Methods of treating hypertension with a combination of lorundrostat and two or more Anti-hypertensive medications

Abstract

This invention provides a method of treating hypertension in a hypertensive subject, the method comprising administering to the subject an amount of an angiotensin II receptor blocker (ARB) once per day, an amount of a thiazide or thiazide-like diuretic once per day, and an amount of lorundrostat or a pharmaceutically acceptable salt thereof once per day, wherein the amounts taken together are sufficient to treat hypertension in the hypertensive subject.

Description

METHODS OF TREATING HYPERTENSION WITH A COMBINATION OF LORUNDROSTAT AND TWO OR MORE ANTI-HYPERTENSIVE MEDICATIONS

[0001] This application claims the priority of U.S. Provisional Application No. 63 / 515,917, filed July 27, 2023, and U.S. Provisional Application No. 63 / 605,957, filed December 4, 2023, the contents of each of which are hereby incorporated by reference.

[0002] Throughout this application, various publications are referenced, including referenced in parenthesis. The disclosures of all publications mentioned in this application in their entireties are hereby incorporated by reference into this application in order to provide additional description of the art to which this invention pertains and of the features in the art which can be employed with this invention.FIELD OF THE INVENTION

[0003] This invention relates to methods of treating hypertension with a combination of lorundrostat and two or more anti -hypertensive medications.BACKGROUND OF THE INVENTION

[0004] Aldosterone is the principal mineralocorticoid in humans, produced in the zona glomerulosa of the adrenal cortex by aldosterone synthase (CYP 11P2 beta hydroxylase). Aldosterone is a key component of the renin-angiotensin-aldosterone system (RAAS), acting primarily as a regulator of electrolyte and fluid homeostasis.

[0005] Mineralocorticoid receptor-blocking agents (mineralocorticoid receptor antagonists, MRA), such as spironolactone and eplerenone, prevent aldosterone from binding with the mineralocorticoid receptor. Several clinical studies have demonstrated their benefit in treating hypertension. Given the role aldosterone plays in RAAS, inhibition of aldosterone synthase represents a possible alternative to mineralocorticoid receptor— blocking agents for the treatment of hypertension. However, previous studies suggest that some of the effects of aldosterone may occur independently of stimulation of the mineralocorticoid receptor / classic steroid-receptor complex modulation (Grossmann, C., & Gekle, M., 2009; Good, D. W., 2007; Mihailidou, A. S., & Funder, J. W., 2005). In addition, mineralocorticoid receptors are not selective for aldosterone, instead having similar affinity for the glucocorticoids cortisol and corticosterone.

[0006] Diuretics are medications designed to increase the amount of water and salt expelled from the body as urine. Thiazide or thiazide-like diuretics are the most commonly prescribed diuretic, often used to treat hypertension. Thiazide and thiazide-like diuretics not only decrease fluids, but also cause blood vessels to relax. Thiazide and thiazide-like diuretics reduce potassium concentration in blood. This reduction in potassium occurs through two indirect mechanisms: (1) inhibition of sodium-chloride symporter at distal convoluted tubule of a nephron and (2) stimulation of aldosterone which activates Na+ / K+-ATPase at the collecting duct. Sodiumchloride symporter inhibition increases the availability of chloride and sodium in urine. When urine reaches the collecting duct, the increase in chloride and sodium availability activates Na+ / K+-ATPase, which in turn increases absorption of sodium and excretion of potassium into urine. Long term administration of thiazide and thiazide-like diuretics reduces total body blood volume. This activates the renin-angiotensin system, stimulating the secretion of aldosterone, thus activating Na+ / K+-ATPase and increasing potassium excretion in urine. Therefore, a combination of ACE inhibitors and thiazide is used to prevent hypokalemia.

[0007] The administration of two or more drugs to treat a given condition, such as the combination of an aldosterone synthase inhibitor and other anti -hypertensive medications to treat hypertension, raises a number of potential problems. In vivo interactions between two drugs 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 can affect the absorption, distribution, and elimination of the other and hence, alter the effects of the other. For instance, one drug may inhibit, activate or induce the production of enzymes involved in a metabolic route of elimination of the other drug (Food and Drug Administration, 2020). Thus, when two or more drugs are administered to treat the same condition, it is unpredictable whether each will complement, have no effect on, or interfere with, the therapeutic activity of the other in a human subject. Interactions between two drugs may also heighten or lessen the side effects of each drug. Hence, upon administration of two or more drugs to treat a disease, it is unpredictable what change will occur in the negative side profile of each drug.

[0008] The renin-angiotensin-aldosterone system (RAAS) is a complex and multi-faceted system, with many different pathways, enzymes, and hormones interacting in positive and negative feedback loops. Given the complexities of the renin-angiotensin-aldosterone system, use of aldosterone synthase inhibitors to treat hypertension in combination with other anti -hypertensivetherapies carries many uncertainties. Further, identification of specific patient populations who benefit most from inhibition of aldosterone synthase in combinations with other anti-hypertensive therapies remains an important goal in the field of cardiovascular health.SUMMARY OF THE INVENTION

[0009] This invention provides a method of treating hypertension in a hypertensive subject, the method comprising administering to the subj ect an amount of an angiotensin II receptor blocker (ARB) once per day, an amount of a thiazide or thiazide-like diuretic once per day, and an amount of lorundrostat or a pharmaceutically acceptable salt thereof once per day, wherein the amounts taken together are sufficient to treat hypertension in the hypertensive subject.

[0010] This invention also provides a method of treating hypertension in a hypertensive subject who has been taking two anti -hypertensive medications, the method comprising ceasing administration of the two anti-hypertensive medications and instead administering to the subject an amount of an angiotensin II receptor blocker (ARB) once per day, an amount of a thiazide or thiazide-like diuretic once per day, and an amount of lorundrostat or pharmaceutically acceptable salt thereof once per day, wherein the amounts taken together are sufficient to treat hypertension in the hypertensive subject.

[0011] This invention also provides a method of treating hypertension in a hypertensive subject, the method comprising administering to the subject an amount of an angiotensin II receptor blocker (ARB) once per day, an amount of a thiazide or thiazide-like diuretic once per day, an amount of a calcium channel blocker (CCB) once per day, and an amount of lorundrostat or pharmaceutically acceptable salt thereof once per day, wherein the amounts taken together are sufficient to treat hypertension in the hypertensive subject.

[0012] This invention also provides a method of treating hypertension in a hypertensive subject who has been taking three to five anti-hypertensive medications, the method comprising ceasing administration of the three to five anti-hypertensive medications and instead administering to the subject an amount of an angiotensin II receptor blocker (ARB) once per day, an amount of a thiazide or thiazide-like diuretic once per day, an amount of a CCB once per day, and an amount of lorundrostat or a pharmaceutically acceptable salt thereof once per day, wherein the amounts taken together are sufficient to treat hypertension in the hypertensive subject.

[0013] This invention also provides a method of treating hypertension in a subject afflicted with hypertension who is taking two anti-hypertensive medications, the method comprising:(a) receiving an identification of the subject as having(i) a systolic blood pressure of 140-180 mmHg and a diastolic BP of 65- 110 mmHg; or(ii) a diastolic BP of 90- 110 mmHg; and(b) ceasing administration of the two anti -hypertensive medications and instead administering to said subject an effective amount of olmesartan, indapamide or hydrochlorothiazide, and lorundrostat or a pharmaceutically acceptable salt thereof.

[0014] This invention also provides a method of treating hypertension in a subject afflicted with hypertension who is taking three to five anti-hypertensive medications, the method comprising:(a) receiving an identification of the subject as having(i) a systolic blood pressure of 140-180 mmHg in said subject and a diastolic BP of 65-110 mmHg in said subject; or(ii) a diastolic BP of 90- 110 mmHg in said subject; and(b) ceasing administration of the three to five anti-hypertensive medications and instead administering to said subject an effective amount of olmesartan, indapamide or hydrochlorothiazide, amlodipine and lorundrostat or a pharmaceutically acceptable salt thereof.

[0015] This invention also provides a method of identifying a subject for hypertension treatment with an angiotensin II receptor blocker (ARB), a thiazide or thiazide-like diuretic, and lorundrostat or pharmaceutically acceptable salt thereof, the method comprising:(a) measuring the subject’s systolic blood pressure and diastolic blood pressure; and(b) selecting a subject who is taking two anti-hypertensive medications, and who has:(i) a systolic blood pressure of 140 mmHg and a diastolic blood pressure of 65-110 mmHg; or(ii) a diastolic blood pressure of 90-110 mmHg; thereby identifying said subject for hypertension treatment with the angiotensin II receptor blocker (ARB), the thiazide or thiazide-like diuretic, and lorundrostat or pharmaceutically acceptable salt thereof.

[0016] This invention also provides a method of identifying a subject for hypertension treatment with an angiotensin II receptor blocker (ARB), a thiazide or thiazide-like diuretic, a calcium channel blocker (CCB), and lorundrostat or a pharmaceutically acceptable salt thereof, the method comprising:(a) measuring the subject’s systolic blood pressure and diastolic blood pressure; and(b) selecting a subject who is taking three to five anti-hypertensive medications and who has:(i) a systolic blood pressure of 140 mmHg and a diastolic blood pressure of 65-110 mmHg; or(ii) a diastolic blood pressure of 90-110 mmHg; thereby identifying said subject for hypertension treatment with the angiotensin II receptor blocker (ARB), the thiazide or thiazide-like diuretic, the CCB, and the lorundrostat or pharmaceutically acceptable salt thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1: Estimate of time above IC50 for various doses of lorundrostat HBr based on PKPD modeling from SAD study.

[0019] Figure 2: Example 2 Study Schema. AB PM = ambulatory blood pressure monitoring; BP = blood pressure; BID = twice daily; EOT = end of treatment; FU = follow up; PRA = plasma renin activity; QD = once daily.a= If Screening results were available, inclusion / exclusion evaluation was performed. If subject was not eligible based on Screening results, they did not continue to Visit 4. If Screening results were not available, subject proceeded to Visit 4. If Screening results were not available at Visit 4, subject should attend Visit 5 to determine final eligibility. If eligible based on Screening results, ABPM assessment begins at Visit 5.b= The ABPM procedure initiated at home approximately 24 hours before Randomization (Study Day 1). Alternatively, sites were permitted choose to schedule an office visit on Study Day 0 (Visit 5) to initiate the ABPM procedure. Training for the ABPM procedure was done either at an office visit or via phone.

[0020] Figure 3: Modelled (MMRM) Least Square Mean (SEM) Change from Baseline at Week 8 in Seated Automated Office-Measured Systolic Blood Pressure (mmHg), Part 1 (Full Analysis Set). Error bars represent SEM. Numbers inside the bars represent the number of subjects with non-missing data. P-values represent statistically significant difference compared with placebo. *p=0.0114. **p=0.042. Abbreviations: BID, twice daily; mg, milligrams; mmHg, millimeters of mercury; QD, once daily; SBP, systolic blood pressure; SEM, standard error of the mean.

[0021] Figure 4: Modelled (MMRM) Least Square Mean (SEM) Change from Baseline at Week 8 in Seated Automated Office-Measured Systolic Blood Pressure (mmHg), Parts 1 & 2 (Full Analysis Set). Error bars represent SEM. Numbers inside the bars represent the number of subjects with non-missing data. Abbreviations: mg, milligrams; mmHg, millimeters of mercury; MMRM, mixed model repeated measures; QD, once daily; SBP, systolic blood pressure; SEM, standard error of the mean.

[0022] Figure 5: Boxplot of Measured Change from Baseline at Week 8 in Seated Automated Office -Measured Systolic Blood Pressure (mmHg), Part 1 (Full Analysis Set). ♢, mean,..., median; • outlier. Upper and lower boundaries of each box represent 1st and 3rd quartiles.Abbreviations: BID, twice daily; mg, milligrams; mmHg, millimeters of mercury; QD, once daily; SBP, systolic blood pressure.

[0023] Figure 6: Boxplot of Measured Change from Baseline at Week 8 in Seated Automated Office-measured Systolic Blood Pressure (mmHg) in Subjects Randomized to 100 mg QD, Parts 1 & 2 (Full Analysis Set). O, mean; median; 1, • outlier. Upper and lower boundaries of each box represent 1st and 3rd quartiles. Abbreviations: mg, milligrams; mmHg, millimeters of mercury; QD, once daily; SBP, systolic blood pressure.

[0024] Figure 7: Proportion of Subjects with Seated Automated Office-Measured SBP / DBP <130 / 80 mmHg at Week 8, Part 1 (Full Analysis Set). Subjects missing an assessment at Week 8 or who had received rescue medications prior to Week 8 were considered as failures. Numbers inside bars represent the number of subjects achieving AOBP <130 / 80 mmHg.

[0025] Figure 8: Proportion of Subjects with Seated Automated Office-Measured SBP / DBP <130 / 80 mmHg at Study Week 8 in Subjects Randomized to 100 mg QD, Parts 1 & 2 (Full Analysis Set). Subjects missing an assessment at Week 8 or who had received rescue medications prior to Week 8 were considered as failures. Numbers inside bars represent the number of subjects achieving AOBP <130 / 80 mmHg.

[0026] Figure 9: Time (Weeks) to First Occurrence of Seated Automated Office-Measured SBP / DBP <130 / 80 mmHg, Part 1 (Full Analysis Set). Subjects who failed to achieve a BP of <130 / 80 mmHg prior to Week 8 / EoT were censored at the Week 8 / EoT date. Subjects who were lost to follow-up prior to Week 8 / EoT were censored at the date of the last known BP assessment. Subjects who took rescue medications were censored on the date of rescue medication initiation. Missing events correspond to subjects who didn’t have post-baseline assessments for BP. For subject 146-040, the study duration (>27 weeks) and treatment duration (>18 weeks) were longer than planned due to AEs leading to temporary discontinuation.

[0027] Figure 10: Time (Weeks) to First Occurrence of Seated Automated Office-Measured SBP / DBP <130 / 80 mmHg in Subjects Randomized to 100 mg QD, Parts 1 & 2 (Full Analysis Set). Subjects who failed to achieve a BP of <130 / 80 mmHg prior to Week 8 / EoT were censored at the Week 8 / EoT date. Subjects who were lost to follow-up prior to Week 8 / EoT were censored at the date of the last known BP assessment. Subjects who took rescue medications were censored on thedate of rescue medication initiation. Missing events correspond to subjects who didn’t have postbaseline assessments for BP.

[0028] Figure 11: A graph showing the change in estimated glomerular filtration rate (eGFR) in different dosing cohorts.

[0029] Figure 12: Mean (SEM) Change in Serum Potassium from Baseline over Time in QD Dose Cohorts, Part 1 (Safety Analysis Set).

[0030] Figure 13: Mean (SEM) Change in Serum Potassium from Baseline over Time in BID Dose Cohorts, Part 1 (Safety Analysis Set).

[0031] Figure 14: Mean (SEM) Change in Serum Potassium from Baseline over Time, Part 2 (Safety Analysis Set).

[0032] Figure 15: Mean (SEM) Change in Serum Sodium from Baseline over Time in QDDose Cohorts, Part 1 (Safety Analysis Set)

[0033] Figure 16: Mean (SEM) Change in Serum Sodium from Baseline over Time in BIDDose Cohorts, Part 1 (Safety Analysis Set)

[0034] Figure 17: Mean (SEM) Change in Serum Sodium from Baseline over Time, Part 2 (Safety Analysis Set)

[0035] Figure 18: Example 3 Study Flow. ABPM, ambulatory blood pressure monitoring; AHT, antihypertensive; AOBP, automated office blood pressure; eGFR, estimated glomerular filtration rate; K+, potassium; meds, medications; mg, milligrams; mmHg, millimeters of mercury; Na+, sodium; OLE, open label extension; QD, once daily; SEP, systolic blood pressure.DETAILED DESCRIPTION OF THE INVENTIONMethods of treating hypertension

[0036] This invention provides a method of treating hypertension in a hypertensive subject, the method comprising administering to the subj ect an amount of an angiotensin II receptor blocker (ARB) once per day, an amount of a thiazide or thiazide-like diuretic once per day, and an amount of lorundrostat or a pharmaceutically acceptable salt thereof once per day, wherein the amounts taken together are sufficient to treat hypertension in the hypertensive subject.

[0037] In an embodiment, the ARB, the thiazide or thiazide-like diuretic, and lorundrostat or pharmaceutically acceptable salt thereof are administered in a combined pharmaceutical composition.

[0038] In an embodiment, the ARB and the thiazide or thiazide-like diuretic are administered in a combined pharmaceutical composition.

[0039] In an embodiment, the ARB and lorundrostat or pharmaceutically acceptable salt thereof are administered in a combined pharmaceutical composition.

[0040] In an embodiment, the thiazide or thiazide-like diuretic and lorundrostat or pharmaceutically acceptable salt thereof are administered in a combined pharmaceutical composition.

[0041] In an embodiment, the ARB, the thiazide or thiazide-like diuretic, and lorundrostat or pharmaceutically acceptable salt thereof are administered simultaneously, contemporaneously or concomitantly.

[0042] In an embodiment, the amounts when taken together are effective to achieve an additive or a greater than additive therapeutic result in treating the subject.

[0043] In an embodiment, the amount of the ARB is lower than the amount of the ARB that is effective to achieve the same level of treatment of hypertension when administered alone.

[0044] In any of the above embodiments, the amount of the thiazide or thiazide-like diuretic is lower than the amount of the thiazide or thiazidc-likc diuretic that is effective to achieve the same level of treatment of hypertension when administered alone.

[0045] In an embodiment, the amount of lorundrostat or pharmaceutically acceptable salt thereof is lower than the amount of the lorundrostat or pharmaceutically acceptable salt thereof that is effective to achieve the same level of treatment of hypertension when administered alone.

[0046] In an embodiment, the amount of the ARB is lower than the amount of the ARB that is effective to achieve the same level of treatment of hypertension when administered in the absence of administration of lorundrostat or pharmaceutically acceptable salt thereof.

[0047] In an embodiment, the amount of the thiazide or thiazide-like diuretic is lower than the amount of the thiazide or thiazide-like diuretic that is effective to achieve the same level of treatment of hypertension when administered in the absence of administration of lorundrostat or pharmaceutically acceptable salt thereof.

[0048] In an embodiment, the amounts of the ARB and the thiazide or thiazide-like diuretic that are effective to treat hypertension when administered together in the absence of administration of lorundrostat or pharmaceutically acceptable salt thereof cause one or more adverse effects in the subject, wherein the one or more adverse effects are reduced when the amounts of the ARB, the thiazide or thiazide-like diuretic, are administered together with the lorundrostat or pharmaceutically acceptable salt thereof.

[0049] In an embodiment, the amount of the ARB, the amount of the thiazide or thiazide-like diuretic, and the amount of lorundrostat or pharmaceutically acceptable salt thereof when administered together are more effective to treat the subject than when each agent at the same amount is administered alone.

[0050] This invention also provides a method of treating hypertension in a hypertensive subject who has been taking two anti -hypertensive medications, the method comprising ceasing administration of the two anti-hypertensive medications and instead administering to the subject an amount of an angiotensin II receptor blocker (ARB) once per day, an amount of a thiazide or thiazide-like diuretic once per day, and an amount of lorundrostat or pharmaceutically acceptable salt thereof once per day, wherein the amounts taken together are sufficient to treat hypertension in the hypertensive subject

[0051] In embodiments, the ARB is olmesartan and the thiazide or thiazide-like diuretic is indap amide.

[0052] In an embodiment:(a) the amount of lonmdrostat or pharmaceutically acceptable salt thereof is 25-75 mg per day, the amount of olmesartan is 10-50 mg per day, and the amount of indapamide is 1-5 mg per day; or(b) the amount of lonmdrostat or pharmaceutically acceptable salt thereof is 75- 125 mg per day, the amount of olmesartan is 10-50 mg per day, and the amount of indapamide is 1-5 mg per day.

[0053] In an embodiment:(a) the amount of lonmdrostat or pharmaceutically acceptable salt thereof is 25 mg per day, the amount of olmesartan is 40 mg per day, and the amount of indapamide is 2.5 mg per day;(b) the amount of lonmdrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 40 mg per day, and the amount of indapamide is 2.5 mg per day;(c) the amount of lonmdrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 40 mg per day, and the amount of indapamide is 2.5 mg per day;(d) the amount of lonmdrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 20 mg per day, and the amount of indapamide is 2.5 mg per day; or(e) amount of lonmdrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 20 mg per day, and the amount of indapamide is 2.5 mg per day.

[0054] In an alternative embodiment, the ARB is olmesartan and the thiazide or thiazide-like diuretic is hydrochlorothiazide (HCTZ).

[0055] In an embodiment:(a) the amount of lonmdrostat or pharmaceutically acceptable salt thereof is 25-75 mg per day, the amount of olmesartan is 10-50 mg per day, and the amount of HCTZ is 12.5-100 or 12-50 mg per day; or(b) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 75- 125 mg per day, the amount of olmesartan is 10-50 mg per day, and the amount of HCTZ is 12.5-100 or 12-50 mg per day.

[0056] In an embodiment:(a) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 25 mg per day, the amount of olmesartan is 40 mg per day, and the amount of HCTZ is 25 mg per day;(b) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 40 mg per day, and the amount of HCTZ is 25 mg per day;(c) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 40 mg per day, and the amount of HCTZ is 25 mg per day;(d) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 40 mg per day, and the amount of HCTZ is 12 mg per day;(e) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 20 mg per day, and the amount of HCTZ is 25 mg per day;(f) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 20 mg per day, and the amount of HCTZ is 12 mg per day;(g) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 40 mg per day, and the amount of HCTZ is 12 mg per day;(h) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 20 mg per day, and the amount of HCTZ is 25 mg per day; or(i) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 20 mg per day, and the amount of HCTZ is 12 mg per day.

[0057] This invention also provides a method of treating hypertension in a hypertensive subject, the method comprising administering to the subject an amount of an angiotensin II receptor blocker (ARB) once per day, an amount of a thiazide or thiazide-like diuretic once per day, an amount of a calcium channel blocker (CCB) once per day, and an amount of lorundrostat or pharmaceutically acceptable salt thereof once per day, wherein the amounts taken together are sufficient to treat hypertension in the hypertensive subject.

[0058] In an embodiment, the ARB, the thiazide or thiazide-like diuretic, the CCB, and lorundrostat or pharmaceutically acceptable salt thereof are administered in a combined pharmaceutical composition.

[0059] In an embodiment, the ARB, the thiazide or thiazide-like diuretic, and the CCB are administered in a combined pharmaceutical composition.

[0060] In an embodiment, the ARB, the thiazide or thiazide-like diuretic, and lorundrostat or pharmaceutically acceptable salt thereof are administered in a combined pharmaceutical composition.

[0061] In an embodiment, the ARB, the CCB, and lorundrostat or pharmaceutically acceptable salt thereof are administered in a combined pharmaceutical composition.

[0062] In an embodiment, the thiazide or thiazide-like diuretic, the CCB, and lorundrostat or pharmaceutically acceptable salt thereof are administered in a combined pharmaceutical composition.

[0063] In an embodiment, the ARB and the thiazide or thiazide-like diuretic are administered in a combined pharmaceutical composition.

[0064] In an embodiment, the ARB and the CCB are administered in a combined pharmaceutical composition.

[0065] In an embodiment, the ARB and lorundrostat or pharmaceutically acceptable salt thereof are administered in a combined pharmaceutical composition.

[0066] In an embodiment, the thiazide or thiazide-like diuretic and the CCB are administered in a combined pharmaceutical composition.

[0067] In an embodiment, the thiazide or thiazide-like diuretic and lorundrostat or pharmaceutically acceptable salt thereof are administered in a combined pharmaceutical composition.

[0068] In an embodiment, the CCB and lorundrostat or pharmaceutically acceptable salt thereof are administered in a combined pharmaceutical composition.

[0069] In an embodiment, the ARB, the thiazide or thiazide-like diuretic, the CCB are administered concomitantly.

[0070] In an embodiment, the amounts when taken together are effective to achieve an additive or a greater than additive therapeutic result in treating the subject.

[0071] In an embodiment, the amount of the ARB is lower than the amount of the ARB that is effective to achieve the same level of treatment of hypertension when administered alone.

[0072] In an embodiment, the amount of the thiazide or thiazide-like diuretic is lower than the amount of the thiazide or thiazide-like diuretic that is effective to achieve the same level of treatment of hypertension when administered alone.

[0073] In an embodiment, the amount of the CCB is lower than the amount of the CCB that is effective to achieve the same level of treatment of hypertension when administered alone.

[0074] In an embodiment, the amount of lorundrostat or pharmaceutically acceptable salt thereof is lower than the amount of the lorundrostat or pharmaceutically acceptable salt thereof that is effective to achieve the same level of treatment of hypertension when administered alone.

[0075] In an embodiment, the amount of the ARB is lower than the amount of the ARB that is effective to achieve the same level of treatment of hypertension when administered in the absence of administration of lorundrostat or pharmaceutically acceptable salt thereof.

[0076] In an embodiment, the amount of the thiazide or thiazide-like diuretic is lower than the amount of the thiazide or thiazide-like diuretic that is effective to achieve the same level of treatment of hypertension when administered in the absence of administration of lorundrostat or pharmaceutically acceptable salt thereof.

[0077] In an embodiment, the amount of the thiazide or thiazide-like diuretic is lower than the amount of the CCB that is effective to achieve the same level of treatment of hypertension whenthe CCB is administered in the absence of administration of lorundrostat or pharmaceutically acceptable salt thereof,

[0078] In an embodiment, the amounts of the ARB, the thiazide or thiazide-like diuretic, and the CCB that are effective to treat hypertension when administered together in the absence of administration of lorundrostat or pharmaceutically acceptable salt thereof cause one or more adverse effects in the subject, wherein the one or more adverse effects are reduced when the amounts ofthe ARB, the thiazide or thiazide-like diuretic, the CCB, are administered together with lorundrostat monohydrobromide.

[0079] In an embodiment, the amount of the ARB, the amount of the thiazide or thiazide-like diuretic, the amount of the CCB, and the amount of lorundrostat or pharmaceutically acceptable salt thereof when administered together are more effective to treat the subject than when each agent at the same amount is administered alone.

[0080] This invention also provides a method of treating hypertension in a hypertensive subject who has been taking three to five anti-hypertensive medications, the method comprising ceasing administration of the three to five anti-hypertensive medications and instead administering to the subject an amount of an angiotensin II receptor blocker (ARB) once per day, an amount of a thiazide or thiazide-like diuretic once per day, an amount of a CCB once per day, and an amount of lorundrostat or a pharmaceutically acceptable salt thereof once per day, wherein the amounts taken together are sufficient to treat hypertension in the hypertensive subject.

[0081] In an embodiment, the ARB is olmesartan, the thiazide or thiazide-like diuretic is indapamide, and the CCB is amlodipine.

[0082] In an embodiment:(a) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 25-75 mg per day, the amount of olmesartan is 10-50 mg per day, the amount of indapamide is 1-5 mg per day, and the amount of amlodipine is 5-10 mg per day; or(b) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 75- 125 mg per day, the amount of olmesartan is 10-50 mg per day, the amount of indapamide is 1-5 mg per day, and the amount of amlodipine is 5-10 mg per day.

[0083] In an embodiment:(a) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 25 mg per day, the amount of olmesartan is 40 mg per day, the amount of indapamide is 2.5 mg per day, and the amount of amlodipine is 10 mg per day;(b) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 40 mg per day, the amount of indapamide is 2.5 mg per day, and the amount of amlodipine is 10 mg per day;(c) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 40 mg per day, the amount of indapamide is 2.5 mg per day, and the amount of amlodipine is 10 mg per day;(d) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 25 mg per day, the amount of olmesartan is 40 mg per day, the amount of indapamide is 2.5 mg per day, and the amount of amlodipine is 5 mg per day;(e) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 40 mg per day, the amount of indapamide is 2.5 mg per day, and the amount of amlodipine is 5 mg per day;(f) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 40 mg per day, the amount of indapamide is 2.5 mg per day, and the amount of amlodipine is 5 mg per day;(g) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 20 mg per day, the amount of indapamide is 2.5 mg per day, and the amount of amlodipine is 10 mg per day;(h) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 20 mg per day, the amount of indapamide is 2.5 mg per day, and the amount of amlodipine is 5 mg per day;(i) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 20 mg per day, the amount of indapamide is 2.5 mg per day, and the amount of amlodipine is 10 mg per day; orG) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 20 mg per day, the amount of indapamide is 2.5 mg per day, and the amount of amlodipine is 5 mg per day.

[0084] In an embodiment the ARB is olmesartan, the thiazide or thiazide-like diuretic is hydrochlorothiazide (HCTZ), and the CCB is amlodipine.

[0085] In an embodiment:(a) the amount of lonmdrostat or pharmaceutically acceptable salt thereof is 25-75 mg per day, the amount of olmesartan is 10-50 mg per day, the amount of HCTZ is 12.5-100 or 12-50 mg per day, and the amount of amlodipine is 5-10 mg per day; or(b) the amount of lonmdrostat or pharmaceutically acceptable salt thereof is 75- 125 mg per day, the amount of olmesartan is 10-50 mg per day, the amount of HCTZ is 12.5-100 or 12-50 mg per day, and the amount of amlodipine is 5-10 mg per day.

[0086] In an embodiment:(a) the amount of lonmdrostat or pharmaceutically acceptable salt thereof is 25 mg per day, the amount of olmesartan is 40 mg per day, the amount of HCTZ is 25 mg per day, and the amount of amlodipine is 10 mg per day;(b) the amount of lonmdrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 40 mg per day, the amount of HCTZ is 25 mg per day, and the amount of amlodipine is 10 mg per day;(c) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 40 mg per day, the amount of HCTZ is 25 mg per day, and the amount of amlodipine is 10 mg per day;(d) the amount of lonmdrostat or pharmaceutically acceptable salt thereof is 25 mg per day, the amount of olmesartan is 40 mg per day, the amount of HCTZ is 25 mg per day, and the amount of amlodipine is 5 mg per day;(e) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 40 mg per day the amount of HCTZ is 25 mg per day, and the amount of amlodipine is 5 mg per day;(f) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 40 mg per day, the amount of HCTZ is 25 mg per day, and the amount of amlodipine is 5 mg per day;(g) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 20 mg per day, the amount of HCTZ is 25 mg per day, and the amount of amlodipine is 10 mg per day;(h) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 20 mg per day, the amount of HCTZ is 25 mg per day, and the amount of amlodipine is 10 mg per day;(i) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 20 mg per day the amount of HCTZ is 25 mg per day, and the amount of amlodipine is 5 mg per day;(j) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 20 mg per day, the amount of HCTZ is 12 mg per day, and the amount of amlodipine is 5 mg per day(k) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 40 mg per day, the amount of HCTZ is 12 mg per day, and the amount of amlodipine is 10 mg per day;(1) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 40 mg per day, the amount of HCTZ is 12 mg per day, and the amount of amlodipine is 10 mg per day;(m) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 40 mg per day the amount of HCTZ is 12 mg per day, and the amount of amlodipine is 5 mg per day;(n) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 40 mg per day, the amount of HCTZ is 12 mg per day, and the amount of amlodipine is 5 mg per day;(o) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 20 mg per day, the amount of HCTZ is 12 mg per day, and the amount of amlodipine is 10 mg per day;(P) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 20 mg per day, the amount of HCTZ is 12 mg per day, and the amount of amlodipine is 10 mg per day;(q) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 20 mg per day the amount of HCTZ is 12 mg per day, and the amount of amlodipine is 5 mg per day; or(r) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 20 mg per day, the amount of HCTZ is 12 mg per day, and the amount of amlodipine is 5 mg per day.

[0087] In an embodiment the lorundrostat or pharmaceutically acceptable salt thereof is the monohydrobromide salt of lorundrostat.

[0088] In an embodiment the hypertensive subject has a body mass index of at least 30, or more than 30.

[0089] In an embodiment the hypertensive subject is a male hypertensive subject having a waist-hip ratio above 0.90, or a female hypertensive subject having a waist-hip ratio above 0.85.

[0090] In an embodiment the hypertensive subject:(a) has a plasma aldosterone concentration of greater than or equal to 6 ng / dL immunoassay in said subject;(b) has a plasma aldosterone concentration of greater than or equal to 1 ng / dL by LC-MS in said subject;(c) has an estimated glomerular filtration rate (eGFR) >45 mL / min / 1.73 m2, preferably wherein the eGFR of the subject is reduced by less than 25% relative to the eGFR of the subject prior to administration of lorundrostat;(d) has a serum potassium <4.8 mmol / L or <5 mmol / L;(e) has a serum sodium >135 mmol / L;(f) does not have a history of clinically significant hyponatremia;(g) does not have a history of adrenal insufficiency;(h) does not have orthostatic hypotension;(i) does not have autonomic dysfunction;0) does not have an arm circumference of >55 centimeters;(k) does not have heart failure, myocardial infarction, stroke, or transient ischemic attack within the previous 6 months;(1) does not have diabetes mellitus with a glycosylated hemoglobin (HbA 1 c) >10%(>86 mmol / mol); and / or(m) does not have a glycosylated hemoglobin (HbAlc) >10% (>86 mmol / mol).

[0091] This invention also provides a method of treating hypertension in a subject afflicted with hypertension who is taking two anti-hypertensive medications, the method comprising:(a) receiving an identification of the subject as having(i) a systolic blood pressure of 140-180 mmHg and a diastolic BP of 65- 110 mmHg; or(ii) a diastolic BP of 90- 110 mmHg; and(b) ceasing administration of the two anti -hypertensive medications and instead administering to said subject an effective amount of olmesartan, indapamide or hydrochlorothiazide, and lorundrostat or a pharmaceutically acceptable salt thereof.

[0092] In an embodiment:(a) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 25-75 mg per day, preferably 25 mg per day or 50 mg per day, the amount of olmesartan is 10-50 mg per day, preferably 40 mg per day, the amount of indapamide, if administered, is 1-5 mg per day, preferably 2.5 mg per day, and the amount of hydrochlorothiazide, if administered is 12.5-100 or 12-50 mg per day; or(b) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 75- 125 mg per day, preferably 100 mg per day, the amount of olmesartan is 10-50 mg per day, preferably 40 mg per day, the amount of indapamide, if administered, is 1 -5 mg per day, preferably 2.5 mg per day, and the amount of hydrochlorothiazide, if administered is 12.5-100 or 12-50 mg per day.

[0093] This invention also provides a method of treating hypertension in a subject afflicted with hypertension who is taking three to five anti-hypertensive medications, the method comprising:(a) receiving an identification of the subject as having(i) a systolic blood pressure of 140-180 mmHg in said subject and a diastolic BP of 65-110 mmHg in said subject; or(ii) a diastolic BP of 90- 110 mmHg in said subject; and(b) ceasing administration of the three to five anti-hypertensive medications and instead administering to said subject an effective amount of olmesartan, indapamide or hydrochlorothiazide, amlodipine and lorundrostat or a pharmaceutically acceptable salt thereof.

[0094] In an embodiment:(a) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 25-75 mg per day, preferably 25 mg per day or 50 mg per day, the amount of olmesartan is 10-50 mg per day, preferably 40 mg per day, the amount of indapamide, if administered, is 1-5 mg per day, preferably 2.5 mg per day, the amount of hydrochlorothiazide, if administered, is 12.5-100 or 12-50 mg per day, preferably 25 mg per day, and the amount of amlodipine is 5-10 mg per day, preferably 5 mg per day or 10 mg per day; or(b) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 75- 125 mg per day, preferably 100 mg per day, the amount of olmesartan is 10-50 mg per day, preferably 40 mg per day, the amount of indapamide, if administered, is 1-5 mg per day, preferably 2.5 mg per day, the amount of hydrochlorothiazide, if administered, is 12.5-100 or 12-50 mg per day, preferably 25 mg per day, and the amount of amlodipine is 5-10 mg per day, preferably 5 mg per day or 10 mg per day.

[0095] In an embodiment step (a) further comprises receiving an identification of the subject as:(a) having a body mass index (BMI) of at least 30 or more than 30, or a waist-hip ratio above 0.90 if the hypertensive subject is male, or a waist -hip ratio above 0.85 in said subject if the hypertensive subject is female;(b) having a plasma aldosterone concentration of greater than or equal to 6 ng / dL as measured by immunoassay;(c) having a plasma aldosterone concentration of greater than or equal to 1 ng / dL as measured by LC-MS;(d) having an estimated glomerular filtration rate (eGFR) >45 mL / min / 1.73 m2;(e) having a serum potassium <4.8 or <5 mmol / L;(f) having a serum sodium >135 mmol / L;(g) not having history of clinically significant hyponatremia;(h) not having a history of adrenal insufficiency;(i) not having orthostatic hypotension;CD not having autonomic dysfunction;(k) not having an arm circumference of >55 centimeters;(1) not having heart failure, myocardial infarction, stroke, or transient ischemic attack within 6 months prior to the administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and CCB, if administered; and / or(m) not having diabetes mellitus with a glycosylated hemoglobin (HbAlc) >10% (>86 mmol / mol).

[0096] Ln an embodiment, the ARB, thiazide or thiazide-like diuretic, lorundrostat or pharmaceutically acceptable salt thereof, and CCB, if administered, are administered in the morning.

[0097] In an embodiment, the ARB, thiazide or thiazide-like diuretic, lorundrostat or pharmaceutically acceptable salt thereof, and CCB, if administered:(a) are administered daily for at least one week;(b) are administered daily for at least two weeks;(c) are administered daily for at least four weeks;(d) are administered daily for at least eight weeks; or(e) are administered daily for at least twelve weeks.

[0098] In an embodiment, the lorundrostat or pharmaceutically acceptable salt thereof is the monohydrobromide salt of lorundrostat.

[0099] In any one of the above embodiments:(a) the hypertensive subject’s systolic blood pressure is reduced by at least 5 mmHg, by 5-10 mmHg, by 5-15 mmHg, by 5-20 mmHg, by 5-25 mmHg, by 5-30 mmHg, 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 hypertensive subject’s systolic blood pressure prior to administration of the ARB, the thiazide or thiazide-like diuretic, lorundrostat or pharmaceutically acceptable salt thereof, and CCB, if administered, for a period of at least four, eight or twelve weeks;(b) the hypertensive subject’s diastolic blood pressure is reduced by at least 5 mmHg, by 5-25 mmHg, by 5-20 mmHg, or by 5-15 mmHg relative to the hypertensive subject’s diastolic blood pressure prior to administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat or pharmaceutically acceptable salt thereof, and CCB, if administered, for a period of at least four, eight or twelve weeks;(C) the hypertensive subject’s systolic blood pressure is reduced to 130mmHg or less; and / or(d) the hypertensive subject’s diastolic blood pressure is reduced to SOmmHg or less.

[0100] In any one of the above embodiments:(a) the hypertensive subject’s 24-hour mean ambulatory systolic blood pressure is reduced by at least 5 mmHg, by 5-10 mmHg, by 5-15 mmHg, by 5-20 mmHg, by 5-25 mmHg, by 5-30 mmHg, by at least 10 mmHg, by 10-55 mmHg, by 1 fl- 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 hypertensive subject’s 24-hour mean ambulatory systolic blood pressure prior to administration of the ARB, the thiazide or thiazide-like diuretic, lorundrostat or pharmaceutically acceptable salt thereof, and CCB, if administered, for a period of at least four, eight or twelve weeks; and / or(b) the hypertensive subject’s 24-hour mean ambulatory diastolic blood pressure is reduced by at least 5 mmHg, by 5-25 mmHg, by 5-20 mmHg, or by 5-15 mmHg relative to the hypertensive subject’s 24-hour mean ambulatory diastolic blood pressure prior to administration of the ARB, thiazide or thiazide-like diuretic,lorundrostat or pharmaceutically acceptable salt thereof, and CCB, if administered, for a period of at least four, eight or twelve weeks;(c) the hypertensive subject’s daytime mean ambulatory systolic blood pressure is reduced by at least 5 mmHg, by 5-10 mmHg, by 5-15 mmHg, by 5-20 mmHg, by 5-25 mmHg, by 5-30 mmHg, by at least 10 mmHg, by 10-55 mmHg, by 1 fl- 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 hypertensive subject’s daytime mean ambulatory systolic blood pressure prior to administration of the ARB, the thiazide or thiazide-like diuretic, lorundrostat or pharmaceutically acceptable salt thereof, and CCB, if administered, for a period of at least four, eight or twelve weeks; and / or(d) the hypertensive subject’s daytime mean ambulatory diastolic blood pressure is reduced by at least 5 mmHg, by 5-25 mmHg, by 5-20 mmHg, or by 5-15 mmHg relative to the hypertensive subject’s daytime mean ambulatory diastolic blood pressure prior to administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat or pharmaceutically acceptable salt thereof, and CCB, if administered, for a period of at least four, eight or twelve weeks;(e) the hypertensive subject’s 24-hour mean central systolic blood pressure is reduced by at least 5 mmHg, by 5-10 mmHg, by 5-15 mmHg, by 5-20 mmHg, by 5-25 mmHg, by 5-30 mmHg, by at least 10 mmHg, by 10-55 mmHg, by 1 fl- 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 hypertensive subject’s 24-hour mean central systolic blood pressure prior to administration of the ARB, the thiazide or thiazide-like diuretic, lorundrostat or pharmaceutically acceptable salt thereof, and CCB, if administered, for a period of at least four, eight or twelve weeks; and / or(0 the hypertensive subject’s 24-hour mean central diastolic blood pressure is reduced by at least 5 mmHg, by 5-25 mmHg, by 5-20 mmHg, or by 5-15 mmHg relative to the hypertensive subject’s 24-hour mean central diastolic blood pressure prior to administration of the ARB, thiazide or thiazide-like diuretic,lorundrostat or pharmaceutically acceptable salt thereof, and CCB, if administered, for a period of at least four, eight or twelve weeks;(g) the hypertensive subject’s 24-hour mean ambulatory systolic blood pressure is reduced to 130mmHg or less; and / or(h) the hypertensive subject’s 24-hour mean ambulatory diastolic blood pressure is reduced to 80mmHg or less.

[0101] In any one of the above embodiments:(a) the hypertensive subject’s aldosterone level follows a substantially normal circadian rhythm;(b) inhibition of CYP l lp2 beta hydroxylase activity by the lorundrostat or pharmaceutically acceptable salt thereof is sufficient to maintain a state of sodium and volume depletion in the hypertensive subject;(c) the method does not produce a persistent state of hyperkalemia or mild nonanion gap metabolic acidosis in the hypertensive subject;(d) the lorundrostat or pharmaceutically acceptable salt thereof does not substantially accumulate in the hypertensive subject, preferably wherein the lack of substantial accumulation of the lorundrostat or pharmaceutically acceptable salt thereof in the hypertensive subject allows for the hypertensive subject’s aldosterone levels to return to pre-drug baseline within 24-48 hours of the lorundrostat or pharmaceutically acceptable salt thereof being administered, more preferably within 16-24 hours of the lorundrostat or pharmaceutically acceptable salt thereof being administered;(e) the hypertensive subject’s potassium levels are generally maintained in a clinically normal range, preferably wherein the hypertensive subject’s potassium levels are mildly elevated relative to the hypertensive subject’s potassium levels prior to administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and CCB, if administered, more preferably wherein the hypertensive subject’s potassium levels are elevated by 0.35 mmol / L or less, more preferably wherein the hypertensive subject’s potassium levels are maintained below a level of 5.5 mmol / L, more preferably wherein thehypertensive subject’s potassium levels are maintained between 3.5 mEq / 1 to 5.1 mEq / 1; and / or(f) the hypertensive subject’s sodium levels are generally maintained in a clinically normal range, preferably wherein the hypertensive subject’s sodium levels are mildly reduced relative to the hypertensive subject’s sodium levels prior to administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and CCB, if administered,, more preferably wherein the hypertensive subject’s sodium levels are maintained above a level of 135 mmoVL;(g) administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, andCCB, if administered, does not cause a reduction of more than 20% 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 administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and CCB, if administered, preferably which does not cause a reduction of more than 10% 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 administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and CCB, if administered;(h) administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and CCB, if administered, does not cause an increase of more than 20% 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 administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and CCB, if administered, preferably which does not cause an increase of more than 10% 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 administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and CCB, if administered; and / or(i) administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and CCB, if administered, does not cause an increase of more than 20% 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 theadministration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, andCCB, if administered, preferably which does not cause an increase of more than 10% 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 ARB, thiazide or thiazide-like diuretic, lorundrostat, and CCB, if administered.

[0102] In any one of the above embodiments:(a) the hypertensive subject’s average systolic blood pressure during sleep is reduced:(i) relative to the hypertensive subject’s average systolic blood pressure during sleep prior to receiving the ARB, thiazide or thiazide-like diuretic, lorundrostat or pharmaceutically acceptable salt thereof, and CCB, if administered;(ii) relative to the hypertensive subject’s average systolic blood pressure during sleep prior to receiving the lorundrostat or pharmaceutically acceptable salt thereof; and / or(iii) relative to the hypertensive subject’s average daytime systolic blood pressure.

[0103] In any one of the above embodiments, the hypertensive subject’s average systolic blood pressure during sleep is reduced:(a) by at least 10%, by between 10% and 40%, by between 10% and 30%, or by between 10% and 20% relative to the hypertensive subject’s average daytime systolic blood pressure;(b) by at least 8 mmHg, by at least lOmmHg, by between 8 and 55 mmHg, by between 10 and 45 mmHg, or by between 10 and 25 mmHg, relative to the hypertensive subject’s average systolic blood pressure during sleep prior to receiving the ARB, thiazide or thiazide-like diuretic, lorundrostat or pharmaceutically acceptable salt thereof, and CCB, if administered; and / or(c) by at least 8 mmHg, by at least lOmmHg, by between 8 and 55 mmHg, by between 10 and 45 mmHg, or by between 10 and 25 mmHg, relative to thehypertensive subject’s average systolic blood pressure during sleep prior to receiving lorundrostat or pharmaceutically acceptable salt thereof.

[0104] In any one of the above embodiments, the hypertensive subject does not have primary aldosteronism, preferably wherein the hypertensive subject has primary hypertension.

[0105] This invention also provides a method of identifying a subject for hypertension treatment with an angiotensin II receptor blocker (ARB), a thiazide or thiazide-like diuretic, and lorundrostat or pharmaceutically acceptable salt thereof, the method comprising:(a) measuring the subject’s systolic blood pressure and diastolic blood pressure; and(b) selecting a subject who is taking two anti-hypertensive medications, and who has:(i) a systolic blood pressure of 140 mmHg and a diastolic blood pressure of 65-110 mmHg; or(ii) a diastolic blood pressure of 90-110 mmHg; thereby identifying said subject for hypertension treatment with the angiotensin II receptor blocker (ARB), the thiazide or thiazide-like diuretic, and lorundrostat or pharmaceutically acceptable salt thereof.

[0106] In an embodiment, the ARB is olmesartan and the thiazide or thiazide-like diuretic is indapamide or hydrochlorothiazide.

[0107] In an embodiment, the subject is identified for treatment with:(a) 25-75 mg per day per day of lorundrostat or pharmaceutically acceptable salt thereof, 10-50 mg per day of olmesartan, and 1 -5 mg per day of indapamide;(b) 25-75 mg per day per day of lorundrostat or pharmaceutically acceptable salt thereof, 10-50 mg per day of olmesartan, and 12.5-100 or 12-50 mg per day of hydrochlorothiazide;(c) 75-125 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 10-50 mg per day of olmesartan, and 1-5 mg per day of indapamide; or(d) 75-125 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 10-50 mg per day of olmesartan, and 12.5-100 or 12-50 mg per day of hydrochlorothiazide.

[0108] In an embodiment, the subject is identified for treatment with:(a) 25 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, and 2.5 mg per day of indapamide;(b) 25 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, and 25 mg per day of hydrochlorothiazide;(c) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, and 2.5 mg per day of indapamide;(d) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, and 25 mg per day of hydrochlorothiazide;(e) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, and 2.5 mg per day of indapamide;(f) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, and 25 mg per day of hydrochlorothiazide;(g) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, and 2.5 mg per day of indapamide;(h) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, and 25 mg per day of hydrochlorothiazide;(i) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, and 2.5 mg per day of indapamide;0) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, and 25 mg per day of hydrochlorothiazide;(k) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, and 12 mg per day of hydrochlorothiazide;(1) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, and 12 mg per day of hydrochlorothiazidel;(m) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, and 12 mg per day of hydrochlorothiazide; or(n) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, and 12 mg per day of hydrochlorothiazide.

[0109] This invention also provides a method of identifying a subject for hypertension treatment with an angiotensin II receptor blocker (ARB), a thiazide or thiazide-like diuretic, acalcium channel blocker (CCB), and lorundrostat or a pharmaceutically acceptable salt thereof, the method comprising:(a) measuring the subject’s systolic blood pressure and diastolic blood pressure; and(b) selecting a subject who is taking three to five anti-hypertensive medications and who has:(i) a systolic blood pressure of 140 mmHg and a diastolic blood pressure of 65-110 mmHg; or(ii) a diastolic blood pressure of 90-110 mmHg; thereby identifying said subject for hypertension treatment with the angiotensin II receptor blocker (ARB), the thiazide or thiazide-like diuretic, the CCB, and the lorundrostat or pharmaceutically acceptable salt thereof.

[0110] In an embodiment, the ARB is olmesartan, the thiazide or thiazide-like diuretic is indapamide or hydrochlorothiazide, and the CCB is amlodipine.

[0111] In an embodiment, the subject is identified for treatment with;(a) 25-75 mg per day per day of lorundrostat or pharmaceutically acceptable salt thereof, 10-50 mg per day of olmesartan, 1-5 mg per day of indapamide, and 5- 10 mg per day of amlodipine;(b) 25-75 mg per day per day of lorundrostat or pharmaceutically acceptable salt thereof, 10-50 mg per day of olmesartan, 12,5-100 or 12-50 mg per day of hydrochlorothiazide, and 5-10 mg per day of amlodipine;(c) 75-125 mg per day per day of lorundrostat or pharmaceutically acceptable salt thereof, 10-50 mg per day of olmesartan, 1-5 mg per day of indapamide, and 5- 10 mg per day of amlodipine; or(d) 75-125 mg per day per day of lorundrostat or pharmaceutically acceptable salt thereof, 10-50 mg per day of olmesartan, 12.5-100 or 12-50 mg per day of hydrochlorothiazide, and 5-10 mg per day of amlodipine.

[0112] In an embodiment, the subject is identified for treatment with:(a) 25 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 2.5 mg per day of indapamide, and 10 mg per day of amlodipine;(b) 25 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 10 mg per day of amlodipine;(c) 25 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 2.5 mg per day of indapamide, and 5 mg per day of amlodipine;(d) 25 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 5 mg per day of amlodipine;(e) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 2.5 mg per day of indapamide, and 10 mg per day of amlodipine;(f) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 10 mg per day of amlodipine;(g) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 2.5 mg per day of indapamide, and 5 mg per day of amlodipine;(h) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 5 mg per day of amlodipine;(i) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 2.5 mg per day of indapamide, and 10 per day mg of amlodipine;(D 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 10 mg per day of amlodipine;(k) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 2.5 mg per day of indapamide, and 5 mg per day of amlodipine;(1) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 5 mg per day of amlodipine;(m) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, 2.5 mg per day of indapamide, and 10 mg per day of amlodipine;(n) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 10 mg per day of amlodipine;(o) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, 2.5 mg per day of indapamide, and 5 mg per day of amlodipine;(P) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 5 mg per day of amlodipine;(q) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, 2.5 mg per day of indapamide, and 10 per day mg of amlodipine;(r) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 10 mg per day of amlodipine;(s) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, 2.5 mg per day of indapamide, and 5 mg per day of amlodipine;(t) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 5 mg per day of amlodipine;(u) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 12 mg per day of hydrochlorothiazide, and 10 mg per day of amlodipine;(V) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 12 mg per day of hydrochlorothiazide, and 5 mg per day of amlodipine;(w) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 12 mg per day of hydrochlorothiazide, and 10 mg per day of amlodipine;(X) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 12 mg per day of hydrochlorothiazide, and 5 mg per day of amlodipine;(y) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, 12 mg per day of hydrochlorothiazide, and 10 mg per day of amlodipine;(z) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, 12 mg per day of hydrochlorothiazide, and 5 mg per day of amlodipine;(aa) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, 12 mg per day of hydrochlorothiazide, and 10 mg per day of amlodipine; or(bb) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, 12 mg per day of hydrochlorothiazide, and 5 mg per day of amlodipine.

[0113] In an embodiment, step (a) further comprises determining one or more or all of the following:(a) the subject’s body mass index and / or waist-hip ratio;(b) the subject’s plasma aldosterone concentration, preferably by immunoassay orLC-MS; and / or(c) the subject’s estimated glomerular filtration rate (eGFR);(d) the subject’s serum potassium;(e) the subject’s serum sodium;(f) the subject’s history of clinically significant hyponatremia;(g) the subject’s history of adrenal insufficiency;(h) the subject’s history of orthostatic hypotension;(i) the subject’s history of autonomic dysfunction;G) the subject’s arm circumference;(k) the subject’s history of heart failure, myocardial infarction, stroke, or transient ischemic attack within the previous 6 months;(1) the subject’s history of having diabetes mellitus with a glycosylated hemoglobin (HbAfc) >10% (>86 mmol / mol); and(m) the subject’s glycosylated hemoglobin (HbAlc).

[0114] In an embodiment, step b) further comprises selecting:(a) a subject who has a body mass index (BMI) of at least 30 or more than 30, or a waist-hip ratio above 0.90 if the subject is male, or a waist-hip ratio above 0.85 if the subject is female;(b) a subject who has a plasma aldosterone concentration of greater than or equal to 6 ng / dL immunoassay in said subject;(c) a subject who has a plasma aldosterone concentration of greater than or equal to 1 ng / dL by LC-MS in said subject;(d) a subject who has an estimated glomerular filtration rate (cGFR) >45 mL / min / 1.73 m2, preferably wherein the eGFR of the subject is reduced by less than 25% relative to the eGFR of the subject prior to administration of lorundrostat;(e) a subject who has a serum potassium <4.8 or <5 mmol / L;(f) a subject who has a serum sodium >135 mmol / L;(g) a subject who does not have a history of clinically significant hyponatremia;(h) a subject who does not have a history of adrenal insufficiency;(i) a subject who does not have orthostatic hypotension;G) a subject who does not have autonomic dysfunction;(k) a subject who does not have an arm circumference of >55 centimeters;(1) a subject who does not have heart failure, myocardial infarction, stroke, or transient ischemic attack within the previous 6 months;(m) a subject who does not have diabetes mellitus with a glycosylated hemoglobin (HbAlc) >10% (>86 mmol / mol);(n) a subject who does not have a glycosylated hemoglobin (HbAlc) >10% (>86 mmol / mol).

[0115] This invention also provides use of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, for treating hypertension in a subject afflicted with hypertension in combination with an angiotensin II receptor blocker (ARB), a thiazide or thiazide-like diuretic, and optionally a CCB, preferably wherein the ARB is olmesartan, the thiazide or thiazide-like diuretic is indapamide or hydrochlorothiazide, and the CCB, if present, is amlodipine.Compositions

[0116] This invention also provides lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, for use in treating hypertension in a subject afflicted with hypertension in combination with an angiotensin II receptor blocker (ARB), a thiazide or thiazide-like diuretic, and optionally a CCB, preferably wherein the ARB is olmesartan, the thiazide or thiazide-like diuretic is indapamide or hydrochlorothiazide, and the CCB, if present, is amlodipine.

[0117] This invention also provides a package comprising:(a) a first pharmaceutical composition comprising an amount of lorundrostat or pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, and a pharmaceutically acceptable carrier;(b) a second pharmaceutical composition comprising an amount of an angiotensin II receptor blocker (ARB) and a pharmaceutically acceptable carrier;(c) a third pharmaceutical composition comprising an amount of a thiazide or thiazide-like diuretic and a pharmaceutically acceptable carrier; and(d) instructions for use of the first, second, and third pharmaceutical compositions together to treat a subject afflicted with hypertension.

[0118] This invention also provides a package comprising:(a) one of:(i) (I) a first pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, an amount of an angiotensin II receptor blocker (ARB), and a pharmaceutically acceptable carrier; and(II) a second pharmaceutical composition comprising an amount of a thiazide or thiazide-like diuretic and a pharmaceutically acceptable carrier;(ii) (I) a first pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, an amount of a thiazide or thiazide- like diuretic, and a pharmaceutically acceptable carrier; and (II) a second pharmaceutical composition comprising an amount of an ARB and a pharmaceutically acceptable carrier; or(iii) (I) a first pharmaceutical composition comprising an amount of an ARB, an amount of a thiazide or thiazide-like diuretic, and a pharmaceutically acceptable carrier; and (IT) a second pharmaceutical composition comprising an aammoouunntt of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, and a pharmaceutically acceptable carrier; and(b) instructions for use of the first and second pharmaceutical compositions together to treat a subject afflicted with hypertension.

[0119] This invention also provides a package comprising:(a) one of following sets of pharmaceutical compositions:(i) a first pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, an amount of an angiotensin II receptor blocker (ARB), and a pharmaceutically acceptable carrier; and a second pharmaceutical composition comprising an amount of a thiazide or thiazide-like diuretic, an amount of a CCB, and a pharmaceutically acceptable carrier;(ii) a first pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, an amount of an ARB, and a pharmaceutically acceptable carrier; aa second pharmaceutical composition comprising an amount of a thiazide or thiazide-like diuretic and a pharmaceutically acceptable carrier, and a third pharmaceutical composition comprising an amount of a CCB, and a pharmaceutically acceptable carrier;(iii) a first pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, an amount of a thiazide or thiazide- like diuretic, and a pharmaceutically acceptable carrier; and a second pharmaceutical composition comprising an amount of an ARB, an amount of a CCB, and a pharmaceutically acceptable carrier;(iv) a first pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, an amount of a thiazide or thiazide- like diuretic, and a pharmaceutically acceptable carrier; a second pharmaceutical composition comprising an amount of an ARB and a pharmaceutically acceptable carrier, and a third pharmaceutical composition comprising an amount of a CCB and a pharmaceutically acceptable carrier;(v) a first pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, an amount of a CCB, and a pharmaceutically acceptable carrier; and a second pharmaceutical composition comprising an amount of thiazide or thiazide-like diuretic, an amount of an ARB, and a pharmaceutically acceptable carrier;(vi) a first pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, an amount of a CCB, and apharmaceutically acceptable carrier; and a second pharmaceutical composition comprising an amount of thiazide or thiazide-like diuretic, and a pharmaceutically acceptable carrier, and a third pharmaceutical composition comprising an amount of an ARB and a pharmaceutically acceptable carrier;(vii) a first pharmaceutical composition comprising an amount of an ARB, an amount of a CCB, and a pharmaceutically acceptable carrier; a second pharmaceutical composition comprising an amount of thiazide or thiazide-like diuretic, and a pharmaceutically acceptable carrier, and a third pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, and a pharmaceutically acceptable carrier;(viii) a first pharmaceutical composition comprising an amount of an thiazide or thiazide-like diuretic, an amount of a CCB, and a pharmaceutically acceptable carrier; a second pharmaceutical composition comprising an amount of an ARB and a pharmaceutically acceptable carrier, and a third pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, and a pharmaceutically acceptable carrier;(ix) a first pharmaceutical composition comprising an amount of an thiazide or thiazide-like diuretic, an amount of an ARB, and a pharmaceutically acceptable carrier; a second pharmaceutical composition comprising an amount of a CCB and a pharmaceutically acceptable carrier, and a third pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, and a pharmaceutically acceptable carrier;(x) a first pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, an amount of an ARB, an amount of a thiazide or thiazide-like diuretic, and a pharmaceutically acceptablecarrier; and a second pharmaceutical composition comprising an amount of a CCB and a pharmaceutically acceptable carrier;(xi) a first pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, an amount of an ARB, an amount of a CCB, and a pharmaceutically acceptable carrier; and a second pharmaceutical composition comprising an amount of a thiazide or thiazide-like diuretic and a pharmaceutically acceptable carrier;(xii) a first pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, an amount of a thiazide or thiazide- like diuretic, an amount of a CCB, and a pharmaceutically acceptable carrier; and a second pharmaceutical composition comprising an amount of an ARB and a pharmaceutically acceptable carrier;(xiii) a first pharmaceutical composition comprising an amount of an ARB, an amount of a thiazide or thiazide-like diuretic, an amount of a CCB, and a pharmaceutically acceptable carrier; and a second pharmaceutical composition comprising an a ammoouunntt of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, and a pharmaceutically acceptable carrier;(b) instructions for use of the pharmaceutical compositions together to treat a subject afflicted with hypertension.

[0120] This invention also provides a package comprising:(a) a first pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, and a pharmaceutically acceptable carrier;(b) a second pharmaceutical composition comprising an amount of an angiotensin II receptor blocker (ARB) and a pharmaceutically acceptable carrier;(c) a third pharmaceutical composition comprising an amount of a thiazide or thiazide-like diuretic;(d) a fourth pharmaceutical composition comprising an amount of a CCB; and(e) instructions for use of the first, second, third, and fourth pharmaceutical compositions together to treat a subject afflicted with hypertension.

[0121] This invention also provides a pharmaceutical composition comprising:(a) an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide;(b) an amount of angiotensin II receptor blocker (ARB) or a pharmaceutically acceptable salt thereof;(c) an amount of thiazide or thiazide-like diuretic or a pharmaceutically acceptable salt thereof;(d) optionally an amount of a calcium channel blocker (CCB) or a pharmaceutically acceptable salt thereof; wherein the lorundrostat or pharmaceutically acceptable salt thereof, ARB, thiazide or thiazide-like diuretic, and CCB, if present, are administered simultaneously, contemporaneously or concomitantly.

[0122] This invention also provides a pharmaceutical composition comprising:(a) an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide;(b) an amount of an angiotensin II receptor blocker (ARB) or a pharmaceutically acceptable salt thereof;(c) an amount of a thiazide or thiazide-like diuretic or a pharmaceutically acceptable salt thereof;(d) optionally an amount of a calcium channel blocker (CCB) or a pharmaceutically acceptable salt thereof; wherein the lorundrostat or a pharmaceutically acceptable salt thereof, ARB, thiazide or thiazide-like diuretic, and CCB, if present, are each present in amounts which together are effective to treat hypertension in a hypertensive subject.

[0123] This invention also provides a pharmaceutical composition comprising an amount of lorundrostat oorr aa pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, for use in treating hypertension in a subject afflicted with hypertension incombination with an angiotensin n receptor blocker (ARB), a thiazide or thiazide-like diuretic, and optionally a calcium channel blocker (CCB).

[0124] This invention also provides a pharmaceutical composition in unit dosage form, useful in treating a subject afflicted with hypertension, which comprises:(a) an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide;(b) an amount of an angiotensin II receptor blocker (ARB) or a pharmaceutically acceptable salt thereof;(c) an amount of a thiazide or thiazide-like diuretic or a pharmaceutically acceptable salt thereof; and(d) optionally an amount of a calcium channel blocker (CCB) or a pharmaceutically acceptable salt thereof; wherein the respective amounts of said lorundrostat a pharmaceutically acceptable salt thereof, said ARB, said thiazide or thiazide-like diuretic, and said CCB, if present, in said composition are effective, upon concomitant administration to said subject of one or more of said unit dosage forms of said composition, to treat the subject.

[0125] This invention also provides a therapeutic package for dispensing to, or for use in dispensing to, a subject afflicted with hypertension, which comprises:(a) one or more unit doses, each such unit dose comprising:(i) an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide;(ii) an amount of an angiotensin II receptor blocker (ARB) or a pharmaceutically acceptable salt thereof;(iii) an amount of a thiazide or thiazide-like diuretic or a pharmaceutically acceptable salt thereof; and(iv) optionally an amount of a calcium channel blocker (CCB) or a pharmaceutically acceptable salt thereof; wherein the respective amounts of said lorundrostat or a pharmaceutically acceptable salt thereof, said ARB, said thiazide or thiazide-like diuretic, and said CCB, if present, in said unit doses are effective, upon concomitant administration to said subject, to treat the subject, and(b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of said subject.

[0126] In embodiments of the above-described packages, pharmaceutical compositions, and therapeutic packages, the ARB is olmesartan, the thiazide or thiazide-like diuretic is indapamide or hydrochlorothiazide, and the CCB, if present, is amlodipine.

[0127] In embodiments of the above-described packages, pharmaceutical compositions, and therapeutic packages, the pharmaceutical composition, unit dose, or unit dosage form comprises:(a) 25-75 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 10-50 mg of olmesartan, 1-5 mg of indapamide, if present, 12.5-100 or 12-50 mg of hydrochlorothiazide, if present, and, 5-10 mg of amlodipine, if present; or(b) 25-75 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 10-50 mg of olmesartan, 1-5 mg of indapamide, if present, 12,5-100 or 12-50 mg of hydrochlorothiazide, if present, and, 5-10 mg of amlodipine, if present.(c) The package, pharmaceutical composition, or therapeutic package of claim 64, wherein the pharmaceutical composition, unit dose, or unit dosage form comprises:(d) 25 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 40 mg of olmesartan, and 2.5 mg of indapamide;(e) 25 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 40 mg of olmesartan, and 25 mg of hydrochlorothiazide;(0 25 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 40 mg of olmesartan, 2.5 mg of indapamide, and 10 mg of amlodipine;(g) 25 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 40 mg of olmesartan, 25 mg of hydrochlorothiazide, and 10 mg of amlodipine;(h) 25 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 40 mg of olmesartan, 2.5 mg of indapamide, and 5 mg of amlodipine;(i) 25 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 40 mg of olmesartan, 25 mg of hydrochlorothiazide, and 5 mg of amlodipine;(j) 50 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 40 mg of olmesartan, and 2.5 mg of indapamide;(k) 50 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 40 mg of olmesartan, and 25 mg of hydrochlorothiazide;(1) 50 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 40 mg of olmesartan, 2.5 mg of indapamide, and 10 mg of amlodipine;(m) 50 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 40 mg of olmesartan, 25 mg of hydrochlorothiazide, and 10 mg of amlodipine;(n) 50 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 40 mg of olmesartan, 2.5 mg of indapamide, and 5 mg of amlodipine;(o) 50 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 40 mg of olmesartan, 25 mg of hydrochlorothiazide, and 5 mg of amlodipine;(P) 100 mg of lorundrostat, 40 mg of olmesartan, and 2.5 mg of indapamide;(q) 100 mg of lorundrostat, 40 mmgg of olmesartan, and 25 mg of hydrochlorothiazide;(r) 100 mg of lorundrostat, 40 mg of olmesartan, 2.5 mg of indapamide, and 10 mg of amlodipine;(s) 100 mg of lorundrostat, 40 mg of olmesartan, 25 mg of hydrochlorothiazide, and 10 mg of amlodipine;(t) 100 mg of lorundrostat, 40 mg of olmesartan, 2.5 mg of indapamide, and 5 mg of amlodipine; or(u) 100 mg of lorundrostat, 40 mg of olmesartan, 25 mg of hydrochlorothiazide, and 5 mg of amlodipine.

[0128] In embodiments of the above-described packages, pharmaceutical compositions, and therapeutic packages, the lorundrostat or pharmaceutically acceptable salt thereof is the monohydrobromide salt of lorundrostat.Definitions

[0129] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions,will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

[0130] In the discussion unless otherwise stated, adjectives such as “substantially” and “about” modifying a condition or relationship characteristic of a feature or features of an embodiment of the invention, are understood to mean that the condition or characteristic is defined to within tolerances that are acceptable for operation of the embodiment for an application for which it is intended. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to + / - 10% of the specified value. In embodiments, about includes the specified value. Unless otherwise indicated, the word “or” in the specification and claims is considered to be the inclusive “or” rather than the exclusive or, and indicates at least one of and any combination of items it conjoins.

[0131] It should be understood that the terms “a” and “an” as used above and elsewhere herein refer to “one or more” of the enumerated components. It will be clear to one of ordinary skill in the art that the use of the singular includes the plural unless specifically stated otherwise. Therefore, the terms “a,” “an” and “at least one” are used interchangeably in this application.

[0132] For purposes of better understanding the present teachings and in no way limiting the scope of the teachings, unless otherwise indicated, all numbers expressing quantities, percentages or proportions, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0133] In the description and claims of the present application, each of the verbs, “comprise," “include” and “have” and conjugates thereof, are used to indicate that the object or objects of the verb are not necessarily a complete listing of components, elements or parts of the subject or subjects of the verb. Other terms as used herein are meant to be defined by their well-known meanings in the art.

[0134] “Hypertension”, also called high blood pressure, is blood pressure that is higher than normal. In 2017, the American College of Cardiology and the American Heart Associationpublished guidelines for hypertension management and defined hypertension as a blood pressure at or above 130 mmHg systolic blood pressure, 80 mmHg diastolic blood pressure. Stage 1 hypertension is defined as a blood pressure of 130-139 mmHg systolic blood pressure, 80-89 mmHg diastolic blood pressure, while stage 2 hypertension is defined as a blood pressure of greater than 140 mmHg systolic blood pressure, 90 mmHg diastolic blood pressure. As used herein, “hypertension” includes both stages 1 and 2 of hypertension unless indicated to the contrary. In an embodiment, the hypertensive subject has stage 1 hypertension. In another embodiment, the hypertensive subject has stage 2 hypertension. Hypertension includes high blood pressure that is multi-factorial and doesn’t have one distinct cause (primary hypertension), and high blood pressure that has a direct cause (secondary hypertension). As used herein, “hypertension" includes both primary and secondary hypertension unless indicated to the contrary. In embodiments, the hypertensive subject has primary hypertension. In other embodiments, the hypertensive subject has secondary hypertension. Primary aldosteronism (hyperaldosteronism), the most common form of secondary hypertension, is a condition that occurs when the adrenal glands produce too much aldosterone. In embodiments where the hypertensive subject has secondary hypertension, the subject has primary aldosteronism.

[0135] “ “CCYYPP11110022””,, “ “CCyyppll llBB22”” oorr “CYP1102 beta hydroxylase” is a cytochrome P450 enzyme, encoded by the CYP11B2 gene in humans, which catalyzes a series of reactions leading from 11 -deoxycorticosterone (i.e., an aldosterone precursor) to aldosterone. Thus, it is referred to in the art as “aldosterone synthase.” Cypl 1B2 is mainly expressed in an adrenal cortex spherical layer and a level of plasma aldosterone is regulated by enzymatic activity of Cypl 1B2 present in the adrenal gland. Aldosterone is expressed in other tissues, such as cardiovascular, kidney, adipose, and brain.

[0136] “CYPl lpl”, “Cypl lBl” or “CYP1101 beta hydroxylase” is a cytochrome P450 enzyme, encoded by the CYP11B1 gene in humans, which is involved in the biosynthesis of adrenal corticosteroids. It is referred to in the art as “steroid 110-hydroxylase.”

[0137] An “inhibitor” refers to a compound (e.g. compounds described herein) that reduces activity when compared to a control, such as absence of the compound or a compound with known inactivity. An inhibitor can be a small molecule inhibitor, an antibody inhibitor, a protein inhibitor,a biomolecule inhibitor, a natural ligand, and the like. An “inhibitor” may be in the form of a pharmaceutically acceptable salt, e.g. of the compounds described herein.

[0138] As used herein “lorundrostat” refers to 7V-[ / rans,-4-(acetylamino)cyclohexyl]-2-{4-[5- (4- methylphenyl)-! , 2, 4-triazin-3-yl]piperazin-l-yl} acetamide. As used herein “lorundrostat HBr” or “lorundrostat hydrobromide” refers to the hydrobromide salt of lorundrostat, i.e. N-Ytrans-4- (acetylamino)cyclohexyl]-2-{4-[5-(4- methylphenyl)-!, 2, 4-triazin-3-yl]piperazin-l-yl} acetamide monohydrobromide. Weights and / or strengths of “lorundrostat” and “the compound” of the invention refer to the weight of the free base in the monohydrobromide salt and not the weight of the salt.

[0139] Lorundrostat can be made by the processes described, for example, in US Patent No. 10,029,993 and European Publication No. 3549935, the disclosures of which are incorporated by reference herein in their entirety.

[0140] “Treating” or “treatment” as used herein (and as well-understood in the art) also broadly includes any approach for obtaining beneficial or desired results in a subject’s condition, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (i.e., not worsening) the state of disease, prevention of a disease’s transmission or spread, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable. In other words, “treatment" as used herein includes any cure, amelioration, or prevention of a disease. Treatment may prevent the disease from occurring; inhibit the disease’s spread; relieve the disease’s symptoms, fully or partially remove the disease’s underlying cause, shorten a disease’s duration, or do a combination of these things.

[0141] “Treating" and “treatment" as used herein include prophylactic treatment. Treatment methods include administering to a subject a therapeutically effective amount of an active agent. The administering step may be a single administration or may include a series of administrations. The length 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 active agent, the activity of the compositions used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of aparticular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In embodiments, chronic administration may be required. For example, the compositions are administered to the subject in an amount and for a duration sufficient to treat the patient. In embodiments, the treating or treatment is not prophylactic treatment.

[0142] A “diuretic” refers to a hypertension medication that increases the production of urine, thereby increasing the amount of water and salt eliminated from the body. A diuretic can be a carbonic anhydrase inhibitor, a loop diuretic, a potassium-sparing diuretic, a thiazide or thiazide- like diuretic, or any other diuretic known in the art. Exemplary carbonic anhydrase inhibitors include acetazolamide, brinzolamide, dorzolamide, dichlorphenamide, ethoxaolamide, zoniamide, indisulam, and methazolamide. Exemplary loop diuretics include bumatenide, ethacrynic acid, torsemide, and furosemide. Exemplary potassium-sparing diuretics include epelerenone, triamterene, spironolactone, and amiloride. Exemplary thiazide or thiazide-like diuretics include indapamide, hydrochlorothiazide, chlorthalidone, metolazone, methyclothiazide, chlorothiazide, methylclothiazide, metolazone, bendroflumethiazide, polythiazide, and hydroflumethiazide. Other diuretics include pamabrom and mannitol.

[0143] AAnn “angiotensin-converting enzyme inhibitor” or “ACE inhibitor” refers to a hypertension medication that block angiotensin I from being converted to angiotensin n, thereby dilating blood vessels and lowering blood pressure. Exemplary ACE inhibitors include benazepril, zofenopril, perindopril, trandolapril, captopril, enalapril, lisinopril, and ramipril.

[0144] An “angiotensin receptor blocker” or “angiotensin II inhibitor" refers to a hypertension medication that blocks the receptor binding of angiotensin II, thereby dilating blood vessels and lowering blood pressure. Exemplary angiotensin receptor blockers include eprosartan, olmesartan, valsartan, candesartan, losartan, telmisartan, irbesartan, valsartan, and azilsartan medoxomil.

[0145] AA “ “ccaallcciiuumm cchhaannnneell bblloocckkeerr”” oorr “CCB” refers to hypertension medication that can block calcium from entering the cells of the heart and arteries via a calcium channel, thereby lowering blood pressure. A calcium channel blocker can be a dihydropyridine calcium channel blocker, a phenylalkyl amine calcium channel blocker, a benzothiazepine calcium channel blocker, a nonselective calcium channel blocker, or any other calcium channel blocker known in the art. Dihydropyridine calcium channel blockers include 481mesartan, aranidipine, azelnidipine,bamidipine, benidipine, cilnidine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, and pranidipine. Phenylalkylamine calcium channel blockers include fendiline, gallipamil, and verapamil. Benzothiazepine calcium channel blockers include diltiazem. Nonselective calcium channel blockers include mibefradil, bepridil, flunarizine, fluspirilene, and fendiline. Other calcium channel blockers include gabapentin, pregabalin, and ziconotide.

[0146] The amounts to be administered of any of the aforementioned ARBs, ACEis, thiazide or thiazide-like diuretics, or calcium channel blockers may be determined by reference to the “Prescriber’s Digital Reference”, accessible at pdr.net, the contents of which is specifically incorporated by reference for its description of the amounts of the aforementioned ARBs, ACEis, thiazide or thiazide-like diuretics, and calcium channel blockers to be used in the treatment of hypertension.

[0147] A “normal circadian rhythm” for aldosterone level follows a diurnal pattern wherein the nadir is in the late evening and the peak is in the early morning, pre-arousaL In an embodiment, the hypertensive subject’s aldosterone level follows a substantially normal circadian rhythm. In one example of such an embodiment, the CYP 1102 beta hydroxylase inhibitor of the invention, when dosed once daily in the morning after waking, suppresses the abnormally elevated production of Aldosterone during waking hours. In the early evening suppression of Aldosterone production starts to wane and the normal increase in serum Aldosterone returns towards normal by dawn, as it would under normal circumstances. The circadian rhythm of aldosterone in normal subjects and subjects with primary aldosteronism is described in Kem, David C., et al. “Circadian rhythm of plasma aldosterone concentration in patients with primary aldosteronism.” The Journal of clinical investigation 52.9 (1973): 2272-2277, the contents of which are specifically incorporated by reference herein.

[0148] This invention provides methods that reduce a hypertensive subject’s systolic blood pressure “during sleep”. In this context, “during sleep” refers to the period of sleep in the hypertensive subject’s normal sleep / wake cycle. In other words, “during sleep” refers to the hypertensive subject’s approximately seven to nine hours of sleep (typically at night) that occurs daily in between their approximately 15 to 17 hours of wakefulness and not to any short period of sleep that may occur outside of the sleep phase of the subject’s normal sleep / wake cycle (i.e. naps).The blood pressure of non-hypertensive individuals typically dips during sleep, with approximately 10% to 15% lower blood pressure values during sleep relative to during wakefulness. In contrast, hypertensive subjects may experience a smaller dip in blood pressure during sleep or may not experience any dip in blood pressure at all. Thus, methods of the invention help hypertensive subj ects restore the dip in blood pressure that normal, non-hypertensive subjects experience during sleep.

[0149] A subject’s “pre-drug level” of serum aldosterone refers to the subject’s level of serum aldosterone, at the same time of day, in the absence of being treated with the CYP 1102 beta hydroxylase inhibitor. As discussed above, aldosterone level follows a diurnal pattern where the nadir is in the late evening and the peak is in the early morning, pre-arousal. Therefore, in embodiments where the dose of CYP 1102 beta hydroxylase inhibitor reduces the serum aldosterone level of the subject by a certain percentage relative to their “pre-drug level”, the reduction in serum aldosterone is measured relative to the same subject’s serum aldosterone level in the absence of administration of the CYP 1102 beta hydroxylase inhibitor at the same time of day. For example, the subject’s serum aldosterone level at 11 AM when administered a CYP 1102 beta hydroxylase inhibitor would be measured relative to that same subject’s serum aldosterone level at 11 AM prior to any administration of the CYP 1102 beta hydroxylase inhibitor.General

[0150] For the foregoing embodiments, each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiment.

[0151] As used herein, all headings are simply for organization and are not intended to limit the disclosure in any manner. The content of any individual section may be equally applicable to all sections. All combinations of the various elements disclosed herein are within the scope of the invention.

[0152] Additional objects, advantages, and novel features ofthe present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each ofthe various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples.

[0153] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable 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.

[0154] Examples are provided below to facilitate a more complete understanding of the invention. The following examples illustrate the exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only.EXAMPLESExample 1

[0155] A randomized, double-blinded, placebo-controlled study was conducted in which 116 patients were randomized and 87 received lorundrostat HBr.

[0156] A single ascending dose (SAD) study was conducted with the following dosing amounts tested:(a) 5mg(b) Hhng(c) 20mg(d) 50mg(e) lOOmg(f) 200mg(g) 400mg(h) 800mg.

[0157] The IC50 of inhibition of CYP 1102 beta hydroxylase by lorundrostat HBr and the time above IC50 for each dosing amount were estimated based on PKPD modeling of data from the SAD study. The estimated number of hours above IC50 and the proportion of a 24 hour periodabove IC50 for proposed dosing in the phase two, proof-of-concept study were extrapolated and

[0158] Time above IC50 was closely correlated with the duration of aldosterone suppression in the SAD study.

[0159] In a Multiple Ascending Dose (MAD) Study, little drug accumulation was observed at 40 mg, 120 mg and 360 mg QD doses.Example 2

[0160] A randomized, double-blinded, placebo-controlled, dose-ranging, multicenter study was conducted to evaluate the effect of orally administered Lorundrostat on blood pressure for the treatment of uncontrolled hypertension in male and female subjects > 18 years of age.Study design

[0161] The study consists of two parts. For enrollment into Part 1 of the study, a subject’s value of plasma renin activity (PRA) must be < 1 ng / mL / h based on morning measurement. If the value of PRA > 1 ng / mL / h based on morning measurement, then subjects may be eligible to enter Part 2 of the study.

[0162] For Part 1, 163 enrolled subjects > 18 years of age were randomized into 6 equal treatment groups (1:1: 1:1: 1:1) to 12.5 mg BID, 25 mg BID, 12.5 mg QD, 50 mg QD, 100 mg QD, or placebo. After a review of interim clinical data, the 2 lowest dose levels (12.5 mg QD and 12.5 mg BID) were stopped for future randomization due to a lack of consistent meaningful reductionof blood pressure, but the patients randomized to that point remained in the study through completion. Thus, after the review of interim clinical data, subjects were randomized into 4 equal treatment groups (1 : 1 : 1 :1) to 25 mg BID, 50 mg QD, 100 mg QD, or placebo.

[0163] For Part 2, 36 enrolled subjects > 18 years of age were randomized (5: 1) to either 100 mg QD Lorundrostat HBr or placebo such that the Lorundrostat treatment group consisted of approximately 30 subjects and the placebo treatment group will consist of approximately 6 subjects.

[0164] Subjects orally administered the assigned study drug (Lorundrostat HBr or placebo) according to the assigned dosing regimen for 8 weeks beginning on Study Day 1. All subjects in Part 1 (regardless of dosing group) received BID dosing to preserve the integrity of the blind; active drug is administered as the morning dose for all QD dose groups. Subjects returned to the research facility or were seen by the clinical investigator or approved home health care professional at the end of Study Weeks 1, 2, 3, 4, 5, 6, 7, and 8 (± 2 days) for protocol-defined efficacy and safety assessments and procedures, assessment of adverse events (Aes), and confirmation of compliance with study drug usage. Subjects also completed a telephone visit and blood pressure (BP) check at home approximately 3 days post last dose of study drug. Subjects attended up to 14 full clinic visits, including a pre-Screening visit, a Screening / start of Placebo Run-in visit, a second visit during Placebo Run-in, a clinic visit to initiate the ABPM procedure, a Randomization visit, 8 weekly visits during double-blind treatment, and an end-of-study visit scheduled 4 weeks after the last study treatment for final efficacy and safety assessments.

[0165] A schematic of the study design is shown in Figure 2.Automated office blood pressure (AOBP) procedure

[0166] An automated oscillometric sphygmomanometer device was used to measure the subjects’ systolic and diastolic blood pressure in office after approximately 5 minutes of rest in the seated position.24-hour ambulatory blood pressure monitoring (ABPM) procedure

[0167] Ambulatory blood pressure monitoring was accomplished with an ambulatory blood pressure monitoring device that consists of a blood pressure cuff worn on a subject’s arm attached to a small recording device that is typically attached to the subject’s belt or waistband.

[0168] The ABPM device is worn for 24 hours. Throughout that period, the device records the subject’s blood pressure at regular intervals, during the subject’s routine daily activities and while they are sleeping. The ABPM thus provides a complete record of the subject’s blood pressure over a 24-hour period.

[0169] 24-hour ABPM was measured in the clinic at baseline and Study Week 7. If, for any reason, the ABPM procedure was deemed a failure at the end of Study Week 7, it may have been repeated at Study Week 8 and therefore no imputation was employed regardless of use of rescue medications. Additionally, ABPM was also collected at the end of Study Week 4 in Part 2. If a repeat test was performed, it supersedes the original test results for that visit.

[0170] Specific derived variables based on ABPM measurements include mean 24-hour, mean Daytime, and mean Nighttime of SBP, DBP, and heart rate.

[0171] Change from baseline to Week 7 in 24-hour mean SBP (and DBP) based on ABPM will be analyzed using an ANCOVA with a term for treatment group and a baseline mean 24-hour value as a covariate.

[0172] The nighttime dip is defined as100% x (mean daytime SBP - mean nighttime SBP) / mean daytime SBP

[0173] It is expressed as a percentage and is summarized by treatment group and visit using descriptive statistics. In addition, the number and percentage of subjects with nighttime dip in each of the dipper categories (Bloomfield & Park, 2015) is presented by treatment group and visit. The categories are:(a) 10%(b) 10-20% inclusive(c) > 20%Eligibility CriteriaInclusion criteria

[0174] The study was conducted using subjects meeting the following inclusion criteria: (a) Male and nonpregnant, nonlactating female subjects > 18 years of age.(b) Automated office blood pressure (AOBP) measurements taken atScreening / start of the Placebo Run-in Visit and Randomization with SBP >130 mmHg.(c) Background antihypertensive treatment of > 2 drugs (note: a combination pill = 2 AHTs) that have been stable at their prescribed doses for at least 4 weeks prior to signing the Screening / main study ICF.(d) Serum cortisol > 18 mcg / dL or serum cortisol >3 and <18 ugill. (morning measurement) at Screening / start of Placebo Run-in visit if there was no evidence of adrenal insufficiency based on normal ACTH stimulation test results.Exclusion criteria

[0175] Subjects were excluded from the study if they met any of the following exclusion criteria:(a) Concomitant use of epithelial sodium channel inhibitors or mineralocorticoid receptor antagonists, including, but not limited to amiloride, triamterene, spironolactone, eplerenone.(b) Subjects with hypokalemia, i.e., serum potassium <3.0 mEq / L at Screening.(c) Subjects with hyperkalemia, i.e., serum potassium >5.2 mEq / L at Screening for Part 1 and >4.8 mEq / L at Screening for Part 2.(d) Subjects with serum cortisol < 3 mcg / dL based on morning measurement at Screening.(e) Subjects with serum sodium < 135 mEq / L(f) Subjects with estimated glomerular filtration rate < 60 mL / min / 1.73m2 at Screening(g) Subjects with type 1 or uncontrolled (hemoglobin Ale > 9%) type 2 diabetes mellitus(h) Subjects with body mass index > 40 kg / m2(i) Subjects with unstable angina who were taking short-acting oral or sublingual nitroglycerin or who had a history of myocardial infarction or stroke within 6 months of Screening, sustained atrial fibrillation, i.e., lasting >12 months, or permanent atrial fibrillation; paroxysmal atrial fibrillation that terminatedspontaneously or with intervention within 7 days was allowed. Chronic long- acting oral nitrates that were stable at their prescribed doses for at least 2 weeks prior to signing the Screening / main study ICF were allowed.0) Subjects with SBP > 175 mm Hg or diastolic blood pressure (DBP) > 100 mm Hg for Part 1 and SBP > 160 mm Hg or DBP > 100 mm Hg for Part 2 (average of last 2 of 5 unattended measurements using an automated oscillometric sphygmomanometer device after approximately 5 minutes of rest in the seated position) aatt Pre-Screening, Screening / Start of Placebo Run-in, or Randomization(k) Subjects with a decrease in SBP > 20 mm Hg or DBF > 10 mm Hg from sitting to standing position at screening(1) Subjects who, in the opinion of the investigator, have suspected nonadherence to antihypertensive treatment(m) Subjects who, in the opinion of the investigator, have any major medical illness or symptoms(n) Subjects who, in the opinion of the investigator, have any acute or chronic medical or psychiatric condition(o) Subjects undergoing treatment with any of the following medications:(i) Topical corticoids(ii) Sympathomimetic decongestants(iii) Theophylline(iv) Phosphodiesterase type 5 inhibitors(v) Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs), other than low dose aspirin (81-325 mg), where chronic use was defined as >3 consecutive or non-consecutive days of treatment per week, within 2 weeks of Screening(vi) Intramuscular steroids(vii) Estrogen(viii) Strong CYP3A and CYP3A4 inhibitors (e.g., clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir,darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir).(ix) Strong CYP3A and CCYYPP33AA44 inducers (e.g., apalutamide, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, St. John’s Wort(x) Subjects with known hypersensitivity to Lorundrostat or any of the excipients(P) Subjects who are night-shift workersArms and Interventions

[0176] The study contained the following arms and corresponding interventions:Table 2once daily.

[0177] *Refers to weight of lorundrostat free base. 29.48 mg of lorundrostat HBr corresponds to 25 mg of lorundrostat, 58.95 mg of lorundrostat HBr corresponds to 50 mg of lorundrostat, and 117.9mg of lorundrostat HBr corresponds to 100 mg of lorundrostat.Study EndpointsPrimary Endpoint

[0178] The primary endpoint is the change in office-measured (mean of last 2 of 5 unattended measurements using an automated oscillometric sphygmomanometer device after approximately 5 minutes of rest in the seated position) systolic blood pressure (SBP) from baseline to the end of Study Week 8.Secondary Endpoint

[0179] Secondary endpoints of this study were:(a) Change in 24-hour ambulatory blood pressure monitoring (AB PM) parameters (systolic and diastolic) from baseline to the end of Study Week 7.(b) Change in office-measured (average of last 2 of 5 unattended measurements using aann automated oscillometric sphygmomanometer device after approximately 5 minutes of rest in the seated position) SBP and DBF from baseline to the end of Study Weeks 1, 2, 3, 4, 5, 6 and 7 (± 2 days); change in office-measured DBP from baseline to the end of Study Week 8 (i.e., Study Day 56 ± 2 or EoT period)(c) Proportion of subjects who achieve office-measured BP of < 130 / 80 mm Hg by the end of Study Week 8.Pharmacodynamic Endpoints

[0180] Pharmacodynamics endpoints of this study were:(a) Change in plasma 11 -deoxycortisol and PRA from baseline to the end of Study Week 4 and to end of follow up (i.e. end of Study Week 12 for Part 1 and end of Study 10 for Part 2).(b) Change in sseerruumm aldosterone, cortisol, aanndd 11 -deoxycorticosterone concentration from baseline to the end of Study Week 4 and to end of follow- up.Pharmacokinetic Endpoints

[0181] Pharmacokinetic endpoints of this study are PK parameters, including, of area under the plasma concentration versus time curve (AUC), maximum plasma concentration (Cmax), time to maximum concentration (Tmax), and half-life (ti.2) will be summarized descriptively for Randomization (baseline) and Study Weeks 1, 4, and 8Safety endpoints

[0182] Safety endpoints of this study are:(a) Incidence and severity of all spontaneously reported adverse events (Aes)(b) Changes in vital signs (standing SBP, standing DBP, body temperature, heart rate, and respiratory rate)(c) Changes in electrocardiogram parameters (including cardiac intervals: PR, QRS, QT, and corrected QT interval using Fridericia’s formula)(d) Changes in clinical laboratory assessments (hematology, chemistry, coagulation, and urinalysis)(e) Change in office-measured SBP from Study Week 8 (end-of-treatment period to end of follow up (i.e. end of Study Week 12 for Part 1 and end of Study 10 for Part 2).Analysis methodology

[0183] The following analysis sets are defined in this study:Full Analysis Set (FAS)

[0184] The FAS includes all randomized subjects who have received at least 1 dose of randomized study treatment (MLS- 101 or placebo). The FAS will be the primary set for efficacy analyses. In analyses performed on the FAS, unless otherwise specified, subjects will be analyzed according to the randomized study treatment group.Per Protocol Set (PPS)

[0185] The Per Protocol Set includes all subjects in the FAS who have completed the Study Week 8 visit without any major protocol violations that could influence the validity of the data for the primary efficacy evaluations, bi the analyses based on PPS, subjects will be analyzed according to the randomized study treatment group. All criteria to exclude subjects from the PPS will be made based on a blinded review of the data prior to the unblinding of the study.

[0186] A subject may be excluded from the Per Protocol Analysis Set if any of the following criteria are met:(a) Not meeting Inclusion / Exclusion criteria(b) Use of prohibited medications. Subjects using rescue medications will not be excluded from the PPS unless subjects have met other criteria excluding them from the PPS(c) Not compliant with the study drug(d) Out of window efficacy assessment at study Week 8 visit

[0187] Alternate criteria for exclusion from the Per Protocol Analysis Set were also applied to accommodate unforeseen events that occurred during the conduct of the study.

[0188] Analyses on Per Protocol Analysis Set will be of supportive purpose and limited to primary endpoint (i.e., “product Estimand”).Safety Analysis Set (SAF)

[0189] 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 according to their actual treatment received.PK / PD Analysis Set (PKPD)

[0190] PK / PD Analysis Set includes all subjects in the SAF who have sufficient data available for the analysis of pharmacokinetic and pharmacodynamic measurements. In the analyses based on PKPD, subjects will be analyzed according to the actual treatment received.Definition of Baseline

[0191] Baseline is defined as the last available observed value of the parameter of interest prior to the first administration of the investigational medicinal product (IMP) for the double-blinded treatment period.

[0192] For AOBP measurements and any other clinical or laboratory variable for which there are replicate evaluations at the screening and baseline visits, baseline is defined as the mean of the last two non-missing values prior to first administration of the IMP for the double-blinded treatment period.

[0193] Change from baseline is calculated as: post-baseline result - baseline result.

[0194] Percentage change from baseline is calculated as: (change from baseline / baseline result) x 100%.Summary of results

[0195] Lorundrostat was effective at lowering BP in individuals with inadequately treated or treatment resistant hypertension.

[0196] There was a dose- and exposure-response relationship, with mean placebo-adjusted reduction in SBP of 9.58 mmHg and 7.81 mmHg seen at doses of 50 mg QD and 100 mg QD, respectively.

[0197] 24-hour ABPM, central BP and nighttime SBP values confirmed the reduction in SBP seen with AOBP, most prominently in the 100 mg QD dose cohort.

[0198] The safety dataset lorundrostat was safe and well tolerated, with no effects on serum cortisol and an expected modest increase in serum potassium with relatively few episodes of clinically meaningful hyperkalemia.

[0199] TThhee rreessuullttss ddeemmoonnssttrraattee a clinically meaningful and statistically significant placebo- adjusted reduction in AOBP SBP of 9.58 mmHg (p=0.0114) and 7.81 mmHg (p=0.0422) in the 50mg and 100 mg QD cohorts, respectively, in Part 1. The reduction in AOBP SBP observed in Part 2 for the 100 mg QD cohort was similar to that observed for the same dose in Part 1 (-11.5 mmHg, p=0.8426).

[0200] The reduction in AOBP SBP was validated and confirmed by comparable reductions in 24-hour ABPM SBP. The ABPM data further demonstrated the benefits of lorundrostat in reducing both central and nighttime SBP.

[0201] Sub-group analyses highlighted statistically and clinically significant reductions in AOBP SBP in subjects with a BMI >30 kgirr, those in the upper tertile of baseline AOBP SBP, and those taking thiazide diuretics.

[0202] Pharmacodynamic responses demonstrated dose-dependent reduction in serum aldosterone levels and a commensurate increase in plasma renin activity. 11 -deoxycorticosterone levels were unaffected. Morning serum cortisol levels were modestly increased. No adrenocortical insufficiency occurred during the trial. Due to supply chain disruption, the ability to perform ACTH stimulation testing was limited during the first part of the trial. However, the majority of subj ects in Part 2 dosed with 100 mg QD, the maximum dose tested, had ACTH- stimulation testing performed at Baseline and after 8 weeks of treatment. There were no individuals with abnormal ACTH- stimulation results.

[0203] Decreases in eGFR were observed in all treatment groups with greater decreases apparent for lorundrostat treatment groups compared with placebo.Primary Efficacy Endpoint: Change from Baseline at Week 8 in Seated Automated Office- measured Systolic Blood Pressure

[0204] The results of a Mixed Model Repeated Measures (MMRM) analysis of the primary efficacy endpoint, change in seated AOBP SBP from Baseline to Week 8, is presented in Figure 3 and Table 3 for Part 1 and in Figure 4 and Table 4 for the 100 mg QD dose cohorts from Part 1 and Part 2.

[0205] At Week 8, a statistically significant reduction in modelled AOBP SBP from baseline was detected in the 50 mg QD cohort (least square mean [LSM] difference: -9.58 mmHg; p=0.0114) and 100 mg QD cohort (LSM difference: -7.81 mmHg; p=0.0422) in Part 1 (Figure 3 and Table 3). While the 12.5 mg BID, 25 mg BID and 12.5 mg QD cohorts exhibited reductionsin BP that were greater than placebo (placebo adjusted reductions of -7.2 mmHg, -6.97 mmHg, and -1.53 mmHg, respectively), none of these demonstrated statistical significance. The results were similar for the sensitivity analysis using the FAS, the analysis using the PPS, and the analysis using the additional estimand.

[0206] The change in SBP from baseline to Week 8 was similar for the 100 mg QD cohorts inPart 1 and Part 2 (LSM difference: 0.74 mmHg; p=0.8426) (Figure 4 and Table 4). Further, no statistically significant appreciable difference in AOBP SBP change from baseline was seen between subjects who received lorundrostat 100 mg QD in Parts 1 and 2 combined who had a baseline PRA of <1 ng / mL / h versus those with a baseline PRA of >1 ng / mL / h (Table 5).

[0207] Boxplots of the mean changes in measured AOBP SBP from baseline to Week 8 are presented in Figure 5 for Part 1 and in Figure 6 for Part 2.Table 3: Modelled (MMRM) Least Square Mean (SEM) Change from Baseline at Week 8 in SeatedAutomated Office-Measured Systolic Blood Pressure (mmHg), Part 1 (Full Analysis Set)

[0208] Analysis used a 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 implemented.

[0209] Abbreviations: BID, twice daily; CI, confidence interval; A, difference; LSM, least square mean; mg, milligrams; mmHg, millimeters of mercury; MMRM, mixed model repeated measures; QD, once daily; SBP, systolic blood pressure; SEM, standard error of the mean.

[0210] Analysis used a 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 implemented.

[0211] Abbreviations: CI, confidence interval; A, difference; LSM, least square mean; mg, milligrams; mmHg, millimeters of mercury; MMRM. mixed model repeated measures; QD, once daily; SBP, systolic blood pressure; SEM, standard error of the mean.Table 5: Modelled (ANCOVA) Least Square Mean (SEM) Change from Baseline at Week 4 andWeek 8 in Seated Automated Office-Measured Systolic Blood Pressure (mmHg) in SubjectsRandomized to 100 mg QD in Parts 1 & 2, according to PRA level at Baseline (Full Analysis Set)

[0212] Analysis used an ANCOVA model with binary baseline PRA (<1 ng / mL / h versus >1 ng / mL / h) as a factor and baseline SBP as a covariate, in the subset of subjects randomized to receive 100 mg QD. The two ANCOVA models (Week 4 and Week 8) were run separately.

[0213] Abbreviations: ANCOVA, analysis of covariance; CI, confidence interval; A, difference; FAS, Full Analysis Set; h, hour; LSM, least square mean; mg, milligrams; mL, milliliter; mmHg, millimeters of mercury; ng, nanograms; PRA, plasma renin activity; QD, once daily; SBP, systolic blood pressure; SEM, standard error mean.Secondary Efficacy EndpointsChange from Baseline at Week 8 in Seated Automated Office-measured Diastolic Blood Pressure

[0214] At Week 4, statistically significant reductions in modelled AOBP DBP from baseline were detected across all cohorts in Part 1 except 12.5 mg QD. At Week 8, a statistically significant reduction in modelled AOBP DBP from baseline was detected in the 50 mg QD cohort only (LSM difference: -5.46 mmHg; p=0.0224), although all lorundrostat dose groups exhibited greater numerical declines than placebo (Table 6). The change in DBP from baseline to Week 8 was not statistically different between the 100 mg QD cohorts in Part 1 and Part 2 (LSM difference:0 98 mmHg; p=0 6406) (Table 7)week, and treatment by week interaction, and baseline DBP as a fixed continuous covariate. P- values <0.05 are bolded. Abbreviations: BID, twice daily; CI, confidence interval; A, difference;DBP, diastolic blood pressure; LSM, least square mean; mmHg, millimeters of mercury; QD, once

[0216] Analysis used a MMRM approach with fixed effects for categorical terms for treatment, week, and treatment by week interaction, and baseline DBF as a fixed continuous covariate.Abbreviations: CI, confidence interval; A, difference; DBF, diastolic blood pressure; FAS, FullAnalysis Set; LSM, least square mean; mg, milligrams; mmHg, millimeters of mercury; MMRM, mixed model repeated measures; QD, once daily; SEM, standard error mean.Change from Baseline to Week 8 in Seated Automated Office-measured Blood PressureParameters

[0217] Mean SBP decreased over the first 4 to 5 weeks of treatment, including in the placebo arm (Table 8 and Table 9). The reductions in mean DBF (Table 10 and Table 11) were smaller than those observed for SBP, and the change from baseline in the placebo group was marginal. In general, the reductions in BP reached a plateau at around 4 weeks of treatment.

[0218] Baseline was defined as the average of the last two non-missing values prior to 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.

[0219] Baseline was defined as the average of the last two non-missing values prior to first dose of study treatment including unscheduled visits. Abbreviations: CFB, change from baseline; mmHg, millimeters of mercury; QD, once daily; SD, standard deviation.

[0220] Baseline was defined as the average of the last two non-missing values prior to 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.

[0221] Baseline was defined as the average of the last two non-missing values prior to 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 Seated Automated Office-Measured Diastolic Blood Pressure<130 / 80 mmHg

[0222] Overall, six subjects in Part 1 and three subjects in Part 2 had AOBP at or below theAHA cut-point for hypertension (130 / 80 mmHg) at baseline (Table 12 and Table 13). By Week 8 the proportion of subjects with AOBP <130 / 80 mmHg across all doses in Part 1 ranged from23.3% for the Placebo cohort to 43.3% for the 25 mg BID cohort (Figure 7). In Part 2, 54.8% of the 100 mg QD cohort achieved this treatment goal compared to 30% in the 100 mg QD cohort ofPart 1 (Figure 8).Table 12: Proportion of Subjects with Seated Automated Office-MeasuredSBP / DBP <130 / 80 mmHg at Week 8 Part 1 (Full Analysis Set)

[0223] Baseline was defined as the average of the last two non-missing values prior to first dose of study treatment including unscheduled visits. Abbreviations: BID, twice daily; DBP, diastolic blood pressure; mmHg, millimeters of mercury; QD, once daily; SBP, systolic blood pressure.Table 13: Proportion of Subjects with Seated Automated Office-Measured SBP / DBP < 130 / 80 mmHg at Week 8, Part 2 (Full Analysis Set)

[0224] Baseline was defined as the average of the last two non-missing values prior to first dose of study treatment including unscheduled visits. Abbreviations: DBP, diastolic blood pressure; mmHg, millimeters of mercury; QD, once daily; SEP, systolic blood pressure.Time to First Occurrence of Seated Automated Office-measured SBP / DBP <130 / 80 mmHg

[0225] With the exception of subjects assigned to the Placebo group, the majority of subjects who achieved SBP / DBP of 130 / 80 mmHg did so between Weeks 2 and 4 of treatment in both Part1 and Part 2 (Figure 9 and Figure 10).Change from Baseline at End of Treatment in 24-hour Ambulatory Blood Pressure MonitoringParameters

[0226] The modelled changes in ABPM parameters (24-hour SBP, DBF, MAP, central SBP, central DBP and central MAP; daytime SBP, DBP and MAP; nighttime SBP and DBP) demonstrated a consistent AHT effect (Table 14 and Table 15). The results are compatible with those reported for AOBP parameters (SBP and DBP).

[0227] The changes from baseline to EoT in measured 24-hour, daytime and nighttime meanABPM SBP, DBP and MAP are summarized in Table 16 and . The changes from baseline in mean 24-hour ABPM SBP and DBP at EoT were numerically smaller than those reported forAOBP which is an expected finding for the different modes of measurement.Table 14: Modelled (ANCOVA) Least Square Mean Change from Baseline at End of Treatment in 24-hour ABPM Parameters, Part 1 (Pull Analysis Set; Post-hoc Analysis)

[0228] P-values in bold indicate p<0.05.Table 15: Modelled (ANCOVA) Least Square Mean Change from Baseline at End of Treatment in 24-hour ABPM Parameters in Subjects Randomized to 100 mg QD, Parts 1 & 2 (Full Analysis Set; Post-hoc Analysis')

[0229] P-values in bold indicate p<0.05.Table 16: Measured Mean 6SD) Change from Baseline to End of Treatment in 24-hour Ambulatory Blood Pressure Monitoring Parameters, Part 1 (Full Analysis Set")

[0230] In many of the treatment cohorts, the proportion of subjects achieving a nighttime dip in ABPM SBP of >10% increased from baseline to the last post-baseline assessment (Table 18 andTable 19).

[0231] Nighttime Dip was defined as 100% x (24 hour ABPM Mean Daytime SBP 24 hourABPM Mean Nighttime SBP) / 24-hour ABPM Mean Daytime SBP.Table 19: Proportion of Subjects with Nighttime Dip in 24-hour Systolic Ambulatory BloodPressure Part 2 (Full Analysis Set)

[0232] The Nighttime Dip was defined as 100% x (24-hour ABPM Mean Daytime SBP - 24- hour AB PM Mean Nighttime SBP) / 24-hour ABPM Mean Daytime SBP.Analysis of factors affecting change in blood pressure

[0233] An analysis was conducted to identify factors affecting the degree of blood pressure reduction in hypertensive subjects. As shown in the tables below, it was discovered thatLorundrostat is particularly effective at reducing the blood pressure of individuals with a body mass index (BMI) of greater than 30. This effect was observed across dosing cohorts.

[0234] Further, as shown in the tables below, it was discovered that Lorundrostat is particularly effective at reducing the blood pressure of individuals who were receiving a thiazide diuretic as one of their background hypertension medications. This effect was observed across dosing cohorts.

[0235] There was no apparent consistent difference between mean change from baseline inAOBP SBP at Week 8 when summarized by sex (Male, Female) age (<65, 65-79, >80 years), race(Black or African American, Other), number of AHT medications at baseline (2, >3), or use of concomitant angiotensin converting enzyme inhibitors (ACEi) or ARBs in Part 1 (Table 20) orPart 2 (Table 21).CFB change from baseline; mg, milligrams; QD, once daily; SD, standard deviation; Wk8, Week8; yr, years.Table 21: Mean (SD) Change from Baseline at Week 8 in Automated Office-Measured SystolicBlood Pressure by Subgroup Part 2 (F ull Analysis Set)

[0237] Abbreviations: AA, African American; ARB, angiotensin receptor blocker; ACEi, angiotensin converting enzyme inhibitor; AHT, antihypertensive; BL, baseline; CFB change from baseline; mg, milligrams; NE, not evaluable; QD, once daily; SD, standard deviation; WkS, Week8; yr, years.

[0238] There was an apparent increase in the AHT effect of lorundrostat with increasing BMI(Table 22) that was most apparent in the 100 mg QD dose cohorts in Part 1 (Table 22) and Part 2(Table 23). Exploratory analysis using MMRM resulted in a placebo-adjusted reduction in AOBPSBP 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).Table 22: Mean (SD) Change from Baseline at Week 8 in Automated Office-Measured SystolicBlood Pressure, by BMI at Baseline, Part 1 (Full Analysis Set)

[0239] Abbreviations: BID, twice daily; BL, baseline; CFB, change from baseline; NE, not evaluable; QD, once daily; SD, standard deviation; WkS, Week 8.Table 23: Mean (SD) Change from Baseline at Week 8 in Automated Office-Measured SystolicCFB -2.50 (11.12) 8.00 (16.62)

[0240] Abbreviations: BL, baseline; CFB, change from baseline; NE, not evaluable; QD, once daily; SD, standard deviation; WkS, Week 8.

[0241] There was an apparent increase in the AHT effect of lorundrostat with increasing baseline AOBP SBP in both Part 1 and Part 2 (Table 24 and Table 25, respectively). It should be noted that a greater AHT effect with increasing baseline AOBP SBP was also observable in thePart 1 placebo cohort and only the 50 mg QD cohort in Part 1 demonstrated a statistically significant placebo-adjusted reduction in AOBP SBP from baseline at Week s (-19.9 mmHg, p=0.0113).Table 24: Mean (SD) Change from Baseline at Week 8 in Automated Office-Measured SystolicBlood Pressure, by Systolic Blood Pressure Tertile at Baseline, Part 1 (Full Analysis Set)[ ] , y; , ; , daily; SD, standard deviation; WkS, Week 8.Table 25: Mean (SD) Change from Baseline at Week 8 in Automated Office-measured SystolicBlood Pressure by Systolic Blood Pressure Tertile at Baseline, Part 2 (Full Analysis Set)

[0243] Abbreviations: BL, baseline; CFB, change from baseline; NE, not evaluable; QD, once daily; SD, standard deviation; Wk8, Week 8.

[0244] There also appeared to be a greater reduction in AOBP SBP from baseline in subjects with concomitant use of thiazide diuretics in Part 1 (Table 26), but this was not as apparent in Part2 (Table 27). In Part 1 , statistically significant placebo-adjusted reductions in AOBP SBP at Week8 were achieved in the 12.5 mg BID and 50 mg QD cohorts with mean changes of -10.7 mmHg(p=0.047) and -12.9 mmHg (p=0.0108), respectively.

[0245] Abbreviations: BID, twice daily; BL, baseline; CFB, change from baseline; QD, once daily; Wk8, Week 8.

[0246] Abbreviations: BL, baseline; CFB, change from baseline; NE, not evaluable; QD, once daily; WkS, Week 8.

[0247] There was no apparent consistent difference between mean change from baseline inAOBP DBP at Week 8 when summarized by sex (male, female), age (<65, 65-79, >80 years), race (Black or African American, Other), BMI (<25, 25-30, >30 kg / m2), seated AOBP DBP at baseline, number of AHT medications at baseline (2, >3), or use of concomitant ACEi or ARBs in Part 1(Table 28) or Part 2 (Table 29).

[0248] 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, meters; QD, once daily; SBP, systolic blood pressure; SD, standard deviation; WkS, Week 8; yr, years.Table 29: Mean (SD) Change from Baseline at Week 8 in Automated Office-Measured Diastolic

[0249] 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, meters; mL, milliliter; ng, nanograms;PRA, plasma renin activity; QD, once daily; SBP, systolic blood pressure; SD, standard deviation;WkS, Week 8; yr, years.

[0250] A modest increase in the AHT effect of lorundrostat was apparent with concomitant use of thiazide diuretics in Part 1 (Table 30), but this was not present in Part 2 (Table 31). In Part 1, a statistically significant placebo-adjusted reduction in AOBP DBP was achieved at Week 8 inpatients with thiazide diuretic use at baseline for the 50 mg QD cohort (-7.7 mmHg, p=0.0291), but not for any of the dose cohorts in patients not on thiazide diuretics at baseline.Table 30: Mean (SD) Change from Baseline at Week 8 in Automated Office-Measured DiastolicBlood Pressure, by Thiazide Diuretic Use at Baseline, Part 1 (Full Analysis Set)CEB -3.00 (8.39) -3.29 (8.80) -6.09 (7.34) 1.56 (17.70) -4.71 (7.77) -4.00 (6.33)Table 31: Mean (SD) Change from Baseline at Week 8 in Automated Office-Measured DiastolicBlood Pressure, by Thiazide Diuretic Use at Baseline, Part 2 (Full Analysis Set)Pharmacokinetic Response

[0251] Systemic exposure to lorundrostat, expressed as Cmax or AUC increased with increasing dose, although there was moderately high inter-subject variability. For the dose of 100 mg QD inCohort 1 and Cohort 2, steady-state (Day 28) Cmax was 1620 ng / mL and 1360 ng / mL, respectively(mean approximately 1490 ng / mL) and AUC0-24 was 14900 ng*h / mL and 7480 ng*h / mL, respectively (mean approximately 11190 ng*h / mL). Other key parameters are summarized inTable 32. Values of trough plasma concentrations are shown in Table 33.Table 32: Summary of Key Steady-State Pharmacokinetic Parameters Following Administration of LorundrostatParameter Statistics 12.5 mg BID 25 mg BID 12.5 mg QD 50 mg QD 100 mg QD 100 mg QD

[0252] Abbreviations: AUG, area under the curve; BID, twice daily; CV, coefficient of variation; geo, geometric; hr, hours; mg, milligrams; mL, milliliters; N, number of subjects; n, number of observations; ng, nanograms; QD, once daily.Table 33: Summary of Trough Plasma Concentrations (ng / mL) Following Administration ofLorundrostat

[0253] Concentrations are in units of ng / mL. Abbreviations: BID, twice daily; CV, coefficient of variation; geo, geometric; mg, milligrams; mL, milliliters; N, number of subjects; n, number of observations; ng, nanograms; QD, once daily.Pharmacodynamic Response

[0254] At baseline in Part 1, active arm mean serum cortisol levels ranged between 9.443 gg / dL and 11.272 gg / dL, compared with 10.507 pg'dL for placebo (Table 34). No consistent substantial changes in serum cortisol levels were observed over the course of treatment and followup relative to baseline values with percent change from baseline values of 3.8% to 19.2% (active) vs -0.8% (placebo) at Week 4, 20.6% to 51.4% (active) vs 37.7% (placebo) at Week 8, and -1.2% to 22.7% (active) vs 17.1% (placebo) at Week 12. A similar pattern was observed in Part 2, with active arm serum cortisol baseline levels of 11.118 pg / dL in the 100 mg QD dose group and no substantial changes observed over the course of treatment and subsequent follow-up. Percent change from baseline was 20.1% at Week 4, 153.4% at Week 8, and 1.5% at Week 12 (Table 35).

[0255] Transient increases in 11 -deoxycorticosterone and 11 -deoxycortisol were seen in Part 1 in the active treatment arms at Week 4 compared with placebo, albeit with large variation within each individual dose cohort. Values returned to a similar range as placebo at Week 12 (Table 34). In Part 2, 11 -deoxycorticosterone and 11 -deoxycortisol were similar to baseline in subjects treated with lorundrostat 100 mg QD at Week 4 and Week 10 (Table 35).

[0256] In Part 1, aldosterone levels generally decreased at Week 4 relative to baseline in lorundrostat-treated subjects (-40.1% to 7.4%) compared with those who received placebo (3.6%), and remained lower relative to placebo at Week 12 (-26.6% to 15.9% vs 38.1 %, respectively; Table 34). In Part 2, aldosterone levels remained consistent although lower than baseline through Week 4 and Week 10 in subjects receiving lorundrostat. (Table 35).

[0257] Renin activity, expressed as a percent change from baseline, increased in all subjects treated with lorundrostat, irrespective of dose and baseline PRA values, reaching highest levels at Week 4 and remaining elevated compared with baseline at Week 12 (Part 1) and Week 10 (Part 2) (Table 34 and Table 35, respectively). Placebo values in Part 1 remained relatively consistent with baseline.Table 34: Mean (SD) Observed and Mean (SD) Percent Change from Baseline in

[0258] Subjects dosed with lorundrostat in Part 1, irrespective of dose, exhibited greater declines in eGFR relative to placebo as early as 1 week after the initiation of treatment that persisted at a consistent level until Week 8 (Table 36), The greatest reductions relative to baseline were seen in the 100 mg QD dose group, reaching a mean maximum decline of10.91 mL / min / 1.73m2at Week 2 (range: - 6.80 mL / min / 1.73m2to -10.91 mL / min / 1.73m2over 8 weeks of treatment). In contrast, mean eGFR for the Placebo group was relatively stable throughout treatment, reaching a mean maximal reduction of 2,80 mL / miiVl,73m2atWeek 2 (range: -0.83 mL / min / 1.73m2to -2.80 mL / min / 1.73m2). Estimated glomerular filtration rate was estimated using the CKD-EPI equation.

[0259] Similar trends were seen with mean eGFR for the 100 mg QD treatment group in Part2, with a rapid initial decline following a lesser reduction persisting out to Week 8 (Table 37).

[0260] At least one on-treatment TEAE was reported by 83 subjects in Part 1 (73 [54.9%] treated with lorundrostat and 10 [33.3%] treated with placebo) and by 20 subjects in Part 2 (19[61.3%] treated with lorundrostat and 1 [16.7%] treated with placebo). Of these subjects, 30 (27[20.3%] treated with active drug and 3 [10%] treated with placebo) from Part 1 and 9 (29.0% with lorundrostat only) from Part 2 experienced TEAEs that were considered at least possibly related to study drug.

[0261] Two (1.5%) subjects in Part 1 and one (3.2%) subject in Part 2 reported an SAE, one of which (a worsening of pre-existing hyponatremia) was considered possibly related to study drug. All events occurred in lorundrostat treated subjects.

[0262] Thirty-six subjects in Part 1 (35 [26.3%] treated with lorundrostat and 1 (3.3) treated with placebo) and four (12.9%) subjects treated with active drug in Part 2 reported at least one AESI.

[0263] Ten subjects in Part 1 and two subjects in Part 2, all in active treatment cohorts, experienced a TEAE that resulted in permanent discontinuation of study drug and 24 in Part 1 and 7 in Part 2 experienced a TEAE that resulted in dose modification.

[0264] No deaths were reported in either Part 1 or Part 2.

[0265] The most frequently reported events by PT were hyperkalemia (1 [3.3%] subject in the Part 1 Placebo cohort, 31 [23.3%] subjects in the Part 1 active treatment cohorts, and 8 [25.8%] subjects in the Part 2 100 mg QD cohort), eGFR decreased (1 [3.3 %] subject in the Part 1 Placebo cohort, and 9 [6.8%] subjects in the Part 1 active treatment cohorts), and urinary tract infection (7 [5.3%] subjects in Part 1 active treatment cohorts, and 2 [6.5%] subjects in Part 2 100 mg QD cohort). Muscle spasms were reported by 3 (9.7%) subjects in the Part 2 100 mg QD cohort.

[0266] There was no apparent association between dose of study drug and frequency of on- treatment TEAEs, on-treatment TEAEs of at least moderate severity, or on-treatment TEAEs considered at least possible related to study drug by the Investigator.

[0267] Serum potassium levels and serum creatinine levels increased in the active treatment cohorts compared with placebo in both Parts 1 and 2 while serum sodium levels decreased. These changes are consistent with the mechanism of action of lorundrostat.

[0268] Seven subjects experienced transient elevated serum potassium (greater than 6.0 mmol / L), none of which were considered an SAE, and all rapidly resolved after intervention (study drug discontinuation or dose adjustment).

[0269] There were no notable findings in terms of vital signs, physical examination, or ECG parameters.Treatment-emergent Adverse Events ( TEAEs)

[0270] Overall, 28 subjects in Part 1 experienced on-treatment TEAEs of moderate intensity (3 [10.0%] subjects in the placebo cohort and 25 [18.8%] subjects in the active treatment cohorts) and one subject (0.8%) in the 12.5 mg QD cohort experienced a severe on-treatment TEAE (Table 38). The only on-treatment TEAEs of moderate severity reported in >2 subjects in any dose group by PT were hyperkalemia (4 [3.0%] subjects) and hypertension (3 [2.3%] subjects), all of which were reported in subjects in the active treatment cohorts. The one severe on-treatment TEAE was a case of hyperkalemia.

[0271] In Part 2, there were 12 (38.7%) subjects who experienced >1 moderate on-treatment TEAS, and one (3.2%) subject who experienced >1 severe on-treatment TEAE, all of whom were in the 100 mg QD cohort (Table 39). The only on-treatment TEAEs of moderate severity reported in >2 subjects were hyperkalemia (5 [16.1 %] subjects) and muscle spasms (2 [6.5%] subjects. The one severe on-treatment TEAE was a case of hyponatremia.Table 38: Severity of On-Treatment Treatment-Emergent Adverse Events by System Organ Class and Preferred Term Reported by >2 Subjects in Any Treatment Group, Part 1 (Safety

[0272] Adverse events occurring in at least two subjects in any dose group by SOC and / or PT and / or severity are presented. SOCs with no PT and / or severity with at least two subjects are presented by SOC only. PTs with no severity with at least two subjects are presented by SOC andPT only.Table 39: Severity of On-Treatment Treatment-Emergent Adverse Events by System Organ Class and Preferred Term Reported by >2 Subjects in Any Treatment Group, Part 1 (Safety Analysis Set)

[0273] Adverse events occurring in at least two subjects in any dose group by SOC and / or PT and / or severity are presented. SOCs with no PT and / or severity with at least two subjects are presented by SOC only. PTs with no severity with at least two subjects are presented by SOC andPT only.

[0274] Ten (7.5%) subjects in Part 1, all in active treatment cohorts, experienced on-treatmentTEAEs that resulted in permanent discontinuation of study drug (Table 40); hyperkalemia(5 [3.8%] subjects) was the only such event that was reported in >2 subjects.

[0275] In Part 2, there were 2 (6.5%) subjects who experienced an on-treatment TEAEs that resulted in permanent discontinuation of study drug, both of whom were in the 100 mg QD cohort(). No such events occurred in both subjects.Table 40: On-Treatment Treatment-Emergent Adverse Events Leadins to Permanent Discontinuation from Study Drug by System Organ Class and Preferred Term, Part 1Table 41: On-Treatment Treatment-Emergent Adverse Events Leadins to Permanent Withdrawal from Study Drug by System Organ Class and Preferred Term, Part 2 (SafetyChange in estimated glomerular filtration rate (eGFR)

[0276] A dose-dependent and reversible reduction in eGFR was observed. This phenomenon has been reported with ACE / ARB and more recently SGLT2 inhibition due to reduced intraglomerular pressure and felt to attenuate progression of hypertensive nephropathy. A graph showing the change in estimated glomerular filtration rate (eGFR) in different dosing cohorts is provided in Figure 11.Clinical Laboratory Evaluations

[0277] 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 in Part 1 or Part 2, or in urinalysis and spot / 24-hour urine parameters.Serum potassium

[0278] Serum potassium levels increased in the active treatment cohorts compared with the placebo cohort in both Parts 1 and 2, with the greatest increases seen in the 100 mg QD cohorts inParts 1 and 2, and the two BID cohorts in Part 1 (Figure 12, Figure 13, and Figure 14).

[0281] 6 / 163 (3.6%) of subjects with one or more observed episodes of serum K+>6.0mmol / L.5 of 6 judged not related to study medication.

[0282] ^Measure in 1 subject was an isolated incident not verified by repeat measurement with study drug discontinuation (protocol deviation).Serum Sodium

[0283] Serum sodium concentration decreased in the active treatment arms (Figure 15, Figure16, and Figure 17).Discussion

[0284] This example describes a multicenter, prospective, randomized, placebo-controlled, double-blind, dose ranging study among adults with uncontrolled hypertension despite treatment with at least 2 background AHT medications. The results of this study demonstrate that aldosterone synthase inhibition with lorundrostat as an add-on therapy to a stable regimen of AHT medications was well tolerated, and induced a reduction in AOBP that was both clinically meaningful and statistically significant following treatment for 8 weeks.

[0285] Overall, 42 clinical trial sites across the USA participated in the trial, with 163 subjects randomized into Part 1 (of which 141 [86.5%] completed the trial on study drug) and 37 subjects randomized into Part 2 (of which 33 [89.2%] completed the trial on study drug). Baseline demographic, lifestyle and cardiovascular history characteristics were similar across all doses and study parts, with a relatively even distribution by sex, relevant race and ethnicity minority groups. As anticipated, the study population was primarily an older, overweighVobese group with a large minority of subjects being treated for Type II diabetes mellitus. Approximately 36% of participants were Black or African American. Furthermore, approximately half of the enrolled subjects had been prescribed a 2-drug AHT regimen, with most subjects (>77%) being treated with an ACEi or ARB, and a large majority (58%) being treated with a thiazide diuretic.

[0286] Analysis of the primary efficacy endpoint demonstrated that the majority of BP reductions achieved were within 4 weeks of starting therapy and were generally well-maintained for the remainder of the 8 -week treatment period. Clinically meaningful placebo-adjusted reductions in AOBP SBP 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 reductions in SBP are salient to the effective treatment of subjects suffering with uncontrolled hypertension. In a recent meta-analysis of 147 randomized trials, 10 mmHg reductions in SBP were shown to reduce the risk of stroke by 41% and coronary heart disease by 22% . (Law, Morris, and Wald 2009) Furthermore, the reductions in AOBP SBP were validated by comparable reductions in 24-hour ABPM SBP, and confirmed with the associated benefit of lorundrostat reducing both central and nighttime ABPM SBP, two indicators of elevated cardiovascular event risk (Hermida et al. 2014; Mousa et al. 2004).

[0287] Beneficial effects were seen despite non-standardized background therapy, supporting the generalizability of effect across all subjects with uncontrolled hypertension. Moreover, the identification of sub-groups with statistically significant and clinically meaningful changes in AOBP SBP (i.e., subjects with a BMI >30 kg / m2and subjects with concomitant thiazide diuretic use) suggest the full efficacy of lorundrostat after 8 weeks oftreatment may still be underestimated. Further studies exploring the effects of standardized background regimens and / or current prescribing paradigms with add-on lorundrostat therapy, or within specific sub-populations are warranted.

[0288] Suppressed renin is common among patients with hypertension and in theory, these patients should benefit most from drugs that decrease aldosterone production. Interestingly, subjects enrolled in Part 2 (i.e., subjects with non-suppressed renin levels) treated with lorundrostat demonstrated similar BP lowering efficacy to subjects with suppressed plasma renin levels (i.e., subjects enrolled in Part 1). While the PATHWAY -2 trial demonstrated other MRAs (such as spironolactone) are effective at lowering BP across a wide range of plasma renin levels, further study of lorundrostat in a population not selected for baseline PRA will be important to confirm the effect seen here.

[0289] Pharmacodynamic responses demonstrated dose-dependent reduction in serum aldosterone levels and a commensurate increase in plasma renin activity, in line with the mechanism of action of lorundrostat. No substantial decreases in serum cortisol levels were observed over the course of treatment and follow-up relative to placebo with percent change from baseline values of 20.6% to 51.4% (active) vs 37.7% (placebo) at Week 8, and -1.2 to 22.6% (active) vs 17.1% (placebo) at Week 12. A similar pattern was observed in Part 2, with active arm serum cortisol baseline levels of 11.1 pg / dL in the 100 mg QD dose group and no substantial changes observed over the course of treatment and subsequent follow-up. Most importantly, no adrenocortical insufficiency occurred during the trial.

[0290] Overall, lorundrostat was safe and well tolerated. Two (1.5%) subjects in Part 1 and one (3.2%) subject in Part 2 reported a treatment emergent SAE, of which the worsening of preexisting hyponatremia was considered possibly related to study drug. No treatment emergent SAEs occurred in a subject treated with placebo. No deaths were reported in either Part 1 or Part 2.

[0291] At least one on-treatment TEAE was reported by 83 subjects in Part 1 (73 [54.9%] treated with lorundrostat versus 10 [33.3%] treated with placebo) and by 20 subjects in Part 2 (19 [61.3%] treated with lorundrostat versus 1 [16.7%] treated with placebo). Of the subjects treated with lorundrostat, 27 (20.3%) and 9 (29.0%) from Part 1 and Part 2, respectively, experienced TEAEs that were considered at least possibly related to study drug. The most commonly reported AE by PT was hyperkalemia and a decreased eGFR. All active doses saw modest increases in potassium levels at Week 8 relative to baseline ranging from 0.208 mmol / L (100 mg QD Part 2) to 0.341 mmol / L (25 mg BID Part 1). While seven subjects experienced transient elevated serum potassium greater than 6.0 mmol / L, none were considered an SAE and all rapidly resolved afterdiscontinuation or dose adjustment, consistent with the short half-life of lorundrostat. It should be noted that one of these events was assessed as erroneous due to incorrect sample processing. In a manner similar to ACE inhibitors and ARBs, the BP lowering effect of lorundrostat led to a beneficial, reversible dose-dependent reduction in eGFR.

[0292] Hypotension related to treatment was seen in three subjects and was reversible with treatment cessation and expected based on lorundrostat’ s mechanism of action. Two of these subjects were randomized to the 100 mg QD cohorts (1 in both Part 1 and Part 2), and one to 12.5 mg BID. In addition, three subjects developed orthostatic hypotension, defined as a fall of 20 mmHg in SBP or 10 mmHg in DBP when going from sitting to standing. In each case, the episode resolved and did not recur for the remainder of the treatment period. Ongoing observation for symptoms of hypotension, even if minimal and reversible, is warranted for future clinical studies.

[0293] In conclusion, the primary objective of the study was to characterize the safety and efficacy of lorundrostat on blood pressure at 5 dosing levels and 2 dosing regimens versus placebo when administered orally for the treatment of uncontrolled hypertension as add-on therapy to stable background treatment. The results of this study indicate:(a) Lorundrostat was effective at lowering BP in individuals with inadequately treated or treatment resistant hypertension;(b) There was a dose- and exposure-response relationship, with mean placebo- adjusted reduction in SBP of 9.58 mmHg and 7.81 mmHg seen at doses of 50 mg QD and 100 mg QD, respectively;(c) 24-hour ABPM, central BP and nighttime SBP values confirmed the reduction in SBP seen with AOBP, most prominently in the 100 mg QD dose cohort; and(d) The safety dataset lorundrostat was safe and well tolerated, with no effects on serum cortisol and an expected modest increase in serum potassium with relatively few episodes of clinically meaningful hyperkalemia.

[0294] Future studies evaluating the long-term efficacy and safety of lorundrostat in patients with uncontrolled hypertension are warranted.Example 3IntroductionStudy Rationale

[0295] Lorundrostat, a selective aldosterone synthase inhibitor (ASI), is being developed for the treatment of uncontrolled and / or treatment-resistant hypertension due, in part, to excess aldosterone production that is inadequately treated by upstream renin-angiotensin-aldosterone system (RAAS) system inhibitors including renin inhibitors, angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB). While the existing class of mineralocorticoid receptor antagonists (MRA) also address this dysregulated biology, the new ASI class has the potential have a more favorable benefiVrisk profile due to the differentiated mechanism of action, which results in a profound decrease in circulating and local aldosterone production, rather than the marked increase seen with the MRA class. In addition, unlike spironolactone, the most commonly prescribed MRA, and other ASIs in development, lorundrostat, because of its short half-life, has the potential to be rapidly reversible should adverse events (Aes) such as hyperkalemia or hypotension be encountered.

[0296] This study will evaluate the safety, efficacy, and tolerability of lorundrostat in subjects with uncontrolled and treatment-resistant hypertension. Phase 1 healthy subject data support the safety profile and selectivity, relative to cortisol production, of the drug while demonstrating relevant changes in aldosterone levels and plasma renin activity consistent with the mechanism of action of the drug. A first-in-patient dose range finding safety and efficacy Phase 2 trial, Target- HTN (NCT05001945), has completed and is discussed in Example 2. Primary and secondary endpoints were met and lorundrostat was safe and well tolerated.

[0297] The primary objective of this proposed Phase 2 trial is to confirm the efficacy, dose range, and safety of lorundrostat observed in the Target-HTN trial. A key secondary objective is to confirm that lorundrostat is particularly effective in individuals with obesity and provide additional mechanistic support for the hypothesis that crosstalk between visceral adipocytes and the adrenal gland defines a unique “endotype” of hypertension that can be treated with lorundrostat. A further objective is to evaluate the efficacy of lorundrostat when administered alongside a specific set of other anti-hypertensive medications as discussed below.

[0298] This Phase 2 trial will evaluate the blood pressure (BP) response in subjects with uncontrolled hypertension on the background of a standardized 2- or 3 -drug antihypertensive (AHT) medication regimen including maximum effective / tolerated doses of an ARB and thiazide and optionally a calcium channel blocker. Doses of 50 mg to 100 mg daily of lorundrostat HBr will be tested to inform additional registration trials.

[0299] If successful, lorundrostat will provide the first targeted therapeutic option for patients with difficult to control hypertension. The underlying mechanism, including obesity-related dysregulation of critical aspects of systems biology, has the potential to define the first endotypespecific AHT agent. As obesity is the single greatest risk factor for hypertension and related adverse cardiorenal outcomes, lorundrostat has the potential to benefit millions of individuals who currently do not achieve BP reduction targets.Background

[0300] Even with significant advances in its diagnosis and treatment, hypertension is a leading modifiable cause of premature death and one of World Health Organization’s global targets for the prevention of non-communicable diseases (NCDRF Collaboration 2021). Population rates of hypertension control have declined in the United States, and additional significant BP increases were seen during the COVID-19 pandemic (Muntner 2020, Laffin 2021).

[0301] The diagnosis and management of hypertension has not materially changed in the past decade, with limited innovation in the development of novel antihypertensive therapeutics with unique mechanisms of action. Antisense inhibition of angiotensinogen, a recently established method of treating hypertension, is an upstream RAAS pathway antagonist mechanistically similar to renin inhibitors, ACE and ARB classes (Morgan 2021). Renal denervation, aside from its more invasive nature, addresses primarily local sympathetic activity without affecting the more complex pathways and system biology affected by humoral mediators (Ahmad 2021). Non-steroidal MRAs address some of the liabilities of spironolactone and similar early generation drugs, but all share the property of dramatically increasing circulating and local aldosterone production (Lainscak 2015). The ASI class has the potential to more effectively manage the pathobiology resulting from excess aldosterone production. That proposition is supported by evolving literature which suggests that non-genomic signaling via receptors other than the mineralocorticoid receptor may contributeto long term cardiorenal pathology, including vascular wall remodeling, endothelial dysfunction and fibrosis (Brief 2013).

[0302] With clinical practice guideline recommendations to manage BP to less than 130 / 80 mmHg (Whelton 2018) and data from the Systolic Blood Pressure Intervention Trial (SPRINT) (Wright 2015) suggesting the benefit of a lower systolic blood pressure (SBP) target in patients with underlying cardiovascular disease, additional options for clinicians to manage BP are warranted. Hypertension is historically considered multi-factorial and as a consequence of aging. The approach to treating hypertension is rarely directed toward a primary underlying mechanism. Recent evidence suggests that up to approximately 30% of individuals (Baudrand 2018), who otherwise would have been classified as primary hypertension (previously known as essential hypertension) may have hypertension that is driven predominantly by the underlying mechanism of autonomous aldosterone overproduction.

[0303] Broadly speaking, there are at least two predominant mechanisms under which inappropriately elevated aldosterone production may occur. The canonical mechanism is through the accumulation of gene mutations (and potentially epigenetic modifications) in the adrenal cortex, resulting in activation of aldosterone-producing cells in the zona glomerulosa (Mulatero 2020). Many of these mutations are shared between inherited forms of hyperaldosteronism and acquired adenomas and autonomous aldosterone producing cell clusters (APCC) in the adrenal (De Sousa 2020). While hereditary hyperaldosteronism is a rare disease, acquired mutations are a more common etiology. Adenomas are generally unilateral and can be addressed with surgical resection, APCCs and adrenal hyperplasia are generally bilateral and require medical treatment.

[0304] Previously, patients with inappropriately elevated aldosterone production were often dichotomized as having primary aldosteronism or primary hypertension. However, accumulating evidence indicates that a much larger and clinically relevant spectrum of renin-independent aldosterone production may exist, particularly among individuals that do not meet accepted thresholds for overt primary aldosteronism (Vaidya 2018, Funder 2022).

[0305] Data from the Prevention and Treatment of Hypertension With Algorithm based Therapy-2 (PATHWAY-2) study (Williams 2015) in patients with resistant hypertension highlighted the BP lowering response of aldosterone blockade using a MRA. Additional recent evidence supports the postulate that obese individuals represent an even larger population withhypertension due, in part, to excess production of aldosterone (Hall 2015). While the factors elevating aldosterone production in obesity are likely complex, one mechanism stands out due to its dysregulation of normal systems biology. As the mass of visceral adipocytes increases, they take on a greater role in regulating the circulating proteome. Two adipokines in particular, leptin, which is increased, and adiponectin, which is decreased, play a central role in establishing a pathological positive feedback loop between visceral adipocytes and the adrenal cortex (Dinh Cat 2016). Leptin is preferentially secreted by visceral adipocytes and, in addition to its pathologic actions on the brain in obesity, may also stimulate the adrenal cortex to produce more aldosterone, independent of upstream RAAS system activity (Faulkner 2019). Reduced adiponectin is also associated with increased circulating aldosterone and upstream activation of the RAAS system (Flynn 2011). To complete the pathological change in systems biology, visceral adipocytes respond to increased aldosterone by maintaining their abnormal secretome, leading to maintenance of a positive feedback loop driving aldosterone production (Packer 2018). Thus, both low renin and normal renin levels are consistent with inappropriate production of aldosterone in the setting of uncontrolled and treatment-resistant hypertension.

[0306] Despite data and clinical practice guidelines (Whelton 2018) that recommend the use of MRAs in patients with resistant hypertension, the use of MRAs is strikingly low and market data from 2019 demonstrated that fewer than 4% of treated patients were receiving MRAs when indicated (Decision Resources Group 2019). Currently, MRAs are the only available aldosterone targeted therapies and their limited use may be explained by tolerability concerns seen with spironolactone, the more modest effects on BP of newer generation MRAs like eplerenone, and the perception of unacceptable frequency and duration of hyperkalemia in MRA-treated patients. Thus, for both mechanistic and clinical reasons, novel approaches to targeting aldosterone production and effects are needed.Benefit / Risk AssessmentRisk Assessment

[0307] Aldosterone synthase inhibitors may cause hyperkalemia and hyponatremia similar to MRAs (Hargovan 2014). Furthermore, the long-term effect of ASIs on kidney function is not known. However, recent evidence suggests less risk for hyperkalemia when antagonizing aldosterone using nonsteroidal MRAs (Bakris et al. 2020).

[0308] The investigational product lorundrostat is an inhibitor of CYP11B2 (aldosterone synthase), which is a rate-limiting enzyme for aldosterone production. In nonclinical studies, single oral administration of lorundrostat significantly decreased plasma aldosterone concentration (PAC) in a sodium-depleted monkey model. Additionally, single oral administration of lorundrostat did not affect plasma cortisol concentrations in adrenocorticotropic hormone (ACTH)-loaded monkeys even at a dose 100-fold higher than that required to reduce PAC. These results indicate that lorundrostat inhibits CYP11B2 with higher selectivity over CYP11B1, which is an enzyme for cortisol production.

[0309] This high selectivity is also shown in the first-in-human study (Example 1). This study confirmed that lorundrostat decreased PAC and did not decrease serum cortisol in healthy subjects, indicating that lorundrostat may have a lower potential risk of hyperkalemia than MRAs. Dizziness / postural hypotension was reported by more lorundrostat-treated subjects compared with those who received placebo, consistent with the desired effect of the investigational product.

[0310] In subjects with uncontrolled and / or treatment -resistant hypertension enrolled in the Phase 2 trial, (Example 2), lorundrostat was deemed safe and well tolerated. One treatment- emergent serious adverse event (SAE) was deemed to be possibly related to lorundrostat in a subject with worsening of pre-existing hyponatremia, which reversed after treatment discontinuation. Transient elevations in serum potassium were observed more frequently in lorundrostat-treated subjects compared with those who received placebo, all of which resolved rapidly after discontinuation or dose adjustment, which is consistent with the short half-life of lorundrostat. As anticipated, and in a manner similar to ACE-inhibitors and ARBs, the BP lowering effect of lorundrostat led to a beneficial, reversible dose-dependent reduction in estimated glomerular filtration rate (eGFR), a measure of kidney function. Finally, the selectivity of lorundrostat for aldosterone inhibition was confirmed as cortisol levels were not observed to be inhibited across the range of doses.Benefit Assessment

[0311] First-line treatment of hypertension includes dietary and lifestyle changes, with pharmacotherapy therapy as an adjunct to lifestyle modification or as second-line treatment. The most common drugs used to treat hypertension include ACE inhibitors, ARBs, calcium channel blockers, thiazide diuretics, and beta-blockers. Despite a plethora of available treatment options,over 50% of patients currently using prescription medication to lower BP have uncontrolled hypertension (Million Hearts 2020; Virani et al. 2021) putting them at greater risk for all-cause mortality and cardiovascular disease outcomes. Furthermore, it is estimated that 10% to 15% of hypertensive patients have resistant hypertension defined as uncontrolled hypertension despite taking >3 AHT drugs (Oparil and Schmieder 2015). In addition, nonadherence or intolerance to available antihypertensive agents contributes to the proportion of hypertensive patients with uncontrolled BP (Oparil and Schmieder 2015).

[0312] Aldosterone is a mineralocorticoid that regulates electrolyte and volume homeostasis in normal subjects, and can contribute to the development of hypertension when elevated. It is synthesized in the zona glomerulosa of the adrenal cortex from 11 -deoxycorticosterone by aldosterone synthase, which is encoded by the cytochrome P450 (CYP) 11B2 (CYP11B2) gene (Oparil and Schmieder 2015). Aldosterone regulates BP mainly by acting via mineralocorticoid receptors (MRs) on organs such as renal tubules and large intestines to increase the amount of sodium reabsorbed into the bloodstream and the amount of potassium removed in the urine. Aldosterone also causes water to be reabsorbed along with sodium, which has the effect of increasing plasma volume and indirectly contributes to vascular disorders via elevated BP. Furthermore, some nonclinical studies report a wide distribution of MRs, not only in the renal tubules, but also in the nonepithelial cells, including vascular smooth muscle cells (Ishizawa et al. 2005) and mesangial cells (Nishiyama et al. 2005), suggesting that overproduction of aldosterone may directly injure the cardiovascular system and kidneys.

[0313] Mineralocorticoid receptor antagonists are used to inhibit the function of aldosterone in the treatment of primary and resistant hypertension, heart failure, and primary aldosteronism. However, blockade of MRs induces a counter-regulatory increase in PAC, potentially limiting the efficacy of the MR blockade and enhancing the MR-independent effect of aldosterone, such as vasoconstriction (Romagni et al. 2003). This suggests that decreasing PAC may be a preferable therapeutic alternative to MR blockade.

[0314] In addition to the negative effects of increasing PAC, MRAs may put patients at risk of hyperkalemia. Cortisol, like aldosterone, binds to the MRs (Arriza et al. 1987), which enhances the excretion of potassium in urine (Mills, Thomas, and Williamson 1960). If the action of the MR is blocked by an MRA, the excretion of potassium in urine will be reduced (Ramsay, Shelton, andTidd 1976). For this reason, MRAs are contraindicated in patients with hyperkalemia. In addition, MRAs require monitoring of plasma potassium, especially in patients who are at high risk for hyperkalemia such as those individuals with renal impairment. Given these limitations, alternative approaches to antagonizing aldosterone activity and its contribution to hypertension and end-organ damage are warranted. Inhibition of aldosterone production in the adrenal gland as opposed to blockade of aldosterone activity at the receptor represents a promising alternative approach.

[0315] In the Phase 2 study described in Example 2, subjects with uncontrolled and / or treatment-resistant hypertension demonstrated clinically and statistically significant reductions in SBP following 8 weeks of treatment with lorundrostat when compared with subjects who received placebo for 8 weeks.Overall Benefit / Risk

[0316] Necessary precautions have been implemented in the design and planned conduct of this study to minimize the risks of participation. The potential risks identified in association with lorundrostat are outweighed by the potential benefits that may be afforded to participants with treatment resistant and / or uncontrolled hypertension.Objectives and Endpoints:Objectives:

[0317] Primary:(a) To assess the blood pressure (BP) lowering effect of lorundrostat taken once daily (QD) in subjects with hypertension on a standardized antihypertensive medication (AHT) regimen.

[0318] Secondary:(a) To determine the effect of obesity on the BP lowering effect of lorundrostat QD in subjects with hypertension on a standardized AHT regimen.(b) To assess the ability of lorundrostat QD to achieve BP control in subjects with hypertension on a standardized AHT regimen.(c) To investigate the safety and tolerability of lorundrostat QD in subjects with on a standardized AHT regimen.(d) To determine the influence of number of antihypertensive (AHT) medications on the BP lowering effect of lorundrostat taken once daily, in subjects with hypertension on a standardized AHT regimen.

[0319] Exploratory:(a) To explore the reversibility of effect of lorundrostat on BP and clinical laboratory parameters of interest in subjects hypertension on a standardized AHT regimen.(b) To explore the effect of lorundrostat on circulating biomarkers.(c) To explore the effect of lorundrostat on self-measured BP (SMBP)

[0320] Pharmacokinetic:(a) To determine the plasma concentrations of lorundrostat and its major metabolite.Endpoints:Efficacy

[0321] Primary Endpoint:(a) Change from baseline in 24-hour average ambulatory blood pressure monitoring (ABPM) systolic blood pressure (SBP) at Week 4 or Week 12 in subjects randomized to lorundrostat 50 mg QD compared to subjects randomized to placebo.

[0322] Key Secondary Endpoints:(a) Proportion of subjects with 24-hour average ABPM SBP <125 mmHg at Week 4 or Week 12 in subjects randomized to lorundrostat 50 mg QD compared to subjects randomized to placebo.(b) Change from baseline in 24-hour average ABPM SBP at Week 4 by obesity status in subjects randomized to lorundrostat 50 mg QD compared to subjects randomized to placebo.(c) Change from baseline in 24-hour average ABPM SBP at Week 4 by obesity status in subjects randomized to lorundrostat 50 mg QD compared to subjects randomized to placebo.(d) Change from baseline in AOBP SBP at Week 12 in subjects randomized to lorundrostat 50 mg QD compared to subject randomized to placebo(e) Change from baseline in 24-hour average ABPM SBP at Week 12 in subjects randomized to lorundrostat 50 mg QD with escalation to lorundrostat 100 mg QD compared to subject randomized to placebo.(f) Change from baseline in AOBP SBP at Week 12 in subjects who were escalated to lorundrostat 100 mg QD at Week 4 (within-subjects analysis).

[0323] Other Secondary Endpoints:(a) Change from baseline in daytime average ABPM SBP at Week 4 or Week 12 in subject randomized to lorundrostat 50 mg QD compared to subjects randomized to placebo.(b) Change from baseline in automated office blood pressure (AOBP) SBP at Week 4 or Week 12 in subjects randomized to lorundrostat 50 mg QD compared to subject randomized to placebo.(c) Change from baseline in nighttime average ABPM SBP at Week 4 or Week 12 in subjects randomized to lorundrostat 50 mg QD compared to subject randomized to placebo.(d) Change from baseline in 24-hour average ABPM SBP at Week 4 or Week 12, by number of AHT medications in the standardized AHT regimen (2 vs. 3) in subjects randomized to lorundrostat 50 mg QD compared to subject randomized to placebo.(e) Change from baseline in 24-hour average ABPM SBP at Week 12 in subjects randomized to lorundrostat (pooled dosages) compared to subjects randomized to placebo.

[0324] Exploratory Endpoints(a) Change from baseline at Week 4 and at Week 12 in subjects randomized to lorundrostat (pooled dosages and by randomized dose arm) compared to subjects randomized to placebo in:(i) 24-hour average ABPM diastolic blood pressure (DBP);(ii) 24-hour average central SBP;(iii) 24-hour average central DBP;(iv) 24-hour average ABPM central Mean Arterial Pressure (MAP);(v) Daytime average ABPM SBP (only Week 12);(vi) Daytime average ABPM DBF;(vii) Nighttime average ABPM SBP (only Week 12);(viii) Nighttime average ABPM DBF;(ix) Average ABPM SBP nighttime dip (%).(b) Change from baseline to Week 12, by visit (when applicable), in subjects randomized to lorundrostat (pooled dosages and by randomized dose arm) compared to subjects randomized to placebo in:(i) AOBP SBP;(ii) AOBP DBF;(iii) AOBP MAP;(iv) Self-measured SBP;(v) Self-measured DBP;(vi) Serum cortisol;(vn) 24-hour urine albumin excretion;(viii) 24-hour urinary aldosterone;(ix) 24-hour urinary free cortisol;(x) 24-hour urinary potassium;(xi) Urine albumin: creatinine ratio (UACR).(C) Proportion of subjects with 24-hour average ABPM SBP <125 mmHg at Week 12 in subjects randomized to lorundrostat (pooled dosages and by randomized dose arm) compared to subjects randomized to placebo.(d) Proportion of subjects at Week 4 and at Week 12 in subjects randomized to lorundrostat (pooled dosages and by randomized dose arm) compared to subjects randomized to placebo with:(i) Daytime average ABPM <130 mmHg;(ii) Daytime average ABPM <130 / 80 mmHg;(iii) AOBP SBP <130 mmHg;(iv) AOBP <130 / 80 mmHg;(v) Average ABPM SBP nighttime dip >10%.(e) Change from Screening at Week 4 and Week 12 in subjects randomized to lorundrostat (pooled dosages and by randomized dose arm) compared to subjects randomized to placebo in:(i) AOBP SBP(ii) Serum potassium;(iii) Serum sodium;(iv) eGFR(f) Change from Week 12 to Week 16, by visit, in subj ects participating in Washout randomized to lorundrostat (pooled dosages and by randomized dose arm) compared to subjects randomized to placebo in:(i) AOBP SBP;(ii) Serum potassium;(iii) Serum sodium;(iv) eGFR;(v) 24-hour urine albumin excretion; (VI) 24-hour urinary aldosterone; (vii) 24-hour urinary free cortisol; (viii) 24-hour urinary potassium; (ix) Urine albumin: creatinine ratio (UACR).(g) Change from baseline to Week 16, by visit, in subj ects participating in Washout randomized to lorundrostat (pooled dosages and by randomized dose arm) compared to subjects randomized to placebo in:(i) AOBP SBP;(ii) Serum potassium;(iii) Serum sodium;(iv) eGFR;(v) 24-hour urine albumin excretion;(vi) 24-hour urinary aldosterone;(vii) 24-hour urinary free cortisol;(viii) 24-hour urinary potassium;(ix) Urine albumin: creatinine ratio (UACR).(h) Change from Screening baseline to Week 16, by visit, in subjects participating in Washout randomized to lorundrostat (pooled dosages and by randomized dose arm) compared to subjects randomized to placebo in:(i) AOBP SBP;(ii) Serum potassium;(iii) Serum sodium;(iv) eGFR.(i) Clinical change in biomarkers.

[0325] Pharmacokinetic Endpoints:(a) Concentrations of lorundrostat and its metabolite.

[0326] Safety Endpoints:(a) Incidence and severity of adverse events (AEs).(b) Clinically significant changes in vital signs (body temperature, heart rate, and respiratory rate), physical examination and electrocardiogram (ECG) parameters.(c) Clinically significant changes in clinical laboratory assessments (hematology, chemistry and urinalysis).(d) Incidence of AEs of special interest (AESIs):(i) Modification of study drug dose due to hyperkalemia (eg, dose reduction, dose hold, or permanent dose discontinuation).(ii) Modification of study drug dose due to hyponatremia (eg, dose reduction, dose hold, or permanent dose discontinuation).(iii) Hypotension with symptoms (eg, light-headedness, dizziness, presyncope, or syncope).(iv) Severely elevated BP (AOBP SBP >180 mmHg or DBP >110 mmHg)(v) Modification of study drug dose due to hypercortisolism (morning serum cortisol >35 p.g / dL, confirmed by 24-hour urinary free cortisol).(vi) Discontinuation of study drug due to hypocortisolism confirmed by adrenocorticotropic hormone (ACTH; Cosyntropin) stimulation test.(vii) Overdose of study drug or standardized AHT regimen.(viii) Modification of study drug dose due to reduction in kidney function (eg, dose reduction, dose hold, or permanent dose discontinuation)Study DesignOverall Study Design

[0327] This study is a Phase 2 trial to evaluate the blood pressure-lowering effect of lorundrostat (an aldosterone synthase inhibitor, ‘'AST'), administered as add-on to a standardized AHT medication regimen, in subjects with uncontrolled and / or treatment-resistant hypertension. The study consists of a 3-week standardized AHT regimen run-in with a single blind (subject is blinded) placebo period followed by a 12-week randomized, double-blind, placebo-controlled, parallel arm period. Following the double-blind period, subjects may be offered the opportunity to participate in an OLE study. Subjects electing not to participate in the OLE will undergo an EoS visit approximately 2 weeks after the last does of study drug to complete their participation in the study. A data monitoring committee (DMC) will meet periodically to monitor the study. The primary function of this committee is safety monitoring, and the committee will not discontinue the study for a finding of positive efficacy for any of the doses being considered.Scientific Rationale for Study Design

[0328] Although there is widespread availability of inexpensive and effective oral BP- lowering medications, rates of hypertension control are poor irrespective of age, race, or sex (Virani 2021).

[0329] Lorundrostat is an inhibitor of CYP11B2 (aldosterone synthase), which is a ratelimiting enzyme for aldosterone production and has been shown to reduce BP. In the Phase 2 study described in Example 2, subjects with uncontrolled and / or treatment-resistant hypertension demonstrated clinically and statistically significant reductions in SBP following 8 weeks of treatment with lorundrostat when compared with subjects who received placebo for 8 weeks (Mineralys Therapeutics, NCT05001945).Number of Subjects / Number of Centers

[0330] Up to 261 subjects (approximately 87 per treatment group) are planned to be enrolled across approximately 100 study centers in the United States.Study Duration

[0331] The expected duration of the study from the first subject randomized to the last subject visit is expected to be approximately 14 months.Justification for Dose

[0332] This Phase 2 study will evaluate the safety and AHT effect of lorundrostat dosed orally to a maximum of 100 mg per day.

[0333] The dose range is based on the results of a Phase 1 first-in-man study (see Example 1) that evaluated single doses of lorundrostat up to 800 mg, and multiple doses of lorundrostat up to 360 mg / day, taken orally once daily for 7 days, in healthy volunteers. No dose-limiting toxicities were observed. Dizziness / dizziness postural was reported by 9 out of 87 (10.3%) lorundrostat- treated subjects compared to 1 out of 29 (3.4%) placebo subjects across all cohorts with no apparent dose relationship.

[0334] Post-dose serum potassium concentrations >5.0 mmol / L were observed in 13 subjects (14.9%) who received lorundrostat (6 subjects in the singe ascending dose cohort and 7 subjects in the multiple ascending dose cohort) across all cohorts. Only 2 of these 13 subjects had postdose serum potassium concentration >5.5 mmol / L (one subject with a post-dose serum potassium concentration >6.0 mmol / L). None of the serum potassium elevations were considered clinically significant, and there was no dose-dependent trend. There were no clinically significant findings with respect to vital signs, ECGs, or physical examinations.

[0335] A separate Phase 2 trial (see Example 2), evaluated the safety and antihypertensive effect of lorundrostat up to doses of 100 mg once daily (QD) taken in the morning, and up to 25 mg twice daily, in hypertensive subjects with low renin. A dose of 100 mg QD taken in the morning was also evaluated in hypertensive subjects with normal or elevated renin. This study met its primary and secondary endpoints and lorundrostat was safe and well-tolerated.End of Study Definition

[0336] The EoS is defined as the date of the last visit of the last subject in the study. A subject is considered to have completed the study if they have completed all periods of the study. For subjects who do not elect to participate in the OLE study, Week 14 is the last study visit. Forsubjects who elect to participate in the OLE study, Week 12 is the last study visit (refer to Schedule of Assessments, Table 46).

[0337] All subjects who are not transitioning to an OLE study will be advised to restart their prescribed AHT medications after Week 12 or early withdrawal (EW) visit (i.e., the Week 12 visit, or EW visit, represents their last dose of standardized AHT medication) and contact their primary care physician to notify them of the end of their participation in the trial, when appropriate.

[0338] At the time of study completion or early withdrawal, subjects will be queried regarding any AEs, concomitant medications, and concurrent procedures, which will be recorded on the appropriate page(s) of the source documents and electronic case report form (eCRF). At the final study visit, subjects with ongoing AEs that are considered by the investigator to be serious, study drug-related, or associated with the target condition will be requested to continue follow-up with the Investigator until the AE resolves, is stable, or follow-up is no longer possible / necessary. The investigator in consultation with the Medical Monitor will determine if a subject should participate in an OLE study based on the totality of the data available. Any death or pregnancy that occurs while on study or within 28 days after the subject’s last dose of study drug must be reported to the sponsor / designee for the study within 24 hours after the center becomes aware of the event.Criteria for Study Termination

[0339] Both the sponsor and the investigator reserve the right to terminate the study according to the study contract. The sponsor may issue a protocol amendment or discontinue the study entirely, based on regulatory authority or Institutional Review Board (IRB) / Independent Ethics Committee (IEC) recommendations, drug safety or availability concerns, discontinuation of the development program for lorundrostat, or at the sponsor’s discretion with at least 30 days’ notice. The data monitoring committee (DMC) may also recommend study termination based on a review of the safety data.Study Conduct

[0340] A schedule of study assessments is presented in Schedule of Assessments (Table 46).Details of study assessments are provided in the “Study Assessments and Procedures” section.Modifications to Study Conduct Due to the Global Pandemics

[0341] As a consequence of the COVID-19 pandemic that has had a worldwide impact, control measures in place may impact the ability to adhere to some of the study procedures described in this protocol. Due to challenges that include, but are not limited to, subject COVED- 19 infections, site closures, travel restrictions, and quarantines, some modifications to study conduct during the COVID- 19 or any other global pandemic may be necessary to ensure study continuity, including conducting virtual visits when on-site study visits are considered not feasible. Such modifications in study conduct must always be in accordance with local regulations / mandates.

[0342] The following are allowable, as necessary, modifications to study conduct during the COVID-19 or any other global pandemic:(a) Prior to a study visit at the site, the subject may be contacted and screened for potential exposure or infection to COVID- 19 or any pathogen associated with a global pandemic per site, local, or federal requirements. If the subject is suspected to be exposed or infected with such a pathogen, the on-site visit should either be re-scheduled or a virtual visit may be performed instead, as applicable.(b) In the event that a subject cannot attend their regularly scheduled study visits in person due to COVID- 19 or any pathogen associated with a global pandemic necessitating a limit on in-person contact, the investigator may perform safety and efficacy assessments by phone or video. The investigator may use the technology platform that is currently available to them. Virtual assessments may include home blood pressure evaluation initiated by the subject, aEs, and concomitant medication review. Virtual assessments will be recorded by site staff in the source documents.(c) Clinical laboratory tests (chemistry and hematology) and pregnancy tests may be performed by local laboratory, if sample collection cannot be performed at the study site due to limitations related to COVID-19 or any pathogen associated with a global pandemic, including but not limited to site closure. Abnormal laboratory results should be promptly communicated to the Medical Monitor. Subjects* anonymity must be maintained when communicating results to the Medical Monitor.(d) At home study drug administration may continue for up to 2 weeks (at multiple times during the study if required due to COVID- 19, although not consecutively) if the subject has no relevant clinically significant out of range values per previous lab reports.(e) Source documentation should note that the visit was performed virtually (not face-to-face) and note the name of the local lab where laboratory tests were done, if applicable.(0 If certain study procedures or assessments cannot be completed per the schedule of events, the reason for the missed assessment (ie, laboratory tests, vital signs, physical examinations, etc) must be noted in the source documentation (eg, COVID-19), captured in the protocol deviations documentation, and reported to the IRB / IEC, as applicable.

[0343] A detailed assessment of risk and mitigation measures related to COVID-19 or any pathogen associated with a global pandemic will be documented in the appropriate study plans.Study Population

[0344] Subjects not meeting all inclusion criteria, or meeting at least one exclusion criterion, may be re-screened once if there is a reasonable possibility of reversal. Retesting of laboratory samples, and a repeat of AOBP and / or ABPM assessment is allowed in the event of a technical failure. Inclusion in the study of any subject who meets all eligibility criteria on re-screening will be at the discretion of the Investigator and the Medical Monitor.Inclusion Criteria

[0345] Subjects eligible for inclusion in this study must meet all of the following criteria:(a) Written informed consent, obtained before any assessment is performed.(b) At least 18 years of age at the time of signing the informed consent form.(c) At Screening: AOBP SEP of 140-180 mmHg and AOBP DBP of 65-110 mmHg, or AOBP DBP of 90-110 mmHg (all inclusive)(d) At Randomization: 24 hour average ABPM SBP of 130-180 mmHg or 24-hour average ABPM DBP >80 mmHg (all inclusive)(e) Taking between 2 and 5 AHT medications, inclusive, at a stable dose for 1 month prior to the Screening Visit. Note: each individual AHT agent in a combination pill counts as one AHT medication(f) History of hypertension lasting at least 6 months prior to Screening.(g) Serum cortisol (morning measurement, blood draw as close to 8 am as possible but before 10 am) between 3 and 22 gg / dL, inclusive, at Screening.(h) Body mass index (BMI) of 18-40 kg / m2inclusive at Screening(i) Fertile male subjects and female subjects of childbearing potential, and their partners, must agree to use either highly effective or acceptable methods of contraception from the screening visit to 28 days after the last dose of study drug(j) Willing and able to comply with the study instructions and attend all scheduled study visits.Exclusion Criteria

[0346] Subjects meeting any of the following criteria are not eligible for inclusion in this study:(a) Women who are pregnant, plan to become pregnant, or are breast-feeding(b) Subjects with known hypersensitivity to lorundrostat or any of the excipients(c) Treatment, or anticipated treatment, with any prohibited medication within the timeframes described in this Example(d) Participation in a trial involving an investigational device or drug within 4 weeks or 5 half-lives (whichever is longer) prior to the Screening Visit(e) Known allergy to olmesartan, indapamide, amlodipine, or hydrochlorothiazide (HCTZ) or documented intolerance to angiotensin receptor blockers, angiotensin converting enzyme inhibitors, dihydropyridine calcium channel blockers, or thiazide-type diuretics(f) Estimated glomerular filtration rate (eGFR) <45 mL / min / 1.73 m2at Screening, calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula(g) Serum potassium >5.0 mmol / L at Screening or >4.8 mmol / L at Randomization(h) Serum sodium <135 mmol / L (corrected for hyperglycemia) at Screening. Rescreening of subjects with an exclusionary serum sodium is only allowed if two consecutive measurements at least one week apart are > 135 mmol / L. A decrease in dose of a prescribed AHT diuretic prior to rescreening is ollowed)(i) Subjects with any of the following laboratory abnormalities at Screening may only be enrolled in the trial with approval of the medical monitor:(i) Total bilirubin >2 x ULN (except for those with a diagnosis of Gilbert’s syndrome)(ii) Total white blood cell count <3.5 or >14.0 x 109ZL except for benign ethnic neutropenia(j) History of clinically significant hyponatremia within 1 year prior to Screening(k) History of adrenal insufficiency or an abnormal ACTH stimulation test within 1 year prior to Screening(1) Hospitalization for the treatment of urgent or emergent hypertension within 1 year prior to Screening(m) Current, known or presumed white coat hypertension / significant white coat effect (>20 mmHg elevation in clinic blood pressure compared with historical home BP assessments, or documented >20 mmHg elevation in clinic compared with historical 24-hour ABPM measurements.)(n) Cunent, known or presumed orthostatic hypotension (as defined in the SRM)(o) Current, known or presumed autonomic dysfunction(P) Current, night-shift worker, or anticipated to become a night-shift worker for >14 days continuously during the duration of the study, may only be enrolled with 24-hour average ABPM meeting study randomization criteria.(q) Arm circumference >55 centimeters at Screening(r) Previously proven secondary cause of hypertension. Subjects with documented sleep apnea or documented primary aldosteronism are eligible to participate if they are able to discontinue use of a MRA during the 3-week standardized AHT run-in period. They should have <20 mmHg increase in AOBP SBP, and AOBP SBP <150 mmHg (or 24-hour average ABPM SBP <145 mmHg) at Randomization. MRA treatment should be tapered over a one-week period.(s) History of heart failure, myocardial infarction, stroke, or transient ischemic attack within 6 months prior to the Screening Visit. Heart failure of New York Heart Association (NYHA) Class II or more requires approval by the Medical Monitor(t) Diabetes mellitus with a glycosylated hemoglobin (HbAlc) >9% (>74.9 mmol / mol) at Screening(u) Diabetes mellitus with >1 severe hypoglycemic event or severe diabetic ketoacidosis event (events requiring external help) in the 12 months prior to Screening, or with a history of impaired hypoglycemia awareness at Screening.(V) Planned major surgery requiring hospitalization during the study period, or performed within 4 weeks prior to the Screening Visit(w) History of malignant neoplasms within the 5 years prior to Screening, except for known history of basal and squamous cell skin cancer and any carcinoma in-situ(X) Known or suspected abuse of illicit drugs or alcohol within 1 year prior to Screening(y) In the opinion of the principal investigator, any other condition that will preclude participation in the study.Lifestyle ConsiderationsMeals and Dietary Restrictions

[0347] Dietary counseling reflecting the current standard of care will be provided to all subjects.Caffeine, Alcohol, and Tobacco

[0348] Subjects will abstain from ingesting caffeine- or xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for 30 minutes before the start of any study-related BP measurement.

[0349] Subjects will abstain from alcohol for 30 minutes before the start of any study-relatedBP measurement.

[0350] Subjects will abstain from smoking and the use of cannabis-derived or nicotine- containing products (including nicotine patches or gums and e-cigarettes) for at least 30 minutes before the start of any study-related BP measurement.

[0351] The same restrictions will be recommended for home BP measurements.Activity / Ex ercise

[0352] Subjects will abstain from strenuous exercise for 30 minutes before the start of BP measurement and for 24 hours before each blood collection for clinical laboratory tests. Subjects may participate in light recreational activities (eg, watching television, reading).Study Drue Administration and ManagementDescription of Study Drug

[0353] The study drug product is an immediate release formulation containing standard excipients generally recognized as safe including bulking agent, disintegrant, glidant, and lubricant that are compressed into a tablet.

[0354] A tabulated summary of lorundrostat characteristics is shown below. The daily dose of lorundrostat will not exceed 100 mg.Table 44: Lorundrostat Characteristics

[0355] The placebo tablets provided will be identical to the tablets containing lorundrostat in terms of color, shape, and packaging.

[0356] Packaged tablets will be assigned a unique identifying number, used by the randomization and trial supply management (RTSM) system to identify the content but maintaining the blind of the subject and site. The test materials will be identified by the lot, batch numbers, retest date, and certificate of analysis.

[0357] The standard AHT medications will be packaged and labelled and administered as described in the “Study Drug Administration and Management” section of this example.Dosing and Administration

[0358] The standardized AHT regimen is described in the sections below.

[0359] During the study all subjects will take the same number of study drug tablets, regardless of treatment allocation, to maintain the blind. Subjects will be instructed to take the tablets orally once daily at approximately the same time each morning.

[0360] Single-blind (subject is blinded) placebo lorundrostat tablets will be administered along with the AHT regimen during the standardized AHT run-in period and the wash-out period.Standardized Antihypertensive Medication Regimen

[0361] Following screening for eligibility, each subject’s prescribed AHT medications (of between 2 and 5 drugs, inclusive) will be discontinued or tapered over a 7-day period, or at the discretion of the investigator, at the start of the standardized AHT run-in period. Each subject will be given a standardized regimen of AHT medications based on their prescribed AHT medications (Table 45). Dose modifications as outlined in Table 45 are permitted when initiating the standardized AHT regimen for cases of documented intolerance. Dose adjustments for the standardized AHT regimen may be made in the first week of the AHT run-in period. The duration of the AHT run-in period will be 3 weeks.

[0362] If it is deemed necessary to taper the dose of certain pre-entry AHT medications rather than stopping abruptly (i.e. chronic high dose beta-blockers or central sympatholytics such asclonidine), this should be performed during the first 7-10 days of the standardized AHT run-in period.

[0363] Prior to randomization, AOBP and AB PM will be assessed to confirm eligibility on the standardized AHT regimen. Subjects will stop taking the standardized AHT regimen and will restart their prescribed AHT medications when all assessments and procedures scheduled for the week 12 visit are completed, if the subject is not transitioning to an OLE study.Table 45: Standardized AHT RegimenMedications at Visit 1 Standardized AHT Modified starting doses in (Screening) Regimen cases of documented intolerance2 baseline medications Olmesartan 40 mg daily, plus Olmesartan 20 mg daily Indapamide 2.5 mg daily or Indapamide: Use HCTZ HCTZ 25mg daily _ HCTZ: 12 mg daily3-5 baseline medications Olmesartan 40 mg daily, plus Olmesartan as above Indapamide 2.5 mg daily or Indapamide as above HCTZ 25 mg daily, plus Amlodipine: 5mg daily Amlodipine 10 mg daily

[0364] Abbreviations: AHT, antihypertensive; AOBP, automated office blood pressure; DBP, diastolic blood pressure; mg, milligrams; mmHg, millimeters of mercury; SBP, systolic blood pressure.Preparation, Handling, Storage, AccountabilityStudy Drug Preparation

[0365] Not applicable.Study Drug Packaging and Labeling

[0366] Study drug will be labelled, packed, and released in accordance with the Clinical Trials Directive 2001 / 20 / EC and Good Manufacturing Practice Directive 2003 / 94 / EC for Investigational Medicinal Products.

[0367] Lorundrostat HBr and matching placebo tablets are packaged in 30 count 60 cc white round high density polyethylene bottles with a child-resistant cap. As this is a double-blind study, labeling of the lorundrostat HBr and matching placebo tablet packaging will not show the treatment allocation. All other information required by regulation will appear on the label.

[0368] Standardized AHT medication packaging and labeling will be supplied in the commercial packaging and labeling for each drug. Each tablet will be administered as directed in the Study Reference Manual.Study Drug Handling and Disposal

[0369] All study drug supplies are to be used only for this clinical study and not for any other purpose. Authorized study personnel must maintain a full record of study drug disposition (ie, a log by date received, dispensation date and subject, date of return from the subject, and detailed study drug usage by each study subject).

[0370] After reconciliation, used study drug will be handled according to instructions provided by the Sponsor. At study conclusion, all remaining unused supplies will be similarly handled. Authorized study personnel will record any unaccounted supplies in the final accountability records.Study Drug Storage

[0371] The study drug should be stored at room temperature (59°F to 77°F [ 15°C to 25°C]) in an approved storage area with access limited to authorized study personnel.Study Drug Accountability

[0372] Study drug (including placebo and the standardized AHT regimen) will be maintained under adequate security by appropriate site personnel (e.g., pharmacist) and in accordance with applicable regulatory requirements. Study drug remaining at the end of the study will be returned to the sponsor or their representative, or destroyed on behalf of the sponsor.

[0373] The investigator or designee must maintain adequate records of receipt and distribution of all study drug, using appropriate accountability records.Randomization and Blinding

[0374] For the double-blind treatment period, subjects will be randomized 1:1: 1 to receive daily doses of:(a) Placebo for 12 weeks, or(b) Lorundrostat HBr 50 mg QD for 12 weeks, or(c) Lonmdrostat HBr 50 mg QD for 4 weeks followed by 8 weeks of lonmdrostat HBr 100 mg QD for subjects who meet the following criteria at the Week 4 Visit:(i) AOBP SBP >130 mmHg;(ii) Serum potassium <4.8 mmol / L;(iii) Serum sodium >135 mmol / L, and(iv) eGFR >45 mL / min / 1.73 m2and <25% reduction in eGFR fromRandomization.Those who do not meet all four criteria will remain on lorundrostat HBr 50 mg QD for the remaining 8 weeks of the double-blind treatment period.

[0375] Randomization will be stratified by the number of AHT medications in the standardizedAHT regimen (2 vs. 3). The sponsor will arrange for randomization of study subjects by study drug dosage group and treatment assignment. Randomization numbers and study drug supplies will be assigned using RTSM. Access to the randomization codes will be controlled and documented.

[0376] The identity of study drug assignments (lonmdrostat HBr or placebo) during the double-blind treatment phase will be concealed from the investigator, the subject, research center staff, and all personnel involved in the conduct of the study, with the exception of the unblinded sponsor drug management staff who will oversee the study drug allocations and RTSM / dispensing compliance at the study centers.

[0377] Except when it is essential for the medical management of the subject, unblinding the treatment assignment will be considered a protocol deviation. Emergency treatment allocation information will be available by secured access to the RTSM system. If possible, the investigator should contact the sponsor before unblinding any subject’s treatment assignment. In the event that this is not possible, the sponsor should be notified within 24 hours after the unblinding event. After unblinding, the subject will be discontinued from study drug treatment, but will be encouraged to continue participation in the study, including participation in all remaining visits and assessments, until the EoS visit. The reason for unblinding must be documented in the eCRF.Study Drug Compliance

[0378] Compliance with study drug dosing and dosing of the standardized AHT regimen will be assessed at each visit as per the Schedule of Assessments (Table 46). Compliance will be assessed by direct questioning and counting returned tablets during the site visits, and will be documented in the source documents and relevant case report form. Deviation^) from the dosage regimen (for study drug and the standardized AHT regimen) must be recorded.

[0379] A record of the quantity of study drug and standardized AHT medication dispensed to and administered by each subject must be maintained and reconciled with study intervention and compliance records. Study drug start and stop dates, including dates for study drug holds and / or dose reductions will also be recorded.

[0380] Study drug compliance will be defined by the treatment compliance ratio: the number of doses taken by the subject divided by the number of doses dispensed. Compliance is defined as taking between 75% and 125% of the study drug provided.

[0381] This study may use a medication adherence monitoring platform. The platform will be provided on a smartphone application. Built-in reminders and a communication system allow realtime intervention in case of missed doses, reinforce the proper dosing schedule and improve data integrity.Dose Modification

[0382] If an unscheduled dose adjustment of lorundrostat or the subject’s standardized AHT medications occurs at any time following randomization, an unscheduled visit to assess safety will be conducted 2 weeks after the dose adjustment occurs (See the Schedule of Assessments [Table 46] for details).Safety Criteria for Dose Adjustment or Discontinuation of Study Drug

[0383] If, at any time during the study, a subject experiences a clinically significant laboratory or medical assessment (eg, hyperkalemia, hyponatremia, symptomatic hypotension, severely elevated BP, hypercortisolemia, hypocortisolemia, reduction in kidney function), laboratory test values will be confirmed using a local laboratory and BP measurements will be repeated. At the discretion of the Investigator in consultation with the Medical Monitor, the dose of the study drug may be modified, or temporarily or permanently discontinued without necessitating the withdrawalof the subject from the study. The Investigator may discontinue study drug without prior consultation with Medical Monitor at their discretion and discuss with the medical monitor within24 hours.Safety Criteria for Modification of AHT Medication

[0384] Dose adjustments due to hypotension without symptoms are outlined in the SRM. Dose adjustments due to hypotension with symptoms or severely elevated BP are outlined in the SRM, and the Study Assessments and Procedures section of this Example.

[0385] If modification of the standardized AHT medication regimen is required, this may occur at the discretion of the Investigator without necessitating withdrawal of the subject from the study. It is strongly recommended that this decision is made following consultation with the Medical Monitor.Concomitant Therapy

[0386] Any medication or vaccine (including over-the-counter or prescription medicines, recreational drugs, vitamins, and / or herbal supplements) that the subject is taking at screening or takes during the study must be recorded along with:(a) Reason for use(b) Dates of administration including start and end dates(c) Dosage information including dose and frequencyProhibited Treatments

[0387] The following medications are prohibited from the start of the standardized AHT run- in phase until the EoS visit, unless otherwise stated:(a) Previous treatment with lorundrostat or other ASIs within 3 months prior to Screening(b) Use of epithelial sodium channel inhibitors or mineralocorticoid receptor antagonists, including, but not limited to amiloride, triamterene, spironolactone, eplerenone, finerenone, from 28 days prior to the screening visit and during study participation(c) Other medications for blood pressure lowering beyond the standardized AHT regimen (See “Dose Modification” section for details regarding subjects with severely elevated blood pressure)(d) Any standard AHT cardiovascular medication for other chronic conditions. Subjects are permitted to continue beta-blockers if taken for non-hypertension conditions, such as supraventricular tachycardia.(e) Potassium supplements from Randomization until the EoS. If hypokalemia occurs during the study potassium supplements may be re-started(f) Chronically administered oral or high-potency topical corticosteroids from 3 months prior to the screening visit and during study participation. Short-term (ie, <2 weeks) use of topical, inhaled and intra-ocular corticosteroids is allowed if taken >1 month prior to Randomization. Continued use of oral or high- potency corticosteroids is allowed if an ACTH stimulation test performed prior to Randomization is within normal limits. Inhaled and intra-ocular corticosteroids are allowed on an as-needed basis.(g) Sympathomimetic decongestants on the morning of any study-related BP assessment(h) Regular use of phosphodiesterase type 5 inhibitors within 1 week prior to the Screening visit and >2 days per week during study participation(i) Non-steroidal anti-inflammatory drugs (NSAIDs) must be taken for no more than one dose up to 3 days per week. Discontinue NSAIDs if eGFR decreases by >20% from Screening value. Subjects who are taking aspirin 81 mg daily (or less frequently) at the time of the enrolment for the prevention of the cardiovascular events are permitted to continue taking it during the study, as prescribed.(D Intramuscular steroids from 3 months prior to the screening visit and during study participation(k) Short-acting nitrates taken for angina or for underlying cardiac disease within 3 months prior to the Screening visit. Occasional use during study participation should be monitored and study drug discontinued if symptoms of hypotensionor orthostatic hypertension occur or SEP <110 mmHg is documented. Chronic, long-acting doses of nitrates are acceptable.(1) Enrollment of subjects requiring treatment with strong CYP3A and CYP3A4 inducers (eg, apalutamide, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, St. John’s Wort) must be approved by the Medical Monitor prior to randomization. Moderate inducers of CYP3A and CYP3 A4 are acceptable.(m) Use of Proton Pump Inhibitors (PPIs) more than 3 days per week from the start of the AHT run-in period. Abstain for 5 days prior to a scheduled visit.

[0388] The decision to administer a prohibited medication / treatment during the study period is done with the safety of the subject as the primary consideration. When possible, the sponsor is to be notified before the prohibited medication / treatment is administered. If the investigator determines that any of the prohibited treatments listed above are necessary for proper care of the subject during the study, the investigator should recommend a treatment plan in consultation with the Medical Monitor that will allow the subject to remain in the study when possible.Permitted Treatments

[0389] Each subject’s prescribed AHT treatment (between 2 and 5 drugs, inclusive) will be discontinued or tapered over a 7 -day period or, at the discretion of the Investigator, at the start of the AHT run-in phase and will be re-started when all assessment and procedures scheduled for the EoS visit are completed, if the Subject is not transitioning to an OLE study. Subjects who withdraw consent prematurely from the trial will discontinue the standardized AHT regimen at the EW visit. Use of highly effective or acceptable forms of contraception are permitted.Discontinuation / Withdrawal CriteriaDiscontinuation of Study Drug

[0390] Subjects who wish to stop treatment for any reason may stop at any time during the study.

[0391] Reasons for discontinuing study drug may include:(a) Unavoidable use of prohibited / excluded medications(b) Administrative decision by the investigator or the sponsor(c) Chronic or repeated subject noncompliance with the study drug dosing schedule(d) Development of an AE or serious AE (SAE), or AESI at the discretion of the site Investigator, in consultation with the Medical Monitor. If the site Investigator deems the event urgent, then study drug should be held and consultation with the Medical Monitor regarding potential restart of study medication at the assigned or a reduced dose.(e) Unblinding of subject’s study drug treatment assignment(0 Subject becomes pregnant or wishes to discontinue birth control measures

[0392] Subjects who permanently discontinue study drug during the double-blind portion and washout periods of the study may continue participation in the study, including the standardized AHT regimen if deemed appropriate by the site Investigator in consultation with the Medical Monitor, Participation in all remaining visits and assessments until the EoS visit will be encouraged. Subjects who do NOT agree to continue participation after permanently discontinuing study drug will discontinue the standardized AHT regimen and will be advised to restart their prescribed AHT medications. These subjects will be advised to follow up with their primary care physician as per standard of care. Subjects who have permanently discontinued study drug will NOT be eligible to participate in an OLE study.

[0393] Details regarding subjects who discontinue study drug will be recorded on the appropriate page(s) of the eCRF. If a subject discontinues study drug because of an AE, the Investigator may be requested to schedule follow-up visits until the event has resolved or stabilized.Withdrawal of a Subject from the Study

[0394] Subjects have the right to withdraw participation in the study at any time and for any reason and will be removed from the study upon request. However, the Investigator will encourage subjects who wish to withdraw from the study during the double-blind phase to return for subsequent observations up to and including the EoS visit. Subjects who withdraw prematurely from the study for any reason will not be eligible to participate in an OLE study. Subjects who withdraw participation will discontinue the standardized AHT regimen and will be advised to restart their prescribed AHT medications. These subjects will be advised to follow up with their primary care physician as per standard of care. If a subject is unable or unwilling to return, thereason for withdrawal will be recorded. Each subject’s right to withdraw will be honored; subjects who desire no further follow-up contact will be asked to declare so in writing. Details regarding subjects who choose to discontinue study participation will be recorded on the appropriate page(s) of the eCRF.

[0395] Reasons for withdrawing, or being withdrawn, from study may include but are not limited to:(a) Subject withdraws consent(b) Withdrawal from participation due to subject convenience (ie, due to a change in the subject’s willingness or ability to attend study visits, eg, resulting from new job, work schedule change, or move to another geographical area)(C) Lost to follow-up (ie the investigator has exhausted all reasonable methods of contacting the subject, which should be documented by at least 3 phone calls to contact the subject)(d) Chronic or recurrent subject non-compliance, defined as failure to comply with protocol requirements as determined by the investigator or Sponsor(e) Death(f) Other

[0396] If a subject withdraws consent, Mineralys may retain and continue to use any data collected before such a withdrawal of consent.Lost to Follow Up

[0397] A subject will be considered lost to follow-up if he / she repeatedly fails to return for scheduled visits and is unable to be contacted by the study site.

[0398] The following actions must be taken if a subject fails to return to the clinic for a required study visit:(a) The site must attempt to contact the subject and reschedule the missed visit as soon as possible, counsel the subject on the importance of maintaining the assigned visit schedule, and ascertain whether the subject wishes to and / or should continue in the study.(b) The investigator or designee must make every effort to regain contact with the subject. Three telephone calls, and if necessary, a certified letter should be sentto the subject’s last known mailing address or local equivalent methods. These contact attempts should be documented in the subject’s medical record.(c) Should the subject continue to be unreachable, the site will continue efforts to contact the subject at each study visit per schedule and document their effort. No subject will be considered a true lost to follow up until the end of the trial.(d) At the end of the trial, vital status can be verified by the study site by contacting the subject’s primary care physician or other sources according to local rules and regulations.Study Assessments and Procedures

[0399] Table 46 and the “Study Design” section outline the Schedule of Assessments and study conduct details, respectively, for all subjects and all study periods. Protocol waivers or exemptions are not allowed.(a) Informed consent must be obtained before any trial related activity. The process of obtaining informed consent must be documented as part subject’s source documentation.(b) At Screening, subjects will be provided with a card stating that they are participating in a trial and giving contact details of relevant trial site staff.(c) Adherence to the study design requirements is essential and required for study conduct.(d) All subjects should attend study visits consistently in either a fasted or a fed state.(e) Any deviation from study conduct as outlined in the Protocol and / or SRM will be captured and recorded as a Protocol Deviation.(f) Acute safety concerns should be discussed with the sponsor immediately upon occurrence or awareness to determine if the subject requires dose modification or discontinuation of study drug.(g) All screening evaluations must be completed and reviewed to confirm that potential subjects meet all eligibility criteria. The investigator will maintain a screening log to record details of all subjects screened and to confirm eligibility or record reasons for screening failure, as applicable.(h) Source data of clinical assessments performed and recorded in the eCRF must be available and will usually be the subject’s medical records. Additional recording to be considered source data includes, but is not limited to laboratory reports, AOBP, ABPM and ECG assessments.(i) Assessments should be carried out according to the institution’s standard of practice unless otherwise specified in the current section. Efforts should be made to limit the bias between assessments.(j) Phone calls may be conducted between study visits to follow up on subject selfmeasured BP (SMBP) compliance (if applicable), study drug compliance and / or ABPM initiation training or as a general follow up for any questions and or clarifications that the subject may have.1 Only subjects who continue to meet all eligibility criteria will be randomized.2 Study visit windows are +5 days for the Randomization visit, ±3 days during the study treatment period, and ±5 days for the EoS visit.3 Phone calls may be conducted between study visits to follow up on subject SMBP compliance, study drug compliance and / or ABPM initiation training (if applicable).4 Subjects who are not randomized will discontinue the standardized AHT regimen, will be advised to re-start their prescribed AHT regimen.5 Written informed consent must be obtained prior to conducting any study procedures.6 Eligibility must be confirmed before subjects discontinue their prescribed AHT regimen and start the study standardized AHT regimen. Eligibility will be reconfirmed at the Randomization visit prior to being randomized.7 Height will be measured at Screening only. s Assessments performed during the unscheduled visit will be done on an as needed basis.9 At the Screening visit a complete physical examination will be performed and should include an evaluation of the head and eyes, and of the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal and neurologic systems. At other visits, a limited, symptom-directed physical examination should be performed. Any abnormality identified should be recorded either as medical history or an AE accordingly.16 To be assessed as per the instructions in the SRM and AOBP Manual.11 AOBP to be assessed before initiating the ABPM assessment. For the AOBP eligibility check; If AOBP SBP <130 mmHg or DBP <80 mmHg contact Medical Monitor prior to initiating ABPM.12 With the exception of the first assessment (ie., pre-randomization), subjects in consultation with the site staff, can decide to have the ABPM self-initiated or initiated in person at the study site. For all other visits sites are strongly encouraged to book an unscheduled visit to initiate the ABPM assessment. For subjects that have the ABPM set-up at home, subjects will be given the ABPM device at the Week 2 and Week 8 visits. The ABPM should be initiated at home up to 3 days prior to the Week 4 and Week 12 visits. For subjects who decide to have their ABPM set-up in person at the study site, the site should book an unscheduled study visit up to 3 days prior to the Week 4 and Week 12 visits to initiate the ABPM assessment. The subj ect will return the ABPM as soon as possible (i.e., same day) after completion of the ABPM assessment to upload the data. If, for any reason, an ABPM assessment is deemed a technical failure, the visit will be rescheduled to allow for a repeat of the ABPM assessment and the visit window will be extended by up to 5 days to accommodate the re-test.13 Subjects will be instructed to take two momingSMBP measurements before taking study drug and two evening blood pressure measurements each day at approximately the same time for the 7 days prior to the designated visit, according to standard, guideline -based instructions.14 SMBP to be assessed for 7 days before and 3 days after the EoT visit.15 Serum potassium values must be reviewed by the Investigator prior to initiating the standardized AHT regimen.16 Serum potassium values must be reviewed by the Investigator prior to randomization.17 First morning mid-stream sample to be collected for analysis. At Screening, a mid-stream sample is collected for analysis after signing of the ICF. In addition, subjects will be given a spot urine collection kit at the standardized AHT regimen run-in visit (Week -3), Week 8, and Week 14 to take home for use on the Randomization, Week 12, and Week 16 visit days. The first morning mid -stream urine sample will be collected prior to morning dose of study drug.18 Blood draw for cortisol assessment should occur as close to 8 am but before 10 am on the morning of die study visit.19 Subjects will be given a 24-hour urine collection kit at the AOBP Check / ABPM Set-up Visit (Day -3), Week 8 and Week 14 for use on the 24-hour period prior to the Randomization, Week 12 and Week 16 visit days, respectively. Urine will be analyzed for free cortisol, aldosterone, sodium, potassium, creatinine and albumin. Subjects with a morning serum cortisol assessment >35 pg / dL will perform an unscheduled 24 -hour urine collection for assessment of 24-hour urinary free cortisol.20 Women of childbearing potential only. A sample for serum pregnancy test will be collected at Screening. Follicle stimulating hormone must be used to confirm postmenopausal status in all postmenopausal women at Screening. Urine pregnancy tests will be done at other visits. If urine pregnancy test is positive, a serum pregnancy test will be performed to confirm results at a local lab.21 Blood draw for serum hsCRP, NTpraBNP, Type 3 procollagen, Cystatin-C, Leptin, Adiponectin and 11- DOC assessments; and a urine sample for KIM-1 assessment. An aliquot of serum will be retained for future biomarker assessments. A sample of whole blood will be collected at randomization and retained for future proteomic and genomic assessments. A mid stream urine sample will also be collected for future biomarker analyses. Blood and urine samples will be processed and stored as described in the laboratory manual.22 ACTH (Cosyntropin) stimulation testing to be performed on a minimum of 75 subjects at the run-in (Week-3) and Week 12 visits; and at unscheduled visits if clinically indicated by signs, including serum cortisol below 3 pg / dL, or below 11 jig / dL accompanied by symptoms of hypocortisolism.23 Adverse events and SAEs will be collected from signing of the ICF until just before the first assessment in the OLE study for subjects continuing into the OLE. For subjects not participating in the OLE, all AEs and SAEs will be collected from signing of the informed consent until Week 1224 To include assessment of both study drug and standardized AHT compliance.23 Subjects will have a blood sample drawn just prior to taking study drug. The time of each blood draw and the time of study drug dosing on the day of the PK blood draws will be noted on the respective eCRF page. The time of the previous dose of study drug (i.e., the day before) will also be collected on the eCRF page.

[0400] ABPM, ambulatory blood pressure monitoring; ACTH, adrenal corticotropic hormone; AE, adverse event; AHT, antihypertensive; AOBP, automated office blood pressure; BP, blood pressure; dL, deciliter; ECG, electrocardiogram; eCRF, electronic case report form; eGFR, estimated glomerular filtration rate; EoS, end of study; EoT, end of treatment; EW, early withdrawal; HbAic , glycosylated hemoglobin; hsCRP, high-sensitivity C-reactive protein; IGF, informed consent form; KIM- 1 , kidney injury molecule 1 ; L, liter; mmol, millimoles; NTproBNP, N-terminal (NT)-pro hormone BNP; OLE, open-label extension; PK, pharmacokinetic; SAE, serious adverse event; SMBP, self-measured blood pressure; SRM, Study Reference Manual; pg, microgram; Wk, week.Efficacy AssessmentsAutomated Office-Measured Blood Pressure

[0401] Measurement of AOBP will be done as per the Schedule of Assessments (Table 46). Office measured BP should be measured by an automatic BP device at the site that is identical for all participating sites and managed by qualified personnel. In addition, the same person should use the AOBP device for a given subject at each visit whenever possible, and the measurement should be performed using the same arm of the subject and the appropriate cuff size, as determined during the screening visit.

[0402] Details on AOBP procedure (measurement and transfer of data) including subject preparation (eg, arm selection, arm position, cuff size) will be provided in the SRM and the AOBP Site Manual. If an AOBP assessment is deemed a technical failure by the Investigator, it may be repeated.

[0403] Heart rate will also be recorded and collected with all AOBP measurements.Self-Measured Blood Pressure (SMBP)

[0404] Subjects will be provided with a validated, brachial home blood pressure machine. Subjects will be instructed to take two blood pressure measurements at approximately the same time each morning before taking study drug, and two BP measurements at approximately the same time each evening, for the 7 days prior to the visit outlined in the Schedule of Assessments (T able 46), according to standard, guideline-based instructions. NOTE: At the End of Treatment (EoT, Week 12) visit subjects will also be asked to take their SMBP for 3 days AFTER the visit. Heartrate will also be recorded. Further details and instructions will be provided in the SMBP SiteManual and the SRM.Ambulatory Blood Pressure Monitoring

[0405] Subjects will attend a visit 3 days prior to the Randomization Visit to check AOBP eligibility and to initiate ABPM assessment. The AOBP eligibility check must be performed prior to initiating the ABPM assessment. For the AOBP eligibility check: if AOBP SBP <130 mmHg or DBP <80 mmHg contact Medical Monitor prior to initiating ABPM.

[0406] Subjects will be given an ABPM devise at Week 2 and at Week 8. ABPM can be initiated up to 3 days prior to the associated study visit to allow for a repeat if necessary.

[0407] Sites are strongly encouraged to book an unscheduled study visit up to 3 days before Week 4 and Week 12 visits to initiate the ABPM assessment. Alternatively, the ABPM procedure may be initiated at home by phone visit up to 3 days before the Week 4 and Week 12 visits as indicated in the Schedule of Assessments (Table 46). The subject will return the ABPM as soon as possible (i.e., same day) after completion of the ABPM assessment to upload the data. If, for any reason, an ABPM assessment is deemed a failure, the visit will be rescheduled to allow for a repeat of the ABPM assessment and the visit window will be extended by up to 5 days to accommodate the re-test. Training for the ABPM procedure will be done during an office visit or via phone.

[0408] Blood pressure will be measured automatically; the ABPM will inflate at a pre-defined sequence across the 24-hour monitoring period and be consistent across all study sites and subjects. Each of the 24-hour ABPM sessions will be evaluated based on a pre-defined set of criteria to determine if the monitoring session was successful using an ABPM device provided to each site by the central BP laboratory or the sponsor for the duration of the study. The ABPM data will be electronically transferred to the central BP laboratory and subsequently to the Contract Research Organization. Details on ABPM procedure (installation, recording, and transfer of data), including subject preparation, will be provided in the ABPM-PWA Site Manual.Population Pharmacokinetic Assessments

[0409] During the double-blind treatment period, at the Week 2, Week 4, Week 6, Week 8 and the Week 12 visits (Table 46), subjects will have blood draws taken for population pharmacokinetics (popPK) analysis at trough (i.e., just before dosing).

[0410] For visits when pharmacokinetic (PK) samples are to be drawn, subjects should arrive at the clinic before taking that day’s dose of study drug.

[0411] The time of each blood draw and the time of study drug dosing on the day of the PK blood draws will be noted on the respective eCRF page. The time of the previous dose of study drug (i.e., the day before) will also be collected on the eCRF page.

[0412] Instructions for collection, preparation, handling, and shipping PK specimens are provided in the Laboratory Manual.Safety AssessmentsMedical History

[0413] Medical history data are to be collected at the Screening visit.Physical Examination

[0414] A thorough physical examination will be carried out by trained medical personnel at Screening and should include an evaluation of the head, eyes, and of the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems. A symptom- directed abbreviated physical examination will be performed at all other designated timepoints and as clinically indicated. Changes from baseline abnormalities should be recorded in subject notes. New or worsened clinically significant abnormalities should be recorded as aEs on the AE eCRF.Vital Signs

[0415] Body temperature, heart rate, and respiratory rate are to be assessed with the subjects in a seated position. Subj ects should be seated for at least 5 minutes before taking the measurement.

[0416] Standardized assessment of standing BP will be performed at each visit per the Schedule of Assessments (Table 46) as described in the SRM. In addition, if a subject reports symptoms of hypotension (eg, light-headedness, dizziness, presyncope, or syncope) during the study, standing BP will be assessed weekly until symptoms resolve.Electrocardiogram

[0417] Single 12-lead ECGs will be recorded as per the Schedule of Assessments (Table 46). In addition, a 12-lead ECG assessment will be performed on subjects with a re-check serum potassium >6.0 mmol / L.Clinical Safety Laboratory Tests

[0418] Clinical safety laboratory tests will be conducted by a central laboratory as per the Schedule of Assessments (Table 46). Serum sodium and potassium concentrations will be collected as per local guidelines and assessed at a local laboratory. Instructions for collection, preparation, handling, and shipping of central clinical laboratory specimens are provided in the Laboratory Manual. Analytes for clinical safety laboratory tests are listed in Table 47. Repeat laboratory samples may be taken for technical issues (eg, incorrect sample collection, hemolysis).

[0419] Refer to the Schedule of Assessments (Table 46) for collection time points.

[0420] *A serum aliquot will be retained for future biomarker analysis. A sample of whole blood will be collected at randomization and retained for future proteomic and genomic assessments. Blood and urine samples will processed and stored.

[0421] Abbreviations: 11 -DOC, 11 -deoxycorticosterone; ACTH, adrenocorticotropic hormone; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; FSH, follicle stimulating hormone; HbAlc, glycosylated hemoglobin; hsCRP, high-sensitivity C-reactive protein; KIM-1, kidney injury molecule 1; NTproBNP, N- terminal (NT)-pro hormone BNP; PRA, plasma renin activity; RBC, red blood cells; WBC, white blood cells; WOCBP, women of child bearing potential.

[0422] +Corrected Sodium (Katz, 1973) = Measured sodium + 0.016 x (Serum glucose - 100); where sodium is in mmol / L and glucose in mg / dL.(a) For example, if the lab reports a sodium value of 132 mmol / L and the subject has an elevated glucose of 325 mg / dL, the corrected sodium value would be calculated as follows:(i) Corrected Sodium = Measured sodium + 0.016 x (Serum glucose - 100)(ii) Corrected Sodium = 132 + 0.016 x (325 - 100)(iii) Corrected Sodium = 135.6 mmol / L

[0423] Subjects will be given a spot urine collection kit to take home for collection of urine as outlined in the Schedule of Assessments (Table 46). A mid-stream sample of the first morning urine will be collected on the day of the designated study visit, prior to the dose of study drug, for determination of aldosterone, creatinine, sodium, potassium, and albumin levels.

[0424] Subjects will be given a 24-hour urine collection kit to take home for collection of urine as outlined in the Schedule of Assessments (Table 46). Urine will be analyzed for free cortisol, and aldosterone, sodium, potassium and creatinine levels. Subjects with a morning serum cortisol assessment >35 gg / dL will perform an unscheduled 24-hour urine collection for assessment of 24- hour urinary free cortisol.Adrenocorticotropic Hormone Stimulation Test

[0425] A minimum of 75 subjects will undergo an ACTH (cosyntropin) stimulation test at the standardized AHT regimen run-in (Week-3) and at the Week 12 study visits.

[0426] An unscheduled ACTH -stimulation test is to be performed if morning serum cortisol is below 3 / ig / dL, or if morning serum cortisol is below 10 |ig / dL AND accompanied by symptoms of hypocortisolism such as weakness, loss of appetite, unintentional weight loss, hyponatremia, hypoglycemia, PLUS clinical findings of orthostatic hypotension, pre-syncope or syncope. Instructions on implementing the test, including administration of cosyntropin and timing, processing, storage, and transport of samples for central laboratory testing are provided in the SRM and the Laboratory Manual.Pregnancy Testing

[0427] A serum pregnancy test will be performed at screening. Urine pregnancy tests will be done at other visits laboratory as per Schedule of Assessments (Table 46). If urine pregnancy test is positive, a serum pregnancy test will be collected to confirm results at a local laboratory.Pregnancy tests are required for women of childbearing potential (WOCBP) only. A high follicle stimulating hormone (FSH) level in the postmenopausal range must be used to confirm postmenopausal status in all postmenopausal women at screening. It may also be required for AEs, serious AEs (SAEs), and other safety reporting.Adverse Events, Serious Adverse Events, and Other Safety Reporting

[0428] The investigator and any qualified designees are responsible for detecting, documenting, and recording events that meet the definition of an AE or SAE, and remain responsible for following up on all AEs and SAEs.Time Period and Frequency for Collecting AE and SAE Information

[0429] For subjects rolling over into the OLE, all AEs and SAEs will be collected from signing of the study ICF until just before the first assessment in the OLE study. All AESIs will be collected from Randomization until just before the first assessment in the OLE study. For subjects not participating in the OLE, all AEs and SAEs will be collected from signing of the ICF to EoS. All AESIs will be collected from Randomization until the EOS visit. Under no circumstance should the reporting of SAEs and AESIs exceed 24 hours of becoming aware of the event. The Investigator will submit any updated SAE data to the sponsor / designee within 24 hours of it being available.

[0430] Adverse events that begin before the start of study drug (lorundrostat or placebo) at Randomization, but after obtaining informed consent will not be considered treatment-emergent AEs (TEAEs). Adverse events collected during the standardized AHT regimen run-in period are not considered treatment-emergent events.

[0431] Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of the study participation. However, if the investigator learns of any SAE, including a death, at any time after a subject has been discharged from the study, and he / she considers the event to be reasonably related to the study drug or study participation, the investigator must promptly notify the sponsor.

[0432] In the event that study drug is interrupted, AEs and SAEs will be collected throughout the interruption. If study drug is permanently discontinued for any reason, the reason will be recorded, and the subject should be encouraged to remain in the study so that important safetyinformation can be obtained. All Aes and SAEs leading to discontinuation of study drug or discontinuation of study will be collected. Once a subject withdraws consent to participate in the study, no further information can be collected from the subject.Method of Detecting AEs and SAEs

[0433] Care will be taken not to introduce bias when detecting AEs and / or SAEs. Open-ended and non-leading verbal questioning of the subject is the preferred method to inquire about AE occurrences. Additionally, AEs may be identified from laboratory reports, imaging or ECG reports, and other records.

[0434] Investigators will seek information on AEs at each subject contact. All AEs, whether reported by the subject or noted by study personnel, will be recorded in the subject’s medical record and on the AE eCRF.

[0435] A consistent, nondirective questioning methodology should be adopted for eliciting AE information at all subject evaluation time points. Examples of nondirective questions include the following:(a) “How have you felt since your last study visit?”(b) “Have you had any new or changed health problems since you were last here?”Follow-up of AEs and SAEs

[0436] After the initial AE / SAE report, the investigator is required to proactively follow each subject at subsequent visits / contacts. All SAEs and AESIs will be followed until resolution, stabilization, the event is otherwise explained, or the subject is lost to follow-up.Regulatory Reporting Requirements for SAEs

[0437] Prompt notification (within 24 hours) by the investigator to the sponsor / designee of an SAE is essential so that legal obligations and ethical responsibilities towards the safety of subject and the safety of a study intervention under clinical investigation are met.

[0438] The sponsor has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a study intervention under clinical investigation. The sponsor will comply with country-specific regulatory requirements relating to safety reporting to the regulatory authority, IRBs / IECs, and investigators.

[0439] An investigator who receives an investigator safety report describing an SAE or other specific safety information (eg, summary or listing of SAEs) from the sponsor will review and then file it along with the Investigator Brochure and will notify the IRB / IEC, if appropriate according to local requirements.

[0440] Investigator safety reports must be prepared for suspected unexpected serious adverse reactions according to local regulatory requirements and sponsor policy and forwarded to investigators as necessary.

[0441] Any life-threatening (ie, imminent risk of death) or fatal AE that occurs while on study drug should be submitted to the Medical Monitor / designee with written case details on a safety event report form within 24 hours.Pregnancy

[0442] Details of all pregnancies in female subjects and female partners of male subjects will be collected from the start of the standardized AHT regimen run-in until 28 days after the subject’s last visit related to this study.

[0443] If a pregnancy is reported, the investigator will record pregnancy information on the appropriate form and submit it to the sponsor within 24 hours of learning of the female subject or female partner of male subject (after obtaining the necessary signed informed consent from the female partner) pregnancy.

[0444] While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or elective termination of a pregnancy for medical reasons will be reported as an AE or SAE.

[0445] Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies, and ectopic pregnancy) are considered SAEs and will be reported as such.

[0446] The subject / pregnant female partner will be followed to determine the outcome of the pregnancy. The investigator will collect follow-up information on the subject / pregnant female partner and the neonate and the information will be forwarded to the sponsor / designee.

[0447] Any post study pregnancy -related SAE considered reasonably related to the study drug by the investigator will be reported to the sponsor. While the investigator is not obligated toactively seek this information in former study subjecVpregnant female partner, he or she may learn of an SAE through spontaneous reporting.Death Events

[0448] Any AE resulting in death will be collected from signing of the ICE until the EoS / EW visit, whichever is later. All aEs resulting in death are considered SAEs and must be reported to the sponsor (or designee) and / or the study Medical Monitor within 24 hours of awareness of the event.

[0449] All deaths that occur during the protocol-specified AE reporting period regardless of attribution, will be recorded on an cCRF and reported in a safety event report form and expeditiously sent to the sponsor / designee. This includes death attributed to progression of disease.

[0450] When recording a death on an eCRF or safety event report form, the event or condition that caused or contributed to the fatal outcome should be recorded as the single medical concept whenever possible. When reporting SAEs, “death” should not be reported as an SAE term, but rather as the outcome of a specific SAE unless the event preceding the death in unknown. If an autopsy was performed, the autopsy report should be provided.Adverse Events of Special Interest

[0451] Treatment-emergent adverse events of special interest (AESIs) are required to be reported by the investigator to the sponsor / designee immediately (ie, no more than 24 hours after learning of the event) regardless of their causality to the study drug treatment. The most appropriate diagnosis should be recorded, or if a diagnosis cannot be established, the abnormal laboratory values should be recorded on the safety event report form and reported to the sponsor / designee immediately, either as an AESI or and / or a SAE.

[0452] The AESIs for all study drugs (lorundrostat and placebo) include the following:(a) Modification of study drug dose due to hyperkalemia (eg, dose reduction, dose hold, or permanent dose discontinuation)(b) Modification of study drug dose due to hyponatremia (eg, dose reduction, dose hold, or permanent dose discontinuation)(c) Hypotension with symptoms (eg, light-headedness, dizziness, presyncope, or syncope)(d) Severely elevated BP (AOBP SBP >180 mmHg or DBP >110 mmHg)(e) Modification of study drug dose due to hypercortisolism (morning serum cortisol >35 gg / dL, confirmed by 24-hour urinary free cortisol)(f) Discontinuation of study drug due to hypocortisolism confirmed by ACTH (Cosyntropin) stimulation test.(g) Overdose of study drug or standardized AHT regimen(h) Modification of study drug dose due to reduction in kidney function (e.g. dose reduction, dose hold, or permanent dose discontinuation)Hyperkalemia

[0453] All subjects will be regularly monitored for the occurrence of hyperkalemia. This includes baseline screening, at regular intervals (as noted in the Schedule of Assessments [Table 46]). The investigator can perform a re-test at any time if they consider it necessary to confirm the serum potassium concentration.

[0454] If hyperkalemia is felt to be spurious in the opinion of the PI (such as from hemolysis), then a repeat value should be obtained within 48 hours and contact the Medical Monitor to discuss potentially holding IMP while confirmatory results are pending.

[0455] Treatment for hyperkalemia including potassium binders is allowed. If a new treatment for hyperkalemia is initiated on study, please notify the Medical Monitor.

[0456] In any instance when an ECG is performed, if the ECG shows new signs consistent with hyperkalemia, refer the subject to an urgent care center or other appropriate care facility for further evaluation and intervention, and consult the Medical Monitor.

[0457] Any subject with serum potassium <5.5 mmol / L will remain on study drug treatment.

[0458] Any subject with a serum potassium >5.5 mmol / L but <6.0 mmol / L will continue on study drug and have a repeat test (re-check) performed within 72 hours of the initial local lab result.(a) If upon re-check serum potassium <5.5. mmol / L, continue on study drug at the same dose.(b) If upon re-check serum potassium is >5.5 mmol / L and <6.0 mmol / L, reduce study drug dose and then re-check serum potassium at the next study visit (or within 2 weeks, whichever is sooner).

[0459] Any subject with a serum potassium >6.0 mmol / L but <6.5 mmol / L will have study drug held immediately and will have a repeat serum potassium and a 12-lead ECG performed within 24 hours of the initial local lab result. Continue to hold study drug until the result of the repeat serum potassium and ECG are assessed.(a) If upon re-check serum potassium is < 5.5 mmol / L, re-start study drug at same dose and repeat serum potassium at the next scheduled study visit.(b) If upon re-check serum potassium is >5.5 mmol / L but <6.0 mmol / L and the ECG is normal, re-start study drug at a reduced dose and re-check serum potassium within 72 hours. If re-check potassium remains > 6.0 mmol / L, follow bullet below.(c) If serum potassium remains >6.0 mmol / L, permanently discontinue study drug, and repeat serum potassium and ECG within 48 hours of the most recent assessment, and continue to monitor serum potassium until value <5.1 mmol / L. Consult with Medical Monitor..

[0460] Any subject with a serum potassium >6.5 mmol / L will have study drug held immediately and should be referred to urgent care center or other appropriate care facility for further evaluation (including repeat potassium and ECG) and intervention. Continue to hold study drug until the result of the repeat serum potassium and ECG within the emergency setting are known and assessed. Consult with Medical Monitor.(a) If upon re-check scrum potassium is <5.5 mmol / L, re-start study drug at same dose and repeat serum potassium at next scheduled study visit.(b) If upon re-check serum potassium is >5.5 but <6.0 mmol / L and the ECG is normal, re-start study drug at a reduced dose and re-check serum potassium within 72 hours. If re-check potassium is >6.0 mmol / L, follow bullet below.(c) If serum potassium remains >6.0 mmol / L, permanently discontinue study drug, repeat serum potassium and ECG within 48 hours of the most recent result, and continue to monitor serum potassium until value <5.1 mmol / L. Consult with Medical Monitor.Hvvonatremia

[0461] All subjects will be regularly monitored for the occurrence of hyponatremia. This includes baseline Screening and regular intervals as noted in Table 46. The Investigator can perform a re-test at any time if they consider it necessary to confirm the serum sodium concentration.

[0462] Any subject with a serum sodium of <135 mmol / L (corrected for hyperglycemia) will be asked to return to the clinic for a repeat test (re-check) of their serum sodium at a local laboratory, as follows:(a) If a subject experiences mild hyponatremia, defined as a corrected serum sodium <135 and >130 mmol / L, and remains asymptomatic, sodium levels should be rechecked within the next 72 — 96 hours. Based on the opinion of the Investigator (in conjunction with Medical Monitor if needed) study drug may be continued or held until re-checked.(i) If upon re-check, the corrected serum sodium returns to normal (i.e., > 135 mmol / L), restart or continue study drug at the same dose prior to event onset.(ii) If upon re-check, the corrected serum sodium remains <135 and >130 mmol / L, the results should be discussed with the Medical Monitor and a decision made if study drug should be continued, held, or dose reduced.(b) If a subject experiences moderate or severe hyponatremia, defined as a corrected serum sodium <130 mmol / L, study drug should be held and sodium levels should be rechecked within the next 48 hours.(i) If upon re-check, the corrected serum sodium returns to normal (i.e., >135 mmol / L), restart study drug at a lower dose. The Investigator should consult with the Medical Monitor to discuss the underlying etiology of hyponatremia.(ii) If upon re-check, the corrected sodium level remains <135 mmol / L, continue to hold study drug and retest serum sodium levels at least weekly until values return to normal (i.e., >135 mmol / L).(c) If a subject experiences severe hyponatremia, defined as a corrected serum sodium level <125 mmol / L, in associations with signs and symptoms (e.g., nausea, vomiting, confusion, headache, loss of energy and fatigue, muscle weakness), the subject should be asked to visit the emergency room for recheck, follow-up, examination and hospitalization (if clinically warranted). The Medical Monitor should be contacted to discuss the appropriateness of ongoing study participation based on etiology, treatment in the emergency room, and repeat sodium levels. If there is no explanation for the occurrence of severe hyponatremia, study drug should be permanently discontinued. If upon recheck, corrected sodium levels return to moderate or mild hyponatremia levels, the actions outlined above should be followed.Symptomatic Hypotension

[0463] If subjects experience symptoms of hypotension (eg, light-headedness, dizziness, presyncope, or syncope) during the study, it will be medically managed by the investigator in communication with the Medical Monitor. Dose reduction of study drug and / or adjustment of the standardized AHT regimen may be considered.Severely Elevated Blood Pressure

[0464] Subjects with systolic AOBP of >180 mmHg or diastolic AOBP of >110 mmHg will have the standardized AHT regimen adjusted.

[0465] . If additional medications are needed, doxazosin 1 mg is recommended, but medication additions are performed at the Investigator’s discretion in consultation with the Medical Monitor. Subjects will be given a prescription by the investigator to obtain any additional antihypertensive medications recommended beyond the standardized AHT regimen.Hyp er co rtiso lism

[0466] All subjects will be monitored for signs and symptoms of hypercortisolism (i.e., new onset or unexplained worsening of: hyperglycemia, hypertension, weight gain, abdominal striae, round facies).

[0467] In addition to the scheduled 24-hour urinary free cortisol, any subject with serum cortisol >35 pg / dL (morning measurement) will perform an unscheduled 24-hour urine collection for assessment of 24-hour urinary free cortisol.(a) Any subject with a 24-hour urinary free cortisol level >40 pg.24h and <50 pg / 24h will perform a repeat test 4 weeks later.(b) Any subject with a 24-hour urinary free cortisol level >50 pg / 24h will have their study drug dose reduced by 50% and will perform a repeat test 4 weeks later.Hypocortisolism

[0468] Subjects will have their serum cortisol measured as per the Schedule of Assessments (Table 46), with the blood draw performed as close to 8 am as possible, but before 10 am.

[0469] Any subject with a morning serum cortisol <3 pg / dL will undergo an ACTH stimulation test within 1 week of the result being known.

[0470] Any subject with morning serum cortisol <10 pg / dL accompanied by >2 signs and symptoms of adrenal insufficiency (ie, weakness, loss of appetite, unintentional weight loss, hyponatremia, hypoglycemia) plus clinical findings of orthostatic hypotension, pre-syncope or syncope, will undergo an ACTH stimulation test within 48 hours of the result being known.

[0471] If associated with a concurrent acute illness, including COVID-19, the ACTH stimulation test timing will be at the discretion of investigator but may be delayed for no more than 5 days from the morning serum cortisol result being known.

[0472] Any subject with morning serum cortisol <10 pg / dL accompanied by >2 signs and symptoms of adrenal insufficiency but no blood pressure or laboratory abnormalities will undergo an ACTH stimulation test within 1 week of the result being known.

[0473] Any subject with morning serum cortisol <10 pg / dL accompanied by asymptomatic orthostatic hypotension with hypoglycemia or hyponatremia will undergo an ACTH stimulation test within 1 week of the result being known.

[0474] Any subject with an ACTH test result diagnostic of adrenal insufficiency will immediately discontinue study drug and will be referred to specialized care (e.g.,endocrinologist / urgent care) for further management. The subject is not required to withdraw from the study in such cases.Oyerdose

[0475] For this study, any dose of study drug greater than 200 mg (eg, 5 or more 50 mg tablets) within a 24-hour time period will be considered an overdose and will be recorded in the eCRF as an AESI.

[0476] If a subject takes more than two doses of the standardized AHT regimen within an 18- hour period, this will be considered an overdose and recorded in the eCRF as an AESI.

[0477] In the event of an overdose, the principal investigator should:(a) Contact the Medical Monitor immediately(b) Evaluate the subject to determine, in consultation with the Medical Monitor, whether study drug should be interrupted or whether the subsequent study dose should be reduced(c) Closely monitor the subject for any AE / SAE and laboratory abnormalitiesRenal Function

[0478] Renal function (including eGFR, calculated using the CKD-EPI formula) will be regularly monitored throughout the study as per the Schedule of Assessments (Table 1.1)(a) The Medical Monitor should be consulted if a subject's eGFR decreases by >40% fiom Screening value, or >25% from Randomization value(b) Study drug should be held and the Medical Monitor consulted if a subject’s eGFR is <30 mL / min / 1.73m2Safety Monitorins Considerations

[0479] A DMC will meet periodically to monitor the study. The primary function of this committee is safety monitoring, and the committee will not discontinue the study for a finding of positive efficacy for any of the doses being considered. As part of these reviews, the DMC will receive summaries of study conduct measures as well as unblinded safety and efficacy data. The DMC may recommend discontinuing enrollment for a dose for safety or lack of efficacy. The remaining sample for a discontinued dose may be shifted to 1 or more of the remaining armssubject to DMC recommendation. The DMC may recommend termination of the washout phase based on their assessment of these data.

[0480] The full scope and responsibilities of the DMC will be described in the DMC Charter per the Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees.Statistical ConsiderationsGeneral Considerations

[0481] Any change to the data analysis methods described in the protocol will require an amendment only if it changes a principal aspect of the protocol. Any other change to the data analysis methods described in the protocol, along with the justification for the change, will be described in the Statistical Analysis Plan (SAP) and its amendments or in the Clinical Study Report (CSR). The SAP will be prepared, finalized, and approved prior to database lock. It will include a more technical and detailed description of the statistical analyses.

[0482] Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, and confidence intervals (Cis) will be calculated at 95%, 2-sided. For subgroup analyses, all tests of interactions between treatment groups and other factors will be conducted at a 2-sided alpha level of 0.10.Analysis Sets

[0483] The Intent-to-treat (ITT) Analysis Set includes all enrolled subjects, regardless of whether treatment was received.

[0484] The Full Analysis Set (FAS) will include all randomized subjects who receive at least one dose of study drug. Subjects will be categorized according to the treatment assignment at randomization.

[0485] The Washout Analysis Set (WAS) is a subset of FAS and will include all FAS subjects who participate in the Washout portion of the trial. The WAS will be used for the primary set for analyses of washout endpoints, if not specified otherwise.

[0486] The Run-In Safety Analysis Set will include all subjects who receive at least one dose of placebo during the run-in phase.

[0487] The Safety Analysis Set (SAF) will include all subjects who receive at least one dose of study drug. Subjects will be categorized according to the treatment received rather than the treatment assigned.

[0488] The popPK analysis set will include all randomized subjects who received at least one dose of lorundrostat and had at least one evaluable popPK sample taken. Subjects in this analysis set will be categorized according to the treatment actually received.Sample Size Determination

[0489] Subjects will be randomized in a 1: 1: 1 ratio (approximately 87 subjects per arm). For analysis of the primary endpoint at Week 4, the comparison groups will consist of N=174 subjects randomized to lorundrostat 50 mg QD (Arm 2 and Arm 3) and 87 subjects randomized to placebo (Arm 1). This sample size will provide 90% power to detect a difference in 24-hour average ABPM SBP between placebo and lorundrostat arms (placebo-adjusted treatment effect) of at least 6.0 mmHg, assuming 14 mmHg as a common standard deviation of change, and 1 -sided alpha of 0.025.Statistical Methods

[0490] For continuous variables, the descriptive statistics of n, mean, standard deviation, median, 25thpercentile, 75thpercentile, maximum and minimum will be summarized. The frequency and percentage of observed levels will be reported for all categorical measures.Disposition, Demographics, and Baseline Characteristics

[0491] The number and disposition of screened subjects, randomized subjects, and treated subjects will be summarized by treatment arm. Reasons for incomplete follow-up and treatment will be summarized. Demographic and baseline characteristics will be summarized for the ITT analysis set, using descriptive statistics, by treatment arm assigned at Randomization.Treatment Adherence

[0492] The proportion of subjects permanently discontinuing study drug, overall and by reasons for discontinuation, will be summarized overall and by treatment arm.

[0493] The proportion of subjects temporarily holding study drug, overall and by reasons for holding, will be summarized by treatment arm. Descriptive statistics of the duration of exposure to study drug adjusted for temporary holds will be summarized by treatment group.

[0494] Treatment adherence will be defined by the treatment adherence ratio: the number of doses taken by the subject divided by the number of doses assigned. Adherence is defined as taking between 75% and 125% of the study drug provided.Efficacy Analyses

[0495] All efficacy outcomes will be analyzed using the FAS.

[0496] The primary analysis of the primary efficacy estimand will assess the superiority of lorundrostat at the starting dose of 50 mg QD compared to placebo in change from baseline in 24- hour ABPM SBP at Week 4. The analysis will compare Arms 2 and 3 to Arm 1. An analysis of covariance (ANCOVA) model including treatment arm (pooled lorundrostat arms and placebo arm) and stratification factor (number of AHT medications in the standardized regime) as fixed effects, and baseline 24-hour average ABPM SBP as a covariate will be used in the primary analysis. An estimate of the least square means, and the associated standard errors and 95% confidence intervals (Cis) of change from baseline at Week 4 will be reported for each arm (lorundrostat and placebo). The primary analysis will be based on the evaluation of the difference in the least square mean change estimate between lorundrostat and a placebo arm (“placebo- adjusted” least square mean change estimate).

[0497] The analysis of secondary and exploratory efficacy endpoints will be described in theSAP.Multiplicity

[0498] Multiplicity approach to control for Type I error will be described in the SAP.Safety Analyses

[0499] Safety outcome analyses will be performed on the SAF.

[0500] Safety analysis will include tabulation of aEs, treatment-emergent aEs (TEAEs), SAEs, AESIs, vital signs, physical examination abnormalities, and clinical laboratory analytes.

[0501] Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and reported by system organ class and preferred term. All aEs and TEAEs will be listed by patient and visit, including the information on treatment, actual term, preferred term, severity, seriousness, and relationship to study drug. Summary statistics will be presented for TEAEs, SAEs, and study discontinuation due to aEs or death during the treatment period. Counts and proportions of patients experiencing aEs will be reported for each treatment group and for the pooled lorundrostat dosages.Phartnacokinetic / Pharmacodynamic Analyses

[0502] Population PK analysis will be performed on the popPK.

[0503] Population PK analysis will use dosing data and lorundrostat concentrations and apply common pharmacostatistical methods. Details will be specified in the separate section in the SAP or in a separate SAP for the PK analysis.Handling of Missing Data

[0504] Imputation of missing data, if needed, will be described in SAP.Planned Subgroup Analyses

[0505] Efficacy analyses of subgroups will be performed by using the same approach as for the efficacy models for the primary estimand and key secondary endpoints with an added term for the 2 -way interaction of treatment-by-subgroup and, when applicable, for a 3-way interaction of visit-by-treatment-by-subgroup and 2 -way interaction of visit-by-subgroup. The following is the list of pre-planned subgroups. The list is not necessarily all-inclusive:(a) Age(b) Sex(c) Race(d) Baseline BMI(e) Baseline 24-hour average ABPM SBP(f) Baseline AOBP SBP(g) Number of AHT medications in the standardized AHT regimen at baseline (2 and 3)Interim Analysis

[0506] The Sponsor may perform an interim analysis of Week 4 endpoints when the last subject randomized completes the Week 4 visit.Results

[0507] The study outlined above shows that administering an amount of olmesartan once per day, an amount of indapamide once per day, and an amount of lorundrostat monohydrobromide once per day, to a hypertensive subject is effective to treat hypertension in the hypertensive subject. The study outlined above shows that this method is effective to treat hypertension in hypertensive subjects who have previously been taking two anti -hypertensive medications.

[0508] The study outlined above shows that administering an amount of olmesartan once per day, an amount of hydrochlorothiazide once per day, and an amount of lorundrostat monohydrobromide once per day, to a hypertensive subject is effective to treat hypertension in the hypertensive subject. The study outlined above shows that this method is effective to treat hypertension in hypertensive subjects who have previously been taking two anti-hypertensive medications.

[0509] The study outlined above shows that the amounts of the olmesartan, indapamide or hydrochlorothiazide, and lorundrostat monohydrobromide when taken together are effective to achieve an additive therapeutic result in treating the subject.

[0510] The study outlined above shows that the amounts of the olmesartan, indapamide or hydrochlorothiazide, and lorundrostat monohydrobromide when taken together are effective to achieve a greater than additive therapeutic result in treating the subject.

[0511] The study outlined above shows that the amount of the olmesartan, when administered in combination with indapamide or hydrochlorothiazide, and lorundrostat monohydrobromide, is lower than the amount of the olmesartan that is effective to achieve the same level of treatment of hypertension when administered alone.

[0512] The study outlined above shows that the amount of the indapamide or hydrochlorothiazide, when administered in combination with olmesartan and lorundrostat monohydrobromide, is lower than the amount of indapamide or hydrochlorothiazide that is effective to achieve the same level of treatment of hypertension when administered alone.

[0513] The study outlined above shows that the amount of lorundrostat monohydrobromide, when administered in combination with olmesartan and indapamide or hydrochlorothiazide, is lower than the amount of lorundrostat monohydrobromide that is effective to achieve the same level of treatment of hypertension when administered alone.

[0514] The study outlined above shows that the amount of the olmesartan, when administered in combination with indapamide or hydrochlorothiazide, and lorundrostat monohydrobromide, is lower than the amount of the olmesartan that is effective to achieve the same level of treatment of hypertension when administered in the absence of administration of lorundrostat monohydrobromide.

[0515] The study outlined above shows that the amount of the indapamide or hydrochlorothiazide, when administered in combination with olmesartan and lorundrostat monohydrobromide, is lower than the amount of the indapamide or hydrochlorothiazide that is effective to achieve the same level of treatment of hypertension when administered in the absence of administration of lorundrostat monohydrobromide.

[0516] The study outlined above shows that the amounts of the olmesartan and the indapamide or hydrochlorothiazide that are effective to treat hypertension when administered together in the absence of administration of lorundrostat monohydrobromide cause one or more adverse effects in the subject, wherein the one or more adverse effects are reduced when the amounts of the olmesartan, and indapamide or hydrochlorothiazide are administered together with lorundrostat monohydrobromide.

[0517] The study outlined above shows that the amount of the olmesartan, the amount of the indapamide or hydrochlorothiazide, and the amount of lorundrostat monohydrobromide when administered together are more effective to treat the subject than when each agent at the same amount is administered alone.

[0518] The study outlined above shows that 25-75 mg per day of lorundrostat monohydrobromide, 10-50 mg per day of olmesartan, and 1-5 mg per day of indapamide, are effective in combination to treat hypertension in the hypertensive subject who was previously taking two anti-hypertensive medications.

[0519] The study outlined above shows that 25-75 mg per day of lorundrostat monohydrobromide, 10-50 mg per day of olmesartan, and 12.5-100 or 12-50 mg per day of hydrochlorothiazide, are effective in combination to treat hypertension in the hypertensive subject who was previously taking two anti-hypertensive medications.

[0520] The study outlined above shows that 50 mg per day of lorundrostat monohydrobromide,40 mg per day of olmesartan, and 2.5 mg per day of indapamide, are effective in combination to treat hypertension in the hypertensive subject who was previously taking two anti-hypertensive medications.

[0521] The study outlined above shows that 50 mg per day of lorundrostat monohydrobromide, 40 mg per day of olmesartan, and 25 mg per day of hydrochlorothiazide, are effective in combination to treat hypertension in the hypertensive subject who was previously taking two antihypertensive medications.

[0522] The study outlined above shows that 75-125 mg per day of lorundrostat monohydrobromide, 30-50 mg per day of olmesartan, and 1-5 mg per day of indapamide, are effective in combination to treat hypertension in the hypertensive subject who was previously taking two anti-hypertensive medications.

[0523] The study outlined above shows that 75-125 mg per day of lorundrostat monohydrobromide, 30-50 mg per day of olmesartan, and 12.5-100 or 12-50mg of hydrochlorothiazide, are effective in combination to treat hypertension in the hypertensive subject who was previously taking two anti-hypertensive medications.

[0524] The study outlined above shows that 100 mg per day of lorundrostat monohydrobromide, 40 mg per day of olmesartan, and 2.5 mg per day of indapamide, are effective in combination to treat hypertension in the hypertensive subject who was previously taking two anti-hypertensive medications.

[0525] The study outlined above shows that 100 mg per day of lorundrostat monohydrobromide, 40 mg per day of olmesartan, and 25 mg per day of hydrochlorothiazide, are effective in combination to treat hypertension in the hypertensive subject who was previously taking two anti-hypertensive medications.

[0526] The study outlined above shows that administering an amount of olmesartan once per day, an amount of indapamide once per day, an amount of amlodipine once per day, and an amount of lorundrostat monohydrobromide once per day, to a hypertensive subject is effective to treat hypertension in the hypertensive subject. The study outlined above shows that this method is effective to treat hypertension in hypertensive subjects who have been taking three to five antihypertensive medications.

[0527] The study outlined above shows that administering an amount of olmesartan once per day, an amount hydrochlorothiazide once per day, an amount of amlodipine once per day, and an amount of lorundrostat monohydrobromide once per day, to a hypertensive subject is effective to treat hypertension in the hypertensive subject. The study outlined above shows that this method is effective to treat hypertension in hypertensive subjects who have been taking three to five antihypertensive medications.

[0528] The study outlined above shows that the amounts of the olmesartan, indapamide or hydrochlorothiazide, amlodipine, and lorundrostat monohydrobromide, when taken together are effective to achieve an additive therapeutic result in treating the subject.

[0529] The study outlined above shows that the amounts of the olmesartan, indapamide or hydrochlorothiazide, amlodipine, and lorundrostat monohydrobromide, when taken together are effective to achieve a greater than additive therapeutic result in treating the subject.

[0530] The study outlined above shows that the amount of the olmesartan, when administered in combination with indapamide or hydrochlorothiazide, amlodipine, and lorundrostat monohydrobromide, is lower than the amount of the olmesartan that is effective to achieve the same level of treatment of hypertension when administered alone.

[0531] The study outlined above shows that the amount of the indapamide or hydrochlorothiazide, when administered in combination with olmesartan, amlodipine, and lorundrostat monohydrobromide, is lower than the aammoouunntt of the indapamide or hydrochlorothiazide that is effective to achieve the same level of treatment of hypertension when administered alone.

[0532] The study outlined above shows that the amount of the amlodipine, when administered in combination with olmesartan, indapamide or hydrochlorothiazide, and lorundrostatmonohydrobromide, is lower than the amount of the amlodipine that is effective to achieve the same level of treatment of hypertension when administered alone.

[0533] The study outlined above shows that the amount of lorundrostat monohydrobromide, when administered in combination with olmesartan, indapamide or hydrochlorothiazide, and amlodipine, is lower than the amount of the lorundrostat monohydrobromide that is effective to achieve the same level of treatment of hypertension when administered alone.

[0534] The study outlined above shows that the amount of the olmesartan, when administered in combination with indapamide or hydrochlorothiazide, amlodipine, and lorundrostat monohydrobromide, is lower than the amount of the olmesartan that is effective to achieve the same level of treatment of hypertension when the olmesartan is administered in the absence of administration of lorundrostat monohydrobromide.

[0535] The study outlined above shows that the amount of the indapamide or hydrochlorothiazide, when administered in combination with olmesartan, amlodipine, and lorundrostat monohydrobromide, is lower than the amount of the indapamide or hydrochlorothiazide that is effective to achieve the same level of treatment of hypertension when administered in the absence of administration of lorundrostat monohydrobromide.

[0536] The study outlined above shows that the amount of the amlodipine, when administered in combination with olmesartan, indapamide or hydrochlorothiazide, and lorundrostat monohydrobromide, is lower than the amount of the amlodipine that is effective to achieve the same level of treatment of hypertension when the amlodipine is administered in the absence of administration of lorundrostat monohydrobromide.

[0537] The study outlined above shows that the amounts of the olmesartan, the indapamide or hydrochlorothiazide, and the amlodipine that are effective to treat hypertension when administered together in the absence of administration of lorundrostat cause one or more adverse effects in the subject, wherein the one or more adverse effects are reduced when the amounts of olmesartan, indapamide or hydrochlorothiazide, and amlodipine, are administered together with lorundrostat monohydrobromide.

[0538] The study outlined above shows that the amount of the olmesartan, the amount of indapamide or hydrochlorothiazide, the amount of the amlodipine, and the amount of lorundrostatmonohydrobromide when administered together are more effective to treat the subject than when each agent at the same amount is administered alone.

[0539] The study outlined above shows that 25-75 mg per day of lorundrostat monohydrobromide, 10-50 mg per day of olmesartan, and 1-5 mg per day of indapamide, and 5- 10 mg of amlodipine, are effective in combination to treat hypertension in the hypertensive subject who was previously taking three to five anti-hypertensive medications.

[0540] The study outlined above shows that 25-75 mg per day of lorundrostat monohydrobromide, 10-50 mg per day of olmesartan, and 12.5-100 or 12-50 mg per day of hydrochlorothiazide, and 5-10 mg of amlodipine, are effective in combination to treat hypertension in the hypertensive subject who was previously taking three to five anti-hypertensive medications.

[0541] The study outlined above shows that 25 mg per day of lorundrostat monohydrobromide,40 mg per day of olmesartan, 2.5 mg per day of indapamide, and 10 mg per day of amlodipine, are effective in combination to treat hypertension in the hypertensive subject who was previously taking three to five anti-hypertensive medications.

[0542] The study outlined above shows that 25 mg per day of lorundrostat monohydrobromide,40 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 10 mg per day of amlodipine, are effective in combination to treat hypertension in the hypertensive subject who was previously taking three to five anti-hypertensive medications.

[0543] The study outlined above shows that 50 mg per day of lorundrostat monohydrobromide, 40 mg per day of olmesartan, 2.5 mg per day of indapamide, and 10 mg per day of amlodipine, are effective in combination to treat hypertension in the hypertensive subject who was previously taking three to five anti-hypertensive medications.

[0544] The study outlined above shows that 50 mg per day of lorundrostat monohydrobromide,40 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 10 mg per day of amlodipine, are effective in combination to treat hypertension in the hypertensive subject who was previously taking three to five anti-hypertensive medications.

[0545] The study outlined above shows that 25 mg per day of lorundrostat monohydrobromide, 40 mg per day of olmesartan, 2.5 mg per day of indapamide, and 5 mg per day of amlodipine, areeffective in combination to treat hypertension in the hypertensive subject who was previously taking three to five anti-hypertensive medications.

[0546] The study outlined above shows that 25 mg per day of lorundrostat monohydrobromide, 40 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 5 mg per day of amlodipine, are effective in combination to treat hypertension in the hypertensive subject who was previously taking three to five anti-hypertensive medications.

[0547] The study outlined above shows that 50 mg per day of lorundrostat monohydrobromide, 40 mg per day of olmesartan, 2.5 mg per day of indapamide, and 5 mg per day of amlodipine, are effective in combination to treat hypertension in the hypertensive subject who was previously taking three to five anti-hypertensive medications.

[0548] The study outlined above shows that 50 mg per day of lorundrostat monohydrobromide,40 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 5 mg per day of amlodipine, are effective in combination to treat hypertension in the hypertensive subject who was previously taking three to five anti-hypertensive medications.

[0549] The study outlined above shows that 75-125 mg per day of lorundrostat monohydrobromide, 10-50 mg per day of olmesartan, 1-5 mg per day of indapamide, and 5-10 mg per day of amlodipine, are effective in combination to treat hypertension in the hypertensive subject who was previously taking three to five anti-hypertensive medications.

[0550] The study outlined above shows that 75-125 mg per day of lorundrostat monohydrobromide, 10-50 mg per day of olmesartan, 12.5-100 or 12-50 mg per day of hydrochlorothiazide, and 5-10 mg per day of amlodipine, are effective in combination to treat hypertension in the hypertensive subject who was previously taking three to five anti-hypertensive medications.

[0551] The study outlined above shows that 100 mg per day of lorundrostat monohydrobromide, 40 mg per day of olmesartan, 2.5 mg per day of indapamide, and 10 mg per day of amlodipine, are effective in combination to treat hypertension in the hypertensive subject who was previously taking three to five anti -hypertensive medications.

[0552] The study outlined above shows that 100 mg per day of lorundrostat monohydrobromide, 40 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 10mg per day of amlodipine, are effective in combination to treat hypertension in the hypertensive subject who was previously taking three to five anti-hypertensive medications.

[0553] The study outlined above shows that 100 mg per day of lorundrostat monohydrobromide, 40 mg per day of olmesartan, 2.5 mg per day of indapamide, and 5 mg per day of amlodipine, are effective in combination to treat hypertension in the hypertensive subject who was previously taking three to five anti-hypertensive medications.

[0554] The study outlined above shows that 100 mg per day of lorundrostat monohydrobromide, 40 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 5 mg per day of amlodipine, are effective in combination to treat hypertension in the hypertensive subject who was previously taking three to five anti-hypertensive medications.

[0555] The study outlined above shows that the methods of treating hypertension are effective to treat hypertension in hypertensive subjects having a body mass index of at least 30, or more than 30.

[0556] The study outlined above shows that the methods of treating hypertension are effective to treat hypertension in male hypertensive subjects having a waist-hip ratio above 0.90, or female hypertensive subject having a waist-hip ratio above 0.85.

[0557] The study outlined above shows that the methods of treating hypertension are effective to treat hypertension in hypertensive subjects with a plasma aldosterone concentration of greater than or equal to 6 ng / dL immunoassay.

[0558] The study outlined above shows that the methods of treating hypertension are effective to treat hypertension in hypertensive subjects with a plasma aldosterone concentration of greater than or equal to 1 ng / dL by LC-MS.

[0559] The study outlined above shows that the methods of treating hypertension are effective to treat hypertension in hypertensive subjects who have an estimated glomerular filtration rate (eGFR) >45 mL / min / 1.73 m2.

[0560] The study outlined above shows that the methods of treating hypertension are effective to treat hypertension in hypertensive subjects who have a serum potassium <4.8 mmol / L.

[0561] The study outlined above shows that the methods of treating hypertension are effective to treat hypertension in hypertensive subjects who have a serum sodium >135 mmol / L.

[0562] The study outlined above shows that the methods of treating hypertension are effective to treat hypertension in hypertensive subjects who do not have a history of clinically significant hyponatremia.

[0563] The study outlined above shows that the methods of treating hypertension are effective to treat hypertension in hypertensive subjects who do not have a history of adrenal insufficiency.

[0564] The study outlined above shows that the methods of treating hypertension are effective to treat hypertension in hypertensive subjects who do not have heart failure, myocardial infarction, stroke, or transient ischemic attack within 6 months prior to the administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and calcium channel blocker, if administered.

[0565] The study outlined above shows that the methods of treating hypertension are effective to treat hypertension in hypertensive subjects who do not have diabetes mellitus with a glycosylated hemoglobin (HbAlc) >10% (>86 mmol / mol).

[0566] The study outlined above shows that the methods of treating hypertension are effective to reduce the hypertensive subject’s systolic blood pressure by at least 5 mmHg, by 5-10 mmHg, by 5-15 mmHg, by 5-20 mmHg, by 5-25 mmHg, by 5-30 mmHg, 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 hypertensive subject’s systolic blood pressure prior to administration of the olmesartan, the indapamide, lorundrostat monohydromide, and amlodipine, if administered, for a period of at least four, eight or twelve weeks.

[0567] The study outlined above shows that the methods of treating hypertension are effective to reduce the hypertensive subject’s diastolic blood pressure by at least 5 mmHg, by 5-25 mmHg, by 5-20 mmHg, or by 5-15 mmHg relative to the hypertensive subject’s diastolic blood pressure prior to administration of the olmesartan, the indapamide, lorundrostat monohydromide, and amlodipine, if administered, for a period of at least four, eight or twelve weeks.

[0568] The study outlined above shows that the methods of treating hypertension are effective to reduce the hypertensive subject’s systolic blood pressure to 130mmHg or less.

[0569] The study outlined above shows that the methods of treating hypertension are effective to reduce the hypertensive subject’s diastolic blood pressure to SOmmHg or less.

[0570] The study outlined above shows that the methods of treating hypertension are effective to reduce the hypertensive subject’s 24-hour mean ambulatory systolic blood pressure by at least 5 mmHg, by 5-10 mmHg, by 5-15 mmHg, by 5-20 mmHg, by 5-25 mmHg, by 5-30 mmHg, 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 hypertensive subject’s 24-hour mean ambulatory systolic blood pressure prior to administration of the olmesartan, the indapamide, lorundrostat monohydromide, and amlodipine, if administered, for a period of at least four, eight or twelve weeks.

[0571] The study outlined above shows that the methods of treating hypertension are effective to reduce the hypertensive subject’s 24-hour mean ambulatory diastolic blood pressure by at least 5 mmHg, by 5-25 mmHg, by 5-20 mmHg, or by 5-15 mmHg relative to the hypertensive subject’s 24-hour mean ambulatory diastolic blood pressure prior to administration of the olmesartan, the indapamide, lorundrostat monohydromide, and amlodipine, if administered, for a period of at least four, eight or twelve weeks.

[0572] The study outlined above shows that the methods of treating hypertension are effective to reduce the hypertensive subject’s daytime mean ambulatory diastolic blood pressure by at least 5 mmHg, by 5-25 mmHg, by 5-20 mmHg, or by 5-15 mmHg relative to the hypertensive subject’s daytime mean ambulatory diastolic blood pressure prior to administration of the ohnesartan, the indapamide, lorundrostat monohydromide, and amlodipine, if administered, for a period of at least four, eight or twelve weeks.

[0573] The study outlined above shows that the methods of treating hypertension are effective to reduce the hypertensive subject’s daytime mean ambulatory diastolic blood pressure by at least 5 mmHg, by 5-25 mmHg, by 5-20 mmHg, or by 5-15 mmHg relative to the hypertensive subject’s daytime mean ambulatory diastolic blood pressure prior to administration of the olmesartan, the indapamide, lorundrostat monohydromide, and amlodipine, if administered, for a period of at least four, eight or twelve weeks.

[0574] The study outlined above shows that the methods of treating hypertension are effective to reduce the hypertensive subject’s 24-hour mean central systolic blood pressure by at least 5 mmHg, by 5-10 mmHg, by 5-15 mmHg, by 5-20 mmHg, by 5-25 mmHg, by 5-30 mmHg, by at least 10 mmHg, by 10-55 mmHg, by 10-50 mmHg, by 10-45 mmHg, by 10-40 mmHg, by 10-35mmHg, by 10-30 mmHg, by 10-25 mmHg, by 10-20 mmHg, or by 10-15 mmHg, relative to the hypertensive subject’s 24-hour mean central systolic blood pressure prior to administration of the olmesartan, the indapamide, lorundrostat monohydromide, and amlodipine, if administered, for a period of at least four, eight or twelve weeks.

[0575] The study outlined above shows that the methods of treating hypertension are effective to reduce the hypertensive subject’s 24-hour mean central diastolic blood pressure by at least 5 mmHg, by 5-25 mmHg, by 5-20 mmHg, or by 5-15 mmHg relative to the hypertensive subject’s 24-hour mean central diastolic blood pressure prior to administration of the olmesartan, the indapamide, lorundrostat monohydromide, and amlodipine, if administered, for a period of at least four, eight or twelve weeks.

[0576] The study outlined above shows that the methods The study outlined above shows that are effective to reduce the hypertensive subject’s 24-hour mean ambulatory systolic blood pressure to 130mmHg or less.

[0577] The study outlined above shows that the methods of treating hypertension are effective to reduce the hypertensive subject’s 24-hour mean ambulatory diastolic blood pressure to 80mmHg or less.

[0578] The study outlined above shows that the hypertensive subject’s aldosterone level follows a substantially normal circadian rhythm when treated according to the study.

[0579] The study outlined above shows that, when treated according to the study, inhibition of CYP 11 [32 beta hydroxylase activity by the lorundrostat monohydrobromide is sufficient to maintain a state of sodium and volume depletion in the hypertensive subject.

[0580] The study outlined above shows that the methods of treating hypertension according to the study do not produce a persistent state of hyperkalemia or mild non-anion gap metabolic acidosis in the hypertensive subject.

[0581] The study outlined above shows that the lorundrostat monohydrobromide salt thereof does not substantially accumulate in the hypertensive subject, preferably wherein the lack of substantial accumulation of the lorundrostat monohydrobromide in the hypertensive subject allows for the hypertensive subject’s aldosterone levels to return to pre-drug baseline within 24-48 hoursof the lonmdrostat monohydrobromide being administered, more preferably within 16-24 hours of the monohydrobromide being administered.

[0582] The study outlined above shows that, when treated according to the study, the hypertensive subject’s potassium levels are generally maintained in a clinically normal range, preferably wherein the hypertensive subject’s potassium levels are mildly elevated relative to the hypertensive subject’s potassium levels prior to administration of the olmesartan, the indapamide, lorundrostat monohydromide, and amlodipine, if administered, more preferably wherein the hypertensive subject’s potassium levels are elevated by 0.35 mmol / L or less, more preferably wherein the hypertensive subject’s potassium levels are maintained below a level of 5.5 mmol / L, more preferably wherein the hypertensive subject’s potassium levels are maintained between 3.5 mEq / 1 to 5.1 mEq / 1.

[0583] The study outlined above shows that the hypertensive subject’s sodium levels are generally maintained in a clinically normal range, preferably wherein the hypertensive subject’s sodium levels are mildly reduced relative to the hypertensive subject’s sodium levels prior to administration of the olmesartan, the indapamide or hydrochlorothiazide, lorundrostat monohydromide, and amlodipine, if administered, more preferably wherein the hypertensive subject’s sodium levels are maintained above a level of 135 mmol / L.

[0584] The study outlined above shows that administration of the ARB, thiazide or thiazide- like diuretic, lonmdrostat, and calcium channel blocker, if administered, does not cause a reduction of more than 20% 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 administration of the ARB, thiazide or thiazide-like diuretic, lonmdrostat, and calcium channel blocker, if administered, preferably which does not cause a reduction of more than 10% in the subj ect* s serum and / or plasma cortisol levels, relative to the subject’s serum and / or plasma cortisol levels prior to administration of the administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and calcium channel blocker, if administered;

[0585] The study outlined above shows that administration of the ARB, thiazide or thiazide- like diuretic, lonmdrostat, and calcium channel blocker, if administered, does not cause an increase of more than 20% 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 administration of the ARB,thiazide or thiazide-like diuretic, lorundrostat, and calcium channel blocker, if administered, preferably which does not cause an increase of more than 10% 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 administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and calcium channel blocker, if administered; and / or

[0586] The study outlined above shows that administration of the ARB, thiazide or thiazide- like diuretic, lorundrostat, and calcium channel blocker, if administered, does not cause an increase of more than 20% 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 administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and calcium channel blocker, if administered, preferably which does not cause an increase ofmore than 10% 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 ARB, thiazide or thiazide-like diuretic, lorundrostat, and calcium channel blocker, if administered.

[0587] The study outlined above shows that hypertensive subject’s average systolic blood pressure during sleep is reduced relative to the hypertensive subject’s average systolic blood pressure during sleep prior to receiving the olmesartan, the indapamide, lorundrostat monohydromide, and amlodipine, if administered.

[0588] t he study outlined above shows that the hypertensive subject’s average systolic blood pressure during sleep is reduced relative to the hypertensive subject’s average systolic blood pressure during sleep prior to receiving the lorundrostat monohydrobromide.

[0589] The study outlined above shows that the hypertensive subject’s average systolic blood pressure during sleep is reduced relative to the hypertensive subject’s average daytime systolic blood pressure.

[0590] The study outlined above shows that the hypertensive subject’s average systolic blood pressure during sleep is reduced by at least 10%, by between 10% and 40%, by between 10% and 30%, or by between 10% and 20% relative to the hypertensive subject’s average daytime systolic blood pressure.

[0591] The study outlined above shows that the hypertensive subject’s average systolic blood pressure during sleep is reduced by at least 8 mmHg, by at least lOmmHg, by between 8 and 55 mmHg, by between 10 and 45 mmHg, or by between 10 and 25 mmHg, relative to the hypertensive subject’s average systolic blood pressure during sleep prior to receiving the olmesartan, the indapamide, lorundrostat monohydromide, and amlodipine, if administered.

[0592] The study outlined above shows that the hypertensive subject’s average systolic blood pressure during sleep is reduced by at least 8 mmHg, by at least lOmmHg, by between 8 and 55 mmHg, by between 10 and 45 mmHg, or by between 10 and 25 mmHg, relative to the hypertensive subject’s average systolic blood pressure during sleep prior to receiving lorundrostat monohydrobromide.

[0593] The study outlined above shows that the methods described herein are effective to treat hypertensive subject who do not have primary aldosteronism.

[0594] The study outlined above shows that the methods described herein are effective to treat hypertensive subject who have primary hypertension.BIBLIOGRAPHY

[0595] 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. 2021 Dec 13;14(23):2614-24.

[0596] 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.

[0597] 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.

[0598] Briet M, Schiffrin EL. Vascular actions of aldosterone. J Vase Res. 2013;50(2):89-99.

[0599] Decision Resources Group. Treatment algorithms: claims data analysis in hypertension. Published June 2019.

[0600] De Sousa K, Boulkroun S, Baron S, et al. G...

Claims

CLAIMSWhat is claimed is:

1. A method of treating hypertension in a hypertensive subject, the method comprising administering to the subject an amount of an angiotensin II receptor blocker (ARB) once per day, an amount of a thiazide or thiazide-like diuretic once per day, and an amount of lorundrostat or a pharmaceutically acceptable salt thereof once per day, wherein the amounts taken together are sufficient to treat hypertension in the hypertensive subject.

2. The method of claim 1, wherein: a) the ARB, the thiazide or thiazide-like diuretic, and lorundrostat or pharmaceutically acceptable salt thereof are administered in a combined pharmaceutical composition; b) the ARB and the thiazide or thiazide-like diuretic are administered in a combined pharmaceutical composition; c) the ARB and lorundrostat or pharmaceutically acceptable salt thereof are administered in a combined pharmaceutical composition; or d) the thiazide or thiazide-like diuretic and lorundrostat or pharmaceutically acceptable salt thereof are administered in a combined pharmaceutical composition.

3. The method of claim 1, wherein the ARB, the thiazide or thiazide-like diuretic, and lorundrostat or pharmaceutically acceptable salt thereof are administered simultaneously, contemporaneously or concomitantly.

4. The method of any one of claims 1 to 3, wherein: a) the amounts when taken together are effective to achieve an additive or a greater than additive therapeutic result in treating the subject; b) the amount of the ARB is lower than the amount of the ARB that is effective to achieve the same level of treatment of hypertension when administered alone; c) the amount of the thiazide or thiazide-like diuretic is lower than the amount of the thiazide or thiazide-like diuretic that is effective to achieve the same level of treatment of hypertension when administered alone;d) the amount of lorundrostat or pharmaceutically acceptable salt thereof is lower than the amount of the lorundrostat or pharmaceutically acceptable salt thereof that is effective to achieve the same level of treatment of hypertension when administered alone; e) the amount of the ARB is lower than the amount of the ARB that is effective to achieve the same level of treatment of hypertension when administered in the absence of administration of lorundrostat or pharmaceutically acceptable salt thereof; f) the amount of the thiazide or thiazide-like diuretic is lower than the amount of the thiazide or thiazide-like diuretic that is effective to achieve the same level of treatment of hypertension when administered in the absence of administration of lorundrostat or pharmaceutically acceptable salt thereof; and / or g) the amounts of the ARB and the thiazide or thiazide-like diuretic that are effective to treat hypertension when administered together in the absence of administration of lorundrostat or pharmaceutically acceptable salt thereof cause one or more adverse effects in the subject, wherein the one or more adverse effects are reduced when the amounts of the ARB, the thiazide or thiazide-like diuretic, are administered together with the lorundrostat or pharmaceutically acceptable salt thereof.

5. The method of any one of claims 1 to 4, wherein the amount of the ARB, the amount of the thiazide or thiazide-like diuretic, and the amount of lorundrostat or pharmaceutically acceptable salt thereof when administered together are more effective to treat the subject than when each agent at the same amount is administered alone.

6. A method of treating hypertension in a hypertensive subject who has been taking two antihypertensive medications, the method comprising ceasing administration of the two antihypertensive medications and instead administering to the subject an amount of an angiotensin II receptor blocker (ARB) once per day, an amount of a thiazide or thiazide- like diuretic once per day, and an amount of lorundrostat or pharmaceutically acceptable salt thereof once per day, wherein the amounts taken together are sufficient to treat hypertension in the hypertensive subject.

7. The method of any one of claims 1 to 6, wherein the ARB is olmesartan and the thiazide or thiazide-like diuretic is indapamide.

8. The method of claim 7, wherein: a) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 25-75 mg per day, the amount of olmesartan is 10-50 mg per day, and the amount of indapamide is 1-5 mg per day; or b) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 75-125 mg per day, the amount of olmesartan is 10-50 mg per day, and the amount of indapamide is 1-5 mg per day.

9. The method of claim 7, wherein: a) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 25 mg per day, the amount of olmesartan is 40 mg per day, and the amount of indapamide is 2.5 mg per day; b) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 40 mg per day, and the amount of indapamide is 2.5 mg per day; c) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 40 mg per day, and the amount of indapamide is 2.5 mg per day; d) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmestartan is 20 mg per day, and the amount of indapamide is 2.5 mg per day; or e) amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 20 mg per day, and the amount of indapamide is 2.5 mg per day.

10. The method of any one of claims 1 to 6, wherein the ARB is olmesartan and the thiazide or thiazide-like diuretic is hydrochlorothiazide (HCTZ).

11. The method of claim 10, wherein:a) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 25-75 mg per day, the amount of olmesartan is 10-50 mg per day, and the amount of HCTZ is 12.5-100 or 12-50 mg per day; or b) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 75-125 mg per day, the amount of olmesartan is 10-50 mg per day, and the amount of HCTZ is 12.5-100 or 12-50 mg per day.

12. The method of claim 10, wherein: a) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 25 mg per day, the amount of olmesartan is 40 mg per day, and the amount of HCTZ is 25 mg per day; b) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 40 mg per day, and the amount of HCTZ is 25 mg per day; or c) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 40 mg per day, and the amount of HCTZ is 25 mg per day; d) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 40 mg per day, and the amount of HCTZ is 12 mg per day; e) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 20 mg per day, and the amount of HCTZ is 25 mg per day;0 the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 20 mg per day, and the amount of HCTZ is 12 mg per day; g) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 40 mg per day, and the amount of HCTZ is 12 mg per day; h) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 20 mg per day, and the amount of HCTZ is 25 mg per day; ori) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 20 mg per day, and the amount of HCTZ is 12 mg per day.

13. A method of treating hypertension in a hypertensive subject, the method comprising administering to the subject an amount of an angiotensin U receptor blocker (ARB) once per day, an amount of a thiazide or thiazide-like diuretic once per day, an amount of a calcium channel blocker (CCB) once per day, and an amount of lorundrostat or pharmaceutically acceptable salt thereof once per day, wherein the amounts taken together are sufficient to treat hypertension in the hypertensive subject.

14. The method of claim 13, wherein: a) the ARB, the thiazide or thiazide-like diuretic, the CCB, and lorundrostat or pharmaceutically acceptable salt thereof are administered in a combined pharmaceutical composition; b) the ARB, the thiazide or thiazide-like diuretic, and the CCB are administered in a combined pharmaceutical composition; c) the ARB, the thiazide or thiazide-like diuretic, and lorundrostat or pharmaceutically acceptable salt thereof are administered in a combined pharmaceutical composition; d) the ARB, the CCB, and lorundrostat or pharmaceutically acceptable salt thereof are administered in a combined pharmaceutical composition; e) the thiazide or thiazide-like diuretic, the CCB, and lorundrostat or pharmaceutically acceptable salt thereof are administered in a combined pharmaceutical composition; f) the ARB and the thiazide or thiazide-like diuretic are administered in a combined pharmaceutical composition; g) the ARB and the CCB are administered in a combined pharmaceutical composition; h) the ARB and lorundrostat or pharmaceutically acceptable salt thereof are administered in a combined pharmaceutical composition; i) the thiazide or thiazide-like diuretic and the CCB are administered in a combined pharmaceutical composition;j) the thiazide or thiazide-like diuretic and lorundrostat or pharmaceutically acceptable salt thereof are administered in a combined pharmaceutical composition; or k) the CCB and lorundrostat or pharmaceutically acceptable salt thereof are administered in a combined pharmaceutical composition.

15. The method of claim 13, wherein the ARB, the thiazide or thiazide-like diuretic, the CCB are administered concomitantly.

16. The method of any one of claims 13 to 15, wherein: a) the amounts when taken together are effective to achieve an additive or a greater than additive therapeutic result in treating the subject; b) the amount of the ARB is lower than the amount of the ARB that is effective to achieve the same level of treatment of hypertension when administered alone; c) the amount of the thiazide or thiazide-like diuretic is lower than the amount of the thiazide or thiazide-like diuretic that is effective to achieve the same level of treatment of hypertension when administered alone; d) the amount of the CCB is lower than the amount of the CCB that is effective to achieve the same level of treatment of hypertension when administered alone; e) the amount of lorundrostat or pharmaceutically acceptable salt thereof is lower than the amount of the lorundrostat or pharmaceutically acceptable salt thereof that is effective to achieve the same level of treatment of hypertension when administered alone; f) the amount of the ARB is lower than the amount of the ARB that is effective to achieve the same level of treatment of hypertension when administered in the absence of administration of lorundrostat or pharmaceutically acceptable salt thereof; g) the amount of the thiazide or thiazide-like diuretic is lower than the amount of the thiazide or thiazide-like diuretic that is effective to achieve the same level of treatment of hypertension when administered in the absence of administration of lorundrostat or pharmaceutically acceptable salt thereof;h) the amount of the thiazide or thiazide-like diuretic is lower than the amount of theCCB that is effective to achieve the same level of treatment of hypertension when the CCB is administered in the absence of administration of lorundrostat or pharmaceutically acceptable salt thereof; and / or i) the amounts of the ARB, the thiazide or thiazide-like diuretic, and the CCB that are effective to treat hypertension when administered together in the absence of administration of lorundrostat or pharmaceutically acceptable salt thereof cause one or more adverse effects in the subject, wherein the one or more adverse effects are reduced when the amounts of the ARB, the thiazide or thiazide-like diuretic, theCCB, are administered together with lorundrostat monohydrobromide.

17. The method of any one of claims 13 to 16, wherein the amount of the ARB, the amount of the thiazide or thiazide-like diuretic, the amount of the CCB, and the amount of lorundrostat or pharmaceutically acceptable salt thereof when administered together are more effective to treat the subject than when each agent at the same amount is administered alone.

18. A method of treating hypertension in a hypertensive subject who has been taking three to five anti -hypertensive medications, the method comprising ceasing administration of the three to five anti-hypertensive medications and instead administering to the subject an amount of an angiotensin II receptor blocker (ARB) once per day, an amount of a thiazide or thiazide-like diuretic once per day, an amount of a CCB once per day, and an amount of lorundrostat or a pharmaceutically acceptable salt thereof once per day, wherein the amounts taken together are sufficient to treat hypertension in the hypertensive subject.

19. The method of any one of claims 13 to 18, wherein the ARB is olmesartan, the thiazide or thiazide-like diuretic is indapamide, and the CCB is amlodipine.

20. The method of claim 19, wherein: a) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 25-75 mg per day, the amount of olmesartan is 10-50 mg per day, the amount of indapamide is 1-5 mg per day, and the amount of amlodipine is 5-10 mg per day; orb) the amount of lonmdrostat or pharmaceutically acceptable salt thereof is 75-125 mg per day, the amount of olmesartan is 10-50 mg per day, the amount of indapamide is 1-5 mg per day, and the amount of amlodipine is 5-10 mg per day.

21. The method of claim 19, wherein: a) the amount of lonmdrostat or pharmaceutically acceptable salt thereof is 25 mg per day, the amount of olmesartan is 40 mg per day, the amount of indapamide is 2.5 mg per day, and the amount of amlodipine is 10 mg per day; b) the amount of lonmdrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 40 mg per day, the amount of indapamide is 2.5 mg per day, and the amount of amlodipine is 10 mg per day; c) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 40 mg per day, the amount of indapamide is 2.5 mg per day, and the amount of amlodipine is 10 mg per day; d) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 25 mg per day, the amount of olmesartan is 40 mg per day, the amount of indapamide is 2.5 mg per day, and the amount of amlodipine is 5 mg per day; e) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 40 mg per day, the amount of indapamide is 2.5 mg per day, and the amount of amlodipine is 5 mg per day; f) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 40 mg per day, the amount of indapamide is 2.5 mg per day, and the amount of amlodipine is 5 mg per day; g) the amount of lonmdrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 20 mg per day, the amount of indapamide is 2.5 mg per day, and the amount of amlodipine is 10 mg per day; h) the amount of lonmdrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 20 mg per day, the amount of indapamide is 2.5 mg per day, and the amount of amlodipine is 5 mg per day; i) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 20 mg per day, the amount of indapamide is 2.5 mg per day, and the amount of amlodipine is 10 mg per day; orj) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 20 mg per day, the amount of indapamide is 2.5 mg per day, and the amount of amlodipine is 5 mg per day.

22. The method of any one of claims 13 to 18, wherein the ARB is olmesartan, the thiazide or thiazide-like diuretic is hydrochlorothiazide (HCTZ), and the CCB is amlodipine.

23. The method of claim 22, wherein: a) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 25-75 mg per day, the amount of olmesartan is 10-50 mg per day, the amount of HCTZ is 12.5-100 or 12-50 mg per day, and the amount of amlodipine is 5-10 mg per day; or b) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 75-125 mg per day, the amount of olmesartan is 10-50 mg per day, the amount of HCTZ is 12.5-100 or 12-50 mg per day, and the amount of amlodipine is 5-10 mg per day.

24. The method of claim 22, wherein: a) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 25 mg per day, the amount of olmesartan is 40 mg per day, the amount of HCTZ is 25 mg per day, and the amount of amlodipine is 10 mg per day; b) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 40 mg per day, the amount of HCTZ is 25 mg per day, and the amount of amlodipine is 10 mg per day; c) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 40 mg per day, the amount of HCTZ is 25 mg per day, and the amount of amlodipine is 10 mg per day; d) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 25 mg per day, the amount of olmesartan is 40 mg per day, the amount of HCTZ is 25 mg per day, and the amount of amlodipine is 5 mg per day; e) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 40 mg per day the amount of HCTZ is 25 mg per day, and the amount of amlodipine is 5 mg per day;0 the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 40 mg per day, the amount of HCTZ is 25 mg per day, and the amount of amlodipine is 5 mg per day; g) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 20 mg per day, the amount of HCTZ is 25 mg per day, and the amount of amlodipine is 10 mg per day; h) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 20 mg per day, the amount of HCTZ is 25 mg per day, and the amount of amlodipine is 10 mg per day; i) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 20 mg per day the amount of HCTZ is 25 mg per day, and the amount of amlodipine is 5 mg per day; j) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 20 mg per day, the amount of HCTZ is 12 mg per day, and the amount of amlodipine is 5 mg per day; k) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 40 mg per day, the amount of HCTZ is 12 mg per day, and the amount of amlodipine is 10 mg per day;1) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 40 mg per day, the amount of HCTZ is 12 mg per day, and the amount of amlodipine is 10 mg per day; m) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 40 mg per day the amount of HCTZ is 12 mg per day, and the amount of amlodipine is 5 mg per day; n) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 40 mg per day, the amount of HCTZ is 12 mg per day, and the amount of amlodipine is 5 mg per day; o) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 20 mg per day, the amount of HCTZ is 12 mg per day, and the amount of amlodipine is 10 mg per day;P) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 20 mg per day, the amount of HCTZ is 12 mg per day, and the amount of amlodipine is 10 mg per day; q) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 50 mg per day, the amount of olmesartan is 20 mg per day the amount of HCTZ is 12 mg per day, and the amount of amlodipine is 5 mg per day; or r) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 100 mg per day, the amount of olmesartan is 20 mg per day, the amount of HCTZ is 12 mg per day, and the amount of amlodipine is 5 mg per day.

25. The method of any one of claims 1 to 24, wherein the lorundrostat or pharmaceutically acceptable salt thereof is the monohydrobromide salt of lorundrostat.

26. The method of any one of claims 1 to 25, wherein the hypertensive subject has a body mass index of at least 30, or more than 30.

27. The method of any one of claims 1 to 26, wherein the hypertensive subject is a male hypertensive subject having a waist-hip ratio above 0.90, or a female hypertensive subject having a waist-hip ratio above 0.85.

28. The method of any one of claims 1 to 27, wherein the hypertensive subject: a) has a plasma aldosterone concentration of greater than or equal to 6 ng / dL immunoassay in said subject; b) has a plasma aldosterone concentration of greater than or equal to 1 ng / dL by LC- MS in said subject; c) has an estimated glomerular filtration rate (eGFR) >45 mL / minT.73 m2, preferably wherein the eGFR of the subject is reduced by less than 25% relative to the eGFR of the subject prior to administration of lorundrostat; d) has a serum potassium <4.8 mmol / L or <5 mmol / L; e) has a serum sodium >135 mmol / L; 0 does not have a history of clinically significant hyponatremia; g) does not have a history of adrenal insufficiency; h) does not have orthostatic hypotension;i) does not have autonomic dysfunction; j) does not have an arm circumference of >55 centimeters; k) does not have heart failure, myocardial infarction, stroke, or transient ischemic attack within the previous 6 months;1) does not have diabetes mellitus with a glycosylated hemoglobin (HbAlc) >10% (>86 mmol / mol); and / or m) does not have a glycosylated hemoglobin (HbAlc) >10% (>86 mmol / mol).

29. A method of treating hypertension in a subject afflicted with hypertension who is taking two anti-hypertensive medications, the method comprising: a) receiving an identification of the subject as having: i) a systolic blood pressure of 140-180 mmHg and a diastolic BP of 65-110 mmHg; or ii) a diastolic BP of 90-110 mmHg; and b) ceasing administration of the two anti-hypertensive medications and instead administering to said subject an effective amount of olmesartan, indapamide or hydrochlorothiazide, and lorundrostat or a pharmaceutically acceptable salt thereof.

30. The method of claim 29, wherein a) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 25-75 mg per day, preferably 25 mg per day or 50 mg per day, the amount of olmesartan is 10-50 mg per day, preferably 40 mg per day, the amount of indapamide, if administered, is 1-5 mg per day, preferably 2.5 mg per day, and the amount of hydrochlorothiazide, if administered is 12.5-100 or 12-50 mg per day; or b) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 75-125 mg per day, preferably 100 mg per day, the amount of olmesartan is 10-50 mg per day, preferably 40 mg per day, the amount of indapamide, if administered, is 1-5 mg per day, preferably 2.5 mg per day, and the amount of hydrochlorothiazide, if administered is 12.5-100 or 12-50 mg per day.

31. A method of treating hypertension in a subject afflicted with hypertension who is taking three to five anti-hypertensive medications, the method comprising:a) receiving an identification of the subject as having i) a systolic blood pressure of 140-180 mmHg in said subject and a diastolic BP of 65-110 mmHg in said subject; or ii) a diastolic BP of 90-110 mmHg in said subject; and b) ceasing administration of the three to five anti-hypertensive medications and instead administering to said subject an effective amount of olmesartan, indapamide or hydrochlorothiazide, amlodipine and lorundrostat or a pharmaceutically acceptable salt thereof.

32. The method of claim 31 , wherein: a) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 25-75 mg per day, preferably 25 mg per day or 50 mg per day, the amount of olmesartan is 10-50 mg per day, preferably 40 mg per day, the amount of indapamide, if administered, is 1-5 mg per day, preferably 2.5 mg per day, the amount of hydrochlorothiazide, if administered, is 12.5-100 or 12-50 mg per day, preferably 25 mg per day, and the amount of amlodipine is 5-10 mg per day, preferably 5 mg per day or 10 mg per day; or b) the amount of lorundrostat or pharmaceutically acceptable salt thereof is 75-125 mg per day, preferably 100 mg per day, the amount of olmesartan is 10-50 mg per day, preferably 40 mg per day, the amount of indapamide, if administered, is 1-5 mg per day, preferably 2.5 mg per day, the amount of hydrochlorothiazide, if administered, is 12.5-100 or 12-50 mg per day, preferably 25 mg per day, and the amount of amlodipine is 5-10 mg per day, preferably 5 mg per day or 10 mg per day.

33. The method of any one of claims 29 to 32, wherein step a) further comprises receiving an identification of the subject as: a) having a body mass index (BMI) of at least 30 or more than 30, or a waist-hip ratio above 0.90 if the hypertensive subject is male, or a waist -hip ratio above 0.85 in said subject if the hypertensive subject is female; b) having a plasma aldosterone concentration of greater than or equal to 6 ng / dL as measured by immunoassay;c) having a plasma aldosterone concentration of greater than or equal to 1 ng / dL as measured by LC-MS; d) having an estimated glomerular filtration rate (eGFR) >45 mL / min / 1.73 m2; e) having a serum potassium <4.8 or <5 mmol / L;9 having a serum sodium >135 mmol / L; g) not having history of clinically significant hyponatremia; h) not having a history of adrenal insufficiency; i) not having orthostatic hypotension; j) not having autonomic dysfunction; k) not having an arm circumference of >55 centimeters;1) not having heart failure, myocardial infarction, stroke, or transient ischemic attack within 6 months prior to the administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and CCB, if administered; and / or m) not having diabetes mellitus with a glycosylated hemoglobin (HbAlc) >10% (>86 mmol / mol).

34. The method of any one of claims 1 to 33, wherein the ARB, thiazide or thiazide-like diuretic, lloorruunnddrroossttaatt oorr pharmaceutically acceptable salt thereof, and CCB, if administered, are administered in the morning.

35. The method of any one of claims 1 to 34, wherein the ARB, thiazide or thiazide-like diuretic, lorundrostat or pharmaceutically acceptable salt thereof, and CCB, if administered: a) are administered daily for at least one week; b) are administered daily for at least two weeks; c) are administered daily for at least four weeks; d) are administered daily for at least eight weeks; or e) are administered daily for at least twelve weeks.

36. The method of any one of claims 1 to 35, wherein the lorundrostat or pharmaceutically acceptable salt thereof is the monohydrobromide salt of lorundrostat.

37. The method of any one of claims 1 to 36, wherein:a) the hypertensive subject’s systolic blood pressure is reduced by at least 5 mmHg, by 5-10 mmHg, by 5-15 mmHg, by 5-20 mmHg, by 5-25 mmHg, by 5-30 mmHg, by at least 10 mmHg, by 10-55 mmHg, by 10-50 mmHg, by 10-45 mmHg, by 1 fl- 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 hypertensive subject’s systolic blood pressure prior to administration of the ARB, the thiazide or thiazide-like diuretic, lorundrostat or pharmaceutically acceptable salt thereof, and CCB, if administered, for a period of at least four, eight or twelve weeks; b) the hypertensive subject’s diastolic blood pressure is reduced by at least 5 mmHg, by 5-25 mmHg, by 5-20 mmHg, or by 5-15 mmHg relative to the hypertensive subject’s diastolic blood pressure prior to administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat or pharmaceutically acceptable salt thereof, and CCB, if administered, for a period of at least four, eight or twelve weeks; c) the hypertensive subject’s systolic blood pressure is reduced to 130mmHg or less; and / or d) the hypertensive subject’s diastolic blood pressure is reduced to 80mmHg or less.

38. The method of any one of claims 1 to 37, wherein: a) the hypertensive subject’s 24-hour mean ambulatory systolic blood pressure is reduced by at least 5 mmHg, by 5-10 mmHg, by 5-15 mmHg, by 5-20 mmHg, by 5-25 mmHg, by 5-30 mmHg, 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 hypertensive subject’s 24-hour mean ambulatory systolic blood pressure prior to administration of the ARB, the thiazide or thiazide-like diuretic, lorundrostat or pharmaceutically acceptable salt thereof, and CCB, if administered, for a period of at least four, eight or twelve weeks; and / or b) the hypertensive subject’s 24-hour mean ambulatory diastolic blood pressure is reduced by at least 5 mmHg, by 5-25 mmHg, by 5-20 mmHg, or by 5-15 mmHg relative to the hypertensive subject’s 24-hour mean ambulatory diastolic blood pressure prior to administration of the ARB, thiazide or thiazide-like diuretic,lorundrostat or pharmaceutically acceptable salt thereof, and CCB, if administered, for a period of at least four, eight or twelve weeks; c) the hypertensive subject’s daytime mean ambulatory systolic blood pressure is reduced by at least 5 mmHg, by 5-10 mmHg, by 5-15 mmHg, by 5-20 mmHg, by 5-25 mmHg, by 5-30 mmHg, 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 hypertensive subject’s daytime mean ambulatory systolic blood pressure prior to administration of the ARB, the thiazide or thiazide-like diuretic, lorundrostat or pharmaceutically acceptable salt thereof, and CCB, if administered, for a period of at least four, eight or twelve weeks; and / or d) the hypertensive subject’s daytime mean ambulatory diastolic blood pressure is reduced by at least 5 mmHg, by 5-25 mmHg, by 5-20 mmHg, or by 5-15 mmHg relative to the hypertensive subject’s daytime mean ambulatory diastolic blood pressure prior to administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat or pharmaceutically acceptable salt thereof, and CCB, if administered, for a period of at least four, eight or twelve weeks; e) the hypertensive subject’s 24-hour mean central systolic blood pressure is reduced by at least 5 mmHg, by 5-10 mmHg, by 5-15 mmHg, by 5-20 mmHg, by 5-25 mmHg, by 5-30 mmHg, 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 hypertensive subject’s 24-hour mean central systolic blood pressure prior to administration of the ARB, the thiazide or thiazide-like diuretic, lorundrostat or pharmaceutically acceptable salt thereof, and CCB, if administered, for a period of at least four, eight or twelve weeks; and / or f) the hypertensive subject’s 24-hour mean central diastolic blood pressure is reduced by at least 5 mmHg, by 5-25 mmHg, by 5-20 mmHg, or by 5-15 mmHg relative to the hypertensive subject’s 24-hour mean central diastolic blood pressure prior to administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat orpharmaceutically acceptable salt thereof, and CCB, if administered, for a period of at least four, eight or twelve weeks; g) the hypertensive subject’s 24-hour mean ambulatory systolic blood pressure is reduced to 130mmHg or less; and / or h) the hypertensive subject’s 24-hour mean ambulatory diastolic blood pressure is reduced to SOmmHg or less.

39. The method of any one of claims 1 to 38, wherein: a) the hypertensive subject’s aldosterone level follows a substantially normal circadian rhythm; b) inhibition of CYP l l |32 beta hydroxylase activity by the lorundrostat or pharmaceutically acceptable salt thereof is sufficient to maintain a state of sodium and volume depletion in the hypertensive subject; c) the method does not produce a persistent state of hyperkalemia or mild non-anion gap metabolic acidosis in the hypertensive subject; d) the lorundrostat or pharmaceutically acceptable salt thereof does not substantially accumulate in the hypertensive subject, preferably wherein the lack of substantial accumulation of the lorundrostat or pharmaceutically acceptable salt thereof in the hypertensive subject allows for the hypertensive subject’s aldosterone levels to return to pre-drug baseline within 24-48 hours of the lorundrostat or pharmaceutically acceptable salt thereof being administered, more preferably within 16-24 hours of the lorundrostat or pharmaceutically acceptable salt thereof being administered; e) the hypertensive subject’s potassium levels are generally maintained in a clinically normal range, preferably wherein the hypertensive subject’s potassium levels are mildly elevated relative to the hypertensive subject’s potassium levels prior to administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and CCB, if administered, more preferably wherein the hypertensive subject’s potassium levels are elevated by 0.35 mmol / L or less, more preferably wherein the hypertensive subject’s potassium levels are maintained below a level of 5.5 mmol / L, more preferably wherein the hypertensive subject’s potassium levels are maintained between 3.5 mEq / 1 to 5.1 mEq / 1; and / or0 the hypertensive subject’s sodium levels are generally maintained in a clinically normal range, preferably wherein the hypertensive subject’s sodium levels are mildly reduced relative to the hypertensive subject’s sodium levels prior to administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and CCB, if administered,, more preferably wherein the hypertensive subject’s sodium levels are maintained above a level of 135 mmol / L; g) administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and CCB, if administered, does not cause a reduction of more than 20% 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 administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and CCB, if administered, preferably which does not cause a reduction of more than 10% 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 administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and CCB, if administered; h) administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and CCB, if administered, does not cause an increase of more than 20% 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 administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and CCB, if administered, preferably which does not cause an increase of more than 10% 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 administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and CCB, if administered; and / or i) administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and CCB, if administered, does not cause an increase of more than 20% in the subject’s serum and / or plasma 11 -deoxycortisol levels relative to the subject’s serum and / or plasma 11 -deoxy cortisol levels prior to administration of the administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and CCB, if administered, preferably which does not cause an increase of more than 10% in the subject’s serum and / or plasma 11 -deoxycortisol levels relative to the subject’s serum and / orplasma 11 -deoxycortisol levels prior to administration of the ARB, thiazide or thiazide-like diuretic, lorundrostat, and CCB, if administered.

40. The method of any one of claims 1 to 39, wherein the hypertensive subject’s average systolic blood pressure during sleep is reduced: a) relative to the hypertensive subject’s average systolic blood pressure during sleep prior to receiving the ARB, thiazide or thiazide-like diuretic, lorundrostat or pharmaceutically acceptable salt thereof, and CCB, if administered; b) relative to the hypertensive subject’s average systolic blood pressure during sleep prior to receiving the lorundrostat or pharmaceutically acceptable salt thereof; and / or c) relative to the hypertensive subject’s average daytime systolic blood pressure.

41. The method of any one of claims 1 to 40, wherein the hypertensive subject’s average systolic blood pressure during sleep is reduced: a) by at least 10%, by between 10% and 40%, by between 10% and 30%, or by between 10% and 20% relative to the hypertensive subject’s average daytime systolic blood pressure; b) by at least 8 mmHg, by at least lOmmHg, by between 8 and 55 mmHg, by between 10 and 45 mmHg, or by between 10 and 25 mmHg, relative to the hypertensive subject’s average systolic blood pressure during sleep prior to receiving the ARB, thiazide or thiazide-like diuretic, lorundrostat or pharmaceutically acceptable salt thereof, and CCB, if administered; and / or c) by at least 8 mmHg, by at least lOmmHg, by between 8 and 55 mmHg, by between 10 and 45 mmHg, or by between 10 and 25 mmHg, relative to the hypertensive subject’s average systolic blood pressure during sleep prior to receiving lorundrostat or pharmaceutically acceptable salt thereof.

42. The method of any one of claims 1 to 41, wherein the hypertensive subject does not have primary aldosteronism, preferably wherein the hypertensive subject has primary hypertension.

43. A method of identifying a subject for hypertension treatment with an angiotensin II receptor blocker (ARB), a thiazide or thiazide-like diuretic, and lorundrostat or pharmaceutically acceptable salt thereof, the method comprising: a) measuring the subject’s systolic blood pressure and diastolic blood pressure; and b) selecting a subject who is taking two anti-hypertensive medications, and who has: i) a systolic blood pressure of 140 mmHg and a diastolic blood pressure of 65- 110 mmHg; or ii) a diastolic blood pressure of 90-110 mmHg; thereby identifying said subject for hypertension treatment with the angiotensin II receptor blocker (ARB), the thiazide or thiazide-like diuretic, and lorundrostat or pharmaceutically acceptable salt thereof.

44. The method of claim 43, wherein the ARB is olmesartan and the thiazide or thiazide-like diuretic is indapamide or hydrochlorothiazide.

45. The method of claim 44, wherein the subject is identified for treatment with: a) 25-75 mg per day per day of lorundrostat or pharmaceutically acceptable salt thereof, 10-50 mg per day of olmesartan, and 1-5 mg per day of indapamide; b) 25-75 mg per day per day of lorundrostat or pharmaceutically acceptable salt thereof, 10-50 mg per day of olmesartan, and 12.5-100 or 12-50 mg per day of hydrochlorothiazide; c) 75-125 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 1 fl- 50 mg per day of olmesartan, and 1-5 mg per day of indapamide; or d) 75-125 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 1 fl- 50 mg per day of olmesartan, and 12.5-100 or 12-50 mg per day of hydrochlorothiazide.

46. The method of claim 44, wherein the subject is identified for treatment with: a) 25 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, and 2.5 mg per day of indapamide; b) 25 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, and 25 mg per day of hydrochlorothiazide;c) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, and 2.5 mg per day of indapamide; d) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, and 25 mg per day of hydrochlorothiazide; e) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, and 2.5 mg per day of indapamide; f) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, and 25 mg per day of hydrochlorothiazide; g) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, and 2.5 mg per day of indapamide; h) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, and 25 mg per day of hydrochlorothiazide; i) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, and 2.5 mg per day of indapamide; j) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, and 25 mg per day of hydrochlorothiazide; k) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, and 12 mg per day of hydrochlorothiazide;1) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, and 12 mg per day of hydrochlorothiazidel; m) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, and 12 mg per day of hydrochlorothiazide; or n) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, and 12 mg per day of hydrochlorothiazide.

47. A method of identifying a subject for hypertension treatment with an angiotensin II receptor blocker (ARB), a thiazide or thiazide-like diuretic, a calcium channel blocker (CCB), and lorundrostat or a pharmaceutically acceptable salt thereof, the method comprising: a) measuring the subject’s systolic blood pressure and diastolic blood pressure; and b) selecting a subject who is taking three to five anti-hypertensive medications and who has:i) a systolic blood pressure of 140 mmHg and a diastolic blood pressure of 65- 110 mmHg; or ii) a diastolic blood pressure of 90-110 mmHg; thereby identifying said subject for hypertension treatment with the angiotensin II receptor blocker (ARB), the thiazide or thiazide-like diuretic, the CCB, and the lorundrostat or pharmaceutically acceptable salt thereof.

48. The method of claim 47, wherein the ARB is olmesartan, the thiazide or thiazide-like diuretic is indapamide or hydrochlorothiazide, and the CCB is amlodipine.

49. The method of claim 48, wherein the subject is identified for treatment with: a) 25-75 mg per day per day of lorundrostat or pharmaceutically acceptable salt thereof, 10-50 mg per day of olmesartan, 1-5 mg per day of indapamide, and 5-10 mg per day of amlodipine; b) 25-75 mg per day per day of lorundrostat or pharmaceutically acceptable salt thereof, 10-50 mg per day of olmesartan, 12.5-100 or 12-50 mg per day of hydrochlorothiazide, and 5-10 mg per day of amlodipine; c) 75-125 mg per day per day of lorundrostat or pharmaceutically acceptable salt thereof, 10-50 mg per day of olmesartan, 1-5 mg per day of indapamide, and 5-10 mg per day of amlodipine; or d) 75-125 mg per day per day of lorundrostat or pharmaceutically acceptable salt thereof, 10-50 mg per day of olmesartan, 12.5-100 or 12-50 mg per day of hydrochlorothiazide, and 5-10 mg per day of amlodipine.

50. The method of claim 48, wherein the subject is identified for treatment with: a) 25 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 2.5 mg per day of indapamide, and 10 mg per day of amlodipine; b) 25 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 10 mg per day of amlodipine;c) 25 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 2.5 mg per day of indapamide, and 5 mg per day of amlodipine; d) 25 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 5 mg per day of amlodipine; e) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 2.5 mg per day of indapamide, and 10 mg per day of amlodipine; f) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 10 mg per day of amlodipine; g) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 2.5 mg per day of indapamide, and 5 mg per day of amlodipine; h) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 5 mg per day of amlodipine; i) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 2.5 mg per day of indapamide, and 10 per day mg of amlodipine; j) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 10 mg per day of amlodipine; k) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 2.5 mg per day of indapamide, and 5 mg per day of amlodipine; or1) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 5 mg per day of amlodipine;m) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, 2.5 mg per day of indapamide, and 10 mg per day of amlodipine; n) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 10 mg per day of amlodipine; o) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, 2.5 mg per day of indapamide, and 5 mg per day of amlodipine;P) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 5 mg per day of amlodipine; q) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, 2.5 mg per day of indapamide, and 10 per day mg of amlodipine; r) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 10 mg per day of amlodipine; s) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, 2.5 mg per day of indapamide, and 5 mg per day of amlodipine; t) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, 25 mg per day of hydrochlorothiazide, and 5 mg per day of amlodipine; u) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 12 mg per day of hydrochlorothiazide, and 10 mg per day of amlodipine; v) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 12 mg per day of hydrochlorothiazide, and 5 mg per day of amlodipine;w) 100 mg per day of lonmdrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 12 mg per day of hydrochlorothiazide, and 10 mg per day of amlodipine;X) 100 mg per day of lonmdrostat or pharmaceutically acceptable salt thereof, 40 mg per day of olmesartan, 12 mg per day of hydrochlorothiazide, and 5 mg per day of amlodipine; y) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, 12 mg per day of hydrochlorothiazide, and 10 mg per day of amlodipine;2) 50 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, 12 mg per day of hydrochlorothiazide, and 5 mg per day of amlodipine; aa) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, 12 mg per day of hydrochlorothiazide, and 10 mg per day of amlodipine; or bb) 100 mg per day of lorundrostat or pharmaceutically acceptable salt thereof, 20 mg per day of olmesartan, 12 mg per day of hydrochlorothiazide, and 5 mg per day of amlodipine.

51. The method of any one of claims 43 to 50, wherein step a) further comprises determining one or more or all of the following: a) the subject’s body mass index and / or waist-hip ratio; b) the subject’s plasma aldosterone concentration, preferably by immunoassay or LC-MS; and / or c) the subject’s estimated glomerular filtration rate (eGFR); d) the subject’s serum potassium; e) the subject’s serum sodium; f) the subject’s history of clinically significant hyponatremia; g) the subject’s history of adrenal insufficiency; h) the subject’s history of orthostatic hypotension; i) the subject’s history of autonomic dysfunction; j) the subject’s arm circumference;k) the subject’s history of heart failure, myocardial infarction, stroke, or transient ischemic attack within the previous 6 months;1) the subject’s history of having diabetes mellitus with a glycosylated hemoglobin(HbAlc) >10% (>86 mmol / mol); and m) the subject’s glycosylated hemoglobin (HbAlc).

52. The method of any one of claims 43 to 51, wherein step b) further comprises selecting: a) a subject who has a body mass index (BMI) of at least 30 or more than 30, or a waist-hip ratio above 0.90 if the subject is male, or a waist-hip ratio above 0.85 if the subject is female; b) a subject who has a plasma aldosterone concentration of greater than or equal to 6 ng / dL immunoassay in said subject; c) a subject who has a plasma aldosterone concentration of greater than or equal to 1 ng / dL by LC-MS in said subject; d) a subject who has an estimated glomerular filtration rate (eGFR) >45 mL / min / 1.73 m2, preferably wherein the eGFR of the subject is reduced by less than 25% relative to the eGFR of the subject prior to an administration of lorundrostat; e) a subject who has a serum potassium <4.8 or <5 mmol / L; f) a subject who has a serum sodium >135 mmol / L; g) a subject who does not have a history of clinically significant hyponatremia; h) a subject who does not have a history of adrenal insufficiency; i) a subject who does not have orthostatic hypotension; j) a subject who does not have autonomic dysfunction; k) a subject who does not have an arm circumference of >55 centimeters;1) a subject who does not have heart failure, myocardial infarction, stroke, or transient ischemic attack within the previous 6 months; m) a subject who does not have diabetes mellitus with a glycosylated hemoglobin (HbAlc) >10% (>86 mmol / mol); n) a subject who does not have a glycosylated hemoglobin (HbAlc) >10% (>86 mmol / mol).

53. Lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, for use in treating hypertension in a subject afflicted with hypertension in combination with an angiotensin II receptor blocker (ARB), a thiazide or thiazide-like diuretic, and optionally a CCB, preferably wherein the ARB is olmesartan, the thiazide or thiazide-like diuretic is indapamide or hydrochlorothiazide, and the CCB, if present, is amlodipine.

54. Use of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, for treating hypertension in a subject afflicted with hypertension in combination with an angiotensin II receptor blocker (ARB), a thiazide or thiazide-like diuretic, and optionally a CCB, preferably wherein the ARB is olmesartan, the thiazide or thiazide-like diuretic is indapamide or hydrochlorothiazide, and the CCB, if present, is amlodipine.

55. A package comprising: a) a first pharmaceutical composition comprising an amount of lorundrostat or pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, and a pharmaceutically acceptable carrier; b) a second pharmaceutical composition comprising an amount of an angiotensin II receptor blocker (ARB) and a pharmaceutically acceptable carrier; c) a third pharmaceutical composition comprising an amount of a thiazide or thiazide- like diuretic and a pharmaceutically acceptable carrier; and d) instructions for use of the first, second, and third pharmaceutical compositions together to treat a subject afflicted with hypertension.

56. A package comprising: a) one of: i) (I) a first pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, an amount of an angiotensin II receptor blocker (ARB), and a pharmaceutically acceptable carrier; and (II) a secondpharmaceutical composition comprising an amount of a thiazide or thiazide- like diuretic and a pharmaceutically acceptable carrier; ii) (I) a first pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, an amount of a thiazide or thiazide-like diuretic, and a pharmaceutically acceptable carrier; and (IT) a second pharmaceutical composition comprising an amount of an ARB and a pharmaceutically acceptable carrier; or ill) (I) a first pharmaceutical composition comprising an amount of an ARB, an amount of a thiazide or thiazide-like diuretic, and a pharmaceutically acceptable carrier; and (II) a second pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, and a pharmaceutically acceptable carrier; and b) instructions for use of the first and second pharmaceutical compositions together to treat a subject afflicted with hypertension.

57. A package comprising: a) one of following sets of pharmaceutical compositions:(1) a first pharmaceutical composition comprising an amount of lorundrostat oorr a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, an amount of an angiotensin II receptor blocker (ARB), and a pharmaceutically acceptable carrier; and a second pharmaceutical composition comprising an amount of a thiazide or thiazide-like diuretic, an amount of a CCB, and a pharmaceutically acceptable carrier;(2) a first pharmaceutical composition comprising an amount of lorundrostat oorr a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, an amount of an ARB, and a pharmaceutically acceptable carrier; a second pharmaceutical composition comprising an amount of a thiazide or thiazide-like diuretic and a pharmaceutically acceptable carrier, and a thirdpharmaceutical composition comprising an amount of a CCB, and a pharmaceutically acceptable carrier;(3) a first pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, an amount of a thiazide or thiazide-like diuretic, and a pharmaceutically acceptable carrier; and a second pharmaceutical composition comprising an amount of an ARB, an amount of a CCB, and a pharmaceutically acceptable carrier;(4) a first pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, an amount of a thiazide or thiazide-like diuretic, and a pharmaceutically acceptable carrier; a second pharmaceutical composition comprising an amount of an ARB and a pharmaceutically acceptable carrier, and a third pharmaceutical composition comprising an amount of a CCB and a pharmaceutically acceptable carrier;(5) a first pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, an amount of a CCB, and a pharmaceutically acceptable carrier; and a second pharmaceutical composition comprising an amount of thiazide or thiazide-like diuretic, an amount of an ARB, and a pharmaceutically acceptable carrier;(6) a first pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, an amount of a CCB, and a pharmaceutically acceptable carrier; and a second pharmaceutical composition comprising an amount of thiazide or thiazide-like diuretic, and a pharmaceutically acceptable carrier, anda third pharmaceutical composition comprising an amount of an ARB and a pharmaceutically acceptable carrier;(7) a first pharmaceutical composition comprising an amount of an ARB, an amount of a CCB, and a pharmaceutically acceptable carrier; a second pharmaceutical composition comprising an amount of thiazide or thiazide-like diuretic, and a pharmaceutically acceptable carrier, and a third pharmaceutical composition comprising an amount of lorundrostat oorr aa pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, and a pharmaceutically acceptable carrier;(8) a first pharmaceutical composition comprising an amount of an thiazide or thiazide -like diuretic, an amount of a CCB, and a pharmaceutically acceptable carrier; a second pharmaceutical composition comprising an amount of an ARB and a pharmaceutically acceptable carrier, and a third pharmaceutical composition comprising aann aammoouunntt of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, and a pharmaceutically acceptable carrier;(9) a first pharmaceutical composition comprising an amount of an thiazide or thiazide-like diuretic, an amount of an ARB, and a pharmaceutically acceptable carrier; a second pharmaceutical composition comprising aann aammoouunntt of aa CCB and a pharmaceutically acceptable carrier, and a third pharmaceutical composition comprising aann amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, and a pharmaceutically acceptable carrier;(W) a first pharmaceutical composition comprising an amount of lorundrostat oorr a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, an amount of an ARB, an amount of a thiazide or thiazide-like diuretic, and a pharmaceutically acceptable carrier; and a second pharmaceuticalcomposition comprising an amount of a CCB and a pharmaceutically acceptable carrier;(11) a first pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, an amount of an ARB, an amount of a CCB, and a pharmaceutically acceptable carrier; and a second pharmaceutical composition comprising an amount of a thiazide or thiazide-like diuretic and a pharmaceutically acceptable carrier;(12) a first pharmaceutical composition comprising an amount of lorundrostat oorr a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, an amount of a thiazide or thiazide-like diuretic, aann aammoouunntt of a CCB, and a pharmaceutically acceptable carrier; and a second pharmaceutical composition comprising aann aammoouunntt of an ARB and a pharmaceutically acceptable carrier;(13) a first pharmaceutical composition comprising an amount of an ARB, an amount of a thiazide or thiazide-like diuretic, an amount of a CCB, and a pharmaceutically acceptable carrier; and a second pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, and a pharmaceutically acceptable carrier; b) instructions for use of the pharmaceutical compositions together to treat a subject afflicted with hypertension.

58. A package comprising: a) a first pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, and a pharmaceutically acceptable carrier; b) a second pharmaceutical composition comprising an amount of an angiotensin II receptor blocker (ARB) and a pharmaceutically acceptable carrier;c) a third pharmaceutical composition comprising an amount of a thiazide or thiazide- like diuretic; d) a fourth pharmaceutical composition comprising an amount of a CCB; and e) instructions for use of the first, second, third, and fourth pharmaceutical compositions together to treat a subject afflicted with hypertension.

59. A pharmaceutical composition comprising: a) an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide; b) an amount of angiotensin II receptor blocker (ARB) or a pharmaceutically acceptable salt thereof; c) an amount of thiazide or thiazide-like diuretic or a pharmaceutically acceptable salt thereof; d) optionally an amount of a calcium channel blocker (CCB) or a pharmaceutically acceptable salt thereof; wherein the lorundrostat or pharmaceutically acceptable salt thereof, ARB, thiazide or thiazide-like diuretic, and CCB, if present, aarree administered simultaneously, contemporaneously or concomitantly.

60. A pharmaceutical composition comprising: a) an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide; b) an amount of an angiotensin II receptor blocker (ARB) or a pharmaceutically acceptable salt thereof; c) an amount of a thiazide or thiazide-like diuretic or a pharmaceutically acceptable salt thereof; d) optionally an amount of a calcium channel blocker (CCB) or a pharmaceutically acceptable salt thereof; wherein the lorundrostat or a pharmaceutically acceptable salt thereof, ARB, thiazide or thiazide-like diuretic, and CCB, if present, are each present in amounts which together are effective to treat hypertension in a hypertensive subject.

61. A pharmaceutical composition comprising an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide, for use in treating hypertension in a subject afflicted with hypertension in combination with an angiotensin II receptor blocker (ARB), a thiazide or thiazide-like diuretic, and optionally a calcium channel blocker (CCB).

62. A pharmaceutical composition in unit dosage form, useful in treating a subject afflicted with hypertension, which comprises: a) an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide; b) an amount of an angiotensin II receptor blocker (ARB) or a pharmaceutically acceptable salt thereof; c) an amount of a thiazide or thiazide-like diuretic or a pharmaceutically acceptable salt thereof; and d) optionally an amount of a calcium channel blocker (CCB) or a pharmaceutically acceptable salt thereof; wherein the respective amounts of said lorundrostat a pharmaceutically acceptable salt thereof, said ARB, said thiazide or thiazide-like diuretic, and said CCB, if present, in said composition are effective, upon concomitant administration to said subject of one or more of said unit dosage forms of said composition, to treat the subject.

63. A therapeutic package for dispensing to, or for use in dispensing to, a subject afflicted with hypertension, which comprises: a) one or more unit doses, each such unit dose comprising: i) an amount of lorundrostat or a pharmaceutically acceptable salt thereof, preferably lorundrostat monohydrobromide; ii) an amount of an angiotensin II receptor blocker (ARB) or a pharmaceutically acceptable salt thereof; iii) an amount of a thiazide or thiazide-like diuretic or a pharmaceutically acceptable salt thereof; and iv) optionally an amount of a calcium channel blocker (CCB) or a pharmaceutically acceptable salt thereof;wherein the respective amounts of said lorundrostat or a pharmaceutically acceptable salt thereof, said ARB, said thiazide or thiazide-like diuretic, and said CCB, if present, in said unit doses are effective, upon concomitant administration to said subject, to treat the subject, and b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of said subject.

64. The package of any one of claims 55 to 58, the pharmaceutical composition of any one of claims 59 to 62, or the therapeutic package of claim 63, wherein the ARB is olmesartan, the thiazide or thiazide-like diuretic is indapamide or hydrochlorothiazide, and the CCB, if present, is amlodipine.

65. The package, pharmaceutical composition, or therapeutic package of claim 64, wherein the pharmaceutical composition, unit dose, or unit dosage form comprises: a) 25-75 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 10-50 mg of olmesartan, 1-5 mg of indapamide, if present, 12.5-100 or 12-50 mg of hydrochlorothiazide, if present, and, 5-10 mg of amlodipine, if present; or b) 25-75 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 10-50 mg of olmesartan, 1-5 mg of indapamide, if present, 12.5-100 or 12-50 mg of hydrochlorothiazide, if present, and, 5-10 mg of amlodipine, if present.

66. The package, pharmaceutical composition, or therapeutic package of claim 64, wherein the pharmaceutical composition, unit dose, or unit dosage form comprises: a) 25 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 40 mg of olmesartan, and 2.5 mg of indapamide; b) 25 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 40 mg of olmesartan, and 25 mg of hydrochlorothiazide; c) 25 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 40 mg of olmesartan, 2,5 mg of indapamide, and 10 mg of amlodipine; d) 25 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 40 mg of olmesartan, 25 mg of hydrochlorothiazide, and 10 mg of amlodipine;e) 25 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 40 mg of olmesartan, 2.5 mg of indapamide, and 5 mg of amlodipine; f) 25 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 40 mg of olmesartan, 25 mg of hydrochlorothiazide, and 5 mg of amlodipine; g) 50 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 40 mg of olmesartan, and 2.5 mg of indapamide; h) 50 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 40 mg of olmesartan, and 25 mg of hydrochlorothiazide; i) 50 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 40 mg of olmesartan, 2.5 mg of indapamide, and 10 mg of amlodipine; j) 50 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 40 mg of olmesartan, 25 mg of hydrochlorothiazide, and 10 mg of amlodipine; k) 50 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 40 mg of olmesartan, 2,5 mg of indapamide, and 5 mg of amlodipine;1) 50 mg of lorundrostat or a pharmaceutically acceptable salt thereof, 40 mg of olmesartan, 25 mg of hydrochlorothiazide, and 5 mg of amlodipine; m) 100 mg of lorundrostat, 40 mg of olmesartan, and 2.5 mg of indapamide; n) 100 mg of lorundrostat, 40 mg of olmesartan, and 25 mg of hydrochlorothiazide; o) 100 mg of lorundrostat, 40 mg of olmesartan, 2.5 mg of indapamide, and 10 mg of amlodipine;P) 100 mg of lorundrostat, 40 mg of olmesartan, 25 mg of hydrochlorothiazide, and 10 mg of amlodipine; q) 100 mg of lorundrostat, 40 mg of olmesartan, 2.5 mg of indapamide, and 5 mg of amlodipine; or r) 100 mg of lorundrostat, 40 mg of olmesartan, 25 mg of hydrochlorothiazide, and 5 mg of amlodipine.

67. The package, pharmaceutical composition, or therapeutic package of any one of claims 64 to 66, wherein the lorundrostat or pharmaceutically acceptable salt thereof is the monohydrobromide salt of lorundrostat.

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