associated with greater reductions in BP. These data are consistent with the hypothesis that increased leptin production in the setting of visceral obesity leads to increased aldosterone-mediated hypertension. They also support the hypothesis that inhibition of aldosterone synthesis eliminates the stimulatory effect of leptin on aldosterone production.

[0556] Table 24: Mean (SD) Change from Baseline in Automated Office-Measured Systolic Blood Pressure at Week 8, by Subgroup, Part 1 (Full Analysis Set)

[0557]

[0558] 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, years.

[0559] Table 25: Mean (SD) Change from Baseline in Automated Office-Measured Systolic Blood Pressure at Week 8, by Subgroup, Part 2 (Full Analysis Set)

[0560]

[0561] 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, years.

[0562] The AHT effect of lorenzastat increased significantly with increasing BMI (Table 26), and this was most evident in the 100 mg QD dose cohorts in Part 1 (Table 26) and Part 2 (Table 27). Exploratory analyses using MMRM resulted in placebo-adjusted AOBP SBP reductions of -16.7 mmHg (p=0.0023) in the Part 1 50 mg QD cohort and -12.3 mmHg (p=0.0297) in the Part 1 100 mg QD cohort (data not shown).

[0563] Table 26: Mean (SD) Change from Baseline in Automated Office-Measured Systolic Blood Pressure at Week 8, by Baseline BMI, Part 1 (Full Analysis Set)

[0564]

[0565] Abbreviations: BID, twice daily; BL, baseline; CFB, change from baseline; NE, not evaluable; QD, once daily; SD, standard deviation; Wk8, week 8.

[0566] Table 27: Mean (SD) Change from Baseline in Automated Office-Measured Systolic Blood Pressure at Week 8, by Baseline BMI, Part 2 (Full Analysis Set)

[0567]

[0568] Abbreviations: BL, baseline; CFB, change from baseline; NE, not evaluable; QD, once daily; SD, standard deviation; Wk8, week 8.

[0569] In both Part 1 and Part 2, the AHT effect of lorenlustat increased significantly with increasing baseline AOBP SBP (Table 28 and Table 29, respectively). It should be noted that a greater AHT effect with increasing baseline AOBP SBP was also observed in the Part 1 placebo cohort, and only the 50 mg QD cohort in Part 1 demonstrated a statistically significant placebo-adjusted decrease in AOBP SBP relative to baseline at Week 8 (-19.9 mmHg, p=0.0113).

[0570] Table 28: Mean (SD) Change from Baseline in Automated Office-Measured Systolic Blood Pressure at Week 8, According to Tertiles of Systolic Blood Pressure at Baseline, Part 1 (Full Analysis Set)

[0571]

[0572] Abbreviations: BID, twice daily; BL, baseline; CFB, change from baseline; QD, once daily; SD, standard deviation; Wk8, week 8.

[0573] Table 29: Mean (SD) Change from Baseline in Automated Office-Measured Systolic Blood Pressure at Week 8, by Tertile of Systolic Blood Pressure at Baseline, Part 2 (Full Analysis Set)

[0574]

[0575] Abbreviations: BL, baseline; CFB, change from baseline; NE, not evaluable; QD, once daily; SD, standard deviation; Wk8, week 8.

[0576] In Part 1, subjects who were concomitantly taking thiazide diuretics also appeared to have greater reductions from baseline in AOBP SBP (Table 30), but this was not evident in Part 2 (Table 31). In Part 1, the 12.5 mg BID and 50 mg QD cohorts achieved statistically significant placebo-adjusted reductions in AOBP SBP at Week 8, with mean changes of -10.7 mmHg (p=0.047) and -12.9 mmHg (p=0.0108), respectively.

[0577] Table 30: Mean (SD) Change from Baseline in Automated Office-Measured Systolic Blood Pressure at Week 8 by Thiazide Diuretic Use [Yes / No] at Baseline, Part 1 (Full Analysis Set)

[0578]

[0579] Abbreviations: BID, twice daily; BL, baseline; CFB, change from baseline; QD, once daily; Wk8, week 8.

[0580] Table 31: Mean (SD) Change from Baseline in Automated Office-Measured Systolic Blood Pressure at Week 8 by Thiazide Diuretic Use [Yes / No] at Baseline, Part 2 (Full Analysis Set)

[0581]

[0582] Abbreviations: BL, baseline; CFB, change from baseline; NE, not evaluable; QD, once daily; Wk8, week 8.

[0583] When divided by sex (male, female), age (<65 years, 65-79 years, ≥80 years), race (Black or African American, other), BMI (<25, 25-30, >30 kg / m 2There were no significant consistent differences between the mean changes from baseline in AOBP DBP at Week 8 when summarized by ≥ 3, seated AOBP DBP at baseline, number of AHT medications at baseline (2, ≥3), or concomitant use of ACEi or ARB in Part 1 (Table 32) or Part 2 (Table 33).

[0584] Table 32: Mean (SD) Change from Baseline in Automated Office-Measured Diastolic Blood Pressure at Week 8 by Subgroup, Part 1 (Full Analysis Set)

[0585]

[0586]

[0587] 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, year.

[0588] Table 33: Mean (SD) Change from Baseline in Automated Office-Measured Diastolic Blood Pressure at Week 8 by Subgroup, Part 2 (Full Analysis Set)

[0589]

[0590]

[0591] 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, year.

[0592] In Part 1, a modest improvement in AHT effect was evident when lorenlustat and thiazide diuretics were used concomitantly (Table 34), but this was not present in Part 2 (Table 35). In Part 1, patients in the 50 mg QD cohort who were taking thiazide diuretics at baseline achieved a statistically significant placebo-adjusted AOBP (DBP) reduction at Week 8 (-7.7 mmHg, p=0.0291), but this was not achieved in any dose cohort among patients who were not taking thiazide diuretics at baseline.

[0593] Table 34: Mean (SD) Change from Baseline in Automated Office-Measured Diastolic Blood Pressure at Week 8 by Thiazide Diuretic Use at Baseline, Part 1 (Full Analysis Set)

[0594]

[0595] Table 35: Mean (SD) Change from Baseline in Automated Office-Measured Diastolic Blood Pressure at Week 8 by Thiazide Diuretic Use at Baseline, Part 2 (Full Analysis Set)

[0596]

[0597] Pharmacokinetic response

[0598] Represented as C max Systemic exposure to lorenlustat, measured by AUC or AUC, increased with dose, but inter-subject variability was moderately high. For the 100 mg QD dose in Cohorts 1 and 2, steady-state (Day 28) C max were 1620 ng / mL and 1360 ng / mL (average was approximately 1490 ng / mL) and AUC 0-24 The values ​​were 14900 ng*h / mL and 7480 ng*h / mL respectively (average was approximately 11190 ng*h / mL). Other key parameters are summarized in Table 36. Trough plasma concentration values ​​are shown in Table 37.

[0599] Table 36: Summary of key steady-state pharmacokinetic parameters following administration of lorenlustat

[0600]

[0601]

[0602] Abbreviations: AUC, area under the curve; BID, twice daily; CV, coefficient of variation; geo, geometry; hr, hour; mg, milligram; mL, milliliter; N, number of subjects; n, number of observations; ng, nanogram; QD, once daily.

[0603] Table 37: Summary of Trough Plasma Concentrations (ng / mL) Following Administration of Lorenzostat

[0604]

[0605] Concentrations are reported in ng / mL. Abbreviations: BID, twice daily; CV, coefficient of variation; geo, geometry; mg, milligram; mL, milliliter; N, number of subjects; n, number of observations; ng, nanogram; QD, once daily.

[0606] Pharmacodynamic response

[0607] In Part 1, at baseline, the mean serum Cortisol levels in the active group ranged from 9.443 μg / dL to 11.272 μg / dL, compared to 10.507 μg / dL for placebo (Table 38). No consistent substantial changes in serum Cortisol levels relative to baseline values ​​were observed during treatment and follow-up, with percentage changes relative to baseline values ​​at Week 4 ranging from 3.8% to 19.2% (active) relative to -0.8% (placebo), at Week 8 from 20.6% to 51.4% (active) relative to 37.7% (placebo), and at Week 12 from -1.2% to 22.7% (active) relative to 17.1% (placebo). A similar pattern was observed in Part 2, where the baseline serum Cortisol level in the active group for the 100 mg QD dose group was 11.118 μg / dL, and no substantial changes were observed during treatment and follow-up. The percent change from baseline was 20.1% at Week 4, 153.4% ​​at Week 8, and 1.5% at Week 12 (Table 39).

[0608] Compared to placebo, transient increases in 11-deoxycorticosterone and 11-deoxycortisol were seen in the active treatment group at Week 4 in Part 1, although the variation within each individual dose cohort was large. At Week 12, values ​​returned to a range similar to placebo (Table 38). In Part 2, 11-deoxycorticosterone and 11-deoxycortisol were similar to baseline in subjects treated with lorenstat 100 mg QD at Weeks 4 and 10 (Table 39).

[0609] In Part 1, aldosterone levels in subjects treated with lorenlustat generally decreased relative to baseline at Week 4 (-40.1% to 7.4%) compared to 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 Part 2, aldosterone levels in subjects receiving lorenlustat remained consistent at Weeks 4 and 10 but were lower than baseline (Table 39).

[0610] Regardless of dose and baseline PRA value, all subjects treated with lorenzostat had increased renin activity (expressed as percent change from baseline), reaching a maximum level at Week 4 and remaining elevated at Weeks 12 (Part 1) and 10 (Part 2) compared to baseline (Table 38 and Table 39, respectively). Placebo values ​​in Part 1 remained relatively consistent with baseline.

[0611] Table 38: Mean (SD) Observed Change and Mean (SD) Percent Change from Baseline for Pharmacodynamic Parameters, Part 1 (PK / PD Analysis Set)

[0612]

[0613] Table 39: Mean (SD) Observed Change and Mean (SD) Percent Change from Baseline for Pharmacodynamic Parameters, Part 2 (PK / PD Analysis Set)

[0614]

[0615] Regardless of dose, subjects administered lorenlustat in Part 1 demonstrated greater eGFR decline relative to placebo as early as 1 week after treatment initiation, which remained at a consistent level until Week 8 (Table 40). The greatest decrease from baseline was seen in the 100 mg QD dose group, reaching 10.91 mL / min / 1.73 m at Week 2. 2 The mean maximum decrease in (range: -6.80 mL / min / 1.73 m) within 8 weeks of treatment 2 to -10.91mL / min / 1.73m 2 In contrast, the mean eGFR in the placebo group remained relatively stable throughout treatment, reaching -2.80 mL / min / 1.73 m2 at week 2. 2 The mean maximum decrease (range: -0.83 mL / min / 1.73 m 2 to -2.80mL / min / 1.73m 2 Estimated glomerular filtration rate was estimated using the CKD-EPI equation.

[0616] A similar trend in mean eGFR was seen in the 100 mg QD treatment group in Part 2, with a rapid initial decline followed by a smaller decrease that persisted through Week 8 (Table 41).

[0617] Table 40: Estimated Glomerular Filtration Rate (mL / min / 1.73m 2 ) Mean (SD) Observed Change and Mean (SD) Change from Baseline, Part 1 (Safety Analysis Set)

[0618]

[0619] Table 41: Estimated Glomerular Filtration Rate (mL / min / 1.73m 2 ) Mean (SD) Observed Change and Mean (SD) Change from Baseline, Part 2 (Safety Analysis Set)

[0620]

[0621] Security

[0622] At least one treatment-emergency TEAE was reported in 83 subjects in Part 1 (73 [54.9%] treated with lorenlustat and 10 [33.3%] treated with placebo) and 20 subjects in Part 2 (19 [61.3%] treated with lorenlustat and 1 [16.7%] treated with placebo). Of these subjects, 30 subjects from Part 1 (27 [20.3%] treated with active drug and 3 [10%] treated with placebo) and 9 subjects from Part 2 (29.0% treated with lorenlustat alone) experienced a TEAE that was considered at least possibly related to study drug.

[0623] Two subjects (1.5%) in Part 1 and one subject (3.2%) in Part 2 reported SAEs, one of which (exacerbation of pre-existing hyponatremia) was considered possibly related to study drug. All events occurred in subjects treated with lorenzostat.

[0624] Thirty-six subjects in Part 1 (35 [26.3%] lorenzostat-treated and 1 (3.3%) placebo-treated) and four (12.9%) active-treated subjects in Part 2 reported at least one AESI.

[0625] Ten subjects in Part 1 and two subjects in Part 2 (all in the active treatment cohort) experienced TEAEs that led to permanent discontinuation of study drug, and 24 subjects in Part 1 and 7 subjects in Part 2 experienced TEAEs that led to dose modifications.

[0626] No deaths were reported in either Part 1 or Part 2.

[0627] The most commonly reported events based on PT were hyperkalemia (1 [3.3%] subject in the Part 1 placebo cohort, 31 [23.3%] subjects in the Part 1 active treatment cohort, and 8 [25.8%] subjects in the Part 2 100 mg QD cohort), decreased eGFR (1 [3.3%] subject in the Part 1 placebo cohort and 9 [6.8%] subjects in the Part 1 active treatment cohort), and urinary tract infection (7 [5.3%] subjects in the Part 1 active treatment cohort and 2 [6.5%] subjects in the Part 2 100 mg QD cohort). Muscle cramps were reported by 3 subjects (9.7%) in the Part 2 100 mg QD cohort.

[0628] There was no clear association between study drug dose and the frequency of treatment-emergent TEAEs, treatment-emergent TEAEs that were at least moderate in severity, or treatment-emergent TEAEs that were considered by the investigator to be at least possibly related to study drug.

[0629] Serum potassium and serum creatinine increased, whereas serum sodium decreased, in the active-treatment cohort compared with placebo in both Parts 1 and 2. These changes are consistent with the mechanism of action of lorenlustat.

[0630] Seven subjects experienced transient elevations in serum potassium (greater than 6.0 mmol / L), none of which were considered SAEs and all resolved rapidly following intervention (discontinuation of study drug or dose adjustment).

[0631] There were no noteworthy findings in vital signs, physical examination, or ECG parameters.

[0632] Treatment-emergent adverse events (TEAEs)

[0633] Overall, 28 subjects in Part 1 experienced treatment-emergency TEAEs of moderate severity (3 [10.0%] subjects in the placebo cohort and 25 [18.8%] subjects in the active treatment cohort), and one subject in the 12.5 mg QD cohort (0.8%) experienced a severe treatment-emergency TEAE (Table 42). The only treatment-emergency TEAEs of moderate severity reported by ≥2 subjects in any dose group based on PT 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-emergency TEAE was hyperkalemia.

[0634] In Part 2, 12 (38.7%) subjects experienced ≥1 moderate treatment-emergency TEAE and one (3.2%) subject experienced ≥1 severe treatment-emergency TEAE, all in the 100 mg QD cohort (Table 43). The only moderate severity treatment-emergency TEAEs reported by ≥2 subjects were hyperkalemia (5 [16.1%] subjects) and muscle cramps (2 [6.5%] subjects). The one severe treatment-emergency TEAE was hyponatremia.

[0635] Table 42: Treatment Period Reported by System Organ Class and Preferred Term for ≥2 Subjects in Any Treatment Group Severity of Treatment-Emergent Adverse Events, Part 1 (Safety Analysis Set)

[0636]

[0637]

[0638] Adverse events occurring in at least two subjects in any dose group are presented according to the SOC and / or PT and / or severity. Adverse events occurring in at least two subjects without PT and / or severity are presented only according to the SOC. PTs occurring in at least two subjects without severity are presented only according to the SOC and PT.

[0639] Table 43: Treatment Period Reported by System Organ Class and Preferred Term for ≥2 Subjects in Any Treatment Group Severity of Treatment-Emergent Adverse Events, Part 1 (Safety Analysis Set)

[0640]

[0641]

[0642] Adverse events occurring in at least two subjects in any dose group are presented according to the SOC and / or PT and / or severity. Adverse events occurring in at least two subjects without PT and / or severity are presented only according to the SOC. PTs occurring in at least two subjects without severity are presented only according to the SOC and PT.

[0643] Ten (7.5%) subjects in Part 1 (all in the active treatment cohort) experienced a treatment-period TEAE that led to permanent discontinuation of study drug (Table 44); hyperkalemia (5 [3.8%] subjects) was the only such event reported by ≥2 subjects.

[0644] In Part 2, two subjects (6.5%) experienced on-treatment TEAEs leading to permanent discontinuation of study drug; both subjects were in the 100 mg QD cohort. No other subjects experienced such events.

[0645] Table 44: On-treatment Adverse Events Leading to Permanent Discontinuation of Study Drug by System Organ Class and Preferred Term Adverse events present, part 1 (safety analysis set)

[0646]

[0647]

[0648] Table 45: On-treatment Adverse Events Leading to Permanent Discontinuation of Study Drug by System Organ Class and Preferred Term Adverse events present, part 2 (safety analysis set)

[0649]

[0650] Changes in estimated glomerular filtration rate (eGFR)

[0651] A dose-dependent and reversible reduction in eGFR was observed. This phenomenon has been reported in the setting of ACE / ARBs and more recently SGLT2 inhibition due to a reduction in intraglomerular pressure and is felt to attenuate the development of hypertensive nephropathy. Graphs showing changes in estimated glomerular filtration rate (eGFR) in the different dosing cohorts are provided in Figure 8 middle.

[0652] Clinical laboratory evaluation

[0653] There were no meaningful changes from baseline to Week 8 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 in Part 1 or Part 2. There were no meaningful changes from baseline to Week 8 in hematology and coagulation parameters or urinalysis and spot / 24-hour urine parameters in Part 1 or Part 2.

[0654] serum potassium

[0655] In both Parts 1 and 2, serum potassium levels increased in the active treatment cohorts compared with the placebo cohort, with the largest increases seen in the 100 mg QD cohort in Parts 1 and 2 and in both BID cohorts in Part 1 ( Figure 20 、 Figure 21 ,as well as Figure 22 ).

[0656] The group mean serum potassium (K+) changes are summarized in the table below.

[0657] Table 46

[0658] Part 1 Part 2 merge Average value (mMol / L) +0.50 +0.23 +0.35 SD 0.96 0.51 0.75 N 26* 31 57 SEM 0.19 0.09 0.10

[0659] The number of subjects in whom serum potassium was verified or increased multiple times above the normal range during treatment is shown in the table below.

[0660] Table 47

[0661]

[0662] One or more serum K + >6.0mmol / L. Five of the six cases were judged to be unrelated to the study drug.

[0663] *Measurements in 1 subject were isolated events not verified by repeated measurements with study drug discontinuation (protocol deviation).

[0664] serum sodium

[0665] The serum sodium concentration decreased in the active treatment group ( Figure 23 、 Figure 24 ,as well as Figure 25 ).

[0666] discuss

[0667] This example describes a multicenter, prospective, randomized, placebo-controlled, double-blind, dose-ranging study in adults with uncontrolled hypertension despite treatment with at least two background AHT medications. The results of this study demonstrate that aldosterone synthase inhibition with lorenlustat as add-on therapy to a stable regimen of AHT medications is well tolerated and induces reductions in AOBP that are both clinically meaningful and statistically significant after 8 weeks of treatment.

[0668] Overall, 42 clinical trial centers in the United States participated in the trial, with 163 subjects randomized to Part 1 (of which 141 [86.5%] completed the study drug trial) and 37 subjects randomized to Part 2 (of which 33 [89.2%] completed the study drug trial). Baseline demographic, lifestyle, and cardiovascular history characteristics were similar across all doses and study parts, with relatively even distribution according to sex, relevant race, and ethnic minority groups. As expected, the study population was primarily an older, overweight / obese group, with the majority of subjects being treated for type 2 diabetes. Approximately 36% of the participants were Black or African American. In addition, approximately half of the enrolled subjects were prescribed a 2-drug AHT regimen, with the majority of subjects (>77%) being treated with ACEi or ARB, and the majority (58%) being treated with thiazide diuretics.

[0669] Analysis of the primary efficacy endpoint demonstrated that most BP reductions were achieved within 4 weeks of initiating therapy and were generally well maintained for the remainder of the 8-week treatment period. Clinically meaningful placebo-adjusted AOBP (SBP) reductions were seen across all doses tested, with statistically significant reductions of 9.58 mmHg (p=0.0114) and 7.81 mmHg (p=0.0422) seen in the 50 mg and 100 mg QD cohorts, respectively, in Part 1. Such SBP reductions are significant for the effective treatment of subjects with uncontrolled hypertension. In a recent meta-analysis of 147 randomized trials, a 10 mmHg SBP reduction was shown to reduce the risk of stroke by 41% and the risk of coronary heart disease by 22%. (Law, Morris, and Wald 2009) Furthermore, AOBP SBP reduction was validated by comparable reductions in 24-hour ABPM SBP and confirmed by the associated benefits of lorenlustat in reducing both central ABPM SBP and nocturnal ABPM SBP, two markers of increased risk for cardiovascular events (Hermida et al. 2014; Mousa et al. 2004).

[0670] The beneficial effects were seen despite nonstandardized background therapy, supporting the generalizability of the effects to all subjects with uncontrolled hypertension. Furthermore, the subgroup with statistically significant and clinically meaningful changes in AOBP and SBP (i.e., BMI ≥ 30 kg / m2) showed a significant difference in AOBP and SBP between the two groups. 2 The identification of subjects with thiazide diuretics and subjects taking concomitant thiazide diuretics suggests that the full efficacy of lorenlustat after 8 weeks of treatment may still be underestimated. Additional studies are warranted to explore the effects of standardized background regimens and / or current prescribing paradigms with the addition of lorenlustat therapy or in specific subpopulations.

[0671] Renin inhibition is common in patients with hypertension, and in theory, these patients should benefit most from drugs that reduce aldosterone production. Interestingly, the subjects who were treated with lorenstat and enrolled in Part 2 (i.e., subjects whose renin levels were not suppressed) showed a BP-lowering effect similar to that of subjects whose plasma renin levels were suppressed (i.e., subjects who enrolled in Part 1). Although the PATHWAY-2 trial demonstrated that other MRAs (such as spironolactone) are effective in lowering BP across a wide range of plasma renin levels, another study of lorenstat in a population not selected for baseline PRA is important for confirming the effects seen here.

[0672] The pharmacodynamic response demonstrated a dose-dependent decrease in serum aldosterone levels and a proportionate increase in plasma renin activity, consistent with the mechanism of action of lorenlustat. No substantial decreases in serum cortisol levels relative to placebo were observed during treatment and follow-up, with percentage changes from baseline values ​​ranging from 20.6% to 51.4% (active) versus 37.7% (placebo) at Week 8 and from -1.2% to 22.6% (active) versus 17.1% (placebo) at Week 12. A similar pattern was observed in Part 2, where baseline serum cortisol levels in the active group were 11.1 μg / dL in the 100 mg Qd dose group, and no substantial changes were observed during treatment and follow-up. Most importantly, no cases of adrenal insufficiency developed during the trial.

[0673] Overall, lorenlustat was safe and well tolerated. Two subjects (1.5%) in Part 1 and one subject (3.2%) in Part 2 reported treatment-emergent SAEs, with worsening of pre-existing hyponatremia considered possibly related to study drug. No subjects treated with placebo experienced treatment-emergent SAEs. No deaths were reported in Part 1 or Part 2.

[0674] At least one treatment-emergency TEAE was reported by 83 subjects in Part 1 (73 [54.9%] lorenlustat-treated vs. 10 [33.3%] placebo-treated) and 20 subjects in Part 2 (19 [61.3%] lorenlustat-treated vs. 1 [16.7%] placebo-treated). Of the lorenlustat-treated subjects, 27 (20.3%) experienced a TEAE in Part 1 and 9 (29.0%) in Part 2 that was considered at least possibly related to study drug. The most frequently reported AEs based on PT were hyperkalemia and decreased eGFR. All active doses saw modest increases in potassium relative to baseline at Week 8, ranging from 0.208 mmol / L (100 mg QD Part 2) to 0.341 mmol / L (25 mg BID Part 1). Although seven subjects experienced transient elevations in serum potassium greater than 6.0 mmol / L, none were considered SAEs and all resolved rapidly after discontinuation or dose adjustment, consistent with the short half-life of lorenzastat. It should be noted that one of these events was incorrectly assessed due to incorrect sample handling. In a manner similar to ACE inhibitors and ARBs, the BP-lowering effect of lorenzastat resulted in a beneficial, reversible, dose-dependent reduction in eGFR.

[0675] Treatment-related hypotension is seen in three subjects and is reversible and is expected based on the mechanism of action of lorenstat when treatment stops. Two subjects in these subjects were randomized to 100mg QD queue (all 1 in both Part 1 and Part 2), and one subject was randomized to 12.5mg BID. In addition, orthostatic hypotension occurred in three subjects, which was defined as a SBP decline of 20mmHg or a DBP decline of 10mmHg when sitting to standing. In each case, the attack was resolved and did not recur in the remaining time of the treatment period. For future clinical studies, continued observation of hypotensive symptoms, even if slight and reversible, was approved.

[0676] In summary, the primary objective of the study was to characterize the safety and efficacy of lorenlustat at 5 dose levels and 2 dose regimens relative to placebo on blood pressure when administered orally as add-on therapy to stable background therapy for the treatment of uncontrolled hypertension. The results of this study indicate that:

[0677] (a) Lorenzostat is effective in lowering BP in individuals with inadequately treated or resistant hypertension;

[0678] (b) There was a dose-response and exposure-response relationship, with placebo-adjusted mean reductions in SBP of 9.58 mmHg and 7.81 mmHg seen at the 50 mg QD and 100 mg QD doses, respectively;

[0679] (c) 24-hour ABPM, central BP, and nocturnal SBP values ​​confirmed that SBP reductions were seen in the setting of AOBP, most significantly in the 100 mg QD dose cohort; and

[0680] (d) Safety Data Set Lorenzostat was safe and well tolerated, with no effect on serum cortisol and the expected modest increase in serum potassium, with relatively few episodes of clinically significant hyperkalemia.

[0681] Future studies are authorized to evaluate the long-term efficacy and safety of lorenzostat in patients with uncontrolled hypertension.

[0682] References

[0683] Ahmad Y, Francis DP, Bhatt DL, Howard JP. Renal denervation for hypertension: a systematic review and meta-analysis of randomized, blinded, placebo-controlled trials. Cardiovascular Interventions. 2021Dec 13;14(23):2614-24.

[0684] Arriza JL, Weinberger C, Cerelli G, et al. Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science. 1987; 237(4812): 268-275.

[0685] Baudrand R, Vaidya A. The low-renin hypertension phenotype: genetics and the role of the mineralocorticoid receptor. Int J Mol Sci. 2018;19(2):546.

[0686] Briet M,Schiffrin EL.Vascular actions of aldosterone.J Vasc Res.2013;50(2):89-99。

[0687] De Sousa K,Boulkroun S,Baron S,et al.Genetic,cellular,and molecularheterogeneity in adrenals with aldosterone-producingadenoma.Hypertension.2020Apr;75(4):1034-44。

[0688] Decision Resources Group.Treatment algorithms:claims data analysis inhypertension.Published June 2019。

[0689] Dinh Cat AN,Friederich-Persson M,White A,Touyz RM.Adipocytes,aldosterone and obesity-related hypertension.Mol Endocrinol.2016Jul;57(1):F7-F21。

[0690] Faulkner JL,Belin de Chantemèle EJ.Leptin and aldosterone.VitamHorm.2019;109:265-284。Flynn C,Bakris GL.Interaction between adiponectin andaldosterone.Cardiorenal Medicine.2011;1(2):96-101。

[0691] Food and Drug Administration,2020.Clinical drug interaction studies-cytochrome P450 enzyme-and transporter-mediated drug interactions guidancefor industry.Center for Drug Evaluation and Research(CDER),USDepartment ofHealth and Human Services Food and Drug Administration,Silver Springs,MD。

[0692] Funder JW,Carey RM.Primary Aldosteronism:Where are we now?Where tofrom here?Hypertension.2022Apr;79(4):726-735。

[0693] Good,D.W.(2007).Nongenomic actions of aldosterone on the renaltubule.Hypertension,49(4),728-739。

[0694] Grossmann,C.,&Gekle,M.(2009).New aspects of rapid aldosteronesignaling.Molecular and cellular endocrinology,308(1-2),53-62。

[0695] Hall JE,do Carmo JM,da Silva AA,Wang Z,Hall ME.Obesity-inducedhypertension:interaction of neurohumoral and renal mechanisms.CircRes.2015Mar 13;116(6):991-1006。

[0696] Hargovan M,Ferro A.Aldosterone synthase inhibitors in hypertension:current status and future possibilities.JRSM Cardiovasc Dis.2014;3:2048004014522440。

[0697] Hermida,R.C.,D.E.Ayala,A.Mojon,M.H.Smolensky,F.Portaluppi,andJ.R.Fernandez.2014.'Sleep-time ambulatory blood pressure as a noveltherapeutic target for cardiovascular risk reduction',J Hum Hypertens,28:567-74。

[0698] Ishikawa K,Izawa Y,Ito H,et al.Aldosterone stimulates vascular smoothmuscle cell proliferation via big mitogen-activated protein kinase 1activation.Hypertension.2005;46(4):1046-1052。

[0699] Laffin LJ,Kaufman HW,Chen Z,et al.Rise in blood pressure observedamong US adults during the COVID-19 pandemic.Circulation.2022 Jan 18;145(3):235-237。

[0700] Lainscak M,Pelliccia F,Rosano G,et al.Safety profile ofmineralocorticoid receptor antagonists:Spironolactone andeplerenone.International journal of cardiology.2015 Dec 1;200:25-9。

[0701] Law,M.R.,J.K.Morris,and N.J.Wald.2009.'Use of blood pressure loweringdrugs in the prevention of cardiovascular disease:meta-analysis of 147randomised trials in the context of expectations from prospectiveepidemiological studies',BMJ,338:b1665。

[0702] Mihailidou,A.S.,&Funder,J.W.(2005).Nongenomic effects ofmineralocorticoid receptor activation in the cardiovascular system.Steroids,70(5-7),347-351。

[0703] Million Hearts.Estimated hypertension prevalence,treatment,andcontrol among U.S.adults.Updated February 5,2020.Accessed February 5,2021。

[0704] Mills JN,Thomas S,Williamson KS.The acute effect of hydrocortisone,deoxycorticosterone and aldosterone upon the excretion of sodium,potassiumand acid by the human kidney.J Physiol.1960;151(2):312-331。

[0705] Mineralys Therapeutics,Trial on the Safety and Efficacy ofLorundrostat in Patients with Un-controlled Hypertension(Target-HTN).ClinicalTrials.gov identifier:NCT05001945.Available at:clinicaltrials.gov

[0706] Morgan ES,Tami Y,Hu K,et al.Antisense inhibition of angiotensinogenwith IONIS-AGT-LRx:results of phase 1 and phase 2 studies.Basic toTranslational Science.2021 Jun 1;6(6):485-96。

[0707] Mulatero P,Monticone S,Deinum J,et al.Genetics,prevalence,screeningand confirmation of primary aldosteronism:a position statement and consensusof the Working Group on Endocrine Hypertension of The European Society ofHypertension.Journal of hypertension.2020 Oct 1;38(10):1919-28。

[0708] Muntner P,Hardy ST,Fine LJ,et al.Trends in blood pressure controlamong US adults with hypertension,1999-2000 to 2017-2018.JAMA.2020 Sep 22;324(12):1190-1200

[0709] NCD Risk Factor Collaboration(NCDRF Collaboration).Worldwide trendsin hypertension prevalence and progress in treatment and control from 1990 to2019:a pooled analysis of 1201population-representative studies with 104million participants.Lancet.2021 Sep 11;398(10304):957-980。

[0710] Nishiyama A,Yao L,Fan Y,et al.Involvement of aldosterone andmineralocorticoid receptors in rat mesangial cell proliferation anddeformability.Hypertension.2005;45(4):710-716。

[0711] Oparil S,Schmieder RE.New approaches in the treatment ofhypertension.Circ Res.2015;116(6):1074-1095。

[0712] Packer M.Leptin-aldosterone-neprilysin axis:identification of itsdistinctive role in the pathogenesis of the three phenotypes of heart failurein people with obesity.Circulation.2018 Apr 10;137(15):1614-31。

[0713] Ramsay LE,Shelton JR,Tidd MJ.The pharmacodynamics of single doses ofprorenoate potassium and spironolactone in fludrocortisone treated normalsubjects.Br J Clin Pharmacol.1976;3(3):475-482。

[0714] Romagni P,Rossi F,Guerrini L,Quirini C,Santiemma V.Aldosteroneinduces contraction of the resistance arteries in man.Atherosclerosis.2003;166(2):345-349。

[0715] Vaidya A,Mulatero P,Baudrand R,Adler GK.The expanding spectrum ofprimary aldosteronism:implications for diagnosis,pathogenesis,andtreatment.Endocr Rev.2018;39(6):1057-1088。

[0716] Virani SS,Alonso A,Aparicio HJ,et al;American Heart AssociationCouncil on Epidemiology and Prevention Statistics Committee and StrokeStatistics Subcommittee.Heart Disease and Stroke Statistics-2021 Update:AReport From the American Heart Association.Circulation.2021 Feb 23;143(8):e254-e743。

[0717] Whelton PK,Carey RM,Aronow WS,et al.2018ACC / AHA / AAPA / ABC / ACPM / AGS / APhA / ASH / ASPC / NMA / PCNA Guideline for the prevention,detection,evaluation,andmanagement of high blood pressure in adults:a report of the American Collegeof Cardiology / American Heart Association Task Force on Clinical PracticeGuidelines.Hypertension.2018;71(6):e13-e115。

[0718] Williams B.MacDonald TM,Morant S,et al.PATHWAY StudyGroup.Spironolactone versus placebo,bisoprolol,and doxazosin to determine theoptimal treatment for drug-resistant hypertension(PATHWAY-2):a randomised,double-blind,crossover trial.Lancet.2015;386(10008):2059-2068。

[0719] Wright JT Jr,Williamson JD,Whelton PK,et al.SPRINT Research Group.Arandomized trial of intensive versus standard blood-pressure control.N Engl JMed.2015;373(22):2103-2116。

Claims

1. A method for treating hypertension in a hypertensive subject, characterized in that The method comprises administering to the subject once or twice daily an amount of a diuretic and an amount of a CYP 11β2β hydroxylase inhibitor, wherein the co-administered amounts are sufficient to treat hypertension in the hypertensive subject.

2. The method according to claim 1, characterized in that The diuretic and the CYP 11β2β hydroxylase inhibitor are administered as a combined pharmaceutical composition.

3. The method according to claim 1, characterized in that The diuretic and the CYP 11β2β hydroxylase inhibitor are administered concomitantly.

4. The method according to any one of claims 1 to 3, characterized in that The combined doses result in greater than additive therapeutic effect in treating the subject.

5. The method according to any one of claims 1 to 4, characterized in that An amount of a CYP 11β2β hydroxylase inhibitor and an amount of a diuretic, when co-administered, are more effective in treating the subject than the same amount of each agent when administered alone.

6. A method for treating hypertension in a hypertensive subject who is taking at least one diuretic, characterized in that The method comprises administering to the subject a CYP 11β2β hydroxylase inhibitor once or twice daily in an amount sufficient to treat hypertension in the hypertensive subject.

7. The method according to any one of claims 1 to 6, characterized in that The diuretic is a thiazide diuretic.

8. The method according to any one of claims 1 to 7, characterized in that The hypertensive subject has a body mass index of at least 30, preferably greater than 30, preferably 30-50, more preferably 30-40.

9. The method according to any one of claims 1 to 8, characterized in that The hypertensive subject is a male hypertensive subject with a waist-to-hip ratio higher than 0.90 or a female hypertensive subject with a waist-to-hip ratio higher than 0.

85.

10. The method according to any one of claims 1 to 9, characterized in that 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 method according to any one of claims 1 to 10, characterized in that The hypertensive subject has: a) a plasma aldosterone concentration greater than or equal to 6 ng / dL as determined by an immunoassay performed in said subject; and / or b) a plasma aldosterone concentration greater than or equal to 1 ng / dL based on LC-MS performed in the subject.

12. A method for treating hypertension in a hypertensive subject in need thereof, characterized in that The method comprises: a) Measured i) the subject's systolic blood pressure is greater than 130 mmHg; ii) the subject's diastolic blood pressure is greater than 80 mmHg; and b) selecting subjects who are currently taking at least one diuretic; and c) administering to the subject an effective amount of a CYP 11β2β hydroxylase inhibitor.

13. A method for treating hypertension in a hypertensive subject in need thereof, characterized in that The method comprises a) receiving a diagnosis of a hypertensive subject as i) systolic blood pressure greater than 130 mmHg; ii) diastolic blood pressure greater than 80 mmHg; as well as iii) taking at least one diuretic; as well as b) administering to the subject an effective amount of a CYP 11β2β hydroxylase inhibitor.

14. The method according to claim 12 or 13, characterized in that The diuretic is a thiazide diuretic.

15. The method according to any one of claims 12 to 13, characterized in that Step a) further comprises measuring or receiving identification of the subject as having a body mass index (BMI) of at least 30, preferably greater than 30, preferably 30-50, more preferably 30-40, or a waist-to-hip ratio above 0.90 if the hypertensive subject is a male or above 0.85 if the hypertensive subject is a female.

16. The method according to any one of claims 12 to 15, characterized in that Step a) further comprises measuring or receiving information identifying the subject as having 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. The method according to any one of claims 12 to 16, characterized in that Step a) further comprises: a) the subject's plasma aldosterone concentration is greater than or equal to 6 ng / dL as measured by an immunoassay; or b) the subject's plasma aldosterone concentration is greater than or equal to 1 ng / dL as measured by LC-MS.

18. The method according to any one of claims 1 to 16, characterized in that The hypertensive subject is taking or has taken a hypertension drug selected from ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, or a combination of two or more thereof.

19. The method according to claim 18, characterized in that The hypertensive subject is taking or has taken at least two of the hypertensive medications.

20. The method according to any one of claims 1 to 19, characterized in that The CYP 11β2β hydroxylase inhibitor is administered to the subject once daily.

21. The method according to any one of claims 1 to 20, characterized in that The CYP 11β2β hydroxylase inhibitor is administered in the morning.

22. The method according to any one of claims 1 to 19, characterized in that The CYP 11β2β hydroxylase inhibitor is administered to the subject twice daily.

23. The method according to any one of claims 1 to 22, characterized in that The CYP 11β2β hydroxylase inhibitors: a) is administered daily for at least one week; b) is administered daily for at least two weeks; c) is administered daily for at least four weeks; or d) is administered daily for at least eight weeks.

24. The method according to any one of claims 1 to 23, characterized in that The ambulatory systolic blood pressure of the hypertensive subject is reduced by at least 10 mmHg, reduced by 10-55 mmHg, reduced by 10-50 mmHg, reduced by 10-45 mmHg, reduced by 10-40 mmHg, reduced by 10-35 mmHg, reduced by 10-30 mmHg, reduced by 10-25 mmHg, reduced by 10-20 mmHg, or reduced by 10-15 mmHg relative to the ambulatory systolic blood pressure of the hypertensive subject prior to administration of the CYP 11β2β hydroxylase inhibitor for a period of at least eight weeks.

25. The method according to any one of claims 1 to 24, characterized in that The ambulatory diastolic blood pressure of the hypertensive subject is reduced by at least 5 mmHg, reduced by 5-25 mmHg, reduced by 5-20 mmHg, or reduced by 5-15 mmHg relative to the ambulatory diastolic blood pressure of the hypertensive subject prior to administration of the CYP 11β2β hydroxylase inhibitor for a period of at least eight weeks.

26. The method according to any one of claims 1 to 25, characterized in that The aldosterone levels of the hypertensive subjects follow a substantially normal circadian rhythm.

27. The method according to any one of claims 1 to 26, characterized in that The hypertensive subject's mean systolic blood pressure during sleep is reduced (a) relative to the hypertensive subject's mean systolic blood pressure during sleep before receiving the CYP 11β2β hydroxylase inhibitor and / or (b) relative to the hypertensive subject's mean daytime systolic blood pressure.

28. The method according to any one of claims 1 to 27, characterized in that The mean systolic blood pressure of the hypertensive subjects during sleep: a) a decrease of at least 10%, a decrease of between 10% and 40%, a decrease of between 10% and 30%, or a decrease of between 10% and 20% relative to the hypertensive subject's mean daytime systolic blood pressure; and / or b) a decrease of at least 8 mmHg, a decrease of at least 10 mmHg, a decrease of between 8 mmHg and 55 mmHg, a decrease of between 10 mmHg and 45 mmHg, or a decrease of between 10 mmHg and 25 mmHg relative to the hypertensive subject's mean systolic blood pressure during sleep prior to receiving the CYP 11β2β hydroxylase inhibitor.

29. The method according to any one of claims 1 to 28, characterized in that The CYP 11β2β hydroxylase inhibitor is selectively useful for inhibiting CYP 11β2β hydroxylase activity relative to inhibiting CYP 11β1β hydroxylase activity, preferably wherein the ratio of the inhibition constant (Ki) for CYP 11β1β hydroxylase to the Ki for CYP 11β2β hydroxylase is greater than 100.

30. The method according to any one of claims 1 to 29, characterized in that The CYP 11β2β hydroxylase inhibitor is a compound of formula (A) or a pharmaceutically acceptable salt thereof:

31. The method according to claim 30, characterized in that The compound is in the form of the HBr salt of the compound of formula (A).

32. The method according to any one of claims 30 to 31, characterized in that: a) orally administering between 5 mg and 50 mg of the CYP 11β2β hydroxylase inhibitor twice a day, 12 hours apart; b) orally administering between 10 mg and 30 mg of the CYP 11β2β hydroxylase inhibitor twice a day, 12 hours apart; c) oral administration of between 30 mg and 120 mg of the CYP 11β2β hydroxylase inhibitor once a day; or d) orally administering between 40 mg and 110 mg of the CYP 11β2β hydroxylase inhibitor once a day.

33. The method according to any one of claims 30 to 31, characterized in that The diuretic is a thiazide diuretic, and wherein: a) orally administering 12.5 mg of the CYP 11β2β hydroxylase inhibitor once a day, and the systolic blood pressure of the hypertensive subject is reduced by at least 5 mmHg, preferably by between 5 mmHg and 10 mmHg after placebo adjustment; b) orally administering 50 mg of the CYP 11β2β hydroxylase inhibitor once a day, and the systolic blood pressure of the hypertensive subject is reduced by at least 10 mmHg, preferably by between 10 mmHg and 15 mmHg after placebo adjustment; or c) orally administering 100 mg of the CYP 11β2β hydroxylase inhibitor once a day, and the systolic blood pressure of the hypertensive subject is reduced by at least 9 mmHg, preferably by between 9 mmHg and 15 mmHg after placebo adjustment.

34. The method according to any one of claims 1 to 33, characterized in that The hypertensive subject does not suffer from primary aldosteronism, preferably wherein the hypertensive subject suffers from essential hypertension.

35. A method for identifying a subject for treatment of hypertension with a CYP 11β2β hydroxylase inhibitor, characterized in that The method comprises: a) Measured: i) the subject's systolic blood pressure is greater than 130 mmHg; and ii) the subject's diastolic blood pressure is greater than 80 mmHg; and b) Select subjects who are taking at least one diuretic; The subject is thereby identified for treatment of hypertension with a CYP 11β2β hydroxylase inhibitor.

36. The method according to claim 35, characterized in that The diuretic is a thiazide diuretic.

37. The method according to any one of claims 35 to 36, characterized in that Step a) further comprises measuring the subject's body mass index (BMI) to be at least 30, preferably greater than 30, preferably 30-50, more preferably 30-40, or measuring the subject's waist-to-hip ratio to be higher than 0.90 if the subject is a male, or measuring the subject's waist-to-hip ratio to be higher than 0.85 if the subject is a female.

38. The method according to any one of claims 35 to 37, characterized in that Step a) further comprises measuring the subject's serum leptin concentration to be 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. The method according to any one of claims 35 to 38, characterized in that Step a) further comprises: a) a plasma aldosterone concentration greater than or equal to 6 ng / dL as measured by an immunoassay performed in said subject; or b) a plasma aldosterone concentration greater than or equal to 1 ng / dL as measured by LC-MS performed in the subject.

40. A package, characterized in that The package contains: a) a first pharmaceutical composition comprising an amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof: and a pharmaceutically acceptable carrier; b) a second pharmaceutical composition comprising an amount of a thiazide diuretic and a pharmaceutically acceptable carrier; as well as c) instructions for using the first pharmaceutical composition and the second pharmaceutical composition together to treat a subject suffering from hypertension.

41. A compound of formula (A) or a pharmaceutically acceptable salt thereof, characterized in that The compound of formula (A) or a pharmaceutically acceptable salt thereof is used as an add-on therapy or in combination with a thiazide diuretic to treat a subject suffering from hypertension.

42. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: a) an amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof: as well as b) an amount of a thiazide diuretic, the pharmaceutical composition is for treating a subject suffering from hypertension, wherein the compound of formula (A) and the thiazide diuretic are administered simultaneously, contemporaneously or concomitantly.

43. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: a) an amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof: as well as b) a certain amount of thiazide diuretics, wherein said compound of formula (A) and said thiazide diuretic are each present in an amount that is jointly effective to treat hypertension in a hypertensive subject.

44. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises a certain amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof: The pharmaceutical composition is used as add-on therapy or in combination with a thiazide diuretic to treat a subject suffering from hypertension.

45. A therapeutic package for distribution to or use in a subject suffering from hypertension, characterized in that The therapeutic package contains: 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: as well as ii) a certain amount of thiazide diuretics, wherein said respective amounts of said compound of formula (A) and said thiazide diuretic in said unit dose are effective to treat said subject upon concomitant administration to said subject, and b) a finished pharmaceutical container for said therapeutic package, said container containing said one or more unit doses, said container further containing or comprising a label directing use of said package for treating said subject.

46. ​​A pharmaceutical composition in unit dosage form for treating a subject suffering from hypertension, characterized in that Include: a) an amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof: as well as b) a certain amount of thiazide diuretics, wherein the respective amounts of the compound of formula (A) and the thiazide diuretic in the composition are effective to treat the subject upon concomitant administration of one or more of the unit dosage forms of the pharmaceutical compositions to the subject.

Images