Methods of treating hypertension with aldosterone synthase inhibitor badoxostat

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 395,680 filed on August 5, 2022; U.S. Provisional Patent Application No. 63 / 374,410 filed on September 2, 2022; U.S. Provisional Patent Application No. 63 / 378,120 filed on October 3, 2022; U.S. Provisional Patent Application No. 63 / 384,594 filed on November 21, 2022; and U.S. Provisional Patent Application No. 63 / 386,683 filed on December 9, 2022; the disclosures of which are incorporated herein by reference. Technical Field

[0003] The present disclosure provides compounds and methods for treating hypertension. Background Art

[0004] Hypertension is responsible for more years of life lost or lived with disability than any other disease combined. Patients with resistant hypertension represent a particularly high-risk subgroup of hypertensive patients because their blood pressure is refractory to the most effective antihypertensive drugs available, exposing them to the deleterious effects of chronically elevated blood pressure on their heart, brain, and kidneys. In a five-year retrospective longitudinal cohort study of nearly 500,000 people at Kaiser Permanente Southern California.

[0005] When compared to patients with non-resistant hypertension, patients with resistant hypertension show significantly increased risks of stroke and end-stage renal disease, 16% and 32%, respectively, as well as higher risks of heart failure, ischemic heart disease, and death. Not only are these conditions associated with some of the most severe and consequential medical disasters that patients and their families can experience, but they also account for a large portion of hospitalizations and medical expenditures in the United States.

[0006] Uncontrolled hypertension is high blood pressure that is not controlled by one or more antihypertensive drugs and is associated with the same adverse medical consequences, but without determination in those patients whose blood pressure will ultimately prove resistant to triple or more drug therapy. Although physicians and patients have many therapeutic drug classes to choose from for the treatment of hypertension, few agents have been shown to be effective in the resistant hypertension (rHTN) population.

[0007] Individuals with uHTN or rHTN are at substantially increased risk for cardiovascular and renal disease because failure to achieve blood pressure goals exposes them to the deleterious effects of chronically elevated blood pressure in the heart, brain, and kidneys.

[0008] Current guidelines that target lower blood pressure levels than before and the presence of millions of patients with rHTN and uncontrolled hypertension (uHTN) in the United States mean there is a large unmet medical need for new antihypertensive drugs that work well with existing common medications. Summary of the invention

[0009] In certain embodiments, the present disclosure provides methods of treating hypertension in a human in need of such treatment, the methods comprising administering to the human 1 mg / day or 2 mg / day of (R)-Compound 1:

[0010] (R)-Compound 1. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 The study design is described.

[0012] Figure 2 Depicted are the mean changes from baseline in the SBP and mITT datasets.

[0013] Figure 3A Mean serum aldosterone is described.

[0014] Figure 3B 24-hour urinary aldosterone is described.

[0015] Figure 3C Plasma renin activity was profiled.

[0016] Figure 3D Serum total cortisol is depicted.

[0017] Figure 4A The summary of the treatment effects of baxdrostat on aldosterone and renin (serum aldosterone) is depicted by sex.

[0018] Figure 4B The summary of the treatment effects of bardoxetine on aldosterone and renin (plasma renin activity) is depicted by sex.

[0019] Figure 5 Serum potassium concentrations, safety population, are depicted. Baseline was defined as the measurement at randomization (Day 1 / Visit 4). If missing, baseline was the last measurement before the first dose of double-blind trial drug. The lower and upper boundaries of the box represent the first and third quartiles, the line within the box represents the median, the points within the box represent the mean, the minimum and maximum data points observed within 1.5× the interquartile range, and the points outside the box represent data points observed outside the 1.5× interquartile range boundaries.

[0020] Figure 6Serum sodium concentration, safety population, is depicted. Baseline is defined as the measurement at randomization (Day 1 / Visit 4). If missing, baseline is the last measurement before the first dose of double-blind trial drug. The lower and upper boundaries of the box represent the first and third quartiles, the line within the box represents the median, the points within the box represent the mean, the minimum and maximum data points observed within 1.5× the interquartile range, and the points outside the box represent data points observed outside the 1.5× interquartile range boundaries.

[0021] Figure 7 Estimated glomerular filtration rate, safety population are depicted. Baseline is defined as the measurement at randomization (Day 1 / Visit 4). If missing, baseline is the last measurement before the first dose of double-blind study drug. The lower and upper boundaries of the box represent the first and third quartiles, the line within the box represents the median, the points within the box represent the mean, the minimum and maximum data points observed within 1.5× the interquartile range, and the points outside the box represent data points observed outside the 1.5× interquartile range boundaries.

[0022] Figure 8 Blinded SBP of patients in Study 124 is depicted.

[0023] Fig. 9 Describes the study 123 design.

[0024] Fig. 10A and Fig. 10B is a bar graph showing bardostat-induced changes in systolic blood pressure in patients with resistant hypertension ( Fig. 10A ) and diastolic blood pressure ( Fig. 10B ). Data are least squares (LS) mean changes ± standard errors (SE) and placebo-corrected changes ± SE. Baseline was defined as the measurement at randomization. LS means, SEs, and p values ​​were derived from mixed-model repeated-measures models 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 BP and baseline glomerular filtration rate as continuous covariates. P values ​​indicate significant placebo-corrected changes.

[0025] Figures 11A-11C is a line graph showing that bardoxstat reduces serum aldosterone ( Fig.11A ) and increase plasma renin activity ( Fig. 11B ), without reducing serum total cortisol ( Fig. 11C). Data are LS means ± SE compared with baseline. Baseline was defined as the measurement at randomization. LS means, SE, and p-values ​​are from analysis of covariance models with change from baseline as dependent variable and baseline mean sitting SBP and baseline glomerular filtration rate as continuous covariates. Statistical significance between bardoxstat and placebo, *p≤0.05; **p≤0.01; ***p≤0.001; ****p≤0.0001.

[0026] Fig. 12A and Fig. 12B is a line graph of plasma bardoxetine concentration versus time. Data are mean ± standard deviation.

[0027] Fig.13 This is the study design for the interim results of Example 9.

[0028] Fig.14 Schematic diagram of patient disposition in Part 1 of the study of Example 9.

[0029] Fig.15A It is a bar graph showing the change in systolic blood pressure (mmHg) in Part 1 of Example 9 at Week 8. Fig. 15B is a bar graph showing the change in systolic blood pressure (mmHg) at Week 8 for Part 1 of Example 9 for non-Hispanic / Latino patients. In these figures, *nominal p-values ​​and the SBP primary endpoint was the change in blood pressure vs. placebo.

[0030] Fig.16 is a line graph showing the mean change in sitting SBP over time for the entire intention-to-treat population.

[0031] Fig.17A is a line graph showing the changes in aldosterone for the entire patient population of Example 9. Fig. 17B is a line graph showing changes in aldosterone for the Hispanic patient population of Example 9. Fig. 17C is a line graph showing changes in aldosterone for the non-Hispanic patient population of Example 9.

[0032] Fig.18A is a line graph showing the changes in plasma renin activity for the entire patient population of Example 9. Fig. 17B is a line graph showing changes in plasma renin activity for the Hispanic patient population of Example 9. Fig. 17C is a line graph showing the change in plasma renin activity for the non-Hispanic patient population of Example 9.

[0033] Fig.19 is a line graph showing the mean serum potassium level over time.

[0034] Fig. 20is a line graph showing plasma metformin concentration versus time. In this graph, the data are mean ± standard deviation.

[0035] Figure 21A-21B are plots of plasma bardoxetine PK parameters versus baseline eGFR. max ( Fig.21A ), AUC 0-last ( Fig.21B ), AUC 0-inf ( Fig. 21C ) and t 1 / 2 ( Fig.21D ) and baseline eGFR. Baseline was defined as the last measurement before administration of bardoxstat. Baseline eGFR values ​​were presented as continuous variables. Linear regression analysis was performed using Graphpad Prism 7.03.

[0036] Fig. 22 It is a line graph of plasma bardoxetine-M concentration and time plasma concentration (ng / mL) from 0-168 hours by renal function group. In this figure, the data are mean ± standard deviation.

[0037] Fig.23 is a line graph of the cumulative amount of bardoxstat excreted into urine. In this graph, the cumulative concentration of bardoxstat (μg) from 0 to 168 hours by renal function group. Data are mean ± standard deviation.

[0038] Fig.24 is the study design for Cohort 1. In this figure, n = number of participants in that category.

[0039] Fig.25 is the study design for Cohort 2. In this figure, n = number of participants in that category. DETAILED DESCRIPTION

[0040] By reference to the following description, including the following definitions and examples, the present disclosure can be more fully understood. Certain features of the disclosed compositions and methods described herein in the context of individual aspects may also be provided in combination in a single aspect. Alternatively, the various features of the disclosed compositions and methods described in the context of individual aspects for the sake of brevity may also be provided separately or in any sub-combination. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those of ordinary skill in the art to which the present disclosure relates. The terms used in this specification are only used to describe specific embodiments and are not intended to limit the present disclosure.

[0041] In this disclosure, the singular forms "a," "an," and "the" include plural referents and a reference to a particular value includes at least that particular value unless the context clearly dictates otherwise.

[0042] When a value is expressed as an approximate value by using the descriptor "about", it should be understood that the particular value forms another embodiment. Generally, the use indication of the term "about" can vary according to the desired characteristics sought to be obtained by the disclosed subject matter, and is explained in the specific context of its use based on its function. Those skilled in the art will be able to explain this conventionally. In some cases, the number of significant figures for a particular value can be a non-limiting method for determining the degree of the word "about". In other cases, the rank used in a series of values ​​can be used to determine the expected range available for the term "about" for each value. When present, all ranges are inclusive and can be combined. That is, the value stated in the range is mentioned to include each value in the range.

[0043] When a list is presented, it should be understood that each individual element of the list and each combination of the list should be interpreted as a separate embodiment unless otherwise specified. For example, a list of embodiments presented as "A, B, or C" should be interpreted to include embodiments "A", "B", "C", "A or B", "A or C", "B or C", or "A, B, or C".

[0044] It should be understood that certain features of the invention described herein in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. That is, unless clearly incompatible or excluded, each separate embodiment is considered to be combinable with any other embodiment, and such combination is considered to be another embodiment. On the contrary, the various features of the invention described in the context of a single embodiment for brevity may also be provided separately or in any sub-combination. It should also be noted that the claims may be written to exclude optional elements. Therefore, this statement is intended to serve as a premise basis for the use of exclusive terms such as "only" or the use of "negative" restrictions associated with the narration of claim elements.

[0045] Application method

[0046] The present disclosure relates to methods for treating hypertension in a human being in need of treatment. These methods include administering (R)-Compound 1 to a human being during a treatment period. In other embodiments, the present disclosure relates to methods for lowering blood pressure using bardoxstat, i.e., ((+)-(R)-N-(4-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide, in the treatment of hypertension.

[0047] Bardostat

[0048] As used herein, the terms "badomostat" and "(R)-Compound 1" 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)propanamide ((R)-Compound 1) having the following structure:

[0049] (R)-Compound 1

[0050] 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 materials that are acceptable to patients / humans from a pharmacological / toxicological perspective, and acceptable to pharmaceutical industry chemists from a physical / chemical perspective, in terms of composition, formulation, stability, patient acceptance, and bioavailability.

[0051] Pharmaceutically acceptable salts of (R)-Compound 1 include salts formed 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 (i.e., 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, cyclohexylaminosulfonic acid (cyclamic acid), ethanedisulfonic 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).

[0052] The terms "subject" and "patient" are used interchangeably and generally refer to mammals. In some embodiments, the patient or subject is a human. In other embodiments, the patient or subject is a veterinary or farm animal, livestock or pet, or an animal used to conduct clinical research. In some embodiments, the subject or patient is at least 18 years old, i.e., an adult.

[0053] According to the present disclosure, in the treatment of hypertension combined with other antihypertensive agents, bardoxstat reduces blood pressure. The expected population of bardoxstat is for treatment-resistant hypertension (rHTN), defined as hypertension that has not been successfully treated with ≥3 antihypertensive agents, and for uncontrolled hypertension (uHTN), defined as hypertension that has not been successfully treated with 1 or 2 antihypertensive agents.

[0054] Hypertension is defined as systolic blood pressure (SBP) >130 mmHg or diastolic blood pressure (DBP) >80 mmHg (Table 1). The goal of treatment is to achieve an SBP of <130 mmHg and a DBP of 80 mmHg.

[0055]

[0056] Hypertension includes stage 1 and stage 2 hypertension and hypertensive crisis. In some embodiments, the patient / human suffers from stage 1 hypertension with a systolic blood pressure of about 130 mm Hg to about 139 mm Hg and / or a diastolic blood pressure of about 80 mm Hg to about 89 mm Hg. In other embodiments, the patient / human suffers from stage 2 hypertension with a systolic blood pressure of about 140 mm Hg or higher and / or a diastolic blood pressure of about 90 mm Hg or higher. In other embodiments, the patient / human suffers from a hypertensive crisis with a blood pressure measurement higher than about 180 / 120 mmHg. "Hypertension" also includes resistant hypertension (rHTN) and uncontrolled hypertension (uHTN). In some embodiments, the human suffers from rHTN. In other embodiments, the human suffers from uHTN. In other embodiments, the subject suffers from chronic kidney disease. In other embodiments, the subject suffers from chronic kidney disease and rHTN. In other embodiments, in certain aspects, the subject suffers from chronic kidney disease and uHTN.

[0057] Before administration of (R)-Compound 1

[0058] In certain embodiments, prior to administration of (R)-Compound 1, the human has ≥45 mL / min / 1.73 m 2 In certain aspects, prior to administration of (R)-Compound 1, 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 / 1.73m 2 In other aspects, 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 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.

[0059] In other embodiments, prior to administration of (R)-Compound 1, the human has an average sitting systolic blood pressure (siSBP) of ≥130 mmHg. In certain aspects, prior to administration of (R)-Compound 1, the human has an average sitting systolic blood pressure (siSBP) of ≥140 mmHg. In other aspects, prior to administration of (R)-Compound 1, the human has an average sitting systolic blood pressure (siSBP) of ≥140 mmHg to <170 mmHg. In additional aspects, prior to administration of (R)-Compound 1, the human has a siSBP of about 140, about 145, about 150, about 155, about 160, or about 165 mmHg. In other aspects, prior to administration of (R)-Compound 1, 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. In additional aspects, prior to administration of (R)-Compound 1, the human has a siSBP of <145 mmHg. In still other aspects, prior to administration of (R)-Compound 1, the human has a siSBP of ≥145 mmHg.

[0060] In additional embodiments, the human has a serum potassium level of ≥3.5 mmol / L and <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, prior to administration of (R)-Compound 1, 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.

[0061] In other embodiments, the human has a morning Cortisol level of >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, prior to administration of (R)-Compound 1, 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.

[0062] (R)-After administration of Compound 1

[0063] (R)-Compound is administered to the human during a treatment period. As used herein, the term "treatment period" refers to the period of time spent administering (R)-Compound 1 to the human.

[0064] Compared to placebo, following treatment with (R)-Compound 1, at or after about 12 weeks of treatment, the mean sitting systolic blood pressure (siSBP) of the human is reduced compared to baseline. In some embodiments, administration results in a sitting systolic blood pressure (siSBP) <130 mmHg after the 12-week treatment period. In other embodiments, administration of (R)-Compound 1 results in a decrease in siSBP relative to baseline of at least about 1 mmHg, at least about 2 mmHg, at least about 3 mmHg, at least about 4 mmHg, at least about 5 mmHg, at least about 6 mmHg, at least about 7 mmHg, at least about 8 mmHg, at least about 9 mmHg, at least about 10 mmHg, at least about 11 mmHg, at least about 12 mmHg, at least about 13 mmHg, at least about 14 mmHg, at least about 15 mmHg, at least about 16 mmHg, at least about 17 mmHg, at least about 18 mmHg, at least about 19 mmHg, at least about 20 mmHg, at least about 21 mmHg, at least about 22 mmHg, at least about 23 mmHg, at least about 24 mmHg, at least about 25 mmHg, at least about 26 mmHg, at least about 27 mmHg, at least about 28 mmHg, at least about 29 mmHg, at least about 30 mmHg, at least about 31 mmHg, at least about 32 mmHg, at least about 33 mmHg, at least about 34 mmHg, at least about 35 mmHg, at least about 36 mmHg, at least about 37 mmHg, at least about 38 mmHg, at least about 39 mmHg, at least about 40 mmHg, at least about 4 3 mmHg, at least about 14 mmHg, at least about 15 mmHg, at least about 16 mmHg, at least about 17 mmHg, at least about 18 mmHg, at least about 19 mmHg, at least about 20 mmHg, at least about 21 mmHg, at least about 22 mmHg, at least about 23 mmHg, at least about 24 mmHg, at least about 25 mmHg, at least about 26 mmHg, at least about 27 mmHg, at least about 28 mmHg, at least about 29 mmHg or at least about 30 mmHg. In other embodiments, administration of (R)-Compound 1 as compared to placebo results in a decrease in siSBP relative to baseline by about 1 mmHg, about 2 mmHg, about 3 mmHg, about 4 mmHg, about 5 mmHg, about 6 mmHg, about 7 mmHg, about 8 mmHg, about 9 mmHg, about 10 mmHg, about 11 mmHg, about 12 mmHg, about 13 mmHg, about 14 mmHg, about 15 mmHg, about 16 mmHg, about 17 mmHg, about 18 mmHg, about 19 mmHg, about 20 mmHg, about 21 mmHg, about 22 mmHg, about 23 mmHg, about 24 mmHg, about 25 mmHg, about 26 mmHg, about 27 mmHg, about 28 mmHg, about 29 mmHg, or about 30 mmHg at or after about 12 weeks of treatment compared to baseline.In other embodiments, administration of (R)-Compound 1 results in a decrease in siSBP relative to baseline of about 1 mmHg to about 30 mmHg, about 1 mmHg to about 25 mmHg, about 1 mmHg to about 20 mmHg, about 1 mmHg to about 15 mmHg, about 1 mmHg to about 10 mmHg, about 1 mmHg to about 5 mmHg, about 5 mmHg to about 30 mmHg, about 5 mmHg to about 25 mmHg, about 5 mmHg to about 20 mmHg, about 1 mmHg to about 15 mmHg, about 1 mmHg to about 10 mmHg, about 1 mmHg to about 5 mmHg, about 5 mmHg to about 30 mmHg, about 5 mmHg to about 25 mmHg, about 5 mmHg to about 20 mmHg, or about 1 mmHg to about 5 mmHg, compared to placebo, at or after about 12 weeks of treatment. In another embodiment, administration of 2 mg / day of (R)-Compound 1 results in a decrease in mean sitting systolic blood pressure (siSBP) compared to baseline in the human at or after the 12 week treatment period, compared to placebo. In other embodiments, administration of 1 mg / day of (R)-compound 1 results in a decrease in the mean sitting systolic blood pressure (siSBP) of the human being compared to baseline at or after the 12-week treatment period, compared to placebo. In other embodiments, 1 mg / day of (R)-compound 1 is administered to the human being, and administration results in a decrease in the mean sitting systolic blood pressure of the human being by about 8 mmHg compared to baseline at or after the 12-week treatment period. In other embodiments, 1 mg / day of (R)-compound 1 is administered to the human being, and administration results in a decrease in the mean sitting systolic blood pressure of the human being by more than 8 mmHg compared to baseline at or after the 12-week treatment period. In yet other embodiments, 2 mg / day of (R)-compound 1 is administered to the human being, and administration results in a decrease in the mean sitting systolic blood pressure of the human being by about 11 mmHg compared to baseline at or after the 12-week treatment period. In other embodiments, 2 mg / day of (R)-Compound 1 is administered to the human, and the administration results in a decrease in the human's mean sitting systolic blood pressure of more than 11 mg Hg compared to baseline at or after the 12 week treatment period.

[0065] Following treatment with (R)-Compound 1, administration results in a decrease in sitting systolic blood pressure (siSBP) compared to baseline at or after the 24-week treatment period, compared to placebo. In some embodiments, administration of (R)-Compound 1 results in a decrease in siSBP relative to baseline of at least about 1 mmHg, at least about 2 mmHg, at least about 3 mmHg, at least about 4 mmHg, at least about 5 mmHg, at least about 6 mmHg, at least about 7 mmHg, at least about 8 mmHg, at least about 9 mmHg, at least about 10 mmHg, at least about 11 mmHg, at least about 12 mmHg, at least about 13 mmHg, at least about 14 mmHg, at least about 15 mmHg, at least about 16 mmHg, at least about 17 mmHg, at least about 18 mmHg, at least about 19 mmHg, at least about 20 mmHg, at least about 21 mmHg, at least about 22 mmHg, at least about 23 mmHg, at least about 24 mmHg, at least about 25 mmHg, at least about 26 mmHg, at least about 27 mmHg, at least about 28 mmHg, at least about 29 mmHg, at least about 30 mmHg, at least about 31 mmHg, at least about 32 mmHg, at least about 33 mmHg, at least about 34 mmHg, at least about 35 mmHg, at least about 36 mmHg, at least about 37 mmHg, at least about 38 mmHg, at least about 39 mmHg, at least about 40 mmHg, at least about 41 mmHg, at least about 42 mmHg, at least about 43 mmHg, at least about 44 mmHg, at least about mmHg, at least about 14 mmHg, at least about 15 mmHg, at least about 16 mmHg, at least about 17 mmHg, at least about 18 mmHg, at least about 19 mmHg, at least about 20 mmHg, at least about 21 mmHg, at least about 22 mmHg, at least about 23 mmHg, at least about 24 mmHg, at least about 25 mmHg, at least about 26 mmHg, at least about 27 mmHg, at least about 28 mmHg, at least about 29 mmHg, or at least about 30 mmHg. In additional embodiments, administration of (R)-Compound 1 as compared to placebo results in a decrease in siSBP relative to baseline by about 1 mmHg, about 2 mmHg, about 3 mmHg, about 4 mmHg, about 5 mmHg, about 6 mmHg, about 7 mmHg, about 8 mmHg, about 9 mmHg, about 10 mmHg, about 11 mmHg, about 12 mmHg, about 13 mmHg, about 14 mmHg, about 15 mmHg, about 16 mmHg, about 17 mmHg, about 18 mmHg, about 19 mmHg, about 20 mmHg, about 21 mmHg, about 22 mmHg, about 23 mmHg, about 24 mmHg, about 25 mmHg, about 26 mmHg, about 27 mmHg, about 28 mmHg, about 29 mmHg, or about 30 mmHg at or after about 24 weeks of treatment compared to baseline.In other embodiments, administration of (R)-Compound 1 results in a decrease in siSBP relative to baseline of about 1 mmHg to about 30 mmHg, about 1 mmHg to about 25 mmHg, about 1 mmHg to about 20 mmHg, about 1 mmHg to about 15 mmHg, about 1 mmHg to about 10 mmHg, about 1 mmHg to about 5 mmHg, about 5 mmHg to about 30 mmHg, about 5 mmHg to about 25 mmHg, about 5 mmHg to about 20 mmHg, about 1 mmHg to about 15 mmHg, about 1 mmHg to about 10 mmHg, about 1 mmHg to about 5 mmHg, about 5 mmHg to about 30 mmHg, about 5 mmHg to about 25 mmHg, about 5 mmHg to about 20 mmHg, or about 1 mmHg to about 5 mmHg, compared to placebo, at or after about 24 weeks of treatment. mHg, about 5 mmHg to about 15 mmHg, about 5 mmHg to about 10 mmHg, about 10 mmHg to about 30 mmHg, about 10 mmHg to about 25 mmHg, about 10 mmHg to about 20 mmHg, about 10 mmHg to about 15 mmHg, about 15 mmHg to about 30 mmHg, about 15 mmHg to about 25 mmHg, about 15 mmHg to about 20 mmHg, about 20 mmHg to about 30 mmHg, about 20 mmHg to about 25, or about 25 mmHg to about 30 mmHg.

[0066] Following treatment with (R)-Compound 1, compared to placebo, at or after about 12 weeks of treatment, the human has a decrease in sitting diastolic blood pressure (siDBP), compared to baseline. In some embodiments, administration of (R)-Compound 1 results in a decrease in siDBP relative to baseline of at least about 1 mmHg, at least about 2 mmHg, at least about 3 mmHg, at least about 4 mmHg, at least about 5 mmHg, at least about 6 mmHg, at least about 7 mmHg, at least about 8 mmHg, at least about 9 mmHg, at least about 10 mmHg, at least about 11 mmHg, at least about 12 mmHg, at least about 13 mmHg, at least about 14 mmHg, at least about 15 mmHg, at least about 16 mmHg, at least about 17 mmHg, at least about 18 mmHg, at least about 19 mmHg, at least about 20 mmHg, at least about 21 mmHg, at least about 22 mmHg, at least about 23 mmHg, at least about 24 mmHg, at least about 25 mmHg, at least about 26 mmHg, at least about 27 mmHg, at least about 28 mmHg, at least about 29 mmHg, at least about 30 mmHg, at least about 31 mmHg, at least about 32 mmHg, at least about 33 mmHg, at least about 34 mmHg, at least about 35 mmHg, at least about 36 mmHg, at least about 37 mmHg, at least about 38 mmHg, at least about 39 mmHg, at least about 40 mmHg, at least about 41 mmHg, at least about 42 mmHg, at least about 43 mmHg, at least about 44 mmHg, at least about mmHg, at least about 14 mmHg, at least about 15 mmHg, at least about 16 mmHg, at least about 17 mmHg, at least about 18 mmHg, at least about 19 mmHg, at least about 20 mmHg, at least about 21 mmHg, at least about 22 mmHg, at least about 23 mmHg, at least about 24 mmHg, at least about 25 mmHg, at least about 26 mmHg, at least about 27 mmHg, at least about 28 mmHg, at least about 29 mmHg, or at least about 30 mmHg. In other embodiments, administration of (R)-Compound 1 as compared to placebo results in a decrease in siDBP relative to baseline by about 1 mmHg, about 2 mmHg, about 3 mmHg, about 4 mmHg, about 5 mmHg, about 6 mmHg, about 7 mmHg, about 8 mmHg, about 9 mmHg, about 10 mmHg, about 11 mmHg, about 12 mmHg, about 13 mmHg, about 14 mmHg, about 15 mmHg, about 16 mmHg, about 17 mmHg, about 18 mmHg, about 19 mmHg, about 20 mmHg, about 21 mmHg, about 22 mmHg, about 23 mmHg, about 24 mmHg, about 25 mmHg, about 26 mmHg, about 27 mmHg, about 28 mmHg, about 29 mmHg, or about 30 mmHg at or after about 12 weeks of treatment compared to baseline.In other embodiments, administration of (R)-Compound 1 results in a decrease in siDBP relative to baseline of about 1 mmHg to about 30 mmHg, about 1 mmHg to about 25 mmHg, about 1 mmHg to about 20 mmHg, about 1 mmHg to about 15 mmHg, about 1 mmHg to about 10 mmHg, about 1 mmHg to about 5 mmHg, about 5 mmHg to about 30 mmHg, about 5 mmHg to about 25 mmHg, about 5 mmHg to about 20 mmHg, about 1 mmHg to about 15 mmHg, about 1 mmHg to about 10 mmHg, about 1 mmHg to about 5 mmHg, about 5 mmHg to about 30 mmHg, about 5 mmHg to about 25 mmHg, about 5 mmHg to about 20 mmHg, or about 1 mmHg to about 5 mmHg, compared to placebo, at or after about 12 weeks of treatment. Hg, about 5 mmHg to about 15 mmHg, about 5 mmHg to about 10 mmHg, about 10 mmHg to about 30 mmHg, about 10 mmHg to about 25 mmHg, about 10 mmHg to about 20 mmHg, about 10 mmHg to about 15 mmHg, about 15 mmHg to about 30 mmHg, about 15 mmHg to about 25 mmHg, about 15 mmHg to about 20 mmHg, about 20 mmHg to about 30 mmHg, about 20 mmHg to about 25, or about 25 mmHg to about 330 mmHg.

[0067] Following treatment with (R)-Compound 1 compared to placebo, the human has a reduction in ambulatory 24-hour mean systolic blood pressure (SBP) compared to baseline at or after about 12 weeks of treatment. In other embodiments, administration of (R)-Compound 1 results in a decrease in ambulatory 24-hour average SBP relative to baseline by about 1 mmHg, about 2 mmHg, about 3 mmHg, about 4 mmHg, about 5 mmHg, about 6 mmHg, about 7 mmHg, about 8 mmHg, about 9 mmHg, about 10 mmHg, about 11 mmHg, about 12 mmHg, about 13 mmHg, about 14 mmHg, about 15 mmHg, about 16 mmHg, about 17 mmHg, about 18 mmHg, about 19 mmHg, about 20 mmHg, about 21 mmHg, about 22 mmHg, about 23 mmHg, about 24 mmHg, about 25 mmHg, about 26 mmHg, about 27 mmHg, about 28 mmHg, about 29 mmHg, or about 30 mmHg relative to baseline at or after about 12 weeks of treatment, compared to baseline. In further embodiments, administration of (R)-Compound 1 results in a decrease in ambulatory 24-hour average SBP relative to baseline of about 1 mmHg to about 30 mmHg, about 1 mmHg to about 25 mmHg, about 1 mmHg to about 20 mmHg, about 1 mmHg to about 15 mmHg, about 1 mmHg to about 10 mmHg, about 1 mmHg to about 5 mmHg, about 5 mmHg to about 30 mmHg, about 5 mmHg to about 25 mmHg, about 5 ...1 mmHg to about 5 mmHg, about 1 mmHg to about 5 mmHg, about 1 mmHg to about 5 mmHg, about 1 mmHg to about 5 mmHg, about 1 mmHg to about 5 mmHg, about 1 mmHg to about 5 mmHg, about 1 mmHg to about 5 mmHg, about 1 mmHg to about 5 mmHg, about 1 mmHg to about 5 mmHg, about 1 mmHg to about 5 mmHg, about 1 mmHg to about 5 mmH 20 mmHg, about 5 mmHg to about 15 mmHg, about 5 mmHg to about 10 mmHg, about 10 mmHg to about 30 mmHg, about 10 mmHg to about 25 mmHg, about 10 mmHg to about 20 mmHg, about 10 mmHg to about 15 mmHg, about 15 mmHg to about 30 mmHg, about 15 mmHg to about 25 mmHg, about 15 mmHg to about 20 mmHg, about 20 mmHg to about 30 mmHg, about 20 mmHg to about 25, or about 25 mmHg to about 330 mmHg.

[0068] In some embodiments, compared to placebo, at or after about 12 weeks of treatment, the human has a decrease in dynamic 24-hour average diastolic blood pressure (DBP) compared to baseline. In other embodiments, compared to placebo, administration of (R)-Compound 1 results in a decrease in dynamic 24-hour average DBP relative to baseline of at least about 1 mmHg, at least about 2 mmHg, at least about 3 mmHg, at least about 4 mmHg, at least about 5 mmHg, at least about 6 mmHg, at least about 7 mmHg, at least about 8 mmHg, at least about 9 mmHg, at least about 10 mmHg, at least about 11 mmHg, at least about 12 mmHg, at least about 13 mmHg, at least about 14 mmHg, at least about 15 mmHg, at least about 16 mmHg, at least about 17 mmHg, at least about 18 mmHg, at least about 19 mmHg, at least about 20 mmHg, at least about 21 mmHg, at least about 22 mmHg, at least about 23 mmHg, at least about 24 mmHg, at least about 25 mmHg, at least about 26 mmHg, at least about 27 mmHg, at least about 28 mmHg, at least about 29 mmHg, at least about 30 mmHg, at least about 31 mmHg, at least about 32 mmHg, at least about 33 mmHg, at least about 34 mmHg, at least about 35 mmHg, at least about 36 mmHg, at least about 37 mmHg, at least about 38 mmHg, at least about 39 mmHg, at least about 40 mmHg, at least about 41 mmHg, at least about 42 mmHg, at least about 43 mmHg, at least about 44 at least about 24 mmHg, at least about 25 mmHg, at least about 26 mmHg, at least about 27 mmHg, at least about 28 mmHg, at least about 29 mmHg or at least about 30 mmHg. In other embodiments, administration of (R)-Compound 1 results in a decrease in the dynamic 24-hour average DBP relative to baseline by about 1 mmHg, about 2 mmHg, about 3 mmHg, about 4 mmHg, about 5 mmHg, about 6 mmHg, about 7 mmHg, about 8 mmHg, about 9 mmHg, about 10 mmHg, about 11 mmHg, about 12 mmHg, about 13 mmHg, about 14 mmHg, about 15 mmHg, about 16 mmHg, about 17 mmHg, about 18 mmHg, about 19 mmHg, about 20 mmHg, about 21 mmHg, about 22 mmHg, about 23 mmHg, about 24 mmHg, about 25 mmHg, about 26 mmHg, about 27 mmHg, about 28 mmHg, about 29 mmHg, or about 30 mmHg relative to baseline at or after about 12 weeks of treatment, compared to baseline.In further embodiments, administration of (R)-Compound 1 results in a decrease in the ambulatory 24-hour average DBP relative to baseline of about 1 mmHg to about 30 mmHg, about 1 mmHg to about 25 mmHg, about 1 mmHg to about 20 mmHg, about 1 mmHg to about 15 mmHg, about 1 mmHg to about 10 mmHg, about 1 mmHg to about 5 mmHg, about 5 mmHg to about 30 mmHg, about 5 mmHg to about 25 mmHg, about 5 ...1 mmHg to about 5 mmHg, about 1 mmHg to about 5 mmHg, about 1 mmHg to about 5 mmHg, about 1 mmHg to about 5 mmHg, about 1 mmHg to about 5 mmHg, about 1 mmHg to about 5 mmHg, about 1 mmHg to about 5 mmHg, about 1 mmHg to about 5 mmHg, about 1 mmHg to about 5 mmHg, about 1 mmHg to about 5 mmHg, about 1 mmHg to about 5 mm 20 mmHg, about 5 mmHg to about 15 mmHg, about 5 mmHg to about 10 mmHg, about 10 mmHg to about 30 mmHg, about 10 mmHg to about 25 mmHg, about 10 mmHg to about 20 mmHg, about 10 mmHg to about 15 mmHg, about 15 mmHg to about 30 mmHg, about 15 mmHg to about 25 mmHg, about 15 mmHg to about 20 mmHg, about 20 mmHg to about 30 mmHg, about 20 mmHg to about 25, or about 25 mmHg to about 330 mmHg.

[0069] In certain aspects, administration of (R)-Compound 1 does not cause clinically significant adverse events in the human compared to placebo. In other aspects, administration does not cause a clinically significant decrease in mean serum Cortisol levels compared to placebo.

[0070] In certain aspects, (R)-Compound 1 is provided for use in any of the methods described herein.

[0071] "Treatment" or variations thereof refers to eliminating or reducing at least one physical parameter of a disease or condition, such as hypertension. In some embodiments, the disease or condition is hypertension. In other embodiments, the disease or condition is resistant hypertension. In some embodiments, the disease or condition is uncontrolled hypertension.

[0072] Pharmaceutical composition

[0073] The present disclosure also provides a pharmaceutical composition comprising (R)-Compound 1 and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises about 0.1 mg to 10 mg, for example 0.5 mg to 10 mg of (R)-Compound 1 and a pharmaceutically acceptable excipient. In other embodiments, the pharmaceutical composition comprises anhydrous lactose, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, colloidal silicon dioxide and magnesium stearate.

[0074] The amount of (R)-compound 1 used alone or in a pharmaceutical preparation can also be expressed in terms of amount. In some embodiments, the pharmaceutical preparation contains about 0.1 mg to about 10 mg of (R)-compound 1, for example, 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 preparation contains about 0.5 mg of (R)-compound 1. In another embodiment, the pharmaceutical preparation contains about 1 mg of (R)-compound 1. In yet other embodiments, the pharmaceutical preparation contains about 2 mg of (R)-Compound 1. In yet other embodiments, the pharmaceutical preparation contains about 3 mg of (R)-Compound 1. In yet other embodiments, the pharmaceutical preparation contains about 4 mg of (R)-Compound 1. In yet other embodiments, the pharmaceutical preparation contains about 5 mg of (R)-Compound 1. In other embodiments, the pharmaceutical preparation contains about 6 mg of (R)-Compound 1. In yet other embodiments, the pharmaceutical preparation contains about 7 mg of (R)-Compound 1. In yet other embodiments, the pharmaceutical preparation contains about 8 mg of (R)-Compound 1. In yet other embodiments, the pharmaceutical preparation contains about 9 mg of (R)-Compound 1. In other embodiments, the pharmaceutical preparation contains about 10 mg of (R)-Compound 1.

[0075] (R)-Compound 1 or a pharmaceutical composition containing (R)-Compound 1 can be administered hourly, daily, or weekly. Ideally, (R)-Compound 1 or a pharmaceutical composition containing (R)-Compound 1 is administered daily. In some embodiments, about 0.1 mg / day to about 30 mg / day of (R)-Compound 1 is administered. In some embodiments, the human is administered about 0.1 mg / day to about 5 mg / day, such as 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 of (R)-Compound 1. In other embodiments, the human is administered about 0.5 mg / day of (R)-Compound 1. In other embodiments, about 1 mg / day of (R)-Compound 1 is administered to the human. In still other embodiments, about 2 mg / day of (R)-Compound 1 is administered to the human. In still other embodiments, about 3 mg / day of (R)-Compound 1 is administered to the human. In still other embodiments, about 4 mg / day of (R)-Compound 1 is administered to the human. In still other embodiments, about 5 mg / day of (R)-Compound 1 is administered to the human. In still other embodiments, about 6 mg / day of (R)-Compound 1 is administered to the human. In still other embodiments, about 7 mg / day of (R)-Compound 1 is administered to the human. In still other embodiments, about 8 mg / day of (R)-Compound 1 is administered to the human. In still other embodiments, about 9 mg / day of (R)-Compound 1 is administered to the human. In still other embodiments, about 10 mg / day of (R)-Compound 1 is administered to the human.

[0076] (R)-Compound 1 can be administered in a single dose or divided doses. In some embodiments, (R)-Compound 1 is administered in a single dose. In other embodiments, (R)-Compound 1 is administered in divided doses. In other embodiments, one tablet is administered. In yet other embodiments, the tablet contains 1 mg of (R)-Compound 1. In other embodiments, the tablet contains 2 mg of (R)-Compound 1. Those skilled in the art will be able to determine and use other combinations of tablet doses based on the desired dose of (R)-Compound 1.

[0077] Route of administration

[0078] (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 other embodiments, administration is oral. In other embodiments, administration is transdermal. In yet other embodiments, administration is parenteral.

[0079] (R)-Compound 1 or a pharmaceutical preparation containing (R)-Compound 1 can be formulated for administration in solid form or liquid form. In some embodiments, (R)-Compound 1 or a pharmaceutical preparation containing (R)-Compound 1 is formulated in the form of a tablet, a caplet, a capsule, a powder, a soft gel, a suspension or a liquid or a combination thereof. In other embodiments, (R)-Compound 1 or a pharmaceutical preparation containing (R)-Compound 1 is formulated in the form of a tablet. In another embodiment, (R)-Compound 1 or a pharmaceutical preparation containing (R)-Compound 1 is formulated in the form of a caplet. In other embodiments, (R)-Compound 1 or a pharmaceutical preparation containing (R)-Compound 1 is formulated in the form of a capsule. In yet other embodiments, each tablet, caplet, capsule, powder, soft gel, suspension or liquid dose contains about 0.5 mg 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, soft gel, suspension or liquid dose contains about 0.5 mg of (R)-Compound 1. In other embodiments, each tablet, caplet, capsule, powder, soft gel, suspension or liquid dose contains about 1 mg of (R)-Compound 1. In still other embodiments, each tablet, caplet, capsule, powder, soft gel, suspension or liquid dose contains about 2 mg of (R)-Compound 1. In still other embodiments, each tablet, caplet, capsule, powder, soft gel, suspension or liquid dose contains about 2 mg of (R)-Compound 1. In other embodiments, each tablet, caplet, capsule, powder, soft gel, suspension or liquid dose contains about 3 mg of (R)-Compound 1. In additional embodiments, each tablet, caplet, capsule, powder, soft gel, suspension or liquid dose contains about 4 mg of (R)-Compound 1. In still other embodiments, each tablet, caplet, capsule, powder, soft gel, suspension or liquid dose contains about 5 mg of (R)-Compound 1.

[0080] In certain aspects, the solid or liquid form contains a patient / human dose of (R)-Compound 1. In other embodiments, two or more doses of the solid or liquid form, i.e., divided doses, may have to be administered to the patient / human in order to achieve the desired dose for the patient / human. In some embodiments, a once-daily 1 mg tablet containing (R)-Compound 1 is orally administered to a human. In other embodiments, a once-daily 2 mg tablet containing (R)-Compound 1 is orally administered to a human.

[0081] Antihypertensive regimen

[0082] In some embodiments, prior to administration of (R)-Compound 1, the human was unresponsive to one or more stable background antihypertensive regimens. "Stable background antihypertensive regimen" includes any regimen that reduces the blood pressure of the patient / human being. The regimen may include performing one or more therapies, such as daily activities or taking one or more antihypertensive agents. In some embodiments, the stable background antihypertensive regimen is one or more daily activities. Examples of daily activities that can be used to treat hypertension or primary aldosteronism include, but are not limited to, healthy eating, reducing salt intake, performing regular physical activity, maintaining a healthy weight, losing weight if recommended by a physician, and limiting alcohol consumption. In other embodiments, the stable background antihypertensive regimen is an antihypertensive agent. In other embodiments, hypertension is uncontrolled hypertension and the stable background antihypertensive regimen includes at least two antihypertensive drugs. In other embodiments, hypertension is treatment-resistant hypertension and the stable background antihypertensive regimen includes at least three antihypertensive drugs.

[0083] As used herein, the term "antihypertensive agent" refers to a drug that lowers the blood pressure of a patient / / human. In some embodiments, the antihypertensive agent is a diuretic, a loop diuretic, a beta-blocker, an ACE inhibitor, an angiotensin II receptor blocker, a calcium channel blocker, an alpha receptor blocker, an alpha-2 receptor agonist, a combined alpha and beta-blocker, a central agonist, a peripheral adrenergic inhibitor, a vasodilator (vasodilator), or a combination thereof. In some embodiments, the antihypertensive agent is a diuretic, such as a thiazide diuretic, a potassium-sparing diuretic, a loop diuretic, or a 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 (AldactoneA), 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), sotalol hydrochloride (Betapace), or timolol maleate (Blocadren). In additional embodiments, the antihypertensive agent is a combined beta-blocker / diuretic. An example of a beta-blocker / diuretic combination is hydrochlorothiazide + bisoprolol (Ziac). In other embodiments, the antihypertensive agent is an ACE inhibitor. Examples of ACE inhibitors include benazepril hydrochloride (Lotensin), captopril (Catonon), enalapril maleate (Vasotec), fosinopril sodium (Monopril), lisinopril (Prinivel, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril hydrochloride (Accupril), ramipril (Altace), or trandolapril (Mavik).In yet other 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 additional embodiments, the antihypertensive agent is an alpha blocker. Examples of alpha blockers include doxazosin mesylate (Cardura), prazosin hydrochloride (Minipress), or terazosin hydrochloride (Hytrin). In other embodiments, the antihypertensive agent is an alpha-2 receptor agonist. An example of an alpha-2 receptor agonist is methyldopa. In yet another embodiment, the antihypertensive agent is a combined alpha and beta-blocker. Examples of combined alpha and beta-blockers include carvedilol (Coreg) or labetalol hydrochloride (Normodyne, Trandate). In other embodiments, the antihypertensive agent is a central agonist. Examples of central agonists include alpha methyldopa (Aldomet), clonidine hydrochloride (Catapres), guanabenzyl acetate (Wytensin) or guanfacine hydrochloride (Tenex). In another embodiment, the antihypertensive agent is a peripheral adrenergic inhibitor. Examples of peripheral adrenergic inhibitors include guanadecyl (Hylorel), guanethidine monosulfate (Ismelin) or reserpine (Serpasil). In another embodiment, the antihypertensive agent is a vasodilator, i.e., a vasodilator. Examples of vasodilators include hydralazine hydrochloride (Apresoline) or minoxidil (Loniten).

[0084] In some embodiments, prior to administration of (R)-Compound 1, the patient / human's hypertension was unresponsive to one or more stable background antihypertensive regimens. In other embodiments, prior to administration of (R)-Compound 1, the patient / human's hypertension was unresponsive to two stable background antihypertensive regimens. In additional embodiments, prior to administration of (R)-Compound 1, the patient / human's hypertension was unresponsive to three stable background antihypertensive regimens. In other embodiments, prior to administration of (R)-Compound 1, the patient / human's hypertension was unresponsive to three or more stable background antihypertensive regimens.

[0085] An antihypertensive agent may be administered to the human in combination with (R)-Compound 1. In some embodiments, (R)-Compound 1 is administered to the human in combination with two antihypertensive agents during the treatment period. In other embodiments, (R)-Compound 1 is administered to the human in combination with three antihypertensive agents during the treatment period. In additional embodiments, (R)-Compound 1 is administered to the human in combination with at least three antihypertensive agents during the treatment period. In still other embodiments, (R)-Compound 1 is administered to the human in combination with two antihypertensive agents during the treatment period, one of which is a diuretic. In yet other embodiments, (R)-Compound 1 is administered to the human in combination with three antihypertensive agents during the treatment period, one of which is a diuretic. In other embodiments, (R)-Compound 1 is administered to the human in combination with at least three antihypertensive agents during the treatment period, one of which is a diuretic.

[0086] Currently, the FDA-approved drugs for the treatment of hypertension are diuretics, renin-angiotensin-aldosterone system (RAAS) inhibitors, β-blockers, calcium channel blockers, mineralocorticoid receptor antagonists (MRA), α-adrenergic receptor antagonists, central α-adrenergic receptor agonists, and direct vasodilators (Table 2). Drugs recommended for initial treatment include diuretics, ACEI, ARB, and calcium channel blockers.

[0087]

[0088] aspect

[0089] Aspect 1. A method substantially as described herein.

[0090] Aspect 2. A compound, which is:

[0091] or a pharmaceutically acceptable salt thereof.

[0092] Aspect 3. A compound, which is:

[0093] or a pharmaceutically acceptable salt thereof.

[0094] Aspect 4. A compound, which is:

[0095] or a pharmaceutically acceptable salt thereof.

[0096] Aspect 5. A compound, which is:

[0097] or a pharmaceutically acceptable salt thereof. Aspect 6. A compound, which is:

[0098] or a pharmaceutically acceptable salt thereof 7. A compound, which is:

[0099] or a pharmaceutically acceptable salt thereof.

[0100] Abbreviations and definitions

[0101]

[0102]

[0103]

[0104] The following examples are provided to illustrate some of the concepts described in this disclosure. Although it is believed that the examples 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 numbers used (e.g., amounts, temperatures, etc.), but some experimental errors and deviations should be considered.

[0105] Example 1: Single ascending dose study: Safety, tolerability, and efficacy of bardoxat in healthy male volunteers Metabolic kinetics and pharmacodynamics

[0106] Eighty-eight healthy male volunteers completed the first human study of bardoxstat. In the first part of the trial, subjects received a single oral dose of bardoxstat ranging from 1mg to 360mg to evaluate safety, tolerability, PK and pharmacodynamics (PD). Part 2 evaluated the PK of a single 3mg intravenous dose of bardoxstat. Under fasting, low-salt and normal-salt diet conditions, bardoxstat significantly reduced aldosterone levels in a dose-dependent manner. Bardoxstat had no significant effect on cortisol levels stimulated by adrenocorticotropic hormone, demonstrating the selectivity of aldosterone synthase inhibition. Over the entire dose range tested, the plasma level of bardoxstat increased in a dose-proportional manner, with an average 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, including headache, nasopharyngitis and diarrhea.

[0107] Example 2: Randomized, double-blind study: Safety of bardoxstat after multiple ascending doses in healthy subjects Pharmacokinetics and pharmacodynamics

[0108] The randomized, double-blind, placebo-controlled Phase 1 study evaluated the safety, pharmacokinetics and pharmacodynamics of multiple increasing doses of bardoxstat in healthy volunteers. Fifty-six subjects were randomly divided into groups to receive oral bardoxstat (0.5mg, 1.5mg, 2.5mg or 5.0mg) or placebo, once a day, for ten days, and placed in a low-salt diet or a normal salt diet during the study duration. Specifically, subjects were randomly divided into 5 queues, and received bardoxstat or placebo once a day for 10 days. Queue 1 and queue 2 were placed in a low-salt diet to stimulate aldosterone production, and 2.5mg or 5.0mg oral bardoxstat was used respectively. Queue 1 and queue 2 also experienced adrenocortical hormone (ACTH) stimulation to increase aldosterone and cortisol levels, to evaluate the specificity of bardoxstat targeting aldosterone synthase. Queue 3, queue 4 and queue 5 were placed in a normal salt diet and 1.5mg, 2.5mg or 0.5mg oral bardoxstat was used respectively. Blood samples were collected before and after dosing on Days 1 and 10 for measurement of plasma bardoxstat concentrations to characterize single-dose and steady-state pharmacokinetics. Pharmacodynamic measurements included plasma aldosterone, cortisol, and electrolytes. Safety assessments included physical examinations, electrocardiograms, orthostatic vital signs, and clinical laboratory evaluations.

[0109] Fifty-four subjects completed the study.There were no deaths or serious adverse events, and the adverse events that occurred in all treatment periods in the subjects receiving bardoxstat were all mild in severity (e.g., headache, dizziness, and postural dizziness). Bardoxstat is rapidly absorbed.The plasma level of bardoxstat increases proportionally with increasing dose, and peak concentrations are observed within 4 hours after administration, and the average half-life is 26 hours to 31 hours, indicating that the concentration of plasma bardoxstat decreases in an obvious biphasic manner.Regardless of diet, when bardoxstat dosage ≥1.5mg, the dose-dependent reduction of plasma aldosterone occurs.Plasma aldosterone continues to decrease, and its level decreases by about 51%-73% on the 10th day.Baridostat has no significant effect on plasma cortisol, and causes a slight dose-dependent reduction in plasma sodium levels and an increase in potassium levels, which is consistent with the observed aldosterone reduction.Baridostat is safe and well tolerated, and its half-life supports once daily administration. Selective blockade of aldosterone synthase was demonstrated by a dose-dependent reduction in plasma aldosterone and the lack of effect on cortisol.

[0110] Oral administration of bardoxstat was safe and well tolerated in all subjects and caused a dose-dependent increase in plasma bardoxstat, with a half-life that supports once-daily dosing. Selective blockade of aldosterone synthase was demonstrated by a dose-dependent decrease in plasma aldosterone and the lack of effect on cortisol.

[0111] Example 3: Randomized, open-label, crossover study: Relative efficacy of a tablet formulation of bardoxetine compared to an oral solution Bioavailability: Evaluation of the effect of food on a bardoxetine tablet formulation in healthy subjects

[0112] The relative bioavailability of the tablet formulation of bardoxstat was compared with the oral solution of bardoxstat used in SAD (Example 1) and MAD (Example 2) studies. The plasma level of bardoxstat determined to be equal in 14 healthy volunteers at a single 5mg dose of each preparation, regardless of whether oral solution or tablets were used. The study also evaluated the effect of a standardized high-fat meal on the PK of bardoxstat. High-fat meals had no significant effect on the plasma level of bardoxstat; there was little effect on the absorption rate, such as the time to reach maximum concentration (T max ) is indicated by a shift from approximately 3 hours after dosing in the fasted state to approximately 4 hours after dosing in the fed state.

[0113] Example 4: A Phase 1, open-label, single-dose, parallel-group study: In subjects with varying degrees of renal function Pharmacokinetics of Bardoxat

[0114] A. Methods

[0115] (i) Subjects

[0116] Subjects were included in the study if they were between 18 and 80 years old and in stable health based on medical and psychiatric history, physical examination, ECG, vital signs (sitting and orthostatic), and routine laboratory tests (blood chemistry, hematology, coagulation, and urinalysis). For subjects with renal impairment, their renal status had to be stable for at least 3 months before screening. In addition, subjects had to have been non-smokers or smoke <10 cigarettes / day and have a BMI ≥18 kg / m 2 And ≤40kg / m 2 .

[0117] Subjects were excluded if they had the following conditions:

[0118] 1) Personal or family history of long QT syndrome, complex ventricular arrhythmias, or family history of sudden death,

[0119] 2) personal history of clinically significant arrhythmia or current clinically significant arrhythmia,

[0120] 3) Prolonged QTcF (>450 ms in men or >470 ms in women),

[0121] 4) Sitting systolic blood pressure (BP)>160mmHg and / or diastolic blood pressure (BP)>100mmHg, or systolic blood pressure (BP)<90mmHG and / or diastolic blood pressure (BP)<50mmHg,

[0122] 5) Resting heart rate is higher than 100 beats per minute (bpm) or lower than 50 bpm,

[0123] 6) postural tachycardia or orthostatic hypotension (i.e., a decrease in systolic BP ≥20 mmHg or a decrease in diastolic BP ≥10 mmHg when standing from a sitting position),

[0124] 7) Clinically significant abnormal serum potassium greater than the ULN of the reference range,

[0125] 8) Clinically significant abnormal serum sodium below the lower limit of the normal reference range,

[0126] 9) Aspartate aminotransferase or alanine aminotransferase value greater than 1.5 times the ULN,

[0127] 10) Total bilirubin greater than 2 times ULN (unless due to Gilbert's syndrome)

[0128] 11) History of porphyria, myopathy, or active liver disease

[0129] 12) Current treatment with weight loss medication or previous weight loss surgery, or

[0130] 13) Use of strong inducers of CYP3A4 (e.g., apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John's wort) within 28 days before study drug administration or use of corticosteroids within 3 months before study drug administration.

[0131] (ii) Study design

[0132] This Phase 1, open-label, single-dose, parallel-group study was designed according to FDA guidance for the design and analysis of studies evaluating the effect of impaired renal function on PK. Subjects were enrolled into three renal function groups defined based on eGFR calculated using the Chronic Kidney Disease Epidemiology Collaboration equation as follows:

[0133] Control (normal renal function or mild renal impairment: eGFR ≥ 60 mL / min)

[0134] Moderate to severe renal impairment (eGFR 15 mL / min to 59 mL / min)

[0135] Renal failure (eGFR <15 mL / min, including subjects on dialysis)

[0136] All subjects received a single 10mg dose of bardoxstat in an open-label manner. Each subject had a screening period of up to 28 days, then entered the clinical site (day -1) and applied bardoxstat (day 1). All subjects needed to fast for at least 10 hours before bardoxstat was applied. Then they were administered in the manner of two 5mg tablets applied with approximately 240mL water at 8:00AM (±2 hours). After administration, the subject continued to fast for at least 4 hours. Other drug treatments were not allowed within 2 hours before administration and 2 hours after bardoxstat administration. Subjects undergoing dialysis received study drugs on non-dialysis days. Blood and urine samples for PK analysis were collected for 7 days and were followed up by telephone 3±1 days after clinical discharge.

[0137] (iii) Analytical methods

[0138] Plasma and urine samples were analyzed using a validated LC-MS / MS method to measure the concentration of bardostat and its primary metabolite (bardostat-M). "Batdostat-M" as used herein refers to a compound having the following structure:

[0139]

[0140] (iv) Pharmacokinetic analysis

[0141] Blood and urine samples were collected before and after dosing to measure plasma and urine bardostat and bardostat-M concentrations to characterize the maximum observed plasma concentrations (C max ), reach C max Time (T max ), AUC 0-last and AUC 0-inf Only plasma bardoxstat t was calculated. 1 / 2 , CL / F and V / F. Urinary PK parameters included the cumulative amount of bardoxstat and bardoxstat-M excreted in urine (A e ), renal clearance (CL) of bardostat and bardostat-M R ), and for bardoxstat the fraction of the dose excreted via the kidney (F e ).

[0142] (v) Safety analysis

[0143] Safety was assessed throughout the study based on adverse events, physical examination, ECG, sitting and orthostatic vital signs, weight measurements, and clinical laboratory evaluations.

[0144] B. Results

[0145] (i) Subjects

[0146] Baseline demographics and clinical characteristics were generally well matched across renal function groups and are presented in Table 3 .

[0147]

[0148] The subjects were mainly white (60.6%) and male (75.8%), with a mean age of 62 years and a mean BMI of 30 kg / m 2 All subjects fully represented the continuum of eGFR values. All subjects in the renal failure group were on hemodialysis.

[0149] (ii) Pharmacokinetics

[0150] The plasma PK parameters of bardoxstat are presented in Table 4.

[0151]

[0152]

[0153] The absorption of bardoxstat was similar between renal function groups. It was rapidly absorbed, with median T values ​​observed within 1.5 hours of dosing in all groups. max ( Fig. 12A and Fig. 12B ) and the mean half-life was 30 to 42 hours. Paired comparisons of moderate to severe renal impairment versus controls and renal failure versus controls showed that renal impairment had no significant effect on C max , AUC (0-last) , AUC (0-inf) There was no meaningful effect on the half-life, apparent plasma clearance, or renal clearance. To understand the relationship between the selected PK parameters and eGFR as a continuous variable, we analyzed the C max , AUC 0-last and AUC 0-inf Relationship with baseline eGFR. No strong linear or nonlinear relationship was indicated. Figure 21A-Figure 21D .

[0154] The plasma bardoxetine-M concentration-time profiles in the moderate to severe renal impairment and renal failure groups were qualitatively similar to those in the control group. Fig. 22 T values ​​of bardoxetine-M were observed in all renal function groups at approximately 22 hours after administration. max .

[0155] Urine PK parameters are also presented in Table 4. For the control group and the moderate to severe renal impairment group, approximately 12% of the bardoxstat was recovered unchanged in the urine. As expected, insufficient urine production in the renal failure group resulted in minimal renal excretion of bardoxstat in these subjects. Fig.23 .

[0156] (iii) Security

[0157] There were no deaths and only one mild drug-related treatment-emergent adverse event (diarrhea) (Table 5).

[0158]

[0159] One subject in the renal failure group experienced two TEAEs of tremor and metabolic encephalopathy, which were determined to be unrelated to the study drug. Metabolic encephalopathy was considered severe and secondary to concomitant medication of gabapentin, primidone, and baclofen and by study day 11, metabolic encephalopathy resolved and the patient was considered recovered. There were no clinically significant changes in laboratory values, vital signs, physical examinations, or ECGs (data not shown).

[0160] C. Discussion

[0161] It has been confirmed that the older MR antagonists, spironolactone and eplerenone, induce changes in biomarkers associated with improved CKD progression, presumably due to their anti-inflammatory and anti-fibrotic effects; however, the main limitation of using these drugs to treat CKD is the high incidence of hyperkalemia. Finerenone is a newer nonsteroidal MR antagonist that has recently been approved for use in CKD patients to slow the progression of CKD, despite the higher incidence of hyperkalemia. However, the effect of finerenone on blood pressure is quite mild. The results of a Phase 1 study of bardoxstat in healthy volunteers indicate that the drug has minimal effects on serum potassium in individuals with normal renal function. Therefore, it seems reasonable to explore the utility of bardoxstat as an antihypertensive agent and a potential therapy for slowing the progression of renal disease in individuals with CKD. In order to safely conduct such studies, it is important to first determine whether the presence of impaired renal function will require different bardoxstat dosing regimens due to changes in the pharmacokinetic tendency of the drug.

[0162] The results presented in this report indicate that renal impairment has no significant effect on any PK parameter measured. Plasma concentration-time curve and systemic exposure to bardoxstat are as expected based on previous studies in healthy subjects. The half-life of bardoxstat is also comparable to previous studies. In addition, there is no trend in the PK parameters across the eGFR continuous zone, and bardoxstat is safe and well tolerated in patients with varying degrees of renal function.

[0163] Kidney disease can change drug clearance, leading to increased exposure and potentially greater drug effects or toxicity. Therefore, for patients with impaired renal function, the dose must usually be adjusted. Previous observations from our single ascending dose study indicate that bardoxstat is mainly metabolized by the liver, which is consistent with the current findings that renal function does not significantly affect the PK or safety characteristics of bardoxstat.

[0164] Since this study is only intended to evaluate the PK in subjects with renal impairment, additional long-term studies are needed to fully evaluate the safety and efficacy of bardoxetine in the expected patient population (e.g., those patients with hypertension, primary aldosteronism or CKD) of the same renal impairment. In addition, this study does not include subjects who are not on dialysis in the renal failure group.

[0165] D. Conclusion

[0166] Our results demonstrate that a single dose of bardoxstat is safe and well tolerated in subjects with varying degrees of renal function, including those with renal failure, and that renal impairment does not significantly affect the systemic exposure or clearance of bardoxstat. These findings suggest that even in patients with advanced renal disease, dose adjustment of bardoxstat due to altered PK properties in patients with impaired renal function does not appear to be necessary.

[0167] E. Summary

[0168] The 1st phase open label study evaluated the safety and pharmacokinetics (PK) of a single oral dose of bardoxstat in subjects with varying degrees of renal function. Based on the estimated glomerular filtration rate (eGFR), thirty-three subjects were recruited to the renal function group. Each group was a control (eGFR ≥ 60 mL / min), moderate to severe renal injury (eGFR 15 to 59 mL / min) and renal failure (eGFR < 15 mL / min, including subjects undergoing dialysis). Control subjects were matched according to age, sex, race, body mass index (BMI) and smoking status. A single 10 mg bardoxstat dose was given, followed by 7 days of blood and urine sampling for PK analysis. Safety was assessed based on adverse events, clinical laboratory evaluations, vital signs, ECG, physical examinations and body weight measurements.

[0169] Thirty-two subjects completed the study. No deaths, and only one mild drug-related adverse event (diarrhea) occurred. There were no clinically significant changes in laboratory values, vital signs, physical examinations, or electrocardiograms (ECGs). The plasma concentration-time curves of bardoxstat were qualitatively similar in all groups. Referring to Figure 12. The urine PK parameters of the moderate to severe renal impairment group were similar to the control (excretion 12%); Insufficient urine production in the renal failure group resulted in expected negligible excretion of bardoxstat.

[0170] A single dose of bardoxstat was well tolerated in all subjects, including those with renal failure. Renal impairment did not significantly affect the systemic exposure or clearance of bardoxstat, suggesting that dose adjustment due to PK differences in these patients is not necessary, even in the setting of advanced renal disease.

[0171] Example 5: A Phase 1, open-label, single-dose, parallel-group study: In subjects with varying degrees of liver function Pharmacokinetics of Bardoxat

[0172] method

[0173] Subjects with moderate hepatic impairment (Child-Pugh B class, n = 10) and healthy controls (n = 10) were each given a single 10 mg oral dose of bardoxstat. Subjects were matched by age, sex, body mass index, race, and smoking status. Continuous blood and urine samples were collected to determine plasma and urine concentrations of bardoxstat 7 days after administration. Safety was assessed based on adverse events, clinical laboratory evaluations, vital signs, electrocardiograms, and physical examinations.

[0174] result

[0175] All 20 subjects completed the study. There were no deaths, serious treatment-emergent adverse events (TEAEs), or study discontinuations. One TEAE of moderate severity, headache, was considered related to bardoxstat in the normal liver function group. One TEAE of hyperkalemia and one TEAE of hypoglycemia occurred in the moderate liver impairment group; both were considered unrelated to bardoxstat. No clinically significant changes following bardoxstat administration were noted for clinical laboratory evaluations, vital signs, electrocardiograms, or physical examinations in either group. Plasma levels of bardoxstat ( Fig. 12A and Fig. 12B ) and urine pharmacokinetic parameters were similar between the two liver function groups, as shown in Table 6.

[0176]

[0177] In summary, based on Child-Pugh classification as moderately impaired (Class B) subjects or healthy control subjects, approximately ten subjects were recruited into each group of 2 liver function groups. Control subjects comparable to the impaired subjects in age, sex, race, BMI and smoking status were selected. In subjects with moderate liver damage, it is not necessary to adjust the bardoxstat dosage.

[0178] Example 6: Randomized, open-label, two-period, crossover study: Bardoxstatin for diazinon in healthy subjects Effects of biguanide pharmacokinetics

[0179] Due to the high comorbidity of type 2 diabetes (T2DM) and hypertension, many patients will need to be treated with common T2DM drug metformin and antihypertensive drugs. In order to evaluate the potential drug-drug interaction of bardoxstat and metformin, 27 healthy volunteers were given 1000mg metformin alone or 1000mg metformin after 10mg dose of bardoxstat. In the presence or absence of bardoxstat, the shape of the PK curve of plasma metformin did not shift or change. Bardoxstat does not significantly affect the renal clearance of metformin. There was no significant increase in death, serious adverse events (SAE), interruption due to adverse events (TEAE) occurring during the treatment period, or adverse events (AE) with any treatment. All reported TEAEs were mild in severity; no subject experienced moderate or severe TEAEs. The most common TEAE was gastrointestinal disorders. No clinically significant changes were observed in physical examination, vital signs, ECG (including no QT prolongation) or clinical laboratory results. Metformin and bardoxstat were safe and well tolerated when co-administered.

[0180] Example 6A: Evaluation of the pharmacokinetics of the aldosterone synthase inhibitor bardoxetine versus metformin in healthy human subjects A randomized, open-label, crossover study of the effects of kinetics

[0181] A. Subjects

[0182] To meet the inclusion criteria for the study, males and females aged 18 to 55 years had to 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 had a BMI ≥ 18 kg / m 2 And ≤30kg / m 2 , with an estimated glomerular filtration rate ≥85 mL / min / 1.73 m 2 adequate renal function and no recent nicotine use.

[0183] Subjects were excluded from the study if they had a personal or family history of long QT syndrome, complex ventricular arrhythmias, current or past history of clinically significant arrhythmias, family history of sudden death, prolonged QTcF (>450 milliseconds), sitting BP>140 / 90 mm Hg or <90 / 50 mm Hg, resting heart rate>100 beats per minute or <50 beats per minute, sinus node dysfunction, clinically significant atrioventricular block, postural tachycardia, or orthostatic hypotension. Other exclusion criteria included any clinical laboratory value significantly outside normal limits; a history of clinically significant or multiple drug allergies; any previous episode of lactic acidosis; a radiographic scan with contrast material within 14 days before the first dose of study drug; or a positive test for HIV antibody, hepatitis C virus antibody, hepatitis B surface antigen, or SARS-CoV-2 RNA. Subjects were excluded if they reported any recent illicit drug use; consumed more than 14 alcoholic beverages per week; or used any prescription medications, including topical medications, herbal / dietary supplements, nutraceuticals, or over-the-counter medications (other than occasional use of acetaminophen or nonsteroidal anti-inflammatory drugs) within the longer of 14 days or 5 half-lives before the first dose of study drug and throughout the hospitalization and discharge period.

[0184] B. Research Design

[0185] The study was designed as a phase 1, randomized, open-label, 2-period, crossover trial. Each subject participated in a screening period of up to 26 days, followed by 2 inpatient treatment periods and telephone follow-up. For the 2 inpatient treatment periods, subjects were randomized in a 1:1 ratio to treatment sequence AB or sequence BA. Treatment A was a single 1000 mg dose of metformin, and treatment B was a single 10 mg dose of bardoxstat, followed by a single 1000 mg dose of metformin 2 hours later.

[0186] There is a minimum 10-day washout period between the use of 2 treatments. The blood and urine samples collected for PK analysis begin before each cycle administration and continue for 3 days after each cycle administration. Samples were collected 2 hours, 1.5 hours, 1 hour, 0.5 hour and 0 hour before administration and 0.5 hour, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 22 hours, 24 hours, 36 hours, 48 ​​hours and 72 hours after administration. In the second administration phase, the subject received a telephone follow-up visit 3 ± 1 days after leaving the clinic.

[0187] (i) Bioanalytical methods

[0188] Plasma and urine samples were analyzed using a validated LC-MS / MS method to measure the concentrations of metformin, bardoxstat, and its primary metabolite, bardoxstat-M.

[0189] The quantifiable range of metformin in plasma is 0.5 ng / mL to 500 ng / mL. 6 As an internal standard. Plasma samples were extracted by precipitating proteins with methanol and subsequently analyzed by LC-MS / MS with electrospray ionization (ESI(+)) and MRM in positive ion mode. Reverse phase chromatography with a mobile phase gradient of 15% to 90% was used for separation, and the total run time was approximately 5 minutes. The ion transitions from precursor to product of metformin and internal standard were 130.1 to 71.1 and 135.4 to 77.0, respectively. Similarly, the quantifiable range of metformin in urine was 1.00 ng / mL to 500 ng / mL (low range) and 2.00 ng / mL to 1250 ng / mL (high range), with similar extraction and LC-MS / MS conditions. The inter-day precision (%CV) values ​​of metformin in plasma and urine were within 5% and 10%, respectively.

[0190] Bazostat-d 5 and bardostat-Md 3 As internal standards, the quantifiable ranges of bardoxstat and its metabolite bardoxstat-M in plasma were 0.05 ng / mL to 50 ng / mL (low range) and 5.00 ng / mL to 2500 ng / mL (high range).

[0191] As used herein, "bardostat-d 5 ” refers to a compound having the following structure:

[0192]

[0193] As used herein, "bardostat-Md 3 ” refers to a compound having the following structure:

[0194]

[0195] Plasma samples were extracted by precipitating proteins with methanol, and then analyzed by LC-MS / MS with ESI (+) and MRM. Utilizing a mobile phase gradient of 20% to 90% reversed phase chromatography separation, and the total run time was about 5 minutes. The precursor to product conversion of bardoxstat and its internal standard was 364.2 to 291.2 and 369.2 to 291.2, respectively. The conversion of bardoxstat-M and its internal standard was 309.2 to 291.2 and 313.2 to 295.2, respectively. The day-to-day precision (%CV) values ​​of bardoxstat and bardoxstat-M in plasma were within 3% and 4%, respectively.

[0196] (ii) PK analysis

[0197] PK parameters were calculated using noncompartmental methods using SAS software version 9.4 (SAS Institute). The plasma PK parameters calculated for metformin, bardoxstat, and bardoxstat-M included the maximum observed plasma concentration (C max );T max ; AUC 0-24 ; AUC 0-t ; AUC 0-inf ; Extrapolated AUC 0-inf ; z ; and t 1 / 2 Only the plasma AUC of bardoxstat and bardoxstat-M were evaluated 0-72 . C max , AUC 0-inf and AUC 0-t There were 3 plasma PK parameters that were statistically analyzed to detect any interaction between bardoxstat and metformin. Urine PK parameters included A e , renal clearance (according to A e / AUC calculation) and the fraction of the dose excreted via the kidney.

[0198] (iii) Safety analysis

[0199] Safety assessments included monitoring of AEs, physical examinations, ECGs, orthostatic vital signs, and clinical laboratory evaluations.

[0200] C. Results

[0201] (i) Subjects

[0202] Baseline demographics and clinical characteristics are presented in Table 7 .

[0203]

[0204]

[0205] Twenty-seven subjects were randomized into 2 cohorts to receive study drug in treatment order AB or BA. The majority of study participants were white (56%), male (70%), and not Hispanic or Latino. The mean age was 37 years and the mean BMI was 25.6 kg / m 2 Demographics and baseline characteristics were generally well matched between the two treatment sequences with respect to sex, race, and ethnicity.

[0206] (ii) Pharmacokinetics

[0207] When administered alone in the current study, the PK profile of metformin was consistent with that expected based on the package insert for immediate-release metformin. In addition, when administered after a dose of bardoxstat, the plasma PK profile of metformin was qualitatively and quantitatively similar to that of metformin alone ( Fig. 20 ).

[0208] After confirming the lack of effect of treatment sequence, PK data for Treatment A were pooled from all subjects, and PK data for Treatment B were pooled from all subjects. Plasma and urine PK parameters following a dose of metformin alone or in the presence of bardoxstat are reported in Table 7. Plasma C was significantly higher in the presence of metformin than in metformin alone. max The 90% CI for the geometric mean ratio of the AUC values ​​fell well within the boundaries required for bioequivalence (80%-125%), demonstrating the absence of a PK drug-drug interaction.

[0209]

[0210]

[0211] Urinary PK parameters of metformin alone and in the presence of bardoxstat are presented in Table 8, and the A values ​​of metformin excreted after administration of metformin in the presence or absence of bardoxstat were measured. e , and the results confirmed that the renal excretion of metformin was not significantly affected by bardoxstat.

[0212]

[0213]

[0214] The PK parameters of bardoxetine and its primary metabolite (Table 9) were similar to previously published data, thus demonstrating the validity of the study.

[0215]

[0216] (iii) Security

[0217] There is no death, serious AE or interruption due to adverse events (TEAE) occurring during the treatment period, and when using metformin in the presence or absence of bardoxstat, the incidence and severity of AE are similar (table 10). In general, 7 subjects experience a total of 15 TEAEs: 5 (19.2%) subjects experience a total of 6 TEAEs after metformin is used alone, and 6 (22.2%) subjects experience a total of 9 TEAEs after metformin and bardoxstat are administered. Four of these subjects experience TEAEs after two treatments (single metformin and metformin after a dose of bardoxstat).

[0218]

[0219]

[0220] All reported TEAEs were mild; no subject experienced moderate or severe TEAEs. The most common TEAE was gastrointestinal disorders. Five (18.5%) subjects reported diarrhea, an AE commonly associated with metformin treatment: 3 (11.5%) subjects after metformin alone, 4 (14.8%) subjects after both metformin and bardoxstat, and 2 subjects after both treatments. No clinically meaningful changes were observed in physical examinations, vital signs, ECGs (including no QT prolongation), or clinical laboratory results.

[0221] D. Conclusion

[0222] The results of the current study prove that when co-administered to healthy subjects with mainly mild gastrointestinal AEs observed, single doses of metformin and bardoxstat were well tolerated, as expected with high-dose metformin. Bardoxstat does not significantly affect the plasma concentration or renal clearance of metformin. Therefore, diabetic patients with hypertension who receive metformin and bardoxstat are unlikely to need a dose adjustment of metformin due to PK interactions.

[0223] Example 7: After a single oral dose in healthy male subjects [ 14 C]-Absorption, metabolism and excretion of bardoxstat Phase 1 open-label study of

[0224] Eight male subjects each received a single oral 10mg (containing approximately 100uCi) dose of bardoxstat. Blood, urine and feces samples were collected to determine the metabolism and excretion pathways of bardoxstat. Preliminary findings indicated that the average excretion rate of radioactive material was 69.4% and 15.3% of the dose in urine and feces, respectively. Unchanged bardoxstat was the main component in urine and feces, accounting for 16.8% and 6.1% of the dose, respectively. In plasma, bardoxstat was the main circulating species, as shown by the AUC curve (AUC 0-inf ) was determined to account for 71% of the total systemic exposure. The mean blood: plasma concentration ratio indicated low association of the radioactive material with blood cells.

[0225] Example 8: Study in Patients with Resistant Hypertension

[0226] The study was a randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of bardoxstat in patients with rHTN. Patients with rHTN were defined as being on a stable regimen of ≥3 antihypertensive agents, one of which was a diuretic, with a mean sitting blood pressure (BP) ≥130 / 80 mmHg. The primary objective was to demonstrate that at least one dose strength of bardoxstat was superior to placebo in the mean change from baseline in sitting SBP after 12 weeks of treatment. Secondary objectives were to evaluate the change from baseline in mean sitting DBP for each selected dose strength of bardoxstat compared with placebo, and to evaluate the percentage of patients who achieved a sitting BP response <130 / 80 mmHg after 12 weeks of treatment for each dose strength of bardoxstat compared with placebo. Patients who have maintained a stable regimen of ≥3 antihypertensive agents (including non-potassium sparing diuretics) for at least two weeks and have an average sitting BP ≥130 / 80 mmHg are eligible for the study and are randomly assigned in an evenly distributed manner to 1 of 4 treatment groups (0.5 mg, 1 mg, 2 mg of bardoxstat regimen or placebo once daily). The study plans to recruit 348 patients.

[0227] 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 bardoxat compared with placebo after 12 weeks of rHTN treatment.

[0228] Point estimates of the primary treatment effects and secondary endpoints were generated by mixed model analysis of covariance, which included responder status as a fixed effect. The primary efficacy analysis was based on a modified intention-to-treat (mITT) population to compare the change in mean sitting SBP from baseline to day 85 between bardoxstat and placebo for each dose intensity. The mixed model of repeated measures (MMRM) will be used to analyze the change in mean sitting SBP relative to baseline. The analysis includes fixed effects of treatment, visit, and treatment-visit interaction, as well as covariates of baseline mean sitting SBP and baseline glomerular filtration rate. The restricted maximum likelihood estimation (REML) method is used with an unstructured covariance matrix.

[0229] Safety was evaluated by comparing the frequency, type, distribution, and severity of adverse events, by analyzing the results of clinical chemistry, hematology, and urinalysis tests, by comparing excursion tables of the number of participants who experienced a change from normal to abnormal values ​​(low or high) from baseline to Week 12, and by detailed evaluation of the circumstances surrounding serious adverse events and events leading to treatment discontinuation.

[0230] result

[0231] A total of 779 candidates agreed to participate in the study, 275 were eligible and randomized to one of four treatment groups (0.5 mg, 1 mg, 2 mg bardoxstat, or placebo once daily), and 248 patients completed the study ( Figure 1 ). Fifteen of the 27 discontinued patients dropped out due to loss to follow-up (n=8) or withdrawal of consent (n=7), most of which occurred when the coronavirus disease 2019 (COVID-19) pandemic situation may have interfered with patient retention. When the study was halfway completed, there was a single discontinuation due to loss to follow-up in each of the placebo, 1 mg, and 2 mg dose groups, and 3 patients were lost to follow-up in the lowest dose group of 0.5 mg. This discontinuation rate was not dose-dependent in the second half of the study. In the first half of the study, the COVID-19 pandemic may have affected the discontinuation rate.

[0232] One patient discontinued study participation due to an adverse event of disc degeneration (n=1), and one patient experienced 3 SAEs of hyperglycemia, hyponatremia, and hyperkalemia, leading to withdrawal from the study (Table 11).

[0233]

[0234] The demographics and baseline characteristics of the patients in the 4 study arms were well balanced (Table 12). Most participants were older, overweight or obese, and had normal renal function or mildly impaired renal function. All but one patient were taking at least 3 antihypertensive medications, including diuretics. In addition, more than 90% of them had taken RAAS antihypertensive agents (Table 13). Overall, this group represents typical rHTN patients.

[0235]

[0236]

[0237]

[0238] effect

[0239] The results of the study proved that 1mg and 2mg of bardoxstat effectively reduce the SBP of rHTN patients. Compared with the placebo response of reducing 9.4mmHg, treatment with 2mg of bardoxstat caused SBP to decrease by 20.3mmHg, producing a model-adjusted, placebo-corrected decline of 11.0mmHg (95% confidence interval [CI] -16.4mmHg, -5.5mmHg) (p value = 0.0001), thus rejecting the null hypothesis and confirming the effectiveness of 2mg bardoxstat. Test the next dose of 1mg of bardoxstat according to the planned hierarchical order. The 1mg dose also produced a significant placebo-adjusted SBP decline of 8.1mmHg (p value = 0.003). The treatment effect of the 0.5mg dose was slightly greater than that of the placebo, but the difference did not reach statistical significance. Improvements in DBP were also observed. After 12 weeks of treatment, DBP in the 2 mg, 1 mg, and 0.5 mg dose groups decreased by 14.3 mmHg, 11.8 mmHg, and 8.6 mmHg, respectively, compared to a decrease of 9.2 mmHg in the placebo group (Table 14).

[0240]

[0241]

[0242] like Figure 2 As shown, SBP decreased rapidly after the start of treatment and continued to decrease throughout the 12 weeks of treatment.

[0243] Prospectively planned sensitivity analyses were performed using the intention-to-treat (ITT) or per-protocol analysis set and showed nearly identical model-adjusted and placebo-corrected changes from baseline in the 2 mg group, -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. These results support the primary endpoint analysis.

[0244] To further elucidate the treatment effect in patients with different 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 bardoxstat and placebo by group. 2 or ≥ 60 mL / min / 1.73 m 2 ), baseline serum aldosterone concentration (<6ng / dL or ≥6ng / dL) and the use of background antihypertensive drugs were analyzed in subgroup. If the patient who is administered with bardoxstat is male, white race, non-Hispanic or Latino, with higher eGFR and the baseline SBP value of ≥145mmHg, then they experience larger SBP reduction (Table 15A and Table 15B). The blood pressure response of the patient whose baseline plasma aldosterone is higher or lower than 6ng / dL shows similar blood pressure reduction. This can be reflected in the extensive variability of single plasma aldosterone measurement during the study visit. The total aldosterone in the 24-hour urine collections in the patient assigned to the active group shows a significant reduction related to treatment.

[0245] The large differences in treatment effects between subgroups appear to be driven by the large reductions in SBP in the placebo arm. For example, female participants assigned to the placebo group showed a 15.3 mmHg reduction in SBP; Hispanic / Latino participants in the placebo arm showed a 11.3 mmHg reduction in SBP. Female Hispanic subjects (N=14) randomized to placebo had a 18.1 mmHg reduction in SBP compared to a 7.1 mmHg reduction in subjects who were not female and Latino (N=55). Even though placebo effects are commonly observed in clinical trials, a mean change of -18.1 mmHg is quite unusual (Tables 15A and 15B).

[0246]

[0247]

[0248]

[0249] Pharmacodynamic evaluation

[0250] Blood and urine samples were collected for determination of pharmacodynamic parameters related to the aldosterone inhibition mechanism of bardoxstat. Serum concentrations of aldosterone, aldosterone excreted in 24-hour urine collections, plasma renin activity (PRA), and serum cortisol were summarized by dose and study day as follows: Figure 3A-3D Pharmacodynamic results demonstrated that bardoxstat treatment-related reductions in serum aldosterone concentrations ( Figure 3A ), decreased aldosterone excretion in 24-hour urine samples ( Figure 3B ), increase in PRA ( Figure 3C ) without significantly affecting total cortisol concentration ( Figure 3D ). These results indicate that treatment with bardoxstat caused a mean decrease in serum aldosterone of 50% to 60%, significantly reduced urinary aldosterone excretion and increased PRA several-fold, without a decrease in total serum cortisol. These hormonal data provide strong biochemical evidence supporting the mechanism by which bardoxstat inhibits aldosterone synthesis to produce a significant effect on blood pressure levels without reducing serum cortisol levels.

[0251] Because significant differences in the effects of treatment on SBP were observed between male and female patients, potential differences in response to bardoxstat treatment were examined by comparing serum aldosterone concentrations and PRA. Figure 4A and Figure 4B The suppression of aldosterone and enhancement of renin activity were shown to be equivalent between male and female patients, suggesting that extrinsic factors may contribute to the unusually high placebo response in the female population, particularly the Hispanic ethnic group.

[0252] Treatment-emergent AEs and SAEs

[0253] It is well tolerated to use bardoxstat once a day for 12 weeks. 120 (43.8%) of 274 patients experienced a total of 232 TEAEs (table 16). Compared with 0.5mg (34.8%) or placebo (40.6%) groups, higher percentage of patients experienced TEAEs in 1mg (52.2%) and 2mg (47.8%) dosage 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 (62.5%) in severity and considered unrelated to study drug (89.2%) by investigators.

[0254]

[0255]

[0256] TEAEs that occurred more frequently at a rate of 2% or more in the 2mg or 1mg group compared to the placebo group are shown in Table 17. These events may be related to a decrease in blood pressure (e.g., dizziness, syncope, palpitations) or the mechanism of action of the study drug (i.e., hyperkalemia, hyponatremia, renal injury). Although more patients experienced urinary tract infection and COVID-19 in the 1mg or 2mg group of bardoxstat, no causal relationship was identified.

[0257]

[0258]

[0259] 10 patients experienced serious adverse events (TESAE) (Table 18) that occurred during 18 treatment periods. There were no deaths in this study, and all SAEs were assessed by the investigators as being unrelated to bardoxstat. A 72-year-old white male subject suspected of having urosepsis in the 2mg dose group experienced 6 SAEs of acute kidney injury, urinary tract infection, dehydration, hyperglycemia, hyperkalemia, and hyponatremia on the 15th day of the study. These events were assessed as being unrelated to bardoxstat, and the patient withdrew from participating in the study due to these metabolic disorders. There were 3 patients who experienced 2 SAEs each: a patient with pyelonephritis and nephrolithiasis in the 1mg dose group, a patient with respiratory failure and cellulitis in the 2mg dose group, and a third patient with pyelonephritis and pneumonia who received placebo. A single patient experienced all other SAEs.

[0260]

[0261]

[0262] Adverse Events of Special Interest (AESI)

[0263] In this study, adverse events of special interest (AESI) were events of hypotension, low sodium levels, or elevated potassium levels requiring clinical intervention. There were a total of 10 AESIs distributed among the treatment arms in 8 patients: placebo arm (0), 0.5 mg arm (1), 1 mg arm (5), and 2 mg arm (2). In the event of hyperkalemia or hyponatremia, close follow-up was required in the protocol, and recommendations for dietary or hydration interventions were made by the study team to the investigators when laboratory abnormalities were recognized.

[0264] The only AESI of hypotension occurred in the patient in the 1mg bardoxstat dose group, and the patient interrupted the study drug, causing the hypotension to subside. There were three AESIs of hyponatremia or hyponatremia. One patient was in the 2mg dose group, suspected of having urosepsis (as described above), experienced 6 SAEs of acute kidney injury, urinary tract infection, dehydration, hyperglycemia, hyperkalemia and hyponatremia, and interrupted the study due to adverse events. Another patient randomized to the 1mg bardoxstat group had an AESI of hyponatremia of moderate severity related to the trial drug, and their study drug and diuretics were permanently interrupted. They were recovered. The third patient who finally received 1mg bardoxstat noted hyponatremia of 129mEq / L at the lowest point; the study drug was discontinued and then restarted. Their AESI was moderately severe, study drug-related, and subsided.

[0265] Of the 6 AESI for hyperkalemia, 2 are discussed above. None were associated with ECG changes or hospitalizations. All patients with hyperkalemia received other medications known to be associated with hyperkalemia (e.g., beta blockers or ACEIs), and no patient discontinued the study specifically due to hyperkalemia.

[0266] Serum electrolytes

[0267] Aldosterone plays a direct role in the pathogenesis of hypertension by increasing the renal absorption of sodium and water while promoting potassium excretion. Therefore, aldosterone synthesis inhibitors have the potential to cause electrolyte abnormalities of hyperkalemia or hyponatremia. Moreover, the expected reduction in SBP by aldosterone inhibitors will reduce blood flow through the afferent arterioles in the kidney, leading to a significant decrease in eGFR measurements. Throughout the study, these potential perturbations in renal physiology were closely monitored by measuring serum electrolytes and eGFR.

[0268] The overall change in serum potassium from baseline to the end of treatment was -0.08 (0.429) mEq / L in the placebo group, and in the bardoxstat 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 (0.380) mEq / L in the 2 mg dose group ( Figure 5 ).

[0269] Moderate hyperkalemia (potassium > 6.0 mEq / L) occurred in 3 patients in the 2 highest dose groups, with an overall rate of 2.2%. The rate for spironolactone in the Pathway-2 study was 2.1%. Hyperkalemia generally presented with isolated values, resolved after dietary advice, and did not require modification of study drug dosing.

[0270] Hypokalemia is a known complication of the therapy with diuretics required for entering the study.Hypokalemia is defined as mild (potassium 3.5mEq / L to 3.1mEq / L), moderate (potassium 3.0mEq / L to 2.5mEq / L) and severe (less than 2.5mEq / L).Two patients in the placebo group had moderate hypokalemia; no case in any bardoxstat dosage group.The absence of moderate hypokalemia in any bardoxstat treated patient indicates that the use of bardoxstat can provide protection against potential thiazide diuretic-induced hypokalemia.

[0271] Similarly, treatment with bardoxstat was associated with a modest decrease in serum sodium concentrations. The decrease in sodium from baseline to the end of treatment ranged from a mean (SD) of -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, to -2.4 (2.94) mEq / L in the 2 mg dose group, which was not of significant clinical concern ( Figure 6 Ten patients developed mild hyponatremia, defined as serum sodium <130 mEq / L, including 1 in the placebo group, 1 in the 0.5 mg bardoxstat group, 7 in the 1 mg bardoxstat group, and 1 in the 2 mg group. Four patients discontinued the study early, including one in the placebo group. During the study, the investigators recognized that sodium was also easily corrected with ambulatory management recommendations, and no discontinuations due to low serum sodium occurred after the midpoint of the trial.

[0272] During the study period, bardoxstat treatment was associated with a slight dose-dependent decrease in mean eGFR change that appeared to be related to the dose of bardoxstat used ( Figure 7 ). Clinical results revealed that there were 3 renal injury AEs in the 1 mg bardoxstat dose group, 1 in the 2 mg dose group and no cases in the 0.5 mg dose group. All patients recovered. In general, the moderate decline in eGFR seen in the figure is consistent with the renal hemodynamic effects observed with all types of RAAS inhibitors, particularly aldosterone antagonists such as spironolactone, which are completely reversible when interrupted. There was no obvious relationship between bardoxstat dose and serum calcium, serum phosphorus or serum phosphorus levels.

[0273] Security Features Overview

[0274] Study 121 demonstrated that 0.5 mg, 1 mg, and 2 mg doses of bardoxstat were safe and well tolerated. There were no deaths in this study. Most TEAEs were mild, and more than 89% were considered unrelated to the study drug. Of the 18 SAEs in 10 patients, only two patients discontinued due to SAEs, and the researchers considered all SAEs to be unrelated to the study drug.

[0275] Initially, there were several study discontinuations due to loss to follow-up or patient decision in the higher-dose bardoxstat group and none in the placebo group, but this imbalance between treatment groups resolved later in the study, suggesting that discontinuations were not related to bardoxstat and were more likely due to external factors.

[0276] With regard to electrolytes and renal function, rates of hyperkalemia and hyponatremia were expected based on the mechanism of action of bardoxstat. Bardoxstat treatment was associated with a decrease in mean eGFR that was expected given experience with aldosterone inhibitors and the mechanism of action of bardoxstat.

[0277] in conclusion

[0278] Results from Study 121 demonstrated that 1 mg and 2 mg doses of bardoxstat were effective in reducing SBP in patients with rHTN. The placebo-corrected changes (standard error) after 12 weeks of treatment were -11.0 (2.78) mmHg and -8.1 (2.7) mmHg in the 2 mg and 1 mg dose groups, respectively, which were statistically significant and clinically meaningful in this difficult-to-treat population. Treatment with 2 mg bardoxstat resulted in a significant reduction in DBP of 5.2 mmHg compared to the placebo group.

[0279] Data from 121 studies prove that bardoxstat can reduce the aldosterone level in the resistant hypertension population, causing SBP to be significantly reduced under 1mg / d and 2mg / d dosages, with good overall safety and tolerability. The study further proves that bardoxstat treatment does not reduce their average serum cortisol levels, and the case of adrenal insufficiency is not reported during the trial. Due to the non-selective inhibition of CYP11B1 (responsible for the enzyme of cortisol synthesis) has become the main obstacle of the aldosterone synthase inhibitor for the treatment of hypertension in previous efforts, so these results support drug development.

[0280] Example 9: Study in patients with uncontrolled hypertension

[0281] Study 124 was a double-blind, placebo-controlled, dose-ranging, multicenter study in uHTN patients receiving background antihypertensive agents, which were ACEI or ARB, ACEI / ARB plus thiazide diuretics, or ACEI / ARB plus calcium channel blockers. The study consisted of two parts; Part 1 consisted of an 8-week treatment period in which patients were equally assigned to one of four dose groups to test the effects of 0.5 mg, 1 mg, and 2 mg of bardoxstat compared to placebo. Patients were administered double-blind bardoxstat tablets once daily while they continued to take background antihypertensive medications. After 8 weeks of double-blind treatment, patients entered Part 2 of the study unless they were assigned to the 2 mg group and SBP remained ≥130 mmHg. In Part 2 of the study, all patients stopped background antihypertensive medication and took only the 2 mg dose of bardoxstat as monotherapy for 4 weeks.

[0282] Patient demographics and baseline characteristics are shown in Tables 19-21.

[0283]

[0284]

[0285]

[0286] Key objectives generally include (i) does bardoxstat work in uHTN patients, (ii) what dose produces robust BP lowering, and (iii) are there subgroups of patients who respond better than others, and if so, (a) is response defined by background BP medication effects? (b) do aldosterone or renin levels predict response? and (c) do demographics or racial / ethnic characteristics contribute to response?

[0287] The primary objective of the trial was to demonstrate that at least one dose intensity of bardoxat was superior to placebo in the change from baseline in mean sitting SBP after 8 weeks of treatment (Part 1 of the study) in these patients.

[0288] The secondary purpose is to evaluate the change in the mean sitting DBP of each selected dose strength of bardoxstat relative to baseline after 8 weeks of treatment (Part 1) compared with placebo, the change in 24-hour urine aldosterone and serum aldosterone levels relative to baseline of each selected dose strength of bardoxstat after 8 weeks of treatment (Part 1) compared with placebo, and the percentage of patients ("responders") who reach a mean sitting SBP<130mmHg for each selected dose strength of bardoxstat after 8 weeks compared with placebo; and the change in 24-hour urine renin and serum renin levels of bardoxstat relative to baseline after 8 weeks of treatment compared with placebo. Patients who complete the Part 2 study at week 12 or are considered to have withdrawn at the end of Part 1 can qualify for entry into a separate open-label extension study (Study 130). Part 2 is an exploratory phase of the trial designed to evaluate the effect of a 4-week monotherapy with 2mg bardoxstat in this hypertensive population, but the primary goal of the Part 2 cycle is to transition patients to a long-term open-label safety extension study of the highest dose of bardoxstat that may be used in the hypertensive population.

[0289] Safety objectives for Parts 1 and 2 were to evaluate vital signs, standing blood pressure, heart rate, physical examination, ECG, weight, and clinical laboratory evaluations including a standard safety chemistry panel, hematology, coagulation, and urinalysis.

[0290] Key inclusion criteria included patients being on a stable regimen of antihypertensive agents for at least 8 weeks; and sitting BP ≥ 140 mmHg. Key exclusion criteria included sitting SBP ≥ 180 mmHg and estimated glomerular filtration rate (eGFR) < 30 mL / min / 1.73 m 2 .

[0291] A. Initial Results

[0292] A total of 249 patients were enrolled in this study, 91 completed the 12-week assessment, and 16 withdrew from their study participation early. Reasons for early withdrawal included withdrawal of consent (n=7), loss to follow-up (n=1), hypertension (n=1), need for prohibited medication (n=1), failure to meet the criteria for participation in Part 2 (n=3), failure to meet the eligibility criteria (n=1), and adverse events (n=2). Ninety patients agreed to continue in the open-label extension study130.

[0293] The mean blood pressure (average of 3 office blood pressure measurements) was 147 mmHg at baseline while patients were on a stable regimen of up to two antihypertensive agents. The combined blinded SBP, including data from both the placebo and active bardoxstat groups, showed a gradual decrease in SBP from a baseline of 147 mmHg to 128 mmHg at Week 8 over the 8 weeks during the Part 1 treatment period. Figure 8). The 18 mmHg reduction in SBP was similar to the aggregate change of approximately 16 mmHg observed in Study 121. Interestingly, in Part 2 of the study when patients stopped their background antihypertensive medications, there was no large increase in mean blood pressure when bardoxstat was the only study medication taken.

[0294] B. Interim Results

[0295] (i) Section 1

[0296] To date, 249 patients have been randomized, 227 have completed the 8-week assessment, 201 have completed the 12-week assessment, and 175 have completed the 12-week assessment and 2-week follow-up period. Fig.13 and Fig.14 The reasons for withdrawal are shown in Table 22.

[0297]

[0298] The primary efficacy endpoint results are shown in Table 23.

[0299]

[0300]

[0301] 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 MMRM models with change from baseline as the dependent variable, randomized treatment, visit, and treatment-by-visit interaction as fixed categorical effects; and covariates of baseline value, race (African American vs. non-African American), and type of background antihypertensive regimen. The restricted maximum likelihood estimation (REML) method will be used with an unstructured covariance matrix and the Kenward-Roger approximation for degrees of freedom.

[0302] The LS mean change in SBP from baseline based on treatment week is shown in Table 24.

[0303]

[0304] The data also showed that patients in the placebo arm had a significant reduction in SBP after randomization; particularly between Weeks 6 and 8. Fig.16 Although the primary endpoint was not reached ( Fig.14 ), but SBP decreased significantly in the non-Hispanic / Latino groups. See Figure 15.

[0305] Hispanic / Latino Patient Subgroups

[0306] After unblinding, it was confirmed that the placebo patients did not receive active drug. It was also noted 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 two non-Hispanic patients were determined to be non-adherent based on PK. Tables 25A and 25B show the subgroup analyses.

[0307]

[0308]

[0309] The results also confirmed the lack of response in Hispanic women. See Tables 26A-26B and 27A-27B.

[0310]

[0311]

[0312]

[0313]

[0314]

[0315] The responses of Hispanic males were less robust than those of non-Hispanic males. See Tables 28A-28B and 29A-29B.

[0316]

[0317]

[0318]

[0319]

[0320]

[0321] The results were further analyzed to determine the effectiveness of the drug in Hispanic patients who adhered to their physician's instructions. See Table 30.

[0322]

[0323] Results showed that bardoxstat (2 mg) was effective in Hispanics / Latinos who adhered to the prescription, but the efficacy response was generally low.

[0324] Black / African American Subgroup

[0325] The black / African American subgroup was also analyzed and 2 mg of bardoxstat was found to be effective.

[0326] See Table 31A and Table 31B.

[0327]

[0328]

[0329]

[0330] Aldosterone Variation by Race

[0331] The effect of race on changes in aldosterone was analyzed. Baseline values ​​are shown in Table 32. See also Figure 17.

[0332]

[0333] Plasma renin activity by ethnicity

[0334] The effect of race on plasma renin activity (PRA) was analyzed. Baseline values ​​are shown in Table 33. See also Figure 18.

[0335]

[0336] Safety Results

[0337] Safety results showed that bardoxstat provided a compelling safety profile. There were two treatment-emergent SAEs (2 patients), neither of which was considered related to bardoxstat. An 81-year-old male died from an unrelated SAE of acute respiratory failure following diagnosis of COVID-19 30 days after his last dose of bardoxstat. See Table 34.

[0338]

[0339] There were also no instances of hyperkalemia leading to study discontinuation in bardoxat recipients, and no off-target side effects.

[0340] Hyperkalemia was also found to be low and isolated. There was an overall modest increase in mean potassium of 0.1 mEq / L at the 2 mg dose. See Tables 35-36 and Fig.19 .

[0341]

[0342]

[0343]

[0344] Three patients receiving bardoxstat (about 1.6% of patients receiving bardoxstat) experienced isolated instances of moderately elevated potassium>6mEq / L. This rate of moderate hyperkalemia is the same as the PBO rate of 1.6%; and compares favorably with the previous result of 2.1%. The average potassium rise of 0.1mEq / L in the 2mg dose group is consistent with the small potassium rise observed in the 2mg group observed earlier. No potassium rise of>6.2mEq / L was recorded in patients taking bardoxstat, and no patient completed the trial with moderate hyperkalemia. No instances of hyperkalemia in patients in the active bardoxstat group led to trial interruption.

[0345] (ii) Results of Part 2

[0346] Part 2 showed that bardoxetine (2 mg) was safe and well tolerated in the 213 patients who entered Part 2. Fourteen patients who completed Part 1 did not enter Part 2 - 12 of whom were ineligible based on BP < 130 mmHg.

[0347] In Part 2, background antihypertensive therapy was interrupted after Part 1, and patients took 2 mg of bardoxstat for another four weeks. When comparing between the start and end of four weeks after withdrawal of background medications and taking only 2 mg of bardoxstat, SBP remained stable. There were two cases of moderate hyperkalemia with K+> / =6.0 mEq / L in 213 patients in Part 2; both patients had stopped diuretics at the beginning of Part 2 and developed transient moderate hyperkalemia within 2 weeks.

[0348] Safety Features

[0349] It is assumed that all patients in Part 2 take 2 mg of bardoxstat. The results of Part 2 emphasize that the 2 mg dose of bardoxstat provides a compelling safety profile. See Table 37.

[0350]

[0351] Treatment-emergent SAEs: 4 events / 3 patients, none of which were considered related to bardoxstat. There were also no instances of hyperkalemia leading to study discontinuation in bardoxstat recipients. There were also no off-target side effects.

[0352] C. Summary of Results

[0353] In summary, the first-line efficacy primary endpoint was not met due to differential response in the Hispanic / Latino cohort. The Hispanic / Latino cohort comprised >50% of the study population. However, a pre-specified non-Hispanic analysis was able to salvage the study / data.

[0354] Results were promising in other subgroups, including black / African American patients and non-Hispanic women.

[0355] The overall safety profile was favorable with low rates of hyperkalemia.

[0356] Example 10: Study in patients with uncontrolled hypertension and chronic kidney disease

[0357] Study 123 is a randomized, double-blind, placebo-controlled, multicenter, parallel-group, dose-ranging study to evaluate bardoxstat for the treatment of patients with uHTN and CKD. The primary objective of the study is to evaluate the treatment effect of bardoxstat on SBP compared with placebo at Week 26. Secondary objectives are to evaluate the effect of bardoxstat on SBP compared with placebo with a high- or low-dose strategy, determine the percentage of patients achieving SBP <130 mmHg, evaluate the change from baseline in urine albumin-to-creatinine ratio (UACR), evaluate the change from baseline in DBP for each dosing strategy, and evaluate the change from baseline in eGFR after 26 weeks of treatment. Safety objectives will evaluate vital signs, standing BP and heart rate, physical examination, electrocardiogram, weight measurement, and clinical laboratory evaluations, including a standard safety chemistry panel, hematology, coagulation, and urinalysis. Approximately 300 patients will be enrolled at 70 planned clinical sites in the United States.

[0358] Male and female adult patients with uHTN and mild to severe CKD were enrolled in the study. Patients with uHTN were defined as those taking a stable dose of antihypertensive medications, ACEI / ARB, and having a sitting office SBP of ≥140 mmHg or ≥130 mmHg if diabetic. Patients with mild to severe CKD were defined as having a blood pressure of 25 to 75 mL / min / 1.73 m2 based on at least 2 of 3 measurements of the first urine collected early in the morning on consecutive days during the screening period. 2 eGFR (based on the CKD-EPI equation) and UACR ≥ 200 mg / g (≥ 22.6 mg / mmol). Patients taking MRA must agree to stop MRA administration to be eligible to start a 2-week run-in period, during which patients will take a single-blind placebo tablet once a day while continuing background antihypertensive medications. Patients who remain eligible will be randomized to one of the three treatment arms of placebo, low-dose strategy, and high-dose strategy and start a 26-week treatment period.

[0359] Patients assigned to the low-dose strategy arm were offered bardoxetine 0.5 mg, administered once daily. The dose could be titrated up to 1 mg at week 3 if the patient did not experience hyperkalemia, hyponatremia, or a significant decline in renal function based on laboratory testing of samples drawn at week 1, and if the mean sitting SBP was ≥130 mmHg at week 3. The dose could be titrated down 6 weeks after randomization if the patient experienced hyperkalemia, hyponatremia, or a decline in renal function based on laboratory testing of samples drawn at week 5. No further dose titration was permitted after 6 weeks. The study design is shown in Fig. 9 middle.

[0360] Embodiment 11

[0361] A. Research Design

[0362] (i) Overall design

[0363] This is a Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety, tolerability, and effects on SBP lowering of 1 mg or 2 mg bardoxetine versus placebo, administered orally once daily (QD), in approximately 720 participants aged ≥18 years with HTN despite a stable regimen of 2 antihypertensive medications at baseline, one of which was a diuretic (uHTN); or ≥3 antihypertensive medications at baseline, one of which was a diuretic (rHTN).

[0364] Consenting participants will be screened within 4 weeks and will then enter a 2-week single-blind run-in period with placebo. Thereafter, participants will be distributed sequentially into 2 cohorts (Cohort 1 and Cohort 2) and randomized in a 1:1:1 ratio to receive 1 of the following 3 treatments once daily during the 12-week double-blind period:

[0365] 2 mg bardoxetine

[0366] 1 mg bardoxetine

[0367] Placebo

[0368] Randomization will be stratified by baseline HTN (uHTN, rHTN) and baseline siSBP (<145 mmHg, ≥145 mmHg).

[0369] After participants in both cohorts completed the 12-week double-blind period:

[0370] Participants who complete treatment with 2 mg of bardoxstat will be randomized in a 1:0 ratio to receive 2 mg of bardoxstat once daily during the 12-week open-label period.

[0371] Participants who complete treatment with 1 mg of bardoxstat will be randomized in a 4:1 ratio to receive 2 mg of bardoxstat once daily or standard of care during the 12-week open-label period (from Week 12 to Week 24). The standard of care period will last for 40 weeks (from Week 12 to Week 52) for participants in Cohort 1 and 12 weeks (from Week 12 to Week 24) for participants in Cohort 2.

[0372] Participants who received placebo will be randomized in a 1:4 ratio to receive either 2 mg of bardoxstat once daily or standard of care during the 12-week open-label period (from Week 12 to Week 24).

[0373] After participants completed the 12-week open-label period of 2 mg bardoxstat:

[0374] Participants in Cohort 1 (who complete treatment with 2 mg bardoxstat) will be randomized a third time in a 2:1 ratio to continue to receive 2 mg bardoxstat once daily or placebo once daily for an 8-week double-blind RWD period. Randomization will be based on baseline HTN (uHTN, rHTN) and by siSBP (<130 mmHg,

[0375] Participants who complete the RWD period will then enter an open-label period, in which they will receive 2 mg of bardoxstat once daily for 20 weeks, followed by a 2-week safety follow-up period.

[0376] Participants in Cohort 2 will begin a 2-week safety follow-up period.

[0377] The study figures for the two cohorts are presented in Fig.24 and Fig.25 If at any time during the study a participant reported K + If the level is >5.5 mEq / L, the laboratory analysis should be repeated within 72 hours. The study is planned to be conducted worldwide.

[0378] (ii) Screening

[0379] All participants who agree to participate in this study will be screened within 4 weeks and then begin a run-in period.

[0380] (iii) Placebo single-blind run-in period

[0381] Eligible participants who complete the screening visit procedure will enter a 2-week single-blind run-in period and receive placebo in addition to any existing background antihypertensive medication.

[0382] The purpose of this period was to reduce the placebo effect after baseline and to ensure that participants had stable background antihypertensive medications.

[0383] (iv) Double-blind placebo-controlled treatment period

[0384] Approximately 720 participants who meet the study inclusion criteria will be distributed sequentially into 2 cohorts (approximately 450 participants in cohort 1 and approximately 270 in cohort 2). Participants in each cohort will be randomized in a 1:1:1 ratio to receive one of the following 3 study treatments once daily: 2 mg bardoxstat, 1 mg bardoxstat, or placebo. Participants will receive this treatment for 12 weeks (from Week 0 to Week 12).

[0385] During this period, participants should maintain their background antihypertensive medication regimen and dose. The dose of background antihypertensive medication should not be changed during this period unless the participant experiences SBP <100 mmHg and hypotensive symptoms.

[0386] (v) Open-label treatment period

[0387] All participants in Cohorts 1 and 2 who complete the 12-week double-blind treatment period with 2 mg bardoxstat once daily will be randomized in a 1:0 ratio at the start of the open-label period to continue receiving 2 mg bardoxstat once daily for 12 weeks (from Week 12 to Week 24).

[0388] Participants in Cohorts 1 and 2 who received bardoxstat 1 mg once daily or placebo once daily during the 12-week double-blind period will be randomized in a 4:1 or 1:4 ratio to receive bardoxstat 2 mg or standard of care, respectively.

[0389] (vi) Bardostatin

[0390] All participants randomized to 2 mg bardoxetine at Week 12 will receive 2 mg bardoxetine in an open-label fashion for 12 weeks (from Week 12 to Week 24) in addition to any existing background antihypertensive medications, and will undergo changes during this open-label period (except for the addition of intolerant MRAs and potassium-sparing diuretics).

[0391] Approximately 300 participants in Cohort 1 and 180 participants in Cohort 2 will receive 2 mg of bardoxstat during this period.

[0392] Participants with hyperkalemia will also follow instructions per treatment interruption criteria and will follow local standard of care.

[0393] (vii) Standard of care

[0394] Approximately 150 participants in Cohort 1 and 90 participants in Cohort 2 will be randomized in an open-label fashion to receive standard of care. Participants in Cohort 1 will receive this treatment for 40 weeks (from Week 12 to Week 52; see Fig.24 ), and participants in cohort 2 will receive this treatment for 12 weeks (from week 12 to week 24; Fig.25 After completing this standard of care treatment period and before completing the overall study, participants will enter a 2-week safety follow-up period.

[0395] (viii) Randomization withdrawal double-blind period - participants in cohort 1 only

[0396] All participants in Cohort 1 who complete the 12-week open-label treatment period with 2 mg bardoxstat will be re-randomized at Week 24 in a 2:1 ratio to continue to receive 2 mg bardoxstat once daily or placebo once daily for an 8-week double-blind withdrawal period (from Week 24 to Week 32) and stratified by baseline HTN (uHTN, rHTN) and SBP at randomization by RWD (≤130 mmHg, >130 mmHg). Approximately 200 participants will be randomized to 2 mg bardoxstat and 100 participants will be randomized to placebo.

[0397] During this period, participants should maintain the same background antihypertensive medication regimen and dose they received at the beginning of this period. The dose of background antihypertensive medication should not be changed unless the participant experiences SBP <100 mmHg and symptoms of hypotension.

[0398] Mineralocorticoid receptor antagonists and potassium-sparing diuretics are contraindicated during this period.

[0399] (ix) Second open-label period in cohort 1

[0400] Participants who complete the 8-week RWD double-blind period in Cohort 1 will enter the 20-week open-label period (weeks 32 to 52) to receive 2 mg of bardoxstat once daily in addition to any existing background antihypertensive medications. During this period, participants' background therapy may be changed, but MRAs or potassium-sparing diuretics are not allowed.

[0401] (x) Safety follow-up

[0402] All study participants will complete a 2-week safety follow-up period prior to completing the entire study. Participants in Cohort 1 will enter this final study period after completing either the 20-week open-label period or the 40-week standard of care period, and participants in Cohort 2 will enter this period after completing the 12-week open-label period.

[0403] (xi) Study end definition

[0404] For the purpose of clinical trial transparency, the definition of study end differs under FDA and EU regulatory requirements:

[0405] The EU requires that study completion be defined as the last visit to the last subject for any protocol-related activity.

[0406] The FDA requires two completion dates to be defined:

[0407] - Initial Completion Date - the date on which the last participant was examined or received the intervention for the final collection of data on the primary outcome measure, regardless of whether the clinical study was completed according to the pre-specified protocol or was terminated. In the case of a clinical study with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection was completed for all primary outcomes.

[0408] - Study Completion Date - the date on which the last participant was examined or received an intervention for the final collection of data on primary and secondary outcome measures and AEs (e.g., the last visit of the last participant), regardless of whether the clinical study was concluded according to the pre-specified protocol or was terminated.

[0409] A participant was considered to have completed the study if he / she had completed all phases of the study, including the last visit or last scheduled procedure. The end of the study was defined as the date of the last visit of the last participant in the study or the date of the last scheduled procedure of the last participant in the global study.

[0410] B. Research Group

[0411] (i) Inclusion criteria

[0412] Participants were eligible for inclusion in the study only if all of the following criteria applied:

[0413] age

[0414] 1. Male or female participants must be ≥18 years old when signing the informed consent form.

[0415] Participant Types and Disease Characteristics

[0416] 2. The mean siSBP of AOBPM was ≥140 mmHg and <170 mmHg at screening.

[0417] 3. Meet at least one of the following two criteria:

[0418] (a) Participants in the uHTN subgroup: A stable regimen of 2 antihypertensive medications from different therapeutic classes (at least one should be a diuretic) at maximally tolerated doses 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.

[0419] (b) Participants in the rHTN subgroup: A stable regimen of ≥3 antihypertensive medications (at least one should be a diuretic) from different therapeutic classes at maximally tolerated doses for at least 4 weeks prior to screening.

[0420] Beta-blockers for HF, coronary artery disease) should not be counted as antihypertensive drugs.

[0421] 4. Good compliance with prescribed antihypertensive medications demonstrated by DOT during Visit 2.

[0422] 5. Estimated glomerular filtration rate ≥ 45 mL / min / 1.73 m at screening 2

[0423] 6. Screening serum potassium (K + ) level ≥3.5mmol / L and <5.0mmol / L.

[0424] 7. Morning cortisol level (measured at 08:00am±2 hours)>3μg / dL.

[0425] (ii) Randomization criteria

[0426] These randomization criteria apply only to the initial randomization of the study. Participants are eligible for randomization to a treatment group only if all of the following criteria apply:

[0427] 1. Mean siSBP of attending clinic AOBPM at baseline (end of run-in period) ≥135 mmHg.

[0428] 2. 80% to 120% compliance to placebo during the run-in period based on pill counts on the morning of randomization.

[0429] 3. No change in background therapy consisting of 2 antihypertensive medications (at least one should be a diuretic) and doses for participants in the uHTN subgroup or ≥3 antihypertensive medications (at least one should be a diuretic) for participants in the rHTN subgroup for at least 4 weeks before randomization. Beta-blockers used to treat other conditions (i.e., migraine, HF, coronary artery disease) should not be counted as antihypertensive medications.

[0430] 4. Good compliance with prescribed antihypertensive medications demonstrated by DOT during Visit 2.

[0431] (iii) Exclusion criteria

[0432] Participants were excluded from the study if any of the following criteria applied:

[0433] Medical conditions

[0434] 1. Mean siSBP of the attending clinic AOBPM at the time of randomization 1 ≥170mmHg.

[0435] 2. Mean sitting DBP of the attending clinic AOBPM at the time of randomization 2 ≥110mmHg.

[0436] 3. Current or previous treatment with angiotensin receptor blockers and ACEI (both taken simultaneously) (within 4 weeks before screening).

[0437] 4. Serum sodium level <135mmol / L during screening.

[0438] 5. With the following known secondary causes of hypertension: renal artery stenosis, uncontrolled or untreated hyperthyroidism, uncontrolled or untreated hypothyroidism, pheochromocytoma, Cushing's syndrome, coarctation of the aorta.

[0439] 6. New York Heart Association functional HF class IV at screening.

[0440] 7. History of stroke, acute coronary syndrome, hypertensive encephalopathy or HF hospitalization within 6 months before screening.

[0441] 8. Planning for percutaneous coronary intervention / coronary artery bypass grafting or having undergone percutaneous coronary intervention / coronary artery bypass grafting within 6 months prior to screening.

[0443] 9. Known current severe left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy and / or severe aortic valvular disease.

[0444] 10. Left bundle branch block and any arrhythmias requiring treatment.

[0445] 11. Persistent atrial fibrillation.

[0446] 12. Known severe hepatic impairment, defined as Child-

[0447] Pugh C category.

[0448] 13. Uncontrolled diabetes with HbA1c>10.0% (86mmol / mol) at screening.

[0449] 14. Baseline QTcF>470 milliseconds.

[0450] 15. Family history of long QT syndrome.

[0451] 16. Heart rate <45 beats / minute or >110 beats / minute when in resting position.

[0452] 17. Participants suspected of having severe cardiac hypertrophy.

[0453] 18. Participants who are pregnant or breastfeeding.

[0454] 19. Participants diagnosed with adrenal insufficiency.

[0455] 20. Any of the following related to COVID-19 infection:

[0456] (a) Suspected or confirmed COVID-19 infection in the last 4 weeks prior to screening or at the time of randomization.

[0457] (b) hospitalization due to COVID-19 in the last 12 weeks before screening.

[0458] Previous / concomitant therapy

[0459] 21. Previous medical treatment with any MRA, antiarrhythmic drugs, or potassium-sparing diuretics within 4 weeks prior to screening.

[0460] 22. Treatment with potassium binders within 2 months prior to screening.

[0461] 23. Are you planning to receive or are currently receiving any exclusion medications, such as cytochrome P450

[0462] Strong inducers of CYP3A, long-term use of NSAIDs and MRAs (more than 10 mg / week)

[0463] 3 times for more than 3 months) and / or long-term use of systemic steroids.

[0464] 24. Drugs that prolong QT should be avoided if possible, and should be preferred if other alternatives without QT propensity exist.

[0465] 25. Current or previous treatment with cytotoxic therapy within 6 months prior to screening.

[0466] 26. No prohibition on using K+ Supplemental treatment, but should be continuously assessed and monitored throughout the trial.

[0467] Previous / concurrent clinical research experience

[0468] 27. Known hypersensitivity to bardoxetine or similar drugs or any of their excipients.

[0469] 28. Participation in another clinical study in which the investigational product was administered within 3 months prior to randomization.

[0470] other

[0471] 29. Participants work rotating shifts (i.e., rotations that include working different hours at different times on different days).

[0472] Participants could undergo the study intervention with or without food.

[0473] C. Study Interventions and Concomitant Therapies

[0474] (i) Study intervention administered

[0475] The study treatments to be administered and investigated in this study are described in Table 38.

[0476]

[0477] (ii) Background antihypertensive drugs

[0478] Participants had a stable regimen of background antihypertensive medications that they were receiving when they were enrolled in the study and that they would continue to receive after they were randomized to study treatment. Background antihypertensive medications could be changed during the open-label period, except for the use of MRAs and potassium-sparing diuretics.

[0479] (iii) Standard of care treatment

[0480] The standard of care treatment that participants randomized into that study period received. Standard of care treatment may change during the standard of care period.

[0481] All participants who meet all eligibility criteria will be sequentially allocated in two cohorts (Cohort 1 and Cohort 2) and will be centrally assigned to the randomized study intervention using an automated IRT / RTSM system that will assign participants to 1 of 3 different treatment groups. There will be a total of 3 randomization periods during the study that will be conducted using the IRT / RTSM system (see Fig.24 ):

[0482] The first randomization will be conducted after the run-in period to assign approximately 720 participants (450 in Cohort 1 and 270 in Cohort 2) to receive 2 mg bardoxstat QD, 1 mg bardoxstat QD, or placebo QD in a 1:1:1 ratio. Randomization will be based on baseline HTN

[0483] The patients were stratified by age (uHTN, rHTN) and baseline siSBP (<145 mmHg, ≥145 mmHg).

[0484] 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 of bardoxstat, 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:

[0485] - Participants who received 2 mg of bardoxetine during the first 12 weeks of treatment will be randomized in a 1:0 ratio to continue receiving 2 mg of bardoxetine QD.

[0486] - Participants who received 1 mg bardoxetine or placebo during the first 12 weeks of treatment will be randomized in a 4:1 or 1:4 ratio to receive 2 mg bardoxetine QD or standard of care, respectively.

[0487] Participants in Cohort 1 only: After participants complete the 12-week open-label period on 2 mg bardoxstat QD (approximately 300 participants in Cohort 1), participants will be randomized a third time in a 2:1 ratio to continue to receive 2 mg bardoxstat QD or receive placebo QD. These participants will be stratified by baseline HTN (uHTN, rHTN) and by siSBP (≤130 mmHg, >130 mmHg) at the time of RWD randomization. Approximately 200 participants will be randomized to 2 mg bardoxstat QD and 100 participants will be randomized to placebo QD.

[0488] Randomization will be performed in balanced blocks of fixed size. Randomization codes will be computer generated and loaded into the IxRS database.

[0489] All randomization will be performed directly using the IRT / RTSM system. There will be no reuse of randomization codes.

[0490] The number of participants randomized in each HTN subgroup (uHTN / rHTN) will be monitored to ensure that a minimum of approximately 40% of participants are recruited in either the uHTN subgroup or the rHTN subgroup. If a predetermined limit is reached, randomization may be restricted (i.e., no more participants may be randomized in a particular subgroup) to avoid over-representation or under-representation.

[0491] (iv) Dose modification

[0492] No modification of study drug dose was permitted in this study.

[0493] (v) Prohibited Concomitant Medications

[0494] The medications and supplements listed below were prohibited during this study except in the standard of care treatment group.

[0495] Concomitant use of angiotensin receptor blockers and ACEIs is not permitted during the study. Participants should be taking a stable dose of either medication class; any changes in medication dose or class must be closely monitored.

[0496] Potassium-sparing diuretics (eg, amiloride, triamterene) and direct renin inhibitors (eg, aliskiren).

[0497] Potassium binders (prohibited at screening but may be started as a corrective action during the study)

[0498] Tacrolimus, calcineurin inhibitors, and cyclosporine. Topical / inhaled immunosuppressants are tolerated.

[0499] - Mineralocorticoid receptor antagonists or aldosterone antagonists (eg, eplerenone, finerenone, spironolactone).

[0500] Any dose of systemic corticosteroids (eg, prednisone, prednisolone, dexamethasone

[0501] [Topical and inhaled steroids are permitted]).

[0502] ·No prohibition on using K + Supplemental treatment, but should be continuously assessed and monitored throughout the trial.

[0503] Chronic NSAID use. Occasional use of NSAIDs is permitted, however closer monitoring is warranted during these times.

[0504] Strong CYP3A4 inducers (e.g., apalutamide, avasimibe, carbamazepine, enzalutamide, lumacaftor, mitotane, phenytoin, rifampin, rifapentine, St. John's wort).

[0505] (vi) Blood pressure measurement

[0506] Sitting blood pressure measurement

[0507] Sitting BP measurements will be recorded using a standardized automated BP machine and the following standardized procedures:

[0508] Participants should not exercise, smoke, or consume caffeinated beverages or foods 30 minutes before assessing the AOBPM.

[0509] At visits when the study intervention is administered at the site, BP will be assessed prior to dosing.

[0510] Blood pressure measurements should be obtained before ECG recording.

[0511] For BP measurements by AOBPM, the following additional standardization procedures are recommended:

[0512] ○ The participant should sit quietly in the examination room for at least 5 minutes with their back supported, feet flat on the floor and the measurement arm supported so that the midpoint of the blood pressure cuff is at heart level.

[0513] ○ A designated AOBPM device will be provided to each clinical site and must be used for all study-related measurements.

[0514] ○ An appropriately sized cuff should be used to center the bladder over the brachial artery.

[0515] ○ The cuff size and arm used for measurement should be recorded.

[0516] ○ The arm with the higher mean BP value at screening should be used for screening and subsequent BP measurements.

[0517] ○ All BP measurements should be obtained at approximately the same time on the day the screening measurement is obtained.

[0518] o Three sitting BP measurements (each approximately 1 minute apart) should be obtained at each clinical site visit using the same arm and AOBPM device. Mean sitting BP was defined as the mean of the last 2 sitting BP measurements out of a total of 3 measurements at any single clinical site visit.

[0519] o If the difference between the last 2 SBP measurements is >20 mmHg, additional readings should be taken (up to 6 additional measurements; two measurements each of 3 sitting BP readings). If the difference between the last 2 SBP measurements of these 2 additional triple measurements is still >20 mmHg, the average of the last 2 measurements will be used.

[0520] o Measure orthostatic BP only at designated visits, immediately after the sitting BP is determined.

[0521] Orthostatic blood pressure measurement

[0522] Orthostatic BP measurement includes standing BP and will be measured using the AOBPM. The following standardized procedure is recommended:

[0523] • After siSBP has been determined, the participant will be asked to stand and after approximately 1 minute, a single standing BP measurement will be obtained as needed.

[0524] Participants should not exercise, smoke, or consume caffeinated beverages or foods 30 minutes before assessing the AOBPM.

[0525] At visits when the study intervention is administered at the site, BP will be assessed prior to dosing.

[0526] Blood pressure measurements should be obtained before ECG recording.

[0527] For BP measurements by AOBPM, the following additional standardization procedures are recommended:

[0528] ○ A designated AOBPM device will be provided to each clinical site and must be used for all study-related measurements.

[0529] ○ An appropriately sized cuff should be used to center the bladder over the brachial artery.

[0530] ○ The cuff size and arm used for measurement should be recorded.

[0531] ○ The arm with the higher mean BP value at screening should be used for screening and subsequent BP measurements.

[0532] ○ All BP measurements should be obtained at approximately the same time on the day the screening measurement is obtained.

[0533] (vi) Pharmacokinetics

[0534] Pre-dose blood samples will be collected for measurement of plasma concentrations of bardoxstat. All PK samples will be collected pre-dose; therefore, participants should be reminded not to take their study medication at home on the days of their clinic visits, as they will receive study medication in the clinic on these days.

[0535] For participants who discontinue investigational product due to hyperkalemia, PK samples should be collected at the EoT visit.

[0536] The timing of sampling may be changed during a study based on the latest available data (eg, to obtain data closer to the time of peak or trough matrix concentrations) to ensure appropriate monitoring.

[0537] Plasma samples will be used to analyze the PK of bardoxstat. Samples collected for analysis of bardoxstat concentrations in plasma may also be used to evaluate safety or efficacy aspects related to concerns that arise during or after the study.

[0538] (viii) Pharmacodynamics

[0539] ·

[0540] C. Purpose / End Point

[0541]

[0542]

[0543] D. Mainly estimated

[0544] The main estimands are described by the following properties:

[0545] Population: Participants with uHTN or rHTN, as defined by inclusion and exclusion criteria. This was achieved using the FAS.

[0546] Endpoint: Change from baseline in siSBP at Week 12.

[0547] Treatment conditions: 2 mg bardoxetine QD and a stable background antihypertensive regimen, or 1 mg bardoxetine QD and a stable background antihypertensive regimen.

[0548] Concomitants: Concomitants of treatment interruption will be handled via a treatment policy strategy, i.e., determine the treatment impact regardless of treatment interruption. Concomitants of rescue therapy will be handled via an assumption strategy, i.e., determine the treatment impact if rescue therapy is not started.

[0549] Population-level summary: Mean change from baseline between bardoxetine (2 mg or 1 mg, respectively) and placebo over a period of up to 52 weeks.

Claims

1. A method of treating hypertension in a human being in need of such treatment, the method comprising administering to the human being 1 mg / day or 2 mg / day of (R)-Compound 1:

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

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

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

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

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

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

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

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

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

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

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

13. The method of any of the preceding claims, wherein prior to said administering, said human has a blood pressure of ≥45 mL / min / 1.73 m 2 Estimated glomerular filtration rate.

14. The method of any of the preceding claims, wherein prior to said administering, said human has a mean sitting systolic blood pressure (siSBP) of ≥140 mmHg to <170 mmHg.

15. The method of claim 14, wherein prior to said administering, said human has a siSBP of <145 mmHg.

16. The method of claim 14, wherein prior to said administering, said human has a siSBP of ≥ 145 mmHg.

17. The method of any one of the preceding claims, wherein prior to said administering, said human has a serum potassium level of ≥3.5 and <5.0 mmol / L.

18. The method of any one of the preceding claims, wherein prior to said administering, said human has a morning Cortisol level of >3 μg / dL.

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

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

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

22. The method according to any one of the preceding claims, wherein the administration results in a sitting systolic blood pressure (siSBP) < 130 mmHg after a 12 week treatment period.

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

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

25. The method of claim 24, wherein the administering results in a decrease in the human's mean sitting systolic blood pressure of about 8 mmHg compared to baseline at or after a 12 week treatment period.

26. The method of claim 24, wherein the administering results in a decrease in the human's mean sitting systolic blood pressure of more than 8 mmHg compared to baseline at or after a 12 week treatment period.

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

28. The method of claim 27, wherein the administering results in a decrease in the human's mean sitting systolic blood pressure of about 11 mmHg compared to baseline at or after a 12 week treatment period.

29. The method of claim 27, wherein the administering results in a decrease in the human's mean sitting systolic blood pressure of more than 11 mg Hg compared to baseline at or after a 12 week treatment period.

30. The method of any one of the preceding claims, wherein administration is oral.

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

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

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

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

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

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

37. The method of any one of the preceding claims, wherein the administration does not result in a clinically significant reduction in mean serum Cortisol levels compared to placebo.

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

39. A (R)-Compound 1 for use in the method of any one of the preceding claims.

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