Methods for treating hypertension with the aldosterone synthase inhibitor baxdrostat

Abstract

The present disclosure provides a method of treating hypertension in a subject in need thereof, comprising administering baxdrostat.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 395,680, filed August 5, 2022, U.S. Provisional Patent Application No. 63 / 374,410, filed September 2, 2022, U.S. Provisional Patent Application No. 63 / 378,120, filed October 3, 2022, U.S. Provisional Patent Application No. 63 / 384,594, filed November 21, 2022, and U.S. Provisional Patent Application No. 63 / 386,683, filed December 9, 2022, the disclosures of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION The present disclosure provides compounds and methods for treating hypertension. [Background technology]

[0003] Hypertension causes more combined years of lost life or disability than any other disease. Patients with resistant hypertension represent a particularly high-risk subgroup among hypertensive patients because their blood pressure is refractory to the effects of the most potent antihypertensive medications available, leaving the heart, brain, and kidneys exposed to the harmful effects of chronically elevated blood pressure. In a 5-year retrospective longitudinal cohort study of nearly 500,000 individuals at Kaiser Permanente (Southern California),

[0004] Patients with resistant hypertension have been shown to have a significantly increased risk of stroke and end-stage renal disease, 16% and 32%, respectively, and a higher risk of heart failure, ischemic heart disease, and death, when compared with patients with non-resistant hypertension. These conditions are not only associated with some of the most serious and consequential medical ill-health patients and their families can experience, but also account for a significant portion of hospitalizations and medical costs in the United States.

[0005] Uncontrolled hypertension is high blood pressure that is not controlled by one or more antihypertensive medications and is associated with the same adverse medical consequences, but is not established in patients whose blood pressure has proven ultimately resistant to triple or more drug therapies. Physicians and patients have many therapeutic drug classes from which to choose for the treatment of hypertension, but few agents have been proven effective in the resistant hypertension (rHTN) population.

[0006] Individuals with uHTN or rHTN are at substantially higher risk for cardiovascular and renal disease because their inability to achieve blood pressure targets leaves the heart, brain, and kidneys exposed to the harmful effects of chronically elevated blood pressure.

[0007] Current guidelines targeting lower blood pressure levels than previously, and the presence of millions of patients in the United States with rHTN and uncontrolled hypertension (uHTN), represent a significant unmet medical need for novel antihypertensive medications that can function well with existing common medications. Summary of the Invention

[0008] In certain embodiments, the present disclosure provides a method of treating hypertension in a human in need thereof, comprising administering 1 mg / day or 2 mg / day of (R)-Compound 1 to the human for a treatment period.

[0009] [ka] [Brief explanation of the drawings]

[0010] [Figure 1] The study design is shown. [Figure 2] SBP, mean change from baseline in the mITT dataset. [Figure 3A] Mean serum aldosterone is shown. [Figure 3B] Shows 24-hour urinary aldosterone. [Figure 3C] Indicates plasma renin activity. [Figure 3D] Serum total cortisol is shown. [Figure 4A] 1 shows a summary of the treatment effects of baxdrostat on aldosterone and renin by gender (serum aldosterone). [Figure 4B] 1 shows a summary of the treatment effects of baxdrostat on aldosterone and renin by gender (plasma renin activity). [Figure 5] Safety population for serum potassium concentrations is shown. Baseline is defined as the measurement at randomization (Day 1 / Visit 4). If baseline is missing, baseline is the last measurement before the first dose of double-blind study medication. The lower and upper boundaries of the box represent the first and third quartiles, the line within the box represents the median, the point within the box represents the mean, the whiskers are the minimum and maximum observed data points within the 1.5 x interquartile range, and points outside the box represent observed data points outside the 1.5 x interquartile range boundaries. [Figure 6] Safety population for serum sodium concentrations is shown. Baseline is defined as the measurement at randomization (Day 1 / Visit 4). If baseline is missing, baseline is the last measurement before the first dose of double-blind study medication. The lower and upper bounds of the box represent the 1st and 3rd quartiles, the line within the box represents the median, the point within the box represents the mean, the whiskers are the minimum and maximum observed data points within the 1.5 x interquartile range, and points outside the box represent observed data points outside the 1.5 x interquartile range boundaries. [Figure 7]Safety population of estimated glomerular filtration rate is shown. Baseline is defined as the measurement at randomization (Day 1 / Visit 4). If baseline is missing, baseline is the last measurement before the first dose of double-blind study medication. The lower and upper boundaries of the box represent the 1st and 3rd quartiles, the line within the box represents the median, the point within the box represents the mean, the whiskers are the minimum and maximum observed data points within the 1.5 x interquartile range, and points outside the box represent observed data points outside the 1.5 x interquartile range boundaries. [Figure 8] Blinded SBP in study 124 patients is shown. [Figure 9] The study 123 design is shown. [Figure 10A] 10A and 10B are bar graphs showing that baxdrostat causes dose-dependent reductions in systolic blood pressure (FIG. 10A) and diastolic blood pressure (FIG. 10B) in patients with resistant hypertension. Data are least squares (LS) mean change ± standard error (SE) and placebo-corrected change ± SE. Baseline is defined as the measurement at randomization. LS means, SEs, and p-values are from a mixed-model repeated measures model with change from baseline as the dependent variable, randomized treatment, visit, and treatment-by-visit interaction as fixed categorical effects, and baseline mean sitting systolic blood pressure and baseline glomerular filtration rate as continuous covariates. P-values for significant placebo-corrected changes are shown. [Figure 10B]10A and 10B are bar graphs showing that baxdrostat causes dose-dependent reductions in systolic blood pressure (FIG. 10A) and diastolic blood pressure (FIG. 10B) in patients with resistant hypertension. Data are least squares (LS) mean change ± standard error (SE) and placebo-corrected change ± SE. Baseline is defined as the measurement at randomization. LS means, SEs, and p-values are from a mixed-model repeated measures model with change from baseline as the dependent variable, randomized treatment, visit, and treatment-by-visit interaction as fixed categorical effects, and baseline mean sitting systolic blood pressure and baseline glomerular filtration rate as continuous covariates. P-values for significant placebo-corrected changes are shown. [Figure 11A] Figure 11B shows line graphs demonstrating that baxdrostat reduces serum aldosterone (Figure 11A) and increases plasma renin activity (Figure 11B) without reducing serum total cortisol (Figure 11C). Data are LS means ± SE compared to baseline. Baseline is defined as the measurement at randomization. LS means, SE, and p-values are from an analysis of covariance model with change from baseline as the dependent variable and baseline mean sitting SBP and baseline glomerular filtration rate as continuous covariates. Statistical significance between baxdrostat and placebo: *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001, ****p ≤ 0.0001. [Figure 11B] Figure 11B shows line graphs demonstrating that baxdrostat reduces serum aldosterone (Figure 11A) and increases plasma renin activity (Figure 11B) without reducing serum total cortisol (Figure 11C). Data are LS means ± SE compared to baseline. Baseline is defined as the measurement at randomization. LS means, SE, and p-values are from an analysis of covariance model with change from baseline as the dependent variable and baseline mean sitting SBP and baseline glomerular filtration rate as continuous covariates. Statistical significance between baxdrostat and placebo: *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001, ****p ≤ 0.0001. [Figure 11C]Figure 11B shows line graphs demonstrating that baxdrostat reduces serum aldosterone (Figure 11A) and increases plasma renin activity (Figure 11B) without reducing serum total cortisol (Figure 11C). Data are LS means ± SE compared to baseline. Baseline is defined as the measurement at randomization. LS means, SE, and p-values are from an analysis of covariance model with change from baseline as the dependent variable and baseline mean sitting SBP and baseline glomerular filtration rate as continuous covariates. Statistical significance between baxdrostat and placebo: *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001, ****p ≤ 0.0001. [Figure 12A] 1 is a line graph of plasma baxdrostat concentration versus time. Data are means ± standard deviations. [Figure 12B] 1 is a line graph of plasma baxdrostat concentration versus time. Data are means ± standard deviations. [Figure 13] 1 is a study design for preliminary results of Example 9. [Figure 14] FIG. 1 is a schematic diagram of patient treatment for Part 1 of the study of Example 9. [Figure 15A] 1 is a bar graph showing the change in systolic blood pressure (mmHg) for week 8 of part 1 of Example 9. [Figure 15B] 1 is a bar graph showing the change in systolic blood pressure (mmHg) for non-Hispanic / Latino patients at week 8 of Part 1 of Example 9. In these figures, *nominal p-value and the SBP primary endpoint is change in blood pressure relative to placebo. [Figure 16] FIG. 1 is a line graph showing the mean change in sited SBP over time for the entire Intent-To-Treat Population. [Figure 17A] 10 is a line graph showing aldosterone changes for the complete patient population of Example 9. [Figure 17B] 10 is a line graph showing aldosterone changes for the Hispanic patient population of Example 9. [Figure 17C]1 is a line graph showing aldosterone changes for the non-Hispanic patient population of Example 9. [Figure 18A] 1 is a line graph showing the change in plasma renin activity for the complete patient population of Example 9. [Figure 18B] 1 is a line graph showing the change in plasma renin activity for the Hispanic patient population of Example 9. [Figure 18C] 1 is a line graph showing the change in plasma renin activity for the non-Hispanic patient population of Example 9. [Figure 19] 1 is a line graph showing mean serum potassium levels over time. [Figure 20] 1 is a line graph showing plasma metformin concentrations versus time. In this figure, data are means±standard deviations. [Figure 21A] Figures 21A and 21B show dot plots of plasma baxdrostat PK parameters versus baseline eGFR. In these figures, plasma baxdrostat C (Figure 21A), AUC (Figure 21B), AUC (Figure 21C), and t (Figure 21D) are plotted against baseline eGFR. Baseline was defined as the last measurement before administration of baxdrostat. Baseline eGFR values are presented as continuous variables. Linear regression analysis was performed using Graphpad Prism 7.03. [Figure 21B] Figures 21A and 21B show dot plots of plasma baxdrostat PK parameters versus baseline eGFR. In these figures, plasma baxdrostat C (Figure 21A), AUC (Figure 21B), AUC (Figure 21C), and t (Figure 21D) are plotted against baseline eGFR. Baseline was defined as the last measurement before administration of baxdrostat. Baseline eGFR values are presented as continuous variables. Linear regression analysis was performed using Graphpad Prism 7.03. [Figure 21C]Figures 21A and 21B show dot plots of plasma baxdrostat PK parameters versus baseline eGFR. In these figures, plasma baxdrostat C (Figure 21A), AUC (Figure 21B), AUC (Figure 21C), and t (Figure 21D) are plotted against baseline eGFR. Baseline was defined as the last measurement before administration of baxdrostat. Baseline eGFR values are presented as continuous variables. Linear regression analysis was performed using Graphpad Prism 7.03. [Figure 21D] Figures 21A and 21B show dot plots of plasma baxdrostat PK parameters versus baseline eGFR. In these figures, plasma baxdrostat C (Figure 21A), AUC (Figure 21B), AUC (Figure 21C), and t (Figure 21D) are plotted against baseline eGFR. Baseline was defined as the last measurement before administration of baxdrostat. Baseline eGFR values are presented as continuous variables. Linear regression analysis was performed using Graphpad Prism 7.03. [Figure 22] 1 is a line graph of plasma baxdrostat M concentration versus time plasma concentration (ng / mL) by renal function group from 0 to 168 hours. In this figure, data are means ± standard deviations. [Figure 23] 1 is a line graph of the cumulative amount of baxdrostat excreted in urine. In this figure, the cumulative concentration of baxdrostat (μg) by renal function group from 0 to 168 hours. Data are means ± standard deviations. [Figure 24] Study design for Cohort 1. In this figure, n = number of participants in that category. [Figure 25] Study design for Cohort 2. In this figure, n = number of participants in that category. DETAILED DESCRIPTION OF THE INVENTION

[0011] The present disclosure may be more fully understood by reference to the following description, including the following definitions and examples. Certain features of the disclosed compositions and methods that are described herein in the context of separate aspects may also be provided in combination in a single aspect. Alternatively, various features of the disclosed compositions and methods that are described for brevity in the context of a single aspect may also be provided separately or in any subcombination. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the disclosure.

[0012] In this disclosure, the singular forms "a," "an," and "the" include plural references, and reference to a particular numerical value includes at least that particular value unless the context clearly dictates otherwise.

[0013] When a value is expressed as an approximation by using the descriptor "about," it will be understood that the particular value forms another embodiment. Generally, the use of the term "about" indicates an approximation that may vary depending on the desired properties sought to be obtained by the disclosed subject matter and should be interpreted in the specific context in which it is used based on its function. Those skilled in the art will be able to interpret this as a matter of routine. In some cases, the number of significant figures used for a particular value can be one non-limiting way of determining the extent of the word "about." In other cases, the step numbers used in a series of values can be used to determine the intended range available to the term "about" for each value. Where present, all ranges are inclusive and combinable. That is, reference to values stated in a range includes all values within that range.

[0014] When a list is presented, it is to be understood that each individual element of that list, and every combination of that list, is to be construed as a separate embodiment unless otherwise stated. For example, a list of embodiments presented as "A, B, or C" should be construed as including the embodiments "A," "B," "C," "A or B," "A or C," "B or C," or "A, B, or C."

[0015] It should be understood that certain features of the invention that are described herein in the context of separate embodiments for clarity may also be provided in combination in a single aspect. That is, unless clearly incompatible or excluded, each individual embodiment is deemed combinable with any other embodiment, and such combinations are deemed to be separate embodiments. Conversely, various features of the invention that are described for brevity in the context of a single embodiment may also be provided separately or in any subcombination. It is further noted that the claims may be drafted to exclude optional elements. Accordingly, this statement is intended to serve as a predicate for use of exclusive terminology such as "only" or a "negative" limitation in connection with the recitation of claim elements.

[0016] Administration method The present disclosure relates to a method of treating hypertension in a human in need thereof. The method comprises administering (R)-Compound 1 to the human during a treatment period. In another embodiment, the present disclosure is directed to a method of lowering blood pressure in the treatment of hypertension using baxdrostat ((+)-(R)-N-(4-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide).

[0017] [ka]

[0018] The terms "baxdrostat" and "(R)-Compound 1," as used herein, are interchangeable and refer to (R)-N-(4-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide ((R)-Compound 1), having the following structure:

[0019] [ka]

[0020] The present disclosure also contemplates salts of (R)-Compound 1, and their use in the methods described herein. In some embodiments, the salts are pharmaceutically acceptable. "Pharmaceutically acceptable" refers to properties and / or substances that are acceptable to patients / humans from a pharmacological / toxicological standpoint and acceptable to pharmaceutical chemists from a physical / chemical standpoint with respect to composition, formulation, stability, patient acceptability, and bioavailability.

[0021] Pharmaceutically acceptable salts of (R)-Compound 1 include salts with pharmaceutically acceptable acids or bases, such as inorganic acids, e.g., hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, hydroiodic acid, nitric acid, and phosphoric acid, and organic acids, e.g., adipic acid, citric acid, fumaric acid, maleic acid, malic acid, malonic acid, mandelic acid, ascorbic acid, oxalic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, cyclohexylsulfamic acid (cyclamic acid), edisylic acid, glutaric acid, or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metals, e.g., sodium or potassium, and alkaline earth metals, e.g., calcium or magnesium, hydroxides, and organic bases, e.g., alkylamines, arylalkylamines, and heterocyclic amines.

[0022] The terms "subject" and "patient" are used interchangeably and typically refer to a mammal. In some embodiments, the patient or subject is a human. In other embodiments, the patient or subject is a veterinary animal or livestock, a farm animal or pet, or an animal used to conduct clinical research. In some embodiments, the subject or patient is at least 18 years of age, i.e., an adult.

[0023] According to the present disclosure, baxdrostat, in combination with other antihypertensive agents, lowers blood pressure in the treatment of hypertension. The intended populations for baxdrostat are treatment-resistant hypertension (rHTN), defined as hypertension not successfully treated with three or more antihypertensive agents, and uncontrolled hypertension (uHTN), defined as hypertension not successfully treated with one or two antihypertensive agents.

[0024] Hypertension is defined as a systolic blood pressure (SBP) greater than 130 mmHg or a diastolic blood pressure (DBP) greater than 80 mmHg (Table 1). The goal of treatment is to achieve an SBP of less than 130 mmHg and a DBP of 80 mmHg.

[0025] [Table 1]

[0026] Hypertension includes stage 1 and stage 2 hypertension and hypertensive crisis. In some embodiments, a patient / human has stage 1 hypertension, with a systolic blood pressure of about 130 to about 139 mmHg and / or a diastolic blood pressure of about 80 to about 89 mmHg. In other embodiments, a patient / human has stage 2 hypertension, with a systolic blood pressure of about 140 mmHg or higher and / or a diastolic blood pressure of about 90 mmHg or higher. In further embodiments, a patient / human has hypertensive crisis, with a blood pressure reading above about 180 / 120 mmHg. "Hypertension" also includes resistant hypertension (rHTN) and uncontrolled hypertension (uHTN). In some embodiments, a human has rHTN. In other embodiments, a human has uHTN. In other embodiments, a subject has chronic kidney disease. In further embodiments, a subject has chronic kidney disease and rHTN. In yet other embodiments, in certain aspects, a subject has chronic kidney disease and uHTN.

[0027] Before administration of (R)-Compound 1 In certain embodiments, the human receives a 45 mL / min / 1.73 m 2 In certain embodiments, the human has an estimated glomerular filtration rate (eGFR) of at least about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, or about 95 mL / min / 1.73 m prior to administration of (R)-Compound 1. 2 In other embodiments, the human has an eGFR of about 45 to about 95, about 45 to about 90, about 45 to about 85, about 45 to about 80, about 45 to about 75, about 45 to about 70, about 45 to about 65, about 45 to about 60, about 45 to about 55, about 50 to about 90, about 50 to about 85, about 50 to about 80, about 50 to about 75, about 50 to about 70, about 50 to about 65, about 50 to about 60, about 60 to about 90, about 60 to about 85, about 60 to about 80, about 60 to about 75, about 60 to about 70, about 70 to about 90, about 70 to about 85, about 70 to about 80, about 80 to about 90, or about 85 to about 90, prior to administration of (R)-Compound 1.

[0028] In other embodiments, the human has a mean seated systolic blood pressure (siSBP) of 130 mmHg or greater prior to administration of (R)-Compound 1. In certain aspects, the human has a mean seated systolic blood pressure (siSBP) of 140 mmHg or greater prior to administration of (R)-Compound 1. In other aspects, the human has a mean seated systolic blood pressure (siSBP) of 140 mmHg or greater to less than 170 mmHg prior to administration of (R)-Compound 1. In further aspects, the human has a siSBP of about 140, about 145, about 150, about 155, about 160, or about 165 mmHg prior to administration of (R)-Compound 1. In other embodiments, the human has a siSBP of about 140 to about 165, about 140 to about 160, about 140 to about 155, about 140 to about 150, about 145 to about 165, about 145 to about 160, about 145 to about 155, about 150 to about 165, about 150 to about 160, or about 160 to about 165 mmHg prior to administration of (R)-Compound 1. In further embodiments, the human has a siSBP of less than 145 mmHg prior to administration of (R)-Compound 1. In yet other embodiments, the human has a siSBP of 145 mmHg or greater prior to administration of (R)-Compound 1.

[0029] In further embodiments, the human has a serum potassium level of greater than or equal to 3.5 mmol / L and less than 5.0 mmol / L prior to administration of (R)-Compound 1. In certain aspects, the human has a serum potassium level of about 3.5, about 3.75, about 4, about 4.25, about 4.5, about 4.75, or about 5 prior to administration of (R)-Compound 1. In other aspects, the human has a serum potassium level of about 3.5 to about 5, about 3.5 to about 3.75, about 3.5 to about 4, about 3.5 to about 3.75, about 3.75 to about 5, about 3.75 to about 4.75, about 3.75 to about 4.5, about 3.75 to about 4.25, about 3.75 to about 4, about 4 to about 5, about 4 to about 4.75, about 4 to about 4.5, about 4 to about 4.25, about 4.25 to about 5, about 4.25 to about 4.75, about 4.25 to about 4.5, about 4.5 to about 5, about 4.5 to about 4.75, or about 4.75 to about 5 prior to administration of (R)-Compound 1.

[0030] In yet other embodiments, the human has a morning cortisol level of greater than 3 μg / dL prior to administration of (R)-Compound 1. In certain aspects, the human has a morning cortisol level of greater than about 3, about 4, about 5, about 7, about 10, about 12, about 15, about 17, about 20, about 22, or about 25 μg / dL prior to administration of (R)-Compound 1. In other aspects, the human has a morning cortisol level of about 3 to about 25, about 3 to about 22, about 3 to about 20, about 3 to about 17, about 3 to about 15, about 3 to about 12, about 3 to about 10, about 3 to about 7, about 5 to about 25, about 5 to about 22, about 5 to about 20, about 5 to about 17, about 5 to about 15, about 5 to about 12, about 5 to about 10, about 10 to about 25, about 10 to about 22, about 10 to about 20, about 10 to about 17, about 10 to about 15, about 15 to about 25, about 15 to about 22, about 15 to about 20, or about 20 to about 25 μg / dL prior to administration of (R)-Compound 1.

[0031] After administration of (R)-Compound 1 The (R)-Compound 1 is administered to a human during a treatment period. The term "treatment period," as used herein, refers to the period of time it takes to administer the (R)-Compound 1 to a human.

[0032] Following treatment with (R)-Compound 1, humans' mean sitting systolic blood pressure (siSBP) is reduced relative to baseline at or after about a 12-week treatment period, compared to placebo. In some embodiments, administration results in a sitting systolic blood pressure (siSBP) of less than 130 mmHg after a 12-week treatment period. In further embodiments, administration of (R)-Compound 1 results in a reduction in siSBP from baseline of at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, or at least about 30 mmHg compared to baseline at or after about 12 weeks of treatment compared to placebo. In other embodiments, administration of (R)-Compound 1 results in a reduction from baseline in siSBP of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30 mmHg compared to baseline at or after about 12 weeks of treatment compared to placebo. In other embodiments, administration of (R)-Compound 1 results in a reduction in siSBP from baseline of about 1 to about 30, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, about 1 to about 5, about 5 to about 30, about 5 to about 25, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 30, about 10 to about 25, about 10 to about 20, about 10 to about 15, about 15 to about 30, about 15 to about 25, about 15 to about 20, about 20 to about 30, about 20 to about 25, or about 25 to about 30 mmHg compared to baseline at or after about 12 weeks of treatment compared to placebo.In a further embodiment, administration of 2 mg / day of (R)-Compound 1 results in a decrease in a human's mean sitting systolic blood pressure (siSBP) compared to baseline after 12 weeks of treatment compared to placebo. In another embodiment, administration of 1 mg / day of (R)-Compound 1 results in a decrease in a human's mean sitting systolic blood pressure (siSBP) compared to baseline after 12 weeks of treatment compared to placebo. In a further embodiment, a human is administered 1 mg / day of (R)-Compound 1, which administration results in an approximately 8 mmHg decrease in the human's mean sitting systolic blood pressure after 12 weeks of treatment compared to baseline. In yet another embodiment, a human is administered 1 mg / day of (R)-Compound 1, which administration results in a greater than 8 mmHg decrease in the human's mean sitting systolic blood pressure after 12 weeks of treatment compared to baseline. In yet a further embodiment, a human is administered 2 mg / day of (R)-Compound 1, which administration results in an approximately 11 mmHg decrease in the human's mean sitting systolic blood pressure compared to baseline at or after 12 weeks of treatment. In other embodiments, a human is administered 2 mg / day of (R)-Compound 1, which administration results in an 11 mmHg decrease in the human's mean sitting systolic blood pressure compared to baseline at or after 12 weeks of treatment.

[0033] Following treatment with (R)-Compound 1, administration results in a reduction in sitting systolic blood pressure (siSBP) compared to baseline at or after 24 weeks of treatment, compared to placebo. In some embodiments, administration of (R)-Compound 1 results in a reduction from baseline in siSBP of at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, or at least about 30 mmHg compared to baseline at or after about 24 weeks of treatment, compared to placebo. In a further embodiment, administration of (R)-Compound 1 results in a reduction from baseline in siSBP of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30 mmHg compared to baseline at or after about 24 weeks of treatment compared to placebo. In other embodiments, administration of (R)-Compound 1 results in a reduction from baseline in siSBP of about 1 to about 30, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, about 1 to about 5, about 5 to about 30, about 5 to about 25, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 30, about 10 to about 25, about 10 to about 20, about 10 to about 15, about 15 to about 30, about 15 to about 25, about 15 to about 20, about 20 to about 30, about 20 to about 25, or about 25 to about 30 mmHg compared to baseline at or after about 24 weeks of treatment, compared to placebo.

[0034] Following treatment with (R)-Compound 1, a human's seated diastolic blood pressure (siDBP) is reduced relative to baseline at or after about 12 weeks of treatment, compared to placebo. In some embodiments, administration of (R)-Compound 1 results in a reduction from baseline in siDBP of at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, or at least about 30 mmHg relative to baseline at or after about 12 weeks of treatment, compared to placebo. In other embodiments, administration of (R)-Compound 1 results in a reduction from baseline in siDBP of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30 mmHg compared to baseline at or after about 12 weeks of treatment compared to placebo. In other embodiments, administration of (R)-Compound 1 results in a reduction from baseline in siDBP of about 1 to about 30, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, about 1 to about 5, about 5 to about 30, about 5 to about 25, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 30, about 10 to about 25, about 10 to about 20, about 10 to about 15, about 15 to about 30, about 15 to about 25, about 15 to about 20, about 20 to about 30, about 20 to about 25, or about 25 to about 330 mmHg compared to baseline at or after about 12 weeks of treatment compared to placebo.

[0035] Following treatment with (R)-Compound 1, a human's 24-hour ambulatory mean systolic blood pressure (SBP) is reduced relative to baseline at or after about 12 weeks of treatment, compared to placebo. In other embodiments, administration of (R)-Compound 1 results in a reduction from baseline in 24-hour ambulatory mean SBP of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30 mmHg compared to baseline at or after about 12 weeks of treatment, compared to placebo. In further embodiments, administration of (R)-Compound 1 results in a reduction from baseline in ambulatory 24-hour mean SBP of about 1 to about 30, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, about 1 to about 5, about 5 to about 30, about 5 to about 25, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 30, about 10 to about 25, about 10 to about 20, about 10 to about 15, about 15 to about 30, about 15 to about 25, about 15 to about 20, about 20 to about 30, about 20 to about 25, or about 25 to about 330 mmHg compared to baseline at or after about 12 weeks of treatment compared to placebo.

[0036] In some embodiments, a human's 24-hour ambulatory mean diastolic blood pressure (DBP) is reduced relative to baseline at or after about 12 weeks of treatment compared to placebo. In further embodiments, administration of (R)-Compound 1 results in a reduction from baseline in 24-hour ambulatory mean DBP of at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, or at least about 30 mmHg compared to baseline at or after about 12 weeks of treatment compared to placebo. In other embodiments, administration of (R)-Compound 1 results in a reduction from baseline in ambulatory 24-hour mean DBP of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30 mmHg compared to baseline at or after about 12 weeks of treatment compared to placebo. In further embodiments, administration of (R)-Compound 1 results in a reduction from baseline in ambulatory 24-hour mean DBP of about 1 to about 30, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, about 1 to about 5, about 5 to about 30, about 5 to about 25, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 30, about 10 to about 25, about 10 to about 20, about 10 to about 15, about 15 to about 30, about 15 to about 25, about 15 to about 20, about 20 to about 30, about 20 to about 25, or about 25 to about 330 mmHg compared to baseline at or after about 12 weeks of treatment compared to placebo.

[0037] In certain embodiments, administration of (R)-Compound 1 does not result in clinically significant adverse events in humans compared to placebo. In other embodiments, administration does not result in clinically significant decreases in mean serum cortisol levels compared to placebo.

[0038] In certain embodiments, provided is (R)-Compound 1 for use in any of the methods described herein.

[0039] "Treating" or variations thereof refers to eliminating or reducing at least one physical parameter of a disease or disorder, such as hypertension. In some embodiments, the disease or disorder is hypertension. In other embodiments, the disease or disorder is resistant hypertension. In some embodiments, the disease or disorder is uncontrolled hypertension.

[0040] Pharmaceutical Composition The present disclosure also provides pharmaceutical compositions comprising (R)-Compound 1 and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains about 0.1-10 mg, e.g., 0.5-10 mg, of (R)-Compound 1 and one or more pharmaceutically acceptable excipients. In other embodiments, the pharmaceutical composition comprises anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.

[0041] The amount of (R)-Compound 1 used alone or in a pharmaceutical formulation can also be expressed in terms of amount. In some embodiments, the pharmaceutical formulation contains about 0.1 to about 10 mg of (R)-Compound 1, e.g., about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg of (R)-Compound 1. In other embodiments, the pharmaceutical formulation contains about 0.5 mg of (R)-Compound 1. In a further embodiment, the pharmaceutical formulation contains about 1 mg of (R)-Compound 1. In yet another embodiment, the pharmaceutical formulation contains about 2 mg of (R)-Compound 1. In yet another embodiment, the pharmaceutical formulation contains about 3 mg of (R)-Compound 1. In yet another embodiment, the pharmaceutical formulation contains about 4 mg of (R)-Compound 1. In yet a further embodiment, the pharmaceutical formulation contains about 5 mg of (R)-Compound 1. In another embodiment, the pharmaceutical formulation contains about 6 mg of (R)-Compound 1. In a further embodiment, the pharmaceutical formulation contains about 7 mg of (R)-Compound 1. In yet another embodiment, the pharmaceutical formulation contains about 8 mg of (R)-Compound 1. In yet a further embodiment, the pharmaceutical formulation contains about 9 mg of (R)-Compound 1. In another embodiment, the pharmaceutical formulation contains about 10 mg of (R)-Compound 1.

[0042] (R)-Compound 1 or a pharmaceutical composition containing (R)-Compound 1 may be administered hourly, daily, or weekly. Desirably, (R)-Compound 1 or a pharmaceutical composition containing (R)-Compound 1 is administered daily. In some embodiments, about 0.1 to about 30 mg / day of (R)-Compound 1 is administered. In some embodiments, about 0.1 to about 5 mg / day of (R)-Compound 1, for example, about 0.1 mg / day, about 0.2 mg / day, about 0.3 mg / day, about 0.4 mg / day, about 0.5 mg / day, about 0.6 mg / day, about 0.7 mg / day, about 0.8 mg / day, about 0.9 mg / day, about 1 mg / day, about 1.5 mg / day, about 2 mg / day, about 2.5 mg / day, about 3 mg / day, about 3.5 mg / day, about 4 mg / day, about 4.5 mg / day, about 5 mg / day, about 5.5 mg / day, about 6 mg / day, about 6.5 mg / day, about 7 mg / day, about 7.5 mg / day, or about 8 mg / day, is administered to a human. In other embodiments, about 0.5 mg / day of (R)-Compound 1 is administered to a human. In a further embodiment, about 1 mg / day of (R)-Compound 1 is administered to a human. In yet another embodiment, about 2 mg / day of (R)-Compound 1 is administered to a human. In yet a further embodiment, about 3 mg / day of (R)-Compound 1 is administered to a human. In another embodiment, about 4 mg / day of (R)-Compound 1 is administered to a human. In a further embodiment, about 5 mg / day of (R)-Compound 1 is administered to a human. In yet another embodiment, about 6 mg / day of (R)-Compound 1 is administered to a human. In yet a further embodiment, about 7 mg / day of (R)-Compound 1 is administered to a human. In another embodiment, about 8 mg / day of (R)-Compound 1 is administered to a human. In a further embodiment, about 9 mg / day of (R)-Compound 1 is administered to a human. In yet another embodiment, about 10 mg / day of (R)-Compound 1 is administered to a human.

[0043] (R)-Compound 1 can be administered in a single dose or in divided doses. In some embodiments, (R)-Compound 1 is administered in a single dose. In further embodiments, (R)-Compound 1 is administered in divided doses. In yet other embodiments, one tablet is administered. In still further embodiments, the tablet contains 1 mg of (R)-Compound 1. In other embodiments, the tablet contains 2 mg of (R)-Compound 1. One of skill in the art can determine and use other combinations of tablet doses based on the dosage of (R)-Compound 1 required.

[0044] Administration route (R)-Compound 1 or a pharmaceutical formulation containing it can be administered by any acceptable route. In some embodiments, administration is oral, transdermal, parenteral, or a combination thereof. In further embodiments, administration is oral. In other embodiments, administration is transdermal. In yet further embodiments, administration is parenteral.

[0045] (R)-Compound 1, or a pharmaceutical formulation containing (R)-Compound 1, can be formulated for administration in solid or liquid form. In some embodiments, (R)-Compound 1, or a pharmaceutical formulation containing (R)-Compound 1, is formulated in the form of a tablet, caplet, capsule, powder, softgel, suspension, or liquid, or a combination thereof. In other embodiments, (R)-Compound 1, or a pharmaceutical formulation containing (R)-Compound 1, is formulated in the form of a tablet. In further embodiments, (R)-Compound 1, or a pharmaceutical formulation containing (R)-Compound 1, is formulated in the form of a caplet. In yet other embodiments, (R)-Compound 1, or a pharmaceutical formulation containing (R)-Compound 1, is formulated in the form of a capsule. In still further embodiments, each tablet, caplet, capsule, powder, softgel, suspension, or liquid dose contains about 0.5 to about 5 mg, i.e., about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, or about 5 mg of (R)-Compound 1. In other embodiments, each tablet, caplet, capsule, powder, softgel, suspension, or liquid dose contains about 0.5 mg of (R)-Compound 1. In further embodiments, each tablet, caplet, capsule, powder, softgel, suspension, or liquid dose contains about 1 mg of (R)-Compound 1. In yet other embodiments, each tablet, caplet, capsule, powder, softgel, suspension, or liquid dose contains about 2 mg of (R)-Compound 1. In still further embodiments, each tablet, caplet, capsule, powder, softgel, suspension, or liquid dose contains about 2 mg of (R)-Compound 1. In other embodiments, each tablet, caplet, capsule, powder, softgel, suspension, or liquid dose contains about 3 mg of (R)-Compound 1. In further embodiments, each tablet, caplet, capsule, powder, softgel, suspension, or liquid dose contains about 4 mg of (R)-Compound 1. In yet other embodiments, each tablet, caplet, capsule, powder, softgel, suspension, or liquid dose contains about 5 mg of (R)-Compound 1.

[0046] In certain aspects, the solid or liquid form contains a patient / human dose of (R)-Compound 1. In other embodiments, it may be necessary to administer more than one dose of the solid or liquid form to the patient / human, i.e., split doses, to achieve the desired dosage for the patient / human. In some embodiments, a human is orally administered a once-daily 1 mg tablet containing (R)-Compound 1. In other embodiments, a human is orally administered a once-daily 2 mg tablet containing (R)-Compound 1.

[0047] Antihypertensive regimens In some embodiments, prior to administration of (R)-Compound 1, the human is unresponsive to one or more stable background antihypertensive regimens. A "stable background antihypertensive regimen" includes any regimen that lowers the patient / human's blood pressure. The regimen may include performing one or more therapies, such as daily activities, or taking one or more antihypertensive medications. In some embodiments, the stable background antihypertensive regimen is one or more daily activities. Examples of daily activities that may be used to treat hypertension or primary aldosteronism include, but are not limited to, a healthy diet, reducing salt intake, engaging in regular physical activity, maintaining a healthy weight, losing weight if advised by a physician, and limiting alcohol consumption. In other embodiments, the stable background antihypertensive regimen is an antihypertensive medication. In further embodiments, the hypertension is uncontrolled hypertension, and the stable background antihypertensive regimen includes at least two antihypertensive medications. In yet other embodiments, the hypertension is treatment-resistant hypertension, and the stable background antihypertensive regimen includes at least three antihypertensive medications.

[0048] The term "antihypertensive agent," as used herein, refers to a medication that lowers blood pressure in a patient / human. In some embodiments, the antihypertensive agent is a diuretic, loop diuretic, beta-blocker, ACE inhibitor, angiotensin II receptor blocker, calcium channel blocker, alpha-blocker, alpha-2 receptor agonist, combined alpha-blocker and beta-blocker, central agonist, peripheral adrenergic inhibitor, vasodilator (vasodilator), or combinations thereof. In some embodiments, the antihypertensive agent is a diuretic, such as a thiazide diuretic, potassium-sparing diuretic, loop diuretic, or combination diuretic. Examples of thiazide diuretics include chlorthalidone (Hygroton), chlorothiazide (Diuril), hydrochlorothiazide (Esidrix, Hydrodiuril, Microzide), indapamide (Lozol), or metolazone (Mykrox, Zaroxolyn). Examples of potassium-sparing diuretics include amiloride hydrochloride (Midamar), spironolactone (Aldactone), eplerenone (Inspra), or triamterene (Dyrenium). Examples of loop diuretics include furosemide (Lasix) or bumetanide (Bumex). Examples of combination diuretics include amiloride hydrochloride + hydrochlorothiazide (Moduretic), spironolactone + hydrochlorothiazide (Aldactazide), or triamterene + hydrochlorothiazide (Dyazide, Maxzide). In other embodiments, the antihypertensive agent is a beta-blocker. Examples of beta-blockers include acebutolol (Sectral), atenolol (Tenormin), betaxolol (Kerlone), bisoprolol fumarate (Zebeta), carteolol hydrochloride (Cartrol), metoprolol tartrate (Lopressor), metoprolol succinate (Toprol-XL), nadolol (Corgard), penbutolol sulfate (Levatol), pindolol (Visken), propranolol hydrochloride (Inderal), solotol hydrochloride (Betapace), or timolol maleate (Blocadren). In a further embodiment, the antihypertensive agent is a beta-blocker / diuretic combination.An example of a beta-blocker / diuretic combination is hydrochlorothiazide and bisoprolol (Ziac). In yet other embodiments, the antihypertensive agent is an ACE inhibitor. Examples of ACE inhibitors include benazepril hydrochloride (Lotensin), captopril (Capoten), enalapril maleate (Vasotec), fosinopril sodium (Monopril), lisinopril (Prinivel, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril hydrochloride (Accupril), ramipril (Altace), or trandolapril (Mavik). In still further embodiments, the antihypertensive agent is an angiotensin II receptor blocker. Examples of angiotensin II receptor blockers include candesartan (Atacand), eprosartan mesylate (Teveten), irbesartan (Avapro), losartan potassium (Cozaar), telmisartan (Micardis), or valsartan (Diovan). In other embodiments, the antihypertensive agent is a calcium channel blocker. Examples of calcium channel blockers include amlodipine besylate (Norvasc, Lotrel), bepridil (Vasocor), diltiazem hydrochloride (Cardizem CD, Cardizem SR, Dilacor XR, Tiazac), felodipine (Plendil), isradipine (DynaCirc, DynaCirc CR), nicardipine (Cardene SR), nifedipine (Adalat CC, Procardia XL), nisoldipine (Sular), or verapamil hydrochloride (Calan SR, Covera HS, Isoptin SR, Verelan). In further embodiments, the antihypertensive agent is an alpha-blocker. Examples of alpha-blockers include doxazosin mesylate (Cardura), prazosin hydrochloride (Minipress), or terazosin hydrochloride (Hytrin). In yet other embodiments, the antihypertensive agent is an alpha-2 receptor agonist. An example of an alpha-2 receptor agonist is methyldopa. In still further embodiments, the antihypertensive agent is a combination of an alpha blocker and a beta blocker.Examples of a combination of an alpha-blocker and a beta-blocker include carvedilol (Coreg) or labetalol hydrochloride (Normodyne, Trandate). In another embodiment, the antihypertensive agent is a central agonist. Examples of central agonists include alpha-methyldopa (Aldomet), clonidine hydrochloride (Catapres), guanabenzacetate (Wytensin), or guanfacine hydrochloride (Tenex). In a further embodiment, the antihypertensive agent is a peripheral adrenergic blocking agent. Examples of peripheral adrenergic blocking agents include guanadrel (Hylorel), guanethidine monosulfate (Ismelin), or reserpine (Serpasil). In yet another embodiment, the antihypertensive agent is a vasodilator, i.e., a blood vessel dilator. Examples of vasodilators include hydrazine hydrochloride (Apresoline) or minoxidil (Loniten).

[0049] In some embodiments, the patient / human's hypertension is unresponsive to one or more stable background blood pressure lowering regimens prior to administering (R)-Compound 1. In other embodiments, the patient / human's hypertension is unresponsive to two stable background blood pressure lowering regimens prior to administering (R)-Compound 1. In further embodiments, the patient / human's hypertension is unresponsive to three stable background blood pressure lowering regimens prior to administering (R)-Compound 1. In other embodiments, the patient / human's hypertension is unresponsive to three or more stable background blood pressure lowering regimens prior to administering (R)-Compound 1.

[0050] An antihypertensive agent may be administered to a human in combination with (R)-Compound 1. In some embodiments, (R)-Compound 1 is administered to a human in combination with two antihypertensive agents during the treatment period. In other embodiments, (R)-Compound 1 is administered to a human in combination with three antihypertensive agents during the treatment period. In further embodiments, (R)-Compound 1 is administered to a human in combination with at least three antihypertensive agents during the treatment period. In still other embodiments, (R)-Compound 1 is administered to a human in combination with two antihypertensive agents during the treatment period, one antihypertensive agent being a diuretic. In still further embodiments, (R)-Compound 1 is administered to a human in combination with three antihypertensive agents during the treatment period, one antihypertensive agent being a diuretic. In other embodiments, (R)-Compound 1 is administered to a human in combination with at least three antihypertensive agents during the treatment period, one antihypertensive agent being a diuretic.

[0051] Current FDA-approved drug classes for the treatment of hypertension are diuretics, renin-angiotensin-aldosterone system (RAAS) inhibitors, beta-blockers, calcium channel blockers, mineralocorticoid receptor antagonists (MRAs), α-adrenergic receptor antagonists, central α-adrenergic receptor antagonists, and direct vasodilators (Table 2). Medications recommended for initial treatment include diuretics, ACEIs, ARBs, and calcium channel blockers.

[0052] [Table 2]

[0053] Aspects Embodiment 1. A method substantially as described herein.

[0054] Aspect 2. Below

[0055] [ka] or a pharmaceutically acceptable salt thereof.

[0056] Aspect 3. Below

[0057] [ka] or a pharmaceutically acceptable salt thereof.

[0058] Aspect 4. Below

[0059] [ka] or a pharmaceutically acceptable salt thereof.

[0060] Aspect 5. Below

[0061] [ka] or a pharmaceutically acceptable salt thereof.

[0062] Aspect 6. Below

[0063] [ka] or a pharmaceutically acceptable salt thereof

[0064] Aspect 7. Below

[0065] [ka] or a pharmaceutically acceptable salt thereof.

[0066] [Table 3-1]

[0067] [Table 3-2] [Example]

[0068] The following examples are provided to illustrate some of the concepts described in this disclosure. Although the examples are intended to provide specific individual embodiments of formulations, preparation methods, and uses, the examples should not be considered to limit the more general embodiments described herein. In the following examples, efforts have been made to ensure accuracy with respect to the numerical values used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be considered.

[0069] Example 1: Single Ascending Dose Study: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Baxdrostat in Healthy Male Volunteers Eighty-eight healthy male volunteers completed a first-in-human study of baxdrostat. In Part 1 of the study, subjects received single oral doses of baxdrostat ranging from 1 to 360 mg to evaluate safety, tolerability, PK, and pharmacodynamics (PD). Part 2 evaluated the PK of a single 3 mg intravenous dose of baxdrostat. Baxdrostat significantly reduced aldosterone levels in a dose-dependent manner under fasting, low-salt, and normal-salt diet conditions. Baxdrostat had no significant effect on cortisol levels following adrenocorticotropic hormone challenge, demonstrating selectivity for aldosterone synthase inhibition. Plasma levels of baxdrostat increased dose-proportionally across the entire dose range tested, with a mean half-life of 29 hours, supporting once-daily dosing. There were no deaths, serious adverse events, or dose-limiting adverse events. Side effects were mild and included headache, nasopharyngitis, and diarrhea.

[0070] Example 2: Randomized, Double-Blind Study: Safety, Pharmacokinetics, and Pharmacodynamics of Baxdrostat After Multiple Ascending Doses in Healthy Subjects This randomized, double-blind, placebo-controlled Phase 1 study evaluated the safety, pharmacokinetics, and pharmacodynamics of multiple ascending doses of baxdrostat in healthy subjects. Fifty-six subjects were randomized to receive oral baxdrostat (0.5, 1.5, 2.5, or 5.0 mg) or placebo once daily for 10 days and followed either a low-salt or normal-salt diet throughout the study. Specifically, subjects were randomized into five cohorts to receive baxdrostat or placebo once daily for 10 days. Cohorts 1 and 2 received 2.5 mg or 5.0 mg of oral baxdrostat, respectively, on a low-salt diet to stimulate aldosterone production. Cohorts 1 and 2 also underwent an adrenocorticotropic hormone (ACTH) challenge to increase aldosterone and cortisol levels, evaluating the specificity of baxdrostat in targeting aldosterone synthase. Cohorts 3, 4, and 5 were fed a normal-salt diet and received 1.5 mg, 2.5 mg, or 0.5 mg of oral baxdrostat, respectively. Pre- and post-dose blood samples were collected on days 1 and 10 for measurement of plasma baxdrostat concentrations to characterize single-dose and steady-state pharmacokinetics. Pharmacodynamic measurements included plasma aldosterone, cortisol, and electrolytes. Safety assessments included physical examination, electrocardiogram, orthostatic vital signs, and clinical laboratory assessments.

[0071] Fifty-four subjects completed the study. There were no deaths or serious adverse events, and all treatment-emergent adverse events in subjects receiving baxdrostat were mild in severity (e.g., headache, dizziness, and postural-induced dizziness). Baxdrostat was rapidly absorbed. Plasma levels of baxdrostat increased proportionally with increasing doses, with peak concentrations observed within 4 hours after administration and a mean half-life of 26 to 31 hours, indicating a clear biphasic decline in plasma baxdrostat concentrations. A dose-dependent decrease in plasma aldosterone occurred at baxdrostat doses ≥ 1.5 mg, regardless of food. The decrease in plasma aldosterone was sustained, with levels decreasing by approximately 51 to 73% by day 10. Baxdrostat had no significant effect on plasma cortisol and produced a mild, dose-dependent decrease in plasma sodium levels and an increase in potassium levels, consistent with the observed decrease in aldosterone. Baxdrostat was safe, had a half-life supporting once-daily dosing, and was well tolerated. The dose-dependent reduction in plasma aldosterone and lack of effect on cortisol indicate selective blockade of aldosterone synthase.

[0072] Oral administration of baxdrostat was safe and well tolerated in all subjects and produced a dose-dependent increase in plasma baxdrostat with a half-life supporting once-daily dosing. The dose-dependent decrease in plasma aldosterone and lack of effect on cortisol indicate selective blockade of aldosterone synthase.

[0073] Example 3: Randomized, Open-Label Crossover Study: Relative Bioavailability of a Tablet Formulation of Baxdrostat Compared to Oral Solution. Evaluating the Effect of Food on a Tablet Formulation of Baxdrostat in Healthy Subjects The relative bioavailability of the tablet formulation of baxdrostat was compared to the oral solution of baxdrostat administered in the SAD (Example 1) and MAD (Example 2) studies. A single 5 mg dose of each formulation in 14 healthy volunteers established that plasma levels of baxdrostat were equivalent whether administered via oral solution or tablet. This study also evaluated the effect of a standardized high-fat meal on the PK of baxdrostat. There was no notable effect of a high-fat meal on plasma levels of baxdrostat. The time to maximum concentration (T) was measured from approximately 3 hours after administration in the fasted state to approximately 4 hours after administration in the fed state. max ) had a small effect on absorption rate.

[0074] Example 4: Phase 1, Open-Label, Single-Dose, Parallel-Group Study: Pharmacokinetics of Baxdrostat in Subjects with Varying Degrees of Renal Function A. Method (i) Subject Subjects were included if they were between 18 and 80 years of age and in stable health based on medical and psychiatric history, physical examination, ECG, vital signs (sitting and standing), and routine laboratory tests (blood chemistry, hematology, coagulation, and urinalysis). For subjects with renal impairment, their renal status must have been stable for a minimum of 3 months prior to screening. In addition, subjects must be nonsmokers or smoke fewer than 10 cigarettes per day and have a BMI of 18 kg / m. 2 More than 40kg / m 2 Must be less than or equal to:

[0075] Subjects were excluded if they had the following: 1) Personal or family history of long QT syndrome, complex ventricular arrhythmias, or family history of sudden death 2) a personal history of clinically significant arrhythmia or current clinically significant arrhythmia; 3) QTcF prolongation (more than 450 msec in men or more than 470 msec in women), 4) Sitting systolic blood pressure (BP) > 160mmHg and / or diastolic BP > 100mmHg, or systolic BP < 90mmHg and / or diastolic BP < 50mmHg, 5) Resting heart rate greater than 100 beats per minute (bpm) or less than 50 bpm; 6) postural tachycardia or orthostatic hypotension (i.e., a decrease in systolic BP ≥ 20 mmHg or diastolic BP ≥ 10 mmHg upon standing from a sitting position); 7) clinically significant abnormal serum potassium above the ULN reference range; 8) Clinically significant abnormal serum sodium below the lower normal limit of the reference range; 9) Aspartate aminotransferase or alanine aminotransferase levels greater than 1.5 times the ULN; 10) total bilirubin greater than 2 times the ULN (unless due to Gilbert syndrome); 11) History of porphyria, myopathy, or active liver disease 12) Current treatment with weight-loss medication or previous weight-loss surgery, or 13) Use of strong inducers of CYP3A4 (e.g., apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John's wort) within 28 days prior to study drug administration, or use of corticosteroids within 3 months prior to study drug administration.

[0076] (ii) Study design This phase 1, open-label, single-dose, parallel-group study was designed in accordance with the FDA guidance for the design and analysis of studies evaluating the effect of renal impairment on PK. Subjects were enrolled in three renal function groups defined based on eGFR calculated using the Chronic Kidney Disease Epidemiology Collaboration equation: ● Control (normal renal function or mild renal dysfunction: eGFR≧60mL / min) Moderate to severe renal dysfunction (eGFR 15-59 mL / min) Renal failure (eGFR < 15 mL / min, including subjects on dialysis)

[0077] All subjects received a single 10 mg dose of baxdrostat in an open-label manner. Each subject had a screening period of up to 28 days, followed by admission to the clinical site (Day -1) and baxdrostat administration (Day 1). All subjects were required to fast for a minimum of 10 hours before baxdrostat administration. Then, at 8:00 AM (± 2 hours), they received two 5 mg tablets, which were administered with approximately 240 mL of water. Subjects continued fasting for a minimum of 4 hours after administration. No other medications were permitted within 2 hours before or 2 hours after baxdrostat administration. Subjects undergoing dialysis received the study drug on non-dialysis days. Collection of blood and urine samples for PK analysis continued for 7 days, proceeding to a follow-up call 3 ± 1 days after clinic discharge.

[0078] (iii) Analysis method Plasma and urine samples were analyzed using a validated LC-MS / MS method to measure concentrations of baxdrostat and its primary metabolite (baxdrostat-M). "Baxdrostat-M," as used herein, refers to a compound having the following structure:

[0079] [ka]

[0080] (iv) Pharmacokinetic analysis

[0081] [Table 4]

[0082] Blood and urine samples were collected pre- and post-dose for measurement of plasma and urinary baxdrostat and baxdrostat-M concentrations, and the maximum observed plasma concentrations (C max ), C max Time to (T max), AUC 0-last , and AUC 0-inf was characterized. 1 / 2 , CL / F, and V / F were calculated for plasma baxdrostat only. Urinary PK parameters included the cumulative amount of baxdrostat and baxdrostat-M excreted in urine (A e ), renal clearance (CL) of baxdrostat and baxdrostat-M R ), and the proportion of the dose excreted renally for baxdrostat (F e ) was included.

[0083] (v) Safety analysis Safety was assessed throughout the study based on adverse events, physical examination, ECG, sitting and standing vital signs, weight measurements, and clinical laboratory assessments.

[0084] B. Results (i) Subject Baseline demographic and clinical characteristics were generally well matched between renal function groups and are shown in Table 3 .

[0085] Subjects were predominantly Caucasian (60.6%) and male (75.8%), with a mean age of 62 years and a mean BMI of 30 kg / m 2 The continuum of eGFR values was well represented by all subjects. All subjects in the renal failure group were receiving hemodialysis.

[0086] (ii) Pharmacokinetics Plasma PK parameters of baxdrostat are shown in Table 4.

[0087] [Table 5]

[0088] Baxdrostat absorption was similar across renal function groups. Baxdrostat was rapidly absorbed, with median T values reaching 1.5 hours after administration for all groups. maxwas observed (Figures 12A and 12B), with mean half-lives ranging from 30 to 42 hours. Pairwise comparisons of moderate to severe renal impairment versus controls, and renal failure versus controls, showed that renal impairment significantly increased C max , AUC (0-last) , AUC (0-inf) The results showed that PK parameters had no meaningful effect on the half-life, apparent plasma clearance, or renal clearance. To understand the relationship between selected PK parameters and eGFR as a continuous variable, the inventors performed a C-value analysis of baseline eGFR for each subject. max , AUC 0-last , and AUC 0-inf were analyzed. There was no indication of a strong linear or non-linear relationship. See Figures 21A-21D.

[0089] The plasma baxdrostat-M concentration-time curves in the moderate to severe renal impairment and renal failure groups were qualitatively similar to those in the control group. See Figure 22. max was observed approximately 22 hours after administration for all renal function groups.

[0090] Urinary PK parameters are also shown in Table 4. In the control and moderate to severe renal impairment groups, approximately 12% of baxdrostat was recovered unchanged in the urine. Insufficient urine production in the renal failure group, as expected, resulted in minimal renal excretion of baxdrostat in these subjects. See Figure 23.

[0091] (iii) Safety There were no deaths and only one mild drug-related treatment-emergent adverse event (diarrhea) (Table 5).

[0092] [Table 6]

[0093] One subject in the renal failure group experienced two TEAEs, tremor and metabolic encephalopathy, that were determined to be unrelated to the study drug. The metabolic encephalopathy was severe and considered secondary to the combination of gabapentin, primidone, and baclofen; by study day 11, the metabolic encephalopathy had resolved and the patient was considered recovered. There were no clinically significant changes in laboratory values, vital signs, physical examination, or ECG (data not shown).

[0094] C. Consideration The older MR antagonists spironolactone and eplerenone have been shown to induce biomarker changes associated with improved CKD progression, likely due to their anti-inflammatory and anti-fibrotic effects. However, a major limitation of using these drugs to treat CKD has been the high incidence of hyperkalemia. Finerenone, a newer nonsteroidal MR antagonist, was recently approved for use in CKD patients to slow CKD progression, despite an even higher incidence of hyperkalemia. However, the effects of finerenone on blood pressure were very modest. Results of a phase 1 trial of baxdrostat in healthy volunteers showed that the drug had minimal effects on serum potassium in individuals with normal renal function. Therefore, investigating the utility of baxdrostat as both an antihypertensive agent and a potential therapy for slowing the progression of kidney disease in individuals with CKD seems warranted. To safely conduct such a study, it was important to first determine whether the presence of renal impairment necessitated a different dosing regimen of baxdrostat due to altered pharmacokinetic properties of the drug.

[0095] The results presented in this report indicate that renal impairment did not have a significant effect on any of the measured PK parameters. The plasma concentration-time curves and systemic exposure to baxdrostat were as expected based on previous studies in healthy subjects. The half-life of baxdrostat was also comparable to previous studies. In addition, there were no trends in PK parameters across the eGFR continuum, and baxdrostat was safe and well tolerated in patients with various degrees of renal function.

[0096] Renal disease can alter drug clearance, resulting in increased exposure and potentially greater drug efficacy or toxicity. Therefore, dose adjustment is generally necessary for patients with impaired renal function. Our previous observations from a single ascending dose study indicated that baxdrostat is primarily metabolized by the liver, which is consistent with our current findings that renal function did not significantly affect the PK or safety profile of baxdrostat.

[0097] Because this study was only intended to evaluate PK in subjects with renal impairment, further long-term studies are needed to fully evaluate the safety and efficacy of baxdrostat in the intended patient population (e.g., those with hypertension, primary aldosteronism, or CKD) who also have renal impairment. Additionally, this study did not include subjects with renal failure not undergoing dialysis.

[0098] D. Conclusion Our results demonstrate that a single dose of baxdrostat was safe and well tolerated in subjects with various degrees of renal function, including those with renal failure, and that renal impairment did not significantly affect the systemic exposure or clearance of baxdrostat. These findings suggest that dose adjustment of baxdrostat due to altered PK properties in patients with renal impairment is unlikely to be necessary, even in patients with end-stage renal disease.

[0099] E. Overview This phase 1, open-label study evaluated the safety and pharmacokinetics (PK) of a single oral dose of baxdrostat in subjects with varying degrees of renal function. Thirty-three subjects were enrolled into renal function groups based on estimated glomerular filtration rate (eGFR). Groups were control (eGFR ≥ 60 mL / min), moderate to severe renal impairment (eGFR 15-59 mL / min), and renal failure (eGFR < 15 mL / min, including subjects on dialysis). Control subjects were matched by age, sex, race, body mass index (BMI), and smoking status. A single 10 mg dose of baxdrostat was administered, followed by 7 days of blood and urine sampling for PK analysis. Safety was assessed based on adverse events, clinical laboratory assessments, vital signs, ECG, physical examination, and weight measurements.

[0100] Thirty-two subjects completed the study. There were no deaths and only one mild drug-related adverse event (diarrhea). There were no clinically significant changes in laboratory values, vital signs, physical examination, or electrocardiogram (ECG). Plasma concentration-time curves of baxdrostat were qualitatively similar in all groups. See Figure 12. Urinary PK parameters in the moderate to severe renal impairment group were similar to controls (12% excretion). Insufficient urine production in the renal failure group resulted in the expected negligible excretion of baxdrostat.

[0101] A single dose of baxdrostat was well tolerated in all subjects, including those with renal insufficiency. Renal impairment did not significantly affect the systemic exposure or clearance of baxdrostat, suggesting that dose adjustments due to PK differences in these patients are not necessary, even in the case of advanced renal disease.

[0102] Example 5: Phase 1, Open-Label, Single-Dose, Parallel-Group Study: Pharmacokinetics of Baxdrostat in Subjects with Varying Degrees of Hepatic Function method Subjects with moderate hepatic impairment (Child-Pugh category B, n = 10) and healthy controls (n = 10) each received a single 10 mg oral dose of baxdrostat. Subjects were matched for age, sex, body mass index, race, and smoking status. Serial blood and urine samples were collected over 7 days post-dose to determine plasma and urinary concentrations of baxdrostat. Safety was assessed based on adverse events, clinical laboratory assessments, vital signs, electrocardiograms, and physical examinations.

[0103] result All 20 subjects completed the study. There were no deaths, serious treatment-emergent adverse events (TEAEs), or study discontinuations. One TEAE of headache of moderate severity in the normal hepatic function group was considered related to baxdrostat. One TEAE of hyperkalemia and one TEAE of hypoglycemia occurred in the moderate hepatic impairment group. Both were considered unrelated to baxdrostat. No clinically significant changes were noted after baxdrostat administration in either group for laboratory assessments, vital signs, electrocardiograms, or physical examinations. Plasma (Figures 12A and 12B) and urinary pharmacokinetic parameters of baxdrostat were similar between the two hepatic function groups, as shown in Table 6.

[0104] [Table 7]

[0105] In summary, approximately 10 subjects were enrolled in each of two liver function groups, either as moderately impaired subjects (category B) or as healthy control subjects according to the Child-Pugh classification.The control subjects were selected to be comparable to the impaired subjects in terms of age, sex, race, BMI and smoking status.Subjects with moderate liver dysfunction do not require adjustment of the baxdrostat dose.

[0106] Example 6: Randomized, Open-Label, Two-Period Crossover Study: Effect of Baxdrostat on the Pharmacokinetics of Metformin in Healthy Subjects Due to the high comorbidity of type 2 diabetes mellitus (T2DM) and hypertension, many patients require combination treatment with metformin, a common T2DM medication, and antihypertensive agents. To evaluate potential drug-drug interactions between baxdrostat and metformin, 27 healthy volunteers were administered either 1000 mg of metformin alone or 1000 mg of metformin followed by a 10 mg dose of baxdrostat. There was no shift or change in the shape of the plasma metformin PK curve in the presence or absence of baxdrostat. Baxdrostat did not significantly affect the renal clearance of metformin. There were no deaths, serious adverse events (SAEs), discontinuations due to treatment-emergent adverse events (TEAEs), or significant increases in adverse events (AEs) with either treatment. All reported TEAEs were mild in severity. No subjects experienced moderate or severe TEAEs. The most common TEAE was gastrointestinal disturbances. No clinically meaningful changes were observed in physical examination, vital signs, ECG (including no QT prolongation), or laboratory test results. Metformin and baxdrostat were safe and well tolerated when administered concomitantly.

[0107] Example 6A: A randomized, open-label, crossover study evaluating the effects of the aldosterone synthase inhibitor baxdrostat on the pharmacokinetics of metformin in healthy human subjects A. Eligibility To meet the inclusion criteria for this study, men and women aged 18-55 years must be in good health based on medical and psychiatric history, physical examination, ECG, vital signs, and routine laboratory tests (serum chemistry, hematology, and urinalysis). Subjects must have a BMI of ≥ 18 and a BMI of ≤ 30 kg / m. 2 with an estimated glomerular filtration rate of ≥ 85 mL / min / 1.73 m 2had adequate renal function, defined as ≥ 18 years of age, and no recent nicotine use.

[0108] Subjects were excluded from participation in this study if they had a personal or family history of long QT syndrome, complex ventricular arrhythmias, a current or past history of clinically significant arrhythmias, a family history of sudden death, a prolonged QTcF (>450 msec), a sitting BP >140 / 90 or <90 / 50 mmHg, a resting heart rate >100 or <50 beats / min, sick sinus syndrome, clinically significant heart block, postural tachycardia, or orthostatic hypotension. Other exclusion criteria included any laboratory test values significantly outside normal boundaries; a history of clinically significant or multiple drug allergies; any previous episode of lactic acidosis; a radiology scan with contrast within 14 days prior to the first dose of study drug; or a positive test for HIV antibodies, hepatitis C virus antibodies, hepatitis B surface antigen, or SARS-CoV-2 RNA. Subjects were excluded if they reported any recent illicit drug use; drinking more than 14 alcoholic drinks per week; or use of any prescription medication, including topical medications, herbal / dietary supplements, nutritional foods, or over-the-counter medications (other than occasional use of acetaminophen or nonsteroidal anti-inflammatory drugs), within 14 days or 5 half-lives, whichever was longer, before the first dose of study drug and throughout the hospital stay and discharge period.

[0109] B. Study Design This study was designed as a Phase 1, randomized, open-label, two-period crossover study. Each subject participated in a screening period of up to 26 days, followed by two inpatient treatment periods and follow-up telephone calls. Subjects were randomized 1:1 to treatment sequence AB or sequence BA for the two inpatient treatment periods. Treatment A was a single 1000 mg dose of metformin, and treatment B was a single 10 mg dose of metformin followed by a single 1000 mg dose of metformin 2 hours later.

[0110] There was a minimum 10-day washout period between the administration of the two treatments. Collection of blood and urine samples for PK analysis began before dosing in each period and continued for 3 days after dosing in each period. Samples were collected 2, 1.5, 1, 0.5, and 0 hours pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 14, 16, 22, 24, 36, 48, and 72 hours post-dose. Subjects received a follow-up call 3±1 days after discharge from the clinic in the second dosing period.

[0111] (i) Biological analysis method Plasma and urine samples were analyzed to determine concentrations of metformin, baxdrostat, and its primary metabolite baxdrostat-M using a validated LC-MS / MS method.

[0112] The quantifiable range of metformin in plasma was 0.5–500 ng / mL using metformin-d6 as the internal standard. Plasma samples were extracted by protein precipitation with methanol and subsequently analyzed by LC-MS / MS with electrospray ionization (ESI(+)) in positive mode and MRM. Reversed-phase chromatographic separation with a 15% to 90% mobile phase gradient was utilized, with a total run time of approximately 5 min. The precursor-to-product ion transitions for metformin and the internal standard were 130.1–71.1 and 135.4–77.0, respectively. Similarly, the quantifiable range of metformin in urine was 1.00–500 ng / mL (low range) and 2.00–1250 ng / mL (high range) under similar extraction and LC-MS / MS conditions. The interday precision (%CV) values for metformin in plasma and urine were within 5% and 10%, respectively.

[0113] Using baxdrostat-d5 and baxdrostat-M-d3 as internal standards, respectively, the quantifiable ranges of both baxdrostat and its metabolite baxdrostat-M in plasma were 0.05–50 ng / mL (low range) and 5.00–2500 ng / mL (high range).

[0114] "Baxdrostat-d5," as used herein, refers to a compound having the following structure:

[0115] [ka]

[0116] "Baxdrostat-M-d3," as used herein, refers to a compound having the following structure:

[0117] [ka]

[0118] Plasma samples were extracted by protein precipitation with methanol and subsequently analyzed by LC-MS / MS using ESI(+) and MRM. Reversed-phase chromatographic separation with a 20% to 90% mobile phase gradient was utilized, with a total run time of approximately 5 minutes. The precursor-to-product transitions for baxdrostat and its internal standard were 364.2 to 291.2 and 369.2 to 291.2, respectively. The transitions for baxdrostat-M and its internal standard were 309.2 to 291.2 and 313.2 to 295.2, respectively. The interday precision (%CV) values for baxdrostat and baxdrostat-M in plasma were within 3% and 4%, respectively.

[0119] (ii)PK analysis PK parameters were calculated using non-compartmental methods with SAS software, version 9.4 (SAS Institute). Plasma PK parameters calculated for metformin, baxdrostat, and baxdrostat-M were calculated based on the maximum observed plasma concentration (C max ), T max , AUC 0-24 , AUC 0-t , AUC 0-inf , extrapolated AUC 0-inf , λ z , and t 1 / 2The plasma AUC 0-72 was evaluated only for baxdrostat and baxdrostat-M. max , AUC 0-inf , and AUC 0-t were the three plasma PK parameters that were statistically analyzed to detect any interaction between baxdrostat and metformin. The urinary PK parameters were: A e , renal clearance (A e The urinary excretion rate (AUC) was calculated as 0.01 / AUC, and the proportion of the dose excreted renally.

[0120] (iii) Safety analysis Safety assessments included monitoring for AEs, physical examination, ECG, orthostatic vital signs, and clinical laboratory assessments.

[0121] C. Results (i) Subject Baseline demographic and clinical characteristics are shown in Table 7.

[0122] [Table 8]

[0123] Twenty-seven subjects were randomized into two cohorts that received the study drug in treatment sequences AB or BA. Most study participants were white (56%), non-Hispanic, non-Latino, and male (70%). The mean age was 37 years, and the mean BMI was 25.6 kg / m. 2 Demographic and baseline characteristics were generally well matched for sex, race, and ethnicity between both treatment sequences.

[0124] (ii) Pharmacokinetics The PK profile of metformin when administered alone in this study was consistent with that expected based on the package insert for immediate-release metformin. Furthermore, when administered after baxdrostat, the plasma PK profile of metformin was qualitatively and quantitatively similar to that of metformin alone (Figure 20).

[0125] After confirming the lack of treatment sequence effect, PK data for Treatment A from all subjects were pooled, and PK data for Treatment B from all subjects were pooled. Plasma and urinary PK parameters following administration of metformin alone or in the presence of baxdrostat are reported in Table 7. Plasma C for metformin in the presence of baxdrostat versus metformin alone max and the 90% CI of the geometric mean ratios of AUC values fell completely within the boundaries of the claimed bioequivalence (80%–125%), indicating the absence of PK drug–drug interactions.

[0126] [Table 9]

[0127] Urinary PK parameters for metformin alone and in the presence of baxdrostat are shown in Table 8, and the A of metformin excreted after metformin administration in the presence or absence of baxdrostat are shown in Table 8. e was measured, and the results confirmed that the renal excretion of metformin was not significantly affected by baxdrostat.

[0128] [Table 10]

[0129] The PK parameters of baxdrostat and its primary metabolite (Table 9) were similar to previously published data, thereby validating the study.

[0130] [Table 11]

[0131] (iii) Safety There were no deaths, serious AEs, or discontinuations due to treatment-emergent adverse events (TEAEs), and the incidence and severity of AEs were similar when metformin was administered with or without baxdrostat (Table 10). Overall, seven subjects experienced a total of 15 TEAEs. Five (19.2%) subjects experienced a total of six TEAEs after receiving metformin alone, and six (22.2%) subjects experienced a total of nine TEAEs after receiving metformin and baxdrostat. Four of these subjects experienced TEAEs after both treatments (metformin alone and metformin followed by baxdrostat).

[0132] [Table 12]

[0133] All reported TEAEs were mild. No subjects experienced moderate or severe TEAEs. The most common TEAE was gastrointestinal disturbances. Five (18.5%) subjects reported diarrhea, an AE commonly associated with metformin treatment: three (11.5%) subjects after metformin alone, four (14.8%) subjects after both metformin and baxdrostat, and two subjects after both treatments. No clinically meaningful changes were observed in physical examination, vital signs, ECG (including no QT prolongation), or laboratory test results.

[0134] D. Conclusion The results of this study demonstrated that single doses of metformin and baxdrostat were well tolerated when coadministered to healthy subjects, with mostly mild gastrointestinal AEs observed, as expected for high-dose metformin. Baxdrostat did not significantly affect metformin plasma concentrations or renal clearance. Therefore, diabetic patients with hypertension taking metformin and baxdrostat are unlikely to require metformin dose adjustment due to PK interactions.

[0135] Example 7: Clinical efficacy of steroids after a single oral dose in healthy male subjects 14 A Phase 1 Open-Label Study of the Absorption, Metabolism, and Excretion of [C]-Baxdrostat Eight male subjects each received a single oral 10 mg (containing approximately 100 uCi) dose of baxdrostat. Blood, urine, and fecal samples were collected to determine the metabolic and excretion pathways of baxdrostat. Preliminary findings indicate that the mean excretion of radioactivity in urine and feces was 69.4% and 15.3% of the dose, respectively. Unchanged baxdrostat was the major component in urine and feces, comprising 16.8% and 6.1% of the dose, respectively. In plasma, baxdrostat was the predominant circulating species, accounting for the total systemic exposure (AUC) according to the AUC curve to infinity. 0-inf ) constituted 71% of the total blood:plasma concentration ratios. The mean blood:plasma concentration ratios indicated a low association of radioactivity with blood cells.

[0136] Example 8: Study in patients with resistant hypertension This study was a randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of baxdrostat in patients with rHTN. Patients with rHTN were defined as receiving a stable regimen of three or more antihypertensive medications, including one diuretic, with a mean sitting blood pressure (BP) of 130 / 80 mmHg or greater. The primary objective was to demonstrate that at least one dose strength of baxdrostat was superior to placebo in the mean change from baseline in sitting SBP after 12 weeks of treatment. Secondary objectives were to assess the change from baseline in mean sitting DBP with each selected dose strength of baxdrostat compared with placebo and to assess the percentage of patients achieving a sitting BP response of <130 / 80 mmHg with each dose strength of baxdrostat compared with placebo after 12 hours of treatment. Patients who maintained a mean sitting BP of ≥ 130 / 80 mmHg on a stable regimen of three or more antihypertensive drugs, including a non-potassium-sparing diuretic, for at least 2 weeks were eligible to participate in the study and were randomly assigned equally to one of four treatment groups (0.5 mg, 1 mg, 2 mg baxdrostat, or placebo once daily). The study was planned to enroll 348 patients.

[0137] The primary endpoint was the placebo-adjusted change in mean office SBP from baseline to week 12. Secondary endpoints included the placebo-adjusted change in sitting office DBP from baseline to week 12 and the percentage of patients achieving a sitting BP response <130 / 80 mmHg with each selected dose strength of baxdrostat compared with placebo after 12 weeks of treatment for rHTN.

[0138] Point estimates for the primary treatment effect and secondary endpoints were generated by mixed-model analysis of covariance, including responder status as a fixed effect. The primary efficacy analysis was to compare the change in mean sitting SBP from baseline to day 85 between each dose strength of baxdrostat and placebo based on a modified intent-to-treat (mITT) population. The change from baseline in mean sitting SBP was analyzed using a mixed model for repeated measures (MMRM). The analysis included fixed effects for treatment, visit, and treatment-by-visit interaction, along with covariates for baseline mean sitting SBP and baseline glomerular filtration rate. A restricted maximum likelihood estimation (REML) approach was used with an unstructured covariance matrix.

[0139] Safety was assessed by comparing the frequency, type, distribution, and severity of adverse events; by analysis of clinical chemistry, hematology, and urinalysis test results; by shift tables comparing the number of participants who experienced a change from normal to abnormal (low or high) values from baseline to week 12; and by detailed evaluation of the circumstances surrounding serious adverse events and events leading to treatment discontinuation.

[0140] result A total of 779 candidates consented to study participation, of which 275 were eligible and randomly assigned to one of four treatment groups (0.5 mg, 1 mg, 2 mg baxdrostat, or placebo once daily). 248 patients completed the study (Figure 1). Of the 27 patients who discontinued, 15 were lost to follow-up (n = 8) or withdrew by consent (n = 7). The COVID-19 pandemic likely hindered patient retention. When the study was half complete, one patient discontinued due to loss to follow-up in each of the placebo, 1 mg, and 2 mg dose groups, and three patients were lost to follow-up in the lowest dose group (0.5 mg). This discontinuation rate in the second half of the study was not dose-dependent. The COVID-19 pandemic likely influenced the discontinuation rate in the first half of the study.

[0141] One patient discontinued study participation due to an adverse event of disc degeneration (n=1), and one patient experienced three SAEs: hyperglycemia, hyponatremia, and hyperkalemia, which led to study discontinuation (Table 11).

[0142] [Table 13]

[0143] The demographics and baseline characteristics of patients in the four study arms were well balanced (Table 12). The majority of participants were elderly, overweight, or obese and had normal or mildly impaired renal function. All but one patient was taking at least three antihypertensive medications, including a diuretic. In addition, more than 90% of participants were taking antihypertensive agents from the RAAS class (Table 13). Overall, the population represented a typical patient with rHTN.

[0144] [Table 14]

[0145] [Table 15]

[0146] Effectiveness The study results demonstrated that 1 mg and 2 mg doses of baxdrostat were effective in lowering SBP in patients with rHTN. Treatment with 2 mg baxdrostat resulted in a 20.3 mmHg reduction in SBP, compared with a placebo response of 9.4 mmHg, resulting in a model-adjusted, placebo-corrected reduction of 11.0 mmHg (95% confidence interval [CI] -16.4 mmHg, -5.5 mmHg) (p-value = 0.0001). Thus, the null hypothesis was rejected and the efficacy of 2 mg baxdrostat was established. Following a planned hierarchical sequence, the next dose of baxdrostat was tested: 1 mg. The 1 mg dose also resulted in a significant, placebo-adjusted SBP reduction of 8.1 mmHg (p-value = 0.003). The treatment effect of the 0.5 mg dose was slightly greater than that of placebo, but this difference did not reach statistical significance. Improvements in DBP were also observed: after 12 weeks of treatment, DBP decreased by 14.3 mmHg, 11.8 mmHg, and 8.6 mmHg in the 2 mg, 1 mg, and 0.5 mg dose groups, respectively, compared to a decrease of 9.2 mmHg in the placebo group (Table 14).

[0147] [Table 16]

[0148] The reduction in SBP was rapid after initiation of treatment and sustained throughout the 12 weeks of treatment, as shown in Figure 2.

[0149] Prospectively planned sensitivity analyses were performed using the intention-to-treat (mITT) or per protocol analysis sets and showed nearly identical model-adjusted and placebo-corrected changes from baseline of -11 mmHg (95% CI -16.4 mmHg to -5.5 mmHg) or -11.1 mmHg (95% CI -16.8 mmHg to -5.4 mmHg), respectively, in the 2 mg group. These results supported the primary endpoint analysis.

[0150] To further elucidate the treatment effect for patients with various baseline characteristics, the same primary analysis model was used to compare the change in mean sitting SBP from baseline to day 85 between each dose strength of baxdrostat and placebo in each subgroup. Subgroup analyses were performed by sex, race, baseline SBP (<145 mmHg or ≥145 mmHg), baseline glomerular filtration rate (GFR) (<60 mL / min / 1.73 m). 2 or ≥ 60 mL / min / 1.73 m 2 ), baseline serum aldosterone concentration (<6 ng / dL or ≥6 ng / dL), and background antihypertensive medication use. Patients receiving baxdrostat experienced greater reductions in SBP if they were male, white, non-Hispanic or non-Latino, had a higher eGFR, and had a baseline SBP value of 145 mmHg or greater (Tables 15A and 15B). Blood pressure responses by patients with baseline plasma aldosterone higher or lower than 6 ng / dL showed similar blood pressure reductions. This may reflect the wide variability of single plasma aldosterone measurements during study visits. Total aldosterone in 24-hour urine collections showed substantial treatment-related decreases in patients assigned to the active treatment group.

[0151] Substantial differences in treatment effects between subgroups appeared to be driven by larger reductions in SBP in the placebo arm. For example, female participants assigned to the placebo arm showed a 15.3 mmHg reduction in SBP. Hispanic / Latino participants in the placebo arm showed an 11.3 mmHg reduction in SBP. Female Hispanic subjects randomized to placebo (N=14) had an 18.1 mmHg reduction in SBP compared with a 7.1 mmHg reduction among female, non-Hispanic subjects (N=55). While placebo effects are commonly observed in clinical trials, a mean change of -18.1 mmHg is highly unusual (Tables 15A and 15B).

[0152] [Table 17]

[0153] [Table 18]

[0154] Pharmacodynamic evaluation Blood and urine samples were collected to determine pharmacodynamic parameters related to baxdrostat's mechanism of aldosterone suppression. Serum concentrations of aldosterone, excreted aldosterone in 24-hour urine collections, plasma renin activity (PRA), and serum cortisol are summarized by dose and study day, as shown in Figures 3A-3D. Pharmacodynamic results demonstrated a decrease in serum aldosterone concentrations (Figure 3A), a decrease in aldosterone excretion in 24-hour urine samples (Figure 3B), and an increase in PRA (Figure 3C) associated with baxdrostat treatment, without significantly affecting total cortisol concentrations (Figure 3D). These data indicated that treatment with baxdrostat resulted in a mean 50%-60% decrease in serum aldosterone, a significant decrease in urinary aldosterone excretion, and a several-fold increase in PRA, but not a decrease in total serum cortisol. These hormonal data provide strong biochemical evidence supporting a mechanism by which baxdrostat's inhibition of aldosterone synthesis significantly affects blood pressure levels without reducing serum cortisol levels.

[0155] Because substantial differences in the treatment effect on SBP were observed between male and female patients, we investigated potential differences in response to baxdrostat treatment by comparing serum aldosterone concentrations and PRA. Figures 4A and 4B show that aldosterone suppression and renin activity enhancement were comparable between male and female patients, suggesting that exogenous factors may have contributed to the unusually high placebo response in female populations, particularly those of Hispanic ethnicity.

[0156] Treatment-emergent AEs and SAEs Administration of once-daily baxdrostat for 12 weeks was well tolerated. 120 of 274 patients (43.8%) experienced a total of 232 TEAEs (Table 16). A higher percentage of patients experienced TEAEs in the 1 mg (52.2%) and 2 mg (47.8%) dose groups compared with the 0.5 mg (34.8%) or placebo (40.6%) groups. The most frequent TEAEs experienced by 5% or more patients in any treatment group were urinary tract infection, hyperkalemia, dizziness, headache, and fatigue. Most TEAEs were mild in severity (62.5%) and considered unrelated to study drug by the investigator (89.2%).

[0157] [Table 19]

[0158] TEAEs that occurred more frequently in ≥2% of patients in the 2 mg or 1 mg group compared with the placebo group are shown in Table 17. These events may be related to the decrease in blood pressure (e.g., dizziness, syncope, palpitations) or the mechanism of action of the study drug (i.e., hyperkalemia, hyponatremia, renal dysfunction). More patients in the baxdrostat 1 mg or 2 mg group experienced urinary tract infections and COVID-19, but no causal relationship was identified.

[0159] [Table 20]

[0160] Ten patients experienced 18 treatment-emergent serious adverse events (TESAEs) (Table 18). There were no deaths in the study, and all SAEs were assessed by the investigator as unrelated to baxdrostat. A 72-year-old Caucasian male subject with suspected urosepsis in the 2 mg dose group experienced six SAEs on Day 15 of the study: acute kidney injury, urinary tract infection, dehydration, hyperglycemia, hyperkalemia, and hyponatremia. These events were assessed as unrelated to baxdrostat, and the patient discontinued participation in the study due to these metabolic abnormalities. Three patients each experienced two SAEs: a patient in the 1 mg dose group with pyelonephritis and kidney stones, a patient in the 2 mg dose group with respiratory failure and cellulitis, and a third patient receiving placebo with pyelonephritis and pneumonia. All other SAEs were experienced by a single patient.

[0161] [Table 21]

[0162] Adverse Events of Special Interest (AESI) In this study, adverse events of particular interest (AESIs) were events of hypotension, low sodium levels, or high potassium levels requiring clinical intervention. A total of 10 AESIs were distributed among the treatment arms of 8 patients: placebo (0), 0.5 mg (1), 1 mg arm (5), and 2 mg arm (2). In cases of hyperkalemia or hyponatremia, close follow-up was protocol mandated, and recommendations for dietary or hydration interventions were made by the study team to the investigator upon recognition of laboratory abnormalities.

[0163] The only AESI of hypotension occurred in a patient in the 1 mg baxdrostat dose group; the hypotension resolved after discontinuation of the study drug. There were three AESIs of hyponatremia or hyponatremia. One patient in the 2 mg dose group with suspected urosepsis (described above) experienced six SAEs: acute kidney injury, urinary tract infection, dehydration, hyperglycemia, hyperkalemia, and hyponatremia; he discontinued the study due to an adverse event. Another patient randomized to the 1 mg baxdrostat group had a moderately severe hyponatremic AESI related to the study drug; the patient's study drug and diuretics were permanently discontinued. These events resolved. The third and final patient receiving 1 mg baxdrostat experienced hyponatremia of 129 mEq / L at nadir. The study drug was interrupted and then resumed. The AESI was moderately severe, study drug-related, and resolved.

[0164] Of the six AESIs with hyperkalemia, two are discussed above. None were associated with ECG changes or hospitalization. All patients with hyperkalemia were receiving other medications known to be associated with hyperkalemia (e.g., beta-blockers or ACEIs), and no patients discontinued the study specifically because of hyperkalemia.

[0165] Serum electrolytes Aldosterone plays a direct role in the pathogenesis of hypertension by increasing renal absorption of sodium and water while promoting potassium excretion. Therefore, aldosterone synthesis inhibitors may cause the electrolyte abnormalities of hyperkalemia or hyponatremia. Furthermore, the expected reduction in SBP with aldosterone inhibitors reduces blood flow through the afferent renal arterioles, resulting in a significant decrease in the eGFR determination. These potential disruptions in renal physiology were closely monitored throughout this study via measurements of serum electrolytes and eGFR.

[0166] The overall change in serum potassium from baseline to the end of treatment was a mean (standard deviation) of -0.08 (0.429) mEq / L in the placebo group, and in the baxdrostat groups, it increased by 0.19 (0.474) mEq / L in the 0.5 mg dose group, 0.36 (0.481) mEq / L in the 1 mg dose group, and 0.29 mEq / L (0.380) in the 2 mg dose group ( Figure 5 ).

[0167] There were three patients with moderate hyperkalemia (potassium >6.0 mEq / L) in the two highest dose groups, for an overall rate of 2.2%. The rate for spironolactone in the PATHWAY-2 trial was 2.1%. Hyperkalemia typically represented isolated events that resolved after dietary advice and without modification of study drug administration.

[0168] Hypokalemia is a known complication of diuretic therapy, which was required for study participation. Hypokalemia was defined as mild (potassium 3.5-3.1 mEq / L), moderate (potassium 3.0-2.5 mEq / L), and severe (<2.5 mEq / L). There were two patients with moderate hypokalemia in the placebo group; there were no cases in either baxdrostat dose group. The absence of moderate hypokalemia in any baxdrostat-treated patient suggests that the use of baxdrostat may provide protection from potential thiazide diuretic-induced hypokalemia.

[0169] Similarly, baxdrostat treatment was associated with a slight decrease in serum sodium concentration. The range of sodium decreases from baseline to the end of treatment was mean (SD) -1.2 (2.73) mEq / L in the 0.5 mg dose group, -1.1 (3.03) mEq / L in the 1 mg dose group, and -2.4 mEq / L (2.94) in the 2 mg dose group, which did not pose significant clinical problems (Figure 6). Ten patients developed mild hyponatremia, defined as a serum sodium below 130 mEq / L: one in the placebo group, one in the 0.5 mg baxdrostat group, seven in the 1 mg baxdrostat group, and one in the 2 mg group. Four patients, including one in the placebo group, discontinued the study prematurely. Over the course of the study, the investigators noted that sodium was also easily corrected with fluid management advice and that no discontinuations from low serum sodium levels occurred after the midpoint of the study.

[0170] During the study, baxdrostat treatment was associated with a mild, dose-dependent decrease in mean eGFR change associated with baxdrostat administration (Figure 7). Clinical outcomes revealed three cases of renal dysfunction in the 1 mg baxdrostat dose group, one in the 2 mg dose group, and no cases in the 0.5 mg dose group. All patients recovered. Overall, the slight decrease in eGFR seen in the figure is consistent with the renal hemodynamic effects observed with all classes of RAAS inhibitors, particularly aldosterone antagonists such as spironolactone, which are sometimes fully reversible. There was no clear relationship between baxdrostat dose and serum calcium, serum phosphorus, or serum phosphorus levels.

[0171] Summary of safety profile Study 121 demonstrated that baxdrostat at doses of 0.5 mg, 1 mg, and 2 mg was safe and well tolerated. There were no deaths in this study. The majority of TEAEs were mild, and more than 89% were considered unrelated to the study drug. Of 18 SAEs in 10 patients, only 2 patients discontinued due to an SAE, and all SAEs were considered unrelated to the study drug by the investigator.

[0172] Initially, there were some study discontinuations due to loss to follow-up or patient decision in the higher-dose baxdrostat group and none in the placebo group, but this imbalance between treatment groups resolved later in the study, suggesting that discontinuations were more likely due to external factors rather than related to baxdrostat.

[0173] Regarding electrolytes and renal function, the rates of hyperkalemia and hyponatremia were predicted based on the mechanism of action of baxdrostat. Baxdrostat treatment was associated with a decline in mean eGFR that was expected given experience with aldosterone inhibitors and the mechanism of action of baxdrostat.

[0174] conclusion Results from Study 121 demonstrated that 1 mg and 2 mg doses of baxdrostat were effective in lowering SBP in patients with rHTN. The placebo-corrected changes (standard error) after 12 weeks of treatment of -11.0 (2.78) mmHg and -8.1 (2.7) mmHg in the 2 mg and 1 mg dose groups, respectively, were statistically significant and clinically meaningful in this difficult-to-treat population. Treatment with 2 mg baxdrostat significantly reduced DBP by 5.2 mmHg compared with the placebo group.

[0175] Data from Study 121 demonstrate that baxdrostat can lower aldosterone levels in a resistant hypertensive population, resulting in substantial SBP reductions at both the 1 mg / day and 2 mg / day doses, with a favorable overall safety and tolerability profile. The study further demonstrated that mean serum cortisol levels were not reduced by baxdrostat treatment, and there were no reported cases of adrenal insufficiency during the trial. These results support drug development, as nonselective inhibition of CYP11B1, the enzyme involved in cortisol synthesis, has been a major barrier to previous efforts to develop aldosterone synthase inhibitors for the treatment of hypertension.

[0176] Example 9: Study in patients with uncontrolled hypertension Study 124 was a double-blind, placebo-controlled, dose-ranging, multicenter study conducted in patients with uHTN receiving background antihypertensive medications: an ACEI or ARB, an ACEI / ARB plus a thiazide diuretic, or an ACEI / ARB plus a calcium channel blocker. The study consisted of two parts. Part 1 consisted of an 8-week treatment period, during which patients were equally assigned to one of four dose groups testing the effects of 0.5 mg, 1 mg, and 2 mg of baxdrostat compared with placebo. Patients received double-blind baxdrostat tablets once daily while continuing to receive their background antihypertensive medication. After 8 weeks of double-blind treatment, patients were assigned to the 2 mg group and entered Part 2 of the study unless their SBP remained ≥130 mmHg. In Part 2 of the study, all patients discontinued their background antihypertensive medications and received only the 2 mg dose of baxdrostat as monotherapy for 4 weeks.

[0177] Patient demographics and baseline characteristics are shown in Tables 19-21.

[0178] [Table 22]

[0179] [Table 23]

[0180] [Table 24]

[0181] The primary objectives generally include (i) whether baxdrostat works in patients with uHTN, (ii) what dose produces strong BP reductions, and (ii) whether there are subgroups of patients who respond better than others, and if so, (a) whether response as defined by background BP influenced, (b) whether aldosterone or renin levels predicted response, and (c) whether demographic or racial / ethnic characteristics contributed to response.

[0182] The primary objective of the trial is to demonstrate that at least one dose strength of baxdrostat is superior to placebo in the change from baseline in mean sitting SBP after 8 weeks of treatment in these patients (Part 1 of the trial).

[0183] Secondary objectives are to assess the change from baseline in mean sitting DBP with each selected dose strength of baxdrostat compared to placebo after 8 weeks of treatment (Part 1), the change from baseline in 24-hour urinary aldosterone and serum aldosterone levels with each selected dose strength of baxdrostat compared to placebo after 8 weeks of treatment (Part 1), the percentage of patients achieving a mean sitting SBP <130 mmHg with each selected dose strength of baxdrostat compared to placebo after 8 weeks of treatment ("responders"), and the change from baseline in 24-hour urinary renin and serum renin levels with baxdrostat compared to placebo after 8 weeks of treatment. Patients who complete Part 2 by Week 12 or who are considered to have discontinued at the end of Part 1 may be eligible to participate in a separate open-label extension study (Study 130). Part 2 is an exploratory phase of the study designed to evaluate the effects of 4 weeks of monotherapy with 2 mg of baxdrostat in this hypertensive population, but the primary goal of the Part 2 period is to transition patients into a long-term, open-label, safety extension study of the highest dose of baxdrostat likely to be used in this hypertensive population.

[0184] Safety objectives for both Parts 1 and 2 are to evaluate vital signs, orthostatic blood pressure, heart rate, physical examination, ECG, weight, and clinical laboratory assessments including a standard safety chemistry panel, hematology, coagulation, and urinalysis.

[0185] Key inclusion criteria included patients receiving a stable regimen of antihypertensive medication for at least 8 weeks and having a sitting BP ≥ 140 mmHg. Key exclusion criteria included a sitting SBP ≥ 180 mmHg and an estimated glomerular filtration rate (eGFR) < 30 mL / min / 1.73 m 2 Includes:

[0186] A. Initial Results A total of 249 patients were enrolled in the study, 91 completed the 12-week evaluation, and 16 discontinued early. Reasons for early discontinuation included consent withdrawal (n=7), loss to follow-up (n=1), hypertension (n=1), need for prohibited medications (n=1), failure to meet criteria for Part 2 (n=3), failure to meet eligibility criteria (n=1), and adverse events (n=2). 90 patients consented to continue in the open-label extension study.

[0187] Mean blood pressure (average of three office blood pressure measurements) was 147 mmHg at baseline, although patients were receiving stable regimens of up to two antihypertensive medications. Total-blinded SBP, including data from the placebo and active baxdrostat groups, demonstrated a progressive reduction in SBP over the 8 weeks of treatment in Part 1, from a baseline of 147 mmHg to 128 mmHg at Week 8 (Figure 8). The 18 mmHg SBP reduction was similar to the total change of approximately 16 mmHg observed in Study 121. Interestingly, mean blood pressure did not increase substantially in Part 2 of the study, even when patients discontinued background antihypertensive medications when baxdrostat was the only study drug they were taking.

[0188] B. Intermediate results (i) Part 1 To date, 249 patients have been randomized, with 227 completing the 8-week assessment, 201 completing the 12-week assessment, and 175 completing the 12-week assessment and the 2-week follow-up period. See Figures 13 and 14. Reasons for discontinuation are listed in Table 22.

[0189] [Table 25]

[0190] The results of the primary efficacy endpoint are shown in Table 23.

[0191] [Table 26]

[0192] In this table, CI = confidence interval, DBP = diastolic blood pressure, LS = least squares, SBP = systolic blood pressure, SE = standard error. LS means, CIs, and p-values are from an MMRM model with change from baseline as the dependent variable and randomized treatment, visit, and treatment-by-visit interaction as fixed categorical effects. Covariates include baseline value, race (African American vs. non-African American), and type of background antihypertensive regimen. A restricted maximum likelihood (REML) approach is used with an unstructured covariance matrix and Kenward-Roger approximation for degrees of freedom.

[0193] The LS mean change from baseline in SBP based on weeks of treatment is shown in Table 24.

[0194] [Table 27]

[0195] The data also showed that patients in the placebo arm had a greater reduction in SBP after randomization, particularly between weeks 6 and 8. See Figure 16. Although the primary endpoint was not met (Figure 14), there was a substantial reduction in SBP in the non-Hispanic / Latino population. See Figure 15.

[0196] Hispanic / Latino patient subgroup After unblinding, it was confirmed that no placebo patients received active medication. Also note that for the 2 mg dose (n=57), 19 / 35 Hispanic patients and 1 non-Hispanic patient were determined to be non-adherent based on PK. For the 1 mg dose (n=57), 7 / 28 Hispanic patients and 2 non-Hispanic patients were determined to be non-adherent based on PK. Table 25A and Figure 25B show subgroup analyses.

[0197] [Table 28]

[0198] [Table 29]

[0199] The results also confirmed the lack of response among Hispanic women. See Tables 26A-26B and Figures 27A-27B.

[0200] [Table 30]

[0201] [Table 31]

[0202] [Table 32]

[0203] [Table 33]

[0204] The responses of Hispanic males were less robust than the responses of non-Hispanic males. See Tables 28A-28B and Figures 29A-29B.

[0205] [Table 34]

[0206] [Table 35]

[0207] [Table 36]

[0208] [Table 37]

[0209] The results were further analyzed to determine drug efficacy in adherent Hispanic patients. See Figure 30.

[0210] [Table 38]

[0211] Results showed that baxdrostat (2 mg) was effective in adherent Hispanic / Latino patients, but the efficacy response was significantly lower.

[0212] Black / African American subgroup The Black / African American subgroup was also analyzed and 2 mg of baxdrostat was found to be effective. See Tables 31A and 31B.

[0213] [Table 39]

[0214] [Table 40]

[0215] Aldosterone changes by ethnicity The effect of ethnicity on aldosterone change was analyzed. Baseline values are shown in Table 32. See also Figure 17.

[0216] [Table 41]

[0217] Plasma renin activity by ethnicity The effect of ethnicity on plasma renin activity (PRA) was analyzed. Baseline values are shown in Table 33. See also Figure 18.

[0218] [Table 42]

[0219] safety results Safety results indicate that baxdrostat offers a remarkable safety profile. There were two treatment-emergent SAEs (two patients), neither of which were considered related to baxdrostat. An 81-year-old man died of an unrelated SAE of acute respiratory failure after being diagnosed with COVID-19 30 days after his last baxdrostat dose. See Figure 34.

[0220] [Table 43]

[0221] Additionally, there were no cases of hyperkalemia in baxdrostat recipients leading to study discontinuation and off-target side effects.

[0222] The rate of hyperkalemia was also found to be low and isolated. There was an overall small increase in mean potassium of 0.1 mEq / L at the 2 mg dose. See Tables 35-36 and Figure 19.

[0223] [Table 44]

[0224] [Table 45]

[0225] Three patients receiving baxdrostat (approximately 1.6% of patients receiving baxdrostat) experienced isolated cases of moderately elevated potassium >6 mEq / L. This rate of moderate hyperkalemia was identical to the PBO rate of 1.6% and compares favorably with previous results of 2.1%. The mean potassium increase of 0.1 mEq / L in the 2 mg dose group was consistent with the small potassium increase previously observed in the 2 mg group. No potassium increases greater than 6.2 mEq / L were recorded in baxdrostat patients, and no patients completed the study with moderate hyperkalemia. There were no cases of hyperkalemia leading to study discontinuation among patients in the active baxdrostat group.

[0226] (i) Part 2 Results Part 2 showed that baxdrostat (2 mg) was safe and well tolerated in the 213 patients who participated in Part 2. Fourteen patients who completed Part 1 did not participate in Part 2, 12 of whom were ineligible based on a BP <130 mmHg.

[0227] In Part 2, background antihypertensive therapy was discontinued after Part 1, and patients received 2 mg of baxdrostat for an additional 4 weeks. SBP remained stable on 2 mg of baxdrostat alone when compared at the beginning and end of the 4-week period after discontinuation of background medication. There were two cases of moderate hyperkalemia (K+ > / = 6.0 mEq / L) among 213 patients in Part 2. Both patients discontinued diuretics at the start of Part 2 and developed transient moderate hyperkalemia within 2 weeks.

[0228] Safety Profile All Part 2 patients were assumed to be receiving 2 mg of baxdrostat. The results of Part 2 highlight that baxdrostat provides a notable safety profile at the 2 mg dose. See Figure 37.

[0229] [Table 46]

[0230] Treatment-emergent serious adverse events (SAEs): 4 events / 3 patients, none considered related to baxdrostat. There were no cases of hyperkalemia in baxdrostat recipients leading to study discontinuation. There were also no off-target adverse events.

[0231] C. Summary of Results In summary, the top-line efficacy primary endpoint was not met due to disparate responses in the Hispanic / Latino cohort, which represented more than 50% of the study population. However, a pre-specified non-Hispanic analysis provided the ability to salvage the study data.

[0232] Results were encouraging in other subgroups, including Black / African American patients and non-Hispanic women.

[0233] Overall safety data were favorable, with low rates of hyperkalemia.

[0234] Example 10: Study in patients with uncontrolled hypertension and chronic kidney disease Study 123 is a randomized, double-blind, placebo-controlled, multicenter, parallel-group, dose-ranging study to evaluate baxdrostat for the treatment of patients with uHTN and CKD. The primary objective of the study is to evaluate the therapeutic effect of baxdrostat on SBP compared with placebo at 26 weeks. Secondary objectives are to evaluate the effect of baxdrostat on SBP compared with placebo using a high-dose or low-dose strategy, determine the percentage of patients achieving an SBP <130 mmHg, assess the change from baseline in urinary albumin-to-creatinine ratio (UACR), assess the change from baseline in DBP with each dose strategy, and assess the change from baseline in eGFR after 26 weeks of treatment. Safety objectives include assessing vital signs, orthostatic BP and heart rate, physical examination, electrocardiography, weight measurement, and clinical laboratory assessments including a standard safety chemistry panel, hematology, coagulation, and urinalysis. Approximately 300 patients are planned to be enrolled at 70 clinical sites across the United States.

[0235] Male and female adult patients with uHTN and mild to severe CKD will be recruited in this study. Patients with uHTN are defined as those taking a stable dose of an antihypertensive ACEI / ARB and having a clinic SBP of ≥140 mmHg or ≥130 mmHg for diabetes. Patients with mild to severe CKD will have a blood pressure of 25-75 mL / min / 1.73 m on at least two of three measurements based on the first urine collected in the morning on consecutive days during the screening period. 2 Patients were defined as having an eGFR (based on the CKD-EPI equation) of ≥ 200 mg / g (≥ 22.6 mg / mmol) and a UACR of ≥ 200 mg / g (≥ 22.6 mg / mmol). Patients taking MRAs must agree to discontinue MRA administration to be eligible to begin a 2-week run-in period in which they take a single-blind placebo tablet once daily while continuing their background antihypertensive medication. Patients who remain eligible will be randomized to one of three treatment arms: placebo, low-dose strategy, or high-dose strategy, and will begin a 26-week treatment period.

[0236] Patients assigned to the low-dose strategy arm will receive baxdrostat 0.5 mg once daily. If patients do not experience hyperkalemia, hyponatremia, or a significant decline in renal function based on laboratory testing of samples collected at week 1, and if mean sitting SBP is ≥ 130 mmHg at week 3, the dose level may be gradually increased to 1 mg at week 3. If patients experience hyperkalemia, hyponatremia, or a decline in renal function based on laboratory testing of samples collected at week 5, the dose may be gradually decreased 6 weeks after randomization. After week 6, no further dose escalation is permitted. The study design is shown in Figure 9.

[0237] Example 11 A. Study Design (i) Overall design This is a Phase III multicenter, randomized, double-blind, placebo-controlled, parallel-group study evaluating the safety, tolerability, and efficacy of 1 mg or 2 mg baxdrostat administered orally QD versus placebo in reducing SBP in approximately 720 participants aged 18 years or older with HTN, despite a stable regimen of two antihypertensive medications at baseline, one of which is a diuretic (uHTN), or three or more antihypertensive medications at baseline, one of which is a diuretic (rHTN).

[0238] Consented participants will be screened within 4 weeks and then enter a 2-week single-blind run-in period using placebo. Participants will then be consecutively distributed into two cohorts (Cohort 1 and Cohort 2) and randomized 1:1:1 to receive one of the following three treatments QD during the 12-week double-blind period: 2mg baxdrostat 1mg baxdrostat Placebo

[0239] Randomization will be stratified by baseline HTN (uHTN, rHTN) and baseline SiSBP (<145 mmHg, ≥145 mmHg).

[0240] After participants in both cohorts completed the 12-week double-blind period, Participants who complete treatment with 2 mg baxdrostat will be randomized 1:0 to receive 2 mg baxdrostat QD during the 12-week open-label period. Participants who completed treatment with 1 mg baxdrostat were randomized in a 4:1 ratio to receive either 2 mg baxdrostat QD (Weeks 12-24) or standard of care during a 12-week open-label period. The standard of care period lasted 40 weeks (Weeks 12-52) for participants in Cohort 1 and 12 weeks (Weeks 12-24) for participants in Cohort 2. Participants receiving placebo will be randomized in a 1:4 ratio to receive 2 mg of baxdrostat QD (from weeks 12 to 24) during a 12-week open-label period or standard of care.

[0241] After participants completed the 12-week open-label period with 2 mg of baxdrostat, Cohort 1 participants (those who completed treatment with 2 mg baxdrostat) will undergo a third randomization in a 2:1 ratio to either continue receiving 2 mg baxdrostat QD or placebo QD during the 8-week double-blind RWD period. Randomization will be stratified by baseline HTN (uHTN, rHTN) and by SiSBP (<130 mmHg, ≥130 mmHg) at RWD randomization. Participants who completed the RWD period will then enter the open-label period, receiving 2 mg baxdrostat QD for 20 weeks, followed by a 2-week safety follow-up period. Cohort 2 participants will begin a 2-week safety follow-up period.

[0242] Study diagrams for both cohorts are shown in Figures 24 and 25. If participants were to receive K + If a level >5.5 mEq / L is reported, the laboratory analysis should be repeated within 72 hours. This study is planned to be conducted worldwide.

[0243] (ii) Screening All participants who agree to be involved in the study will be screened within four weeks prior to starting the run-in period.

[0244] (iii) Placebo single-blind run-in period Eligible participants who complete the screening visit procedures will enter a two-week single-blind run-in period in which they will receive a placebo in addition to any existing background antihypertensive medication intervention.

[0245] The purpose of this period is to allow post-baseline placebo effects to diminish and to ensure that participants have stable background antihypertensive medication.

[0246] (iv) a double-blind, placebo-controlled treatment period Approximately 720 participants who meet the study inclusion criteria will be sequentially distributed into two cohorts (approximately 450 participants in Cohort 1 and 270 participants in Cohort 2). Participants in each cohort will be randomized in a 1:1:1 ratio to receive one of three study treatments: 2 mg baxdrostat, 1 mg baxdrostat, or placebo QD. Participants will receive this treatment for 12 weeks (Weeks 0 to 12).

[0247] During this period, participants should continue their background antihypertensive medication regimen and dose. Background antihypertensive medication doses should not be changed during this period unless the participant experiences an SBP <100 mmHg with symptoms of hypotension.

[0248] (v) Open-label treatment period All participants in Cohort 1 and Cohort 2 who completed the 12-week double-blind treatment period with 2 mg baxdrostat QD will be randomized 1:0 at the start of the open-label period to continue receiving 2 mg baxdrostat QD for 12 weeks (Weeks 12-24).

[0249] Participants in cohorts 1 and 2 who received 1 mg baxdrostat QD or placebo QD during the 12-week double-blind period will be randomized in a 4:1 or 1:4 ratio, respectively, to receive either 2 mg baxdrostat or standard of care.

[0250] (vi) Baxdrostat All participants randomized to 2 mg baxdrostat at week 12 will receive 2 mg baxdrostat in an open-label fashion for 12 weeks (weeks 12-24) in addition to any existing background antihypertensive medications that are changed during this open-label period (excluding the addition of MRAs and potassium-sparing diuretics, which are not permitted).

[0251] Approximately 300 participants in Cohort 1 and approximately 180 participants in Cohort 2 will receive 2 mg of baxdrostat during this period.

[0252] Participants with hyperkalemia will also be directed to follow treatment discontinuation criteria and adhere to local standard of care.

[0253] (vii) Standard of care Approximately 150 participants in Cohort 1 and approximately 90 participants in Cohort 2 will be randomized to receive standard of care in an open-label fashion. Participants in Cohort 1 will receive this care for 40 weeks (weeks 12 to 52, see Figure 24), and participants in Cohort 2 will receive this care for 12 weeks (weeks 12 to 24, see Figure 25). After completing this period of standard of care, participants will enter a 2-week safety follow-up period before completing the full study.

[0254] (viii) Randomized Treatment Withdrawal Double-Blind Period - Cohort 1 Participants Only All participants in Cohort 1 who completed the 12-week open-label treatment period with 2 mg baxdrostat will be re-randomized in a 2:1 ratio at Week 24 to continue receiving 2 mg baxdrostat QD or placebo QD during the 8-week double-blind withdrawal period (Weeks 24-32). The randomized control group will be stratified by baseline HTN (uHTN, rHTN) and SBP (≤130 mmHg, >130 mmHg) at RWD randomization. Approximately 200 participants will be randomized to 2 mg baxdrostat and 100 participants will be randomized to placebo.

[0255] During this period, participants should continue the same background antihypertensive medication regimen and dose as they received at the beginning of this period. Background antihypertensive medication doses should not be changed during this period unless the participant experiences an SBP <100 mmHg along with symptoms of hypotension.

[0256] Mineralocorticoid receptor antagonists and potassium-sparing diuretics are prohibited during this period.

[0257] (ix) Second open-label period in Cohort 1 Cohort 1 participants who completed the 8-week RWD double-blind period entered the 20-week open-label period (Weeks 32-52) during which they received 2 mg of baxdrostat QD in addition to any existing background antihypertensive medication. During this period, participants' background therapy could be changed, but MRAs or potassium-sparing diuretics were not permitted.

[0258] (x) Safety Follow-up All study participants will complete a 2-week safety follow-up period before exiting the full study. Participants in Cohort 1 will enter this final study period after completing a 20-week open-label period or a 40-week standard-of-care period, and participants in Cohort 2 will enter this period after completing a 12-week open-label period.

[0259] (xi) Definition of end of test For clinical trial transparency purposes, the definition of end of trial differs under FDA and EU regulatory requirements. • European Union requirements define study completion as the last subject's last visit for any protocol-related activity. ●Food and Drug Administration requirements define two completion dates: - Primary Completion Date - The date on which the last participant is examined or receives the intervention for the purpose of final collection of data for the primary outcome measure, regardless of whether the clinical trial is completed according to the pre-specified protocol or discontinued. In the case of clinical trials with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all primary outcomes. Study Completion Date - The date on which the last participant is examined or receives the intervention for the purposes of final collection of data for primary and secondary outcome measures and AEs (e.g., last clinic visit for the last participant), regardless of whether the clinical trial is completed according to the pre-specified protocol or discontinued.

[0260] A participant is considered to have completed the study if they have completed all phases of the study, including the last visit or last scheduled procedure. The end of the study is defined globally as the date of the last visit of the last participant in the study or the date of the last scheduled procedure for the last participant in the study.

[0261] B. Study Population (i) Inclusion criteria Participants were eligible for inclusion in the study only if all of the following criteria applied:

[0262] age 1. Male or female participants must be 18 years of age or older at the time of signing the informed consent.

[0263] Participant type and disease characteristics 2. Mean siSBP ≥ 140mmHg and < 170mmHg for AOBPM at screening. 3. Meet at least one of the following two criteria: (a) Participants in the uHTN subpopulation: Have a stable regimen of two antihypertensive medications from different therapy classes (at least one of which should be a diuretic) at the maximally tolerated dose for at least 4 weeks prior to screening. Beta-blockers used to treat other conditions (i.e., migraine, HF, coronary artery disease) should not be counted as antihypertensive medications. (b) Participants in the rHTN subpopulation: Have a stable regimen of three or more antihypertensive medications from different therapy classes (at least one of which should be a diuretic) at the maximally tolerated dose for at least 4 weeks prior to screening. Beta-blockers used to treat other conditions (i.e., migraine, HF, coronary artery disease) should not be counted as antihypertensive medications. 4. Performing DOT during Visit 2 demonstrated good adherence to prescribed antihypertensive medication. 5. Estimated glomerular filtration rate at screening ≥ 45 mL / min / 1.73 m 2 6. Serum potassium level (K + ) levels ≥ 3.5 and < 5.0 mmol / L. 7. Morning cortisol level (measured at 8:00 AM ± 2 hours) > 3 μg / dL.

[0264] (ii) Randomization criteria These randomization criteria apply only to the initial randomization of the study. A participant is eligible to be randomized to a treatment group only if all of the following criteria apply: 1. Mean siSBP ≥ 135 mmHg for inpatient clinic AOBPM at baseline (end of run-in period). 2. Have 80-120% adherence to placebo during the run-in period based on the number of pills taken in the morning of randomization. 3. No change in background therapy regimen and dose at least 4 weeks prior to randomization consisting of either two antihypertensive medications (at least one should be a diuretic) for participants in the uHTN subpopulation or three or more antihypertensive medications (at least one should be a diuretic) for participants in the rHTN subpopulation. Beta-blockers used to treat other conditions (i.e., migraine, HF, coronary artery disease) should not be counted as antihypertensive medications. 4. Performing DOT during Visit 2 demonstrated good adherence to prescribed antihypertensive medication.

[0265] (iii) Exclusion criteria Participants will be excluded from the study if any of the following criteria apply:

[0266] medical conditions 1. Mean siSBP for inpatient clinic AOBPM at randomization 1 ≥170 mmHg. 2. At randomization, mean sitting DBP for inpatient clinic AOBPM 2 ≥110 mmHg. 3. Current or previous treatment (within 4 weeks prior to screening) with angiotensin receptor blockers and ACEIs (both taken simultaneously). 4. Serum sodium level <135mmol / L at screening. 5. Known secondary causes of hypertension: renal artery stenosis, uncontrolled or untreated hyperthyroidism, uncontrolled or untreated hypothyroidism, pheochromocytoma, Cushing's syndrome, and aortic coarctation. 6. New York Heart Association functional HF class IV at screening. 7. History of stroke, acute coronary syndrome, hypertensive encephalopathy, or hospitalization for HF within 6 months prior to screening. 8. Planned percutaneous coronary intervention / coronary artery bypass grafting or percutaneous coronary intervention / coronary artery bypass grafting performed within 6 months prior to screening. 9. Currently known severe left ventricular outflow tract obstruction, e.g., obstructive hypertrophic cardiomyopathy and / or severe aortic valve disease. 10. Left bundle branch block and any cardiac rhythm abnormalities requiring treatment. 11. Persistent atrial fibrillation. 12. Known severe hepatic dysfunction defined as Child-Pugh class C based on records confirming documented medical history. 13. Uncontrolled diabetes with HbA1c > 10.0% (86 mmol / mol) at screening. 14. Baseline QTcF > 470 msec. 15. Family history of long QT syndrome. 16. Resting heart rate <45 or >110 beats / min. 17. Participants suspected of having severe cardiac hypertrophy. 18. Participants who are pregnant or breastfeeding. 19. Participants diagnosed with adrenal insufficiency. 20. Any of the following related to COVID-19 infection: (a) Suspected or confirmed COVID-19 infection within the last 4 weeks prior to screening or at the time of randomization. (b) hospitalization due to COVID-19 within the last 12 weeks before screening;

[0267] Upfront / concomitant therapy 21. Previous medical treatment with any MRA, antiarrhythmic medication, or potassium-sparing diuretics used within 4 weeks prior to screening. 22. Treatment with potassium binders within 2 months prior to screening. 23. Anticipated or current use of any excluded medications, such as strong inducers of cytochrome P450 (CYP) 3A, NSAIDs, chronic use of MRAs (taken more than three times a week for more than three months), and / or chronic use of systemic steroids. 24. Drugs that prolong the QT interval should be avoided if possible, and if alternatives that do not have the potential to produce QT dependence are available, these alternatives should be preferred. 25. Current or previous treatment within 6 months prior to screening with cytotoxic therapy. 26.K + Supplemental treatment is not prohibited, but should be serially evaluated and monitored through clinical trials.

[0268] Prior / concurrent clinical trial experience 27. Known hypersensitivity to baxdrostat or any of the drugs in the same class or its excipients. 28. Participation in another clinical trial in which an investigational product was administered within 3 months prior to randomization in this study.

[0269] others 29. Participant work shift (i.e., shifts involving work hours at different times on different days).

[0270] Participants can receive the study intervention with or without food.

[0271] C. Study Interventions and Concomitant Therapies (i) the study intervention to be administered The study treatments administered and investigated in this study are listed in Table 38.

[0272] [Table 47]

[0273] (ii) Background antihypertensive medication A stable regimen of background antihypertensive medication that the participant received when enrolled in the study and continues to receive after randomization to study treatment. Background antihypertensive medication may be changed during the open-label period, with the exception of the use of MRAs and potassium-sparing diuretics.

[0274] (iii) Treatment with standard of care Standard of care treatment was received by randomized participants during this study period. Standard of care treatment may be changed during the standard of care period. Allocation to study intervention

[0275] All participants who meet all eligibility criteria will be sequentially distributed into both cohorts (Cohort 1 and Cohort 2) and centrally assigned to the randomized trial intervention using an automated IRT / RTSM system that assigns participants to one of three different treatment groups. There will be a total of three randomization stages during the trial, which will be conducted using the IRT / RTSM system (see Figure 24). Approximately 720 participants (450 in Cohort 1 and 270 in Cohort 2) will be randomized after the run-in period using a 1:1:1 ratio to receive either 2 mg baxdrostat QD, 1 mg baxdrostat QD, or placebo QD. Randomization will be stratified by baseline HTN (uHTN, rHTN) and baseline siSBP (<145 mmHg, ≥145 mmHg). The second randomization will occur after the initial 12-week double-blind period. Approximately 480 participants (300 in Cohort 1 and 180 in Cohort 2) will be randomized to 2 mg baxdrostat, and 240 participants (150 in Cohort 1 and 90 in Cohort 2) will be randomized to standard of care. The randomization will be as follows: Participants who received 2 mg of baxdrostat during the first 12 weeks of treatment will be randomized in a 1:0 ratio to continue receiving 2 mg of baxdrostat QD. Participants who received 1 mg baxdrostat or placebo during the first 12 weeks of treatment will be randomized in a 4:1 or 1:4 ratio, respectively, to receive either 2 mg baxdrostat or standard of care. Cohort 1 participants only: After participants complete the 12-week open-label period with 2 mg baxdrostat QD (approximately 300 participants in Cohort 1), participants will undergo a third randomization in a 2:1 ratio to continue receiving 2 mg baxdrostat QD or placebo QD. These participants will be stratified by baseline HTN (uHTN, rHTN) and by siSBP (≤130 mmHg, >130 mmHg) at RWD randomization. Approximately 200 participants will be randomized to 2 mg baxdrostat QD and approximately 100 to placebo QD.

[0276] Randomization will be performed in fixed-size, balanced blocks. Randomization codes will be computer-generated and loaded into the IxRS database.

[0277] All randomization will be performed directly using the IRT / RTSM system. Randomization codes will not be reused.

[0278] The number of randomized participants in each HTN subpopulation (uHTN / rHTN) will be monitored to ensure that a minimum of approximately 40% of participants are enrolled in the uHTN or rHTN subpopulation. When a predetermined limit is reached, randomization may be capped (i.e., no more participants can be randomized in a particular subpopulation) to avoid over- or under-representation.

[0279] (iv) Dose modification Dose modifications of the investigational drug are not permitted in this study.

[0280] (v) Prohibited Concomitant Medications The medications and supplements listed below are prohibited during this study, except in the standard of care treatment group. Concurrent use of angiotensin receptor blockers and ACEIs is not permitted during the study. Participants should be on a stable dose of either medication class. Any changes to medication dose or class must be closely monitored. • Potassium-sparing diuretics (e.g., amiloride, triamsterene) and direct renin inhibitors (e.g., aliskiren). • Potassium binders (prohibited at screening but may be initiated as a corrective measure during the study). Tacrolimus, calcineurin inhibitors and cyclosporine. Topical / inhaled immunosuppressants are acceptable. • Mineralocorticoid receptor antagonists or aldosterone antagonists (e.g., eplerenone, finerenone, spironolactone). • Systemic corticosteroids in any dose (e.g., prednisone, prednisolone, dexamethasone [topical and inhaled steroids are acceptable]). ●K + Supplemental treatment is not prohibited, but should be serially evaluated and monitored through clinical trials. Chronic NSAID use. Occasional NSAID use is acceptable, but closer monitoring is warranted at these times. Strong CYP3A4 inducers (e.g., apalutamide, avasimibe, carbamazepine, enzalutamide, lumacaftor, mitotane, phenytoin, rifampin, rifapentine, St. John's wort).

[0281] (vi) Blood pressure measurement Sitting blood pressure measurement Sitting BP measurements are recorded using a standardized automated BP machine using the following standardized procedure. Participants should not exercise, smoke, or consume caffeinated beverages or foods 30 minutes before the AOBPM assessment. • At the time of the visit, if the study intervention is administered on-site, BP will be assessed prior to administration. • Blood pressure measurements should be obtained prior to ECG recording. For measuring BP by AOBPM, the following additional standardization steps are recommended: Participants must be seated in the testing room for at least 5 minutes with their backs leaning back, their feet flat on the floor, and the measuring arm supported so that the midpoint of the manometer cuff is at heart level. o Designated AOBPM devices must be provided to each clinical site and used for all study-related measurements. o An appropriately sized cuff should be used with the bladder centered over the brachial artery. ○ The cuff size and arm used for the measurement should be recorded. The arm with the higher mean BP value at screening should be used for screening and subsequent BP measurements. All BP measurements should be obtained at approximately the same time on the day that the screening measurements were obtained. Three sitting BP measurements (each approximately 1 minute apart) should be obtained using the same arm and AOBPM device at each clinical visit. Mean sitting BP is defined as the average of the last two sitting BP measurements out of a total of three measurements at any one clinical visit. If the difference between the last two SBP measurements is more than 20 mmHg, additional readings should be taken (up to six additional measurements, taken as three sitting BP readings taken twice). If the difference between the last two SBP measurements of these two additional triplicate measurements is still more than 20 mmHg, the average of the last two measurements is used. o Standing BP will be measured only at designated visits immediately after the sitting BP is determined.

[0282] Standing blood pressure measurement Orthostatic BP measurements, including orthostatic BP, are measured using AOBPM. The following standardized procedure is recommended: After the siSBP is determined, participants are asked to stand, if necessary, and approximately 1 minute later, a single standing BP measurement is obtained. Participants should not exercise, smoke, or consume caffeinated beverages or foods 30 minutes before the AOBPM assessment. • At the time of the visit, if the study intervention is administered on-site, BP will be assessed prior to administration. • Blood pressure measurements should be obtained prior to ECG recording. For measuring BP by AOBPM, the following additional standardization steps are recommended: o Designated AOBPM devices must be provided to each clinical site and used for all study-related measurements. o An appropriately sized cuff should be used with the bladder centered over the brachial artery. ○ The cuff size and arm used for the measurement should be recorded. The arm with the higher mean BP value at screening should be used for screening and subsequent BP measurements. All BP measurements should be obtained at approximately the same time on the day that the screening measurements were obtained.

[0283] (vi) Pharmacokinetics A pre-dose blood sample will be collected for measurement of baxdrostat plasma concentrations. All PK samples will be collected pre-dose. Therefore, participants should be reminded not to take their study medication at home on the day of their visit, as they will be taking the study medication at the clinic on that day.

[0284] For participants who discontinue investigational product due to hyperkalemia, PK samples should be collected at the EoT visit.

[0285] Sampling timing may be changed during a study based on newly available data (e.g., to obtain data closer to the peak or to obtain trough matrix concentrations) to ensure adequate monitoring.

[0286] Plasma samples will be used to analyze the PK of baxdrostat. Samples collected for analysis of plasma baxdrostat concentrations may also be used to evaluate safety or efficacy aspects related to concerns that arise during or after the study.

[0287] (viii) Pharmacodynamics ●Olink (registered trademark)

[0288] C. Objectives / Endpoints

[0289] [Table 48]

[0290] D. Primary estimand The primary estimand is described by the following attributes: Population: Participants with uHTN or rHTN as defined by the inclusion and exclusion criteria. Implemented by use of the FAS. ●Endpoint: Change from baseline in siSBP at 12 weeks. Treatment condition: stable regimen of 2 mg baxdrostat QD and background antihypertensive medications, or stable regimen of 1 mg baxdrostat QD and background antihypertensive medications. Intercurrent events: Intercurrent events of treatment discontinuation are handled via a treatment policy strategy, i.e., to confirm the treatment effect despite treatment discontinuation. Intercurrent events of rescue therapy are handled via a hypothetical strategy, i.e., to confirm the treatment effect if rescue therapy had not been initiated. Population-level summary: Difference in mean change from baseline between baxdrostat (2 mg or 1 mg separately) versus placebo over time to week 52.

Claims

1. 1. A method for treating hypertension in a human in need thereof, comprising administering 1 mg / day or 2 mg / day of (R)-Compound 1: 【Chemical 1】 to said human.

2. 2. The method of claim 1, wherein administration of 2 mg / day of the (R)-Compound 1 results in a reduction in the human's mean sitting systolic blood pressure (siSBP) compared to baseline at or after a 12-week treatment period compared to placebo.

3. 2. The method of claim 1, wherein administration of 1 mg / day of the (R)-Compound 1 results in a reduction in the human's mean sitting systolic blood pressure (siSBP) compared to baseline at or after a 12-week treatment period compared to placebo.

4. 4. The method of any one of claims 1 to 3, wherein the human is on a stable background antihypertensive regimen prior to said administration and during said treatment period.

5. The method of any one of claims 1 to 4, wherein (R)-Compound 1 is administered to said human in combination with two antihypertensive agents during said treatment period.

6. 5. The method of any one of claims 1 to 4, wherein (R)-Compound 1 is administered to said human in combination with three antihypertensive agents during said treatment period.

7. The method of any one of claims 1 to 4, wherein (R)-Compound 1 is administered to said human in combination with at least three antihypertensive agents during said treatment period.

8. The method according to any one of claims 1 to 7, wherein the hypertension is uncontrolled hypertension.

9. 9. The method of claim 8, wherein the stable background antihypertensive regimen comprises at least two antihypertensive medications.

10. The method according to any one of claims 1 to 7, wherein the hypertension is treatment-resistant hypertension.

11. 11. The method of claim 10, wherein the stable background antihypertensive regimen comprises at least three antihypertensive medications.

12. 12. The method of claim 9 or 11, wherein one antihypertensive medication is a diuretic.

13. The person has a blood pressure of 45 mL / min / 1.73 m before the administration ２ The method according to any one of claims 1 to 12, wherein the patient has an estimated glomerular filtration rate of at least 100 mg / kg.

14. 14. The method of any one of claims 1 to 13, wherein the human has a mean sitting systolic blood pressure (siSBP) of 140 mmHg or greater and 170 mmHg or less prior to said administering.

15. 15. The method of claim 14, wherein the human has a siSBP of less than 145 mmHg prior to the administration.

16. 15. The method of claim 14, wherein the human has a siSBP of 145 mmHg or greater prior to the administration.

17. 17. The method of any one of claims 1 to 16, wherein the human has a serum potassium level greater than or equal to 3.5 mmol / L and less than 5.0 mmol / L prior to said administering.

18. 18. The method of any one of claims 1 to 17, wherein the human has a morning cortisol level greater than 3 μg / dL prior to said administering.

19. 19. The method of any one of claims 1-18, wherein the administration results in a reduction compared to baseline in sitting systolic blood pressure (siSBP) at or after a 24-week treatment period compared to placebo.

20. 20. The method of any one of claims 1-19, wherein the administration results in a reduction compared to baseline in sitting diastolic blood pressure (siDBP) at or after a 12-week treatment period compared to placebo.

21. 21. The method of any one of claims 1-20, wherein the administration results in a reduction compared to baseline in 24-hour ambulatory mean diastolic blood pressure (DBP) at or after a 12-week treatment period compared to placebo.

22. 22. The method of any one of claims 1-21, wherein said administering results in a sitting systolic blood pressure (siSBP) of less than 130 mmHg after a 12 week treatment period.

23. 23. The method of any one of claims 1-22, wherein the administration results in a reduction compared to baseline in 24-hour ambulatory mean systolic blood pressure (SBP) at or after a 12-week treatment period compared to placebo.

24. 24. The method of any one of claims 1 to 23, comprising administering 1 mg / day of (R)-Compound 1 to the human.

25. 25. The method of claim 24, wherein said administration results in a decrease of about 8 mmHg in mean sitting systolic blood pressure of said human at or after 12 weeks of treatment compared to baseline.

26. 25. The method of claim 24, wherein said administration results in a greater than 8 mmHg reduction in mean sitting systolic blood pressure of said human at or after a 12 week treatment period compared to baseline.

27. 24. The method of any one of claims 1 to 23, comprising administering 2 mg / day of (R)-Compound 1 to the human.

28. 28. The method of claim 27, wherein said administration results in a decrease of about 11 mmHg in mean sitting systolic blood pressure for said human at or after 12 weeks of treatment compared to baseline.

29. 28. The method of claim 27, wherein said administration results in a reduction in mean sitting systolic blood pressure of greater than 11 mgHg in said human at or after a 12 week treatment period compared to baseline.

30. 30. The method of any one of claims 1 to 29, wherein administration is oral.

31. The method of any one of claims 1 to 30, wherein the (R)-Compound 1 is administered in a tablet.

32. 32. The method of claim 31 , wherein the tablet contains 1 mg of (R)-Compound 1.

33. 32. The method of claim 31, wherein the tablet contains 2 mg of (R)-Compound 1.

34. 34. The method of any one of claims 31 to 33, wherein one tablet is administered to the human per day.

35. 35. The method of any one of claims 1 to 34, wherein said amount of (R)-Compound 1 is administered to said human in a single dose.

36. 36. The method of any one of claims 1-35, wherein said administration of said (R)-Compound 1 results in no clinically significant adverse events in said human compared to placebo.

37. 37. The method of any one of claims 1 to 36, wherein said administration does not result in a clinically important decrease in mean serum cortisol levels compared to placebo.

38. 38. The method of any one of claims 1 to 37, wherein the human is at least 18 years old.

39. (R)-Compound 1 for use in the method according to any one of claims 1 to 38.

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