How to use aldosterone synthase inhibitors

Abstract

The present disclosure provides a method for inhibiting human aldosterone synthase, treating hypertension, or treating primary aldosteronism in a subject in need thereof, comprising administering to the subject an effective amount of (R)-Compound 1, wherein (R)-Compound 1 is a compound represented by the formula (I): [Formula 1] Provide a method for TIFF2024523559000041.tif37160.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 214,521, filed June 24, 2021, and U.S. Provisional Patent Application No. 63 / 290,364, filed December 16, 2021, which are incorporated by reference in their entireties herein.

[0002] The present disclosure provides compounds and methods for treating hypertension or primary aldosteronism. [Background technology]

[0003] Aldosterone is a hormone that has been implicated in a variety of cardiovascular and renal diseases. Aldosterone is the major mineralocorticoid in humans and is synthesized in the adrenal cortex by aldosterone synthase. Aldosterone is a key component of the renin-angiotensin-aldosterone system (RAAS) and functions as a key regulator of fluid and electrolyte homeostasis through agonism of the mineralocorticoid receptor (MR). The effects of aldosterone on end organs have been shown to occur via direct interaction with the MR (genomic effects) in addition to mechanisms independent of direct interaction (non-genomic or non-receptor mediated effects).

[0004] Blood pressure (BP) can be significantly reduced by partially inhibiting the activity of the RAAS with angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), direct renin inhibitors, or MR antagonists (MRAs). The mechanism of action of these drugs is associated with a reduction in aldosterone levels. These effects have been demonstrated to occur both when aldosterone levels are normal and when they are inappropriately elevated. Many patients with hypertension have inappropriately high aldosterone concentrations that promote cardiac, renal, and vascular damage. Inhibition of aldosterone synthesis represents a promising target for lowering BP and reducing BP-dependent target organ damage. An association between plasma aldosterone and long-term survival has been demonstrated in patients with congestive heart failure, acute myocardial infarction, and coronary artery disease other than heart failure or acute myocardial infarction. Thus, aldosterone blockade represents a means not only to lower BP but also to reduce target organ damage. Therefore, directly inhibiting the synthesis of aldosterone is a promising target for lowering BP and mitigating genomic and non-genomic influences on end-organ damage.

[0005] One of the challenges affecting the development of aldosterone synthase inhibitors (ASIs) is the difficulty of selectively inhibiting aldosterone synthase and not affecting the synthesis of cortisol. The cortisol synthesis pathway is catalyzed by 11β-hydroxylase (encoded by the cytochrome P450 family 11 subfamily B member 1 [CYP11B1] gene), which shares high sequence homology with aldosterone synthase (encoded by the CYP11B2 gene). Unfavorable inhibition of 11β-hydroxylase leads to suppression of cortisol levels, reduced stress and immune responses, adverse effects on some metabolic functions, and increased mortality. LCI699, an ASI, was adopted by Novartis in clinical trials but was discontinued for both antihypertensive and primary aldosteronism indications due to lack of specificity for aldosterone synthase.

[0006] Compound 1 is a highly potent and selective competitive inhibitor of human aldosterone synthase. In preclinical in vivo studies (mainly performed in primates), Compound 1 significantly reduced aldosterone without affecting cortisol levels over a wide dose range. Methods of using Compound 1 to safely and effectively treat humans are needed. Summary of the Invention [Means for solving the problem]

[0007] The present disclosure provides a method for treating hypertension or primary aldosteronism in a human, comprising administering 0.1 to 10 mg / day of (R)-Compound 1: [ka] to a human.

[0008] Other aspects and embodiments of the present invention will become readily apparent from the following detailed description of the invention.

[0009] The foregoing summary and the following detailed description will be better understood when read in conjunction with the accompanying drawings, which show, by way of example, exemplary embodiments. [Brief description of the drawings]

[0010] [Figure 1] Figure 1 shows a plot of mean (± standard deviation) plasma (R)-Compound 1 concentrations versus time (Day 10, 0-24 hours, after repeated daily dosing) by treatment in a linear scale-pharmacokinetic population. In this figure, the lower limit of quantification for (R)-Compound 1 = 0.05 ng / mL. Actual sampling times that fell outside the analytical sampling time window were excluded from the mean plot. [Diagram 2] Figure 2 shows the plot of Cmax vs. (R)-Compound 1 dose (Day 10 after repeated dosing-pharmacokinetic population). In this figure, the solid line represents the predicted value, and the dashed line represents the 90% confidence interval around the regression line. The black dots represent the geometric mean of the PK parameters. [Diagram 3] Figure 3 shows the plot of AUC0-tau versus (R)-Compound 1 dose (Day 10 after repeated dosing - pharmacokinetic population). In this figure, the solid line represents the predicted value, and the dashed line represents the 90% confidence interval around the regression line. The black dots represent the geometric mean of the PK parameters. AUC0-tau is the area under the plasma concentration-time curve over the dosing interval. [Figure 4] FIG. 4 shows plots of mean (standard deviation) plasma (R)-Compound 1 concentrations versus time (Day 1, single dose) by treatment in a linear scale-pharmacokinetic population. [Diagram 5] FIG. 5 shows plots of mean aldosterone plasma concentrations over time by treatment for the normal salt treatment group-pharmacodynamic population (excluding outlier subjects). [Figure 6] FIG. 6 shows plots of mean aldosterone plasma concentrations over time by treatment for the low-salt diet treatment group-pharmacodynamic population (excluding outlier subjects). [Figure 7] FIG. 7 shows the mean plasma concentration versus time profiles of (R)-Compound 1 following single and multiple oral doses of (R)-Compound 1 (a) SAD study, (b) MAD study. [Figure 8] FIG. 8 shows the mean plasma concentration versus time profiles of (R)-Compound 1 following a single intravenous dose and a single oral dose of 3 mg of (R)-Compound 1. [Figure 9] FIG. 9 shows the mean (+SD) plasma concentration versus time (0-24 hours) profiles of (R)-Compound 1 following administration of a single dose of (R)-Compound 1 oral solution and tablet. [Figure 10] FIG. 10 shows mean aldosterone plasma concentrations versus time by dose group following administration of a single dose of (R)-Compound 1 or placebo. [Figure 11] FIG. 11 shows the mean change from baseline in aldosterone plasma concentrations versus time by dose group following multiple dose administration of (R)-Compound 1 or placebo. [Figure 12] FIG. 12 shows the mean change from baseline in aldosterone plasma concentrations versus time by dose group following multiple dose administration of (R)-Compound 1 or placebo. [Figure 13]Figure 1 shows a plot of mean (±SD) plasma metformin concentrations by treatment in the linear scale-PK population through 24 hours. In this figure, the LLOQ (lower limit of quantification) for metformin is 0.5 ng / mL. Treatment A is a single 1000 mg dose of immediate release metformin administered and Treatment B is a single 1000 mg dose of immediate release metformin co-administered with a 10 mg dose of Compound 1. Scheduled time points are shown relative to metformin administration. [Figure 14] Figure 14 shows a plot of the mean (±SD) Ae of metformin by treatment in the linear scale-PK population through 24 hours. In this figure, Treatment A is a single 1000 mg dose of immediate release metformin administered and Treatment B is a single 1000 mg dose of immediate release metformin co-administered with a 10 mg dose of Compound 1. Ae is the cumulative amount of drug excreted in the urine. [Figure 15] Figure 15 shows a plot of mean (±SD) plasma metformin concentrations by treatment in the linear and semi-log scale-PK populations through 24 hours. In this figure, the LLOQ for metformin is 0.5 ng / mL. Treatment A is a single 1000 mg dose of immediate release metformin administered. Treatment B is a single 1000 mg dose of immediate release metformin co-administered with a 10 mg dose of Compound 1. Scheduled time points are shown relative to metformin administration. [Figure 16] Figure 16 shows a plot of the mean (±SD) Ae of metformin by treatment in the linear scale-PK population through 24 hours. In this figure, Treatment A is a single 1000 mg dose of immediate release metformin administered and Treatment B is a single 1000 mg dose of immediate release metformin co-administered with a 10 mg dose of Compound 1. Ae is the cumulative amount of drug excreted in urine. [Figure 17]Figure 17 shows a plot of the mean (±SD) Ae of metformin by treatment in the linear scale-PK population (extending to 72 hours). In this figure, Treatment A is a single 1000 mg dose of immediate release metformin administered and Treatment B is a single 1000 mg dose of immediate release metformin co-administered with a 10 mg dose of Compound 1. Ae is the cumulative amount of drug excreted in urine. [Figure 18] Figure 18 shows plots of mean (±SD) plasma Compound 1 concentrations by treatment in the linear and semi-log scale-PK populations through 24 hours. In this figure, the LLOQ for Compound 1 is 5 ng / mL. Treatment B is a single 1000 mg dose of immediate release metformin co-administered with a 10 mg dose of Compound 1. Scheduled time points are shown relative to Compound 1 administration, which occurred 2 hours prior to metformin administration. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

[0012] In this disclosure, the singular forms "a," "an," and "the" include plural references and references to a particular numerical value, including at least that particular value, unless the context clearly indicates otherwise. For example, a reference to "a material" is a reference to at least one such material and equivalents thereof known to those of skill in the art, and so forth.

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

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

[0015] It should be understood that certain features of the invention, which are described herein in the context of separate embodiments for clarity, may also be provided in combination in a single embodiment. That is, unless expressly incompatible or excluded, each individual embodiment is deemed combinable with any other embodiment, and such combinations are deemed to be separate embodiments. Conversely, various features of the invention, which are described for brevity in the context of a single embodiment, may also be provided separately or in any subcombination. It should be further noted that the claims may be drafted to exclude optional elements. As such, this statement is intended to serve as a predicate for using exclusive language, such as "only" in connection with the recitation of claim elements or the use of "negative" limitations. Finally, an embodiment may be described as part of a series of steps or as part of a more general structure, and each of the steps described above may be considered an independent embodiment in itself.

[0016] The present disclosure provides a method of treating hypertension or primary aldosteronism in a human, comprising administering 0.1-30 mg / day, e.g., 0.1-25 mg / day, 0.1-20 mg / day, 0.1-15 mg / day, 0.1-10 mg / day, or 0.5-10 mg / day, of Compound 1 or (R)-Compound 1 to the human. In some embodiments, hypertension or primary aldosteronism in a human is treated by administering 0.1-20 mg / day, 0.1-15 mg / day, 0.1-10 mg / day, or 0.5-10 mg / day of (R)-Compound 1 to the human. In some embodiments, hypertension or primary aldosteronism in a human is treated by administering 0.1-10 mg / day or 0.5-10 mg / day of (R)-Compound 1 to the human.

[0017] The terms "subject" and "patient" are used interchangeably and typically refer to a mammal. In some embodiments, the patient or subject is a human. In other embodiments, the patient or subject is a veterinary or livestock animal, a farm animal or pet, or an animal used in the conduct of a clinical trial. In some embodiments, the patient or subject is at least 18 years of age, i.e., an adult.

[0018] The terms "hypertension" and "high blood pressure" are used interchangeably and refer to a condition in which a patient's blood pressure is consistently greater than or equal to about 130 / 80 mmHg. Hypertension includes stage 1 and stage 2 hypertension, as well as hypertensive crisis. In some embodiments, the patient has stage 1 hypertension, with a systolic blood pressure of about 130 to about 139 mmHg and / or a diastolic blood pressure of about 80 to about 89 mmHg. In other embodiments, the patient has stage 2 hypertension, with a systolic blood pressure of about 140 mmHg or greater and / or a diastolic blood pressure of about 90 mmHg or greater. In further embodiments, the patient has a hypertensive crisis, with a blood pressure reading greater than about 180 / 120 mmHg.

[0019] The terms "primary aldosteronism" and "hyperaldosteronism" are used interchangeably and refer to a condition caused by the adrenal glands producing too much aldosterone. In some embodiments, primary aldosteronism results in elevated blood pressure. Prior to administration of Compound 1 or (R)-Compound 1, the subject or patient has a blood pressure of ≧130 / 80 mmHg. In some embodiments, the subject or patient has a mean sitting blood pressure of ≧130 / 80 mmHg. In some embodiments, the patient is in a fasting state. In other embodiments, the patient is in a fed state. The term "fasting state" as used herein refers to the patient not consuming food prior to administration of Compound 1 or (R)-Compound 1. In some embodiments, a patient is in a "fasting state" when no food is consumed for at least about 8 hours prior to administration of Compound 1 or (R)-Compound 1. The term "fasting state" may also include refraining from eating after administration of Compound 1 or (R)-Compound 1. In a further embodiment, a patient is in a "fasted state" when no food is consumed for at least about 4 hours after administration of Compound 1 or (R)-Compound 1.

[0020] "Treatment" or variations thereof refers to eliminating or reducing at least one physical parameter of a disease or disorder, such as hypertension or primary aldosteronism. In some embodiments, the disease or disorder is hypertension. In other embodiments, the disease or disorder is primary aldosteronism.

[0021] As used herein, compound 1 is N-(4-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide having the following structure: [ka] In some embodiments, compound 1 is (R)-N-(4-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide having the following structure: [ka]

[0022] In some embodiments, a mixture of enantiomers of Compound 1 is administered to a human. In other embodiments, a racemic mixture of enantiomers of Compound 1 (i.e., (R,S)-Compound 1) is administered to a human. In further embodiments, (R)-Compound 1 having an enantiomeric purity of 50% enantiomeric excess (ee) or greater is administered to a human. In still other embodiments, (R)-Compound 1 having an enantiomeric purity of 60% ee or greater is administered to a human. In still further embodiments, (R)-Compound 1 having an enantiomeric purity of 70% ee or greater is administered to a human. In other embodiments, (R)-Compound 1 having an enantiomeric purity of 80% ee or greater is administered to a human. In further embodiments, (R)-Compound 1 having an enantiomeric purity of 90% ee or greater is administered to a human. In still other embodiments, (R)-Compound 1 having an enantiomeric purity of 95% ee or greater is administered to a human. In yet further embodiments, (R)-Compound 1 having an enantiomeric purity of 98% ee or greater is administered to a human. In other embodiments, (R)-Compound 1 having an enantiomeric purity of 99% ee or greater is administered to a human.

[0023] The present disclosure also contemplates salts of Compound 1, such as salts of (R)-Compound 1. In some embodiments, the salts are pharma- ceutically acceptable. "Pharmaceutically acceptable" refers to properties and / or substances that are acceptable to a patient for their pharmacological / toxicological merits, and to a manufacturing pharmaceutical chemist for their physical / chemical merits with respect to composition, formulation, stability, patient acceptance, and bioavailability.

[0024] Pharmaceutically acceptable salts of Compound 1 or (R)-Compound 1 include salts with pharma- ceutically acceptable acids or bases, such as inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, hydroiodic acid, nitric acid, and phosphoric acid, and organic acids, such as adipic acid, citric acid, fumaric acid, maleic acid, malic acid, malonic acid, mandelic acid, ascorbic acid, oxalic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, cyclohexylsulfamic acid (cyclamic acid), edisylic acid, glutaric acid, or butenesulfonic acid. Pharmaceutically acceptable bases include alkali metals, such as sodium or potassium, and alkaline earth metals, such as calcium or magnesium, hydroxides, and organic bases, such as alkali amines, arylalkyl amines, and heterocyclic amines.

[0025] The present disclosure further provides hydrates and / or polymorphs of Compound 1. In some embodiments, Compound 1 is a hydrate. In other embodiments, the compound is a monohydrate. In other embodiments, Compound 1 is in anhydrous form.

[0026] Compound 1 may also be in crystalline and / or amorphous form. In some embodiments, Compound 1 is in amorphous form. In other embodiments, Compound 1 is in crystalline form.

[0027] The present disclosure also provides pharmaceutical compositions comprising Compound 1 or (R)-Compound 1 and one or more pharma- ceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains about 0.1-10 mg, e.g., 0.5-10 mg, of (R)-Compound 1 and a pharma- ceutically acceptable excipient. In other embodiments, the pharmaceutical composition comprises anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.

[0028] The amount of Compound 1 or (R)-Compound 1 used alone or in a pharmaceutical formulation may also be expressed by amount. In some embodiments, the pharmaceutical formulation contains about 0.1 to about 10 mg of Compound 1 or (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 Compound 1 or (R)-Compound 1. In other embodiments, the pharmaceutical formulation contains about 0.5 mg of Compound 1 or (R)-Compound 1. In a further embodiment, the pharmaceutical formulation contains about 1 mg of Compound 1 or (R)-Compound 1. In yet another embodiment, the pharmaceutical formulation contains about 2 mg of Compound 1 or (R)-Compound 1. In yet another embodiment, the pharmaceutical formulation contains about 3 mg of Compound 1 or (R)-Compound 1. In yet another embodiment, the pharmaceutical formulation contains about 4 mg of Compound 1 or (R)-Compound 1. In yet another embodiment, the pharmaceutical formulation contains about 5 mg of Compound 1 or (R)-Compound 1. In another embodiment, the pharmaceutical formulation contains about 6 mg of Compound 1 or (R)-Compound 1. In a further embodiment, the pharmaceutical formulation contains about 7 mg of Compound 1 or (R)-Compound 1. In yet another embodiment, the pharmaceutical formulation contains about 8 mg of Compound 1 or (R)-Compound 1. In yet another embodiment, the pharmaceutical formulation contains about 9 mg of Compound 1 or (R)-Compound 1. In another embodiment, the pharmaceutical formulation contains about 10 mg of Compound 1 or (R)-Compound 1.

[0029] When used alone, about 0.1 to about 10 mg, for example, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, 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 Compound 1 or (R)-Compound 1 may be administered to a human. In another embodiment, about 0.5 mg of Compound 1 or (R)-Compound 1 is administered to a human. In a further embodiment, about 1 mg of Compound 1 or (R)-Compound 1 is administered to a human. In yet another embodiment, about 2 mg of Compound 1 or (R)-Compound 1 is administered to a human. In yet a further embodiment, about 3 mg of Compound 1 or (R)-Compound 1 is administered to a human. In another embodiment, about 4 mg of Compound 1 or (R)-Compound 1 is administered to a human. In a further embodiment, about 5 mg of Compound 1 or (R)-Compound 1 is administered to a human. In yet another embodiment, about 6 mg of Compound 1 or (R)-Compound 1 is administered to a human. In yet a further embodiment, about 7 mg of Compound 1 or (R)-Compound 1 is administered to a human. In another embodiment, about 8 mg of Compound 1 or (R)-Compound 1 is administered to a human. In a further embodiment, about 9 mg of Compound 1 or (R)-Compound 1 is administered to a human. In yet another embodiment, about 10 mg of Compound 1 or (R)-Compound 1 is administered to a human.

[0030] Compound 1 or (R)-Compound 1, or a pharmaceutical composition containing Compound 1 or (R)-Compound 1, may be administered hourly, daily, or weekly. Desirably, Compound 1 or (R)-Compound 1, or a pharmaceutical composition containing Compound 1 or (R)-Compound 1, is administered on a daily basis. In some embodiments, about 0.1 to about 30 mg / day of Compound 1 or (R)-Compound 1 is administered. In some embodiments, about 0.1 to about 5 mg / day, for example, about 0.1 mg / day, about 0.2 mg / day, about 0.3 mg / day, about 0.4 mg / day, about 0.5 mg / day, about 0.6 mg / day, about 0.7 mg / day, about 0.8 mg / day, about 0.9 mg / day, about 1 mg / day, about 1.5 mg / day, about 2 mg / day, about 2.5 mg / day, about 3 mg / day, about 3.5 mg / day, about 4 mg / day, about 4.5 mg / day, about 5 mg / day, about 5.5 mg / day, about 6 mg / day, about 6.5 mg / day, about 7 mg / day, about 7.5 mg / day, or about 8 mg / day of Compound 1 or (R)-Compound 1 is administered to a human. In other embodiments, about 0.5 mg / day of Compound 1 or (R)-Compound 1 is administered to a human. In a further embodiment, about 1 mg / day of Compound 1 or (R)-Compound 1 is administered to a human. In yet another embodiment, about 2 mg / day of Compound 1 or (R)-Compound 1 is administered to a human. In yet a further embodiment, about 3 mg / day of Compound 1 or (R)-Compound 1 is administered to a human. In another embodiment, about 4 mg / day of Compound 1 or (R)-Compound 1 is administered to a human. In a further embodiment, about 5 mg / day of Compound 1 or (R)-Compound 1 is administered to a human. In yet another embodiment, about 6 mg / day of Compound 1 or (R)-Compound 1 is administered to a human. In a still further embodiment, about 7 mg / day of Compound 1 or (R)-Compound 1 is administered to a human. In another embodiment, about 8 mg / day of Compound 1 or (R)-Compound 1 is administered to a human. In a further embodiment, about 9 mg / day of Compound 1 or (R)-Compound 1 is administered to a human. In yet other embodiments, about 10 mg / day of Compound 1 or (R)-Compound 1 is administered to a human.

[0031] Compound 1 or (R)-Compound 1 may be administered in a single dose or in divided doses. In some embodiments, Compound 1 or (R)-Compound 1 is administered in a single dose. In further embodiments, Compound 1 or (R)-Compound 1 is administered in divided doses. For example, Compound 1 or (R)-Compound 1 is administered in divided doses, such as two doses, three doses, or four doses. For example, in some aspects, a patient is administered 4 mg of Compound 1 or (R)-Compound by administering a total of two 2 mg tablets. In other examples, a patient is administered 6 mg of Compound 1 or (R)-Compound by administering a total of three 2 mg tablets. In further examples, a patient is administered 8 mg of Compound 1 or (R)-Compound by administering a total of four 2 mg tablets. One skilled in the art could determine and use other combinations of tablet doses based on the required dose of Compound 1 or (R)-Compound 1.

[0032] Compound 1 or (R)-Compound 1 or a pharmaceutical formulation containing same may be administered by any acceptable route. In some embodiments, administration is oral, transdermal, parenteral, or a combination thereof. In further embodiments, administration is oral.

[0033] Compound 1 or (R)-Compound 1 or a pharmaceutical formulation containing Compound 1 or (R)-Compound 1 may be formulated for administration in solid or liquid form. In some embodiments, Compound 1 or (R)-Compound 1 or a pharmaceutical formulation containing Compound 1 or (R)-Compound 1 is formulated in the form of a tablet, caplet, capsule, powder, softgel, suspension, or liquid, or a combination thereof. In other embodiments, Compound 1 or (R)-Compound 1 or a pharmaceutical formulation containing Compound 1 or (R)-Compound 1 is formulated in the form of a tablet. In further embodiments, Compound 1 or (R)-Compound 1 or a pharmaceutical formulation containing Compound 1 or (R)-Compound 1 is formulated in the form of a caplet. In yet other embodiments, Compound 1 or (R)-Compound 1 or a pharmaceutical formulation containing Compound 1 or (R)-Compound 1 is formulated in the form of a capsule. In yet further embodiments, each tablet, caplet, capsule, powder, softgel, suspension, or liquid dose contains about 0.5 to about 5 mg, i.e., about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, or about 5 mg of Compound 1 or (R)-Compound 1. In other embodiments, each tablet, caplet, capsule, powder, softgel, suspension, or liquid dose contains about 0.5 mg of Compound 1 or (R)-Compound 1. In further embodiments, each tablet, caplet, capsule, powder, softgel, suspension, or liquid dose contains about 1 mg of Compound 1 or (R)-Compound 1. In yet other embodiments, each tablet, caplet, capsule, powder, softgel, suspension, or liquid dose contains about 2 mg of Compound 1 or (R)-Compound 1. In still further embodiments, each tablet, caplet, capsule, powder, softgel, suspension, or liquid dose contains about 2 mg of Compound 1 or (R)-Compound 1. In other embodiments, each tablet, caplet, capsule, powder, softgel, suspension, or liquid dose contains about 3 mg of Compound 1 or (R)-Compound 1. In further embodiments, each tablet, caplet, capsule, powder, softgel, suspension, or liquid dose contains about 4 mg of Compound 1 or (R)-Compound 1.In yet other embodiments, each tablet, caplet, capsule, powder, softgel, suspension, or liquid dose contains about 5 mg of Compound 1 or (R)-Compound 1.

[0034] In certain aspects, the solid or liquid form contains a patient dose of Compound 1 or (R)-Compound 1. In other embodiments, it may be necessary to administer more than one dose, i.e., a split dose, of the solid or liquid form to the patient to achieve the desired dose for the patient.

[0035] Compound 1 or (R)-Compound 1 described herein is useful in inhibiting aldosterone synthase. Compound 1 or (R)-Compound 1 is useful in various therapeutic methods. In some embodiments, the disclosure provides a method of treating hypertension with Compound 1 or (R)-Compound 1. In further embodiments, the disclosure provides a method of treating primary aldosteronism with Compound 1 or (R)-Compound 1. In further embodiments, the disclosure provides a method of treating CKD with Compound 1 or (R)-Compound 1. The method includes administering to a patient Compound 1 or (R)-Compound 1, or a pharmaceutical formulation comprising Compound 1 or (R)-Compound 1.

[0036] After treatment with Compound 1 or (R)-Compound 1, the patient's sitting blood pressure (BP) is reduced to approximately <130 / 80 mmHg, such as after about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks of treatment. For example, in some embodiments, administration of Compound 1 or (R)-Compound 1 results in a mean reduction in SBP from baseline of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, 19, about 20, about 21, about 22, about 23, about 24, 25, about 26, about 27, about 28, about 29, or about 30 mmHg. In some embodiments, administration of Compound 1 or (R)-Compound 1 results in a mean reduction from baseline in sitting systolic blood pressure (SBP) after about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks of treatment. For example, administration of Compound 1 or (R)-Compound 1 can result in the following: about 1 to about 12, about 1 to about 11, about 1 to about 10, about 1 to about 9, about 1 to about 8, about 1 to about 7, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 12, about 2 to about 11, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 12, about 3 to about 11, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 12, about 4 to about 11, about 4 to about 10, about 4 to about 9, about 4 about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 12, about 5 to about 11, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 12, about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks later, an average decrease from baseline in sitting SBP is achieved. In other embodiments, administration of Compound 1 or (R)-Compound 1 results in a mean reduction in baseline sitting diastolic blood pressure (DBP) after about 12 weeks of treatment.For example, in some embodiments, administration of Compound 1 or (R)-Compound 1 results in a mean reduction from baseline in DBP of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30 mmHg. In further embodiments, administration of Compound 1 or (R)-Compound 1 results in a mean reduction from baseline in sitting SBP and a mean reduction from baseline in sitting DBP after about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks of treatment. For example, administration of Compound 1 or (R)-Compound 1 can result in the following: about 1 to about 12, about 1 to about 11, about 1 to about 10, about 1 to about 9, about 1 to about 8, about 1 to about 7, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 12, about 2 to about 11, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 12, about 3 to about 11, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 12, about 4 to about 11, about 4 to about 10, about 4 to about 9, about 4 about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 12, about 5 to about 11, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 12, about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks later, the average reduction from baseline in seated DBP is achieved.

[0037] After treatment with Compound 1 or (R)-Compound 1, the patient's aldosterone levels, renin levels, or a combination thereof are reduced, such as after about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks of treatment. For example, in some embodiments, administration of Compound 1 or (R)-Compound 1 results in a mean reduction in SBP from baseline of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30 mmHg. In some embodiments, administration of Compound 1 or (R)-Compound 1 results in a mean reduction from baseline in sitting systolic blood pressure (SBP) after about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks of treatment. For example, administration of Compound 1 or (R)-Compound 1 can result in the following: about 1 to about 12, about 1 to about 11, about 1 to about 10, about 1 to about 9, about 1 to about 8, about 1 to about 7, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 12, about 2 to about 11, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 12, about 3 to about 11, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 12, about 4 to about 11, about 4 to about 10, about 4 to about 9, about 4 about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 12, about 5 to about 11, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 12, about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks later.

[0038] In some embodiments, the patient is unresponsive to one or more stable background hypertension regimens. A "stable background hypertension regimen" includes any regimen that reduces the patient's blood pressure. The regimen may include performing one or more therapies, such as daily activities, or taking one or more antihypertensive medications. In some embodiments, the stable background hypertension regimen is one or more daily activities. Examples of daily activities that may be used to treat hypertension or primary aldosteronism include, but are not limited to, a healthy diet, reducing salt intake, regular physical activity, maintaining a healthy weight, losing weight if advised by a physician, and limiting alcohol intake. In other embodiments, the stable background hypertension regimen is an antihypertensive medication.

[0039] The term "antihypertensive agent" as used herein refers to an agent that lowers the blood pressure of a patient. 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 blocker, an alpha-2 receptor agonist, a combined alpha and beta-blocker, a central agonist, a peripheral adrenergic inhibitor, a 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 of diuretics. Examples of thiazide diuretics include chlorthalidone (Hygroton), chlorothiazide (Diuril), hydrochlorothiazide (Esidrix, Hydrodiuril, Microzide), indapamide (Lozol), or metolazone (Mykrox, Zaroxolyn). Examples of potassium-sparing diuretics include amiloride hydrochloride (Midamar), spironolactone (Aldactone), eplerenone (Inspra), or triamterene (Dyrenium). Examples of loop diuretics include furosemide (Lasix) or bumetanide (Bumex). Examples of combination diuretics include amiloride hydrochloride + hydrochlorothiazide (Moduretic), spironolactone + hydrochlorothiazide (Aldactazide), or triamterene + hydrochlorothiazide (Dyazide, Maxzide). In other embodiments, the antihypertensive agent is a beta-blocker. Examples of beta-blockers include acebutolol (Sectral), atenolol (Tenormin), betaxolol (Kerlone), bisoprolol fumarate (Zebeta), carteolol hydrochloride (Cartrol), metoprolol tartrate (Lopressor), metoprolol succinate (Toprol-XL), nadolol (Corgard), penbutolol sulfate (Levatol), pindolol (Visken), propranolol hydrochloride (Inderal), solotol hydrochloride (Betapace), or timolol maleate (Blocadren). In a further embodiment, the antihypertensive agent is a beta-blocker / diuretic combination.An example of a beta-blocker / diuretic combination is hydrochlorothiazide + bisoprolol (Ziac). In yet another embodiment, the antihypertensive agent is an ACE inhibitor. Examples of ACE inhibitors include benazepril hydrochloride (Lotensin), captopril (Capoten), enalapril maleate (Vasotec), fosinopril sodium (Monopril), lisinopril (Prinivel, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril hydrochloride (Accupril), ramipril (Altace), or trandolapril (Mavik). In yet a further embodiment, the antihypertensive agent is an angiotensin II receptor blocker. Examples of angiotensin II receptor blockers include candesartan (Atacand), eprosartan mesylate (Teveten), irbesartan (Avapro), losartan potassium (Cozaar), telmisartan (Micardis), or valsartan (Diovan). In other embodiments, the antihypertensive agent is a calcium channel blocker. Examples of calcium channel blockers include amlodipine besylate (Norvasc, Lotrel), bepridil (Vasocor), diltiazem hydrochloride (Cardizem CD, Cardizem SR, Dilacor XR, Tiazac), felodipine (Plendil), isradipine (DynaCirc, DynaCirc CR), nicardipine (Cardene SR), nifedipine (Adalat CC, Procardia XL), nisoldipine (Sular), or verapamil hydrochloride (Calan SR, Covera HS, Isoptin SR, Verelan). In further embodiments, the antihypertensive agent is an alpha blocker. Examples of alpha blockers include doxazosin mesylate (Cardura), prazosin hydrochloride (Minipress), or terazosin hydrochloride (Hytrin). In still other embodiments, the antihypertensive agent is an alpha-2 receptor agonist. An example of an alpha-2 receptor agonist is methyldopa. In yet a further embodiment, the antihypertensive agent is a combined alpha and beta-blocker.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), guanabenzacetate (Wytensin), or guanfacine hydrochloride (Tenex). In further embodiments, the antihypertensive agent is a terminal adrenergic inhibitor. Examples of terminal adrenergic inhibitors include guanadrel (Hylorel), guanethidine monosulfate (Ismelin), or reserpine (Serpasil). In yet other embodiments, the antihypertensive agent is a vasodilator, i.e., a vasodilator. Examples of vasodilators include hydralazine hydrochloride (Apresoline), or minoxidil (Loniten).

[0040] In some embodiments, the patient's hypertension or primary aldosteronism is unresponsive to one or more stable background hypertension regimens prior to administration of Compound 1 or (R)-Compound 1. In other embodiments, the patient's hypertension or primary aldosteronism is unresponsive to two stable background hypertension regimens prior to administration of Compound 1 or (R)-Compound 1. In further embodiments, the patient's hypertension or primary aldosteronism is unresponsive to three stable background hypertension regimens prior to administration of Compound 1 or (R)-Compound 1. In other embodiments, the patient's hypertension or primary aldosteronism is unresponsive to three or more stable background hypertension regimens prior to administration of Compound 1 or (R)-Compound 1.

[0041] The present disclosure also provides a method of treating hypertension or primary aldosteronism, wherein administration of Compound 1 or (R)-Compound 1 does not result in clinically significant adverse events in humans. As used herein, the term "clinically significant" refers to an outcome that affects a patient that requires follow-up by a physician.

[0042] The following examples are provided to illustrate some of the concepts described within this disclosure. Although the examples are believed to provide specific individual embodiments of the formulations, methods of preparation, and uses, the examples should not be construed as limiting the more general embodiments described herein.

[0043] In the following examples, efforts have been made to ensure accuracy with respect to numbers used (eg, amounts, temperatures, etc.) but some experimental error and deviation should be accounted for.

[0044] List of abbreviations and definitions Abbreviation Definition ACEi Angiotensin-Converting Enzyme Inhibitors ACTH (adrenocorticotropic hormone) AE Adverse Event AESI Adverse events of particular interest AOBPM Automated Office Blood Pressure Monitoring API Active Pharmaceutical Ingredient ARB Angiotensin receptor blockers ARR Aldosterone / plasma renin activity ratio ASI Aldosterone synthase inhibitor AUC Area under the concentration time curve AUC 0-∞ Extrapolated area under the concentration-time curve from time 0 to infinity AUC 0-tlast Area under the concentration-time curve from time 0 to the time of the last quantifiable concentration BMI Body Mass Index BNP B-type natriuretic peptide BP Blood Pressure bpm beats per minute CABG Coronary Artery Bypass Grafting CCB Calcium Channel Blockers CI Confidence Interval CKD Chronic Kidney Disease CKD-EPI Epidemiology of Chronic Kidney Disease CL R Renal clearance C max maximum plasma concentration CV cardiovascular CYP Cytochrome P450 DBP Diastolic Blood Pressure DDI Drug-Drug Interactions ECG Electrocardiogram eGFR Estimated glomerular filtration rate EOT End of treatment ET early cancellation FSH Follicle-stimulating hormone GDF-15 Growth differentiation factor-15 Glomerular filtration rate (GFR) GMP Good Manufacturing Practice HBA1c glycosylated hemoglobin HBsAg Hepatitis B surface antigen HCV Hepatitis C virus HIV Human Immunodeficiency Disease HTN High Blood Pressure IRT Interactive Response Technology ITT Treatment Intention IV Intravenous KIM-1 Kidney injury molecule-1 LLOQ Lower limit of quantification MAD Repeat Dose Escalation MATE Multidrug and Toxic Compound Excretion MCP1 Monocyte chemotactic protein-1 MedDRA ICH International Medical Terminology mITT Modified Intention to Treat MMRM Repeated Measures Mixed Models MR mineralocorticoid receptor MRA Mineralocorticoid Receptor Agonist MTD maximum capacity NGAL Neutrophil gelatinase-binding lipocalin NSAIDs Nonsteroidal Anti-inflammatory Drugs OLE (open label continuous administration) PA Primary Aldosteronism PAC Plasma aldosterone concentration PCI Percutaneous Coronary Intervention PD Pharmacodynamics PGx Pharmacogenomics PK Pharmacokinetics POC Point of Care or Point of Contact PP Conforms to protocol PRA Plasma renin activity QD Once a day QTc Corrected QT interval QTcB Corrected QT interval using Fridericia's formula QTcF Heart rate corrected QT interval using Frederica's formula RAAS Renin-angiotensin-aldosterone system rHTN Treatment-resistant hypertension RNA Ribonucleic acid SAD Single Ascending Dose SAE Serious Adverse Event SAP Statistical Analysis Plan SBP Systolic blood pressure SB-RI Single-blind run-in SD standard deviation SGLT2 sodium glucose cotransporter 2 t 1 / 2 Apparent terminal elimination half-life TEAE Treatment-emergent adverse events TESAE Treatment-emergent serious adverse events TGF-β Transforming growth factor beta T max Median time to maximum plasma concentration UACR Urinary albumin to creatinine ratio ULN Upper limit of normal EXAMPLES

[0045] Example 1 A phase 1, open-label study of the absorption, metabolism, and excretion of [14C]-(R)-Compound 1 following a single oral dose in healthy male subjects.

[0046] [Table 1]

[0047] Potential subjects will be screened within 28 days prior to dose administration to assess eligibility to participate in the study. Subjects will be admitted to the study site on Day 1 and will be confined to the study site until at least Day 9. All subjects will receive a single oral dose of [14C]-(R)-compound on the morning of Day 1. Subjects will be discharged if they meet the following discharge criteria: plasma radioactivity concentrations below the limit of quantification on two consecutive collections, mass balance recovery of ≥ 90%, and ≤ 1% of the total total radioactivity dose recovered in combined excreta (urine and feces) over two consecutive 24-hour periods. If discharge criteria are not met by Day 9, subjects will remain in the study site until all discharge criteria are met, up to Day 15, and 24-hour blood, urine, and feces collections will continue, unless otherwise agreed by the sponsor and investigator. The study site will contact the subject by phone 3 days (± 1 day) after discharge from the study site.

[0048] Diagnosis and criteria for inclusion Body mass index: 18.0-32.0 kg / m 2 Healthy male subjects aged 18–55 years (inclusive) with (inclusive)

[0049] Subjects must meet all of the following criteria at the screening visit unless otherwise specified: 1. Men of any race, ages 18-55 (inclusive). 2. Body mass index: 18.0-32.0 kg / m 2 (inclusive). 3. Good health as determined by the absence of clinically significant findings as assessed by the Investigator (or medically qualified designee) from medical history, 12-lead ECG, vital signs measurements (sitting and standing), and clinical laboratory evaluations at screening and / or check-in (congenital nonhemolytic hyperbilirubinemia [e.g., suspected Gilbert's syndrome based on total and direct bilirubin] will not be accepted), and physical examination at check-in. 4. Normal renal function is defined as an estimated GFR ≥ 70 mL / min / 1.73 m at screening and check-in, calculated using the Chronic Kidney Disease Epidemiology Collaborative Study method. 2 It is defined as: 5. Subject agrees to use contraception. 6.Understand and willing to sign the ICF and be able to comply with the study restrictions. 7. History of at least one bowel movement per day. 8. Subjects will be required to refrain from donating sperm for 90 days from check-in until discharge from the hospital.

[0050] Subjects will be excluded from the study if they meet any of the following criteria at the screening visit, unless otherwise specified:

[0051] Medical conditions 1. Significant medical history or clinical manifestations of autoimmune, immunological, metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological (including seizures), neuromuscular, musculoskeletal, respiratory, endocrine, or psychiatric disease, cancer (excluding basal or squamous cell carcinoma of the skin, and cancer that has been cured or in remission for >5 years prior to the Screening visit) as determined by the Investigator (or medically qualified designee). 2. Personal or family history of Long QT Syndrome, Torsades de Pointes, other complex ventricular arrhythmias, or sudden death. 3. History or current clinically significant arrhythmia, including ventricular tachycardia, ventricular fibrillation, atrial fibrillation, sinus node dysfunction, or clinically significant heart block, as determined by the Investigator (or medically qualified designee). Subjects with mild ectopic symptoms (e.g., atrial premature beats) will not necessarily be excluded and may be discussed with the Medical Monitor for inclusion. 4. Prolonged QTcF (>450 ms). 5. History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator (or medically qualified designee). 6. Surgical condition or any condition that in the opinion of the Investigator (or medically qualified designee) may alter the absorption, distribution, metabolism, and / or excretion of orally administered drugs (uncomplicated appendectomy and hernia repair are permitted, but cholecystectomy and gastric bypass are prohibited). 7. Confirmed (e.g., two consecutive measurements) systolic BP >140 or <90 mmHg, diastolic BP >90 or <50 mmHg, and pulse rate >100 or <45 beats per minute (bpm). 8. Postural tachycardia (i.e., >30 bpm on standing) or orthostatic hypotension (i.e., a decrease in systolic BP ≥20 mmHg or diastolic BP ≥10 mmHg on standing). 9. Serum potassium > upper limit of normal range (5.3 mmol / L; ULN) and serum sodium < lower limit of normal range (135 mmol / L) (repeatedly check). 10. Aspartate aminotransferase, alanine aminotransferase, or total bilirubin >1.2 x ULN. 11. Any other laboratory value that, in the opinion of the Investigator (or medically qualified designee), is significantly above the normal range (based on normal ranges for the laboratory test). 12. Known history of porphyria, myopathy, or active liver disease. 13. Positive hepatitis panel and / or positive human immunodeficiency virus test. 14. Positive COVID-19 test result upon screening or check-in.

[0052] Previous Therapy / Concomitant Therapy 15. Administration of a COVID-19 vaccine within the past 30 days prior to administration. 16. Use of any prescription or over-the-counter medications, including topical medications (except for occasional use of acetaminophen or nonsteroidal anti-inflammatory drugs such as ibuprofen or naproxen, according to package inserts); herbal supplements; dietary supplements; or functional foods within 14 days or 5 half-lives prior to dosing, whichever is longer, or willingness to refrain from these medications until discharge from the study site. Use of over-the-counter topical medications may be permitted in consultation with the sponsor. In addition, use of medications with a 5-fold half-life of more than 14 days must be discussed and approved by the sponsor prior to subject enrollment. 17. Use of corticosteroids (systemic or widespread topical use) within 3 months (90 days) prior to treatment.

[0053] Investigational drug, dosage, and administration method After an overnight fast, a single oral dose of 10 mg of [14C]-(R)-Compound 1 containing approximately 100 μCi as a capsule.

[0054] Duration of participation of subjects involved in the study Planned screening duration: Approximately 4 weeks.

[0055] Planned study duration (from screening to follow-up call): Approximately 7 weeks maximum.

[0056] Instructions, storage, packaging and labelling The Active Pharmaceutical Ingredient (API; radiolabeled) will be supplied by the sponsor (or designee) as a blend of hot / cold [14C]-(R)-compound 1 along with the batch / lot number and Certificate of Analysis. The supplied blend will be fully tested for purity (radiochemical and UV) and must meet all specifications prior to release.

[0057] Each subject dose contains a total of 10 mg (may be administered as multiple capsules) containing approximately 100 μCi of [14C]-(R)-Compound 1. The finished drug product is released by a Good Manufacturing Practice (GMP) quality auditor under GMP conditions prior to administration to subjects.

[0058] Study treatment administration Each dose of [14C]-(R)-Compound 1 is administered orally with 240 mL of room temperature water. All subjects fast overnight (at least 10 hours) and refrain from drinking water for 1 hour prior to dosing. Subjects refrain from drinking water until 2 hours after dosing, excluding the amount of water consumed at the time of dosing, and then fast until approximately 4 hours after dosing. At all other times during the study, subjects may consume water ad libitum.

[0059] Subjects will be dosed in numerical order in a seated position and will not be allowed to lie supine for 4 hours following administration of [14C]-(R)-Compound 1, unless required by the occurrence of an AE and / or study procedures.

[0060] Subjects are to be observed for the first four hours after dosing, during which time they are to be taken to the bathroom as needed.

[0061] Pharmacokinetic analysis Mass balance recovery of total radioactivity (proportion of the administered dose recovered in urine, feces, and total excreta) will be calculated by the radioanalytical laboratory. Pharmacokinetic parameters will be determined from individual (unpooled) plasma and urinary concentrations of (R)-Compound 1 and metabolites, and total radioactivity concentrations in plasma and whole blood, using standard noncompartmental methods. Full details of PK parameters are described in the statistical analysis plan for this study.

[0062] Example 2 The SAD study involved single oral administration of up to 360 mg of (R)-Compound 1, which was well tolerated in healthy subjects. There were no deaths, serious adverse events (SAEs), or dose-limiting events, and the maximum tolerated dose observed was the highest dose tested (360 mg). Overall, the most frequently reported AEs following administration of a single dose of (R)-Compound 1 were headache, nasopharyngitis, diarrhea, asthenia, dizziness, and nausea.

[0063] A dose-dependent mild decrease in plasma sodium levels and an increase in plasma potassium levels were observed, with corresponding changes in urinary sodium and potassium levels. Notably, despite an initial increase in the urinary sodium:potassium ratio, indicating that urinary sodium loss was greater than potassium retention, this ratio normalized by day 10, suggesting that the balance between sodium excretion and potassium absorption had been restored.

[0064] This change in ratio appears to be mediated by a greater excretion of urinary sodium on day 1 compared with day 10, as potassium appears to remain unchanged throughout the 10-day treatment period.

[0065] After administration of (R)-Compound 1, increases in blood urea nitrogen and creatinine were observed, along with a mild decrease (<15%) in glomerular filtration rate (GFR). The presence of an increase in blood urea nitrogen:creatinine ratio accompanied by a decrease in GFR suggests that (R)-Compound 1 produces a mild diuretic effect. Finally, perhaps due to the mild diuretic effect noted previously, subjects receiving (R)-Compound 1 experienced a significant decrease in body weight and body mass index compared to subjects receiving placebo. Values ​​returned to normal by follow-up.

[0066] The SAD test was carried out to determine whether (R)-Compound 1 was able to reach the maximum observed concentration (C) between 0.5 and 2 hours after oral administration. max ) indicating rapid absorption. A second, generally lower peak was often observed 3-4 hours after dosing. Concentrations then declined biphasically from the peak, with a prolonged median terminal elimination half-life of approximately 25-31 hours. Across the dose range (up to 10 mg), peak and total exposure (C max and AUC from time 0 to infinity [AUC 0-inf [Evaluated by ] generally increased in proportion to dose. Approximately 11% of the dose was recovered unchanged in the urine.

[0067] A single dose of (R)-Compound 1 dose-dependently reduced plasma and urinary aldosterone levels.

[0068] Following oral dosing, an average of 10.8% of the dose (individual values ​​ranged from 4.97% to 22.5% across all dose groups) was recovered unchanged in urine collected up to 48 hours after dosing ((R)-Compound 1), while an average of 0.22% of the dose (0.039% to 0.599% across all dose groups) was recovered as active metabolites in urine.

[0069] The observed CLR (range 278–443 mL / h, depending on dose) was calculated based on the product of the unbound fraction in plasma and the GFR in healthy subjects (fu * GFR=0.26 * The renal clearance was smaller than the mean plasma clearance of 15.5% (range of individual values ​​from active metabolites in urine was 6.53% to 31.8% across all dose groups) of the total plasma clearance.

[0070] Following oral administration, (R)-Compound 1 exhibited a C max Median time to max ) was rapidly absorbed. A second, generally lower, peak was often observed 3-4 hours after dosing. Concentrations then declined biphasically from the peak, with a prolonged median terminal elimination half-life of approximately 25-31 hours. Over the expected therapeutically relevant dose range (up to 10 mg), peak and total exposure (C max The concentration-time curve (as assessed by area under the concentration-time curve [AUC]) generally increased in a dose-proportional manner. Approximately 11% of the dose was recovered unchanged in the urine.

[0071] Single oral doses of (R)-Compound 1 up to 360 mg did not affect serum electrolyte (chloride, potassium, sodium, and phosphate) levels, which did not differ between active-treated and placebo-treated subjects. Urinary sodium and sodium-to-potassium ratios were both increased, with urinary sodium loss greater than potassium retention. No changes in urinary creatinine were evident.

[0072] A single dose of (R)-Compound 1 dose-dependently reduced plasma and urinary aldosterone levels by approximately 85%-90%, consistently reaching maximal effects at a dose of 10 mg of (R)-Compound 1 under the various conditions tested (Cortrosyn® challenge, orthostatic, normal salt, and low salt diet conditions). No significant changes in plasma cortisol levels were observed across the entire dose range tested (0-360 mg of (R)-Compound 1).

[0073] The maximal effect on aldosterone reduction was consistently achieved at the 10 mg dose under the various conditions tested (Cortrosyn® challenge, orthostatic, normal salt diet, and low salt diet conditions) in healthy subjects. No significant changes in plasma cortisol levels were observed following Cortrosyn challenge across the entire dose range tested (0-360 mg (R)-Compound 1). Although cortisol levels were unaffected up to 360 mg, partial inhibition of the CYP11B1 enzyme may occur at exposures well above those considered therapeutically relevant based on observed increases in 11-deoxycortisol (at doses 180 mg and 360 mg) and 11-DOC (at doses ≥ 90 mg).

[0074] Example 3 A double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of multiple dose strengths of (R)-Compound 1 compared with placebo after 8 weeks of treatment in patients with uncontrolled hypertension receiving one antihypertensive agent.

[0075] Indications Lowering systolic blood pressure (SBP) in patients with hypertension (HTN)

[0076] the goal One goal is to demonstrate that at least one dose intensity of (R)-Compound 1 is superior to placebo with respect to change from baseline in mean sitting SBP after 8 weeks of treatment in patients with uncontrolled HTN with elevated serum aldosterone levels and receiving one background antihypertensive agent (Part 1).

[0077] Other goals are to evaluate the following parameters in a study population of individuals with high serum aldosterone levels and uncontrolled hypertension receiving one background antihypertensive agent: Change from baseline in mean sitting diastolic blood pressure (DBP) with each of the selected dose strengths of (R)-Compound 1 compared to placebo after 8 weeks of treatment (Part 1). Changes from baseline in 24-hour urinary aldosterone and serum aldosterone levels with each of the selected dose strengths of (R)-Compound 1 compared with placebo after 8 weeks of treatment (Part 1); and Proportion of patients ('responders') achieving a mean sitting SBP <130mmHg with each selected dose strength of (R)-Compound 1 compared to placebo after 8 weeks (Part 1).

[0078] Other goals are to assess: Changes in 24-hour urinary aldosterone and serum aldosterone levels from values ​​measured at the end of Part 1 to values ​​measured at the end of Part 2 after 4 weeks of treatment with a 2 mg dose strength of (R)-Compound 1 and no background antihypertensive medications The proportion of patients who maintain a mean sitting SBP of <130mmHg ("responders") when treated with the 2mg dose strength of (R)-Compound 1 alone and without background antihypertensive medications for 4 weeks during Part 2.

[0079] safety goals The safety objectives for both Parts 1 and 2 will be to evaluate: · Clinical laboratory evaluation including vital signs, orthostatic blood pressure (BP) and heart rate, physical examination, electrocardiogram (ECG), weight, and standard safety chemistry panel, hematology, coagulation, and urinalysis; Treatment-emergent adverse events (TEAEs); Treatment-emergent serious adverse events (TESAEs); · TEAEs leading to early discontinuation of study drug; - significant treatment-emergent laboratory abnormalities; and · Change in orthostatic SBP (measured pre-dose at the clinical site) from baseline to end of treatment (EOT) (Visit 9).

[0080] Pharmacokinetic-pharmacodynamic goals The pharmacokinetic (PK)-pharmacodynamic (PD) objectives for both Part 1 and Part 2 are to evaluate the exposure-response relationship of (R)-Compound 1 using measures of safety, PD, and / or efficacy.

[0081] Inclusion criteria To be eligible to participate in the study, patients must meet all of the following criteria: 1. Adult male and female patients aged ≥ 18 years; 2. On a stable regimen for at least 8 weeks at maximum tolerated dose (MTD) of a single background antihypertensive agent (in the investigator's opinion) and considered a candidate for the addition of a second antihypertensive agent at screening; Acceptable classes of antihypertensive drugs used as first-line treatment for systemic HTN include angiotensin-converting enzyme inhibitors (ACEi) / angiotensin receptor blockers (ARBs), calcium channel blockers, and diuretics (other than mineralocorticoid receptor antagonists [MRAs] or potassium-sparing diuretics). Antianginal nitrates, including nitroglycerin, isosorbide mononitrate, and isosorbide dinitrate, are not considered antihypertensive agents. Patients who are not receiving the maximum tolerated dose of antihypertensive medication should have a source document that explains the investigator's rationale for defining the dose the patient is receiving as the MTD for that patient. Medications that consist of two active agents (i.e., ACE inhibitor + diuretic, CCB + ARB, etc.) are not considered single antihypertensive agents. 3. Mean sitting SBP ≥140 mmHg at screening (Visit 1) and Visit 2; Patients with a mean sitting SBP ≥ 130 mmHg may be eligible if they have diabetes. Mean sitting SBP is defined as the average of three sitting SBP measurements during any single clinical visit. 4. Adherence to antihypertensive medication and (R)-Compound 1 placebo during the run-in period ≥ 70% and ≤ 120%, based on morning pill count at Visit 2; 5. Serum aldosterone ≥ 7 ng / dL at screening; Patients taking ACEi or ARBs can be enrolled if their serum aldosterone is ≥ 6 ng / dL. 6. If taking a sodium-glucose cotransporter type 2 (SGLT2) inhibitor at screening (Visit 1), the regimen must have been stable for at least 8 weeks prior to Visit 2 and will be expected to remain on that dose for the duration of the study; Patients not currently taking an SGLT2 inhibitor are expected not to initiate medications of this class throughout their treatment horizon. 7. Agree to adhere to the contraceptive and reproductive restrictions of the study as follows: Postmenopausal female patients must have been free of menstrual bleeding for at least 1 year at screening, be over 60 years old, or have elevated plasma follicle-stimulating hormone levels >40mIU / mL at screening; ·Female patients of childbearing potential (i.e., not ovulating, premenopausal, and surgically infertile) must have documented negative pregnancy tests at screening (Visit 1) and Visit 2; ·Female patients of childbearing potential must use highly effective contraception (i.e., failure rate less than 1%) for 30 days starting 1 day after the last dose of study drug. Acceptable contraception methods for female patients enrolled in the study include: o Surgical sterilization (tubal ligation); o Intrauterine contraceptive device for at least 12 weeks prior to screening; o Hormonal contraception (oral, implant, injection, ring, or patch) for at least 12 weeks prior to screening; or o Contraceptive diaphragms used in combination with spermicides. Male patients must agree to refrain from donating sperm for 90 days starting from day 1 after the last dose of study drug. 8.Able and willing to give informed consent to participate in a clinical trial.

[0082] Exclusion criteria Patients who meet any of the following criteria will be excluded from participating in the study: 1. Mean sitting SBP ≥ 180mmHg at screening (Visit 1) or baseline (Visit 2); 2. Body mass index >50 kg / m at screening 2 is; 3. Having upper arm circumference that does not meet the cuff measurement criteria of the selected BP device at screening; 4. Using alpha or beta blockers to treat systemic HTN or another primary condition / indication (e.g., benign prostatic hyperplasia, migraine, heart failure); 5. Unwilling or unable to discontinue MRA or potassium-sparing diuretics as part of an existing antihypertensive regimen; 6. Unwillingness to stop taking potassium supplements; 7. Planning to receive or receiving any of the following excluded medications (potent cytochrome P4503A inducers and / or chronic use of nonsteroidal anti-inflammatory drugs [NSAIDs]); patients taking chronic NSAIDs who are willing to discontinue at screening for the duration of the study may be allowed to participate. 8. Known renal artery stenosis, poorly controlled or untreated hyperthyroidism, poorly controlled or untreated hypothyroidism, hyperparathyroidism, pheochromocytoma, Cushing's syndrome, or coarctation of the aorta; Patients with primary aldosteronism may be considered for enrollment unless adrenalectomy is anticipated before completion of study participation. 9. Estimated glomerular filtration rate < 30 mL / min / 1.73 m as calculated using the Chronic Kidney Disease Epidemiology Collaboration Study equation at screening 2 It has been documented that; 10. Known and documented New York Heart Association stage III or IV chronic heart failure at screening; 11.Has had stroke, transient ischemic attack, hypertensive encephalopathy, acute coronary syndrome, or hospitalization for heart failure within 6 months prior to screening; 12. Known current severe left ventricular outflow tract obstruction, such as hypertrophic obstructive cardiomyopathy and / or severe aortic valvular disease, diagnosed on a previous echocardiogram; 13. Planned coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) or any major surgical procedure; 14.Has undergone CABG or other major cardiac surgery (e.g., valve replacement), peripheral artery bypass surgery, or PCI within 6 months prior to screening; 15. Have chronic persistent atrial fibrillation; 16.Has uncontrolled diabetes mellitus with glycated hemoglobin >10% at screening; 17. Scheduled for dialysis or kidney transplant during the course of this study; 18. Previous solid organ and / or cell transplantation; 19. Known hypersensitivity to (R)-Compound 1, drugs of the same class, or any of its excipients; 20. Any clinically relevant medical or surgical condition, including unstable medical conditions and / or conditions being treated with systemic immunosuppressants, including corticosteroids, that in the opinion of the investigator may put the patient at risk by participating in the study; 21.Has any of the following evidence (retesting is permitted once at screening): A white blood cell count >15 x 10 at screening 9 / L or absolute neutrophil count <1×10 9 / L; b. Sodium <130 mEq / L at screening (Visit 1); If the investigator chooses to modify serum sodium concentration and / or requests management of medical conditions, one repeat screening test will be permitted at least 1 week prior to Visit 2. If serum sodium is repeatedly <130 mEq / L, the patient will be disqualified from the study. c. Potassium <3.5 mEq / L at screening (Visit 1); d. Potassium >5 mEq / L at screening (Visit 1); If the investigator chooses to modify serum potassium levels and / or requests management of medical conditions, one repeat screening test will be permitted at least 1 week prior to Visit 2. If serum potassium is repeatedly >5 mEq / L, the patient will be disqualified from the study. e. Hemoglobin <10 g / dL at screening and / or when erythropoietin-stimulating agents are scheduled to be started and / or when a planned transfusion occurs within 2 months after screening; or f. Serum aspartate aminotransferase and / or alanine aminotransferase >3× upper limit of normal with corresponding total bilirubin >2 mg / dL at screening. If the patient has a history of Gilbert's syndrome, bilirubin may be >2 mg / dL at screening. 22. Positive for HIV antibody, hepatitis C virus RNA, or hepatitis B surface antigen at screening; 23. Have a typical intake of ≥ 14 alcoholic drinks per week; One drink of alcohol is equivalent to half a pint of beer (285 mL), one glass of spirits (25 mL), or one glass of wine (125 mL); 24. Pregnant, breastfeeding, or planning to become pregnant during the study; 25.Has participated in another clinical trial involving any investigational drug within 30 days prior to screening, or plans to participate in another clinical trial within 30 days after discontinuing the investigational drug; 26. Having received experimental treatment with a small molecule within 30 days or 5 half-lives of Day 1, whichever is longer, or experimental treatment with a large molecule within 90 days or 5 half-lives of Day 1, whichever is longer; or 27. Deemed unsuitable by the Investigator, after review of medical and psychiatric history, physical examination, and clinical laboratory evaluation, for any other reason that may endanger the patient during participation or that may interfere with the interpretation of the study results.

[0083] Study design and duration This is a Phase 2 randomized, multicenter study to evaluate the efficacy and safety of multiple dose strengths of (R)-Compound 1 in treating patients with HTN. To be considered for study entry, patients must have uncontrolled HTN (mean sitting SBP ≥ 140mmHg [or if diabetic, ≥ 130mmHg]) and be considered candidates for the addition of a second antihypertensive agent at screening despite being on a stable regimen of a single background antihypertensive agent for at least 8 weeks (in the investigator's opinion) at the MTD. Eligible patients must have serum aldosterone ≥ 7ng / dL (if ACEi or ARB, ≥ 6ng / dL) and meet all other screening criteria.

[0084] Screening laboratory evaluations, if abnormal, may be repeated once for eligibility purposes before excluding the patient. If screening is failed, rescreening may be performed less than 5 days after the last study visit, with consultation and approval of the Sponsor and / or Medical Monitor.

[0085] During the study, patients will complete 8-10 scheduled visits, including 7-9 clinical site visits and 1 telephone visit. Scheduled visits may be scheduled at any time during the study, based on the investigator's discretion. The study will consist of the following periods / visits: A screening period of at least 4 weeks consisting of: o Screening visit (Visit 1); o A telephone visit to inform the patient of their study eligibility; and o A run-in period of up to 4 weeks to ensure patient adherence to background antihypertensive medications and placebo prior to randomization (Visit 2) (see Inclusion Criterion 4). A two-part treatment period consisting of: o Part 1: an 8-week double-blind treatment period (Weeks 1-8; Visits 2-6); and o Part 2: 4-week treatment period (Weeks 9-12; starting the day after Visit 6 and running through Visit 9). A safety follow-up period of approximately 2 weeks after the last dose of study drug (Visit 10).

[0086] Once screening eligibility test results, including serum aldosterone, are returned, patients will be contacted by telephone (telephone visit) to inform them of their eligibility and, if eligible, to begin the run-in period and schedule their next visit: scheduled outpatient or Visit 2. For patients with serum sodium <130 mEq / L and / or serum potassium >5 mEq / L at screening that the investigator chooses to modify or manage, one repeat test (at a scheduled outpatient) will be permitted at least 1 week prior to Visit 2 (see Exclusion Criteria 21). Eligible patients will also be instructed to begin a run-in period in which they will take a placebo tablet once daily (QD) in addition to their background antihypertensive medication through Visit 2. Patients who demonstrate treatment adherence (see Inclusion Criteria 4) and continue to meet all inclusion criteria at Visit 2 and do not meet any of the exclusion criteria will be randomized into the Part 1 treatment period.

[0087] The clinical site will provide patients with 24-hour urine collection kits at Visits 1, 5, and 8. Patients will be instructed to begin collection no later than 3 days prior to Visits 2 (after confirming eligibility via phone visit), 6, and 9, to refrigerate collected samples, and to bring the entire sample to the clinical site.

[0088] During the double-blind Part 1 treatment period (Weeks 1-8; Visits 2-6), patients will be randomly assigned (1:1:1:1) to one of four treatment arms: 0.5 mg (R)-Compound 1, 1 mg (R)-Compound 1, 2 mg (R)-Compound 1, or placebo as add-on to a single background antihypertensive agent. On the day of the clinical site visit, patients will self-administer a morning dose of background antihypertensive medication at home and withhold study medication. At the clinical site, patients will self-administer one tablet of study medication in the presence of site staff after pre-dose assessments and clinical laboratory sampling are completed. During the clinical site visits, patients will continue to orally self-administer one tablet of study medication QD at approximately the same time each morning. Endpoints will be assessed at the end of Week 8.

[0089] During the Part 2 treatment period (Weeks 9-12; starting the day after Visit 6 and ending at Visit 9), all responders (defined as achieving a mean sitting SBP <130 mmHg) at the end of Part 1 will transfer to Part 2. They will receive a 2 mg dose of (R)-Compound 1 (the maximum dose in this study) and will discontinue any single background antihypertensive medication. Non-responders who received any study drug except 2 mg of (R)-Compound 1 in Part 1 will transfer to Part 2, receive a 2 mg dose of (R)-Compound 1, and will discontinue any single background antihypertensive medication. Non-responders who decide not to participate in Part 2 or who have already received the maximum dose strength (2 mg) of (R)-Compound 1 in Part 1 will be considered to have discontinued study drug and must complete their EOT (Visit 9) procedures and 2 weeks of safety follow-up at the end of Part 1 (Visit 6).

[0090] Patients will be instructed to bring their study medication and background antihypertensive medications to all clinical site visits. Patients should not exercise, smoke, or consume caffeinated beverages or foods for at least 2 hours prior to each clinical site visit. All clinical site visits should occur at approximately the same time (within a patient), with efforts to have visits occur between 6:00 AM and 11:00 AM.

[0091] During safety follow-up (Visit 10), patients will be evaluated for vital signs, clinical laboratory assessments, adverse events (AEs), and use of concomitant medications, including antihypertensive regimens, since study completion.

[0092] The safety of (R)-Compound 1 will be assessed from the time of informed consent through the end of the safety follow-up period. Patients will be followed for pre-specified efficacy and adherence throughout the treatment period. PD variables analyzed during the study may include, but are not limited to, measurements of aldosterone and its precursors, cortisol and its precursors, plasma renin activity (PRA), and calculation of the aldosterone / PRA ratio. PK variables analyzed during the study will include plasma concentrations of (R)-Compound 1 and any measured metabolites. A Data Safety Monitoring Board (DSMB) is planned to periodically evaluate new safety data and evaluate reports of cumulative SAEs.

[0093] Dosage forms and routes of administration Dose strengths of (R)-Compound 1 are 0.5 mg QD, 1 mg QD, and 2 mg QD. During the run-in period, all patients orally self-administer one placebo tablet QD at approximately the same time each morning.

[0094] During clinical site visits during the treatment period (Parts 1 and 2), patients will self-administer 1 tablet of study drug in the clinic after pre-dose assessments and clinical laboratory sampling are completed and witnessed by site staff. Between clinical site visits, patients will continue to orally self-administer 1 tablet of study drug QD at approximately the same time each morning.

[0095] Evaluation items The efficacy outcome measure was the change from baseline in mean sitting SBP after 8 weeks of treatment in patients with uncontrolled HTN, elevated serum aldosterone levels, and receiving one background antihypertensive agent (Part 1).

[0096] Other efficacy endpoints in this study in the same populations described for the endpoints are: · Change from baseline in mean seated DBP with (R)-Compound 1 compared to placebo after 8 weeks of treatment (Part 1); Changes from baseline in 24-hour urinary aldosterone and serum aldosterone levels with (R)-Compound 1 compared to placebo after 8 weeks of treatment (Part 1); and Proportion of patients ("responders") who achieved a mean sitting SBP <130mmHg with (R)-Compound 1 compared to placebo after 8 weeks of treatment (Part 1: Weeks 1-8).

[0097] Other efficacy endpoints in the study included: Changes in 24-hour urinary aldosterone and serum aldosterone levels from values ​​measured at the end of Part 1 to values ​​measured at the end of Part 2 after 4 weeks of treatment with a 2 mg dose strength of (R)-Compound 1 and no background antihypertensive medications; and Proportion of patients who maintain a mean sitting SBP <130mmHg when treated with (R)-Compound 1 2mg alone and without background antihypertensive medications for 4 weeks during Part 2 ("responders").

[0098] Safety evaluation items Safety endpoints of the study included: · Clinical laboratory evaluation including vital signs, orthostatic BP and heart rate, physical examination, ECG, weight, and standard safety chemistry panel, hematology, coagulation, and urinalysis; ·TEAE; ·TESAE; · TEAEs leading to early discontinuation of study drug; - significant treatment-emergent laboratory abnormalities; and · Change in orthostatic SBP (measured pre-dose at the clinical site) from baseline to EOT (Visit 9).

[0099] Safety analysis The safety analysis set is the safety analysis population. All safety endpoints will be summarized narratively from records collected in Part 1. Further safety endpoint analyses will be performed including records collected in Part 2 and post-treatment follow-up surveys / end of study.

[0100] Pharmacokinetic analysis Individual plasma concentration data for (R)-Compound 1 and any measured metabolites will be tabulated and summarized by visit, time point, and treatment group for the PK population.

[0101] For patients enrolled in Part 2, relevant parameters for (R)-Compound 1 and any measured metabolites will be listed for each individual patient and tabulated using descriptive statistics. Mean and individual plasma concentrations of (R)-Compound 1 and any measured metabolites will be plotted against patient time points in Part 2.

[0102] Pharmacodynamic analysis The PD population is the population for the PD analysis. All PD variables are summarized descriptively.

[0103] Pharmacokinetic / pharmacodynamic analysis When data permit, attempts will be made to correlate plasma concentrations and parameters with measures of safety, PD, and / or efficacy.

[0104] Formulation and Packaging (R)-Compound 1 tablets are provided in the following dosage strengths: 0.5 mg, 1 mg, and 2 mg. The tablets are packaged in blister packs to achieve the dose required for the study. (R)-Compound 1 tablets contain (R)-Compound 1 as the active ingredient and inactive ingredient.

[0105] Example 4 A randomized, double-blind, placebo-controlled, multicenter, parallel-group, dose-ranging study to evaluate the efficacy and safety of (R)-Compound 1 for the treatment of patients with primary aldosteronism (PA).

[0106] Indications Lowering blood pressure (BP) in patients with primary aldosteronism (PA)

[0107] the goal One goal is to demonstrate that at least one dose strength of (R)-Compound 1 is superior to placebo in mean change from baseline in sitting systolic blood pressure (SBP) by automated office blood pressure monitoring (AOBPM) after 4 weeks of treatment in patients with PA.

[0108] Other goals are: To evaluate the change from baseline in mean sitting diastolic blood pressure (DBP) by AOBPM with each selected dose strength of (R)-Compound 1 compared with placebo after 4 weeks of treatment in patients with PA; To evaluate the proportion of patients who achieved a sitting BP response of <140 / 90 mmHg with each selected dose strength of (R)-Compound 1 compared with placebo after 4 weeks of treatment for PA; To evaluate the proportion of patients who achieved a sitting BP response of <130 / 80mmHg with each selected dose strength of (R)-Compound 1 compared with placebo after 4 weeks of treatment for PA; To evaluate the proportion of patients with each selected dose intensity of (R)-Compound 1 compared to placebo after 4 weeks of treatment for PA who achieve either: o Plasma aldosterone concentration (PAC) < 15 ng / dL and plasma renin activity (PRA) ≥ 0.5 ng / mL / h; or Aldosterone-to-renin ratio (ARR) < 30; and To evaluate the change from baseline in potassium levels and / or potassium supplementation requirements with each selected dose strength of (R)-Compound 1 compared to placebo after 4 weeks of treatment in patients with PA.

[0109] Other goals are: To assess changes in concentrations from baseline to the end of treatment; Pharmacodynamic (PD) variables include, but are not limited to: PAC, 11-deoxycorticosterone, PRA, direct renin concentration, calculated aldosterone-to-renin ratio (ARR), and 24-hour urinary aldosterone, sodium, and potassium at each of the following selected dose strengths: (R)-Compound 1, compared with placebo after 4 weeks of treatment in patients with PA; and To evaluate the relationship between BP reduction and change in aldosterone and renin levels with each selected dose strength of (R)-Compound 1 compared to placebo from baseline to the end of treatment.

[0110] Pharmacokinetic PK / PD Goals The pharmacokinetic (PK)-PD goal is to evaluate the exposure-response relationship of (R)-Compound 1 in PA patients using measures of safety, PD, and / or efficacy.

[0111] Inclusion criteria Patients who met all of the following criteria were eligible to participate: 1. Adult male or female patient aged ≥ 18 years; 2. Previously diagnosed with PA or suspected PA as determined by the investigator; 3. Starting at Visit 2 (if applicable), patients may wash out renin-angiotensin-aldosterone system (RAAS) modifiers until return at Visit 3 for at least the following periods: 4 weeks: diuretics, mineralocorticoid receptor antagonists (MRAs); and 2 weeks: beta-blockers, clonidine, methyldopa, minoxidil, nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and / or dihydropyridine calcium channel blockers (CCBs); Patients will continue to discontinue all RAAS modifiers starting at Visit 2 through the end of treatment. Patients may receive non-RAAS modifier antihypertensives, defined as non-dihydropyridine CCBs (e.g., diltiazem, verapamil), hydralazine, or alpha-blockers monotherapy or combination therapy, to maintain BP >130 / 80mmHg and <160 / 100mmHg during the remainder of the screening period, regardless of washout status, and minimize effects on PAC and PRA. Patients taking beta-blockers should be appropriately managed by the investigator during washout, which should include gradual tapering and monitoring these patients for discontinuation symptoms (e.g., palpitations, chest pain, etc.). 4. Willingness to maintain BP >130 / 80mmHg and <160 / 100mmHg during the screening period and <160 / 100mmHg during the double-blind treatment period with an acceptable non-RAAS-modifying antihypertensive drug; 5. Willing to agree to comply with the contraceptive and reproductive restrictions of the study as follows: ·Male subjects must agree to refrain from sperm donation for 90 days starting from day 1 after the last dose of study drug; · Postmenopausal women must have been free of menstrual bleeding for at least 1 year prior to the first dose and be >60 years of age or have an elevated follicle-stimulating hormone (FSH) level >40 mIU / mL at the screening visit; Female patients of childbearing potential (i.e., not ovulating, premenopausal, and surgically infertile) must have a documented negative pregnancy test at the screening and randomization visits; and All male patients (not surgically sterile) must use highly effective methods of contraception, including: ·Contraception for 90 days from day 1 after the last dose of study drug (i.e., failure rate <1%); Contraceptive methods acceptable to male patients enrolled in the study included: o Condoms with spermicide; or o Surgery to prevent pregnancy (vasectomy) for at least 26 weeks prior to the screening visit Female patients of childbearing potential should · Highly effective contraception (i.e., failure rate less than 1%) must be used for 30 days starting from day 1 after the last dose of study drug. Contraceptive methods accepted by FPCBPs enrolled in the study included: o Surgical sterilization (tubal ligation); o Intrauterine contraceptive device for at least 12 weeks prior to the screening visit; o Hormonal contraception (oral, implant, injection, ring, or patch) for at least 12 weeks prior to the screening visit; or Contraceptive diaphragms used in combination with spermicides; and 6.Able and willing to give informed consent to participate in the study.

[0112] Exclusion criteria Patients who meet any of the following criteria will be excluded from participating in the study: 1. A single occurrence of mean sitting SBP >180mmHg or DBP >110mmHg or two consecutive occurrences of mean sitting SBP ≥160mmHg or DBP ≥100mmHg by AOBPM during the screening period (if such BPs are recorded at Visit 1, patients will attend an interim visit for additional BP measurements and reassessment of inclusion / exclusion criteria); Mean sitting BP is defined as the average of three measurements obtained during any one clinical site visit. If a patient has not taken their regularly scheduled antihypertensive medication prior to the visit (Visits 1, 2, 3, or 4) and is otherwise adhering to their antihypertensive regimen, as determined by the investigator, one BP recheck will be permitted ≥2 hours after taking the medication or after reestablishing the regularly scheduled antihypertensive regimen on the following day or later. 2. Body mass index >40 kg / m at screening visit 2 is; 3. Upper arm circumference <7 inches or >17 inches at the screening visit; 4. Previous surgical intervention or planned surgical intervention during the study period for adrenal adenoma or adrenal carcinoma, adrenalectomy, renal denervation, or adrenalectomy; Patients who received treatment >6 months prior to randomization but still had elevated PAC (>15 ng / dl), BP and met other eligibility criteria may be considered. 5. Estimated glomerular filtration rate <45 mL / min / 1.73 m using the Chronic Kidney Disease Epidemiology Collaboration Study equation at Screening Visit or Visit 4. 2 It has been documented that; 6. Scheduled to undergo dialysis or kidney transplant during the course of the study; 7. Have known documented chronic heart failure; 8.Has had stroke, transient ischemic attack, hypertensive encephalopathy, acute coronary syndrome, or hospitalization for heart failure within 6 months prior to the screening visit; 9. Current severe left ventricular outflow tract obstruction, such as diagnosed obstructive hypertrophic cardiomyopathy and / or severe aortic valvular disease, as determined by a previous echocardiogram; 10. Coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]) or any major surgical procedure planned during the study; 11.Has undergone PCI, CABG, other major cardiac surgery (e.g., valve replacement), or peripheral artery bypass surgery within 6 months prior to the screening visit; 12.Having chronic persistent atrial fibrillation; 13. History or current clinically significant arrhythmias as determined by the investigator, including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and supraventricular arrhythmias. Patients with mild ectopic symptoms (e.g., atrial premature beats) will not necessarily be excluded, at the investigator's discretion; 14. Previous solid organ or cell transplantation; 15. Excluded medications include potent inducers of cytochrome P4503A, drugs known to prolong the QT interval, and / or chronic use of NSAIDs or steroids within 28 days or 5 half-lives prior to the first dose of study drug, whichever is longer, until the end of treatment; patients using the above medications at screening and willing to discontinue during the study period will be allowed to participate. 16. Known hypersensitivity to any of the following: Compound 1 or a drug of the same class; Captopril or a drug in the same class; or (R)-Compound 1, captopril, or an excipient in a drug of the same class; 17. Any clinically relevant medical or surgical condition (including unstable medical conditions and / or conditions requiring treatment with systemic immunosuppressants, including corticosteroids) that, in the opinion of the investigator, may put the patient at risk by participating in the study; 18. Have evidence of any of the following at Screening, Visit 4, or Randomization Visit: ·White blood cell count>15×10 9 / L or absolute neutrophil count <1×10 9 / L; · Serum potassium <2.5 mEq / L; Patients with serum potassium levels below the normal range could continue on the study if the investigator chose to correct their serum potassium levels with supplements and suggested management of their medical condition. · Serum potassium >5.0 mEq / L; Applies to Visit 4 and randomization only. Patients with serum potassium levels >5.0 mEq / L at Visit 1 may continue in the study if the investigator chooses to correct the serum potassium level and / or suggests that the patient manage their condition while washing out the RAAS modifier. Hemoglobin <10.0 g / dL or planned initiation of erythropoietin stimulating agents or planned transfusion within 2 months of screening; Serum aspartate aminotransferase or alanine aminotransferase >3 × upper limit of normal (ULN); or · Total bilirubin >2×ULN unless due to Gilbert's syndrome; 19.Has uncontrolled diabetes with glycosylated hemoglobin >9.5% at the screening visit; 20. Positive for HIV antibody, hepatitis C virus RNA, or hepatitis B surface antigen; 21. Have a typical intake of >14 alcoholic drinks per week; One drink of alcohol is equivalent to half a pint of beer (285 mL), one glass of spirits (25 mL), or one glass of wine (125 mL); 22.Has participated in another clinical trial involving any investigational drug within 30 days prior to the screening visit, or plans to participate in another clinical trial within 30 days after discontinuing the investigational drug; 23.Has received experimental treatment with a small molecule within 30 days or 5 half-lives of the screening visit, whichever is longer, or experimental treatment with a large molecule within 90 days or 5 half-lives of the screening visit, whichever is longer; 24.Has worked night shifts at any time during the 4 weeks prior to the screening visit and / or plans to start night shifts at any time during the screening and / or double-blind treatment period; 25. Pregnant, breastfeeding, or planning to become pregnant during the study; or 26. Deemed unsuitable by the Investigator, after review of medical and psychiatric history, physical examination, and clinical laboratory evaluation, for any other reason that may endanger the patient during participation or that may interfere with the interpretation of the study results.

[0113] Study design and duration This is a Phase 2, randomized, placebo-controlled, multicenter, parallel-group, dose-ranging study in patients with PA to evaluate the efficacy and safety of selected dose strengths of (R)-Compound 1 compared with placebo after 4 weeks of treatment. Adult patients with a previous diagnosis of or suspected PA are eligible to be screened for study participation.

[0114] Safety of (R)-Compound 1 will be assessed from the time of informed consent through the end of the follow-up period. Patients will be followed for efficacy and adherence during the double-blind treatment period. Plasma PD variables analyzed during the study include measurements of aldosterone and its related precursors, cortisol and its related precursors, PRA, direct renin concentrations, and calculated ARR. PK variables analyzed during the study include plasma concentrations of (R)-Compound 1 and any additional metabolites.

[0115] Patients will be instructed to bring medications (antihypertensives (if applicable) and study medication) and a daily paper diary to all clinical site visits for assessment of treatment adherence and review of home BP monitoring, respectively. Patients should not exercise, smoke, or consume caffeinated beverages or foods for at least 2 hours prior to each clinical site visit. All clinical site visits should occur between 6:00 AM and 11:00 AM, and if possible, at the same time for each visit.

[0116] Study visit Patients will complete at least 10 visits over an approximate 7-15 week period, including 9 clinic visits and 1 telephone visit. Additional interim visits may occur at the investigator's discretion to manage BP during the screening period.

[0117] The study consisted of three periods and corresponding visits: The screening period of approximately 2-9 weeks will include: o Screening visit (Visit 1); o Washout visit (visit 2); Beginning after Visit 2, patients will begin washout of the applicable RAAS modifier before returning for Visit 3 for at least the following periods: ■ 4 weeks: diuretics, mineralocorticoid receptor antagonists (MRAs); and ■ 2 weeks: beta-blockers, clonidine, methyldopa, minoxidil, nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and / or dihydropyridine calcium channel blockers (CCBs); Patients will continue to discontinue all RAAS modifiers starting at Visit 2 through the end of treatment. Patients may receive non-RAAS modifier antihypertensives, defined as non-dihydropyridine CCBs (e.g., diltiazem, verapamil), hydralazine, or alpha-blockers monotherapy or combination therapy, to maintain BP >130 / 80mmHg and <160 / 100mmHg during the remainder of the screening period, regardless of washout status, and minimize effects on PAC and PRA. Patients taking beta-blockers should be appropriately managed by the investigator during washout, which should include gradual tapering and monitoring these patients for discontinuation symptoms (e.g., palpitations, chest pain, etc.). Patients not taking a RAAS-modifying drug at Visit 1 do not need to complete Visit 2 and can proceed directly to Visit 3. o Blood test visit (Visit 3); and o Confirmatory testing visit (Visit 4); Upon washout of the RAAS modifier, additional interim visits may occur to control BP. · A 4-week double-blind treatment period (Visits 5-9); Patients entering the double-blind treatment period were required to maintain a stable non-RAAS antihypertensive regimen (if applicable) and o Blood pressure must be maintained at <160 / 100 mmHg throughout treatment; and o Maximum follow-up period of 1 week (phone call [10th visit]).

[0118] Screening Period Patients who provide written informed consent at visit 1 will be assessed for the following:

[0119] Inclusion / Exclusion Criteria At Visit 1, site staff will measure BP; collect blood samples for PAC, PRA, and direct renin concentration measurements, and perform routine safety assessments. Patients will monitor adherence to their antihypertensive regimen (if applicable) using daily electronic diaries during the screening period.

[0120] Beginning at Visit 2, patients will be required to wash out any currently used RAAS-modifying medications, if applicable, and will refrain from these for the duration of study participation. If patients are taking diuretics, including MRAs, a washout of at least 4 weeks prior to Visit 3 is required. If patients are taking beta-blockers, clonidine, methyldopa, minoxidil, NSAIDs, ACEIs, ARBs, and / or dihydropyridine CCBs, a washout of at least 2 weeks prior to Visit 3 is required. Patients taking beta-blockers should be appropriately managed by the investigator during washout, which should include gradual tapering and monitoring these patients for discontinuation symptoms (e.g., palpitations, chest pain, etc.).

[0121] Patients may receive non-RAAS-modifying antihypertensives, defined as non-dihydropyridine CCBs (e.g., diltiazem, verapamil), hydralazine, or alpha-blockers monotherapy or combination therapy, regardless of washout status. Patients have the option to receive generic non-RAAS-modifying antihypertensives through a central pharmacy during the study. Interim visits may be scheduled to check BP status as new antihypertensive agents are introduced during the screening period. Patients will be provided with a home BP monitoring device at visit 2 to monitor their home BP every morning and evening during the study.

[0122] Patients not taking RAAS-modifying drugs at Visit 1 do not need to complete Visit 2 (the washout visit) and can proceed directly to Visit 3.

[0123] Patients will return to Visit 3 after completion of the applicable washout period. At Visit 3, site staff will measure BP, perform routine safety assessments, and collect blood samples for PAC, PRA, and direct renin concentration measurements. Patients with either (1) PAC ≥ 15 ng / dL and PRA < 0.5 ng / mL / h or (2) ARR ≥ 30 will be eligible to proceed to Visit 4.

[0124] At visit 4, a postural captopril challenge is administered as a confirmatory test for PA.

[0125] Patients receive a single oral dose of captopril 50 mg after being seated for at least 1 hour (Time 0). Blood samples for PAC, PRA, and cortisol are collected at Time 0 and at Time 1 and Time 2 after captopril administration while the patient remains seated during this sampling period. Patients with PAC suppression <30% at Hour 1 or 2 compared to Time 0 and / or PAC >11 ng / dL at Hour 1 or 2 after Time 0 of the seated captopril challenge are eligible to proceed to randomization (Visit 5).

[0126] It may be necessary to extend the length of the screening period to ensure that patients are on a stable (≧2 weeks) non-RAAS antihypertensive regimen with BP >130 / 80 mmHg and <160 / 100 mmHg prior to the randomization visit (Visit 5). The time from Visit 3 to Visit 5 may be included within the 2-week stable BP period.

[0127] Patients who are screened but do not meet the study inclusion / exclusion or randomization criteria (i.e., screen failure) may be rescreened less than 5 days after their last study visit, with consultation and approval of the sponsor and / or medical monitor. Patients who fail screening based on the results of the captopril challenge at Visit 4 may not be rescreened.

[0128] Double-blind treatment period Measurements obtained at Visit 5 before the patient receives study drug constitute "baseline" measurements. Measurements of efficacy and safety variables recorded prior to administration of study drug at the clinical site constitute "pre-dose" measurements.

[0129] Adaptive Design At visit 5, eligible patients will be randomly assigned in a 1:1:1 ratio to one of three treatment arms (two active [2 mg and 4 mg of (R)-Compound 1] and one placebo). Randomized patients will be stratified by baseline PAC (<35 ng / dL and ≥35 ng / dL). Patients must maintain an applicable non-RAAS antihypertensive regimen and maintain blood pressure <160 / 100 mmHg during the double-blind treatment period. After approximately 10 randomized patients per group have completed the 4-week double-blind treatment period, an interim analysis will be performed and a Data Review Committee (DRC) will evaluate new safety and efficacy data. Study enrollment is planned to continue during the interim analysis. Based on unblinded safety and efficacy evaluations, the DRC may decide to expand one or both of the current treatment arms, continue one arm (e.g., 2 mg QD or 4 mg QD of (R)-Compound 1), and potentially add one additional dose level of up to 8 mg QD of (R)-Compound 1. After the interim analysis, patients will be enrolled using a randomization schedule that allows for approximately equal distribution among the various treatment arms (2, 3, or 4 arms) according to power and sample size calculations determined at the interim analysis.

[0130] Based on ongoing safety monitoring of the study, additional DRC reviews may be performed, which may or may not lead to formal unlabeled interim analyses. Details of the DRC's responsibilities, authority, and procedures will be documented in the DRC Charter. Between clinical site visits, adherence to both the antihypertensive regimen (if applicable) and study medication will be monitored using daily electronic diaries. During clinical site visits, adherence to study medication and antihypertensive regimen (if applicable) will be calculated using pill counts.

[0131] Pre-dose blood samples for PD analysis will be collected at Visits 5-9. Pre-dose blood samples for PK analysis will be collected at Visits 6 and 9. Post-dose blood sampling for PD and PK analysis will be performed at Visit 9, 2 hours (± 5 minutes) after study drug administration. Urine samples for PD and electrolyte measurements will be collected over 24 hours at Visit 2 (patients not taking a RAAS modifier at Visit 1 do not need to complete a 24-hour urine sample collection as these patients do not need to complete Visit 2), Visit 5, and Visit 9 / End of Treatment (24-hour urine collection). Efficacy endpoints will be assessed at the end of treatment (Visit 9).

[0132] Observation period (telephone call) Patients will receive a phone call from the clinical site 1 week ± 3 days after their last dose of study medication to assess adverse events (AEs) and concomitant medications after study completion.

[0133] Dosage forms and routes of administration The doses of (R)-Compound 1 tested in this study are 2 mg QD, 4 mg QD, and optionally one additional dose level up to 8 mg QD. (R)-Compound 1 is provided as a 2 mg tablet. The placebo tablet is indistinguishable from the (R)-Compound 1 tablet. The study drug is stored at controlled room temperature between 20°C and 25°C (68°F and 77°F). Consistent with United States Pharmacopeia (USP) references, transient excursions in the range of 15°C to 30°C are permitted during storage. Transient excursions to 40°C are permitted for up to one week during shipping. The intended route of administration to patients is by oral delivery. To keep the study blinded, randomized patients are instructed to take a total of four tablets orally once daily (QD), consisting of (R)-Compound 1 and / or placebo tablets.

[0134] Study medication ((R)-Compound 1 or placebo) will be dispensed at Visit 5 and Visit 7. At Visit 5, patients will self-administer the first single dose of study medication at the clinical site. Subsequent doses of study medication will be taken orally by patients once daily at approximately the same time each morning at home. On the day of the clinical site visit, patients will take their morning dose of applicable antihypertensive medication at home prior to their scheduled visit (including medications for other comorbid conditions, if any) and will abstain from study medication. At the clinical site, patients will self-administer study medication in the presence of site staff after pre-dose assessments and clinical laboratory sampling are completed.

[0135] Efficacy endpoints The efficacy outcome measure was the change from baseline in mean sitting SBP measured by AOBPM after 4 weeks of treatment in patients with PA.

[0136] Other efficacy outcomes included: · Change from baseline in mean sitting DBP by AOBPM with (R)-Compound 1 compared to placebo after 4 weeks of treatment in patients with PA; · Proportion of patients who achieved a sitting BP response of <140 / 90mmHg with (R)-Compound 1 compared to placebo after 4 weeks of treatment for PA; The proportion of patients who achieved a seated BP response of <130 / 80 mmHg with (R)-Compound 1 compared to placebo after 4 weeks of treatment for PA; and The proportion of patients with (R)-Compound 1 compared to placebo after 4 weeks of treatment for PA who achieve either: oPAC < 15 ng / dL and PRA ≥ 0.5 ng / mL / h; or oARR<30.

[0137] Other evaluation items included: -Changes from baseline to the end of treatment in concentrations of PD markers, including, but not limited to, PAC, 11-deoxycorticosterone, PRA, direct renin concentration, calculated ARR, and 24-hour urinary aldosterone, B-type natriuretic peptide, sodium, and potassium, with (R)-Compound 1 compared to placebo after 4 weeks of treatment; and The relationship between BP reduction and change in aldosterone and renin levels with (R)-Compound 1 compared to placebo from baseline to end of treatment.

[0138] Safety evaluation items The safety of (R)-Compound 1 will be assessed from the time of informed consent to the end of the follow-up period. All safety endpoints will be summarized narratively. Safety endpoints include: · Change from baseline in potassium levels and / or potassium supplementation requirements with (R)-Compound 1 compared to placebo after 4 weeks of treatment in patients with PA; · Clinical laboratory evaluation including vital signs (heart rate, respiratory rate, temperature), mean SBP, mean DBP, orthostatic vitals (orthostatic BP and heart rate), physical examination, electrocardiogram, weight measurement, and standard safety chemistry panel, hematology, coagulation, and urinalysis; Treatment-emergent adverse events (TEAEs); Treatment-emergent serious adverse events (SAEs); · TEAEs leading to early discontinuation of study drug; - significant treatment-emergent laboratory abnormalities; and Change in orthostatic SBP and DBP (measured at the clinical site prior to study drug administration) from baseline to end of treatment.

[0139] Adverse events of particular interest include those requiring clinical intervention: hypotensive events, abnormal potassium test values, and / or abnormal sodium test values.

[0140] Efficacy Analysis Efficacy analyses will compare the change in mean sitting SBP from baseline (Visit 5) to the end of treatment (Visit 9) between each dose strength of (R)-Compound 1 and placebo.

[0141] Efficacy endpoints will be analyzed using an analysis of covariance model with treatment group as a factor and baseline mean seated SBP and baseline plasma aldosterone concentrations as covariates. Pairwise comparisons between each dose strength of (R)-Compound 1 and placebo will be estimated along with their 95% confidence intervals. Efficacy analyses will be performed based on the ITT population with the last observation carried forward method used to impute any missing endpoint values. Other imputation methods will be considered using missing at random or missing at random assumptions. Endpoint analyses will be repeated on the PP population to test the robustness of the results. A repeated measures mixed model (MMRM) method will be used for sensitivity analysis of efficacy endpoints. Multiplicity will not be adjusted due to the exploratory nature of this study.

[0142] Other continuous efficacy outcomes will be summarized and analyzed using similar models. Categorical efficacy outcomes will be summarized by frequency and proportion of defined responders and analyzed with logistic regression models.

[0143] Changes from baseline in mean SBP, mean DBP, and potassium will be analyzed via MMRM methods for efficacy analyses. Analyses will include fixed effects of treatment, visit, and treatment-by-visit interactions along with baseline value covariates. Analyses will consist of observed data only (i.e., no imputation of missing data will be performed). No adjustments will be made for multiplicity when testing efficacy endpoints.

[0144] Safety analysis The safety analysis set is the safety analysis population. All safety endpoints will be summarized narratively.

[0145] Safety assessment will be based primarily on the frequency of AEs, clinical laboratory assessments, vital signs, and 12-lead ECGs. Other safety data will be summarized as appropriate.

[0146] AEs will be coded using the ICH International Medical Terminology. TEAEs will be defined as AEs that are new or worsening in severity during the double-blind treatment period and are summarized by system organ class and preferred term. Lists of patients with SAEs and those who discontinued the study due to AEs will be provided.

[0147] Summary statistics will be provided by treatment group at baseline, at each visit, and for changes from baseline to each visit in laboratory parameters, vital signs, and other safety measures. The incidence of significant abnormalities in changes from baseline in clinical laboratory values ​​will be summarized by treatment group. Physical examination data will be tabulated.

[0148] Pharmacokinetic analysis Individual plasma concentration data for (R)-Compound 1 and any measured metabolites will be tabulated and summarized by visit, time point, and treatment group.

[0149] Pharmacodynamic analysis All PD variables are summarized descriptively.

[0150] Pharmacokinetic / pharmacodynamic analysis Attempts will be made to correlate plasma concentration data with measures of safety, PD, and / or efficacy.

[0151] treatment group At study initiation, eligible patients will be randomly assigned 1:1:1 to one of three treatment arms: 2 mg of (R)-compound 1; 4 mg of (R)-Compound 1; or Matching placebo.

[0152] After approximately 10 randomized patients per group have completed the 4-week double-blind treatment period, the DRC will evaluate new safety and efficacy data and may decide to expand either or both of the current treatment arms, either to continue with one of the treatment arms (e.g., 2 mg or 4 mg of (R)-Compound 1) or to add an additional treatment arm of up to 8 mg of (R)-Compound 1 with or without one of the previous treatment arms.

[0153] Drug Supply (R)-Compound 1 is provided as a 2 mg tablet. (R)-Compound 1 tablets contain active and inactive ingredients.

[0154] Pharmacokinetic evaluation Pre-dose PK samples will be collected within 15 minutes prior to study drug administration. Post-dose samples will be collected approximately 2 hours ± 5 minutes after study drug administration. The actual date and time of collection of each PK sample will be recorded.

[0155] Samples for measurement of pre-dose concentrations will be collected prior to study drug administration at Visits 6 and 9 of the double-blind treatment period. Samples for post-dose plasma concentrations at or near peak (R)-Compound 1 levels will be collected after study drug administration at Visit 9. Additional PK samples may also be collected in the event of an SAE, AE leading to discontinuation, or any other safety event at the discretion of the Investigator, DRC, and / or Sponsor, if necessary for comparison with safety and tolerability data.

[0156] Samples are analyzed to measure plasma concentrations of (R)-Compound 1 and any measured metabolites using a validated liquid chromatography-mass spectrometry method. Analyses are performed by Medpace Bioanalytical Laboratories, LLC.

[0157] Pharmacodynamic evaluation Screening Period PD sampling will be performed during Visits 1, 2, 3, and 4. Patients with either (1) PAC ≥ 15 ng / dL and PRA < 0.5 ng / mL / h or (2) ARR ≥ 30 at Visit 3 will be eligible to proceed to Visit 4. At Visit 4, blood samples for PAC, PRA, and cortisol will be collected at Time 0 and at Hours 1 and 2 after captopril administration as part of a seated captopril challenge, with patients remaining seated during this sampling period. Patients with PAC suppression < 30% at Hours 1 or 2 compared to Time 0 and / or PAC > 11 ng / dL at Hours 1 or 2 will be eligible to proceed to randomization (Visit 5).

[0158] Example 5 A randomized, double-blind, placebo-controlled, multicenter, parallel-group, dose-ranging study to evaluate (R)-Compound 1 for the treatment of patients with uncontrolled hypertension and chronic kidney disease (CKD).

[0159] Indications Treatment of uncontrolled hypertension and hypertension in patients with chronic kidney disease (CKD)

[0160] the goal One goal of the study is to evaluate the therapeutic effect of (R)-Compound 1 on systolic blood pressure (SBP) compared with placebo at 26 weeks in patients with uncontrolled hypertension and CKD. Other objectives of the study are to: To evaluate the therapeutic effect of (R)-Compound 1 at various dose intensities on SBP compared to placebo at 26 weeks To determine the proportion of patients who achieve an SBP <130mmHg after 26 weeks of treatment using dosing strategies; To evaluate the change from baseline in urinary albumin-to-creatinine ratio (UACR) with each dosing strategy of (R)-Compound 1 compared with placebo after 26 weeks of treatment; To evaluate the change from baseline in diastolic blood pressure (DBP) measured by AOBPM with each dosing strategy of (R)-Compound 1 compared with placebo at week 26; To assess the change from baseline in estimated glomerular filtration rate (eGFR) after 26 weeks of treatment; To evaluate the change from baseline in pharmacodynamic (PD) variables at each dose strength of (R)-Compound 1 compared to placebo after 26 weeks of treatment in patients with hypertension and CKD. To evaluate the relationship between changes in UACR and changes in aldosterone and renin levels with each dose strength of (R)-Compound 1 compared to placebo after 26 weeks of treatment; To evaluate the relationship between change in UACR and change in blood pressure (BP) with each dose strength of (R)-Compound 1 compared with placebo after 26 weeks of treatment; To evaluate the relationship between change in eGFR and change in BP with each dose strength of (R)-Compound 1 compared with placebo after 26 weeks of treatment;

[0161] safety goals Safety objectives of the study include: · Assessing vital signs, orthostatic BP and heart rate, physical examination, electrocardiogram, weight measurement, and clinical laboratory evaluation including standard safety chemistry panel, hematology, coagulation, and urinalysis; To assess treatment-emergent adverse events (TEAEs); To assess treatment-emergent adverse events of interest (AEOIs); To evaluate TEAEs leading to early discontinuation of study drug; - evaluate any significant treatment-emergent clinical laboratory abnormalities; and To assess the change in orthostatic SBP and DBP (measured pre-dose at the clinical site) from baseline to the end of treatment (Visit 11).

[0162] PK-PD Goals The pharmacokinetic (PK)-PD objective of the study is to evaluate the exposure-response relationship of (R)-Compound 1 in patients with uncontrolled hypertension and CKD using measures of safety, PD, and / or efficacy.

[0163] Inclusion criteria Patients who meet all of the following criteria are eligible to participate in the study: Adult male or female patient aged ≥ 18 years; · Mean sitting SBP ≥140mmHg at screening (Visit 1) and Visit 2; Patients with a mean sitting SBP ≥ 130 mmHg may be eligible if they have diabetes. Mean sitting SBP is defined as the average of three sitting SBP measurements during any single clinical visit. At the first visit, patients had diabetic nephropathy and / or hypertensive nephrosclerosis, and their eGFR (based on the CKD-EPI formula) was 25-75 mL / min / 1.73 m 2 have a diagnosis of mild to severe CKD defined as (inclusive); All other types of CKD and known overlapping renal diseases are excluded. To ensure that patients with moderate and severe renal impairment are represented, the number of patients with eGFR>60 is limited to 45 (approximately 15% of the total population). · UACR ≥ 200 mg / g (≥ 22.6 mg / mmol) on at least two of three measurements based on the first urine collected in the morning on consecutive days during the screening period; Currently taking an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) at the maximum tolerated daily dose for >4 weeks prior to Visit 1, as determined by the investigator; Patients not currently taking an ACEi or ARB at screening (Visit 1) are expected not to initiate medications in this class throughout the study period. If taking a sodium-glucose cotransporter type 2 (SGLT2) inhibitor at screening (Visit 1), the regimen must have been stable for at least 8 weeks prior to Visit 1 and will be expected to remain on a stable dose for the duration of the study; Patients not currently taking an SGLT2 inhibitor at screening (Visit 1) are expected not to initiate this class of medication throughout the study period. Willing to agree to comply with the study's contraceptive and reproductive restrictions as follows: Female patients of childbearing potential (i.e., not ovulating, premenopausal, and surgically infertile) must have documented negative pregnancy tests at Visit 1 and the randomization visit (Visit 3); and Female patients of childbearing potential must use highly effective contraception (i.e., failure rate less than 1%) for 30 days starting from day 1 after the last dose of study drug. Acceptable contraceptive methods for female patients of childbearing potential enrolled in the study included: Surgical sterilization (tubal ligation); intrauterine device for at least 12 weeks prior to Visit 1; Hormonal contraception (oral, implant, injection, ring, or patch) for at least 12 weeks prior to Visit 1; or A contraceptive diaphragm used in combination with a spermicide. Postmenopausal women must have been free of menstrual bleeding for at least 1 year prior to the first dose and be >60 years of age or have an elevated follicle-stimulating hormone level >40 mIU / mL at visit 1; -Able and willing to give informed consent to participate in the study. After a 2-4 week run-in period, all patients will need to ensure that their BP and UACR measurements still meet the eligibility criteria.

[0164] Exclusion criteria Patients who meet any of the following criteria will be excluded from participating in the study: · Have a documented diagnosis of type 1 diabetes; Unwilling or unable to discontinue mineralocorticoid receptor antagonists (MRAs) or potassium-sparing diuretics as part of an existing antihypertensive regimen; Patients taking MRAs or potassium-sparing diuretics (e.g., triamterene, amiloride, etc.) as antihypertensive agents must be willing to discontinue these medications for study eligibility. Potassium-sparing diuretics may be discontinued and substituted with non-potassium-sparing diuretics. All patients who have been on a stable regimen of antihypertensive agents, including non-potassium-sparing diuretics, for at least 6 weeks are eligible to enter the single-blind run-in. A single occurrence of mean sitting SBP >180mmHg or DBP >110mmHg during the screening period (if such BP is recorded during the screening period, patients may attend an interim visit for additional BP measurements and reassessment of inclusion / exclusion criteria); Mean sitting BP is defined as the average of three measurements obtained during any one clinical visit. If a patient does not take their regularly scheduled antihypertensive medication prior to the visit (Visit 1 or 2), one BP recheck is permitted after 2 hours or more have elapsed since taking the medication and after reestablishing the regularly scheduled antihypertensive regimen on the following day or later. Body mass index (BMI) >45 kg / m at first visit 2 is; ·Documented clinically relevant bilateral renal artery stenosis ≥70%; -Receiving dialysis for acute kidney injury / acute kidney failure within 12 weeks prior to screening, or scheduled for dialysis or kidney transplant during the course of the study; Known and documented New York Heart Association stage III or IV chronic heart failure; and / or hospitalization for heart failure within 6 months of first visit; - Stroke, transient ischemic attack, hypertensive encephalopathy, acute coronary syndrome, or hospitalization for heart failure within 6 months of the first visit; ·Current severe left ventricular outflow tract obstruction, such as diagnosed obstructive hypertrophic cardiomyopathy and / or severe aortic valvular disease, as determined by a previous echocardiogram or another imaging study; - Coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]) or any major surgical procedure planned during the study; - PCI, CABG, other major cardiac surgery (e.g., valve replacement), or peripheral artery bypass surgery within 6 months of the first visit; Previous solid organ or cell transplantation; - planning to receive or currently receiving any of the following excluded medications: strong inducers of cytochrome P4503A, nonsteroidal anti-inflammatory drugs, chronic use of spironolactone / eplerenone, and / or chronic use of steroids; ·Known hypersensitivity to any of the following: (R)-Compound 1 or a drug of the same class; or (R)-Compound 1 or an excipient in drugs of the same class. -Has received immunotherapy for the treatment of CKD within 6 months of Visit 1 or is scheduled to receive immunotherapy for the treatment of CKD during study participation; ·Any clinically relevant medical or surgical condition, including unstable medical conditions and / or conditions requiring regular transfusions or treatment with systemic immunosuppressants, including corticosteroids, that, in the opinion of the investigator, may put the patient at risk by participating in the study; Evidence at Visit 1 or Randomization Visit (one repeat test is permitted) of any of the following: ·White blood cell count>15×10 9 / L or absolute neutrophil count <1×10 9 / L; serum potassium <3.5 mEq / L; Patients with serum potassium levels below the normal range could continue on the study if the investigator chose to correct their serum potassium levels with supplements and suggested management of their medical condition. serum potassium >5.0 mEq / L; serum sodium <130 mEq / L; Hemoglobin <8.5 g / dL; Serum aspartate aminotransferase or alanine aminotransferase >3 × upper limit of normal (ULN); or Total bilirubin >2×ULN unless due to Gilbert's syndrome. -Having uncontrolled diabetes with glycosylated hemoglobin >10.5% at visit 1; - positive for HIV antibody, hepatitis B surface antigen, or hepatitis C viral RNA; have a typical intake of ≥ 14 alcoholic drinks per week; One drink of alcohol is equivalent to half a pint of beer (285 mL), one glass of spirits (25 mL), or one glass of wine (125 mL); Participation in another clinical trial involving any investigational drug within 30 days prior to Visit 1 or planned participation in another clinical trial within 30 days after discontinuation of the investigational drug; Receiving experimental treatment for disease intervention with a small molecule within 30 days or 5 half-lives of the first visit, whichever is longer, or experimental treatment with a large molecule within 90 days or 5 half-lives of the first visit, whichever is longer; Vaccination, including against coronavirus disease 2019 (COVID-19), is not excluded if administered during the screening period. - pregnant, breastfeeding, or planning to become pregnant during the study; or Deemed unsuitable by the investigator, after review of medical and psychiatric history, physical examination, and laboratory evaluation, for any other reason that may endanger the patient during participation or interfere with the interpretation of the study results.

[0165] Study design This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter, parallel-group, dose-ranging study to evaluate the efficacy and safety of (R)-Compound 1 for the treatment of uncontrolled hypertension and hypertension in patients with CKD.

[0166] The safety of (R)-Compound 1 will be evaluated from the time of randomization through the end of the follow-up period. Patients will be followed for efficacy and adherence during the double-blind treatment period. Plasma, serum, and urine PD variables analyzed during the study include renal function and measures of aldosterone and its related precursors. PK variables analyzed during the study include plasma concentrations of (R)-Compound 1 and any additional metabolites.

[0167] Patients will be instructed to bring study medication to all clinical site visits after randomization to assess treatment adherence.

[0168] Study visit Patients will complete at least 10 visits over an approximately 8 month period.

[0169] The study consisted of three periods and corresponding visits: A screening period of up to 4 weeks (Visits 1 and 2), including a 2-week run-in period (starting at Visit 2 and ending at Visit 3); A 26-week double-blind treatment period (Visits 3-9); and - 2-week follow-up period (10th visit).

[0170] Screening period including a two-week run-in period Patients who provide written informed consent at visit 1 will be assessed for inclusion / exclusion criteria.

[0171] At Visit 1, site staff will measure BP and vitals, collect blood samples for eGFR and PD marker assessment, and perform routine safety assessments and pre-screening dipstick urinalysis to exclude patients with negative albuminuria. Patients will be provided with materials to collect urine at home with their first morning void on 2 consecutive days prior to Visit 2 (days -21 to -7) and on the morning of Visit 2. At least 4 days prior to Visit 2, site staff will call patients to remind them to collect samples in the morning on the following 3 consecutive days. A third sample will be collected so that the collection date is the same as Visit 2.

[0172] At Visit 2, patients bring collected urine samples to the clinical site, where site staff will send samples to the central laboratory for UACR measurement. Site staff will assess inclusion / exclusion criteria, measure BP, obtain vitals, and assess concomitant medications. Patients will be provided with materials and instructions to collect a 24-hour urine starting on the morning of Day -1. On Day -3 (± 1 day), site staff will call patients to remind them to collect a 24-hour urine so that the 24-hour completion date and Visit 3 (randomization visit) are on the same day.

[0173] Patients who consent to study participation but do not meet the study inclusion / exclusion criteria (i.e., fail screening) may be rescreened less than 5 days after their last study visit, with consultation and approval from the sponsor and / or medical monitor.

[0174] At visit 2, patients will be provided with a 2-week supply of single-blind (R)-Compound 1 placebo infusion and instructions for lifestyle management, hydration reminders, and the prospect of continuing background antihypertensive medications and, if necessary, an SGLT2 inhibitor.

[0175] Once the UACR screening eligibility test results are returned, patients will be contacted by phone to inform them of their eligibility and, if eligible, will begin taking the study medication once daily and schedule their next clinic visit (Visit 3).

[0176] Double-blind treatment period At Visit 3 (randomization visit), inclusion criteria for SBP and UACR will be confirmed. Patients who remain eligible will be randomly assigned 1:1:1 to one of three treatment arms (0.5 mg tablet of Compound 1, 1 mg tablet of (R)-Compound 1, and placebo tablet of (R)-Compound 1). Randomization will be based on SGLT2 inhibitor use, baseline SBP (≦155 mmHg or >155 mmHg), and CKD category (eGFR ≦45 mL / min / 1.73 m 2 or >45 mL / min / 1.73 m 2 ) are used to organize the hierarchy.

[0177] Dose levels of (R)-Compound 1 may be titrated within the first 8 weeks after the date of randomization. At week 2 (Visit 4), blood pressure will be measured and blood samples will be taken for serum electrolyte measurements. If the patient does not achieve the SBP<130mmHg goal and does not experience hyperkalemia or hyponatremia based on the sample taken at week 2, the dose may be titrated at week 4 (Visit 5).

[0178] At week 8 (visit 6), blood pressure will be measured and blood samples will be taken for serum electrolyte measurements. If the patient does not achieve the SBP<130mmHg goal and does not experience hyperkalemia or hyponatremia based on the sample taken at week 4, the dose may be escalated at week 8. No further dose escalation will be permitted after week 8. Tapering will not be permitted in this study.

[0179] For UACR measurements, baseline is defined as the geometric mean of the three samples returned at Visit 2. For BP measurements, baseline is defined as the mean of the three measurements obtained prior to randomization at Visit 3. Measurements of efficacy and safety variables recorded prior to the first dose of double-blind study drug administration constitute pre-dose measurements.

[0180] During clinical site visits, adherence to study drug administration will be calculated using pill counts. Pre-dose blood samples for PD will be collected at Visits 3-9. Pre-dose blood samples for PK analysis will be collected at Visits 7 and 9. PD and PK blood samples will be collected within approximately 15 minutes prior to dosing.

[0181] Urine samples for PD and electrolyte measurements will be collected over a 24-hour period (24-hour urine collection) at Visit 3 (baseline), Visit 7 (Week 16), Visit 9 (Week 26), and Visit 10 (Week 28, 2 weeks after the last dose).

[0182] Urine samples for UACR will be collected on 2 consecutive days leading up to Visits 5, 6, 8, 9, and 10, and from first morning voids at Visits 5, 6, 8, 9, and 10. Assessments of key efficacy endpoints will be performed at the end-of-treatment visit (Visit 9).

[0183] Dosage and Administration (R)-Compound 1 tablets, active drug, or placebo will be provided in blister packs. Placebo tablets will be indistinguishable from (R)-Compound 1 tablets. Two tablets will be orally self-administered per day.

[0184] Patients are allowed to eat their usual meals on the morning of study medication administration. At the randomization visit (Visit 3), patients will receive either (R)-Compound 1 tablets or matching placebo tablets in the assigned dose strength. Patients will self-administer the first dose of study medication in two tablets at the clinical site. Subsequent doses of study medication will be taken orally by patients at home once daily (QD) at approximately the same time each morning. On the clinical site visit day, patients will take their scheduled morning doses of ACEi, ARB, and SGLT2 inhibitor (if applicable) at home and retain their dose of study medication until the morning of their next visit. Patients must bring study medication and background ACEi or ARB medication to the clinical site for all visits. At the clinical site, patients will self-administer study medication in the presence of site staff after pre-dose assessments and clinical laboratory sampling are completed.

[0185] Evaluation items One efficacy endpoint will be the change in mean sitting SBP from baseline to week 26 for (R)-Compound 1 compared to placebo. SBP will be measured by seated automated office blood pressure monitoring (AOBPM).

[0186] Other endpoints of the study included: Change from baseline in SBP for (R)-Compound 1 compared to placebo at week 26 in various dose groups (hierarchically ordered: >2mg, 2mg, 1mg, 0.5mg, and 4mg); · Proportion of patients achieving SBP < 130mmHg after 26 weeks of treatment with the dosing strategy; Percent change from baseline in urinary albumin-to-creatinine ratio (UACR) with each dosing strategy of (R)-Compound 1 compared with placebo after 26 weeks of treatment; · Change from baseline in diastolic blood pressure (DBP) measured by AOBPM with each dosing strategy of (R)-Compound 1 compared to placebo at Week 26; · Change from baseline in estimated glomerular filtration rate (eGFR) after 26 weeks of treatment; Changes from baseline for each dose strength of (R)-Compound 1 compared to placebo after 26 weeks of treatment in pharmacodynamic (PD) variables, including but not limited to: Serum and / or plasma parameters: electrolytes, plasma aldosterone concentration (PAC), 11-deoxycorticosterone, B-type natriuretic peptide (BNP), plasma renin activity (PRA), direct renin concentration, angiotensinogen, and angiotensin II; or 24-hour urine parameters: electrolytes, aldosterone, renin, kidney injury molecule-1 (KIM-1), cystatin C, growth differentiation factor-15 (GDF-15), neutrophil gelatinase-associated lipocalin (NGAL), transforming growth factor beta (TGF-β), and monocyte chemotactic protein-1 (MCP1). The relationship between the percentage change in UACR and the percentage change in aldosterone and renin levels with each dose strength of (R)-Compound 1 compared to placebo after 26 weeks of treatment; · Relationship between change in UACR and change in blood pressure (BP) with each dose strength of (R)-Compound 1 compared to placebo after 26 weeks of treatment; Relationship between change in eGFR and change in BP with each dose strength of (R)-Compound 1 compared with placebo after 26 weeks of treatment;

[0187] The pharmacokinetic (PK)-PD objective of the study is to evaluate the exposure-response relationship of (R)-Compound 1 in patients with uncontrolled hypertension and CKD using measures of safety, PD, and / or efficacy.

[0188] The safety evaluation items are as follows: · Changes in vital signs, orthostatic BP and heart rate, physical examination, electrocardiogram, weight measurement, and clinical laboratory evaluations including standard safety chemistry panel, hematology, coagulation, and urinalysis; Treatment-emergent adverse events (TEAEs); Treatment-emergent adverse events of interest (AEOI) · TEAEs leading to early discontinuation of study drug; any significant treatment-emergent laboratory abnormality; and Change in orthostatic SBP and DBP (pre-dose measurements at the clinical site).

[0189] The safety of (R)-Compound 1 will be evaluated from the time of randomization to the end of the follow-up period. Safety endpoints include: · Change in potassium levels from baseline to Week 26 across each dose strength of (R)-Compound 1 compared to placebo; · Clinical laboratory evaluations including vital signs (heart rate, respiratory rate, and temperature), mean SBP, mean DBP, orthostatic vitals (orthostatic BP and heart rate), physical examination, electrocardiogram (ECG), weight measurement, and standard safety chemistry panel, hematology, coagulation, and urinalysis; · incidence of treatment-emergent adverse events (TEAEs); · incidence of treatment-emergent SAEs; · Incidence of TEAEs leading to premature discontinuation of study drug; The incidence of significant treatment-emergent laboratory abnormalities; and Changes in orthostatic SBP and DBP (measured at the clinical site prior to study drug administration) from baseline to week 26;

[0190] AEs of particular interest include: hypotensive events requiring clinical intervention, abnormal potassium laboratory values ​​requiring clinical intervention, and abnormal sodium laboratory values ​​requiring clinical intervention.

[0191] Efficacy Analysis Efficacy analyses will compare the change in mean sitting SBP from baseline to week 26 for (R)-Compound 1 and placebo. A repeated measures mixed model (MMRM) will be used to perform this analysis. The analysis will include fixed effects for treatment, visit, and treatment-by-visit interactions, along with baseline covariates. An estimate of the treatment difference at week 26 will be generated, along with an assessment of whether this estimate is significantly different when comparing placebo with each dosing strategy at a two-sided significance level of 0.05. Least squares means, standard errors, and two-sided 95% confidence intervals (CIs) are provided for pairwise comparisons of each dosing strategy of (R)-Compound 1 against each treatment and placebo group.

[0192] Missing data are imputed using multiple imputation methods. Results are fitted using the Rubin method. Full details of the model and imputation are provided in SAP.

[0193] Efficacy analyses compare the change in SBP, DBP, and UACR from baseline (Visit 3) to the end of treatment (Visit 9) between each dose of (R)-Compound 1 and placebo. Percentage change in UACR is calculated by analysis of covariance using log-transformed UACR values ​​with baseline log-transformed UACR as a covariate. A repeated measures mixed model is used to perform this analysis. The analysis includes fixed effects of treatment, visit, and treatment-by-visit interaction, along with baseline value covariates. A restricted maximum likelihood estimation approach is used with an unstructured covariance matrix. Least squares means, standard errors, and two-sided 95% CIs are provided for pairwise comparisons of each dosing strategy of (R)-Compound 1 against each treatment and placebo group. Adjustments for multiple comparisons are performed using Dunnett's test according to the power and sample size calculations used for the study. Missing data are imputed using multiple imputation methods. Results are fitted using Rubin's method. Full details of the model and imputations are provided by SAP.

[0194] Similar models will be used to analyze eGFR and PD variables. Logistic regression analysis will be used to analyze binary endpoints to model covariates of treatment group, baseline BP, baseline DBP, and baseline eGFR. No adjustment for multiplicity will be made when testing efficacy endpoints.

[0195] Safety analysis The safety analysis set is the safety analysis population. All safety endpoints will be summarized narratively.

[0196] Safety assessment will be based primarily on the frequency of AEs, clinical laboratory assessments, vital signs, and 12-lead ECG. Other safety data will be summarized as appropriate.

[0197] AEs will be coded using the ICH International Medical Terminology. TEAEs will be defined as AEs that are new or worsening in severity during the double-blind treatment period and are summarized by system organ class and preferred term. Lists of SAEs, patients with AEs of special interest, and patients who discontinued the study due to AEs are provided.

[0198] Summary statistics will be provided by treatment strategy group at baseline and each visit, as well as changes from baseline to each visit in laboratory parameters, vital signs, and other safety measures. The incidence of significant abnormalities in changes from baseline in clinical laboratory values ​​will be summarized by treatment group. Physical examination data will be tabulated.

[0199] Clinical trials in patients with renal impairment Of particular relevance to the test subjects enrolled in this study is the investigation of the pharmacokinetics of (R)-Compound 1 in individuals with various degrees of renal impairment. The PK profiles of (R)-Compound 1 and its primary metabolites following administration of a single 10 mg dose in individuals with renal impairment were qualitatively and quantitatively similar to those measured in healthy subjects. Pairwise comparisons of plasma PK parameters of (R)-Compound 1 in the moderate to severe renal impairment groups revealed a significant improvement in C when compared to the control group. max , AUC (0-inf) , and AUC (0-last) No notable effect was observed across groups with geometric mean ratios of 1.02, 1.21, and 1.17 for (R)-Compound 1, respectively. No higher exposure to (R)-Compound 1 was observed in the renal failure group compared to the control group, and C max , AUC (0-inf) , and AUC (0-last), with respective geometric mean ratios of 0.88, 0.68, and 0.68. The conclusions of these studies demonstrated that a single 10 mg dose of (R)-Compound 1 was well tolerated when administered to individuals with various degrees of renal function, including those with moderate to severe renal impairment or renal failure (receiving hemodialysis). There was no significant increase in systemic exposure or decrease in clearance in individuals with renal impairment. Thus, no dose adjustment of (R)-Compound 1 was necessary based on renal function.

[0200] Results of the renal impairment study demonstrated that a single 10 mg dose of (R)-Compound 1 was well tolerated by subjects with varying degrees of renal function, ranging from normal renal function to end-stage disease undergoing hemodialysis. One subject with end-stage disease experienced an SAE of unrelated metabolic encephalopathy as well as a moderate unrelated adverse event (AE) of tremor. One control subject experienced a mild AE of diarrhea, which the investigator deemed to be related to study drug. There were no clinically significant changes in laboratory values ​​(including potassium), ECG, or vital signs. PK data from this study demonstrated no significant increase in systemic exposure or decrease in renal clearance in individuals with moderate or severe renal impairment (estimated glomerular filtration rate [eGFR] 15-59 mL / min) compared with control subjects (normal renal function or mild renal impairment; eGFR>60 mL / min). Similarly, no significant increase in plasma exposure to (R)-Compound 1 was observed in subjects with end-stage renal disease (eGFR<15 mL / min or undergoing hemodialysis); however, these subjects did not produce enough urine to assess differences in renal clearance in this population. No dose adjustment of (R)-Compound 1 is necessary for patients with renal impairment.

[0201] The results of the renal impairment study demonstrated that (R)-Compound 1 was well tolerated when administered to individuals with various degrees of renal function, including those with moderate to severe renal impairment or renal failure (receiving hemodialysis). Overall, there were no deaths, one (3.0%) subject experienced an SAE, and no subjects discontinued due to a TEAE. Overall, two (6.1%) subjects experienced a total of three TEAEs: one (10.0%) subject in the control group experienced a TEAE of mild diarrhea after administration of (R)-Compound 1 that was considered related to the study drug; no subjects in the moderate to severe renal impairment group experienced a TEAE; and one (8.3%) subject in the renal failure group experienced two TEAEs after administration of (R)-Compound 1, moderate tremor and severe metabolic encephalopathy (recorded as SAEs), which were not considered related to the study drug. The SAEs were considered to be secondary to concomitant medications. As such, there was no apparent increase in the incidence or severity of AEs with decreasing renal function. There were no clinically meaningful changes in AEs, trends, or laboratory parameters. There were no clinically meaningful changes observed in AEs, vital signs, physical examination, or 12-lead ECG.

[0202] The results of the renal impairment study demonstrated that the plasma concentration-time curves of (R)-Compound 1 in each renal function group were qualitatively similar to each other.

[0203] Based on pairwise comparisons, there was no substantial effect of renal impairment on the PK of (R)-Compound 1, and no strong or nonlinear relationships were observed between estimated GFR and PK parameters. Findings for the primary metabolites of (R)-Compound 1 were similar to those for the parent, with no clinically meaningful differences observed between groups. The percentage of the dose excreted via the kidney was approximately 12% in the control and moderate to severe renal impairment groups. Insufficient urine production in the renal failure group resulted in negligible renal excretion in this group. Based on the results of this study, dose adjustment of (R)-Compound 1 in individuals with renal impairment is not considered necessary.

[0204] Drug Supply Formulation and Packaging (R)-Compound 1 is provided as 0.5 mg, 1 mg, and 2 mg tablets in a blister pack. (R)-Compound 1 tablets contain active and inactive ingredients.

[0205] Example 6 A Randomized, Double-Blind Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of (R)-Compound 1 Following Multiple Oral Doses in Healthy Subjects

[0206] Test Objectives The objectives of this exam include: To evaluate the safety and tolerability of (R)-Compound 1 following oral administration once daily for 10 days under normal and reduced-salt conditions; To characterize the pharmacokinetics (PK) of (R)-Compound 1 following oral administration once daily for 10 days under normal and reduced-salt conditions; and To characterize the pharmacodynamic (PD) effects of (R)-Compound 1 following oral administration once daily for 10 days under normal and reduced-salt conditions;

[0207] methodology This was a randomized, double-blind study to evaluate the safety, tolerability, PK, and PD of multiple oral doses of (R)-Compound 1 when administered to healthy adult subjects. The study consisted of 5 cohorts with up to 12 subjects per cohort: Subjects were randomly assigned in a 3:1 ratio to receive (R)-Compound 1 or placebo once daily for 10 days as follows: Cohort 1: 2.5 mg of (R)-Compound 1 or matching placebo (reduced salt diet in 9 subjects receiving (R)-Compound 1 and 3 subjects receiving placebo); Cohort 2: 5.0 mg of (R)-Compound 1 or matching placebo (reduced salt diet in 9 subjects receiving (R)-Compound 1 and 3 subjects receiving placebo); Cohort 3: 1.5 mg of (R)-Compound 1 or matching placebo (normal salt diet in 9 subjects receiving (R)-Compound 1 and 3 subjects receiving placebo); Cohort 4: 2.5 mg of (R)-Compound 1 or matching placebo (normal salt diet in 6 subjects receiving (R)-Compound 1 and 2 subjects receiving placebo); and Cohort 5: 0.5 mg of (R)-Compound 1 or matching placebo (normal salt diet in 9 subjects receiving (R)-Compound 1 and 3 subjects receiving placebo).

[0208] Cohorts 1 and 2 were dosed simultaneously, with a minimum lag of 5 days between the first dose of cohort 2 and the first dose of cohort 1. Cohorts 3 to 5 were dosed simultaneously.

[0209] For each subject, the study consisted of the following: · Maximum screening period of 28 days; A 5-day inpatient run-in period during which subjects adhere to a controlled, standardized diet and undergo baseline PD assessments; A 15-day inpatient treatment phase in which subjects receive (R)-Compound 1 or placebo once daily for 10 days while adhering to a controlled, standardized diet, followed by an additional 5 days of PK and PD sampling; and Follow-up visit 3 days (1 day) after discharge from the treatment unit. Cortisol stimulation testing (cohorts 1 and 2 only) and orthostatic aldosterone assessments (all cohorts) were performed on days 1 and 10. Serial blood samples for PK and PD were collected at specific time points pre-dose and 24 hours post-dose on day 1 and pre-dose and 120 hours post-dose on day 10. In addition, blood samples for PK were collected pre-dose on days 8 and 9. Urine for PK and PD measurements was collected immediately prior to dosing for 24 hours on day 1 and immediately prior to dosing for 120 hours on day 10.

[0210] Subjects were discharged from the clinic upon completion of discharge procedures 5 days after the last dose of (R)-Compound 1 or placebo and returned to the clinic for a follow-up visit 3 days (day 1) after discharge to collect PK samples and capture adverse events (AEs) and concomitant medications.

[0211] Safety was assessed throughout the study based on AEs, physical examination, weight measurements, electrocardiogram (ECG), orthostatic vital sign assessments, and clinical laboratory evaluations. To thoroughly evaluate any potential effects of (R)-Compound 1 on QT interval, continuous ECG recordings were also performed beginning approximately 1 hour prior to dosing and continuing for approximately 24 hours post-dose on Days 1 and 10.

[0212] Subjects with clinically significant abnormal laboratory findings, unresolved treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) requiring follow-up laboratory and review, and clinically significant AEs may require unscheduled procedures or visits, and / or additional follow-up.

[0213] Inclusion criteria Subjects who meet all of the following criteria based on screening and check-in results are eligible to participate in the study: 1. Healthy subjects aged 18-55 years (inclusive) who are in good health based on medical and psychiatric history, physical examination, ECG, orthostatic vital signs, and routine laboratory tests (blood chemistry, hematology, coagulation, urinalysis); 2. Body mass index (BMI) between 18 and 30 kg / m 2 (inclusive); 3. Non-smokers who had not used nicotine-containing products for at least 6 months prior to the screening visit; 4. Male subjects with female partners of childbearing potential must agree to use two medically accepted highly effective methods of contraception for 90 days beginning on Day 1 after the last dose of study drug; 5. Male subjects must agree to refrain from sperm donation for 90 days beginning on day 1 after administration of the last dose of study drug; 6. Female subjects with male partners must be surgically sterilized (hysterectomy and / or bilateral oophorectomy), be postmenopausal for at least 1 year (follicle-stimulating hormone in the postmenopausal range), or agree to use two medically accepted highly effective methods of contraception from Day -14 through Day 60 after the last dose of study drug. 7. Able to understand and willingly comply with study procedures and restrictions (including confinement to clinical facilities and restrictions on physical activity, recreational drug or alcohol use, and medications) and provide written informed consent in accordance with institutional and regulatory guidelines.

[0214] Exclusion criteria Based on the screening and check-in results, subjects who meet any of the following criteria (or day -4 results of the cortisol stimulation test [Cohorts 1 and 2] or cortisol levels [Cohorts 3-5]) will be excluded from study participation: 1. Actively participating in an experimental therapeutic trial; had received experimental treatment with a small molecule within 30 days or 5 half-lives of day 1, whichever is longer, or experimental treatment with a large molecule within 90 days or 5 half-lives of day 1, whichever is longer; 2. Had a personal or family history of long QT syndrome, Torsades de Pointes, or other complex ventricular arrhythmias, or sudden death; 3. History or current clinically significant arrhythmias as determined by the investigator, including ventricular tachycardia, ventricular fibrillation, or atrial fibrillation. Subjects with mild ectopic symptoms (e.g., atrial premature beats) were not necessarily excluded; 4. There was QTcF prolongation (>450 ms) based on the average of three ECGs; 5. Sitting BP greater than 150 / 90 mmHg or less than 90 / 50 mmHg based on the average of ≥3 BP measurements; 6. Resting heart rate >100 beats per minute (bpm) or <50 bpm, sinus node dysfunction, or clinically significant cardiac dysfunction based on the average of ≥3 BP measurements. There was a block; 7. Body temperature >37.6°C (99.68°F, measured by mouth) and respiratory rate <12 breaths / min and >20 breaths / min; 8. Had postural tachycardia (i.e., >30 bpm on standing) or orthostatic hypotension (i.e., a decrease in systolic blood pressure [SBP] of ≥20 mmHg or diastolic blood pressure of ≥10 mmHg on standing); 9. Serum potassium > upper limit of normal range (ULN) and serum sodium < lower limit of normal range; 10. Had aspartate aminotransferase and alanine aminotransferase values ​​>1.2 ULN; 11. Tested positive for HIV antibody, hepatitis C virus antibody, or hepatitis B surface antigen; 12. Had any other laboratory value that, in the opinion of the investigator, was significantly above the normal range (based on normal ranges for the laboratory test); 13. Cohorts 1 and 2 had an abnormal cortisol stimulation test (<13.5 μg / 100 mL) based on the results of a test performed on the morning of day -4. Cohorts 3-5 had an abnormal cortisol level (<5 μg / dL) based on the results of a test performed on the morning of day -4. 14. Had a known history of porphyria, myopathy, or active liver disease; 15. Evidence or history of any clinically significant immune, hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, musculoskeletal, hepatic, psychiatric, neurological, or allergic disease (including clinically significant or multiple drug allergies); surgical condition; cancer (except for basal or squamous cell carcinoma of the skin and cancers that have been cured or in remission for ≥5 years prior to the screening visit); or any condition that, in the opinion of the investigator, may confound the study procedures or results, affect the subject's safety, or interfere with the absorption, distribution, metabolism, or excretion of the study drug (appendectomy is permitted, but cholecystectomy is prohibited); 16. Used any prescription or over-the-counter medication (including topical medications) (except for occasional use of acetaminophen or nonsteroidal anti-inflammatory drugs [NSAIDs] such as ibuprofen or naproxen, according to the package insert), herbal supplements, dietary supplements, or functional foods within 14 days or 5 half-lives prior to the first dose of study medication, whichever is longer, or was not willing to refrain from these medications until the follow-up visit; use of over-the-counter topical medications may be permitted in consultation with the study sponsor. In addition, medications with a 5-fold half-life greater than 14 days had to be discussed and approved by the sponsor prior to subject enrollment. 17. Use of corticosteroids (systemic or widespread topical) within 3 months prior to treatment; 18. A positive drug or alcohol test result or a history of alcoholism or drug abuse within 2 years prior to the first dose of study medication, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition: DSM-IV; 19. Typical intake of ≥ 14 alcoholic drinks per week (1 drink was equivalent to half a pint of beer (285 mL), 1 drink of spirits (25 mL), or 1 drink of wine (125 mL); 20. Have a history or evidence of illegal drug use within the past two years; 21. Donated or lost ≥ 400 mL of blood or blood products within 30 days prior to the first dose of study drug. 22.Has had a surgical procedure within 4 weeks of check-in or has elective surgery scheduled during the study period. 23. Had any illness in the 4 weeks prior to check-in unless the investigator judged it to be clinically significant; 24. Suffered from allergies to any component of the study medication ((R)-Compound 1 or placebo). History of severe allergic reactions (including to drugs, foods, insect bites, or environmental allergens). 25. Had known intolerance to ACTH stimulation test products; 26. Had inadequate venous access; 27.Currently receiving weight loss medication or have previously undergone weight loss surgery (e.g. gastric bypass surgery); 28. Pregnant, breastfeeding, or planning to become pregnant during the study; or 29. Deemed unsuitable by the investigator, after review of medical and psychiatric history, physical examination, and clinical laboratory evaluation, for any other reason that may endanger the subject during participation or interfere with the interpretation of the study results.

[0215] Duration of treatment: For each subject, participation in the study lasted a maximum of 56 days. Treatment with (R)-Compound 1 or placebo lasted for 10 days (administered once daily).

[0216] Investigational and comparator information: Study subjects were administered (R)-Compound 1 (oral drinking solution) or a matching placebo. The administered doses of (R)-Compound 1 were 2.5 and 5.0 mg with a low-salt diet, and 1.5, 2.5, and 0.5 mg with a normal-salt diet.

[0217] Pharmacokinetics: As data permitted, the following plasma PK parameters were determined for (R)-Compound 1 and its primary metabolites following the first dose of (R)-Compound 1: Maximum plasma concentration observed on day 1 (C max , D1). Directly observed data, time vs. C max , D1(T max , D1); and -Area under the plasma concentration-time curve (AUC) from 0 to 24 hours after administration (AUC0-24h).

[0218] As data permitted, the following plasma PK parameters were determined for (R)-Compound 1 and its primary metabolites following the final dose of (R)-Compound 1 on Day 10: Maximum plasma concentration observed on day 10 (C max ,D10); Directly observed data, time vs. C max , D10(T max ,D10); AUC (i.e., tau) over the dosing interval (AUC 0-tau ); AUC from time 0 to the time of the last quantifiable plasma concentration (Clast) (AUC 0-t ); AUC from time 0 to infinity (AUC 0-inf ); Extrapolated AUC, 100(AUC 0-inf -AUC 0-t ) / AUC 0-inf Percentage of extrapolated AUC, calculated as; · apparent terminal first-order elimination rate constant (λz); · Terminal elimination half-life (t1 / 2), calculated as ln(2) / λz; ·Dose / AUC 0-tau Apparent plasma clearance (CLss / F), calculated as ((R)-Compound 1 only); and ·Dose / [λz AUC 0-tau ], the apparent volume of distribution (Vss / F) (only for (R)-compound 1).

[0219] The steady-state accumulation rate was reported as: C max , D10 / C maxThe maximum plasma concentration (C) observed after the first and last doses, calculated as D1, D2, D3, D4, D5, D6, D7, D8, D9, D10, D11, D12, D13, D14, D15, D16, D17, D18, D19, D20, D21, D22, D23, D24, D25, D26, D27, D28, D29, D3 max ) based on the accumulation ratio (RC max );and AUC 0-tau Accumulation ratio (RAUC) based on the AUC after the first and last doses, calculated as / AUC0-24h.

[0220] The following urinary PK parameters were determined for (R)-Compound 1 and its primary metabolites after the first dose: · Cumulative amount of drug excreted in urine on day 1 (Ae, D1); Percentage of dose excreted via the kidney on day 1 (Fe, D1) (for compound 1 only), calculated as 100Ae, D1 / dose; and · Renal clearance on day 1 (CLR, D1), calculated as Ae, D1 / AUC0-24h.

[0221] The following urinary PK parameters are determined for (R)-Compound 1 and its primary metabolites after the final dose: · Cumulative amount of drug excreted in urine on day 10 (Ae, D10); the fraction of the dose excreted via the kidney on day 10 (Fe, D10) (for compound 1 only), calculated as 100Ae, D10 / dose; and Ae, D10 / AUC 0-inf Renal clearance on day 10 (CLR, D10), calculated as: Pharmacodynamics: Plasma PD measurements include concentrations of: · Aldosterone and its precursors 18-hydroxycorticosterone, corticosterone, and 11-deoxycorticosterone. · Cortisol (free and total) and its precursor 11-deoxycortisol; Plasma renin activity (PRA); and Adrenocorticotropic hormone (ACTH). Plasma electrolyte measurements include concentrations of: o Sodium; o Chloride; and o Potassium.

[0222] For analysis, AUC values ​​are calculated for aldosterone and cortisol (free and total), and all precursor parameters, using non-compartmental methods where possible, as appropriate, over the following time periods: · Area under the PD effect-time curve from 0 to 4 hours after administration (AUC0-4h); · Area under the PD effect-time curve from 4 hours post-dose to 12 hours post-dose (AUC4-12h); Area under the PD effect-time curve from 0 to 12 hours after administration (AUC0-12h); and -Area under the PD effect-time curve from 0 to 24 hours after administration (AUC0-24h).

[0223] A linear trapezoidal / linear interpolation method was used to calculate AUC. Nominal time points were used to calculate AUC.

[0224] Urine PD measurements include concentrations of: Aldosterone; Cortisol (free and total); and Tetrahydroaldosterone.

[0225] For analysis, urinary PD concentrations were converted to the total amount of analyte: total amount (units) = concentration (units / volume). ·Urine volume

[0226] (Urine volume may have been calculated from urine mass collected using 1 mg = 1 mL) Urine electrolyte measurements included concentrations of: ·sodium; ·Chlorides; ·potassium; Creatinine; and Phosphorus.

[0227] For analysis, urinary sodium-to-potassium ratios were also calculated.

[0228] Safety: Safety will be assessed based on AEs, physical examination, weight measurements, ECG, vital signs (including orthostatic) assessment, and clinical laboratory evaluations throughout the study. To thoroughly evaluate any potential effects of (R)-Compound 1 on QT interval, continuous ECG recordings were also performed beginning approximately 1 hour prior to dosing and continuing for approximately 24 hours post-dose on Days 1 and 10. If cardiodynamic analysis is performed, 12-lead ECGs will be drawn at predefined time points in combination with PK samples.

[0229] Summary of results Results from the MAD study indicate that multiple ascending doses of (R)-Compound 1 up to 5 mg QD for 10 days were well tolerated in healthy subjects under reduced salt (2.5 and 5 mg (R)-Compound 1) and normal salt conditions (0.5, 1.5, and 2.5 mg (R)-Compound 1). Specifically, there were no treatment-emergent adverse events (TEAEs) leading to death, SAE, or treatment discontinuation, and no clinically significant changes in electrocardiograms (ECGs that did not include significant changes in QT interval corrected by Fridericia's formula [QTcF]) or vital signs. The most common TEAEs following multiple doses of (R)-Compound 1 were headache, postural dizziness, and vertigo. No clinically significant changes were observed in safety clinical trial outcomes over time. PK data from the MAD study indicate that exposure to (R)-Compound 1 (C max Exposures (assessed based on AUC and AUC) generally indicate that exposures are 2-2.5-fold higher at steady state compared to exposures observed after a single dose. Exposures within the dose range studied increased approximately dose-proportionally. PD data from this study confirmed the ability of (R)-Compound 1 to lower aldosterone at doses of 5 mg or less without affecting levels of cortisol or its precursor, 11-deoxycortisol, in healthy subjects. As expected with reduced aldosterone levels, plasma potassium concentrations increased moderately in a dose-dependent manner, and plasma sodium concentrations decreased.

[0230] Pharmacokinetics: Pharmacokinetic results from the MAD study showed that exposure to (R)-Compound 1 (C maxand AUC) are generally 2- to 2.5-fold higher at steady state compared with that observed after a single dose. Exposure increases approximately dose-proportionally within the dose range studied.

[0231] Following oral administration, (R)-Compound 1 was rapidly absorbed, with peak concentrations typically observed within 4 hours after dosing (median observed time to maximum plasma concentration [T max (T1 / 2 ranged from 0.98 to 4 hours across treatment groups.) Exposure was clearly biphasic and declined slowly from the peak, with long mean t1 / 2 ranging from approximately 26 to 31 hours.

[0232] At steady state, exposure was typically approximately 2-2.5-fold higher than after a single dose (average RC across treatment groups). max (R)-Compound 1 is expected to be dose proportional over the dose range tested.

[0233] On average, approximately 7% (range 6.3%-10.8% across treatment groups) of the (R)-Compound 1 dose was recovered unchanged in the urine.

[0234] The primary metabolites of (R)-Compound 1 were formed slowly over time after the first dose of (R)-Compound 1 (T max The median Tmax ranged from approximately 4 to 24 hours across treatment groups), and the steady-state (day 10) median Tmax was observed within 4 hours (T max Median values ​​ranged from 3.5 to 4.0 hours across treatment groups. See Figure 1. Metabolite levels increased with increasing dose. Plasma concentrations of metabolites generally declined slowly from the peak, with long mean t1 / 2 values ​​ranging from approximately 31 to 38 hours. At steady state, exposure (RC max The C-values ​​(based on the RAUC values) were approximately 2.4-3.5 times higher than after a single dose.max , 8.0%-11% of the parent based on D10, AUC 0-inf Based on the results, it corresponds to 10% to 22% of the parent. max and AUC 0-tau Plots of (R)-Compound 1 dose (Day 10 - Pharmacokinetic Population) versus (R)-Compound 1 dose (Day 10 - Pharmacokinetic Population) are shown in Figures 2 and 3, respectively.

[0235] Pharmacodynamics: Significant inhibition of aldosterone synthesis was observed after the first dose of (R)-Compound 1 and persisted throughout the 10-day treatment period under both normal-salt and low-salt diet conditions; however, the effect of 0.5 mg of (R)-Compound 1 was similar to that of placebo.

[0236] Measurements after subjects prematurely discontinued study drug were excluded. AUC0-12h = area under the pharmacodynamic effect-time curve from 0 to 12 hours post-dose; LS = least squares.

[0237] The effect of (R)-Compound 1 on aldosterone at doses ≥ 1.5 mg was observed both with and without Cortrosyn challenge, typically resulting in approximately 70%-85% reduction in mean AUC0-12h compared to baseline. Levels of the intermediate aldosterone precursors 18-hydroxycorticosterone and corticosterone showed gradual changes indicative of the progressive impact of cytochrome P450 11B2 inhibition on the aldosterone synthesis pathway.

[0238] Specifically, levels of 18-hydroxycorticosterone (an intermediate to aldosterone) were generally similar to or decreased from baseline, but to a lesser extent than the observed decrease in aldosterone. Levels of corticosterone, which is further upstream of aldosterone, increased in a clear dose-dependent manner. Finally, levels of 11-deoxycorticosterone, the first aldosterone precursor, showed a small (approximately 2- to 3-fold) increase over pre-treatment values ​​compared to baseline, with the change being most pronounced under low-salt diet conditions in which subjects also underwent cortisol stimulation testing.

[0239] There was no apparent effect of (R)-Compound 1 on cortisol (total or free) or 11-deoxycortisol, including in the presence of a Cortrosyn challenge (which occurred in the low-salt diet treatment group). Consistent with the observations from the mean cortisol time course and AUC data, (R)-Compound 1 had no apparent effect on the response to Cortrosyn challenge, with responses on days 1 and 10 in subjects treated with (R)-Compound 1 being similar to baseline responses and to those in subjects receiving placebo.

[0240] The low-salt diet condition (Cohorts 1 and 2) resulted in an increase in ACTH. This increase was somewhat more pronounced in subjects receiving (R)-Compound 1 compared to subjects receiving placebo. However, following (R)-Compound 1 under normal-salt diet conditions, (R)-Compound 1 produced a clear dose-dependent decrease in ACTH.

[0241] There were no clinically significant changes in sitting vital signs or dose-related trends. Sitting BP was slightly reduced across (R)-Compound 1 treatment groups compared to across pooled placebo groups, although there was no clear dose-dependence. A slight trend toward a mild decrease in orthostatic BP and a moderate increase in orthostatic heart rate with the drug was observed. As observed in sitting vital signs, these trends in orthostatic measures were not consistently dose-dependent. However, the most significant effect on heart rate was observed at the 5 mg (R)Compound 1 dose level. Changes in blood pressure when moving from supine to standing were smaller at day 10 compared to baseline for all treatment groups (Compound 1 and placebo).

[0242] In general, however, the reductions, particularly in systolic blood pressure (SBP), were greater in subjects receiving (R)-Compound 1 compared to subjects receiving placebo. Similarly, the increase in heart rate observed 1 minute after moving from supine to standing was more pronounced in subjects receiving (R)-Compound 1 compared to subjects receiving placebo. Although there were no clear and consistent dose-related trends, the most significant changes in standing heart rate over 1 minute were typically seen at the 5 mg dose level of (R)Compound 1.

[0243] As expected with a reduction in aldosterone levels, a dose-dependent mild decrease in plasma sodium levels and an increase in plasma potassium levels were observed. Urinary sodium and potassium values ​​corresponded to the changes observed in plasma. Specifically, on day 1 after the first dose of (R)-Compound 1, the sodium:potassium ratio increased, with urinary sodium loss greater than potassium retention. However, this effect diminished by day 10, suggesting that the balance between sodium excretion and potassium absorption was restored. As potassium appears unchanged throughout the 10-day treatment period, the change in sodium:potassium ratio appears to be mediated by a greater excretion of sodium in urine on day 1 compared to day 10.

[0244] There were mild increases in blood urea nitrogen, creatinine, and the blood urea nitrogen:creatinine ratio. A mild decrease (<15%) in glomerular filtration rate was also observed. The presence of an increase in blood urea nitrogen:creatinine ratio accompanied by a decrease in glomerular filtration rate suggests that (R)-Compound 1 produces a mild diuretic effect.

[0245] Mean body weight and BMI decreased slightly from baseline during the treatment period in all groups, including placebo, in both the low-salt and normal-salt diet conditions. However, the reductions in mean body weight and BMI in subjects receiving (R)-Compound 1 were smaller than those in subjects receiving placebo (−1.31 kg and −0.442 kg / m2, respectively, in the pooled placebo group). 2) compared with the (R)-compound 1 group (−0.02 kg and −0.016 kg / m, respectively). 2 ).

[0246] The reductions observed in the (R)-Compound 1 treatment group did not appear to be dose-dependent, and values ​​generally returned to baseline at follow-up visits.

[0247] Safety: Treatment with (R)-Compound 1 was safe and well tolerated. There were no deaths, SAEs, or discontinuations due to TEAEs, and no apparent increase in the incidence or severity of AEs with increasing dose. The most common organ system class of TEAEs was nervous system disorders. All TEAEs were mild in severity, except for one moderate TEAE, ventricular tachycardia. Among subjects receiving (R)-Compound 1, four (9.5%) subjects experienced headache, three (7.1%) subjects experienced postural dizziness (basic term for dizziness postural), and two (4.8%) subjects experienced dizziness. In general, there were no clinically meaningful changes from baseline in clinical laboratory parameters during the study, although there were isolated abnormal sodium and potassium values, which were likely due to a combination of protocol-specified dietary sodium requirements and the effects of (R)-Compound 1. There were no clinically meaningful changes in physical examination results or clinically significant changes in 12-lead ECG findings during the study, including no meaningful changes in QTcF.

[0248] Conclusion: Once-daily dosing of (R)-Compound 1 for 10 days was safe and well tolerated in healthy subjects. (R)-Compound 1 is rapidly absorbed and exhibits a long t1 / 2 that is useful for once-daily dosing, with predictable increases in exposure over the dose range tested. Steady-state (R)-Compound 1 accumulation is typically approximately 2-2.5-fold higher than after a single dose.

[0249] Treatment with (R)-Compound 1 produced a significant, sustained, selective, and generally dose-dependent inhibition of aldosterone synthesis under both normal-salt and low-salt diet conditions, without affecting cortisol or 11-deoxycortisol levels. Inhibition of aldosterone synthase with administration of (R)-Compound 1 produced the expected changes in aldosterone precursors, with increases observed in corticosterone and 11-deoxycorticosterone, whereas 18-hydroxycorticosterone remained similar or was decreased.

[0250] There were no clinically significant changes in BP with (R)-Compound 1 compared with placebo.

[0251] Despite normotensive conditions, subjects receiving (R)-Compound 1 experienced a smaller reduction in SBP compared to subjects receiving placebo, especially in the standing position. The increase in orthostatic heart rate was also greater after administration of (R)-Compound 1 compared to placebo.

[0252] A dose-dependent mild decrease in plasma sodium levels and an increase in plasma potassium levels were observed, with corresponding changes in urinary sodium and potassium levels. A mild increase in blood urea nitrogen:creatinine ratio and a mild decrease in glomerular filtration rate were also observed following administration of (R)-Compound 1.

[0253] Of the randomized subjects, 41 (97.6%) subjects across all (R)-Compound 1 arms and 13 (92.9%) subjects across all pooled placebo arms completed the study. Among all (R)-Compound 1 arms, one subject (subject 001-082) discontinued the study early. This subject received 2.5 mg of (R)-Compound 1 with a normal salt diet and discontinued at the physician's discretion after steady state disruption, pending clinical laboratory results again. Among all pooled placebo arms, one subject (subject 001-101) discontinued the study early. This subject received placebo with a normal salt diet and discontinued due to subject withdrawal (subject did not wish to continue).

[0254] Single-dose and steady-state plasma pharmacokinetics of (R)-Compound 1 Following oral administration, (R)-Compound 1 was rapidly absorbed, with peak concentrations typically observed within 4 hours after dosing. Concentrations declined from the peak in a clear biphasic manner. The plasma concentration-time profile of (R)-Compound 1 over the 10-day dosing interval was qualitatively similar to that observed on day 1.

[0255] FIG. 4 shows treatment-specific plots of mean (SD) plasma (R)-Compound 1 concentrations versus time for all (R)-Compound 1 treatment groups over 24 hours following the first dose of (R)-Compound 1 (Day 1) on a linear scale for the PK population.

[0256] Single dose (Day 1) and steady state (Day 10) plasma pharmacokinetic parameters of (R)-Compound 1 are summarized in Table 1. Mean (% CV) pharmacokinetic parameters are summarized in Tables 2 and 3.

[0257] [Table 2]

[0258] [Table 3]

[0259] [Table 4]

[0260] Plots of mean aldosterone plasma concentrations over time by treatment for the normal salt and low salt diet treatment groups are shown in Figures 5 and 6 and summarized in Tables 4 and 5.

[0261] [Table 5]

[0262] [Table 6]

[0263] Plasma 11-deoxycorticosterone concentrations over time for each treatment for the normal salt and low salt diet treatment groups are shown in Tables 6-9.

[0264] [Table 7]

[0265] [Table 8]

[0266] [Table 9]

[0267] [Table 10]

[0268] Table 10 shows the mean pre-dose plasma ACTH concentrations over time by treatment group for the PD population, as well as the change and percent change in pre-dose concentrations from day 1 to day 10. The low-salt diet condition resulted in an increase in ACTH. This increase was somewhat more pronounced in subjects receiving (R)-Compound 1 compared to subjects receiving placebo. However, following (R)-Compound 1 under normal salt conditions, (R)-Compound 1 resulted in a clear dose-dependent decrease in ACTH.

[0269] [Table 11]

[0270] Pharmacokinetic and Pharmacodynamic Conclusions (R)-Compound 1 is rapidly absorbed and exhibits a long t1 / 2 useful for once-daily dosing, with predictable t1 / 2 increases in exposure across the dose range tested. Steady-state accumulation of (R)-Compound 1 is typically approximately 2-2.5-fold higher.

[0271] Treatment with (R)-Compound 1 produced a significant, sustained, selective, and generally dose-dependent inhibition of aldosterone synthesis under both normal-salt and low-salt diet conditions, without affecting cortisol or 11-deoxycortisol levels. Inhibition of aldosterone synthase with administration of (R)-Compound 1 produced the expected changes in aldosterone precursors, with increases observed in corticosterone and 11-deoxycorticosterone, whereas 18-hydroxycorticosterone remained similar or was decreased.

[0272] There were no clinically significant changes in BP with (R)-Compound 1 compared with placebo.

[0273] Consistent with what would be expected of an aldosterone synthase inhibitor, a dose-dependent mild decrease in plasma sodium levels and an increase in plasma potassium levels were observed, with corresponding changes in urinary sodium and potassium levels. A mild increase in the blood urea nitrogen:creatinine ratio and a mild decrease in glomerular filtration rate were also observed following administration of (R)-Compound 1.

[0274] Summary of adverse events There were no deaths, SAEs, or discontinuations due to TEAEs. In total, 11 (26.2%) subjects receiving (R)-Compound 1 and 3 (21.4%) subjects receiving placebo experienced TEAEs. Nearly all TEAEs were mild in severity, with one subject receiving placebo under the reduced salt diet condition experiencing a moderate TEAE (ventricular tachycardia). No subjects experienced severe TEAEs.

[0275] Overall, six subjects (14.3%) receiving (R)-Compound 1 and three subjects (21.4%) receiving placebo experienced TEAEs (deemed by the investigator to be related to study drug). Nearly all study drug-related TEAEs were mild in severity, with one subject receiving placebo under the reduced-salt diet condition experiencing a moderate study drug-related TEAE (ventricular tachycardia). No subjects experienced severe study drug-related TEAEs.

[0276] Table 11 provides an overview of AEs by treatment at onset for the safety analysis population.

[0277] [Table 12]

[0278] The most common SOC for TEAEs was nervous system disorders. Among subjects receiving (R)-Compound 1, 4 (9.5%) subjects experienced headache (1 subject each [11.1%] in the 2.5 mg (R)-Compound 1 low-salt diet, 5.0 mg (R)-Compound 1 low-salt diet, and 0.5 mg (R)-Compound 1 normal-salt diet groups, and 1 subject [16.7%] in the 2.5 mg (R)-Compound 1 normal-salt diet group); 3 (7.1%) subjects experienced postural dizziness ( Four subjects (11.1%) experienced postural nausea and vomiting (one [11.1%] subject in the 2.5 mg (R)-Compound 1 low-salt diet group and two [33.3%] subjects in the 2.5 mg (R)-Compound 1 normal-salt diet group); two (4.8%) subjects experienced dizziness (one [11.1%] subject in the 5.0 mg (R)-Compound 1 low-salt diet group and one [16.7%] subject in the 2.5 mg (R)-Compound 1 normal-salt diet group).

[0279] All other TEAEs experienced by subjects receiving (R)-Compound 1 were experienced by one subject each of the following: presyncope (2.5 mg (R)-Compound 1 low-salt diet group), eye irritation (2.5 mg (R)-Compound 1 normal-salt diet group), abdominal pain (5.0 mg (R)-Compound 1 low-salt diet group), constipation (1.5 mg (R)-Compound 1 normal-salt diet group), viral infection (2.5 mg (R)-Compound 1 low-salt diet group), rhinitis (2.5 mg (R)-Compound 1 normal-salt diet group), back pain (5.0 mg (R)-Compound 1 low-salt diet group), anxiety (2.5 mg (R)-Compound 1 normal-salt diet group), dry throat (2.5 mg (R)-Compound 1 normal-salt diet group), and dysphonia (5.0 mg (R)-Compound 1 low-salt diet group).

[0280] Among subjects receiving placebo, 1 (12.5%) subject (normal salt diet) experienced palpitations, 1 (16.7%) subject (low-salt diet) experienced ventricular tachycardia, and 1 (16.7%) subject (low-salt diet) experienced nausea.

[0281] safety Treatment with (R)-Compound 1 was safe and well tolerated. There were no deaths, SAEs, or discontinuations due to TEAEs, and no apparent increase in the incidence or severity of AEs with increasing dose. The majority of TEAEs were mild in severity. There were no clinically meaningful changes from baseline in any clinical laboratory parameters during the study, no clinically significant changes in physical examination results during the study, including significant changes in QTcF, or no clinically significant changes in 12-lead ECG findings.

[0282] Consideration The study was conducted in an escalating fashion with interim data review to ensure subject safety as dose levels increased, and the dose levels tested were aimed at characterizing the safety, PK, and PD of (R)-Compound 1 across a meaningful dose range. The dosing period was aimed at achieving steady-state PK and PD effects. Subjects in the first two cohorts were on a low-salt diet to stimulate aldosterone levels and to allow for the evaluation of safety in potential patients who may be on a low-salt diet. Subjects in these cohorts also underwent an ACTH challenge, which elevated both aldosterone and cortisol levels, allowing for the evaluation of the specificity of (R)-Compound 1 for aldosterone synthase. Subsequent cohorts at equivalent or lower doses (Cohorts 3-5) were on a normal-salt diet.

[0283] Once-daily administration of (R)-Compound 1 for 10 days was safe and well tolerated in healthy subjects. There were no deaths, SAEs, or discontinuations due to TEAEs, and no apparent increase in the incidence or severity of AEs with increasing dose. The most common SOC for TEAEs was nervous system disorders. Among subjects receiving (R)-Compound 1, 4 (9.5%) subjects experienced headache, 3 (7.1%) subjects experienced postural dizziness (PT for dizziness postural), and 2 (4.8%) subjects experienced dizziness. All TEAEs were mild in severity, except for 1 (7.1%) subject in the entire pooled placebo group who received placebo under reduced salt diet conditions who experienced moderate ventricular tachycardia that was considered study drug related. In general, there were no clinically meaningful changes from baseline in clinical laboratory parameters during the study, except for the isolated presence of abnormal sodium and potassium values, which were likely due to a combination of protocol-specified dietary sodium requirements and the effects of (R)-Compound 1. There were no clinically meaningful changes in physical examination results during the study, including no meaningful change in QTcF, or clinically significant changes in 12-lead ECG findings.

[0284] Consistent with findings from previous SAD studies, levels of (R)-Compound 1 increased with increasing dose in a clearly dose-proportional manner across the dose range tested. Following oral administration, (R)-Compound 1 was rapidly absorbed, with peak concentrations typically observed within 4 hours after dosing. Exposure declined slowly from the peak in a clearly biphasic manner, with long average t1 / 2 ranging from approximately 26 to 31 hours, and at steady state, exposure was typically approximately 2-2.5 times higher than after a single dose. On average, approximately 7% (6.3%-10.8% across treatment groups) of the (R)-Compound 1 dose was recovered unchanged in urine. Levels of (R)-Compound 1-M, the primary metabolite of (R)-Compound 1, increased with increasing dose, and on average, at steady state, C max Based on the parental AUC of 8.0% to 11% 0-infAfter the first dose of (R)-compound 1, peak primary metabolite concentrations were reached more slowly compared to steady state, when peak primary metabolite concentrations were observed within 4 h (T max (Median values ​​ranged from approximately 4 to 24 hours across treatment groups). Similar to the parent, plasma concentrations of the primary metabolites generally declined slowly from the peak, with long mean t1 / 2 values ​​ranging from approximately 31 to 38 hours. At steady state, exposure (RC max and R AUC The mean plasma concentration (based on the mean plasma concentration) was approximately 2.4-3.5 times higher than after a single dose.

[0285] The PD results of this study support the ability of (R)-Compound 1 to significantly reduce aldosterone levels under both low-salt and normal-salt diet conditions at doses >0.5 mg, where (R)-Compound 1 induces a dose-dependent blunting of plasma aldosterone levels compared to baseline and compared to placebo. Effects were observed after the first dose and persisted throughout the 10-day dosing period. The effect of (R)-Compound 1 on aldosterone at doses ≥1.5 mg was observed both with and without Cortrosyn challenge, typically with a reduction of about 70%-85% in mean AUC0-12h compared to baseline. Levels of the intermediate aldosterone precursors 18-hydroxycorticosterone and corticosterone showed stepwise changes indicative of the progressive impact of CYP11B2 inhibition on the aldosterone synthesis pathway. Specifically, levels of 18-hydroxycorticosterone (an intermediate to aldosterone) were generally comparable to or decreased from baseline, but to a lesser extent than the observed decrease in aldosterone. Levels of corticosterone, which is further upstream of aldosterone, increased in a clear dose-dependent manner. Finally, levels of 11-deoxycorticosterone, the first aldosterone precursor, showed a slight increase in pre-dose values ​​compared to baseline, with the change being most pronounced under low-salt diet conditions in which subjects also underwent cortisol stimulation testing. However, the magnitude of increase in pre-dose 11-deoxycorticosterone levels was minimal (2-3 fold) compared to the maximum 10-fold increase in pre-dose 11-deoxycorticosterone levels previously observed with another aldosterone synthase inhibitor (LCI1699).

[0286] The results of this study indicate that the selectivity for aldosterone synthase is maintained with repeated dosing, as levels of cortisol and 11-deoxycortisol (which are mediated exclusively by CYP11B1) remained unaffected by (R)-Compound 1, indicating that (R)-Compound 1 has no undesirable effects on these steroids, even in the presence of ACTH stimulation.

[0287] The low-salt diet condition (Cohorts 1 and 2) resulted in an increase in ACTH. This increase was somewhat more pronounced in subjects receiving (R)-Compound 1 compared to subjects receiving placebo. However, following administration of (R)-Compound 1 under normal-salt diet conditions, (R)-Compound 1 produced a clear dose-dependent decrease in ACTH. In contrast, the reduction in aldosterone observed with LCI1699 was consistently associated with a corresponding increase in ACTH.

[0288] The changes in relevant laboratory values, as well as weight and BMI, were consistent with those expected in the presence of an aldosterone synthase inhibitor. A dose-dependent mild decrease in plasma sodium levels and an increase in plasma potassium levels were observed, with corresponding changes in urinary sodium and potassium levels. Of note, despite an initial increase in the urinary sodium:potassium ratio, indicating that urinary sodium loss was greater than potassium retention, this ratio normalized by day 10, suggesting that the balance between sodium excretion and potassium absorption had been restored. As potassium appears unchanged throughout the 10-day treatment period, the change in the sodium:potassium ratio appears to be mediated by a greater excretion of sodium in the urine on day 1 compared to the excretion of sodium in the urine on day 10.

[0289] Consistent with observations of other RAAS modifiers, increases in blood urea nitrogen and creatinine were observed following administration of (R)-Compound 1, along with a mild decrease (<15%) in glomerular filtration rate. The presence of an increase in blood urea nitrogen:creatinine ratio accompanied by a decrease in glomerular filtration rate suggests that (R)-Compound 1 produces a mild diuretic effect. Finally, perhaps due to the mild diuretic effect noted previously, subjects receiving (R)-Compound 1 experienced a significant decrease in weight and BMI compared to subjects receiving placebo. Values ​​typically returned to baseline at follow-up visits.

[0290] Although the study was conducted in healthy subjects in whom significant changes in BP are unlikely to be detected, the results of this study showed a slight trend toward a mild reduction in sitting and orthostatic BP induced by the study drug after administration of (R)-Compound 1 compared with placebo, but there was no clear dose-dependence of the (R)-Compound 1-related changes. Furthermore, the change in BP when moving from supine to standing was smaller at day 10 compared with baseline in all treatment groups ((R)-Compound 1 and placebo). In general, however, the reduction in SBP in particular was greater in subjects receiving (R)-Compound 1 compared with subjects receiving placebo. Similarly, the increase in heart rate observed 1 minute after moving from supine to standing was more pronounced in subjects receiving (R)-Compound 1 compared with subjects receiving placebo. Although there was no clear and consistent dose-related trend, the most pronounced changes in standing heart rate over 1 minute were generally observed at the 5 mg dose level of (R)-Compound 1.

[0291] Taken together, the results of this study indicate that (R)-Compound 1 continues to show promise as a once-daily treatment for the adverse health effects of elevated aldosterone. The molecule exhibits a favorable safety profile, desirable and predictable PK attributes, and PD properties suggestive of potential beneficial effects in the target patient population at doses >0.5 mg per day.

[0292] Pharmacokinetics Single- and multiple-dose plasma pharmacokinetics of (R)-Compound 1. Single- and multiple-dose PK profiles of (R)-Compound 1 have been characterized in healthy subjects in a Phase 1 study. Figure 7 shows the mean plasma concentration versus time profiles of (R)-Compound 1 following single oral dose administration of (R)-Compound 1 in the range of 1 mg to 360 mg (under reduced salt conditions) and in the range of 0.5 mg to 5 mg (under reduced salt and / or normal salt conditions) at steady state. Following oral administration, (R)-Compound 1 is rapidly absorbed, with peak concentrations observed within 3 hours (range 0.5 to 4 hours) after dosing. (R)-Compound 1 concentrations decline from the peak in a clearly biphasic manner, with long mean t1 / 2 ranging from approximately 26 to 31 hours.

[0293] Absolute Bioavailability The plasma concentration versus time profile of (R)-Compound 1 following IV administration of a 3 mg dose is shown in Figure 8. An absolute bioavailability of 97.9% was measured for (R)-Compound 1 at 3 mg.

[0294] The relative bioavailability of the tablet formulation, intended for use in future clinical trials, was assessed following a single 5 mg dose of each formulation compared to an oral solution of (R)-Compound 1 administered at the SAD and MAD. The mean (+SD [standard deviation]) plasma concentration-time profiles following administration of the oral solution and tablet formulations are shown in Figure 9.

[0295] The mean (SD) PK parameters of (R)-Compound 1 following administration of the oral solution and tablet formulations are shown in FIG.

[0296] [Table 13]

[0297] Aldosterone and precursors Single dose with Cortrosyn challenge (R)-Compound 1 induced a dose-dependent blunting of plasma aldosterone levels compared to baseline on day -1 and compared to placebo, with the maximal effect achieved at the 10 mg dose level (approximately 85%-90% reduction compared to day -1). This effect was observed both in the post-Cortrosyn challenge readings (time interval 0-4 hours) and in the standing aldosterone peak (time interval 4-12 hours) (see FIG. 10).

[0298] NOTE: Plasma aldosterone levels below the limit of quantification were set to the lower limit of quantification (5 pg / mL) to allow for further calculations.

[0299] Cortrosyn challenge was performed 1 hour after dosing on days −1 and 1, inducing plasma aldosterone peaks in the time interval 0 to 3 hours.

[0300] Both on day -1 and 6 hours after dosing on day 1, subjects were asked to stand for 30 minutes, thus inducing plasma aldosterone peaks over a time interval of 4 to 12 hours.

[0301] The decrease in plasma aldosterone levels was associated with a dose-dependent decrease in the urinary excretion of both aldosterone and tetrahydroaldosterone that began on day 1 and remained constant on day 2. Submaximal effects in changes in urinary excretion of aldosterone were also achieved at the 10 mg dose.

[0302] Aldosterone precursors remained unchanged until doses were ≥90 mg, at which point 11-DOC (the precursor to aldosterone and cortisol) began to increase, but corticosterone levels did not change, suggesting partial inhibition of this pathway at doses well above the expected therapeutic range.

[0303] Figures 11 and 12 show plots of mean 11-deoxycorticosterone concentrations over time by treatment for the normal salt and low salt diet treatment groups, respectively, in the PD population. Treatment with (R)-Compound 1 results in an increase in 11-deoxycorticosterone on day 10 compared to day -1 in both low salt and normal salt diet conditions, and with and without Cortrosyn stimulation.

[0304] The dietary sodium and potassium restrictions during the run-in period for cohort 1 were 50–60 mEq Na + / day and 70-100mEq K + On day 1 of the treatment period, dietary restrictions for cohort 1 were 65–70 mEq Na + / day and 70-100mEq K + / day and maintained until the end of the treatment period. + / day and 70-100mEq K +The restriction of 10 mg / day was applied in cohort 2 from the start of the run-in period until the end of the treatment period. Further small changes in salt intake were made on an individual basis in both cohorts, as needed, to control electrolyte levels.

[0305] Multiple doses Following administration of multiple doses of (R)-Compound 1 ≦5 mg, there were no apparent differences in cortisol or 11-deoxycortisol levels compared to placebo on either day 1 or day 10. These findings were consistent in the presence of a Cortrosyn challenge (occurring in the low-salt treatment group) and in the absence of challenge (normal-salt group) (Table 13).

[0306] [Table 14]

[0307] Consistent with observations from the cortisol AUC data, (R)-Compound 1 had no apparent effect on the response to Cortrosyn challenge, with responses on days 1 and 10 in subjects treated with (R)-Compound 1 being similar to baseline responses and to responses in subjects receiving placebo.

[0308] Safety of (R)-Compound 1 in humans AEs were reported in a small number of subjects and incidence was not dose-related (Table 14). There were no severe AEs, SAEs, discontinuations due to AEs, or deaths. Overall, the most frequently reported AEs across dose levels were headache, nasopharyngitis, diarrhea, asthenia, and nausea; however, the only events reported by >1 subject at any dose level were toothache (2 subjects [12.5%] with placebo), nasopharyngitis (2 subjects [12.5%] with placebo), and headache (2 subjects [33.3%] with 180 mg). The majority of AEs were considered unrelated to study drug. Two events of moderate gastroenteritis were reported (with 180 mg and placebo); all other AEs were mild in severity.

[0309] [Table 15]

[0310] Isolated significantly abnormal safety laboratory values ​​were reported, but no dose-related pattern was evident. No AEs associated with significantly abnormal safety laboratory values ​​were reported. Mean decreases in hemoglobin, hematocrit, red blood cell count, urine osmolality, and urine specific gravity were observed at all dose levels, including placebo, with no apparent dose-related association.

[0311] No clinically significant or dose-related changes were observed over time in ECG parameters, vital signs, or visual assessments. A transient, but not dose-related, decrease in BW was observed in the active treatment group compared with placebo.

[0312] There was no dose-related increase in the incidence of AEs (Table 15). No severe AEs, SAEs, discontinuations due to AEs, or deaths were reported. A higher proportion of subjects (75%) reported AEs during 3 mg IV dosing compared with any oral dosing (up to 66.7% at 3 mg on low-salt diet and 10 mg on both low-salt and normal-salt diets). Overall, the most frequently reported AEs were nasopharyngitis, asthenia, and dizziness. AEs reported by >1 subject at any dose level and any salt diet were asthenia (2 subjects [33.3%] on 10 mg low-salt diet, 2 subjects [33.3%] on placebo low-salt diet), nasopharyngitis (3 subjects [37.5%] on 3 mg IV, 2 subjects [33.3%] on 10 mg low-salt diet), dizziness (2 subjects [33.3%] on 3 mg low-salt diet), and gum pain (2 subjects [33.3%] on 10 mg low-salt diet). Only one AE (dizziness) reported by a subject receiving 10 mg of (R)-Compound 1 under normal salt diet conditions was considered related to study drug. One coccyx fracture and one concussion (both reported in subjects receiving the IV dose) were moderate in intensity; all other AEs were mild in severity.

[0313] [Table 16]

[0314] No clinically significant or dose-related changes were observed over time in safety clinical trial results. Isolated significantly abnormal safety laboratory values ​​were reported, but no dose-related pattern was evident. Mean decreases in hemoglobin, hematocrit, and red blood cell count were observed at all dose levels except placebo under low-salt diet. At each dose level, increases were greater under normal-salt diet conditions than under low-salt diet conditions. The 3 mg IV dose produced smaller increases compared with the 3 mg oral dose (under both low-salt and normal-salt diet conditions). Decreases in mean urine osmolality and urine specific gravity were observed at all dose levels except 1 mg and 3 mg under low-salt diet conditions.

[0315] No clinically relevant trends were observed for changes in ECG parameters or vital signs over time or between dose levels. Mean BW decreased from baseline at all dose levels, including placebo, from days 1 to 4 and returned to normal at the follow-up visit. The decreases were not dose-dependent; however, in the active treatment groups, greater decreases were observed with the low-salt diet compared with the normal-salt diet.

[0316] (R)-Compound 1 administered QD for 10 days was well tolerated in healthy subjects under reduced salt (2.5 and 5 mg (R)-Compound 1) and normal salt conditions (0.5, 1.5, and 2.5 mg (R)-Compound 1). There were no TEAEs leading to death, SAE, or discontinuation. The most common TEAEs after multiple doses of (R)-Compound 1 were headache (4 subjects), postural dizziness (3 subjects), and dizziness (2 subjects). TEAEs in the placebo group included nausea (1 subject), nonsustained ventricular tachycardia (1 subject), and palpitations (1 subject). All AEs after administration of (R)-Compound 1 were mild in nature.

[0317] The overall incidence of AEs in subjects receiving (R)-Compound 1 was similar to that in subjects receiving placebo, with no trend toward increased incidence or relevance of AEs with increasing dose (Table 16).

[0318] [Table 17]

[0319] No clinically significant changes were observed in the safety clinical trial results over time. Significantly abnormal safety laboratory values ​​were reported and were likely due to a combination of protocol-specified dietary sodium requirements and the effects of (R)-Compound 1, although no dose-dependent pattern was evident. A dose-dependent mild decrease in plasma sodium levels and an increase in plasma potassium levels were observed, with corresponding changes in urinary sodium and potassium levels. Of note, despite an initial increase in the urinary sodium:potassium ratio, indicating that urinary sodium loss was greater than potassium retention, this ratio normalized by day 10, suggesting that the balance between sodium excretion and potassium absorption had been restored. As potassium appears unchanged throughout the 10-day treatment period, this change in ratio appears to be mediated by a greater excretion of sodium in the urine on day 1 compared to urinary sodium excretion on day 10.

[0320] Consistent with observations of other RAAS modifiers, increases in blood urea nitrogen and creatinine were also observed following administration of (R)-Compound 1, along with a mild decrease (<15%) in glomerular filtration rate. The presence of an increase in blood urea nitrogen:creatinine ratio accompanied by a decrease in glomerular filtration rate suggests that (R)-Compound 1 produces a mild diuretic effect. Finally, perhaps due to the mild diuretic effect noted previously, subjects receiving (R)-Compound 1 experienced a significant decrease in body weight and body mass index (BMI) compared to subjects receiving placebo. Values ​​returned to normal by follow-up.

[0321] There were no clinically relevant ECG findings, including significant changes in QTcF. There were also no clinically relevant changes in vital signs. However, there were mild drug-induced decreases in sitting and orthostatic BP and some trends toward a moderate increase in orthostatic heart rate. These trends were not consistently dose-related, but the most significant effects on heart rate were observed at the 5 mg dose level.

[0322] Mean BW and body mass index decreased slightly from baseline (≤2 kg or <0.65 kg / m2) during the treatment period at all dose levels, including placebo. 2 ), which then returned to normal at the follow-up visit. The observed reductions had no apparent dose-dependence, but the reductions in subjects receiving (R)-Compound 1 were greater than those in subjects receiving placebo.

[0323] Example 7 This placebo-controlled Phase 2 study is to evaluate the efficacy and safety of multiple dose intensities of (R)-Compound 1 in the treatment of rHTN patients receiving a stable background hypertension regimen. Efficacy will be analyzed by change from baseline in SBP, DBP, PK, and PD parameters. AEs will be monitored from the time of informed consent until the end of the follow-up period. All patients will receive their background antihypertensive medication unless otherwise requested through the central pharmacy from the time of the SB-RI period (Visit 3) until the end-of-treatment visit (Visit 11).

[0324] Test Purpose Part A OBJECTIVE:To demonstrate that at least one dose strength of (R)-Compound 1 is superior to placebo in mean change from baseline in sitting SBP after 12 weeks of treatment in patients with rHTN.

[0325] Other purposes To evaluate the change from baseline in mean sitting DBP with each selected dose strength of (R)-Compound 1 compared to placebo after 12 weeks of treatment in patients with rHTN; and To evaluate the proportion of patients achieving a sitting BP response of <130 / 80mmHg with each selected dose strength of (R)-Compound 1 compared to placebo after 12 weeks of treatment for rHTN. • Assess vital signs, orthostatic BP and heart rate, physical examination, electrocardiogram, weight measurement, and clinical laboratory evaluation including standard safety chemistry panel, hematology, coagulation, and urinalysis; • Assessing TEAEs; • To evaluate TEAEs leading to early discontinuation of study drug; - assessing significant treatment-emergent clinical laboratory abnormalities; and • To assess the change in orthostatic SBP and DBP (measured pre-dose at the clinical site) from baseline to the end of treatment (Visit 11).

[0326] The PK-PD goal is to evaluate the exposure-response relationship (pharmacokinetic / pharmacodynamic) of (R)-Compound 1 using measures of safety, PD, and / or efficacy.

[0327] Part B Part B is a substudy to characterize the PK of (R)-Compound 1 in patients with rHTN and obtain additional data to support the PK-PD objectives of Part A.

[0328] Test Description (i) Summary of study design This is a Phase 2, two-part, randomized, double-blind, placebo-controlled, multicenter, parallel-group, dose-ranging study to evaluate the efficacy and safety of multiple dose strengths of (R)-Compound 1 compared with placebo after 12 weeks of treatment in patients with rHTN.

[0329] Patients with rHTN were defined as being on a stable regimen of ≥3 antihypertensive drugs (including one diuretic) and having a mean sitting BP ≥130 / 80 mmHg.

[0330] The safety of (R)-Compound 1 will be assessed from the time of informed consent until the end of the follow-up period. Patients will be followed for efficacy and adherence during the double-blind treatment period. PD variables analyzed during the study may include, but are not limited to, measurements of aldosterone and its precursors, cortisol and its precursors, PRA, and calculations of ARR and UACR. PK variables analyzed during the study include plasma concentrations of (R)-Compound 1 and any measured metabolites.

[0331] Patients must not exercise, smoke, or consume caffeinated beverages or foods for at least 2 hours prior to each clinical visit. All clinical visits must occur between 6:00 AM and 11:00 AM.

[0332] Part A Part A is a Phase 2, randomized, double-blind, placebo-controlled, multicenter, parallel-group, dose-ranging study to evaluate the efficacy and safety of multiple dose strengths of (R)-Compound 1 compared with placebo after 12 weeks of treatment in patients with rHTN.

[0333] (i) Adaptive Design During the double-blind treatment period, eligible patients will be randomly assigned 1:1:1 to one of three treatment arms (two active [1 mg and 2 mg of (R)-Compound 1] and one placebo). After the first approximately 25 randomized patients per arm reach approximately 4 weeks of study drug administration, new data will be evaluated and reported for cumulative SAEs. Based on the evaluation, the next dose level to be tested is 0.05 mg QD. Patient enrollment into the study will not be stopped during the initial review.

[0334] In Part A, patients will be enrolled using a randomization plan that will allow for approximately equal allocation between treatment arms at the end of the study.

[0335] (ii) Study Visit Part A of the study consisted of four periods: ● Screening period of up to 8 weeks (screening visit [visit 1] and phone call 1 [visit 2]); ● 2-week SB-RI period (visit 3); ●A 12-week double-blind treatment period (Visits 4 to 11); and ● Follow-up period of up to 1 week (2nd telephone call [12th visit]).

[0336] Patients will complete a total of at least 12 visits over an approximately 6 month period, including 10 clinic visits and 2 telephone visits.

[0337] (iii) Screening period (Visits 1 and 2) Patients provide informed consent at the screening visit (Visit 1) and are assessed for inclusion / exclusion criteria.

[0338] Patients taking MRA or potassium-sparing diuretics (e.g., triamterene, amiloride, etc.) as antihypertensives must be willing to discontinue this medication for study eligibility. Potassium-sparing diuretics must be discontinued and replaced with non-potassium-sparing diuretics. If the MRA is the fourth antihypertensive drug, an alternative drug does not need to be initiated. If the MRA is the third antihypertensive drug, an alternative drug must be initiated. All patients who have been on a stable dosing regimen of ≥ 3 antihypertensive drugs, including a non-potassium-sparing diuretic, for at least 2 weeks are eligible to enter the SB-RI period. Eligible patients will be contacted by phone call 1 (visit 2), informed of study eligibility, and scheduled for the SB-RI period.

[0339] If taking MRA as part of an antihypertensive regimen, patients may have a mean sitting BP <130 / 80 mmHg at screening; however, to be eligible for the study, they must have a mean sitting BP ≥130 / 80 mmHg in the SB-RI period after MRA cessation (Visit 3), with or without substitution medication.

[0340] Screening clinical laboratory assessments, if abnormal, may be repeated once for eligibility purposes before excluding the patient. Patients who are screened but do not meet the study inclusion / exclusion criteria or randomization criteria (screening failures) may be rescreened less than 5 days after their last study visit.

[0341] (iv) SB-RI period (third visit) The SB-RI period lasted approximately 2 weeks (± 2 days), and the purpose of this period was to determine whether medication adherence was a factor in preventing patients from achieving their target BP.

[0342] All patients will receive their background antihypertensive medications unless otherwise requested through the central pharmacy between Visits 3 and 11. The clinical site will send prescriptions for background antihypertensive medications to the central pharmacy at Visit 2 or at least 1 week prior to Visit 3. These medications will be delivered directly to the clinical site. Background antihypertensive medications and study medication (single-blind placebo) will be dispensed at Visit 3.

[0343] (v) Double-blind treatment period (Visits 4 to 11) Measurements of efficacy and safety variables at the time of randomization (Visit 4) will represent "baseline" measurements. Measurements of efficacy and safety variables recorded prior to administration of study drug at the clinical site will constitute "pre-dose" measurements.

[0344] Patients with adherence ≥ 70% and ≤ 120 (based on pill counts) to each antihypertensive and study drug during the SB-RI period and baseline mean sitting BP ≥ 130 / 80 mmHg will continue through the randomization eligibility procedure.

[0345] Eligible patients will be randomly assigned 1:1:1 to one of three treatment arms (two active [1 mg and 2 mg of (R)-Compound 1] and one placebo). After the first approximately 25 randomized patients per arm reach approximately 4 weeks of study drug administration, new data will be evaluated and reported for cumulative SAEs. Based on the evaluation, the next dose level to be tested is 0.05 mg QD. Following review, Part A will enroll patients using a randomization plan that allows for approximately equal distribution between treatment arms at the end of the study.

[0346] Dispensation of study medication ((R)-Compound 1 or placebo) may occur any time between Visit 4 and prior to Visit 11. The clinical site will send prescriptions for background antihypertensive medications to the central pharmacy at Visit 4, and these medications will be dispensed at Visit 5 or Visit 6. It is expected that patients' background antihypertensive regimens will not change or be titrated during the treatment period. On the day of the clinical site visit, patients will self-administer their morning dose of background hypertension medication at home and withhold study medication. At the clinical site, patients will self-administer their morning dose of study medication in the presence of site staff after pre-dose assessments and clinical laboratory sampling are completed. During clinical site visits, patients will continue to take study medication orally QD at approximately the same time each morning. Primary endpoint assessments will be performed at the end of treatment (Visit 11).

[0347] Pre-dose blood samples for PD analyses will be collected at Visits 4, 7, 8, and 11. Pre-dose blood samples for PK analyses will be collected at Visits 8 and 11. Safety and adherence will be monitored throughout the double-blind treatment period.

[0348] Urine for PD and electrolyte measurements will begin collection 24 hours prior to the Visit 4 dose and 24 hours prior to the Visit 11 / EOT dose.

[0349] (vi) Follow-up period (2nd telephone call, 12th visit) Patients will have a second telephone call (visit 12) 1 week ± 3 days after the last dose of study medication to assess adverse events (AEs) and concomitant medications, including background antihypertensive regimens, after study completion.

[0350] Study visits will follow the procedure schedule, see Tables 17A and 17B.

[0351] [Table 18]

[0352] [Table 19]

[0353] [Table 20]

[0354] [Table 21]

[0355] [Table 22]

[0356] Part B After participating in the Part A pre-visit and procedures, approximately 10-15% of patients are expected to participate in the optional Part B substudy at the end of treatment (Visit 11).

[0357] Patients participating in Part B will present to the clinical site at Visit 11 in an 8-hour fasting state relative to study drug administration, which will continue for 4 hours after study drug administration. Patients will not be able to eat or drink anything other than water during the 12-hour fast. Additional post-dose PK sampling will be performed at the following time points at Visit 11: 1, 2, 3, 4, 6, and 8 hours. A time window of ±5 minutes will be allowed for collection of post-dose PK samples.

[0358] Patient Selection and Withdrawal All inclusion, exclusion, and randomization criteria for patients participating in Part A are applicable to patients participating in Part B. There are no new patients enrolled in Part B and there are no additional criteria for participating in Part B.

[0359] (i) Inclusion criteria Patients who met all of the following criteria were eligible to participate: 1. Adult male and female patients aged ≥ 18 years; 2. Receiving a stable regimen of >3 antihypertensive drugs at screening, one of which is a diuretic at the MTD based on the investigator's judgment - Patients taking an MRA or a potassium-sparing diuretic (e.g., triamterene, amiloride, etc.) as an antihypertensive must be willing to discontinue this drug for study eligibility. The potassium-sparing diuretic must be discontinued and replaced with a non-potassium-sparing diuretic. If the MRA is the fourth antihypertensive drug, an alternative drug does not need to be initiated. If the MRA is the third antihypertensive drug, an alternative drug must be initiated. All patients who have been on a stable regimen of ≥3 antihypertensive drugs, including a non-potassium-sparing diuretic, for at least 2 weeks are eligible to enter the SB-RI period; Antianginal nitrates, including nitroglycerin, isosorbide mononitrate, and isosorbide dinitrate, are not considered antihypertensive agents. 3. Have a mean sitting BP ≥ 130 / 80 mmHg, defined as the average of three sitting BP measurements at any single clinical site visit. If taking an MRA as part of an antihypertensive regimen, patients may have a mean sitting BP < 130 / 80 mmHg at screening; however, at visit 3 after discontinuation of the MRA, the mean sitting BP must be ≥ 130 / 80 mmHg, with or without substitution medication. 4. Agree to adhere to the contraceptive and reproductive restrictions of the study as follows: • Male subjects must agree to refrain from sperm donation for 90 days beginning on day 1 after the last dose of study drug; • Postmenopausal women must have been free of menstrual bleeding for at least 1 year and be over 60 years of age or have an elevated plasma follicle-stimulating hormone (FSH) level of more than 40 mIU / mL at screening; • Female patients of childbearing potential (i.e., not ovulating, premenopausal, and surgically infertile) must have a documented negative pregnancy test at the time of screening and randomization; • All male patients (not surgically sterilized) must use a highly effective method of contraception (i.e., failure rate <1%) for 90 days beginning on day 1 after the last dose of study drug; Acceptable contraceptive methods for male patients enrolled in the study included: ○ Spermicide-containing condoms; or ○ Surgical contraception (vasectomy) for at least 26 weeks prior to screening; and • Female patients of childbearing potential must use highly effective contraception (i.e., failure rate less than 1%) for 30 days starting from day 1 after the last dose of study drug; Contraceptive methods acceptable to female patients enrolled in the study included: o Surgical sterilization (tubal ligation); ○ intrauterine contraceptive device for at least 12 weeks prior to screening; Hormonal contraception (oral, implant, injection, ring, or patch) for at least 12 weeks prior to screening; or Contraceptive diaphragms used in combination with spermicides; and 5.Able and willing to give informed consent to participate in a clinical trial.

[0360] (ii) Exclusion criteria Patients who meet any of the following criteria will be excluded from participating in the study: 1. Mean sitting SBP ≥ 180 mmHg or DBP ≥ 110 mmHg, with mean sitting BP defined as the average of three sitting BP measurements during any single clinical visit. If patients miss their regularly scheduled antihypertensive medication prior to the visit (Visits 1, 3, or 4), one BP recheck within 2 days of taking the medication is permitted. 2. Body mass index (BMI) > 45 kg / m at screening 2 (If upper arm circumference requirement is met, see Exclusion Criterion #3). 3. Upper arm circumference <7 inches or >17 inches at screening; 4. Have worked a night shift any time during the 4 weeks prior to screening; 5. Using beta-blockers for any primary condition other than systemic hypertension (e.g., migraine headache); 6. Unwilling or unable to discontinue MRA or potassium-sparing diuretics as part of an existing antihypertensive regimen; 7. Unwillingness to stop taking potassium supplements; 8. Plan to receive or are receiving any of the following excluded medications (potent cytochrome P4503A inducers and / or chronic use of nonsteroidal anti-inflammatory drugs [NSAIDs]); patients using chronic NSAIDs at screening and willing to discontinue during the study period will be allowed to participate; 9. Have a known secondary cause of hypertension (e.g., renal artery stenosis, poorly controlled or untreated hyperthyroidism, poorly controlled or untreated hypothyroidism, hyperparathyroidism, pheochromocytoma, Cushing's syndrome, or coarctation of the aorta) excluding obstructive sleep apnea; patients with primary aldosteronism may be considered for enrollment unless adrenalectomy is anticipated before the end of study participation. 10. Estimated glomerular filtration rate <45 mL / min / 1.73 m using the Chronic Kidney Disease Epidemiology Collaboration Method equation at screening 2 It has been documented that; 21 11. Known and documented New York Heart Association stage III or IV chronic heart failure at screening; 12.Has had stroke, transient ischemic attack, hypertensive encephalopathy, acute coronary syndrome, or hospitalization for heart failure within 6 months prior to screening; 13. Known current severe left ventricular outflow tract obstruction, such as obstructive hypertrophic cardiomyopathy and / or severe aortic valvular disease, diagnosed on a previous echocardiogram; 14. Planned coronary revascularization (PCI or CABG) or any major surgical procedure; 15.Having undergone CABG or other major cardiac surgery (e.g., valve replacement), peripheral artery bypass surgery, or PCI within 6 months prior to screening; 16.Having chronic persistent atrial fibrillation; 17.Having uncontrolled diabetes with HbA1c >9.5% at screening; 18. Scheduled for dialysis or kidney transplant during the course of this study; 19. Previous solid organ and / or cell transplantation; 20. Have known hypersensitivity to (R)-Compound 1 or any of the drugs in the same class, or any of its excipients: 21. Any clinically relevant medical or surgical condition (including patients with unstable medical conditions and / or being treated with systemic immunosuppressants including corticosteroids) that may place the patient at risk from participating in the study; 22. Have evidence of the following at screening or the start of the SB-RI period (one repeat test is permitted): ●White blood cell count>15×10 9 / L or absolute neutrophil count <1×10 9 / L; ● Potassium < 3.5 mEq / L; ● Potassium >5.0 mEq / L; Hemoglobin <10.0 g / dL, and / or planned initiation of erythropoietin stimulating agents, and / or planned transfusion within 2 months of screening; or • Serum aspartate aminotransferase and / or alanine aminotransferase >3× upper limit of normal with corresponding bilirubin >2 mg / dL (unless the patient has a history of Gilbert's syndrome); 23. Test positive for HIV antibodies, HCV RNA, or HBsAg; 24. Have a typical intake of ≥ 14 alcoholic drinks per week; 1 alcoholic drink is equivalent to half a pint of beer (285 mL), 1 glass of spirits (25 mL), or 1 glass of wine (125 mL); 25. Pregnant, breastfeeding, or planning to become pregnant during the study; 26.Has participated in another clinical trial involving any investigational drug within 30 days prior to screening, or plans to participate in another clinical trial within 30 days after discontinuing the investigational drug; 27. Having received experimental treatment with a small molecule within 30 days or 5 half-lives of Day 1, whichever is longer, or experimental treatment with a large molecule within 90 days or 5 half-lives of Day 1, whichever is longer; or 28. Deemed unsuitable for any other reason that, after review of medical and psychiatric history, physical examination, and clinical laboratory evaluation, may endanger the patient during participation or may interfere with the interpretation of the study results.

[0361] (iii) Randomization criteria Patients must meet all of the following criteria at randomization (Visit 4): 1.Continue to meet all inclusion / exclusion criteria; 2. No change in background therapy consisting of ≥ 3 antihypertensive medications for at least 4 weeks prior to randomization. 3. Adherence to each antihypertensive drug and placebo during the SB-RI period is ≥ 70% and ≤ 120%, based on the morning pill count at randomization; and 4. Have a mean (average of three measurements) sitting BP ≥ 130 / 80 mmHg at randomization.

[0362] (iv) Stopping criteria A patient will be discontinued from this clinical trial for any of the following reasons: • The patient withdraws consent or requests to discontinue the study for any reason; • Patients have a mean sitting BP >175 / 105 mmHg on two separate occasions during the double-blind treatment period; • The patient has any medical condition or situation that places the patient at significant risk and / or prevents the patient from complying with the requirements of the clinical trial protocol; • The patient has any SAE, clinically significant AE, severe laboratory abnormality, intercurrent illness, or other medical condition indicating continued participation is not in the patient's best interest; • The patient has a need for a prohibited concomitant medication; • The patient fails to comply with protocol requirements or study-related procedures; The patient becomes pregnant; or ●The exam ends.

[0363] If a patient prematurely discontinues the study due to the above criteria or for any other reason, they will be required to undergo an early termination procedure and site staff should make every effort to complete the entire evaluation panel scheduled at the end of treatment (Visit 11). The reason for the patient's discontinuation must be documented. Patients will be required to attend study visits after early termination for safety monitoring.

[0364] Criteria for suspending administration Enrollment of patients in this clinical trial will be suspended for any of the following reasons: • Any SAE deemed related to the study drug, including death; • Discontinuation of patients who received one or more doses of study drug for safety-related reasons after randomization; • Study drug-related AEs considered to be severe in intensity (severity) in ≥ 2 patients; Drug-related AEs from a single system organ class considered to be of moderate intensity (severity) in ≥ 4 patients; or Potassium ≥ 6 mEq / L; patient must discontinue study medication and immediately present to the clinical site for retesting. Note: This criterion is specific only to the individual subject who is temporarily discontinued. Patient may resume study medication following consultation and approval from the medical monitor.

[0365] The following events must be reported as soon as possible: ● Patient has evidence of hyponatremia (sodium concentration <130 mmol / L, reconfirmed within 72 hours after notification) or has an SBP ≤ 90 mmHg with symptoms consistent with orthostatic hypotension; this criterion is specific only to the individual subject who is being suspended. Other enrolled subjects do not need to be suspended. Patients may resume study medication upon approval.

[0366] Study treatment (i) Treatment group Eligible patients will be randomly assigned in a 1:1:1 ratio to one of the following arms: ● 1 mg of (R)-compound 1; 2 mg of (R)-Compound 1; or ●Placebo.

[0367] The next dose level to be tested is 0.5 mg QD. Following review, Part A will enroll patients using a randomization plan that will allow for approximately equal allocation between the following treatment arms at the end of the study: ● 1 mg of (R)-compound 1; ● 2 mg of (R)-compound 1; ● 0.5 mg of (R)-compound 1; ●Placebo.

[0368] (ii) Single-blind run-in period A placebo tablet, indistinguishable from the (R)-Compound 1 tablet, will be administered during the SB-RI period to determine whether medication adherence is a factor in patients failing to achieve target BP. The single-blind placebo will be included in the ongoing stable antihypertensive regimen.

[0369] (iii) Randomization and double-blind treatment period Patients who meet all eligibility criteria will be randomly assigned in a 1:1:1 ratio to one of three treatment arms (two active [1 mg and 2 mg (R)-Compound 1] and one placebo) for Part A. After the first approximately 25 randomized patients per arm reach approximately 4 weeks of study drug administration in the double-blind treatment period, new data will be evaluated and reported regarding cumulative SAEs collected during the study. Based on the evaluation, the next dose level of (R)-Compound 1 to be tested is 0.5 mg QD.

[0370] In Part A, patients will be enrolled using a randomization plan that will allow for approximately equal allocation between treatment arms at the end of the study.

[0371] Patients were randomized to receive randomized controlled trials based on baseline SBP (<145 or ≥145 mmHg) and baseline glomerular filtration rate (<60 or ≥60 mL / min / 1.73 m 2 ) are hierarchically organized according to

[0372] After randomization, study medication will be dispensed in a double-blind fashion. Randomization information will be concealed until the end of the study, except in emergency situations involving patients needing to be unblinded from treatment assignment.

[0373] (iv) Providing (R)-Compound 1 formulation (R)-Compound 1 tablets are provided in the following strengths: 0.5 mg, 1 mg, and 2 mg. The tablets are packaged in blister packs to achieve the required dose for the study. (R)-Compound 1 tablets contain the study drug as the active ingredient and the following inactive ingredients: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.

[0374] The corresponding placebo tablets contain no active ingredient and contain the same inactive ingredients.

[0375] Study drug administration Patients will be allowed to eat their usual meal each morning of study medication administration. On the day of the clinical visit, patients will self-administer their morning dose of background hypertension medication at home and will refrain from taking the morning dose of study medication. Patients will self-administer their morning dose of study medication in the clinic in the presence of site staff after pre-dose assessments and clinical laboratory sampling are completed.

[0376] Patients participating in Part B will arrive at the clinical site at Visit 11 in an 8-hour fasting state prior to study drug administration and will remain in that state for 4 hours after study drug administration. Patients will not be allowed to eat or drink anything other than water during the 12-hour fast.

[0377] Treatment Adherence Patients will self-administer their morning dose of study medication at the clinic in the presence of site staff during all clinic visits.

[0378] For all doses specified in the protocol when patients are not at the clinical site, patients will self-administer study medication at home and continue taking background antihypertensive medications.

[0379] Excluded Drugs and / or Procedures Use of the following investigational, prescription, or over-the-counter drugs is not permitted during the study: -Strong CYP3A inducers such as those in Table 18.

[0380] [Table 23]

[0381] • Beta-blockers for any presenting condition other than systemic hypertension; ● MRAs; • Chronic use of NSAIDs; Patients who were using chronic NSAIDs at screening and were willing to discontinue during the study period were allowed to participate. Potassium-sparing diuretics; and / or ●Potassium supplement.

[0382] Test procedure (i) Informed consent Written informed consent will be obtained from all patients prior to performing any protocol-specified procedures.

[0383] Patients who enter the optional Part B substudy at Visit 11 will first participate in the Part A pre-visit and procedures.

[0384] Patients who have provided written informed consent to participate in the optional Part B substudy will present to the clinical site at Visit 11 in an 8-hour fasting state for study drug administration, which will continue for 4 hours after study drug administration. Patients will not be allowed to eat or drink anything other than water during the 12-hour fast. Post-dose PK blood sampling will be performed at the following time points at Visit 11: 1, 2, 3, 4, 6, and 8 hours. A time window of ±5 minutes will be allowed for collection of post-dose PK samples.

[0385] In some cases, collection of specific individual PK samples (including but not limited to collection of a sample at 8 hours post-dose) may not be necessary.

[0386] (ii) Early Discontinuation Visit and Discontinuation Procedures The end of treatment for patients who complete the study is Visit 11. For patients who discontinue the study prior to completion, all Visit 11 procedures will be performed at the early discontinuation visit.

[0387] Efficacy assessment (i) Primary efficacy endpoint The primary efficacy outcome measure was the change from baseline in mean sitting SBP after 12 weeks of treatment in patients with rHTN.

[0388] (ii) Secondary efficacy endpoints Secondary efficacy endpoints included: - the change from baseline in mean locomotive DBP with (R)-Compound 1 compared to placebo after 12 weeks of treatment in patients with rHTN; and Proportion of patients achieving a sitting BP response of <130 / 80mmHg with (R)-Compound 1 compared to placebo after 12 weeks of treatment for rHTN.

[0389] Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic Evaluation (i) Pharmacokinetic evaluation Part A Blood samples for PK analysis will be collected pre-dose at Visits 8 and 11 as specified in Table 17. Additional PK samples may also be collected in the event of an SAE, AE leading to discontinuation, or any other safety event. PK samples should be collected within approximately 15 minutes prior to dosing.

[0390] Samples are analyzed to measure plasma concentrations of (R)-Compound 1 and any measured metabolites using a validated liquid chromatography mass spectrometry method.

[0391] Part B The date and time that study drug is taken at the clinical site will be recorded on Visit 11. The actual date and time of collection of each post-dose PK sample will also be recorded.

[0392] Patients in the optional Part B substudy will have additional post-dose PK sampling performed at the following time points: 1, 2, 3, 4, 6, and 8 hours at Visit 11. A time window of ±5 minutes will be allowed for collection of post-dose PK samples.

[0393] As data permitted, the following plasma PK parameters were determined for (R)-Compound 1 and any measured metabolites using concentration data from the end of treatment visit (Visit 11): ●C max : ●T max and • AUC from time 0 to the time of the last measured plasma concentration.

[0394] (ii) Pharmacodynamic evaluation Blood samples for PD analyses will be collected pre-dose at Visits 4, 7, 8, and 11 as specified in Table 17. Urine samples from a 24-hour urine collection will be collected over the 24 hours between Visits 4 and 11 as specified in Table 17.

[0395] Plasma PD variables include, but are not limited to, the following: • Aldosterone and its precursors (18-hydroxycorticosterone, corticosterone, and 11-deoxycorticosterone); ● PRA; and • Cortisol (total) and its precursor 11-deoxycortisol.

[0396] If a change in total cortisol is noted, free cortisol is measured.

[0397] Plasma electrolyte levels (collected as part of a standard safety chemistry panel, see Table 19) will be used in the PD analysis.

[0398] [Table 24]

[0399] [Table 25]

[0400] Urinary aldosterone and urinary electrolyte levels will also be assessed from 24-hour urine collections prior to Visits 4 and 11. Urinary electrolyte levels include, but are not limited to, urinary sodium and potassium (see Table 18).

[0401] PD samples are collected in the morning at the clinical site after the patient has been out of bed and has been sitting for 5-15 minutes, approximately 2 hours. Samples are analyzed using validated methods, if necessary.

[0402] (iii) Pharmacogenomic evaluation A single, optional, pharmacogenomic blood sample may be collected any time after randomization. The pharmacogenomic sample may be used for genetic studies to investigate the underlying causes of response variability and / or differences in PK, PD, and / or safety data following administration of (R)-Compound 1.

[0403] Patients will be given the option to participate in a pharmacogenomic evaluation during the consent process. For patients who have provided written informed consent to participate in an optional pharmacogenomic evaluation, blood samples will be collected any time after randomization. Patients may withdraw consent to participate in a pharmacogenomic evaluation at any time during the study without withdrawing consent to participate in the study.

[0404] Safety assessment (i) Safety endpoints The safety of (R)-Compound 1 will be assessed from the time of informed consent to the end of the follow-up period. All safety endpoints will be summarized narratively.

[0405] Safety endpoints included: • Clinical laboratory evaluation including vital signs, orthostatic BP and heart rate, physical examination, electrocardiogram, weight measurement, and standard safety chemistry panel, hematology, coagulation, and urinalysis; ● TEAEs; • Treatment-emergent SAEs; • TEAEs leading to early discontinuation of study drug; - significant treatment-emergent clinical laboratory abnormalities; and ● Change in mean orthostatic SBP and DBP (measured pre-dose at the clinical site) from baseline to end of treatment (Visit 11).

[0406] (ii) Adverse events An AE is defined in clinical research as an untoward medical occurrence occurring in a patient receiving a medicinal product, not necessarily having a causal relationship to this treatment. Thus, an AE can be any untoward and / or unintended sign (including laboratory abnormalities), symptom, or disease that is temporarily associated with the use of a study drug, whether or not related to the study drug. All AEs, including observed or spontaneously occurring problems, complaints, or symptoms, must be recorded. Clinical sites will record the time of occurrence (hours, minutes) of AEs that began and / or ended at the first randomized study drug administration visit (Visit 4) or Visit 11 (EOT).

[0407] AEs, including clinical laboratory test variables, will be monitored and documented from the time of informed consent until the end of the follow-up period. Patients must be instructed to report any adverse events they experience, regardless of whether they believe the event is due to the study drug. Assessment of AEs should occur at each visit, beginning with screening.

[0408] Whenever possible, specific diseases and syndromes should be identified rather than individual associated signs and symptoms. However, if an observed or reported sign or symptom is not considered a component of a specific disease or syndrome, it should be recorded. In addition, conditions that prompted a medical or surgical procedure (e.g., surgery, endoscopy, dental extraction, or blood transfusion) should be recorded as an AE rather than the procedure itself.

[0409] Any medical condition already present at screening must be recorded in the medical history and will not be reported as an AE unless at any time during the study there is a change in the severity, frequency, or severity of the medical condition or signs or symptoms present at baseline, in which case it must be reported as an AE.

[0410] Clinically significant abnormal laboratory findings or other test (e.g., ECG) findings detected during the study or present at screening and that worsen significantly during the study must be reported as an AE as explained below. Clinically significant abnormal laboratory values ​​that occur during a clinical trial will be followed until repeat tests return to normal, are stable, or are no longer clinically significant. Abnormal test results that are determined to be errors should not be reported as AEs. Laboratory abnormalities or other abnormal clinical findings (e.g., ECG abnormalities) must be reported as AEs if any of the following are true: • When intervention is required as a result of an abnormality; or • If action taken with the test drug is necessary as a result of the abnormality.

[0411] Adverse drug reactions All adverse and unintended reactions to a study drug, regardless of dose, must be considered an adverse reaction. A "response" to a study drug means that there is at least a reasonable possibility of a causal relationship between the study drug and the AE, i.e., the relationship cannot be excluded.

[0412] Unexpected drug side effects An unexpected adverse drug reaction is defined as an adverse reaction whose nature or severity is inconsistent with the applicable product information.

[0413] Assessment of adverse events The severity (intensity) of each AE will be rated as mild, moderate, or severe, and each AE will be classified with respect to its potential relationship to study drug using the categories "yes" or "no."

[0414] Rating severity Mild - an event that is easily tolerated and generally does not interfere with normal daily activities. Moderate - an event that is sufficiently annoying to interfere with normal daily activities. Severe - an event that prevents you from working or carrying out normal daily activities.

[0415] Causal assessment The relationship of AEs to administration of study drug will be assessed according to the following definitions: No (not related, possibly unlikely related) – The time lapse between administration of study drug and the onset or worsening of the AE rules out a causal relationship and another cause (e.g., concomitant medication, treatment, comorbidity) is suspected. Yes (possibly, probably, or definitely related) - The time course from administration of study drug to the onset or worsening of the AE is consistent with a causal relationship and no other causes (e.g., concomitant medications, treatments, comorbid conditions) can be identified.

[0416] This definition means that there is a reasonable possibility of a causal relationship between the event and the study drug. This means that there is fact (evidence) or argument that suggests a causal relationship.

[0417] The following factors must also be taken into account: Time sequence of study drug administration. The event must occur after administration of the study drug. The length of time between exposure to the study drug and the occurrence of the event must be evaluated according to the clinical context of the event. Underlying, concomitant, and intercurrent diseases. Each report should be evaluated taking into account the original medical history and course of the disease being treated and any other diseases the patient may have. Concomitant medications. Other drugs the patient is taking or treatments the patient is receiving should be examined to determine whether any of these could be perceived as causing the event in question. • The known response pattern of this class of test agent. Clinical and / or preclinical data may indicate whether a particular response is likely to be a class effect. Exposure to physical and / or mental stress. Exposure to stress may induce adverse changes in the recipient, providing a logical and more appropriate explanation for the events. • Pharmacology and PK of the study drug. The known pharmacological properties of the study drug (absorption, distribution, metabolism, and excretion) must be considered.

[0418] Adverse events of particular interest Each patient will be monitored for clinical and laboratory evidence of predefined adverse events of interest (AESIs) throughout the patient's participation in this study.

[0419] Any additional information regarding the AESI will be evaluated in detail.

[0420] For this study, the AESI includes: • Hypotensive events requiring clinical intervention; sodium levels requiring clinical intervention; or • Potassium levels requiring clinical intervention.

[0421] AESIs must be recorded.

[0422] (iii) Serious adverse events An AE or adverse reaction is considered serious if it results in any of the following: ●Death; Life-threatening AEs. An AE or adverse event is considered "life-threatening" if it occurs and puts the patient at immediate risk of death. This does not include events that may have caused death if they occurred in a more severe form. Requiring hospitalization or extension of existing hospitalization: Any hospital admission with at least an overnight stay is considered inpatient hospitalization. Emergency room or urgent care visits without hospitalization are not recorded as SAEs under this criterion, nor are admissions for procedures scheduled or planned before the signing of informed consent or for elective treatment of pre-existing conditions that did not worsen from baseline. However, unanticipated complications occurring during elective surgery and / or prolonged hospitalization must be recorded as AEs and assessed for severity. Hospitalizations for social or situational reasons (e.g., no place to stay, living too far away to travel to hospital, respite care, etc.) are not considered inpatient admissions; • Persistent or significant impairment / inability, or substantial impairment in the ability to perform normal life functions; Birth abnormality / birth defect; or ● Major Medical Events. A major medical event that does not meet any of the above criteria may be considered an SAE if, based on sound medical judgment, it is likely to endanger the patient and may require medical or surgical intervention to prevent one of the above outcomes. Examples of such medical events include allergic bronchospasm requiring intensive care in an emergency room or at home, blood disorders, or convulsions that do not result in hospitalization as an inpatient or the development of a drug dependency.

[0423] (iv) Reports of overdosage An overdose refers to the administration of an amount of study drug given in a single dose or cumulatively (either accidentally or intentionally) that exceeds the maximum recommended dose recommended according to the clinical trial protocol.

[0424] In the case of inconsistencies in drug tolerability, an overdose can only be established if it is known or suspected that the patient has taken an extra dose.

[0425] (v) Safety monitoring and management of potassium levels Serum potassium levels will be monitored systematically throughout the study. Potassium will be measured in a central laboratory at each visit as described in Table 17. Unscheduled evaluations of potassium levels should be completed as needed for the acute management of the patient (e.g., follow-up following elevated central laboratory potassium, acute change in clinical status, suspected dehydration, etc.).

[0426] If serum potassium is ≧5.5 mEq / L and <6 mEq / L, patients must immediately present to the clinical site for retesting, but may continue receiving study medication.

[0427] If serum potassium is ≥ 6 mEq / L, patients should discontinue study medication and immediately present to the clinical site for retesting.

[0428] (vi) Clinical laboratory evaluation Blood samples for standard safety chemistry panel, hematology, and coagulation will be collected and evaluated as shown in Table 17. PD samples will be collected and evaluated as shown in Table 17. PK samples will be collected and evaluated as shown in Table 17. For a complete list of specimens, see Table 18.

[0429] As shown in Table 17, serum or POC pregnancy tests are performed on female patients of childbearing potential.

[0430] Urine specimens (including 24-hour specimens) will be collected as shown in Table 17 and evaluated at a central laboratory according to institutional guidelines for complete urinalysis.

[0431] Blood samples for pharmacogenomic evaluation will be stored and analyzed at Cincinnati Children's Hospital Medical Center.

[0432] Screening laboratory evaluations, if abnormal, may be repeated once for eligibility purposes.

[0433] (vii) Vital signs and blood pressure measurement Vital signs include heart rate, respiratory rate, and temperature. Orthostatic vitals include orthostatic BP and orthostatic heart rate. Vital signs and BP will be measured at the time of visit using the following standardized procedures, as shown in Table 17: • Patients should not exercise, smoke, or consume caffeinated beverages or foods 30 minutes prior to assessment of vital signs and AOBPM; • At visits when study medication is administered, vital signs and BP are assessed prior to administration; Vital signs and BP measurements must be obtained prior to ECG recording; and When measuring BP by AOBPM, the following additional standardized procedures are recommended: o The patient must be seated in the examination room for at least 5 minutes with their back supported, feet flat on the floor, and the measuring arm supported so that the midpoint of the manometer cuff is at heart level; o Designated AOBPM equipment must be provided to each clinical site and used for all study-related measurements; o An appropriately sized cuff must be used to ensure that the bladder is centered over the brachial artery; o The size of the cuff and the arm used for the measurement must be recorded; o The arm with the higher mean BP value at screening should be used for screening and subsequent BP measurements; o All BP measurements should be obtained at approximately the same time that screening measurements are obtained. Three sitting BP measurements, with each measurement taken 1-2 minutes apart, must be obtained using the same arm and AOBPM device at each clinical visit. Mean sitting BP is defined as the average of the three sitting BP measurements during any single clinical visit. If the difference between the lowest and highest SBP measurements is >15 mmHg apart, an additional reading should be taken; and Once sitting BP has been determined, ask the patient to stand and measure orthostatic BP and heart rate once after 60 seconds, if desired.

[0434] (viii) Electrocardiogram Standard 12-lead ECGs will be performed as described in Table 17 at Visits 1, 4, and 11. ECGs will be performed after the patient has rested in the supine position for at least 10 minutes. The 12-lead ECG will be printed and interpreted as soon as possible. All ECGs collected at randomization, end of treatment, and early discontinuation visits must be evaluated for the presence of abnormalities. Standard ECG parameters will be measured and the following ECG parameters will be recorded: ●QRS interval; ●Heart rate; ●RR interval; QT interval; and ●QTc (QTcF).

[0435] Clinically meaningful changes from baseline electrocardiogram include, but are not limited to, the following: ●QTcF ≥ 450 ms (male); ●QTcF ≥ 470 ms (female); QTcF increase from baseline of >60 ms; or • QTcF increase ≥ 6% from baseline. New onset findings include, but are not limited to: • Second-degree atrioventricular (AV) block (Mobitz type II); • Third degree atrioventricular block (complete heart block); ● Acute myocardial infarction; • New left bundle branch block; • Severe bradycardia (ventricular rate ≤ 40 bpm); • Supraventricular tachycardia (ventricular rate ≥ 150 bpm); ● Torsades de pointes; • Ventricular tachycardia (≥3 beats regardless of rate); Ventricular fibrillation; or ●Atrial fibrillation / atrial flutter (ventricular rate ≥ 150 bpm).

[0436] (ix) Physical examination A complete physical examination, including evaluation of general appearance, skin, head, eyes, ears, mouth, oropharynx, neck, heart, lungs, abdomen, extremities, and neuromuscular system, will be performed at Visits 1 and 11 as shown in Table 17.

[0437] A limited physical examination will consist minimally of general appearance, skin, heart, lungs, and abdomen and will be performed at another clinical visit.

[0438] (x) Height and weight Weight will be measured at the visits indicated in Table 17. Height measured at Visit 1 will be used to calculate BMI at subsequent visits. Patients will have their shoes removed and height will be measured. Weight will be measured after the patient has removed their shoes and the patient's bladder has been emptied.

[0439] statistics (i) Analysis population Intent to Treat Population (ITT): The ITT population includes all patients randomized into the study. Treatment classification is based on randomized treatment.

[0440] Modified Intent to Treat Population (mITT): The mITT population includes all patients in the ITT population who received at least one dose of any study drug and have a baseline SBP assessment. Efficacy measures obtained after patients received restricted BP-altering therapy, outside the scope of the current study design, are omitted from the mITT analysis. Treatment classification is based on randomized treatment. The mITT population will be used for the primary analysis of all efficacy endpoints.

[0441] Per Protocol Population (PP): The PP population includes all patients in the mITT population who have a baseline SBP assessment, an end-of-treatment visit (Visit 11) SBP assessment, and have not experienced any significant protocol deviations that could impact the primary efficacy endpoint. The PP population, along with reasons for exclusions, will be finalized prior to unblinding of the study.

[0442] Safety Analysis Set: The safety analysis set will include all patients who receive at least one dose of any randomized study drug. Treatment classification will be based on the actual treatment received. The safety analysis set will be the primary population used for safety analysis.

[0443] Pharmacokinetic Population: The PK population includes all patients in the mITT population with at least one quantifiable plasma concentration.

[0444] Pharmacodynamics Population: The PD population includes all patients in the mITT population with at least one quantifiable concentration of the PD variable.

[0445] (ii) Statistical methods All data collected in the study will be summarized by treatment group using descriptive statistics, graphs, and / or raw data listings. Descriptive statistics for continuous variables will include number of patients (n), mean, standard deviation (SD), median, minimum, and maximum. Analysis of categorical variables will include frequency and percentages.

[0446] Efficacy Analysis The PP population will be the primary population for efficacy analyses. Efficacy will be analyzed using the ITT and mITT populations as supportive analyses.

[0447] The primary efficacy analysis will compare the change in mean seated SBP from baseline (Visit 4) to the end of treatment (Visit 11) between each dose strength of (R)-Compound 1 and placebo. A repeated measures mixed model will be used to perform this analysis. The analysis will include fixed effects for treatment, visit, and treatment-by-visit interactions, along with baseline value covariates. A restricted maximum likelihood estimation approach will be used with an unstructured covariance matrix. Least squares means, standard errors, and two-sided 95% confidence intervals will be provided for pairwise comparisons of each dose strength of (R)-Compound 1 to each treatment and placebo group. To protect the overall alpha level of the primary endpoint, hypothesis testing will be performed sequentially. The first comparison will be between the highest active treatment arm and placebo at the two-sided alpha = 0.05 level; if significant, the next highest active treatment arm will be compared to placebo at the two-sided alpha = 0.05 level. Hypothesis testing will proceed in this step-down fashion until the comparison is no longer significant. At that point, all remaining consecutive tests are considered to be non-significant.

[0448] Missing data will be imputed using multiple imputation methods, and results will be fitted using the method of Rubin.

[0449] Similar models will be used to analyze DBP and PD variables. Logistic regression analysis will be used to analyze binary endpoints using model covariates of treatment group, baseline SBP, and baseline DBP. No adjustment for multiplicity will be made when testing secondary efficacy endpoints.

[0450] Safety Analysis: The safety analysis set will be the primary population for the safety analysis. All safety endpoints will be summarized narratively.

[0451] Pharmacokinetic analysis Individual plasma concentration data for (R)-Compound 1 and any measured metabolites will be listed and summarized by visit, time point, and treatment group for the PK population.

[0452] For patients enrolled in Part B of the study, relevant parameters for (R)-Compound 1 and any measured metabolites will be listed for each individual patient and summarized by treatment for active treatment. Mean and individual plasma concentrations of (R)-Compound 1 and any measured metabolites will be plotted against time points for each patient's regimen in Part B.

[0453] Pharmacodynamic Analysis: The PD population will be the primary population for the PD analysis. All PD variables will be summarized descriptively.

[0454] Pharmacokinetic-pharmacodynamic analyses: When data permit, attempts will be made to correlate plasma concentrations and parameters with safety, PD, and / or efficacy measures.

[0455] Interim Analysis: A formal open-label interim analysis may be performed based on prior review of safety data.

[0456] (iii) Determining sample size Part A A sample size of at least 308 evaluable patients (i.e., 77 patients per treatment group) will provide >80% power to detect a difference of 5 mmHg in mean sitting SBP (SD = 11 mmHg) after 12 weeks of treatment with three dose strengths of (R)-Compound 1 compared with placebo at a two-sided significance level of 0.05.

[0457] The sample size for this study was determined to provide sufficient power for the analysis of the primary efficacy endpoints described above. Thus, assuming an approximate 13% dropout rate, the study is planned to enroll approximately 348 patients (i.e., 87 patients per treatment group).

[0458] Patients were randomized to receive randomized controlled trials based on baseline SBP (<145 or ≥145 mmHg) and baseline glomerular filtration rate (<60 or ≥60 mL / min / 1.73 m 2 ) are used to organize the hierarchy.

[0459] Part B Approximately 10-15% of patients are expected to participate in this optional substudy. The sample size was chosen empirically, without formal statistical considerations, to support the stated objectives. The proposed sample size is believed to be adequate to characterize the PK of (R)-Compound 1 in patients with rHTN.

[0460] Example 8 Test Objectives: The objectives of this study were to: To evaluate the effect of Compound 1 on the pharmacokinetics (PK) of immediate release metformin; and To evaluate the safety and tolerability of co-administration of Compound 1 and metformin compared with metformin alone.

[0461] Methodology: This was a randomized, open-label, two-period, crossover, Phase 1 study to evaluate the effect of Compound 1 on the PK of metformin and the safety and tolerability of coadministration of Compound 1 and metformin compared to metformin alone. A maximum of 32 subjects were to be enrolled in the study, with the intention that a minimum of 24 subjects would complete both treatment periods. Subjects were randomly assigned to one of the following two treatment sequences (AB or BA) on Day 1 of Treatment Period 1: Treatment A: A single 1000 mg dose of immediate-release metformin; and ● Treatment B: A single 1000 mg dose of immediate release metformin co-administered with a 10 mg dose of Compound 1.

[0462] NOTE: Metformin was administered 2 hours after administration of a single 10 mg dose of Compound 1.

[0463] Subjects received study medication on the morning of day 1 of each treatment period.

[0464] For each subject, the study consisted of: ● A screening period of up to 26 days; Two 4-day hospitalization periods (from check-in to completion of treatment), each consisting of a single dose of study drug (metformin alone or coadministered with Compound 1) followed by 3 days of PK sampling; and • Follow-up call 3 days (± 1 day) after completion of treatment period 2.

[0465] There was a minimum of 10 days washout between administration of study drug in each treatment period. Subjects were confined from check-in the day before dosing of each treatment period until collection of the final PK sample in each treatment period.

[0466] Safety was assessed throughout the study based on adverse events (AEs), physical examination, weight measurements, electrocardiogram (ECG), vital signs assessments (sitting and orthostatic), and clinical laboratory evaluations.

[0467] Subjects with clinically significant abnormal laboratory findings, unresolved treatment-emergent AEs (TEAEs), serious AEs (SAEs) requiring follow-up laboratory and review, and clinically significant AEs may require unscheduled procedures or visits, and / or additional follow-up.

[0468] Duration of treatment: There were two 4-day hospitalization periods (from check-in to completion of treatment), each consisting of a single dose of study medication (metformin alone or coadministered with Compound 1). There was a minimum of 10 days of washout between doses of study medication during each treatment period.

[0469] Number of subjects: Plan: Up to 32 planned subjects Screening: 51 screened subjects Randomization: 27 randomized subjects Completed: 26 completed subjects Discontinuation: 1 subject discontinued the study

[0470] Diagnostic and main criteria for inclusion: The population for this study was a body mass index (BMI) between 18 and 30 kg / m 2 Healthy subjects are included who are 18 to 55 years of age (inclusive); in good health based on medical / surgical and psychiatric history, physical examination, ECG, vital signs (sitting and orthostatic), and routine laboratory tests (serum chemistry, hematology, and urinalysis); have normal renal function; and are non-smokers.

[0471] Investigational and comparator information: Compound 1 was supplied as a 5 mg oral tablet. Immediate release metformin was obtained from a commercial supplier as a 500 mg oral tablet.

[0472] Evaluation criteria: Pharmacokinetics: The following plasma PK parameters were determined for Compound 1 and its primary metabolites (Compound 1-Metabolites): The maximum observed plasma concentration (C max ); If the maximum occurs at multiple time points, C is defined as the first time point with the maximum value. max Time to max ); The apparent terminal first-order elimination rate constant (λ) calculated from a semi-log plot of the plasma concentration versus time curve, calculated by linear least-squares (LS) regression analysis using the terminal log-linear phase points. z ); Area under the concentration-time curve (AUC) from 0 to 24 hours (AUC 0-24 ); • AUC from time 0 to 72 hours; AUC from time 0 to the time of the last quantifiable plasma concentration (AUC 0-t ) + last quantifiable plasma concentration (C last ) / λ z The AUC from time 0 to infinity, calculated as AUC 0-inf ) (compound 1 only); and ●(1-AUC 0-t / AUC 0-inf ) × 100, and the extrapolated AUC 0-inf Percentage of (AUC %extrap ) (Compound 1 only).

[0473] For metformin, the following plasma PK parameters were determined: Determined directly from the concentration-time profile, C max ; If the maximum occurs at multiple time points, T is defined as the first time point with the maximum value. max ; λ, calculated by linear LS regression analysis using the terminal log-linear phase points z ; ●AUC 0-24 ; ●AUC 0-t ; ●(AUC0-t +C last / λ z ), the AUC 0-inf ; ●(1-AUC 0-t / AUC 0-inf ) × 100, AUC%, extrap and ●ln(2) / λ z Terminal phase elimination half-life, calculated as:

[0474] For metformin, the following urinary PK parameters were determined: • The cumulative amount of metformin excreted in urine (cumulative amount of drug excreted in urine [Ae]); Renal clearance, calculated as Ae / AUC; and • The fraction of the dose excreted via the kidney, calculated as 100 × Ae / dose.

[0475] Safety: The following safety assessments were performed: ●AE and SAE; ● Clinical laboratory test evaluation; • Vital signs including heart rate, blood pressure (BP) (including orthostatic BP if indicated), respiratory rate, and temperature; ●12-lead ECG: ●Physical examination; and ●Height, weight, and BMI.

[0476] Statistical method: Analysis population: The safety analysis population consisted of all randomized subjects who received any study medication (Compound 1 or metformin).

[0477] The PK population included all subjects who received any study drug (Compound 1 or metformin) and had at least one quantifiable post-dose plasma concentration of Compound 1, metformin, or any measured metabolite.

[0478] The PK-evaluable population included all subjects who received any study drug (Compound 1 or metformin) and had sufficient plasma concentration data to characterize at least one PK parameter of Compound 1, metformin, or any measured metabolite.

[0479] Pharmacokinetic Analysis: Plasma concentrations of Compound 1, its primary metabolites (Compound 1-metabolites), and metformin were listed for each individual subject and summarized by treatment using descriptive statistics of the PK-evaluable population. Plasma concentrations of Compound 1, Compound 1-metabolites, and metformin were plotted against time points by treatment (mean and individual). Mean concentrations were plotted against nominal sampling times and individual concentrations were plotted against actual sampling times.

[0480] Urinary concentrations of metformin were listed by individual subject and summarized by treatment using descriptive statistics for the PK-evaluable population. Plots of Ae by time point and treatment (individual and mean) are also presented.

[0481] Plasma and urinary PK parameters were determined using noncompartmental methods as appropriate. Parameters were listed by individual subject and summarized by treatment using descriptive statistics of the PK population.

[0482] Log-transformed metformin PK parameters were analyzed using a mixed model with sequence, treatment group, and period terms as fixed effects, and subject nested within sequence as the randomization effect.

[0483] PK parameter analysis was based on the PK population.

[0484] Safety: Safety analyses were performed throughout the study based on the safety analysis set. Safety was assessed through evaluation of AEs, physical examinations, ECGs, weight measurements, vital signs assessments (sitting and orthostatic), and clinical laboratory evaluations.

[0485] TEAEs were summarized by ICH System Organ Class (SOC) and Preferred Term (PT) for each treatment and overall.

[0486] The safety analysis set was used for all safety analyses. The following AEs were summarized in each section: • An overall summary of TEAEs by treatment and overall, broken down by AE severity (worst case); • TEAEs by treatment-specific SOC and PT; • TEAEs by treatment-specific SOC, PT, and relationship to study drug or metformin; TEAEs by treatment-specific SOC, PT, and severity (worst case); and - TEAEs by treatment-specific SOC, PT, severity (worst case), and relationship to study drug.

[0487] Separate lists were prepared for SAEs, AEs leading to death, and AEs leading to study discontinuation.

[0488] Safety laboratory values ​​and changes from baseline were summarized narratively by treatment group at each time point of collection, as appropriate. Laboratory test results were provided with shift tables indicating shifts outside of normal ranges. All safety laboratory data were provided in data listings.

[0489] Pregnancy test results, drug and alcohol test results, and viral serology results were listed.

[0490] Vital signs; continuous ECG parameters; height, weight, and BMI values, as well as changes from baseline, were summarized descriptively by treatment group at each time point of collection. All data were tabulated.

[0491] Physical examination results by body system were summarized by treatment group at each time point of collection, and findings were tabulated.

[0492] Summary of results: Pharmacokinetics: The plasma concentration-time curves for metformin were nearly identical in the presence and absence of Compound 1. See Figures 13 and 14.

[0493] Metformin plasma C max , AUC 0-inf , and AUC 0-t The ratios of treatment B:treatment A geometric LS means for all approached 100% with 90% confidence interval values ​​falling within the acceptable range of 80% to 125%, indicating that systemic exposure to metformin was not affected by compound 1.

[0494] Consistent with the observed lack of effect of Compound 1, urinary excretion of metformin was qualitatively and quantitatively similar in the presence and absence of Compound 1.

[0495] Safety: Safety results from this study showed that metformin was well tolerated when administered alone or 2 hours after a single 10 mg dose of Compound 1. There were no deaths, SAEs, or discontinuations due to TEAEs, and there was no notable increase in the incidence of AEs when metformin and Compound 1 were coadministered versus metformin administered alone. All TEAEs experienced by subjects were mild in severity. As expected with a single high dose of metformin, the most frequent TEAEs were gastrointestinal-related. There were no trends or clinically meaningful changes in laboratory parameters or physical examination results. There were no clinically significant changes observed in vital signs or 12-lead ECG findings (including no meaningful changes in QTcF).

[0496] Conclusion: Metformin was well tolerated when administered alone or 2 hours after administration of Compound 1. Compound 1 did not result in increased metformin plasma concentrations or decreased metformin renal clearance when compared to administration of metformin alone. Based on the results from this study, no dose adjustment of metformin is believed to be necessary when it is co-administered with Compound 1.

[0497] This was a randomized, open-label, two-period, crossover, Phase 1 study to evaluate the effect of Compound 1 on the PK of metformin and the safety and tolerability of coadministration of Compound 1 and metformin compared to metformin alone. A maximum of 32 subjects were to be enrolled in the study, with the intention that a minimum of 24 subjects would complete both treatment periods. Subjects were randomly assigned to one of the following two treatment sequences (AB or BA) on Day 1 of Treatment Period 1: Treatment A: A single 1000 mg dose of immediate-release metformin; and Treatment B: A single 1000 mg dose of immediate release metformin co-administered with a 10 mg dose of Compound 1.

[0498] NOTE: Metformin was administered 2 hours after administration of a single 10 mg dose of Compound 1.

[0499] Subjects received study medication on the morning of day 1 of each treatment period.

[0500] For each subject, the study consisted of the following: · Screening period of up to 26 days; Two 4-day hospital stays (from check-in to completion of treatment), each consisting of a single dose of study drug (metformin alone or coadministered with Compound 1) followed by 3 days of PK sampling; and Follow-up call 3 days (± 1 day) after completion of treatment period 2.

[0501] There was a minimum of 10 days washout between administration of study drug in each treatment period. Subjects were confined from check-in the day before dosing of each treatment period until collection of the final PK sample in each treatment period.

[0502] Safety was assessed throughout the study based on AEs, physical examination, weight measurements, ECG, vital signs assessments (sitting and orthostatic), and clinical laboratory evaluations.

[0503] Subjects with clinically significant abnormal laboratory findings, unresolved TEAEs, SAEs requiring follow-up laboratory and review, and clinically significant AEs may require unscheduled procedures or visits, and / or additional follow-up.

[0504] Selection of study population Inclusion criteria Subjects were eligible to participate in the study if they met all of the following criteria based on the results of screening and check-in (Treatment Period 1): 1. Healthy subjects aged 18-55 years (inclusive) at screening; 2. Body mass index (BMI) between 18 and 30 kg / m 2 (inclusive); 3. Good health based on medical / surgical and psychiatric history, physical examination, ECG, vital signs (sitting and orthostatic), and routine laboratory tests (serum chemistry, hematology, and urinalysis); 4. Estimated glomerular filtration rate ≥ 85 mL / min / 1.73 m at screening and day -1 2 normal renal function, defined as; 5. Non-smokers who had not used nicotine-containing products (i.e., cigarettes, nicotine patches, nicotine chewing gum, or e-cigarettes) for at least 6 months prior to the screening visit; 6. Male subjects with female partners of childbearing potential had to agree to use two medically accepted highly effective methods of contraception for 90 days beginning on Day 1 after the last dose of study drug (per Section 5.6.2 of the Clinical Trial Protocol [Appendix 16.1.1]); 7. Male subjects had to agree to refrain from sperm donation for 90 days starting from day 1 after the last dose of study drug; 8. Female subjects with male partners had to be surgically sterilized (hysterectomy and / or bilateral oophorectomy), be postmenopausal for at least 1 year (follicle-stimulating hormone in the postmenopausal range), or agree to use two medically accepted highly effective methods of contraception from Day -14 to Day 60 after the last dose of study drug (per Section 5.6.2 of the Clinical Trial Protocol [Appendix 16.1.1]); and 9. Understood and were willing and able to comply with the study procedures and restrictions (including confinement to the study facility, fasting and dietary restrictions, and restrictions on physical activity, recreational drug or alcohol use, and medications) and provided written informed consent in accordance with institutional and regulatory guidelines.

[0505] Exclusion criteria Subjects who met any of the following criteria based on the screening and check-in results were excluded from participating in the study: 1. Actively participating in an experimental treatment trial; had received experimental treatment with a small molecule other than Compound 1 within 30 days or 5 half-lives of the first dose of the study drug, whichever is longer, or experimental treatment with a larger molecule within 90 days or 5 half-lives of the first dose of the study drug, whichever is longer; 2. Had a personal or family history of long QT syndrome, Torsades de Pointes, other complex ventricular arrhythmias, or sudden death; 3. Had a history of or had current clinically significant arrhythmias, including ventricular tachycardia, ventricular fibrillation, atrial fibrillation, sinus node dysfunction, or clinically significant heart block, as determined by the investigator. Subjects with mild ectopic symptoms (e.g., atrial premature beats) were not necessarily excluded; 4. Had QTcF prolongation (>450 ms); 5. Sitting systolic blood pressure (BP) >140mmHg and / or diastolic BP >90mmHg, or systolic BP <90mmHg and / or diastolic BP <50mmHg; 6. Resting heart rate >100 or <50 bpm; 7. Oral temperature >37.6°C (99.68°F) or respiratory rate <12 breaths / min or >20 breaths / min; 8. Had postural tachycardia (i.e., >30 bpm on standing) or orthostatic hypotension (i.e., a decrease in systolic BP ≥20 mmHg or diastolic BP ≥10 mmHg on standing); 9. Had serum potassium > upper limit of normal (ULN) and serum sodium < lower limit of normal; 10. Had aspartate aminotransferase, alanine aminotransferase, or total bilirubin levels >1.2 × ULN; 11. Tested positive for human immunodeficiency virus antibody, hepatitis C virus antibody, hepatitis B surface antigen, or SARS-CoV-2 RNA; 12. Had any other laboratory value that, in the opinion of the investigator, was significantly above the normal range (based on normal ranges for the laboratory test); 13. Had a known history of porphyria, myopathy, or active liver disease; 14. Evidence or history of any clinically significant immune, hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, musculoskeletal, hepatic, psychiatric, neurological, or allergic disease (including clinically significant or multiple drug allergies); surgical condition; cancer (except basal or squamous cell carcinoma of the skin and cancers that have been cured or in remission for ≥5 years prior to screening); or any condition that, in the opinion of the investigator, may confound the study procedures or results, affect the subject's safety, or interfere with the absorption, distribution, metabolism, or excretion of the study drug (appendectomy is permitted, but cholecystectomy is prohibited); 15. Had evidence or history of acute or chronic metabolic acidosis, including diabetic ketoacidosis; 16. Had any previous episode of lactic acidosis; 17. Had undergone radiological scan with contrast within 14 days prior to the first dose of study drug; 18. Has used any prescription or over-the-counter medication, including topical medications (excluding occasional use of acetaminophen or nonsteroidal anti-inflammatory drugs such as ibuprofen or naproxen, according to the package insert); herbal supplements; dietary supplements; or functional foods within 14 days or 5 half-lives prior to the first dose of study drug, whichever is longer, or has not intended to refrain from these medications until discharge from the study site; Note: Use of over-the-counter topical medications may be permitted in consultation with the study sponsor. In addition, use of medications with a 5-fold half-life of more than 14 days had to be discussed and approved by the study sponsor prior to subject enrollment. 19. Use of corticosteroids (systemic or widespread topical use) within 3 months (90 days) prior to the first dose of study drug; 20.Has a positive drug or alcohol test result at screening or check-in, or a history of alcoholism or drug abuse within 2 years prior to the first dose of study medication, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; 21. Had a typical intake of ≥ 14 alcoholic drinks per week; Note: One drink of alcohol was equivalent to half a pint of beer (285 mL), one glass of spirits (25 mL), or one glass of wine (125 mL); 22. Have a history or evidence of illegal drug use within the past two years; 23. Had a surgical procedure (excluding minor cosmetic surgery or minor dental procedures) within 4 weeks prior to check-in or had elective surgery planned during the treatment period; 24. Had any illness within 4 weeks prior to check-in unless the investigator judged it to be not clinically significant; 25. Had known allergies to any component of Compound 1 or metformin; 26. Had any history of severe allergic reactions (including to drugs, food, insect stings, or environmental allergens); 27. Had inadequate venous access; 28.Currently receiving weight loss medication or have previously undergone weight loss surgery (e.g. gastric bypass surgery); 29. Pregnant, breastfeeding, or planning to become pregnant during the study; or 30. Deemed unsuitable by the investigator, after review of medical and psychiatric history, physical examination, and clinical laboratory evaluation, for any other reason that may endanger the subject during participation or interfere with the interpretation of the study results.

[0506] Exclusion of a subject from treatment or evaluation A subject may be discontinued from this study for any of the following reasons: The subject withdraws consent or requests to discontinue the study for any reason; The occurrence of any medical condition or circumstance which places the subject at significant risk and / or prevents the subject from complying with the requirements of the clinical trial protocol; Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent illness, or other medical condition indicated to the sponsor that continued participation is not in the patient's best interest; ·pregnancy; · the need for prohibited concomitant medications (after consultation with the sponsor); A subject who does not comply with protocol requirements or study-related procedures; or Termination of a trial by a sponsor or regulatory authority.

[0507] treatment Treatment given Each subject received each treatment once during the study. All subjects were randomly assigned once during each period to receive one of the following: Treatment A: A single 1000 mg dose of immediate-release metformin; or Treatment B: A single 1000 mg dose of immediate release metformin co-administered with a 10 mg dose of Compound 1.

[0508] NOTE: Metformin was administered 2 hours after administration of a single 10 mg dose of Compound 1.

[0509] Identification of investigational drug Compound 1 tablets were provided in 5 mg strength and packaged in high density polyethylene bottles. Compound 1 tablets contained the test drug as the active ingredient and the following inactive ingredients: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.

[0510] Immediate release metformin (500 mg) was obtained from a commercial supplier.

[0511] How subjects are assigned to treatment groups Subjects were randomly assigned to one of two treatment sequences (AB or BA) on Day 1 of Treatment Period 1 according to a pre-generated randomization scheme:

[0512] Dose Selection for the Study Data from previously completed SAD and MAD studies suggest that therapeutic doses of compound 1 ≤ 10 mg are expected in the intended patient population. Results of nonclinical evaluations indicated that compound 1 is an inhibitor of the renal transporters MATE-1 and MATE2-K (in a time-independent manner). As such, consistent with Food and Drug Administration (FDA) guidance for evaluating drug interactions, a single 10 mg dose of compound 1 was evaluated in this study to maximize the likelihood of detecting interactions. See US Department of Health and Human Services · Food and Drug Administration · Center for Drug Evaluation and Research (CDER). Clinical Drug Interaction Testing - Cytochrome P450 Enzyme and Transporter-Mediated Drug Interactions - Guidance for Industry (January 2020).

[0513] Metformin is approved for use in doses up to 2550 mg / day, and individual doses of immediate-release metformin typically do not exceed 1000 mg. See Glucophage (metformin hydrochloride) [package insert] Princeton, NJ, Bristol-Myers Squibb Company, May 2018. As such, a 1000 mg dose of immediate-release metformin was used in this study to maximize the likelihood of detecting an interaction.

[0514] The safety and tolerability of these proposed single doses were considered acceptable to be administered to healthy subjects participating in this study, taking into account the described inclusion / exclusion criteria and the specified safety monitoring.

[0515] Choice and timing of dosing for each subject Each subject received each treatment once during the study. All study medications were administered at 8:00 AM (± 2 hours). For Treatment B, to maximize the chance of detecting an interaction, Compound 1 was administered 2 hours (± 2 minutes) before metformin administration to allow sufficient time for tissue distribution of Compound 1. Subjects were required to fast (defined as abstaining from food or drink other than water) for a minimum of 10 hours prior to metformin administration in each treatment period, and then continued to fast for a minimum of 4 hours after each metformin dose. Water was allowed ad libitum for up to 1 hour prior to and 1 hour after administration of Compound 1 and / or metformin. Each dose was administered with approximately 240 mL of water.

[0516] Blinding This was an open-label study and no blinding procedures were required.

[0517] Previous and concomitant therapies Excluded and Restricted Drugs and / or Procedures Subjects were not permitted to take the following medications within 14 days or 5 half-lives, whichever is longer, prior to the first dose of study medication until discharge from the study site: Any prescription medications, including topical medications; Over-the-counter medications (except for occasional use of acetaminophen or nonsteroidal anti-inflammatory drugs such as ibuprofen or naproxen, according to the package insert); · Herbal supplements; dietary supplements; or ·Functional food.

[0518] The use of over-the-counter topical medications may be permitted in consultation with the study sponsor. In addition, the use of medications with a 5-fold half-life of more than 14 days (other than those mentioned above) had to be discussed with and approved by the study sponsor prior to subject enrollment.

[0519] Subjects were not permitted to use corticosteroids (systemic or widespread topical) within 3 months (90 days) prior to the first dose of study drug.

[0520] Subjects were excluded if they had a radiological scan with contrast within 14 days prior to the first dose of study drug. Subjects were excluded if they had a surgical procedure (excluding minor cosmetic or minor dental procedures) within 4 weeks of check-in or if they had elective surgery planned during the treatment period.

[0521] Subjects were excluded if they were currently being treated with weight-loss medication or had previously undergone weight-loss surgery (eg, gastric bypass surgery).

[0522] Subjects who were actively participating in an experimental treatment trial; subjects receiving experimental treatment with a small molecule other than Compound 1 within 30 days or 5 half-lives of the first dose of study drug, whichever is longer, or experimental treatment with a larger molecule within 90 days or 5 half-lives of the first dose of study drug, whichever is longer, were excluded.

[0523] contraception Reproductive potential subjects were required to use two medically approved and highly effective methods of contraception.

[0524] Medically accepted, highly effective methods of contraception for male subjects with female partners of childbearing potential must be used for 90 days beginning on Day 1 after the last dose of study drug and include: · Latex condoms with spermicide; · Use by a partner of a contraceptive diaphragm with intravaginal spermicide; · Use by the partner of a spermicide-containing cervical cap; · Use by the partner of an intrauterine device (hormonal or non-hormonal); Use by a partner of an implanted contraceptive; or · Partner's use of oral contraceptives.

[0525] Medically accepted, highly effective methods of contraception for female subjects with male partners must be used from Day -14 to Day 60 after the last dose of study drug and include: · Contraceptive diaphragms with intravaginal spermicide; · Cervical cap with spermicide; Intrauterine device (for at least 12 weeks prior to the screening visit); or · Use of spermicide-containing latex condoms by your partner.

[0526] Diet and lifestyle considerations Subjects were required to fast (defined as abstaining from any food or drink other than water) for a minimum of 10 hours prior to each metformin dose during each treatment period and then continued to fast for a minimum of 4 hours after each metformin dose. Water was allowed ad libitum up to 1 hour prior to and 1 hour after administration of Compound 1 and / or metformin.

[0527] Subjects had to abstain from the following foods from 1 week prior to the first dose of study medication until discharge for Treatment Period 2: alcohol; caffeine and / or xanthine containing products (i.e., coffee, tea, chocolate, and caffeinated carbonated drinks, cola drinks, energy drinks, etc.); grapefruit and grapefruit products; starfruit and starfruit products; bitter orange; marmalade; cranberry juice; garlic; charbroiled / barbecued meats; broccoli, Brussels sprouts; Hypericum perforatum or any food substance that may inhibit or induce CYPs or drug transporters or affect coagulation; and vitamin water.

[0528] Subjects were required to refrain from contact sports and strenuous exercise from 5 days prior to the first dose of study drug until discharge for Treatment Period 2.

[0529] Documentation of previous and concomitant medication use All medications or supplements taken from 28 days before the first dose of study medication through the follow-up phone call were recorded in the subject's medical record and corresponding eCRF.

[0530] Measurement Appropriateness The PK and safety measures from this study are widely used and recognized to be reliable, accurate, and relevant.

[0531] Pharmacokinetic endpoints: The following plasma PK parameters were determined for Compound 1 and its primary metabolites (Compound 1-Metabolites): Determined directly from the concentration-time profile, C max ; If the maximum occurs at multiple time points, T is defined as the first time point with the maximum value. max ; The apparent terminal first-order elimination rate constant (λ) calculated from a semi-log plot of the plasma concentration versus time curve, calculated by linear least-squares (LS) regression analysis using the points of the terminal log-linear phase z ); AUC from time 0 to 24 hours (AUC0-24 ); · AUC from time 0 to 72 hours; AUC from time 0 to the time of the last quantifiable plasma concentration (AUC 0-t ) + last quantifiable plasma concentration (C last ) / λ z The AUC from time 0 to infinity, calculated as AUC 0-inf ) (Compound 1 only); and (1-AUC 0-t / AUC 0-inf ) × 100, and the extrapolated AUC 0-inf Percentage of (AUC %extrap ) (Compound 1 only).

[0532] For metformin, the following plasma PK parameters were determined: Determined directly from the concentration-time profile, C max ; If the maximum occurs at multiple time points, T is defined as the first time point with the maximum value. max ; · λ, calculated by linear LS regression analysis using the terminal log-linear phase points z ; AUC 0-24 ; AUC 0-t ; (AUC 0-t +C last / λ z ), the AUC 0-inf ; (1-AUC 0-t / AUC 0-inf ) × 100, AUC %extrap and ln(2) / λ z t is calculated as 1 / 2 .

[0533] For metformin, the following urinary PK parameters were determined: · Cumulative amount of metformin excreted in urine (cumulative amount of drug excreted in urine [Ae]); Renal clearance, calculated as Ae / AUC; and · Proportion of dose excreted via the kidney (Fe), calculated as 100 × Ae / dose.

[0534] Safety evaluation items The following safety assessments were performed: ·AE and SAE; · Clinical laboratory test evaluation; · Vital signs, including heart rate, BP (including orthostatic BP if indicated), respiratory rate, and temperature; ·12-lead ECG; · Physical examination; and Height, weight, and BMI.

[0535] Population demographics and baseline characteristics The following demographic and baseline characteristics were listed, summarized by treatment sequence, and summarized overall as descriptive statistics or numbers and percentages for subjects in the safety population and repeated for all other analysis populations if different from the safety population: Age (years); ·sex; Possible pregnancy; F ethnicity (Hispanic or Latino, not Hispanic or Latino, not reported, unknown); Race (Asian, American Indian or Alaska Native, Black or African American, Native Hawaiian or Other Pacific Islander, White, Other); Height (cm); Weight (kg); and BMI (kg / m 2 ).

[0536] Medical and surgical history Medical / surgical history was collected at screening. Medical history was reassessed at check-in for treatment period 1 to confirm eligibility, and any new signs / symptoms were reported as updated medical history. Terms reported in medical history were coded to SOC and PT using the ICH International Medical Terminology (Version 23.1). Medical history by SOC and PT were summarized and tabulated by treatment sequence and across the safety population.

[0537] Previous and concomitant medications Past and concomitant medications were coded using the WHO Drug Dictionary (Version September 2020G B3). All medications or supplements taken from 28 days before the first dose of study medication until the follow-up telephone call were recorded. Past medications were defined as medications (both prescription and over-the-counter) taken before the first dose of study medication. Medications taken at the time of the first dose and afterwards during the study were defined as concomitant medications.

[0538] All prior and concomitant medications were listed and summarized by ATC class, PT, and treatment group for the safety analysis population.

[0539] Study Drug Exposure and Compliance Study drug dosing data were listed by treatment group for all subjects in the safety analysis population.

[0540] Pharmacokinetic analysis Pharmacokinetic sample collection Blood and urine samples were collected to assess PK. All PK time points were relative to the time of metformin administration. However, it should be noted that for Compound 1, the total period of PK sampling after metformin administration was 2 hours longer than the corresponding metformin PK sampling. The ac...

Claims

1. A medicament for treating human hypertension or primary aldosteronism, comprising (R)-Compound 1: 【Chemical Formula 1】 and the human is administered 0.1 to 10 mg / day of (R)-Compound 1.

2. The medicament according to Claim 1, wherein the human has a mean seated blood pressure of ≧130 / 80 mmHg.

3. The medicament according to Claim 1, wherein the human is in a stable background hypertension regimen before administration of the (R)-Compound 1.

4. The medicament according to Claim 3, wherein the stable background hypertension regimen comprises ≧3 antihypertensive agents.

5. The medicament according to Claim 4, wherein one of the antihypertensive agents is a diuretic.

6. The medicament according to Claim 1, wherein administration of the (R)-Compound 1 results in a mean decrease from the baseline in seated systolic blood pressure (SBP) after 4 weeks of treatment.

7. The medicament according to Claim 1, wherein administration of the (R)-Compound 1 results in a mean decrease from the baseline in seated systolic blood pressure (SBP) after 12 weeks of treatment.

8. The medicament according to Claim 1, wherein administration of the (R)-Compound 1 results in a mean decrease in the baseline of seated diastolic blood pressure (DBP) after 4 weeks of treatment.

9. The medicament according to Claim 1, wherein administration of the (R)-Compound 1 results in a mean decrease in the baseline of seated diastolic blood pressure (DBP) after 12 weeks of treatment.

10. The medicament according to Claim 1, wherein administration of the (R)-Compound 1 results in a seated blood pressure (BP) of <130 / 80 mmHg after about 4 weeks of treatment.

11. The pharmaceutical according to claim 1, wherein administration of the (R)-Compound 1 results in a seated blood pressure (BP) of <130 / 80 mmHg after about 12 weeks of treatment.

12. The pharmaceutical according to claim 1, wherein about 0.5 mg / day of (R)-Compound 1 is administered to the human.

13. The pharmaceutical according to claim 1, wherein about 1 mg / day of (R)-Compound 1 is administered to the human.

14. The pharmaceutical according to claim 1, wherein about 2 mg / day of (R)-Compound 1 is administered to the human.

15. The pharmaceutical according to claim 1, wherein about 4 mg / day of (R)-Compound 1 is administered to the human.

16. The pharmaceutical according to claim 1, wherein the amount of (R)-Compound 1 is administered to the human as a single dose.

17. The pharmaceutical according to claim 1, wherein the administration of the (R)-Compound 1 does not result in clinically serious adverse events in the human.

18. The pharmaceutical according to claim 1, wherein the human is at least 18 years old.

19. The pharmaceutical according to claim 1, wherein hypertension is treated.

20. The pharmaceutical according to claim 1, wherein primary aldosteronism is treated.

21. A pharmaceutical composition comprising about 0.1 to about 10 mg of (R)-Compound 1 and a pharmaceutically acceptable excipient.

22. The pharmaceutical composition according to claim 21, comprising about 1 mg of (R)-Compound 1 and a pharmaceutically acceptable excipient.

23. The pharmaceutical composition according to claim 21, comprising about 2 mg of (R)-Compound 1 and a pharmaceutically acceptable excipient.

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