Methods of treating chronic kidney disease (CKD) or CKD and hypertension with luspatercept or a combination of luspatercept and an SGLT2 inhibitor

Abstract

The present invention provides a method for treating a subject with chronic kidney disease (CKD) or CKD and hypertension, the method comprising administering to the subject once daily a certain amount of lorenstat or a pharmaceutically acceptable salt thereof, said amount being effective in treating the subject's CKD or CKD and hypertension.

Description

[0001] This application claims priority to U.S. Provisional Application No. 63 / 513,999, filed July 17, 2023, and U.S. Provisional Application No. 63 / 596,658, filed November 7, 2023, the contents of each of which are incorporated herein by reference.

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

[0003] This invention relates to a method for treating chronic kidney disease. Background Technology

[0004] Chronic kidney disease (CKD) is a condition in which the kidneys’ ability to function properly diminishes over time.

[0005] Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of drugs that work by inhibiting sodium-glucose transporter 2 (SGLT2). SGLT2 is responsible for reabsorbing glucose from the blood filtered by the kidneys. These drugs prevent glucose reabsorption and promote its excretion in the urine by inhibiting SGLT2.

[0006] Studies of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes have investigated the cardiovascular safety of this type of glucose-lowering therapy. Compared with placebo, in addition to reducing the risk of cardiovascular events, SGLT2 inhibitors also reduced the risk of clinically relevant renal outcomes (persistent loss of renal function, decreased eGFR, progression or worsening of albuminuria, novel end-stage renal disease (ESKD), death from renal causes, and / or combined renal outcomes), indicating that SGLT2 inhibitors are significantly associated with a reduced risk of renal function deterioration (Perkovic et al. 2018, Wanner et al. 2016, and Wiviott et al. 2019). However, these studies were not designed to evaluate the treatment benefit in patients with CKD, with only 7%–26% of participants having a flow rate of less than 60 mL / min / 1.73 m 2eGFR. Perkovic, V. et al. (2018), Wanner, C., et al. (2016), and Wiviott, S. et al. (2019). Subsequently, designated renal outcome trials showed that SGLT2 inhibitors reduced the risk of CKD progression in patients with diabetic nephropathy (DKD) using canagliflozin in CREDENCE and DKD, and in patients with non-diabetic CKD using dapagliflozin in DAPA-CKD. Perkovic, V., et al. (2019), and Heerspink, HJ, et al. (2020).

[0007] Aldosterone is the primary mineralocorticoid in humans, produced by aldosterone synthase (CYP 11β2β-hydroxylase) in the zona glomerulosa of the adrenal cortex. Mineralocorticoid receptor blockers (MRAs), such as spironolactone and eplerenone, prevent aldosterone from binding to mineralocorticoid receptors. Mineralocorticoid receptor antagonists (MRAs) are drugs that antagonize the action of aldosterone at mineralocorticoid receptors. The FIDELIO-DKD trial evaluated the long-term effects of the MRA fenelone on renal and cardiovascular outcomes and reported a reduced risk of CKD progression in patients with DKD (Bakris et al., 2020). Fenelone, a selective oral nonsteroidal MRA, reduces the risk of CKD progression and cardiovascular events in patients with CKD and T2DM (Bakris et al., 2020). However, the increased incidence of hyperkalemia and the potential decline in renal function are concerns associated with long-term use of MRAs for CKD.

[0008] However, previous studies have shown that some of the effects of aldosterone may be independent of the regulatory activation of the mineralocorticoid receptor / classical steroid receptor complex (Grossmann, C., & Gekle, M., 2009; Good, DW, 2007; Mihailidou, AS, & Funder, JW, 2005). Furthermore, the mineralocorticoid receptor is not selective for aldosterone; instead, it has similar affinity for glucocorticoid receptors such as cortisol and corticosterone, as well as androgen and progesterone receptors.

[0009] The treatment of chronic kidney disease needs to be improved. Summary of the Invention

[0010] The present invention provides a method for treating CKD in a subject suffering from chronic kidney disease (CKD), the method comprising administering to the subject once daily a certain amount of lorenstat or a pharmaceutically acceptable salt thereof, wherein the amount is effective in treating the subject's CKD.

[0011] The present invention also provides a method for treating CKD in a subject suffering from chronic kidney disease (CKD), the method comprising: (a) Identification of the subject as suffering from: (i) CKD, in the following situations: when taking a stable dose of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB), preferably the maximum tolerated dose of ACEi or ARB: 1. The urinary albumin to creatinine ratio (UACR) in the 24-hour urine or the first morning urine is 200-3500 mg / g or 200-5000 mg / g; and / or 2. When taking the maximum tolerated dose of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs), the estimated glomerular filtration rate (eGFR) should be at least 30 mL / min / 1.73 mcg. 2 Or at least 45 mL / min / 1.73m 2 And preferably less than 90 mL / min / 1.73m 2 ;or (ii) Mild to moderate CKD, when taking a stable dose of ACEi or ARB, preferably the maximum tolerated dose of ACEi or ARB: 1. Albuminuria is present, characterized by a UACR of 300-3500 mg / g in the 24-hour urine or the first morning urine; and 2. Estimate the glomerular filtration rate (eGFR) to be at least 45 mL / min / 1.73m 2 And less than 90 mL / min / 1.73m 2 ;or (iii) Moderate to severe CKD, in the following situations: when taking a stable dose of ACEi or ARB, preferably the maximum tolerated dose of ACEi or ARB: 1. Albuminuria is present, characterized by a UACR of 300-3500 mg / g in the 24-hour urine or the first morning urine; and 2. Estimate the glomerular filtration rate (eGFR) to be at least 30 mL / min / 1.73m 2 And less than 45 mL / min / 1.73m 2 ;as well as (b) Administer an effective amount of lorenstat or a pharmaceutically acceptable salt thereof to the subject once daily, wherein the amount is effective in treating the subject's CKD.

[0012] The present invention also provides a method for treating hypertension in a subject suffering from hypertension and CKD, the method comprising: (a) identifying the subject as suffering from: (i) Hypertension, preferably, with systolic blood pressure between 135 and 180 mmHg (including extreme values). (ii) CKD, characterized by one of the following: 1. CKD, in the following situations: when taking a stable dose of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB), preferably the maximum tolerated dose of ACEi or ARB: a. The urinary albumin to creatinine ratio (UACR) in the 24-hour urine or the first morning urine is 200-3500 mg / g or 200-5000 mg / g; and / or b. When taking the maximum tolerated dose of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs), the estimated glomerular filtration rate (eGFR) should be at least 30 mL / min / 1.73 mcg. 2 Or at least 45 mL / min / 1.73m 2 And preferably less than 90 mL / min / 1.73m 2 ;or 2. Mild to moderate CKD, when taken at a stable dose of ACE inhibitor or ARB, preferably at the maximum tolerated dose of ACE inhibitor or ARB: a. Albuminuria is present, with a UACR of 300-3500 mg / g in the 24-hour urine or the first morning urine; and b. Estimate the glomerular filtration rate (eGFR) to be at least 45 mL / min / 1.73 m 2 And less than 90 mL / min / 1.73m 2 ;or 3. Moderate to severe CKD, in the following situations: when taking a stable dose of ACE inhibitor or ARB, preferably the maximum tolerated dose of ACE inhibitor or ARB: a. Albuminuria is present, with a UACR of 300-3500 mg / g in the 24-hour urine or the first morning urine; and b. Estimate the glomerular filtration rate (eGFR) to be at least 30 mL / min / 1.73 m 2 And less than 45 mL / min / 1.73m 2 ;as well as (b) Administer to the subject once daily an effective amount of lorenstat or a pharmaceutically acceptable salt thereof, wherein the amount is effective in treating the subject’s hypertension.

[0013] The present invention also provides a method for identifying a subject treated with lorenstat or a pharmaceutically acceptable salt thereof, the method comprising: (a) Measure the urinary albumin to creatinine ratio (UACR) and / or estimate the glomerular filtration rate (eGFR) of the subject in the 24-hour urine or first morning urine. (b) Subjects with the following conditions while taking the maximum tolerated dose of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) were selected: (i) Chronic kidney disease (CKD), characterized by: 1. The urinary albumin to creatinine ratio (UACR) in the 24-hour urine or the first morning urine is 200-3500 mg / g or 200-5000 mg / g; and / or 2. Estimate the glomerular filtration rate (eGFR) to be at least 30 mL / min / 1.73m 2 Or at least 45 mL / min / 1.73m 2 And preferably less than 90 mL / min / 1.73m 2 ; (ii) Mild to moderate CKD, characterized by: 1. Albuminuria is present; the urinary albumin-to-creatinine ratio (UACR) in the 24-hour urine or the first morning urine is 300-3500 mg / g; and 2. Estimate the glomerular filtration rate (eGFR) to be at least 45 mL / min / 1.73m 2 And less than 90 mL / min / 1.73m 2 ;or (iii) Moderate to severe CKD, characterized by: 1. Albuminuria is present; the urinary albumin-to-creatinine ratio (UACR) in the 24-hour urine or the first morning urine is 300-3500 mg / g; and 2. Estimate the glomerular filtration rate (eGFR) to be at least 30 mL / min / 1.73m 2 And less than 45 mL / min / 1.73m 2 ; This allows for the identification of the subjects treated with lorenstat or its pharmaceutically acceptable salts.

[0014] The present invention also provides a method for identifying a subject treated with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and lorensta or a pharmaceutically acceptable salt thereof, the method comprising: (a) Measure the urinary albumin to creatinine ratio (UACR) and / or estimate the glomerular filtration rate (eGFR) of the subject in the 24-hour urine or first morning urine. (b) Subjects with the following conditions while taking the maximum tolerated dose of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) were selected: (i) Chronic kidney disease (CKD), characterized by: 1. The urinary albumin to creatinine ratio (UACR) in the 24-hour urine or the first morning urine is 200-3500 mg / g or 200-5000 mg / g; and / or 2. Estimate the glomerular filtration rate (eGFR) to be at least 30 mL / min / 1.73m 2 Or at least 45 mL / min / 1.73m 2 And preferably less than 90 mL / min / 1.73m 2 ; (ii) Chronic kidney disease (CKD), characterized by: 1. The urinary albumin to creatinine ratio (UACR) in 24-hour urine or the first morning urine is 200-3500 mg / g; and / or 2. Estimate the glomerular filtration rate (eGFR) to be at least 45 mL / min / 1.73m 2 And less than 90 mL / min / 1.73m 2 ; (iii) Mild to moderate CKD, characterized by: 1. Albuminuria is present; the urinary albumin-to-creatinine ratio (UACR) in the 24-hour urine or the first morning urine is 300-3500 mg / g; and 2. Estimate the glomerular filtration rate (eGFR) to be at least 45 mL / min / 1.73m 2 And less than 90 mL / min / 1.73m 2 ;or (iv) Moderate to severe CKD, characterized by: 1. Albuminuria is present; the urinary albumin-to-creatinine ratio (UACR) in the 24-hour urine or the first morning urine is 300-3500 mg / g; and 2. Estimate the glomerular filtration rate (eGFR) to be at least 30 mL / min / 1.73m 2 And less than 45 mL / min / 1.73m 2 ; This allows for the identification of subjects treated with sodium-glucose cotransporter 2 (SGLT2) inhibitors and lorensta or pharmaceutically acceptable salts thereof.

[0015] The present invention also provides lorensta or a pharmaceutically acceptable salt thereof for the treatment of CKD in subjects with chronic kidney disease (CKD), wherein the use is in combination with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and optionally an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), preferably wherein the SGLT2 inhibitor is dapagliflozin.

[0016] The present invention also provides the use of lorensta or a pharmaceutically acceptable salt thereof for the treatment of CKD in a subject with chronic kidney disease (CKD) in combination with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and optionally an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), wherein preferably the SGLT2 inhibitor is dapagliflozin.

[0017] The present invention also provides lorensta or a pharmaceutically acceptable salt thereof for the treatment of CKD in subjects with chronic kidney disease (CKD), wherein the use is in combination with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and optionally an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), preferably wherein the SGLT2 inhibitor is dapagliflozin.

[0018] The present invention also provides the use of lorensta or a pharmaceutically acceptable salt thereof for the treatment of CKD in a subject with chronic kidney disease (CKD) in combination with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and optionally an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), wherein preferably the SGLT2 inhibitor is dapagliflozin.

[0019] The present invention also provides a package comprising: (a) A first pharmaceutical composition comprising a certain amount of lorenstat or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; (b) A second pharmaceutical composition comprising a certain amount of sodium-glucose cotransporter 2 (SGLT2) inhibitor; (c) Optionally, a third pharmaceutical composition comprising an angiotensin-converting enzyme inhibitor (ACEi); and (d) Optionally, a fourth pharmaceutical composition comprising an angiotensin receptor blocker (ARB). (e) Instructions for use for the treatment of a subject with CKD or CKD and hypertension together with the first pharmaceutical composition, the second pharmaceutical composition, the third pharmaceutical composition, and the fourth pharmaceutical composition (if present).

[0020] The present invention also provides a package comprising: (a) A first pharmaceutical composition comprising a quantity of lorenstat or a pharmaceutically acceptable salt thereof, a quantity of a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and a pharmaceutically acceptable carrier; and (b) Optionally, a second pharmaceutical composition comprising an amount of an angiotensin-converting enzyme inhibitor (ACEi) and / or an angiotensin receptor blocker (ARB) and a pharmaceutically acceptable carrier. (c) Instructions for use of the pharmaceutical composition for the treatment of subjects with chronic kidney disease (CKD) or CKD and hypertension.

[0021] The present invention also provides a pharmaceutical composition comprising: (a) A certain amount of lorenstat or its pharmaceutically acceptable salt; (b) A certain amount of sodium-glucose cotransporter 2 (SGLT2) inhibitor or a pharmaceutically acceptable salt thereof; (c) Optionally, a certain amount of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) or a pharmaceutically acceptable salt thereof. The lorensta or its pharmaceutically acceptable salts, SGLT2 inhibitors and ACEi or ARB (if present) are administered simultaneously, concurrently or concurrently.

[0022] The present invention also provides a pharmaceutical composition comprising a certain amount of lorenstat or a pharmaceutically acceptable salt thereof, said lorenstat or a pharmaceutically acceptable salt thereof for use in combination with a certain amount of sodium-glucose cotransporter 2 (SGLT2) inhibitor and optionally a certain amount of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) for the treatment of a subject with chronic kidney disease (CKD) or CKD and hypertension.

[0023] The present invention also provides a unit dosage form of pharmaceutical composition for treating subjects with chronic kidney disease (CKD) or CKD and hypertension, the pharmaceutical composition comprising: (a) A certain amount of lorenstat or its pharmaceutically acceptable salt; (b) A certain amount of a sodium-glucose cotransporter 2 (SGLT2) inhibitor or a pharmaceutically acceptable salt thereof; and (c) Optionally, a certain amount of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) or a pharmaceutically acceptable salt thereof. The appropriate amounts of the lorensta or its pharmaceutically acceptable salt, the SGLT2 inhibitor, and the ACEi or ARB (if present) in the composition are effective in treating the subject when the composition in one or more of the unit dosage forms is administered concurrently.

[0024] The present invention also provides a therapeutic package for distribution to a subject suffering from chronic kidney disease (CKD) or CKD and hypertension, or for use in a subject suffering from chronic kidney disease (CKD) or CKD and hypertension, the therapeutic package comprising: (a) One or more unit doses, each such unit dose comprising: (i) A certain amount of lorenstat or a pharmaceutically acceptable salt thereof; (ii) a certain amount of a sodium-glucose cotransporter 2 (SGLT2) inhibitor or a pharmaceutically acceptable salt thereof; and (iii) Optionally, a certain amount of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) or a pharmaceutically acceptable salt thereof. The corresponding amount of the lorensta or its pharmaceutically acceptable salt, the SGLT2 inhibitor, and the ACEi or ARB (if present) in the unit dose are effective in treating the subject's CKD or CKD and hypertension when administered concomitantly. (b) A refined drug container for the treatment package, the container containing the one or more unit doses, the container also containing or including a label instructing the use of the package to treat the subject. Attached Figure Description

[0025] Figure 1 Estimates of the time when different doses of lorundrostat hydrobromide (HBr) exceed IC50 based on PKPD modeling from the SAD study.

[0026] Figure 2 Research process. Abbreviations: OLE, Open Tag Extensions; QD, Once a Day. Detailed Implementation

[0027] method The present invention provides a method for treating CKD in a subject suffering from chronic kidney disease (CKD), the method comprising administering to the subject once daily a certain amount of lorenstat or a pharmaceutically acceptable salt thereof, wherein the amount is effective in treating the subject's CKD.

[0028] The present invention provides a method for treating hypertension in a subject suffering from hypertension and CKD, the method comprising administering to the subject once daily a certain amount of lorenstat or a pharmaceutically acceptable salt thereof, wherein the amount is effective in treating the subject's hypertension.

[0029] The present invention also provides a method for treating CKD in a subject suffering from chronic kidney disease (CKD), the method comprising: (a) Identification of the subject as suffering from: (i) CKD, under the following conditions: with a stable dose of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB), preferably the maximum tolerated dose of ACEi or ARB: 1. The urinary albumin to creatinine ratio (UACR) in the 24-hour urine or the first morning urine is 200-3500 mg / g or 200-5000 mg / g; and / or 2. Estimate the glomerular filtration rate (eGFR) to be at least 30 mL / min / 1.73m 2 Or at least 45 mL / min / 1.73m 2 And preferably less than 90 mL / min / 1.73m 2 ; (ii) Mild to moderate CKD, when taking a stable dose of ACEi or ARB, preferably the maximum tolerated dose of ACEi or ARB: 1. Albuminuria is present; the albuminuria reflux rate (UACR) in the 24-hour urine or the first morning urine is 300-3500 mg / g; and 2. Estimate the glomerular filtration rate (eGFR) to be at least 30 mL / min / 1.73m 2 Or at least 45 mL / min / 1.73m 2 And preferably less than 90 mL / min / 1.73m 2 ;or (iii) Moderate to severe CKD, in the following situations: when taking a stable dose of ACEi or ARB, preferably the maximum tolerated dose of ACEi or ARB: 1. Albuminuria is present, with a UACR of 300-3500 mg / g in the 24-hour urine or the first morning urine; and 2. Estimate the glomerular filtration rate (eGFR) to be at least 30 mL / min / 1.73m 2 And less than 45 mL / min / 1.73m 2 ;as well as (b) Administer an effective amount of lorenstat or a pharmaceutically acceptable salt thereof to the subject once daily, wherein the amount is effective in treating the subject's CKD.

[0030] In one implementation of the method described above, step (a) includes identifying the subject: (a) Suffering from hypertension, preferably with a systolic blood pressure between 135 and 180 mmHg (inclusive). (b) Does not have type 1 diabetes; (c) Serum cortisol levels in the morning were between 3 µg / dL and 22 µg / dL; (d) Has 18-40 kg / m 2 Body Mass Index (BMI); (e) serum potassium levels less than 4.8 mmol / L; and / or (f) having a serum sodium level greater than 135 mmol / L, preferably wherein the serum sodium measurement result needs to be corrected if hyperglycemia is present.

[0031] The present invention also provides a method for treating hypertension in subjects suffering from hypertension and CKD, the method comprising: (a) Identification of the subject as suffering from: (i) Hypertension, preferably, with systolic blood pressure between 135 and 180 mmHg (including extreme values). (ii) CKD, which occurs in one of the following situations: 1. CKD, in the following situations: when taking a stable dose of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB), preferably the maximum tolerated dose of ACEi or ARB: a. The urinary albumin to creatinine ratio (UACR) in the 24-hour urine or the first morning urine is 200-3500 mg / g or 200-5000 mg / g; and / or b. When taking the maximum tolerated dose of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs), the estimated glomerular filtration rate (eGFR) should be at least 30 mL / min / 1.73 mcg. 2 Or at least 45 mL / min / 1.73m 2 And preferably less than 90 mL / min / 1.73m 2 ;or 2. Mild to moderate CKD, when taken at a stable dose of ACE inhibitor or ARB, preferably at the maximum tolerated dose of ACE inhibitor or ARB: a. Presence of albuminuria, characterized by an albumin creatinine reflux rate (UACR) of 300-3500 mg / g in the 24-hour urine or the first morning urine; and b. Estimate the glomerular filtration rate (eGFR) to be at least 45 mL / min / 1.73 m 2 And less than 90 mL / min / 1.73m 2 ;or 3. Moderate to severe CKD, in the following situations: when taking a stable dose of ACE inhibitor or ARB, preferably the maximum tolerated dose of ACE inhibitor or ARB: a. Presence of albuminuria, characterized by an albumin creatinine reflux rate (UACR) of 300-3500 mg / g in the 24-hour urine or the first morning urine; and b. Estimate the glomerular filtration rate (eGFR) to be at least 30 mL / min / 1.73 m 2 And less than 45 mL / min / 1.73m 2 ;as well as (b) Administer to the subject once daily an effective amount of lorenstat or a pharmaceutically acceptable salt thereof, wherein the amount is effective in treating the subject’s hypertension.

[0032] In an embodiment of the present invention, the subject suffering from CKD is being treated with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs).

[0033] In an embodiment of the invention, the subject suffering from CKD is being treated with the maximum tolerated dose of ACEi or ARB.

[0034] In an embodiment of the present invention: (a) When administered with the ACEi or ARB or a pharmaceutically acceptable salt thereof, the amount of the ACEi or ARB is lower than the amount at which the ACEi or ARB inhibitor is effective in treating CKD when administered alone. (b) When administered with lorenlstat or a pharmaceutically acceptable salt thereof, the amount of the ACEi or ARB is lower than the amount at which the ACEi or ARB would be effective in treating CKD when administered without lorenlstat or a pharmaceutically acceptable salt thereof; and / or (c) When administered without the use of the ACEi or ARB or a pharmaceutically acceptable salt thereof, the amount of the ACEi or ARB that is effective in treating CKD in the subject causes one or more side effects, wherein the one or more side effects are not caused by the amount of the ACEi or ARB and the ACEi or ARB that is effective in treating CKD when administered together.

[0035] In embodiments of the invention, when administered in combination with the ACEi or ARB, the amount of lorensta or a pharmaceutically acceptable salt thereof is more effective in treating the subject than when the same amount of each agent is administered alone.

[0036] In an embodiment of the present invention, the amount of lorenstat or a pharmaceutically acceptable salt thereof is: (a) 10-15 mg daily, preferably 12.5 mg daily; (b) 20-30 mg daily, preferably 25 mg daily; or (c) 40-60 mg daily, preferably 50 mg daily.

[0037] In an embodiment of the invention, the lorenstat or a pharmaceutically acceptable salt thereof is administered in the morning.

[0038] In an embodiment of the invention, the lorensta or a pharmaceutically acceptable salt thereof is administered daily: (a) lasting at least one week; (b) lasting at least two weeks; (c) lasting at least four weeks; (d) lasting at least eight weeks; or (e) lasting at least 12 weeks.

[0039] In an embodiment of the invention, the lorenstat or a pharmaceutically acceptable salt thereof is lorenstat hydrobromide.

[0040] In an embodiment of the invention, the method further comprises administering a sodium-glucose cotransporter 2 (SGLT2) inhibitor to the subject once daily, wherein the amount of the SGLT2 inhibitor taken together with the amount of lorenstastat or a pharmaceutically acceptable salt thereof is sufficient to treat the subject's CKD.

[0041] In embodiments of the invention, the SGLT2 inhibitor and lorensta or a pharmaceutically acceptable salt thereof are administered as a combination pharmaceutical composition.

[0042] In embodiments of the present invention, the SGLT2 inhibitor and lorensta or a pharmaceutically acceptable salt thereof are administered simultaneously, concurrently, or concurrently.

[0043] In an embodiment of the present invention, the subject suffering from CKD is being treated with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs).

[0044] In an embodiment of the invention, the subject suffering from CKD is being treated with the maximum tolerated dose of ACEi or ARB.

[0045] In an embodiment of the present invention: (a) When administered with the SGLT2 inhibitor and lorensta or a pharmaceutically acceptable salt thereof, the amount of the ACEi or ARB is lower than the amount at which the ACEi or ARB inhibitor is effective in treating CKD when administered alone. (b) When administered with the SGLT2 inhibitor and lorenstat or a pharmaceutically acceptable salt thereof, the amount of the ACEi or ARB is lower than the amount at which the ACEi or ARB is effective in treating CKD when administered without the SGLT2 inhibitor and / or lorenstat or a pharmaceutically acceptable salt thereof; and / or (c) When administered without the SGLT2 inhibitor and / or lorenstat or a pharmaceutically acceptable salt thereof, the amount of the ACEi or ARB that is effective in treating CKD causes one or more side effects in the subject, wherein the one or more side effects are not caused by the amount of the ACEi or ARB, SGLT2 inhibitor and lorenstat or a pharmaceutically acceptable salt thereof that is effective in treating CKD when administered together.

[0046] In an embodiment of the present invention: (a) When taken together, the amounts of the SGLT2 inhibitor and lorensta or their pharmaceutically acceptable salts are effective in achieving greater than the sum of their therapeutic outcomes in the subjects; (b) The amount of the SGLT2 inhibitor is lower than the amount at which the SGLT2 inhibitor is effective in treating CKD when administered alone; (c) The amount of lorenstat or a pharmaceutically acceptable salt thereof is lower than the amount at which lorenstat or a pharmaceutically acceptable salt thereof is effective in treating CKD when administered alone; (d) The amount of the SGLT2 inhibitor is lower than the amount at which the SGLT2 inhibitor is effective in treating CKD when administered without the use of lorenstat or its pharmaceutically acceptable salts; and / or (e) When administered without the use of lorenlstat or a pharmaceutically acceptable salt thereof, the amount of the SGLT2 inhibitor that is effective in treating CKD in the subject causes one or more side effects, wherein the one or more side effects are not caused by the amount of the SGLT2 inhibitor and lorenlstat or a pharmaceutically acceptable salt thereof that are effective in treating CKD when administered together.

[0047] In embodiments of the invention, when administered together, the amount of the SGLT2 inhibitor and the amount of lorensta or a pharmaceutically acceptable salt thereof are more effective in treating the subject than when the same amount of each agent is administered alone.

[0048] In an embodiment of the present invention, the SGLT2 inhibitor is selected from: dapagliflozin, empagliflozin, ioggliflozin, luggliflozin, canagliflozin, etoragliflozin, and betagliflozin.

[0049] In an embodiment of the present invention, the SGLT2 inhibitor is dapagliflozin.

[0050] In an embodiment of the present invention, the amount of dapagliflozin is 8-12 mg per day, preferably 10 mg per day.

[0051] In an embodiment of the invention, the SGLT2 inhibitor and the lorenstat or a pharmaceutically acceptable salt thereof are administered in the morning.

[0052] In embodiments of the present invention, the SGLT2 inhibitor and the lorensta or a pharmaceutically acceptable salt thereof: (a) Apply daily for at least one week; (b) Apply daily for at least two weeks; (c) Apply daily for at least four weeks; or (d) Apply daily for at least eight weeks.

[0053] In embodiments of the present invention, the method is effective: (a) Treating the subject's proteinuria, preferably, wherein the method is effective in treating the subject's albuminuria; and / or (b) Slow the progression of kidney disease.

[0054] In an embodiment of the present invention: (a) The urinary albumin to creatinine ratio (UACR) of the subject’s 24-hour urine or first morning urine was lower than the UACR of the subject’s 24-hour urine or first morning urine before the subject received the lorensta or its pharmaceutically acceptable salt and SGLT2 inhibitor (as administered); (b) The subject’s 24-hour total urinary albumin (TUA) was reduced relative to the subject’s TUA prior to administration of the lorensta or its pharmaceutically acceptable salts and SGLT2 inhibitors (as administered); (c) The subject's 24-hour urinary protein to creatinine ratio (UPCR) was lower than the subject's UPCR prior to administration of the lorenstat or its pharmaceutically acceptable salts and SGLT2 inhibitors (as administered); and / or (d) The subject’s 24-hour urinary protein was lower than the subject’s 24-hour urinary protein before receiving the lorensta or its pharmaceutically acceptable salt and SGLT2 inhibitor (as administered).

[0055] In an embodiment of the present invention: (a) The urinary albumin to creatinine ratio (UACR) of the subject's 24-hour urine or first morning urine was reduced by at least 30%, at least 40%, between 30% and 70%, between 30% and 60%, between 30% and 50%, between 40% and 80%, between 40% and 70%, and between 40% and 60%; (b) The subject’s 24-hour total urinary albumin (TUA) was reduced by at least 30%, at least 40%, between 30% and 70%, between 30% and 60%, between 30% and 50%, between 40% and 80%, between 40% and 70%, and between 40% and 60% compared to the subject’s TUA prior to administration of the lorensta or its pharmaceutically acceptable salts and SGLT2 inhibitors (as administered). (c) The subject's 24-hour urine protein to creatinine ratio (UPCR) was reduced by at least 30%, at least 40%, between 30% and 70%, between 30% and 60%, between 30% and 50%, between 40% and 80%, between 40% and 70%, between 40% and 60%; and / or (d) The subject’s 24-hour urinary protein was reduced by at least 30%, at least 40%, between 30% and 70%, between 30% and 60%, between 30% and 50%, between 40% and 80%, between 40% and 70%, and between 40% and 60% compared to the 24-hour urinary protein of the subject before the subject received the lorenstat or its pharmaceutically acceptable salt and SGLT2 inhibitor (as administered).

[0056] In an embodiment of the invention, the subject's aldosterone levels follow a substantially normal circadian rhythm.

[0057] In an embodiment of the present invention: (a) The duration for which the amount of lorenstat or a pharmaceutically acceptable salt thereof inhibits CYP 11β2β hydroxylase activity is sufficient to maintain the subject’s sodium and volume depletion state; (b) The method does not produce persistent hyperkalemia or mild non-anion gap metabolic acidosis in the subjects; (c) The lorenstat or a pharmaceutically acceptable salt thereof does not substantially accumulate in the subject, preferably, wherein the lorenstat or a pharmaceutically acceptable salt thereof does not substantially accumulate in the subject such that the subject's aldosterone level returns to the pre-administration baseline within 24-48 hours of administration of the lorenstat or a pharmaceutically acceptable salt thereof, more preferably, within 16-24 hours of administration of the lorenstat or a pharmaceutically acceptable salt thereof; (d) The subject's potassium level is generally maintained within the clinically normal range; preferably, the subject's potassium level is slightly elevated relative to the subject's potassium level prior to administration of the lorenstat or its pharmaceutically acceptable salt; more preferably, the subject's potassium level is elevated by 0.35 mmol / L or less; more preferably, the subject's potassium level is maintained below 5.5 mmol / L; even more preferably, the subject's potassium level is maintained between 3.5 mEq / L and 5.1 mEq / L; and / or (e) The lorensta or its pharmaceutically acceptable salt is administered to the subject in the following amounts: (i) Inhibit the production of aldosterone in the subjects; (ii) Increase the serum and / or plasma potassium levels of the subjects; and / or (iii) Increase the plasma renin activity (PRA) of the subject; Preferably, wherein: (i) The subject’s serum and / or plasma aldosterone AUC-24 was reduced by at least 25% relative to the subject’s aldosterone levels prior to administration of the lorensta or its pharmaceutically acceptable salts; (ii) The subject's serum and / or plasma potassium levels increased by at least 0.2 mMol / L relative to the subject's serum and / or plasma potassium levels prior to administration of the lorenstat or its pharmaceutically acceptable salts; and / or (iii) The subject’s PRA increased by at least 5 ng / ml / hr relative to the subject’s PRA prior to administration of the lorensta or its pharmaceutically acceptable salt.

[0058] In an embodiment of the present invention, the subject suffers from CKD, which has one or more or all of the following characteristics: (a) The urinary albumin to creatinine ratio (UACR) in 24-hour urine or first morning urine is 200-3500 mg / g or 200-5000 mg / g; (b) Estimate the glomerular filtration rate (eGFR) to be at least 25 mL / min / 1.73 m 2 Preferably at least 30 mL / min / 1.73m 2 More preferably at least 30 mL / min / 1.73m 2 And less than 90 mL / min / 1.73m 2 ; (c) Nephropathy; (d) Proteinuria, such as albuminuria; (e) Abnormal urine sediment; (f) Abnormalities, such as electrolyte abnormalities due to renal tubular disease; (g) Abnormalities detected by histology; and (h) Structural anomalies detected by imaging.

[0059] In an embodiment of the present invention, the subject suffers from mild to moderate CKD, characterized by the following: (a) eGFR is at least 45 mL / min / 1.73 m 2 And less than 90 mL / min / 1.73 m 2 ;as well as (b) Presence of albuminuria, with a UACR of ≥300 mg / g to 3500 mg / g.

[0060] In an embodiment of the present invention, the subject suffers from moderate to severe CKD, characterized by the following: (a) eGFR is at least 30 mL / min / 1.73 m 2 And less than 45 mL / min / 1.73 m 2 ;as well as (b) Presence of albuminuria, with a UACR of ≥300 mg / g to 3500 mg / g.

[0061] In an embodiment of the invention, the subject also suffers from hypertension, preferably, wherein the subject has a systolic blood pressure of at least 120 mmHg and a systolic blood pressure of at least 80 mmHg, more preferably, wherein the subject has a systolic blood pressure between 135 and 180 mmHg (inclusive).

[0062] In embodiments of the present invention, the method is effective: (a) A reduction in the subject's systolic blood pressure by at least 10 mmHg, 10-55 mmHg, 10-50 mmHg, 10-45 mmHg, 10-40 mmHg, 10-35 mmHg, 10-30 mmHg, 10-25 mmHg, 10-20 mmHg, or 10-15 mmHg relative to the subject's systolic blood pressure prior to a period of at least eight weeks of administration of the SGLT2 inhibitor and lorenlustat or a pharmaceutically acceptable salt thereof; and / or (b) The subject’s diastolic blood pressure was reduced by at least 5 mmHg, 5-25 mmHg, 5-20 mmHg or 5-15 mmHg relative to the subject’s diastolic blood pressure prior to the administration of the SGLT2 inhibitor and lorensta or a pharmaceutically acceptable salt thereof for at least eight weeks. (c) Reduce the subject’s mean systolic blood pressure during sleep relative to the following: (i) The average systolic blood pressure during sleep prior to the subject’s administration of the SGLT2 inhibitor and lorensta or a pharmaceutically acceptable salt thereof for at least eight weeks; (ii) the subject's average systolic blood pressure during sleep prior to a period of at least eight weeks of continuous administration of the lorenstat or its pharmaceutically acceptable salts; and / or (iii) The mean daytime systolic blood pressure of the subjects; (d) The subject’s average sleep-time systolic blood pressure was reduced by at least 10%, between 10% and 40%, between 10% and 30%, or between 10% and 20% relative to the subject’s average daytime systolic blood pressure; (e) A reduction in the subject's mean sleep-time systolic blood pressure relative to the subject's mean sleep-time systolic blood pressure prior to a period of at least eight weeks prior to receiving the SGLT2 inhibitor and lorenstat or a pharmaceutically acceptable salt thereof, by at least 8 mmHg, at least 10 mmHg, between 8 mmHg and 55 mmHg, between 10 mmHg and 45 mmHg, or between 10 mmHg and 25 mmHg; and / or (f) The subject’s mean sleep-time systolic blood pressure was reduced by at least 8 mmHg, at least 10 mmHg, between 8 mmHg and 55 mmHg, between 10 mmHg and 45 mmHg, or between 10 mmHg and 25 mmHg relative to the subject’s mean sleep-time systolic blood pressure prior to the period of at least eight weeks of receiving lorensta or a pharmaceutically acceptable salt thereof.

[0063] In embodiments of the invention, when administered with the ACEi or ARB or a pharmaceutically acceptable salt thereof, the amount of the ACEi or ARB inhibitor is lower than the amount at which the ACEi or ARB inhibitor is effective in treating CKD and / or hypertension when administered alone.

[0064] In embodiments of the invention, the amount of the ACEi or ARB when administered with lorenlstat or a pharmaceutically acceptable salt thereof is lower than the amount at which the ACEi or ARB is effective in treating CKD and / or hypertension when administered without lorenlstat or a pharmaceutically acceptable salt thereof; and / or In an embodiment of the invention, when administered without the use of the ACEi or ARB or a pharmaceutically acceptable salt thereof, an amount of the ACEi or ARB that is effective in treating CKD and / or hypertension causes one or more side effects in the subject, wherein the one or more side effects are not caused by the amount of the ACEi or ARB and the ACEi or ARB and the ACEi or ARB that is effective in treating CKD and / or hypertension when administered together.

[0065] In embodiments of the invention, when administered in combination with the ACEi or ARB, the amount of lorensta or a pharmaceutically acceptable salt thereof is more effective in treating the subject’s CKD and / or hypertension than when the same amount of each agent is administered alone.

[0066] In an embodiment of the present invention, the subject also suffers from type 2 diabetes (T2DM).

[0067] In an embodiment of the present invention, the subject: (a) Does not have type 2 diabetes (T2DM); and / or (b) Does not have type 1 diabetes.

[0068] In an embodiment of the present invention, the subject did not suffer from primary aldosteronism.

[0069] The present invention also provides a method for identifying a subject treated with lorenstat or a pharmaceutically acceptable salt thereof, the method comprising: (a) Measure the urinary albumin to creatinine ratio (UACR) and / or estimate the glomerular filtration rate (eGFR) of the subject in the 24-hour urine or first morning urine. (b) Select subjects who, when taking the maximum tolerated dose of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs), have the following characteristics: (i) Chronic kidney disease (CKD), characterized by: 1. The urinary albumin to creatinine ratio (UACR) in the 24-hour urine or the first morning urine is 200-3500 mg / g or 200-5000 mg / g; and / or 2. Estimate the glomerular filtration rate (eGFR) to be at least 30 mL / min / 1.73m 2 Or at least 45 mL / min / 1.73m 2 And preferably less than 90 mL / min / 1.73m 2 ; (ii) Mild to moderate CKD, characterized by: 1. Albuminuria is present; the urinary albumin-to-creatinine ratio (UACR) in the 24-hour urine or the first morning urine is 300-3500 mg / g; and 2. Estimate the glomerular filtration rate (eGFR) to be at least 45 mL / min / 1.73m 2 And less than 90 mL / min / 1.73m 2 ;or (iii) Moderate to severe CKD, characterized by: 1. Albuminuria is present; the urinary albumin-to-creatinine ratio (UACR) in the 24-hour urine or the first morning urine is 300-3500 mg / g; and 2. Estimate the glomerular filtration rate (eGFR) to be at least 30 mL / min / 1.73m 2 And less than 45 mL / min / 1.73m 2 ; This allows for the identification of the subjects treated with lorenstat or its pharmaceutically acceptable salts.

[0070] In one implementation, step (a) further includes measuring the subject's systolic blood pressure and step (b) further includes selecting subjects with hypertension, preferably characterized by a systolic blood pressure of 135-180 mmHg.

[0071] In an embodiment of the invention, the subject treated with the following methods is identified: (a) 10-15 mg of lorenstat or a pharmaceutically acceptable salt thereof daily, preferably 12.5 mg of lorenstat or a pharmaceutically acceptable salt thereof daily; (b) 20-30 mg of lorenstat or a pharmaceutically acceptable salt thereof daily, preferably 25 mg of lorenstat or a pharmaceutically acceptable salt thereof daily; or (c) 40-60 mg of lorenstat or a pharmaceutically acceptable salt thereof daily, preferably 50 mg of lorenstat or a pharmaceutically acceptable salt thereof daily.

[0072] The present invention also provides a method for identifying a subject treated with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and lorensta or a pharmaceutically acceptable salt thereof, the method comprising: (a) Measure the urinary albumin to creatinine ratio (UACR) and / or estimate the glomerular filtration rate (eGFR) of the subject in the 24-hour urine or first morning urine. (b) Select subjects who, when taking the maximum tolerated dose of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs), have the following characteristics: (i) Chronic kidney disease (CKD), characterized by: 1. The urinary albumin to creatinine ratio (UACR) in the 24-hour urine or the first morning urine is 200-3500 mg / g or 200-5000 mg / g; and / or 2. Estimate the glomerular filtration rate (eGFR) to be at least 30 mL / min / 1.73m 2 Or at least 45 mL / min / 1.73m 2 And preferably less than 90 mL / min / 1.73m 2 ; (ii) Mild to moderate CKD, characterized by: 1. Albuminuria is present; the urinary albumin-to-creatinine ratio (UACR) in the 24-hour urine or the first morning urine is 300-3500 mg / g; and 2. Estimate the glomerular filtration rate (eGFR) to be at least 45 mL / min / 1.73m 2 And less than 90 mL / min / 1.73m 2 ;or (iii) Moderate to severe CKD, characterized by: 1. Albuminuria is present; the urinary albumin-to-creatinine ratio (UACR) in the 24-hour urine or the first morning urine is 300-3500 mg / g; and 2. Estimate the glomerular filtration rate (eGFR) to be at least 30 mL / min / 1.73m 2 And less than 45 mL / min / 1.73m 2 ; This allows for the identification of subjects treated with sodium-glucose cotransporter 2 (SGLT2) inhibitors and lorensta or pharmaceutically acceptable salts thereof.

[0073] In an embodiment of the present invention, the SGLT2 inhibitor is selected from: dapagliflozin, empagliflozin, ioggliflozin, luggliflozin, canagliflozin, etoragliflozin, and betagliflozin.

[0074] In an embodiment of the present invention, the SGLT2 inhibitor is dapagliflozin.

[0075] In an embodiment of the invention, the subject treated with the following methods is identified: (a) 10-15 mg of lorenstat or a pharmaceutically acceptable salt thereof daily, preferably 12.5 mg of lorenstat or a pharmaceutically acceptable salt thereof daily and 8-12 mg of dapagliflozin daily, preferably 10 mg of dapagliflozin daily; (b) 20-30 mg of lorenstat or a pharmaceutically acceptable salt thereof daily, preferably 25 mg of lorenstat or a pharmaceutically acceptable salt thereof daily, and 8-12 mg of dapagliflozin daily, preferably 10 mg of dapagliflozin daily; or (c) 40-60 mg of lorenstat or a pharmaceutically acceptable salt thereof daily, preferably 50 mg of lorenstat or a pharmaceutically acceptable salt thereof daily and 8-12 mg of dapagliflozin daily, preferably 10 mg of dapagliflozin daily.

[0076] In an embodiment of the invention, the lorenstat or a pharmaceutically acceptable salt thereof is lorenstat hydrobromide.

[0077] In an implementation of the method for identifying subjects to receive treatment, step (b) further includes selecting subjects who do not have type 1 diabetes.

[0078] In the implementation plan of the method for identifying subjects undergoing treatment: (a) Step (a) further includes measuring the subject’s serum cortisol in the morning, and step (b) further includes selecting subjects with serum cortisol levels between 3 µg / dL and 22 µg / dL; (b) Step (a) further includes determining the subject's body mass index (BMI), and step (b) further includes selecting a BMI of 18-40 kg / m². 2 The subjects; (c) Step (a) further includes measuring the serum potassium of the subject, and step (b) further includes selecting subjects with serum potassium less than 4.8 mmol / L; (d) Step (a) further includes measuring the serum sodium of the subject, and step (b) further includes selecting subjects with serum sodium greater than 135 mmol / L; (e) Step (a) further includes measuring the systolic blood pressure of the subject, and step (b) further includes selecting subjects with hypertension, preferably characterized by a systolic blood pressure of at least 135 mmHg, more preferably between 135 mmHg and 180 mmHg (including the extreme values).

[0079] Composition The present invention also provides lorenstat or a pharmaceutically acceptable salt thereof for use in any of the methods described herein.

[0080] The present invention also provides a pharmaceutical composition comprising lorenstat or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, said pharmaceutical composition being used in any of the methods described herein.

[0081] The present invention also provides lorensta or a pharmaceutically acceptable salt thereof for the treatment of CKD in subjects with chronic kidney disease (CKD), wherein the use is in combination with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and optionally an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), preferably wherein the SGLT2 inhibitor is dapagliflozin.

[0082] The present invention also provides the use of lorensta or a pharmaceutically acceptable salt thereof for the treatment of CKD in a subject with chronic kidney disease (CKD) in combination with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and optionally an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), preferably wherein the SGLT2 inhibitor is dapagliflozin.

[0083] The present invention also provides lorensta or a pharmaceutically acceptable salt thereof for the treatment of CKD and hypertension in subjects with chronic kidney disease (CKD) and hypertension, wherein the use is in combination with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and optionally an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), preferably wherein the SGLT2 inhibitor is dapagliflozin.

[0084] The present invention also provides the use of lorensta or a pharmaceutically acceptable salt thereof for the treatment of CKD and hypertension in subjects with chronic kidney disease (CKD) and hypertension in combination with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and optionally an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), preferably wherein the SGLT2 inhibitor is dapagliflozin.

[0085] The present invention also provides lorensta or a pharmaceutically acceptable salt thereof for the treatment of hypertension in subjects with CKD and hypertension, wherein the use is in combination with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and optionally an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), preferably wherein the SGLT2 inhibitor is dapagliflozin.

[0086] The present invention also provides the use of lorensta or a pharmaceutically acceptable salt thereof for the treatment of hypertension in subjects with CKD and hypertension in combination with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and optionally an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), preferably wherein the SGLT2 inhibitor is dapagliflozin.

[0087] The present invention also provides a package comprising: (a) A first pharmaceutical composition comprising a certain amount of lorenstat or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; (b) A second pharmaceutical composition comprising a certain amount of sodium-glucose cotransporter 2 (SGLT2) inhibitor; (c) Optionally, a third pharmaceutical composition comprising an angiotensin-converting enzyme inhibitor (ACEi); and (d) Optionally, a fourth pharmaceutical composition comprising an angiotensin receptor blocker (ARB). (e) Instructions for use for the treatment of a subject with CKD or CKD and hypertension together with the first pharmaceutical composition, the second pharmaceutical composition, the third pharmaceutical composition, and the fourth pharmaceutical composition (if present).

[0088] The present invention also provides a package comprising: (a) A first pharmaceutical composition comprising a quantity of lorenstat or a pharmaceutically acceptable salt thereof, a quantity of a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and a pharmaceutically acceptable carrier; and (b) Optionally, a second pharmaceutical composition comprising an amount of an angiotensin-converting enzyme inhibitor (ACEi) and / or an angiotensin receptor blocker (ARB) and a pharmaceutically acceptable carrier; and (c) Instructions for use of the pharmaceutical composition for the treatment of subjects with chronic kidney disease (CKD) or CKD and hypertension.

[0089] The present invention also provides a pharmaceutical composition comprising: (a) A certain amount of lorenstat or its pharmaceutically acceptable salt; (b) A certain amount of sodium-glucose cotransporter 2 (SGLT2) inhibitor or a pharmaceutically acceptable salt thereof; (c) Optionally, a certain amount of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) or a pharmaceutically acceptable salt thereof. The lorensta or its pharmaceutically acceptable salts, SGLT2 inhibitors and ACEi or ARB (if present) are administered simultaneously, concurrently or concurrently.

[0090] The present invention also provides a pharmaceutical composition comprising a certain amount of lorenstat or a pharmaceutically acceptable salt thereof, said lorenstat or a pharmaceutically acceptable salt thereof for use in combination with a certain amount of sodium-glucose cotransporter 2 (SGLT2) inhibitor and optionally a certain amount of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) for the treatment of a subject with chronic kidney disease (CKD) or CKD and hypertension.

[0091] The present invention also provides a pharmaceutical composition comprising a certain amount of lorenstat or a pharmaceutically acceptable salt thereof, said lorenstat or a pharmaceutically acceptable salt thereof for use in combination with a certain amount of sodium-glucose cotransporter 2 (SGLT2) inhibitor and optionally a certain amount of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) for the treatment of hypertension in subjects with CKD or CKD and hypertension.

[0092] The present invention also provides a unit dosage form of pharmaceutical composition for treating subjects with chronic kidney disease (CKD) or CKD and hypertension, the pharmaceutical composition comprising: (a) A certain amount of lorenstat or its pharmaceutically acceptable salt; (b) A certain amount of a sodium-glucose cotransporter 2 (SGLT2) inhibitor or a pharmaceutically acceptable salt thereof; and (c) Optionally, a certain amount of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) or a pharmaceutically acceptable salt thereof. The appropriate amounts of the lorensta or its pharmaceutically acceptable salt, the SGLT2 inhibitor, and the ACEi or ARB (if present) in the composition are effective in treating the subject when the composition in one or more of the unit dosage forms is administered concurrently.

[0093] The present invention also provides a therapeutic package for distribution to a subject suffering from chronic kidney disease (CKD) or CKD and hypertension, or for use in a subject suffering from chronic kidney disease (CKD) or CKD and hypertension, the therapeutic package comprising: (a) One or more unit doses, each such unit dose comprising: (i) A certain amount of lorenstat or a pharmaceutically acceptable salt thereof; (ii) a certain amount of a sodium-glucose cotransporter 2 (SGLT2) inhibitor or a pharmaceutically acceptable salt thereof; and (iii) Optionally, a certain amount of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) or a pharmaceutically acceptable salt thereof. The corresponding amount of the lorensta or its pharmaceutically acceptable salt, the SGLT2 inhibitor, and the ACEi or ARB (if present) in the unit dose are effective in treating the subject's CKD when administered concomitantly. (b) A refined drug container for the treatment package, the container containing the one or more unit doses, the container also containing or including a label instructing the use of the package to treat the subject.

[0094] In embodiments of the packaging, pharmaceutical composition, or therapeutic packaging of the present invention, the SGLT2 inhibitor is dapagliflozin.

[0095] In embodiments of the packaging, pharmaceutical composition, or therapeutic packaging, the lorenstat or a pharmaceutically acceptable salt thereof is lorenstat hydrobromide.

[0096] In embodiments of the packaging, pharmaceutical composition, or therapeutic packaging, the pharmaceutical composition, unit dose, or unit dosage form comprises 10-15 mg, 20-30 mg, or 40-60 mg of lorenstat or a pharmaceutically acceptable salt thereof, preferably 12.5 mg, 25 mg, or 50 mg of lorenstat or a pharmaceutically acceptable salt thereof, and 8-12 mg of dapagliflozin, preferably 10 mg of dapagliflozin.

[0097] definition Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. While similar or equivalent methods and materials may be used in the practice or testing of embodiments of the invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification (including definitions) shall prevail. Furthermore, the materials, methods, and examples described are illustrative only and are not intended to be limiting.

[0098] In this discussion, unless otherwise stated, adjectives such as “substantially” and “about” modifying one or more features of embodiments of the invention should be understood to mean that the condition or feature is defined as being within acceptable tolerances for operation of the embodiment to its intended application. In embodiments, using measurements generally acceptable in the art, “about” means within the standard deviation. In embodiments, “about” means a range extending to + / - 10% of a specified value. In embodiments, “about” includes the specified value. Unless otherwise indicated, the word “or” in the specification and claims is considered inclusive rather than exclusive, and indicates at least one and any combination of items combined.

[0099] It should be understood that the term "a / an" as used above and elsewhere herein refers to "one or more" of the listed components. Those skilled in the art will appreciate that, unless otherwise specifically stated, the use of the singular includes the plural. Therefore, the terms "a / an" and "at least one" are used interchangeably in this application.

[0100] For the purpose of better understanding this teaching and in no way limiting its scope, all figures and other numerical values ​​expressing quantities, percentages, or proportions as used in the specification and claims, unless otherwise indicated, should be understood to be modified in all cases by the term "about". Therefore, unless indicated to the contrary, the numerical parameters set forth in the following specification and appended claims are approximations that may vary depending on the desired properties being sought. At a minimum, each numerical parameter should be interpreted based on the number of significant figures reported and by applying common rounding techniques.

[0101] In the specification and claims of this application, the verbs “comprising,” “including,” and “having,” and each of their variations, are used to indicate one or more objects of the verb, which is not necessarily a complete list of components, elements, or parts of one or more subjects of the verb. Other terms as used herein are intended to be defined by their meanings well known in the art.

[0102] Chronic kidney disease (CKD) is defined as a structural or functional abnormality of the kidneys that has persisted for more than 3 months and may have an impact on health. CKD is classified into 5 stages based on the extent of kidney damage. CKD is also classified into 5 stages according to the Kidney Disease: Improving Global Outcomes (KDIGO) classification (Chen et al., 2019; Kovesdy, 2022). Stage 3 consists of mild to moderate impairment of kidney function and is further subdivided into CKD stage 3a (eGFR 45-59 mL / min / 1.73 m³ / min). 2 () and phase 3b (eGFR 3044 mL / min / 1.73 m) 2 Phase 4 (eGFR 1529 mL / min / 1.73 m) 2 It is composed of severely impaired kidney function (Chen et al., 2019).

[0103] "CYP11β2", "Cyp11B2", or "CYP11β2 β-hydroxylase" is a cytochrome P450 enzyme encoded by the CYP11B2 gene in humans that catalyzes a series of reactions from 11-deoxycorticosterone (i.e., aldosterone precursor) to aldosterone. Therefore, it is referred to in the art as "aldosterone synthase". Cyp11B2 is primarily expressed in the globular layer of the adrenal cortex, and plasma aldosterone levels are regulated by the enzymatic activity of Cyp11B2 present in the adrenal glands. Aldosterone is expressed in other tissues such as the cardiovascular system, kidneys, adipose tissue, and brain.

[0104] "CYP11β1", "Cyp11B1", or "CYP11β1 β-hydroxylase" is a cytochrome P450 enzyme encoded by the CYP11B1 gene in humans, involved in the biosynthesis of adrenal cortical steroids. It is known in the art as "steroid 11β-hydroxylase".

[0105] "Inhibitor" refers to a compound that reduces activity when compared to a control, such as a compound that is absent or has a known inactive form (e.g., the compound described herein). Inhibitors can be small molecule inhibitors, antibody inhibitors, protein inhibitors, biomolecule inhibitors, natural ligands, etc. "Inhibitors" can be in the form of pharmaceutically acceptable salts of compounds such as those described herein.

[0106] As used in this article, "lorenstatin" refers to... N- [ trans[-4-(acetamido)cyclohexyl]-2-{4-[5-(4-methylphenyl)-1,2,4-triazin-3-yl]piperazin-1-yl}acetamide. As used herein, "lorenstat HBr" refers to lorenstat hydrobromide, i.e. N- [ trans [-4-(acetamido)cyclohexyl]-2-{4-[5-(4-methylphenyl)-1,2,4-triazin-3-yl]piperazin-1-yl}acetamide monohydrobromide. The weight and / or strength of "lorensta" and "compound" in this invention refer to the weight of the free base in the monohydrobromide, not the weight of the salt.

[0107] Lorenztastat can be manufactured by methods described, for example, in U.S. Patent No. 10,029,993 and European Publication No. 3,549,935, the contents of which are incorporated herein by reference in their entirety.

[0108] As used in this article, "dapagliflozin" refers to a mixture (1:1:1) of D-glucanol, 1,5-dehydrated-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, (1S)- and (2S)-1,2-propanediol hydrates.

[0109] As used herein (and as well understood in the art), “treating” also broadly includes any method used to obtain a beneficial or desired outcome (including clinical outcome) in a subject’s condition. Beneficial or desired clinical outcome may include, but is not limited to, relief or improvement of one or more symptoms or conditions, reduction of disease severity, stabilization of the disease state (i.e., no worsening), prevention of disease spread or diffusion, delay or slowing of disease progression, improvement or relief of the disease state, reduction of disease recurrence, and relief, whether partial or complete and detectable or undetectable. In other words, as used herein, “treatment” includes any cure, improvement, or prevention of disease. Treatment may prevent the onset of disease; inhibit the spread of disease; relieve disease symptoms; completely or partially eliminate the underlying cause of disease; shorten the duration of disease; or do a combination of these things.

[0110] As used herein, "treating" includes preventative treatment. Treatment methods include administering a therapeutically effective amount of an active agent to a subject. Administration may be a single application or may include a series of applications. The duration of treatment depends on various factors, such as the severity of the condition, the patient's age, the concentration of the active agent, the activity of the composition used in the treatment, or a combination thereof. It should also be understood that the effective dose of the agent used for treatment or prevention may be increased or decreased during the course of a particular treatment or prevention regimen. Dosage changes can be produced and become apparent by standard diagnostic assays known in the art. In embodiments, prolonged administration may be required. For example, the composition may be administered to the subject in an amount sufficient to treat the patient and for a duration sufficient to treat the patient. In embodiments, treatment is not preventative treatment.

[0111] "Angiotensin-converting enzyme inhibitors," "ACE inhibitors," or "ACEi" are antihypertensive drugs that block the conversion of angiotensin I to angiotensin II, thereby dilating blood vessels and lowering blood pressure. Exemplary ACE inhibitors include benazepril, zolfenpril, perindopril, trandopril, captopril, enalapril, lisinopril, and ramipril.

[0112] "Angiotensin receptor blockers," "ARBs," or "angiotensin II inhibitors" are antihypertensive drugs that block the binding of angiotensin II receptors, thereby dilating blood vessels and lowering blood pressure. Exemplary angiotensin receptor blockers include eprosartan, olmesartan, valsartan, candesartan, losartan, telmisartan, irbesartan, valsartan, and azisartan medoxomil.

[0113] The “normal circadian rhythm” of aldosterone levels follows a diurnal pattern, with the lowest point occurring late at night and the highest point in the early morning, before waking. In one implementation, the subject’s aldosterone levels follow a substantially normal circadian rhythm. In one example of such an implementation, when administered once daily upon waking in the morning, the CYP 11β2β-hydroxylase inhibitor of the present invention inhibits the abnormally increased aldosterone production during wakefulness. In the evening, the inhibition of aldosterone production begins to weaken, and the normal increase in serum aldosterone returns to normal before dawn, just as it would under normal circumstances. (Kem, David C. et al., “Circadian rhythm of plasma aldosterone concentration in patients with primary aldosteronism”). The Journal of clinical investigation The diurnal rhythm of aldosterone in normal subjects and subjects with primary aldosteronism is described in 52.9 (1973):2272-2277, the contents of which are specifically incorporated herein by reference.

[0114] This invention provides a method for reducing systolic blood pressure during sleep in subjects. In this context, "sleep period" refers to a sleep segment within a subject's normal sleep / wake cycle. In other words, "sleep period" refers to approximately seven to nine hours of sleep (typically at night) that occurs daily between approximately 15 and 17 hours of wakefulness, and not to any short periods of sleep (i.e., naps) that may occur outside the sleep segments of a subject's normal sleep / wake cycle. An individual's blood pressure typically decreases during sleep, with blood pressure values ​​during sleep being approximately 10% to 15% lower than during wakefulness. Conversely, hypertensive subjects may experience a smaller drop in blood pressure during sleep or may not experience any drop at all. Therefore, the method of this invention helps hypertensive subjects restore the blood pressure drop experienced by normal, non-hypertensive subjects during sleep.

[0115] The “pre-drug level” of a subject’s serum aldosterone refers to the subject’s serum aldosterone level at the same time of day when not being treated with the described drug. As discussed above, aldosterone levels follow a diurnal pattern, with the lowest point at night and the highest point in the early morning, before waking up. Therefore, in the implementation where the dose of the CYP 11β2β-hydroxylase inhibitor reduces a subject’s serum aldosterone level by a specific percentage relative to their “pre-drug level,” the reduction in serum aldosterone is measured relative to the serum aldosterone level of the same subject at the same time of day when not administering the CYP 11β2β-hydroxylase inhibitor. For example, the subject’s serum aldosterone level at 11 a.m. when administering the CYP 11β2β-hydroxylase inhibitor will be measured relative to the same subject’s serum aldosterone level at 11 a.m. before any administration of the CYP 11β2β-hydroxylase inhibitor.

[0116] Overview With respect to the foregoing implementation schemes, each of the implementation schemes disclosed herein is considered applicable to each of the other disclosed implementation schemes.

[0117] As used herein, all headings are for organization purposes only and are not intended to limit this disclosure in any way. The content of any individual section is equally applicable to all sections. All combinations of the various elements disclosed herein are within the scope of this invention.

[0118] Additional objects, advantages, and novel features of the present invention will become apparent to those skilled in the art upon examination of the following embodiments, which are not intended to be limiting. Furthermore, each of the various embodiments and aspects of the invention as explained above and claimed in the claims section below can be experimentally supported in the following embodiments.

[0119] It should be understood that, for clarity, certain features of the invention described in the context of individual embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the invention described in the context of a single embodiment may also be provided individually or in any suitable sub-combination or as appropriate in any other described embodiment of the invention. Certain features described in the context of various embodiments are not considered essential features of those embodiments unless the embodiment is invalid without those elements.

[0120] The following examples are provided to provide a more complete understanding of the invention. These examples illustrate exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to the specific embodiments disclosed in these examples, which are for illustrative purposes only.

[0121] Example Example 1 A randomized, double-blind, placebo-controlled study was conducted in which 116 patients were randomized and 87 received lorenstatin HBr.

[0122] The following dosage was used in a single-dose escalation (SAD) study: (a) 5 mg (b) 10 mg (c) 20 mg (d) 50 mg (e) 100 mg (f) 200 mg (g) 400 mg (h) 800 mg.

[0123] Based on PKPD modeling using SAD study data, the IC50 and time above IC50 of lorenstatin HBr inhibition of CYP 11β2β-hydroxylase for each dosage were estimated. Estimates of hours above IC50 and the proportion of 24-hour periods above IC50 for the recommended dosage in the Phase II proof-of-concept study were extrapolated and are shown in the table below. Figure 1 middle.

[0124] Table 1

[0125] In the SAD study, the time above IC50 was closely related to the duration of aldosterone inhibition.

[0126] In the multiple escalation dose (MAD) study, very little drug accumulation was observed at QD doses of 40 mg, 120 mg, and 360 mg.

[0127] Example 2 introduce Chronic kidney disease (CKD) is an increasingly prevalent global disease and is strongly associated with the incidence of cardiovascular disease (CVD, Pugh 2019). Hypertension is both a cause and a consequence of CKD, affecting many CKD patients (Pugh 2019). Controlling hypertension is crucial for patients with CKD because it slows disease progression and reduces the risk of CVD (Fay 2020). Current guidelines do not reach a consensus on optimal blood pressure (BP) targets, and CKD clinical practice guidelines suggest that for stages 1–4, treatment should focus on comorbidities (e.g., hypertension, metabolic acidosis, and hyperkalemia) rather than correcting and reversing impaired kidney function itself (Levin 2013). As CKD progresses, slowing its progression becomes more difficult (Pugh 2019). Therefore, it is essential to develop effective treatments that not only aim to slow CKD progression but also target its progression as early as possible. Although patients with hypertension and CKD require a combination of medications to achieve blood pressure and estimated glomerular filtration rate (eGFR) targets, the medications are often suboptimal, resulting in inadequate treatment (Fay 2020). In summary, these issues highlight unmet needs in the treatment of hypertension and CKD.

[0128] Despite the existence of upstream renin-angiotensin-aldosterone system (RAAS) inhibitors (including angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs)) treatments, lorenstastat, a selective aldosterone synthase inhibitor (ASI), is still under development for the treatment of hypertension in chronic kidney disease (CKD) with persistent albuminuria.

[0129] While existing classes of mineralocorticoid receptor antagonists (MRAs) address the dysregulation associated with hypertension, newer classes of aldosterone inhibitors (ASIs) have the potential to offer a more favorable benefit / risk profile due to their different mechanisms of action, resulting in a significant reduction in circulating and local aldosterone production rather than the pronounced increase seen in MRA cases. Furthermore, unlike spironolactone (the most commonly prescribed MRA) and other ASIs under development, lorenlustat, due to its short half-life, may be rapidly reversible in the event of adverse events (AEs) such as hyperkalemia or hypotension. Regarding CKD, mounting evidence supports the role of sodium-glucose cotransporter 2 inhibitors (SGLT2i) therapy in patients with CKD (Mende, 2022).

[0130] These therapies do not increase the risk of severe hyperkalemia or severe hypokalemia (Neuen et al, 2022), suggesting that there may be a synergistic effect with combination therapy of SGLT2 inhibitors and selective ASIs such as lorenlustat in reducing the incidence of hyperkalemia and slowing the progression of kidney disease.

[0131] This study will evaluate the safety, efficacy, and tolerability of lorensustat in subjects with hypertension and CKD with albuminuria, in addition to SGLT2i, despite the presence of ACEi or ARB treatment.

[0132] discuss Hypertension is a major risk factor for the development of CVD, and its prevalence is increasing (Forouzanfar 2017). Despite improved awareness and treatment, hypertension still results in longer disability life years and longer combined life years than any other cause of morbidity and death (Murray 2013). Lowering blood pressure reduces the risk of end-organ damage, and patients who fail to achieve their blood pressure targets despite multi-drug therapy are designated as having refractory hypertension (RH, Carey 2018). Refractory hypertension is common in individuals with CKD and is becoming more prevalent, especially with impaired renal function (Tanner 2013). An analysis of over 3,300 patients in the Chronic Renal Insufficiency Cohort (CRIC) study was conducted on patients with an eGFR of 20 mL / min / 1.73 m 2 Up to 70 mL / min / 1.73 m 2 A multicenter prospective observational study of adults found that the prevalence of RH in hypertensive patients was 40.4%.

[0133] CKD affects more than 10% of the global population and is one of the leading causes of death worldwide (Kovesdy, 2022). According to the US Centers for Disease Control and Prevention (CDC), an estimated one in seven American adults has CKD (CDC, 2021). CKD is characterized by progressive loss of kidney function and can be classified into five stages (Levin 2012). Stage 1 is characterized by normal or high kidney function (eGFR ≥ 90 mL / min / 1.73 m³ / min). 2 Phase 2 showed a slight decrease (eGFR was 60-89 mL / min / 1.73 m). 2 Phase 3 is divided into two additional phases: phase 3a and phase 3b. Phase 3a is characterized by mild to moderate attenuation (eGFR 45-59 mL / min / 1.73 m). 2 Phase 3b showed moderate to severe attenuation (eGFR 30-44 mL / min / 1.73 m), while phase 3b showed moderate to severe attenuation (eGFR 30-44 mL / min / 1.73 m). 2 Phase 4 was characterized by severe attenuation (eGFR 15-29 mL / min / 1.73 m). 2 The final stage, stage 5, is kidney failure (eGFR < 15 mL / min / 1.73 m). 2 CKD is incurable, and despite the availability of various treatment options, the risk of adverse events (AEs) and disease progression remains high, highlighting the unmet need in CKD treatment.

[0134] While hypertension is a significant cause of CKD (Hanratty 2011), CKD itself increases blood pressure (BP) through several mechanisms, including impaired sodium excretion and premature vascular aging, subsequently reducing baroreceptor sensitivity, increasing sympathetic nerve tone, and activating the renal artery apnea-associated syndrome (RAAS) (Pugh 2019). Aldosterone contributes to the progression of kidney disease by activating mineralocorticoid receptors (MR) in renal cells, leading to podocyte dysplasia, tubulointerstitial inflammation, and tubulointerstitial fibrosis (Epstein, 2021) (Vaidya 2018). Serum aldosterone concentration is negatively correlated with eGFR, positively correlated with 24-hour urinary protein, and independently associated with CKD progression and the incidence of end-stage renal disease (ESRD) (Verma 2022). This suggests that pathogenic aldosteronism plays a role in CKD progression.

[0135] A strategy for reducing aldosterone-related risk in fibrotic kidney disease is the use of aldosterone inhibitors (ASIs) (Weldon and Brown 2019; Brown 2020). ASIs may work more effectively than MR blockade because aldosterone not only confers MR-mediated genomic effects but also non-genomic and MR-independent effects leading to kidney fibrosis (Chen 2013). The clinical development of ASIs is complicated by the difficulty in obtaining sufficiently selective blockades of aldosterone synthases instead of cortisol synthases. Using ASIs such as lorenstat to inhibit aldosterone production in the adrenal glands rather than blocking aldosterone activity at the receptor site is a promising alternative treatment for CKD.

[0136] A review of trials conducted in patients with CKD indicates that there are currently five classes of treatments available to slow CKD progression or reduce the decline in eGFR (Mende, 2022). These treatments include ACE inhibitors, ARBs, SGLT2 inhibitors, glucagon-like peptide-1 receptor agonists (GLP1-RAs), and the MRA fenelrenone (Mende, 2022).

[0137] RAAS inhibitors, such as ACEi and ARBs, are commonly used to reduce albuminuria and slow disease progression in patients with CKD (Mukoyama and Kuwabara, 2022). These therapies have shown beneficial clinical effects in patients with CKD and those without diabetes (Xie 2016). While current guidelines recommend the use of RAAS inhibitors (ACEi or ARBs) to delay or prevent CKD progression (Mukoyama and Kuwabara, 2022), aldosterone levels often return to pre-treatment levels. This resulting failure of aldosterone suppression is known as "aldosterone breakthrough" and can contribute to the development of RH, hyperkalemia, and the progression of cardiovascular and kidney disease (Mogi, 2022; Ando 2023). Patients are often advised to reduce their dose or even discontinue their treatment (Mukoyama and Kuwabara, 2022). One way to reduce the effects of "aldosterone breakthrough" is to reduce aldosterone production by inhibiting aldosterone synthase (Weldon and Brown, 2019; Ando 2023). Short-term studies in patients with CKD and type 2 diabetes (T2DM) have shown promise in reducing albuminuria when MRAs are used as an adjunct to ACEi or ARBs. However, these studies have also shown an increased incidence of hyperkalemia-related discontinuation in patients treated with MRAs (Bakris 2020). Fennellone, a selective oral nonsteroidal MRA, has been shown to reduce the risk of CKD progression and cardiovascular events in patients with CKD and T2DM (Bakris 2020).

[0138] The standard of care for the treatment of albuminuria has recently changed, and many guidelines recommend adding SGLT2i to ACEi or ARBs (Mende, 2022). A review of SGLT2i studies suggests they can reduce the risk of ESRD in patients with T2DM and CKD (Braunwald, 2022). Data from large randomized, placebo-controlled renal outcome trials in patients with T2DM (CREDENCE) and those with or without T2DM (DAPA-CKD) have shown a reduced risk of CKD progression with the use of SGLT2i (Perkovic 2019; Heerspink 2020). Improved renal outcomes were also observed in the EMPA-KIDNEY trial in patients with CKD with or without diabetes, and the data monitoring committee (DMC) stopped the trial early due to the positive efficacy (Herrington 2023). Data from the CREDENCE, DAPA-CKD, and FIDELIO-DKD trials suggest that adding an appropriate SGLT2i or MRA to standard-of-care RAAS inhibition can improve a range of renal and cardiovascular outcomes in patients with or without T2DM (Garcia Sanchez 2022). SGLT2i does not increase the risk of severe hyperkalemia or severe hypokalemia (Neuen 2022), suggesting a potential synergistic effect with combination therapy of SGLT2i and selective ASIs such as lorenrustat. This combination therapy could reduce the incidence of hyperkalemia and potentially slow the progression of kidney disease, thus warranting further investigation.

[0139] While existing classes of MRAs have addressed the "aldosterone breakthrough," newer classes of ASIs may offer a more favorable benefit / risk profile due to differences in their mechanisms of action, resulting in a reduction in circulating and local aldosterone production rather than the significant increase seen in MRA classes. Lorenstat is a selective ASI that inhibits cytochrome P450 11B2 (CYP11B2; aldosterone synthase, a rate-limiting enzyme for aldosterone production). A series of pharmacological studies have demonstrated that lorenstat is a selective inhibitor of CYP11B2 and is not associated with side effects on the central nervous system, respiratory system, or cardiovascular system. Unlike spironolactone (the most commonly prescribed MRA) and other ASIs under development, lorenstat has the potential for rapid reversibility in the event of adverse events (AEs) such as hyperkalemia or hypotension due to its short half-life of approximately 9–12 hours, as shown in Example 1. Without being limited to specific theories, the short half-life of lorenstat relative to MRAs and other ASIs offers additional benefits, particularly when used to treat CKD. For example, aldosterone levels typically follow a diurnal pattern, with the lowest point in the late night and the highest point in the early morning, before waking. When lorenlstat is administered once daily upon waking, it inhibits the abnormal increase in aldosterone production during wakefulness. In the evening, due to the half-life of lorenlstat, the inhibition of aldosterone production begins to weaken, and the normal increase in serum aldosterone in subjects returns to normal before dawn, just as it would under normal circumstances. Furthermore, the reduction in aldosterone production as inhibition weakens provides additional benefit. Data from a phase 1 study (NCT02953132) in healthy subjects and a phase 2 study (NCT05001945) in patients with uncontrolled hypertension indicate that lorenlstat has an acceptable safety profile and is well-tolerated.

[0140] Benefits / Risk Assessment Lorenzta's benefits and risks assessment Clinical data from healthy volunteers and patients with uncontrolled hypertension and RH indicate that lorenlustat is well tolerated and has an acceptable safety profile.

[0141] Risk of hyperkalemia Elevated potassium levels have been observed in nonclinical studies of lorensta, and this is generally a known risk factor for MRA.

[0142] Early studies of lorenstat in healthy volunteers showed a trend toward mild increases in serum potassium, but these increases were not assessed as clinically significant. In a phase 2 study (MLS-101-201) of 200 subjects with uncontrolled hypertension, hyperkalemia was the most frequently reported adverse event (AE). After adjusting for events that did not meet quality control criteria (to exclude non-reproducible and pseudohyperkalemia, such as elevated lactate dehydrogenase (LDH) levels that did not recur in a second blood sample collected as soon as possible while the subject maintained the same dose of lorenstat), the number of events classified as mild, moderate, and severe laboratory abnormalities were 42 (21), 28 (12), and 4 (3), respectively. Electrocardiograms (ECGs) were obtained in all cases, and no clinically significant abnormalities were identified in any of them.

[0143] In this study, to mitigate the potential risks associated with hyperkalemia, participants will be required to have serum potassium ≤4.8 mmol / L before starting the study drug and to return to the clinic regularly at each outpatient visit after starting lorenlustat treatment for assessment of local potassium levels. Clinical monitoring will allow for early detection of potentially concerning adverse events or trends, particularly those related to increased potassium levels.

[0144] Risk of hyponatremia Clinically insignificant decreases in serum sodium were observed in early studies of lorenrustat in healthy volunteers. Two episodes of hyponatremia were reported in the completed phase 2 lorenrustat study (MLS-101-201). One subject randomized to the lorenrustat 100 mg QD cohort experienced a severe episode of hyponatremia. This subject had a history of chronic, mild hyponatremia and serum sodium levels of 132 mmol / L, 140 mmol / L, and 142 mmol / L in the two weeks prior to randomization. One week after randomization, serum sodium was 135 mmol / L, and two weeks later, it was 113 mmol / L. There were no symptoms or abnormal findings on physical examination. After discontinuation of the study drug, serum sodium levels recovered to a maximum of 137 mmol / L and remained between 134 mmol / L and 137 mmol / L over the subsequent five-week observation period, without the need for aggressive treatment or hospitalization. Another event involved a subject receiving a 100 mg QD dose who experienced a moderate episode of hyponatremia with a baseline sodium level of 136 mmol / L. This baseline sodium level decreased to 128 mmol / L at week 4 of treatment and increased to 137 mmol / L over the following four weeks after the dose was reduced to lorenstastat 50 mg QD. Muscle cramps were the only reported symptom, and the patient responded to brief treatment with ropinirole.

[0145] To mitigate the potential risks associated with hyponatremia, participants with a clinically significant history of hyponatremia within one year prior to screening will be excluded. Serum electrolytes, including serum sodium, will be monitored frequently under the supervision of a medical monitor throughout the study.

[0146] Risk of low blood pressure and dizziness In healthy subjects, the incidence of dizziness / postural dizziness was slightly higher in subjects treated with lorenlustat compared with those treated with placebo.

[0147] In addition, symptomatic hypotension was observed in 3 subjects (1.8%) receiving lorenlustat in a phase 2 study (MLS-101-201) with uncontrolled hypertension. Based on the mechanism of action of lorenlustat, these events were reversible upon discontinuation of treatment, as expected. Furthermore, in the absence of orthostatic hypotension, orthostatic hypotension occurred in 3 subjects, defined as a decrease in systolic blood pressure (SBP) of 20 mmHg or a decrease in diastolic blood pressure (DBP) of 10 mmHg upon standing from a sitting position. In each case, the hypotensive episode resolved spontaneously and did not recur for the remainder of the treatment period. Two of these events were assessed by the investigators as unlikely to be related to the study drug; one event was assessed as possibly related.

[0148] Throughout this study, participants' blood pressure will be assessed regularly in both sitting and standing positions. Episodes of low blood pressure will be treated according to site / institutional standards of care and medical guidelines.

[0149] Risk of cortisol inhibition or overdose To date, no clinically significant events of decreased serum cortisol or impaired cortisol production stimulated by adrenocorticotropic hormone (ACTH) have been observed in completed clinical trials.

[0150] In a phase 2 trial in subjects with uncontrolled hypertension, a slight increase in morning serum cortisol was observed after 8 weeks of treatment in most active drug cohorts and in subjects receiving placebo. Three subjects in the 100 mg once daily (QD) cohort had morning serum cortisol levels above the normal range. These increases were modest and not associated with symptoms or signs of clinical hypercortisolism.

[0151] In this trial, all subjects will be monitored for signs and symptoms of hypercortisolism. Serum cortisol levels will be measured periodically, with blood drawn as close to 8:00 AM but before 10:00 AM as possible. If necessary, a 24-hour urinary free cortisol assessment and an unplanned ACTH stimulation test will be performed.

[0152] Specific entry and dose adjustment criteria have been added to the protocol to minimize potential risks to subjects.

[0153] Benefits and risks assessment of dapagliflozin All benefits and risks associated with dapagliflozin are available in the current product packaging instructions.

[0154] Low blood pressure risk Symptomatic hypotension may occur after starting dapagliflozin, especially in patients with impaired renal function (eGFR < 60 mL / min / 1.73 m). 2 Subjects included in the study, elderly subjects (≥65 years), subjects with low SBP, and subjects taking diuretics. Volume status will be assessed and corrected before initiating dapagliflozin, if instructed. Subjects will be educated about the symptoms of hypotension and volume depletion, and signs and symptoms of hypotension will be monitored at least every 3 weeks (and more frequently if instructed) after initiation of therapy, as instructed above for lorenlustat.

[0155] Risk of ketoacidosis Ketoacidosis is infrequently reported in diabetic subjects taking SGLT2i (estimated to be no more than 0.1%), including rare fatal cases. Subjects with a history of at least one severe hypoglycemic event or severe diabetic ketoacidosis event within the 12 months prior to screening will be excluded from the trial. Signs and symptoms of ketoacidosis, as well as precipitating conditions such as volume depletion, will be monitored in subjects.

[0156] Risk of acute kidney injury and impaired kidney function Post-marketing reports of acute kidney injury have been reported in patients receiving SGLT2i, some requiring hospitalization and dialysis. Otherwise, a small, clinically insignificant, and reversible decrease in eGFR is typically observed after initiation of SGLT2i, and this may be associated with mild volume depletion. Many of these events may be related to volume depletion, congestive heart failure (CHF), and ketoacidosis. Subjects with severe CHF, ketoacidosis, or requiring renal replacement therapy will be excluded. Signs and symptoms of acute kidney injury will be monitored in subjects.

[0157] Risk of hypoglycemia Hypoglycemia is rare in non-diabetic subjects. A recent systematic review of SGLT2i (Teo 2021) found an incidence of hypoglycemia of <0.5% in non-diabetic individuals. Adding SGLT2i to T2DM treatment regimens is expected to lower blood glucose levels and may cause hypoglycemia. Signs and symptoms of hypoglycemia will be monitored in all subjects. Subjects with T2DM may be instructed to monitor their blood glucose levels more closely after initiating the study drug. Baseline treatment for T2DM will be adjusted as needed to avoid hypoglycemia.

[0158] Urosecoma and pyelonephritis, lower limb amputation, genital fungal infection, perineal necrotizing fasciitis (Fournier) Fournier's gangrene risk All of these conditions have been rarely observed in SGLT2i clinical trials. Subjects with a history of these conditions will be excluded from this study. Signs and symptoms of these conditions will be monitored in all subjects.

[0159] Other risks Additional risks to study participants may include, but are not limited to: (a) Study the potential complications (e.g., blood draws may cause temporary discomfort due to needle prick, bruising, bleeding, and, rarely, infection). (b) Increased risk of exposure to pathogens that cause infectious diseases, including COVID-19, due to regular outpatient visits. (c) Risk of loss of confidentiality.

[0160] Potential benefits The benefits to study participants may include, but are not limited to: (a) Potential benefits of receiving research treatment (b) Contributions to the development / improvement of methods for therapies addressing unmet medical needs. (c) Medical evaluation / assessment (e.g., physical examination, ECG, laboratory assessment).

[0161] Overall Benefits-Risk Conclusion Considering the measures taken to minimize the risks to participants in this study, the anticipated benefits that participants with hypertension and CKD may receive justify the potential risks.

[0162] Research objectives and endpoints Research Objectives Target Main objectives To evaluate the effect of lorensta 25 mg once daily (QD) on systolic blood pressure (SBP) in subjects with hypertension and chronic kidney disease (CKD) with albuminuria who are receiving stable treatment with ACEi or ARB, excluding sodium-glucose cotransporter-2 inhibitors (SGLT2i).

[0163] Exploratory goals To explore the effect of adding lorenzuta to SGLT2i on albuminuria in subjects with hypertension and CKD with albuminuria who are receiving stable ACEi / ARB therapy.

[0164] To explore the effect of adding lorenzuta to SGLT2i on DBP in subjects with hypertension and CKD with albuminuria who are receiving stable ACEi / ARB therapy.

[0165] To explore the effect of adding lorenzuta to SGLT2i on biomarkers in subjects with hypertension and CKD with albuminuria who are receiving stable ACEi / ARB therapy.

[0166] To explore changes in renal function in subjects with hypertension and CKD with albuminuria who were receiving stable ACEi / ARB therapy, after adding lorenlustat to SGLT2i.

[0167] security goals The study investigated the safety and tolerability of lorenlustat, in addition to SGLT2i, in subjects with hypertension and CKD with albuminuria treated with ACEi / ARB stabilization therapy.

[0168] Pharmacokinetic Targets Determine the plasma concentrations of lorensta and its major metabolites.

[0169] Study endpoints end Primary endpoint The study investigated the placebo-regulated changes in automated clinic blood pressure (AOBP) relative to baseline at week 4.

[0170] Exploratory endpoint The study investigated the placebo-regulated changes in 24-hour urinary albumin relative to baseline at week 4.

[0171] The study investigated the placebo-regulated changes in AOBP and DBP relative to baseline at week 4.

[0172] During the treatment with lorenstat, the changes in AOBP and SBP relative to baseline were studied at week 4.

[0173] During the lorensta treatment period, the percentage change in 24-hour urinary albumin relative to baseline was studied at week 4.

[0174] The study investigated the percentage change in 24-hour urinary protein relative to baseline at week 4, as determined by placebo regulation.

[0175] The percentage change in urinary albumin to creatinine ratio (UACR) relative to baseline at week 4 of the study.

[0176] Changes in biomarkers from baseline to week 4 of the study during lorenstat treatment.

[0177] Changes in placebo regulation of glomerular filtration rate (eGFR) from baseline to week 4 of the study.

[0178] Percentage change in eGFR from week 4 to week 8 of the study.

[0179] Safety endpoint Incidence and severity of AE Clinically significant changes in vital signs (body temperature, heart rate, and respiratory rate), physical examination, and electrocardiogram (ECG) parameters.

[0180] Clinically significant changes in clinical laboratory assessments (hematology, chemistry, and urinalysis).

[0181] Incidence of AEs of particular interest (AESI) (a) Adjustments to the dosage of research drugs due to hyperkalemia (e.g., dose reduction, dose suspension, or permanent dose cessation). (b) Adjustments to the dosage of investigational drugs due to hyponatremia (e.g., dose reduction, dose suspension, or permanent dose cessation). (c) Low blood pressure with symptoms (e.g., dizziness, lightheadedness, syncope, or fainting). (d) Significantly elevated blood pressure (AOBP SBP > 180 mmHg or AOBP DBP > 110 mmHg) (e) Adjustment of study drug dosage due to Cushing's syndrome (morning serum cortisol >35 µg / dL, confirmed by 24-hour urinary free cortisol). (f) Discontinuation of investigational drugs due to hypocortisol confirmed by ACTH (tecoclidin) stimulation test. (g) Investigating drug overdose (h) Dosage adjustments for research drugs due to impaired renal function (e.g., dose reduction, dose suspension, or permanent dose cessation). Pharmacokinetic endpoints Plasma concentrations of lorensta and its main metabolites.

[0182] Research Design Overall research design This is a randomized, double-blind (DB), placebo-controlled crossover study with a two-phase, two-sequence (2×2) design to evaluate the efficacy and safety of 25 mg QD lorenstastatin (ASI) in addition to SGLT2i for the treatment of hypertension in subjects with CKD and albuminuria, despite receiving ACEi or ARB stabilization therapy.

[0183] Participants will be at least 18 years old and will have hypertension (AOBP / SBP 135–180 mmHg, including extreme values) and mild to severe CKD (eGFR ≥ 30 mL / min / 1.73 m2) with albuminuria (UACR 200–5000 mg / g, including extreme values) at the screening visit. The study consists of a 2-week screening period, a 2-week induction period (during which participants will start with the study-provided dapagliflozin 10 mg or continue with their regular prescription SGLT2i), and two 4-week treatment periods of DB with a 4-week washout interval. Figure 2 Subjects will be randomly assigned (1:1) to two treatment sequences: lorenlstat-placebo (LP) and placebo-lorenlstat (PL).

[0184] Treatment allocation will be organized as follows: (a) Treatment period 1 (week 0 to week 4 of the DB study): Subjects will receive a QD oral administration of lorenstat 25 mg (sequence LP) or one matched lorenstat-placebo tablet (sequence PL).

[0185] (b) Washout (weeks 4 to 8 of the study): All subjects will receive a matched placebo administered orally via QD.

[0186] (c) Treatment period 2 (week 0 to week 4 of the DB study): Subjects will receive one matched lorenstat-placebo tablet (sequence LP) or lorenstat 25 mg (sequence PL) orally administered via QD.

[0187] During the DB and washout periods, subjects will continue their background therapies, including ACEi / ARB and SGLT2i.

[0188] If, at any time during the DB period, the eGFR decreases by ≥30% since randomization, the investigator and medical monitor will consult to decide whether to reduce, pause, or discontinue the dose.

[0189] After the study is completed, participants will have the opportunity to participate in a separate open-label extension (OLE) study. If a participant does not enter the OLE, a final study end (EoS) safety visit will be conducted 2 weeks after the last dose of the study drug.

[0190] Scientific Principles of Research Design Although inexpensive and effective oral blood pressure-lowering medications are widely available, hypertension control rates are poor regardless of age, race, or sex (Virani 2021). CKD is currently incurable, and despite various treatment options, the risk of adverse events (AEs) and CKD progression remains high (Bakris 2020). In summary, these issues highlight unmet needs in the treatment of hypertension and CKD.

[0191] Lorensta is an inhibitor of CYP11B2 (aldosterone synthase, the rate-limiting enzyme in aldosterone production). In the phase 2 Target-HTN (MLS-101-201) study, patients with uncontrolled hypertension showed a clinically relevant reduction in SBP after 8 weeks of lorensta treatment compared to placebo, resulting in a beneficial, reversible, dose-dependent reduction in eGFR (Mineralys Therapeutics, NCT05001945). This demonstrates the selectivity of lorensta in aldosterone inhibition, as cortisol levels were not inhibited across the dose range.

[0192] This phase 2 study will evaluate the efficacy, safety, and tolerability of lorenlustat in subjects with hypertension and CKD with persistent albuminuria, in addition to SGLT2i, despite the presence of ACEi or ARB treatment.

[0193] The study was designed as a crossover study with randomized, bottom-group (DB) allocation. Choosing a crossover design was more effective in avoiding inter-subject variation, thus reducing the total sample size requirement. Available data demonstrated the reversibility of BP following short-term lorenlustat treatment. This reversibility, combined with a 4-week single-blind placebo washout period, minimized the possibility of residual effects in phase 2 of treatment. The use of a placebo-controlled period was justified given the short trial duration and clinical balance. Placebo control allows for a fair assessment of treatment efficacy.

[0194] Number of subjects / Number of centers Approximately 60 participants will join 30-40 research centers in the United States.

[0195] Study duration The expected study duration for each participant, from screening to the final visit, is approximately 18 weeks.

[0196] Dosage rationalization This study will evaluate the safety, hypertension-reducing effect, and albumin-reducing effect of lorenstat HBr administered orally at a maximum dose of 25 mg once daily.

[0197] The dosage is based on the results of a Phase 1 first-in-human study (MT-4129-E01), a Phase 1 study (MLS-101-005) in subjects with normal renal function and subjects with severe renal impairment, and a Phase 2 dose range trial (MLS-101-201) in subjects with uncontrolled hypertension.

[0198] In MT-4129-E01, single-dose lorenlustat up to 800 mg and multiple-dose lorenlustat up to 360 mg / day were evaluated in healthy subjects for 7 days via once-daily oral administration. No dose-limiting toxicities were observed. In all cohorts, 9 out of 87 subjects treated with lorenlustat reported dizziness / postural dizziness, compared to 1 out of 29 placebo subjects (3.4%) who reported dizziness / postural dizziness, with no apparent dose relationship.

[0199] In all cohorts, post-dose serum potassium concentrations >5.0 mmol / L were observed in 13 subjects (14.9%) receiving lorenlustat (6 in the single-dose escalation cohort and 7 in the multiple-dose escalation cohort). Only 2 of these 13 subjects had post-dose serum potassium concentrations >5.5 mmol / L (one subject had a post-dose serum potassium concentration >6.0 mmol / L). None of the serum potassium elevations were considered clinically significant, and no dose-dependent trend was observed. No clinically significant findings were observed with respect to vital signs, ECG, or physical examination.

[0200] In MLS-101-005, a single oral dose of 100 mg lorenlustat was safe and well-tolerated in subjects with severe renal impairment (n=8, eGFR < 30 mL / min) and subjects with normal renal function (n=9, eGFR ≥ 90 mL / min). Based on the area under the curve (AUC) and maximum observed plasma concentration (Cmax), renal impairment had no statistically significant effect on the pharmacokinetics (PK) of lorenlustat or its major metabolite. No deaths, serious adverse events (SAEs), or major treatment-related adverse events (TEAEs) were reported in the MLS 101 005 study.

[0201] In the MLS-101-201 Phase 2 study, statistically significant placebo-regulated reductions in SBP were observed at week 8 in the 50 mg once-daily and 100 mg once-daily cohorts, as measured by AOBP, at 9.6 mmHg (p=0.0114) and 7.8 mmHg (p=0.042), respectively.

[0202] Three subjects reported treatment-associated sarcopenic encephalopathy (SAE), one of which was thought to be possibly related to lorenlstatin in a subject with a pre-existing worsening of hyponatremia, which was reversed upon discontinuation of treatment. In each cohort, both actives at once-daily doses resulted in a moderate increase of potassium levels of 0.25 mmol / L at 50 mg once-daily and 0.29 mmol / L at 100 mg once-daily. Six subjects experienced transient increases in serum potassium greater than 6.0 mmol / L, none of which were considered SAEs and all resolved rapidly upon discontinuation or dose adjustment, consistent with the short half-life of lorenlstatin. One of these events was assessed as an error due to sample mishandling. As expected and in a manner similar to ACEi and ARBs, the BP-lowering effect of lorenlstatin resulted in a beneficial, reversible, dose-dependent decrease in eGFR (a measure of renal function). Finally, the selectivity of lorenlstatin in aldosterone inhibition was confirmed, as no inhibition of cortisol levels was observed across the dose range. No noteworthy findings were found in vital signs, physical examination, or ECG parameters.

[0203] This study also provides commercially available dapagliflozin 10 mg QD to subjects who have not previously received SGLT2i or who have opted to take the study-provided dapagliflozin instead of their regular prescription SGLT2i. Dapagliflozin 10 mg has been selected because this dose is approved by the Food and Drug Administration (FDA) for reducing eGFR ≥25 mL / min / 1.73 m 2 This dose is indicated for adults with chronic kidney disease at risk of progressive disease, including those with persistently declining eGFR, end-stage renal disease, cardiovascular death, and hospitalization due to heart failure. In the DAPA-CKD trial, this dose was also shown to reduce albuminuria in both diabetic and non-diabetic patients with CKD (Jongs et al., 2021).

[0204] End of study definition Study completion is defined as the date of the last visit for the last participant in the study. Participants who have completed all periods of the study from screening to the EoS visit (including the EoS visit) and who are not non-participants in OLE are considered to have completed the study. Participants who withdraw from the study early will attend the EoS visit and will not be eligible for the OLE study.

[0205] At study completion or EoS visit, subjects will be questioned about any AEs, concomitant medications, and concurrent surgeries, and these will be recorded on the appropriate pages of the source file and electronic case report form (eCRF). At the final study visit, subjects with persistent AEs deemed serious by the investigator, related to the study drug, or related to the target condition will be required to continue to be followed by the investigator until the AE is resolved, stabilized, or no longer possible / needed for follow-up. Any death or pregnancy occurring during the study (or, for subjects not participating in OLE studies, within 28 days of the subject's last dose of the study drug) must be reported to the study sponsor / designated personnel within 24 hours of the center becoming aware of the event.

[0206] Research behavior The research evaluation plan is presented in the evaluation plan (Table 3).

[0207] research group If a reasonable probability of reversal exists, subjects who do not meet all inclusion criteria or at least one exclusion criterion may be rescreened. Laboratory samples will be retested, and repeated AOBP assessments are permitted in case of technical malfunction. The inclusion of any subjects who meet all eligibility criteria at the time of rescreening will be determined by the investigator and medical monitor.

[0208] Inclusion criteria Participants eligible for inclusion in this study must meet all of the following criteria: (a) Written informed consent obtained prior to the performance of any research-related assessments; (b) Be at least 18 years of age when signing the Informed Consent Form (ICF); (c) At the time of screening, the UACR of the first morning urine was 200-5000 mg / g (inclusive). (d) At the screening visit, the eGFR was ≥30 mL / min / 1.73 m 2 ; (e) When randomly grouped, the AOBP SBP is 135-180 mmHg (including the extreme values). (f) Stabilize with ACEi or ARB for at least 4 weeks prior to screening; (g) At screening, serum cortisol (measured in the morning, blood drawn as close to 8 a.m. as possible) is between 3 µg / dL and 22 µg / dL (inclusive). (h) At the time of screening, the body mass index (BMI) is ≥18 kg / m². 2 ; (i) Fertility-bearing male subjects and fertile female subjects must agree to use an acceptable method of contraception in each study phase, from the screening visit to 28 days after the last dose of study drug; and (j) Willing and able to comply with the research instructions and participate in all planned research visits, and able to provide informed consent.

[0209] Exclusion criteria Subjects who meet any of the following criteria are not eligible for inclusion in this study: (a) A woman who is pregnant, planning to become pregnant, or breastfeeding; (b) Subjects known to have hypersensitivity to lorensta or any of its corresponding excipients; (c) Subjects known to have hypersensitivity to dapagliflozin or any of its corresponding excipients (subjects who have just started dapagliflozin). (d) Treatment or intended treatment with any prohibited medication within the timeframe described herein; (e) Treatment or anticipated treatment with triamterene and amiloride; (f) Participate in a trial involving an investigational device or drug within 4 weeks or 5 half-lives (whichever is longer) prior to the screening visit; (g) Previous treatment with lorenstat or other ASI within 4 weeks prior to the screening visit; (h) At the time of screening, serum potassium > 5.0 mmol / L; (i) Serum potassium > 5.0 mmol / L at the time of randomization (before the first dose of the study drug). (j) At screening, serum sodium <135 mmol / L (in case of hyperglycemia, correction should be made using the Katz formula. Subjects with exclusionary serum sodium are only allowed to be rescreened if two consecutive measurements at least one week apart are ≥135 mmol / L). (k) Total bilirubin > 2 times the upper limit of normal (ULN), except for those diagnosed with Gilbert's syndrome, unless approved by a medical monitor; (l) A clinically significant history of hyponatremia within one year prior to screening; (m) History of adrenal insufficiency or abnormal ACTH stimulation test within 1 year prior to screening; (n) Hospitalized within one year prior to screening for treatment of urgent or emergency hypertension; (o) Current, known or presumed white coat hypertension / significant white coat effect; (p) Current, known or presumed orthostatic hypotension (as defined in SRM); (q) Current, known or presumed autonomic dysfunction; (r) During screening, arm circumference > 55 cm; (s) Subjects with a previously established secondary cause of hypertension are excluded, with the following exceptions: (i) Subjects with a history of sleep apnea are eligible to participate; (i) Subjects with a history of primary aldosteronism were eligible to participate if they discontinued MRA. At randomization, their AOBP SBP increase was <20 mmHg and AOBP SBP was <150 mmHg. MRA treatment could be gradually reduced over a one-week period.

[0210] (t) Use of epithelial sodium channel (ENaC) inhibitors or MRAs, including but not limited to amiloride, triamterene, spironolactone, eplerenone, or fenelinone, within 4 weeks prior to the screening visit and during participation in the study. MRAs are an exception in cases of primary aldosteronism. (u) History of kidney disease associated with autoimmune diseases (lupus, antineutrophil cytoplasmic antibody [ANCA] vasculitis), multiple myeloma or other known paraprotein, infiltrative kidney disease, obstructive kidney disease, cystic kidney disease and kidney transplantation; (v) History of advanced liver disease (including cirrhosis); (w) History of active autoimmune disease or recent or anticipated need for immunosuppressive therapy; (x) Subjects with a history of urosepsis and pyelonephritis, lower limb amputation, genital fungal infection, or perineal necrotizing fasciitis (Fournier's gangrene); (y) A history of heart failure, myocardial infarction, stroke, or transient ischemic attack within 6 months prior to screening. New York Heart Association (NYHA) Class II or higher heart failure requires approval from a medical monitor; (z) Glycated hemoglobin (HbA1c) was present during screening. 1c >10% (>86 mmol / mol) of diabetes; (aa) Major surgery requiring hospitalization performed during the study period or within 4 weeks prior to the screening visit; (bb) In addition to a known history of basal cell and squamous cell skin cancer and any carcinoma in situ, a history of malignant growths must be present within 5 years prior to screening. (cc) Known or suspected abuse of illegal drugs or alcohol within one year prior to the screening visit; (dd) Any other condition that the principal investigators believe would prevent participation in the study.

[0211] Dietary adjustments and blood sugar control All participants will be provided with simple dietary advice that reflects current standards of care, including a low-potassium diet for patients with CKD.

[0212] For subjects with type 2 diabetes mellitus enrolled in the study, given the possibility of starting dapagliflozin, the principal investigator (PI) will work with the subjects before randomization to evaluate their current diet, diabetes treatment regimen, and blood glucose monitoring regimen to determine if any of these aspects need adjustment.

[0213] For subjects using insulin therapy and / or metformin who are prone to hypoglycemic events based on their medical history, additional glycemic monitoring should be incorporated into their standard of care, as determined by the PI and if clinically indicated.

[0214] Lifestyle considerations Caffeine, alcohol and tobacco Subjects will avoid consuming caffeinated or xanthine-containing products (such as coffee, tea, cola drinks, and chocolate) for at least 30 minutes before starting any study-related BP measurements.

[0215] Participants will abstain from alcohol for at least 30 minutes before starting any study-related BP measurements.

[0216] Subjects will abstain from smoking and avoid using cannabis-derived or nicotine-containing products (including nicotine patches, chewing gum, and e-cigarettes) for at least 30 minutes before starting any study-related BP measurements.

[0217] Activities / Exercises Subjects should avoid strenuous exercise for at least 30 minutes before starting any study-related BP measurements and for 24 hours before each blood draw for clinical laboratory testing. Subjects may engage in light recreational activities (such as watching television or reading).

[0218] Study drug administration and management The investigational drug in this study is lorenlustat, along with a matched placebo. Additionally, commercially available dapagliflozin will be provided to participants who have not previously received an SGLT2i or who wish to switch to the study-provided SGLT2i. Participants may also choose to continue using their current prescribed SGLT2i.

[0219] The formulation and manufacture of research drugs follow recognized standard procedures.

[0220] Study drug description The research drug product lorensta is an immediate-release formulation containing recognized safe standard excipients compressed into tablets, including swelling agents, disintegrants, glidants, and lubricants.

[0221] The following section provides an overview of the characteristics of lorensta and a list of matching placebos.

[0222] Table 2: Overview of Lorenzat and Matched Placebo Characteristics

[0223] All packaged tablets will be assigned a unique identification number, which will be used by the Randomization and Trial Supply Management (RTSM) system to identify the contents while maintaining blinding of subjects and sites. Test materials will be identified by batch, lot number, retesting date, and test report.

[0224] Administration and application During the study, regardless of treatment allocation, all participants will take the same number of tablets to maintain blindness. Participants will be instructed to take the tablets orally at approximately the same time each morning.

[0225] Preparation, processing, storage, and inventory Research on drug packaging and labeling The investigational drug will be labeled, packaged, and released in accordance with all applicable laws, regulations, and administrative provisions relating to the implementation of good manufacturing practice and good clinical practice in conducting clinical trials of human drugs.

[0226] Lorenzal, dapagliflozin, and a matched placebo tablet / capsule are packaged in 30 white, round, high-density polyethylene bottles with child-proof caps. Because this study is a DB study, the treatment allocation will not be indicated on the lorenzal label or in the matched placebo tablet / capsule packaging. All other information required by regulations will be present on the label.

[0227] Study drug processing and disposal All investigational drug supplies are for this clinical study only and may not be used for any other purpose. Authorized investigators must maintain a complete record of the disposal of investigational drugs (i.e., a log of the date of receipt, the date of distribution to the subject, the date of return from the subject, and a detailed record of the use of investigational drugs for each study subject).

[0228] After verification, used investigational drugs will be disposed of according to the instructions provided by the sponsor. At the end of the study, all remaining unused supplies will be disposed of in a similar manner. Authorized researchers will record any uncounted supplies in the final inventory record.

[0229] Study drug storage The investigational drug should be stored in an approved storage area accessible only to authorized researchers at room temperature (59℉ to 77℉ [15℃ to 25℃]).

[0230] Study drug inventory The investigational drugs (including placebos) will be stored under adequate safety conditions by appropriate site personnel (e.g., pharmacists) and in accordance with applicable regulatory requirements. Any remaining investigational drugs at the end of the study will be returned to the sponsor or their representative, or destroyed on behalf of the sponsor.

[0231] Researchers or designated personnel must maintain adequate records of all receipts and dispensing of investigational drugs using appropriate inventory records.

[0232] Randomization and blinding Subjects will be randomly assigned (1:1) to two treatment sequences: LP and PL. Randomization numbers and study drug supplies will be assigned using the RTSM. Access to the randomization codes will be controlled and documented.

[0233] The identity of the investigators who receive the investigational drug (lorenlustat or placebo) during the DB treatment period will be kept confidential from investigators, subjects, research center staff, and all personnel involved in the study, with the exception of non-blinded sponsor drug administration staff who will oversee investigational drug allocation and RTSM / distribution compliance at the research center.

[0234] Unblinding of treatment allocations will be considered a protocol deviation unless it is critical to the medical management of the participant. Urgent treatment allocation information will be obtained through secure access to the RTSM system. If possible, the investigator should contact the sponsor before unblinding any participant's treatment allocation. If this is not possible, the sponsor should be notified within 24 hours of the unblinding event. Following unblinding, the participant will cease treatment with the investigational medication but will continue to participate in the study, including all remaining visits and assessments until the EoS visit. The reason for unblinding must be documented in the eCRF.

[0235] Study drug adherence Adherence to the study drug will be assessed at each visit. Assessment will be conducted through direct questioning, counting tablets returned during site visits, and using a drug adherence monitoring platform, and will be documented in source files and relevant case report forms. Dosing deviations should be recorded.

[0236] Records of the quantity of investigational drug distributed to and administered to each subject must be maintained and reconciled with study intervention and adherence records. The start and stop dates of the investigational drug, including the dates of suspension and / or dose reduction, will also be recorded.

[0237] Study drug adherence will be defined as the ratio of the number of doses taken by the subject to the number of doses dispensed. Adherence is defined as taking between 75% and 125% of the provided study drug.

[0238] This study may utilize a drug compliance monitoring platform. This platform will be available via a smartphone application. Built-in reminders and communication systems allow for real-time intervention in case of missed doses, reinforcing appropriate dosing schedules and improving data integrity.

[0239] Dosage adjustment If an unplanned dose adjustment of lorenlustat or SGLT2i occurs at any time during the study, an unplanned visit will be conducted no more than 2 weeks after the dose adjustment to assess safety (see Table 3 for details). Note that the SGLT2i dose should remain stable throughout the study. Subjects who have had an unplanned dose adjustment of lorenlustat or have temporarily discontinued the study drug (i.e., not permanently discontinued the study drug) are eligible to participate in the OLE study.

[0240] Study the safety criteria for drug dosage adjustment or discontinuation. If, at any time during the study, a subject experiences a clinically significant laboratory or medical assessment (e.g., hyperkalemia, hyponatremia, symptomatic hypotension, severely elevated blood pressure, hypercortisolemia, hypocortisolemia, impaired renal function), the laboratory test results will be confirmed using a local laboratory, and the AOBP measurement will be repeated. In consultation with the medical monitor, the investigator may decide to adjust the dosage of the study drug or temporarily or permanently discontinue it. Investigators may temporarily interrupt the study drug without prior consultation with the medical monitor and must discuss their decision and whether the interruption should be converted into discontinuation with the medical monitor within 24 hours. Subjects whose study drug is adjusted will not be withdrawn from the study.

[0241] Companion therapy Any medications or vaccines (including over-the-counter or prescription drugs, recreational drugs, vitamins and / or herbal supplements) that the subject was taking at the time of screening or during the study will be recorded along with the following: (a) Reasons for use (b) Application date, including start and end dates. (c) Dosage information, including dose and frequency Contraindicated treatment Unless otherwise stated, the following medications should be discontinued from the start of the screening visit until the end of treatment (EOT): (a) Prior treatment with lorenstat or other ASIs within 4 weeks or 5 half-lives (whichever is longer) prior to the screening visit.

[0242] (b) Use of ENaC inhibitors or MRAs, including but not limited to amiloride, triamterene, spironolactone, eplerenone, or feneformin, starting 4 weeks prior to the screening visit and during participation in the study. MRAs are an exception in cases of primary aldosteronism.

[0243] (c) Use of antihypertensive medications (AHT) other than lorenrustat, and any medications prescribed at the screening visit during the duration of the study must be approved by the investigator and reported to the medical monitor. Consultation with the medical monitor is recommended.

[0244] (d) Oral corticosteroids should be administered for 3 months prior to the screening visit and for an extended period during participation in the study. Short-term (i.e., ≤2 weeks) use of topical corticosteroids is permitted if the medication was taken ≥1 month prior to randomization.

[0245] (e) Use a sympathomimetic decongestant in the morning of any study-related BP assessment.

[0246] (f) Intramuscular steroids shall be administered 3 months prior to the screening visit until the completion of the study. Inhaled and intraocular corticosteroids are permitted.

[0247] (g) Short-acting nitrates may be taken during the study for angina or underlying heart disease, but if symptoms of hypotension or orthostatic hypertension occur or SBP <110 mmHg is recorded, monitoring should be conducted and the study drug should be discontinued. Chronic, long-acting doses of nitrates are acceptable.

[0248] (h) Digoxin is permitted, but its content should be monitored.

[0249] (i) Admission of subjects requiring treatment with potent CYP3A and CYP3A4 inducers (e.g., apalutamide, carbamazepine, enzalutamide, fosphenytoin, rumacotto, mitotane, phenobarbital, phenytoin, primidone, rifampin, St. John's Wort) must be approved by a medical monitor. Moderate CYP3A and CYP3A4 inducers are acceptable.

[0250] (j) Use of proton pump inhibitors (PPIs) for more than 3 days per week. These events must be avoided for at least 5 days prior to a planned visit.

[0251] (k) Digoxin is permitted, but its content should be monitored.

[0252] The decision to administer prohibited drugs / treatments during the study period was made with the safety of the subjects as the primary consideration.

[0253] Stop / Exit Criteria Research drug discontinuation Subjects who wish to discontinue treatment for any reason may do so at any time during the study.

[0254] Reasons for discontinuing investigational drugs may include: (a) Unavoidable use of prohibited / excluded drugs (b) Administrative decision of the researcher or sponsor. (c) Subjects have a long-term or repeated failure to adhere to the study drug dosing schedule. (d) The site investigator and medical monitor shall consult to determine the occurrence of an AE / SAE / AESI. If the site investigator deems the event urgent, the investigational drug should be suspended, and the investigator should consult with the medical monitor regarding the possibility of restarting the investigational drug at the allocated dose or a reduced dose. (e) Unblinding of drug treatment allocation in study participants (f) The subject becomes pregnant (or wishes to stop using birth control). (g) Any other reason that the researchers believe would prevent the subject from further participation in the trial.

[0255] Subjects who have permanently discontinued the investigational drug will continue to participate in the study, including all remaining visits and assessments until the EoS visit. Subjects who have permanently discontinued the investigational drug will not progress to the OLE study.

[0256] Details regarding subjects who discontinue the study drug will be documented on the appropriate page of the eCRF. If a subject discontinues the study drug due to an adverse event (AE), the investigator may be asked to schedule follow-up until the event is resolved or stabilized.

[0257] Subjects withdraw from study Participants have the right to withdraw from the study at any time for any reason or no reason, and will be required to withdraw upon request. Researchers will encourage participants who wish to withdraw to return for follow-up observation until, and including, a safety follow-up / EW visit. Participants who withdraw early for any reason will not be eligible to participate in the OLE study. These participants will be followed up according to standards of care. If a participant is unable or unwilling to return to the research center, the reason for withdrawal will be recorded. Each participant's right to withdraw will be respected; participants who do not expect further follow-up contact will be asked to state this in writing. Details regarding participants who choose to discontinue participation will be recorded on the appropriate page of the eCRF.

[0258] Reasons for withdrawing from or in the process of withdrawing from research may include, but are not limited to: (a) Subject withdrawal of consent form (b) Cancellation of participation for the convenience of the participants (i.e., due to changes in the participants' willingness or ability to participate in the research visit, such as due to a new job, a change in work plans, or a move to another geographic area). (c) Loss to follow-up (i.e., the researcher has exhausted all reasonable methods of contacting the subject, which should be documented by at least 3 failed attempts to contact the subject) (d) Long-term or recurring non-compliance, defined as non-compliance with protocol requirements set by the researcher or sponsor. (e) death (f) Other reasons If a subject withdraws their consent, the data collected prior to such withdrawal can be retained and used.

[0259] Lost to visit If a subject fails to return for a planned visit multiple times and the research site is unable to contact him / her, the subject will be considered lost to follow-up.

[0260] If the subject fails to return to the clinic for the required study visit, the following actions must be taken: (a) The site must attempt to contact the subject and reschedule the missed visit as quickly as possible, inform the subject of the importance of maintaining the designated visit schedule, and determine whether the subject wishes and / or should continue the study.

[0261] (b) The researcher or designated personnel must make every effort to re-establish contact with the subject. Three telephone calls should be made, and, if necessary, a registered letter should be sent to the subject's last known mailing address or a local equivalent. These attempts to contact the subject should be documented in the subject's medical record.

[0262] (c) If a participant cannot be reached, the site will continue to make efforts to contact the participant at each study visit as planned and record their efforts. No participant will be considered truly lost to follow-up until the end of the trial.

[0263] (d) At the end of the trial, the research site may verify the vital signs of the subjects by contacting their primary care physician or other sources, in accordance with local regulations.

[0264] Research evaluation and procedures Table 3 and the study design section detail the assessment plans and research procedures for all participants and for all study periods. Protocol waivers / exemptions are not permitted. Table 3

[0265] Abbreviations: ACTH, Adrenocorticotropic hormone; AE, Adverse events; AESI, Adverse events of particular interest; AOBP, Automated office blood pressure; ECG, Electrocardiogram; eGFR, Estimated glomerular filtration rate; EoS, End of study; EOT, End of treatment; EW, Early withdrawal; HbA1c 1C Glycated hemoglobin; SAE (serious adverse event); UNS (unplanned visit).

[0266] 1 The screening period is 2 weeks. However, if necessary, the screening window can be extended to 4 weeks without the approval of a medical monitor.

[0267] 2 Only subjects who consistently meet all eligibility criteria are eligible for randomization.

[0268] 3 This study is only applicable to participants who are not participating in the open-label extended study. The study visit window is ±5 days.

[0269] 4 Assessments during unscheduled visits will be conducted as needed clinically.

[0270] 5 The study visit window is ±3 days.

[0271] 6 Written informed consent must be obtained before any research procedure can be carried out.

[0272] 7 A physical examination should be performed during the screening visit, including assessments of the cardiovascular, skin, musculoskeletal, respiratory, digestive, and neurological systems. Height should only be measured during screening. Targeted, limited physical examinations should be performed during other visits. Any abnormalities found should be appropriately documented as part of the medical history or adverse events (AEs).

[0273] 8 Serum potassium must be collected within 3 days prior to randomization, and the researcher must review the values ​​to confirm randomization eligibility.

[0274] 9 During the screening period, participants must submit their first morning urine sample within the first week after screening to determine eligibility. Unplanned visits for submitting the first morning urine sample during the screening period must be at least 7 days earlier than the introductory visit to ensure results are available before eligibility review. Sample UACR must be within the range of 200–5000 mg / g (inclusive) to be considered eligible. Samples will be tested for albumin, protein, and creatinine.

[0275] 10 A 24-hour urine collection kit will be provided to participants during the initial visit to take home. Some urine samples will be retained for subsequent biomarker analysis.

[0276] 11 Participants must begin urine collection on Day 1 and submit 24-hour urine samples at the randomization visit in Week 0. The 24-hour urine sample will be used to detect albumin, protein, creatinine, sodium, potassium, cortisol, and aldosterone. A portion of the urine sample will be retained for subsequent analysis.

[0277] 12 This is only applicable to women of childbearing potential. A serum pregnancy test is performed during screening. All postmenopausal women must have their follicle-stimulating hormone (FSH) levels tested at screening to confirm menopause. A urine pregnancy test is performed during other visits. If the urine pregnancy test is positive, a serum pregnancy test must be performed at a local laboratory to confirm the result.

[0278] 13 All adverse events (AEs) and special concerns (SAEs) must be collected from the time the informed consent is signed until the subject completes the end-of-study (EoS / EW) visit or transitions to the open-label extension study. All adverse events of particular concern (AESIs) must be collected from the start of treatment until the completion of the EoS / EW visit or transition to the open-label extension study.

[0279] 14 This is only applicable to SGLT2i-naïve patients or patients switching to a sponsor-provided SGLT2i.

[0280] 15 Serum samples were retained for subsequent biomarker analysis. Whole blood samples were collected during randomization for subsequent proteomic and genomic analysis. Midstream urine samples were also collected for subsequent biomarker analysis.

[0281] 16Blood and urine samples will be processed and stored according to the laboratory manual. Blood samples for cortisol testing should be collected around 8:00 AM if possible, and no later than 10:00 AM.

[0282] 17 Subjects need to have their blood drawn once before administration and again 1–2 hours after administration.

[0283] 18 If clinical symptoms suggest a decrease in cortisol (including serum cortisol <3 µg / dL, or <10 µg / dL accompanied by symptoms of low cortisol), an ACTH (tecokinetic) stimulation test should be performed during an unplanned visit.

[0284] Informed consent must be obtained before any trial-related activities.

[0285] During the screening process, participants will be given a card explaining that they are participating in a trial and providing contact information for staff at the relevant trial site.

[0286] Compliance with research design requirements is necessary and required for research activities.

[0287] All participants should attend the study visit after fasting for at least 8 hours, unless the researchers determine there is a medical reason for not fasting.

[0288] Any deviation from the protocol and / or the research behavior described in the SRM will be captured and recorded as a protocol deviation.

[0289] If an acute safety issue occurs or becomes apparent, the sponsor should be consulted immediately to determine whether the subject needs a dose adjustment or to discontinue the investigational drug.

[0290] All screening assessments must be completed and reviewed to confirm that potential participants meet all eligibility criteria. Researchers will maintain a screening log to record details of all screened participants and to verify eligibility or document reasons for screening failures (if applicable).

[0291] The source data for the clinical assessments performed and recorded in the eCRF must be available and typically the subject's medical records. Additional records considered as source data include, but are not limited to, laboratory reports, AOBP, and ECG assessments.

[0292] Unless otherwise specified in this section, assessments should be conducted in accordance with the institution’s standard of practice. Efforts should be made to limit deviations between assessments.

[0293] You can call between study visits to follow up on study medication adherence and / or to clarify any questions or concerns that subjects may have during general follow-up.

[0294] Clinical laboratory testing The central laboratory will conduct clinical safety laboratory tests according to the time points specified in the evaluation plan (Table 3). Analytes used for clinical safety laboratory tests are listed in Table 4. Investigators must review laboratory reports, document this review, and record any clinically significant changes that occur during the study as adverse events (AEs). Laboratory reports must be archived along with the source documents. All laboratory tests with values ​​deemed clinically significant abnormalities during the study or after the last dose of the study drug should be repeated until the values ​​return to normal or baseline or are no longer considered clinically significant by the investigator or medical monitor. If a clinically significant value does not return to normal / baseline within a period deemed reasonable by the investigator, the cause should be identified and the sponsor notified.

[0295] Table 4: Clinical Laboratory Analytes

[0296]

[0297] Demographic data and other baseline characteristics Medical history data will be collected during the screening visit. For female participants with fertility potential, the date of their last menstrual period should be recorded. Data will be updated appropriately during subsequent visits.

[0298] Accompanying drugs Detailed medication history and surgeries for each subject will be recorded during screening visits. Concurrent medications (especially changes in medication) for each patient will be recorded at each planned visit.

[0299] The investigator may discontinue any drug that he or she believes will interfere with the investigational drug (see “Discontinued Therapies”).

[0300] Demographic data Demographic data of the participants will be collected during the screening visit. This data includes year of birth, age, sex, ethnicity, and other relevant baseline characteristics.

[0301] Efficacy evaluation First morning urine measurement First morning urine collection will be performed according to the assessment plan (Table 3) and described in the SRM. Subjects will be given a first morning urine collection kit to take home. A midstream sample of the first morning urine will be collected upon waking in the morning and before administration of the study drug. The date and time of urine collection should be recorded. A detailed description of urine collection and storage will be provided in the laboratory manual and instructions will be provided to subjects. During screening, a first morning urine sample should be brought in within the first week after the screening visit to determine eligibility. Unplanned visits to return the first morning urine to subjects during screening must be conducted at least 7 days prior to the week 0 visit to ensure results are available for eligibility review. The sample must be ≥300 mg / g to meet the eligibility criteria. Albumin, protein, and creatinine levels in the sample will be assessed. 24-hour urine measurement.

[0302] 24-hour urine collection will be performed according to the assessment plan (Table 3).

[0303] Subjects will be provided with a 24-hour urine collection kit to take home and collect urine prior to the analysis day outlined in the assessment plan (Table 3). 24-hour urine collection will begin after the first morning urine and continue for 24 hours, with the last urine collected the following morning. The start and end dates and times of urine collection should be recorded.

[0304] 24-hour urine samples will be used to measure 24-hour albumin, protein, sodium, potassium, cortisol, and aldosterone. Aliquots of urine will be retained for future evaluation.

[0305] Blood pressure measurement BP measurements will be performed according to the assessment plan (Table 3). This is crucial for classifying individuals and recording the effects of research treatments; therefore, BP should be measured using an automated BP device at the sites provided by the sponsor. All participating sites should use identical automated BP devices, and the devices should be managed by qualified personnel. Any deviations from this plan must be approved by the sponsor before implementation. Subjects should be seated when performing AOBP assessments. Furthermore, the same person should use the BP device for the designated subjects whenever possible at each visit, and measurements should be performed using the same arm of the subject and an appropriate armband size, as determined during the screening visits.

[0306] Details of the BP procedure (data measurement and transmission) will be provided, including subject preparation (e.g., arm selection, arm position, arm cuff size).

[0307] Heart rate will also be recorded and collected along with all AOBP measurements. Seated and standing SBP and DBP, along with their corresponding heart rates, will be recorded and collected. Orthostatic BP changes will be calculated and recorded.

[0308] Biomarker analysis For efficacy and safety assessment of the study, biomarkers will be measured in a central laboratory to allow for estimation of changes relative to baseline. These measurements will be performed according to the assessment plan (Table 3).

[0309] Population pharmacokinetic assessment At week 2, 4, 10, and 12 visits (Table 3), blood samples will be drawn from subjects at troughs (i.e., immediately before administration) and 1–2 hours after administration for popPK analysis. For visits involving PK sample collection, subjects should arrive at the clinic before taking the day's dose of the study drug. The time of each blood draw and the time of study drug administration on the day of PK blood draw will be recorded on the corresponding eCRF page. Instructions for the collection, preparation, handling, and transport of PK samples are provided in the laboratory manual.

[0310] Security assessment physical examination During screening, a comprehensive physical examination will be performed by trained medical personnel, and this examination should include assessments of the cardiovascular, skin, musculoskeletal, respiratory, gastrointestinal, and neurological systems. Height will only be measured at screening. At other visits, a restricted, symptom-oriented physical examination should be performed. Any abnormal changes relative to baseline should be documented in the source file. New or worsening clinically significant abnormalities should be documented as AEs on the AE eCRF.

[0311] vital signs In addition to blood pressure and heart rate, body temperature and respiratory rate will be assessed while the subject is seated. Subjects should be seated for at least 5 minutes before the measurements are taken.

[0312] electrocardiogram A single 12-lead ECG will be recorded according to the assessment plan (Table 3). Clinically significant abnormal ECG findings should be reported as adverse events (AEs) and treated as clinically appropriate. Additionally, a 12-lead ECG assessment will be performed on the subject, and serum potassium will be repeated as described below.

[0313] Clinical safety laboratory testing Blood and urine samples will be collected and will be tested for clinical safety by the central or local laboratory according to the evaluation plan (Table 3). Serum sodium, potassium, and creatinine concentrations will be collected according to local guidelines and evaluated at the local laboratory. Instructions for the collection, preparation, handling, and transport of central clinical laboratory samples are provided in the laboratory manual for use in studies. Analytes used for clinical safety laboratory testing are listed in Table 4.

[0314] Subjects will be given a 24-hour urine collection kit to take home and collect urine as outlined in the assessment plan (Table 3). Urine albumin, total protein, free cortisol, aldosterone, sodium, potassium, and creatinine levels will be analyzed. Subjects with morning serum cortisol levels >35 µg / dL will undergo unplanned 24-hour urine collection for 24-hour urinary free cortisol assessment.

[0315] Adrenocorticotropic hormone stimulation test An unplanned ACTH (ticokinetic) stimulation test will be performed if morning serum cortisol is <3 µg / dL, or if morning serum cortisol is <10 µg / dL, accompanied by symptoms of hypocortisolism such as weakness, loss of appetite, involuntary weight loss, hyponatremia, hypoglycemia, plus clinical findings of orthostatic hypotension, syncope precursors, or syncope. Instructions for performing the test, including the administration of ticokinetic and the timing, handling, storage, and delivery of test samples in the central laboratory, are provided in the laboratory manual.

[0316] Pregnancy test: Pregnancy testing is only required for women of childbearing potential (WOCBP). Serum pregnancy testing will be performed at screening. Urine pregnancy testing will be performed at other visits according to the assessment plan (Table 3). If the urine pregnancy test is positive, a serum pregnancy test will be collected at a local laboratory to confirm the result.

[0317] Adverse events, serious adverse events and other safety reports Researchers and any qualified designated personnel are responsible for detecting, documenting, and recording events that meet the definition of AE or SAE, and continue to be responsible for following up on all AEs and SAEs.

[0318] Time period and frequency for collecting AE and SAE information For subjects transitioning to OLE, all adverse events (AEs) and subarachnoid injuries (SAEs) will be collected from the signing of the study ICF until the immediate eligibility assessment. All adverse events resulting in sequelae (AESIs) will be collected from the start of randomization until the immediate eligibility assessment. For subjects not participating in OLE, all AEs and SAEs will be collected from the signing of the ICF until 28 days after the last dose of study drug. All AAESIs will be collected from the start of randomization until the EOS visit.

[0319] Adverse events that occur before the start of treatment with the investigational drug (lorenlustat or placebo) at randomization but after informed consent has been obtained will not be considered TEAEs. Under no circumstances should SAEs and AESIs be reported later than 24 hours after the start of treatment. Investigators will submit any updated SAE data to the sponsor within 24 hours of receiving it.

[0320] Researchers are not obligated to proactively seek information about adverse events (AEs) or severe adverse events (SAEs) after the end of participation in the study (i.e., after the completion of the EoS / EW visit). However, if a researcher becomes aware of any SAE (including death) at any time after a subject has withdrawn from the study, and he / she believes that the event is reasonably related to the investigational drug or participation in the study, the researcher must immediately inform the sponsor.

[0321] If the study drug is discontinued, all adverse events (AEs) and safety emergencies (SAEs) throughout the discontinuation process will be collected. If the study drug is permanently discontinued for any reason, the reason will be documented and the subject should be encouraged to remain in the study so that important safety information can be obtained. All AEs and SAEs that led to the discontinuation of the study drug or the termination of the study will be collected. Once a subject withdraws their consent to participate in the study, no further information can be collected from the subject.

[0322] Methods for detecting AE and SAE When detecting adverse events (AEs) and / or severe adverse events (SAEs), care should be taken to avoid introducing bias. Open-ended and unguided verbal questioning of subjects is the preferred method for inquiring about the occurrence of AEs.

[0323] Researchers will seek information about adverse events (AEs) at each participant contact. All AEs will be recorded, whether reported by the participants or recorded by the researchers.

[0324] At all subject evaluation time points, a consistent undirected questioning approach should be used to elicit AE information. Examples of undirected questions include the following: (a) "How have you been feeling since your last research visit?" (b) "Have you had any new or changed health problems since your last visit here?" AE and SAE follow-up Following the initial AE / SAE report, investigators are required to proactively follow up with each participant during subsequent visits / contacts. All SAEs and AESIs will be followed up until they are resolved, stabilized, have alternative explanations, or the participant is lost to follow-up.

[0325] SAE's regulatory reporting requirements It is essential for researchers to immediately notify the sponsor / designated personnel (within 24 hours) of the SAE to ensure compliance with regulatory obligations and ethical responsibilities regarding the safety of subjects and the safety of research interventions in clinical studies.

[0326] Sponsors are responsible for informing local regulatory authorities and other regulatory bodies about the safety of the investigational intervention in clinical studies. Sponsors will comply with country-specific regulatory requirements related to reporting safety to regulatory authorities, IRBs, and investigators.

[0327] Investigators who receive an Investigational New Drug (IND) safety report from the sponsor that describes the SAE or other specific safety information (such as an SAE overview or list) will review the report, file it with the IB, and inform the IRB as appropriate, based on local and institutional requirements.

[0328] An IND safety report for suspected unexpected serious adverse reactions must be prepared in accordance with local regulatory requirements and sponsor policies and forwarded to the investigator.

[0329] pregnancy All pregnancy details of female participants and female partners of male participants will be collected from the start of screening until just before the start of the OLE study or until 28 days after the last participant visit (for participants not participating in the OLE study).

[0330] If a pregnancy is reported, the researcher will record the pregnancy information on the appropriate form and submit it to the sponsor within 24 hours of learning that the female subject or the male subject's female partner is pregnant (after obtaining the necessary informed consent from the female partner).

[0331] Although pregnancy itself is not considered an AE or SAE, any pregnancy complications or termination of pregnancy for medical reasons will be reported as an AE or SAE.

[0332] Abnormal pregnancy outcomes (such as spontaneous abortion, fetal death, stillbirth, congenital abnormalities, and ectopic pregnancy) are considered SAEs and will be reported as SAEs.

[0333] Participants / pregnant female partners will be followed up to determine pregnancy outcomes. Researchers will collect follow-up information on participants / pregnant female partners and newborns and forward the information to the sponsor / designated personnel.

[0334] Any post-study pregnancy-related SAE that the investigator deems reasonably related to the investigational drug will be reported to the sponsor. While the investigator is not obligated to actively seek this information from previous study participants / pregnant female partners, he or she may become aware of SAEs through voluntary reporting.

[0335] Death In OLE studies, any fatal adverse events (AEs) occurring in subjects transitioning to OLE from the signing of the study ICF until the initial assessment is performed. For subjects not participating in OLE, any fatal AEs will be collected from the signing of the ICF until 28 days after the last dose of the study drug. All fatal AEs are considered SAEs and must be reported to the sponsor (or designated person) and / or the study medical monitor within 24 hours of becoming aware of the event.

[0336] All deaths occurring during the AE reporting period specified in the plan, regardless of the cause, will be recorded on the eCRF, reported in the Security Incident Report Form, and promptly sent to the sponsor / designated personnel.

[0337] When recording a death on an eCRF or Safety Event Reporting Form, the event or condition that caused or contributed to the fatal outcome should be recorded as a single medical concept whenever possible. When reporting a SAE, "death" should not be reported as an SAE term, but rather as the outcome of the specific SAE, unless the events preceding death are unknown. If death is attributable to overall disease progression and cannot be attributed to other medical concepts, disease progression should be reported as an event term. If an autopsy was performed, an autopsy report should be provided.

[0338] Adverse events of particular interest Researchers are required to report adverse events of particular interest to the sponsor / designated personnel immediately (i.e., no more than 24 hours after becoming aware of the event), regardless of their causal relationship with the investigational drug treatment. The most appropriate diagnosis should be recorded, or if a diagnosis cannot be established, the abnormal laboratory value should be recorded on a safety event report form and immediately reported to the sponsor / designated personnel as an AESI or, and / or SAE.

[0339] Note: If any of the following events is reported as an SAE, a separate AESI form does not need to be completed.

[0340] The AESI for all investigational drugs (lorenrustat and placebo) are as follows: (a) Adjustments to the dosage of research drugs due to hyperkalemia (e.g., dose reduction, dose suspension, or permanent dose cessation). (b) Adjustments to the dosage of investigational drugs due to hyponatremia (e.g., dose reduction, dose suspension, or permanent dose cessation). (c) Low blood pressure with symptoms (e.g., dizziness, lightheadedness, syncope, or fainting). (d) Severely elevated blood pressure (AOBP SBP > 180 mmHg or AOBP DBP > 110 mmHg) (e) Adjustment of study drug dosage due to Cushing's syndrome (morning serum cortisol >35 µg / dL, confirmed by 24-hour urinary free cortisol). (f) Discontinuation of investigational drugs due to hypocortisol confirmed by ACTH (tecoclidin) stimulation test. (g) Overdose of the investigational drug or dapagliflozin (h) Adjustments to the dosage of research drugs due to impaired renal function (e.g., dose reduction, dose suspension, or permanent dose cessation). hyperkalemia The incidence of hyperkalemia will be monitored regularly in all subjects. This includes baseline screening and regular intervals (as indicated in the assessment plan [Table 3]). If the investigators deem it necessary to confirm serum potassium or sodium concentrations, they may perform a repeat test at any time.

[0341] If the PI believes the hyperkalemia is spurious (e.g., based on hemolysis), a repeat value should be obtained within 48 hours, and the medical monitor should be contacted while awaiting confirmatory results to discuss the possibility of suspending the study drug. Treatment for hyperkalemia, including potassium binders, is permitted. If a new hyperkalemia treatment is started during the study, the medical monitor should be informed.

[0342] In any event during an ECG, if the ECG reveals new signs consistent with hyperkalemia, the subject should be referred to an urgent care center or other appropriate care facility for further evaluation and intervention, in consultation with a medical monitor.

[0343] Any subject with serum potassium <5.5 mmol / L will continue to be treated with the study drug.

[0344] Any subject with serum potassium >5.5 mmol / L but ≤6.0 mmol / L will continue to receive the study drug and undergo a repeat test (retest) within 72 hours of the initial local laboratory result.

[0345] (a) If serum potassium is <5.5 mmol / L after retesting, continue with the same dose of the study drug.

[0346] (b) If serum potassium is >5.5 mmol / L and ≤6.0 mmol / L after retesting, the dose of the study drug should be reduced and serum potassium should be retested at the next study visit (or within 2 weeks, whichever is earlier).

[0347] Any subject with serum potassium >6.0 mmol / L but ≤6.5 mmol / L will immediately discontinue the study drug and undergo repeat serum potassium and 12-lead ECG tests within 24 hours of the initial local laboratory results. The study drug will remain discontinued until the repeated serum potassium and ECG results are evaluated.

[0348] (a) If serum potassium is ≤5.5 mmol / L after retesting, the same dose of the study drug shall be restarted and serum potassium shall be retested at the next planned study visit.

[0349] (b) If, after retesting, serum potassium is >5.5 mmol / L but ≤6.0 mmol / L and ECG is normal, restart with a reduced dose of the study drug and retest serum potassium within 72 hours. If the retested potassium is still >6.0 mmol / L, continue with the following procedure.

[0350] (c) If serum potassium remains >6.0 mmol / L, permanently discontinue the study drug and repeat serum potassium and ECG within 48 hours of the most recent assessment, continuing to monitor serum potassium until the value is ≤5.1 mmol / L. Consult with a medical monitor.

[0351] Any subject with serum potassium > 6.5 mmol / L should immediately discontinue the study drug and be transferred to an urgent care center or other appropriate facility for further evaluation (including repeat serum potassium and ECG) and intervention. Continue discontinuation of the study drug until the results of repeat serum potassium and ECG in an emergency setting are known and assessed. Consult with the medical monitor.

[0352] (a) If serum potassium is ≤5.5 mmol / L after retesting, the same dose of the study drug shall be restarted and serum potassium shall be retested at the next planned study visit.

[0353] (b) If, after retesting, serum potassium is >5.5 mmol / L and ≤6.0 mmol / L and ECG is normal, restart the study drug at a reduced dose and retest serum potassium within 72 hours. If the retested serum potassium is >6.0 mmol / L, continue as follows.

[0354] (c) If serum potassium remains >6.0 mmol / L, permanently discontinue the study drug, repeat serum potassium and ECG within 48 hours of the most recent assessment, and continue monitoring serum potassium until the value is ≤5.1 mmol / L. Consult with the medical monitor.

[0355] hyponatremia The incidence of hyponatremia will be monitored regularly in all subjects. This includes baseline screening and regular intervals, as indicated in Table 3. If the investigators deem it necessary to confirm serum sodium concentration, they can perform a repeat test at any time.

[0356] Any subject with serum sodium <135 mmol / L (corrected for hyperglycemia) will be required to return to the clinic for a repeat test (retest) of their serum sodium levels as processed at their local laboratory, as follows: (a) If a subject experiences mild hyponatremia (defined as corrected serum sodium <135 mmol / L and ≥130 mmol / L) and remains asymptomatic, sodium levels should be rechecked within the next 72–96 hours. Based on the PI's opinion (and, if necessary, in conjunction with the medical monitor), the study drug may be continued or discontinued until the recheck.

[0357] (i) If the corrected serum sodium returns to normal after retesting (i.e., ≥135 mmol / L), the study drug can be restarted or continued at the same dose as before the event occurred.

[0358] (ii) If the corrected serum sodium level after retesting is still <135 mmol / L and ≥130 mmol / L, the results should be discussed with the medical monitor to determine whether to continue the study drug, suspend the study drug, or reduce the study drug dosage.

[0359] (b) If a subject experiences moderate or severe hyponatremia (defined as corrected serum sodium <130), the study drug should be discontinued and sodium levels should be rechecked within the next 48 hours.

[0360] (i) If the corrected serum sodium level returns to normal after a follow-up examination (i.e., ≥135 mmol / L), the study drug should be restarted at a lower dose. The investigator should consult with the medical monitor to discuss the potential causes of hyponatremia.

[0361] (ii) If the corrected sodium level after retesting is still <135 mmol / L, the study drug should be discontinued and serum sodium levels should be retested at least weekly until the value returns to normal (i.e., ≥135 mmol / L).

[0362] (c) If a subject experiences severe hyponatremia (defined as a corrected serum sodium level <125 mmol / L) accompanied by signs and symptoms such as nausea, vomiting, confusion, headache, loss of energy and fatigue, and muscle weakness, the subject should be asked to go to the emergency room for re-examination, follow-up, examination, and hospitalization (if clinically necessary). The medical monitor should be contacted to discuss the appropriateness of ongoing study participation based on the etiology, emergency room treatment, and repeated sodium levels. If the incidence of severe hyponatremia cannot be explained, the study drug should be permanently discontinued. If the corrected sodium level returns to a level consistent with moderate or mild hyponatremia upon re-examination, the actions described above should be followed.

[0363] Symptomatic hypotension and asymptomatic hypotension If a subject experiences symptoms of low blood pressure during the study (such as dizziness, lightheadedness, presyncope, or syncope), the researcher will communicate with the medical monitor to manage the symptoms. A reduction in the study drug dosage may be considered in accordance with the instructions in the SRM.

[0364] In cases of asymptomatic hypotension (AOBP < 65 mmHg, DBP < 65 mmHg, or DBP between ≥ 65 mmHg and < 85 mmHg plus AOBP < 100 mmHg), the lorenlustat dose should be reduced first. If the subject experiences symptoms of hypotension (e.g., frequent dizziness, syncope, lightheadedness) but does not reach the hypotension BP threshold defined above, the study drug dose should be reduced. Reducing the study drug dose is the first step. If symptoms and / or the BP threshold persist after dose reduction, consultation with the medical monitor is recommended to discontinue the study drug in the subject.

[0365] Severely elevated blood pressure Any prescribed AHT regimen for subjects with systolic AOBP > 180 mmHg or diastolic AOBP > 110 mmHg, as described in the SRM. If additional medication is required, doxazosin 1 mg is recommended, but medication addition shall be decided in consultation between the investigator and the medical monitor.

[0366] Cushing's syndrome All subjects will be monitored for signs and symptoms of Cushing's syndrome (i.e., new or unexplained worsening of the following: hyperglycemia, hypertension, weight gain, abdominal stretch marks, and round face).

[0367] Any subject with serum cortisol >35 µg / dL (morning measurement) will undergo unplanned 24-hour urine collection for 24-hour urinary free cortisol assessment. Subjects will continue with the study drug without dose adjustment.

[0368] (a) Any subject with a 24-hour urinary free cortisol level >40 µg / 24h and ≤50 µg / 24h will be subject to a repeat test after 4 weeks.

[0369] (b) Any subject with a 24-hour urinary free cortisol level >50 µg / 24h will have their study drug dose reduced by 50% and will undergo a repeat test after 4 weeks.

[0370] hypocortisol Serum cortisol levels will be measured according to the assessment plan, with blood drawn as close to 8 a.m. as possible and before 10 a.m.

[0371] (a) Any subject with morning serum cortisol <3 µg / dL will undergo ACTH stimulation testing within 1 week of knowing the results.

[0372] (b) Any subject with a morning serum cortisol level <10 µg / dL and ≥2 signs and symptoms of adrenal insufficiency (i.e., weakness, loss of appetite, involuntary weight loss, hyponatremia, hypoglycemia) plus a clinical finding of orthostatic hypotension, syncope, or syncope will be subject to ACTH stimulation testing within 48 hours of knowing the results.

[0373] (i) If associated with a concurrent acute illness (including COVID-19), the timing of the ACTH stimulation test will be determined by the investigator, but may be delayed by no more than 5 days from the time the morning serum cortisol results are known.

[0374] (c) Any subject with a morning serum cortisol level <10 µg / dL and ≥2 signs and symptoms of adrenal insufficiency, but without BP or laboratory abnormalities, will be subject to ACTH stimulation testing within 1 week of knowing the results.

[0375] (d) Any subject with morning serum cortisol <10 µg / dL and accompanied by asymptomatic orthostatic hypotension and hypoglycemia or hyponatremia will be subject to ACTH stimulation test within 1 week of knowing the results.

[0376] (e) Any subject diagnosed with adrenal insufficiency by ACTH testing will be immediately discontinued from the study medication and placed under specialist care (e.g., by an endocrinologist / urgent care) for further management. In such cases, the subject is not required to withdraw from the study.

[0377] Safety monitoring considerations The DMC will meet periodically to monitor research. The primary function of this committee is safety monitoring. As part of these reviews, the DMC will receive an overview of research conduct procedures, as well as unblinded safety and efficacy data. For safety reasons, the DMC may recommend withdrawal.

[0378] According to the Clinical Trial Sponsor Guidelines, the full scope and responsibilities of the DMC will be described in the DMC Bylaws: the establishment and operation of the Clinical Trial Data Monitoring Committee.

[0379] Statistical considerations This is a randomized, placebo-controlled crossover study with a two-phase, two-sequence (2×2) design. Details of the statistical analysis, including the handling of missing values, will be described in the Statistical Analysis Plan (SAP). This section provides key elements of the statistical methods anticipated when planning the study.

[0380] Analysis set The intention-to-treat (ITT) analysis set included all participants, regardless of whether they received treatment.

[0381] The full analysis set (FAS) will include all subjects who have received at least one dose of the study drug. Subjects will be categorized according to treatment allocation.

[0382] The Safety Analysis Set (SAF) will include all subjects who received at least one dose of the study drug. Subjects will be categorized based on the actual treatment received.

[0383] The popPK analysis set will include all subjects who have received at least one dose of lorenlustat and have had at least one evaluable popPK sample collected. Subjects in this analysis set will be categorized according to the treatment received.

[0384] Statistical analysis Unless otherwise specified, demographic and baseline characteristics will be aggregated for the ITT analysis set by treatment group. Unless otherwise specified, efficacy outcomes will be analyzed using the FAS. Safety outcome analysis will be performed on the SAF.

[0385] For continuous variables, descriptive statistics will be summarized for n, mean, standard deviation, median, 25th percentile, 75th percentile, minimum, and maximum. The frequency and percentage of observed levels for all categorical variables will be reported.

[0386] The primary analysis to estimate the primary efficacy will assess the superiority of lorenlstat treatment over placebo in terms of change in AOBP and SBP relative to baseline at week 4 of the study. Each subject will contribute two pairs of treatment observations (change at week 4 relative to week 0 and change at week 12 relative to week 8). Repeated measures mixed models (MMRM) will be used in the analysis, including the treatment group (lorenlstat and placebo) as a fixed effect, the sequence (LP and PL) and treatment period (phase 1 and phase 2), the subject (sequence) as a random (repeated) effect, and the baseline (week 0 and week 8) AOBP and SBP as covariates. The least squares mean of the change relative to baseline at week 4 of the study for each group, along with estimates of the relevant standard error and 90% confidence interval (CI), will be reported. The primary analysis will be based on the evaluation of the least squares estimates of the treatment group effect, which represents the placebo-modulated effect of the lorenlstat treatment period. Prior to the primary estimation, a general linear model with effect on sequence, subject (sequence), period, and treatment will be fitted to assess the presence of possible residual / sequence effects.

[0387] The statistical methods for secondary endpoints and exploratory endpoints will be described in SAP.

[0388] Alpha value: The overall alpha (α) value is set to 0.05 for one-sided applications. No adjustment will be made for multiplicity.

[0389] Security Analysis AEs will be tabulated according to the Systemic Organ Classification (SOC) of the Medical Dictionary of Regulatory Activities (MedDRA), Preferred Terminology (PT), and according to severity, causality, and time of occurrence.

[0390] Sample quantity determination Assuming 14 mmHg as the standard deviation of variation and a one-sided α of 0.05, approximately 60 subjects randomly assigned in a 1:1 ratio to two sequences (LP and PL) would provide 85% power to detect placebo-modulated changes in AOBP SBP at a level of at least 5.5 mmHg.

[0391] Missing data processing Missing value imputation will be described in SAP.

[0392] Subgroup analysis of the plan Subgroup analyses will be performed on the FAS population for the primary endpoint and selected secondary endpoints, based on age, sex, race, and BMI.

[0393] result Based on the research described above, it was determined that lorenstat HBr is effective in treating subjects with chronic kidney disease (CKD).

[0394] Based on the studies summarized above, it was determined that lorenstat HBr is effective in treating hypertension in subjects with chronic kidney disease (CKD) and hypertension.

[0395] Based on the studies summarized above, a 24-hour urine or first morning urine albumin-to-creatinine ratio (UACR) of 300-3500 mg / g and / or an estimated glomerular filtration rate (eGFR) of at least 30 mL / min / 1.73 m 2 Or at least 45 mL / min / 1.73m 2 And less than 90 mL / min / 1.73m 2 Lorenzat HBr was effective in treating subjects who were taking the maximum tolerated dose of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs).

[0396] Based on the studies described above, lorenstat HBr was found to be effective in treating the following subjects: (a) those without type 1 diabetes; (b) those with serum cortisol levels between 3 μg / dL and 22 μg / dL in the morning; and (c) those with serum cortisol levels between 18 and 40 kg / m³. 2 (d) having a body mass index (BMI); and / or (e) having a serum potassium level less than 4.8 mmol / L; and / or having a serum sodium level greater than 135 mmol / L.

[0397] Based on the studies summarized above, lorensta HBr was found to be effective in treating subjects with chronic kidney disease (CKD) who were being treated with angiotensin-converting enzyme inhibitors (ACEi) and / or angiotensin receptor blockers (ARBs).

[0398] Based on the studies summarized above, lorensta HBr was found to be effective in treating subjects with chronic kidney disease (CKD) who were being treated with the maximum tolerated dose of angiotensin-converting enzyme inhibitors (ACEi) and / or angiotensin receptor blockers (ARBs).

[0399] Based on the research described above, it is determined that: (a) When administered with lorensta or a pharmaceutically acceptable salt thereof, the amount of ACEi or ARB is lower than the amount at which ACEi or ARB inhibitors are effective in treating CKD when administered alone. (b) When administered with lorenlstat or a pharmaceutically acceptable salt thereof, the amount of ACEi or ARB is lower than the amount at which ACEi or ARB is effective in treating CKD when administered without lorenlstat or a pharmaceutically acceptable salt thereof; and / or (c) When administered without the use of lorenstat or a pharmaceutically acceptable salt thereof, an amount of ACEi or ARB that is effective in treating CKD causes one or more side effects in a subject, wherein such one or more side effects are not caused by the amount of ACEi or ARB and lorenstat or a pharmaceutically acceptable salt thereof that is effective in treating CKD when administered together.

[0400] Based on the studies described above, it was determined that when lorensta or a pharmaceutically acceptable salt thereof is administered in combination with ACEi or ARB, it is more effective in treating subjects than when the same amount of each drug is administered alone.

[0401] Based on the research summarized above, the effective amount of lorenstat or its pharmaceutically acceptable salts was determined to be: (a) 10-15 mg daily; (b) 12.5 mg daily; (c) 20-30 mg daily; (d) 25 mg daily; (e) 40-60 mg daily; or (f) 50 mg daily.

[0402] Based on the research summarized above, it was determined that the method is effective when the stated amount of lorenstat HBr is administered in the morning.

[0403] Based on the studies outlined above, it was determined that administering a dose of lorenstat or a pharmaceutically acceptable salt thereof once daily and a dose of dapagliflozin once daily to a subject with chronic kidney disease (CKD) was sufficient to treat the subject's CKD.

[0404] Based on the studies summarized above, it was determined that the combination of lorenstahat HBr and dapagliflozin was effective in treating subjects whose 24-hour urine or first morning urine albumin-to-creatinine ratio (UACR) was 200-3500 mg / g and / or whose estimated glomerular filtration rate (eGFR) was at least 30 mL / min / 1.73 m2 or at least 45 mL / min / 1.73 m2 and less than 90 mL / min / 1.73 m2, when taking the maximum tolerated dose of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB).

[0405] Based on the studies described above, the combination of lorenstat HBr and dapagliflozin was found to be effective in treating the following subjects: (a) without type 1 diabetes; (b) with serum cortisol levels between 3 μg / dL and 22 μg / dL in the morning; (c) with a body mass index (BMI) of 18–40 kg / m²; (d) with serum potassium levels less than 4.8 mmol / L; and / or (e) with serum sodium levels greater than 135 mmol / L.

[0406] Based on the studies summarized above, the combination of lorensta HBr and dapagliflozin has been shown to be effective in treating patients with chronic kidney disease (CKD) who are being treated with angiotensin-converting enzyme inhibitors (ACEi) and / or angiotensin receptor blockers (ARBs).

[0407] Based on the studies summarized above, the combination of lorensta HBr and dapagliflozin has been shown to be effective in treating hypertension in subjects with hypertension and chronic kidney disease (CKD) who are being treated with angiotensin-converting enzyme inhibitors (ACEi) and / or angiotensin receptor blockers (ARBs).

[0408] Based on the studies summarized above, the combination of lorensta HBr and dapagliflozin has been shown to be effective in treating patients with chronic kidney disease (CKD) who are being treated with the maximum tolerated dose of angiotensin-converting enzyme inhibitors (ACEi) and / or angiotensin receptor blockers (ARBs).

[0409] Based on the studies summarized above, the combination of lorensta HBr and dapagliflozin has been shown to be effective in treating hypertension in subjects with hypertension and chronic kidney disease (CKD) who are being treated with the maximum tolerated dose of angiotensin-converting enzyme inhibitors (ACEi) and / or angiotensin receptor blockers (ARBs).

[0410] Based on the research described above, it is determined that: (a) When used in combination with lorensta HBr and dapagliflozin, the amount of ACEi or ARB is lower than the amount of ACEi or ARB inhibitors that are effective in treating CKD when used alone. (b) When administered with lorenstatin HBr and dapagliflozin, the amount of ACEi or ARB is lower than the amount at which ACEi or ARB inhibitors are effective in treating CKD when administered without lorenstatin HBr and / or dapagliflozin; and / or (c) When administered without the use of lorenstat HBr and / or dapagliflozin, the amount of ACEi or ARB that is effective in treating CKD causes one or more side effects in the subject, wherein the one or more side effects are not caused by the amount of ACEi or ARB, lorenstat HBr and dapagliflozin that is effective in treating CKD when administered together.

[0411] Based on the research described above, it is determined that: (a) When taken together, the amounts of lorenstat HBr and dapagliflozin can effectively achieve greater than the sum of their therapeutic effects in treated subjects; (b) The amount of dapagliflozin used was lower than the amount at which dapagliflozin is effective in treating CKD when used alone; (c) The amount of lorenstat HBr was lower than the amount at which lorenstat HBr was effective in treating CKD when administered alone. (d) The amount of dapagliflozin is lower than the amount at which dapagliflozin is effective in treating CKD when administered without lorenstat HBr; and / or (e) When administered without lorenstat HBr, the amount of dapagliflozin that is effective in treating CKD causes one or more side effects in the subject, wherein the one or more side effects are not caused by the amount of dapagliflozin and lorenstat HBr that are effective in treating CKD when administered together.

[0412] Based on the studies outlined above, the effective dose of dapagliflozin was determined to be 8-12 mg or 10 mg daily.

[0413] Based on the research summarized above, the method was determined to be effective when the stated amount of dapagliflozin was administered in the morning.

[0414] Based on the research summarized above, it has been determined that a method involving once-daily administration of a certain amount of lorenrustat HBr to subjects is effective: (a) Treating proteinuria in subjects; (b) Treating the subject's albuminuria; and / or (c) Slows the progression of kidney disease.

[0415] Based on the research described above, it is determined that: (a) The urinary albumin to creatinine ratio (UACR) of the subject’s 24-hour urine or first morning urine was lower than the UACR of the subject’s 24-hour urine or first morning urine before receiving lorenstah HBr; (b) The subjects' 24-hour total urinary albumin (TUA) decreased compared to the subjects' TUA before receiving lorensta HBr; (c) A decrease in the subject's 24-hour urinary protein to creatinine ratio (UPCR) compared to the subject's UPCR prior to receiving lorenlustat HBr; and / or (d) The subjects’ 24-hour urinary protein was lower than the subjects’ 24-hour urinary protein before receiving lorenstat HBr.

[0416] Based on the study described above, it was determined that when subjects were given the stated amount of lorenstah HBr, their aldosterone levels followed a essentially normal circadian rhythm.

[0417] Based on the research described above, it is determined that: a) The amount of lorenstatin HBr can inhibit CYP 11β2β hydroxylase activity for a duration sufficient to maintain the subject's sodium and volume depletion state; a) The method described does not produce persistent hyperkalemia or mild non-anion gap metabolic acidosis in subjects; b) Lorenzat HBr does not accumulate substantially in the subject, preferably, wherein the non-accumulation of lorenzat HBr in the subject causes the subject's aldosterone levels to return to the pre-administration baseline within 24-48 hours of administration of lorenzat or a pharmaceutically acceptable salt thereof, more preferably, within 16-24 hours of administration of lorenzat HBr. c) The subjects' potassium levels were generally maintained within the clinically normal range; d) The subjects' potassium levels were slightly elevated compared to their potassium levels before administration of lorensta HBr; e) The subject's potassium level increased by 0.35 mmol / L or less. f) The subjects' potassium levels were maintained below 5.5 mmol / L. g) The subjects' potassium levels were maintained between 3.5 mEq / l and 5.1 mEq / l; and / or h) Lorenzat HBr was administered to the subject in the following amounts: i) Inhibit the production of aldosterone in the subject; ii) Increase the serum and / or plasma potassium levels in the subjects; and / or iii) Increase plasma renin activity (PRA) in subjects; Based on the research described above, it is determined that: (a) The subject’s serum and / or plasma aldosterone AUC-24 was reduced by at least 25% compared to the subject’s aldosterone levels prior to administration of lorenstah HBr; (b) The subject's serum and / or plasma potassium levels increased by at least 0.2 mMol / L compared to the subject's serum and / or plasma potassium levels prior to administration of lorenstatin HBr; and / or (c) The subject’s PRA increased by at least 5 ng / ml / hr compared to the subject’s PRA prior to administration of lorensta HBr.

[0418] Based on the studies summarized above, it has been determined that a method involving once-daily administration of a certain amount of lorenrustat HBr and a certain amount of dapagliflozin to subjects is effective: (a) Treating hypertension in the subjects; (b) Treatment of proteinuria in subjects; (c) Treating the subject's albuminuria; and / or (d) Slows the progression of kidney disease.

[0419] Based on the research described above, it is determined that: (a) The urinary albumin to creatinine ratio (UACR) of the subject’s 24-hour urine or first morning urine was lower than the UACR of the subject’s 24-hour urine or first morning urine before receiving lorenstahine HBr and dapagliflozin; (b) The subjects’ 24-hour total urinary albumin (TUA) was lower than the subjects’ TUA before receiving lorensta HBr and dapagliflozin; (c) A decrease in the subject's 24-hour urinary protein to creatinine ratio (UPCR) compared to the subject's UPCR prior to receiving lorenstatin HBr and dapagliflozin; and / or (d) The subjects’ 24-hour urinary protein was lower than the subjects’ 24-hour urinary protein before receiving lorensta HBr and dapagliflozin.

[0420] Based on the research described above, it is determined that: (a) The urinary albumin to creatinine ratio (UACR) of the subject's 24-hour urine or first morning urine was reduced by at least 30%, at least 40%, between 30% and 70%, between 30% and 60%, between 30% and 50%, between 40% and 80%, between 40% and 70%, between 40% and 60%; (b) The subject’s 24-hour total urinary albumin (TUA) was reduced by at least 30%, at least 40%, between 30% and 70%, between 30% and 60%, between 30% and 50%, between 40% and 80%, between 40% and 70%, and between 40% and 60% compared to the subject’s TUA before receiving lorensta HBr and dapagliflozin (if administered); (c) The subject's 24-hour urine protein to creatinine ratio (UPCR) was reduced by at least 30%, at least 40%, between 30% and 70%, between 30% and 60%, between 30% and 50%, between 40% and 80%, between 40% and 70%, between 40% and 60%; and / or (d) The subject’s 24-hour urinary protein was reduced by at least 30%, at least 40%, between 30% and 70%, between 30% and 60%, between 30% and 50%, between 40% and 80%, between 40% and 70%, and between 40% and 60% compared to the subject’s 24-hour urinary protein before receiving lorenstat HBr and dapagliflozin (if administered).

[0421] Based on the studies described above, the tested method was determined to be effective in treating hypertension and / or CKD in subjects with CKD and hypertension. Based on the studies described above, the tested method was determined to be effective in treating hypertension in subjects with CKD and hypertension. Based on the studies described above, the tested method was determined to be effective in treating hypertension in subjects with a systolic blood pressure of at least 135 mmHg and a systolic blood pressure of at least 80 mmHg.

[0422] Based on the research summarized above, it has been determined that methods involving the administration of a certain amount of lorenrustat HBr to subjects are effective: (a) A reduction in the subject's systolic blood pressure by at least 10 mmHg, 10-55 mmHg, 10-50 mmHg, 10-45 mmHg, 10-40 mmHg, 10-35 mmHg, 10-30 mmHg, 10-25 mmHg, 10-20 mmHg, or 10-15 mmHg relative to the subject's systolic blood pressure prior to the administration of lorenstat HBr for at least eight weeks; and / or (b) The subject’s diastolic blood pressure was reduced by at least 5 mmHg, 5-25 mmHg, 5-20 mmHg or 5-15 mmHg relative to the subject’s diastolic blood pressure prior to the period of administration of lorensta HBr for at least eight weeks. (c) The subject's mean systolic blood pressure during sleep was reduced relative to the following: (i) The subject’s average systolic blood pressure during sleep prior to a period of at least eight weeks of continuous administration of lorensta HBr; (ii) the subject's mean sleep-wake systolic blood pressure prior to a period of at least eight weeks of continuous lorenstatin HBr administration; and / or (iii) The subject’s mean daytime systolic blood pressure; (d) The subject’s mean sleep-time systolic blood pressure was reduced by at least 10%, between 10% and 40%, between 10% and 30%, or between 10% and 20% relative to the subject’s mean daytime systolic blood pressure; (e) A reduction in the subject's mean sleep-time systolic blood pressure relative to the subject's mean sleep-time systolic blood pressure prior to a period of at least eight weeks of continuous lorenstat HBr administration; and / or (f) The subject’s mean sleep-time systolic blood pressure was reduced by at least 8 mmHg, at least 10 mmHg, between 8 mmHg and 55 mmHg, between 10 mmHg and 45 mmHg, or between 10 mmHg and 25 mmHg relative to the subject’s mean sleep-time systolic blood pressure prior to the subject’s administration of lorenstat HBr for at least eight weeks.

[0423] Based on the studies summarized above, it has been determined that methods involving the administration of a certain amount of lorenstah HBr and a certain amount of dapagliflozin to subjects are effective: (a) A reduction in the subject's systolic blood pressure by at least 10 mmHg, 10-55 mmHg, 10-50 mmHg, 10-45 mmHg, 10-40 mmHg, 10-35 mmHg, 10-30 mmHg, 10-25 mmHg, 10-20 mmHg, or 10-15 mmHg relative to the subject's systolic blood pressure prior to administration of lorenzuta HBr and dapagliflozin for at least eight weeks; and / or (b) A reduction in the subject's diastolic blood pressure of at least 5 mmHg, 5-25 mmHg, 5-20 mmHg, or 5-15 mmHg relative to the subject's diastolic blood pressure prior to the administration of lorensta HBr and dapagliflozin for at least eight weeks; (c) A reduction in the subject's mean systolic blood pressure during sleep relative to the following: (i) The average systolic blood pressure during sleep prior to the period of at least eight weeks prior to the administration of lorensta HBr and dapagliflozin; (ii) the subject's mean sleep-wake systolic blood pressure prior to a period of at least eight weeks of continuous lorenstatin HBr administration; and / or (iii) The subject’s mean daytime systolic blood pressure.

[0424] (d) The subject’s mean sleep-time systolic blood pressure was reduced by at least 10%, between 10% and 40%, between 10% and 30%, or between 10% and 20% relative to the subject’s mean daytime systolic blood pressure; (e) A reduction in the subject's mean sleep-time systolic blood pressure relative to the subject's mean sleep-time systolic blood pressure prior to a period of at least eight weeks of continuous administration of lorenstat HBr and dapagliflozin, of at least 8 mmHg, at least 10 mmHg, between 8 mmHg and 55 mmHg, between 10 mmHg and 45 mmHg, or between 10 mmHg and 25 mmHg; and / or (f) The subject’s mean sleep-time systolic blood pressure was reduced by at least 8 mmHg, at least 10 mmHg, between 8 mmHg and 55 mmHg, between 10 mmHg and 45 mmHg, or between 10 mmHg and 25 mmHg relative to the subject’s mean sleep-time systolic blood pressure prior to the subject’s administration of lorenstat HBr for at least eight weeks.

[0425] Based on the studies summarized above, a 24-hour urine or first morning urine albumin-to-creatinine ratio (UACR) of 200-5000 mg / g or 300-3500 mg / g and / or an estimated glomerular filtration rate (eGFR) of at least 30 mL / min / 1.73 m 2 Or at least 45 mL / min / 1.73m 2And less than 90 mL / min / 1.73m 2 Lorensta HBr was effective in treating hypertension or CKD in subjects taking a stable dose of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs).

[0426] Based on the research described above, lorensta HBr was found to be effective in treating CKD and hypertension in the following subjects: (a) those without type 1 diabetes; (b) those with serum cortisol levels between 3 μg / dL and 22 μg / dL in the morning; and (c) those with serum cortisol levels between 18 and 40 kg / m². 2 (d) having a body mass index (BMI); and / or (e) having a serum potassium level less than 4.8 mmol / L; and / or having a serum sodium level greater than 135 mmol / L.

[0427] Based on the studies summarized above, lorensta HBr was found to be effective in treating subjects with chronic kidney disease (CKD) and hypertension who were being treated with angiotensin-converting enzyme inhibitors (ACEi) and / or angiotensin receptor blockers (ARBs).

[0428] Based on the studies summarized above, lorensta HBr was found to be effective in treating subjects with chronic kidney disease (CKD) and hypertension who were being treated with the maximum tolerated dose of angiotensin-converting enzyme inhibitors (ACEi) and / or angiotensin receptor blockers (ARBs).

[0429] Based on the research described above, it is determined that: (a) When administered with lorensta or a pharmaceutically acceptable salt thereof, the amount of ACEi or ARB is lower than the amount at which ACEi or ARB inhibitors are effective in treating CKD and / or hypertension when administered alone. (b) When administered with lorenstat or its pharmaceutically acceptable salts, the amount of ACEi or ARB is lower than the amount at which ACEi or ARB inhibitors are effective in treating CKD and / or hypertension when administered without lorenstat or its pharmaceutically acceptable salts; and / or (c) When administered without the use of lorenstat or its pharmaceutically acceptable salts, the amount of ACEi or ARB that is effective in treating CKD and hypertension caused one or more side effects in the subject, wherein the one or more side effects were not caused by the amount of ACEi or ARB and lorenstat or its pharmaceutically acceptable salts that are effective in treating CKD and / or hypertension when administered together. Based on the studies described above, it was determined that when lorenstad or a pharmaceutically acceptable salt thereof is administered in combination with ACEi or ARB, it is more effective in treating CKD and / or hypertension in subjects than when the same amount of each drug is administered alone.

[0430] Based on the research summarized above, the effective amount of lorenstat or its pharmaceutically acceptable salts was determined to be: (a) 10-15 mg daily; (b) 12.5 mg daily; (c) 20-30 mg daily; (d) 25 mg daily; (e) 40-60 mg daily; or (f) 50 mg daily.

[0431] Based on the studies outlined above, it has been determined that the method is effective in treating CKD and / or hypertension when the stated amount of lorenstat HBr is administered in the morning.

[0432] Based on the studies outlined above, it was determined that once-daily administration of a dose of lorenstat or a pharmaceutically acceptable salt thereof and once-daily administration of a dose of dapagliflozin to subjects with CKD and / or hypertension was sufficient to treat the subjects' CKD and / or hypertension.

[0433] Based on the studies summarized above, it was determined that the combination of lorensta HBr and dapagliflozin was effective in treating CKD and / or hypertension in subjects whose 24-hour urine or first morning urine albumin-to-creatinine ratio (UACR) was 200-5000 mg / g or 300-3500 mg / g and / or whose estimated glomerular filtration rate (eGFR) was at least 30 mL / min / 1.73m2 or at least 45 mL / min / 1.73m2 and less than 90 mL / min / 1.73m2, when taking the maximum tolerated dose of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB).

[0434] Based on the studies described above, the combination of lorenstat HBr and dapagliflozin was found to be effective in treating CKD and / or hypertension in the following subjects: (a) without type 1 diabetes; (b) with serum cortisol levels between 3 μg / dL and 22 μg / dL in the morning; and (c) with serum cortisol levels between 18 and 40 kg / m². 2 (d) having a body mass index (BMI); and / or (e) having a serum potassium level less than 4.8 mmol / L; and / or having a serum sodium level greater than 135 mmol / L.

[0435] Based on the studies summarized above, the combination of lorensta HBr and dapagliflozin has been shown to be effective in treating CKD and / or hypertension in subjects with chronic kidney disease (CKD) and hypertension who are being treated with angiotensin-converting enzyme inhibitors (ACEi) and / or angiotensin receptor blockers (ARBs).

[0436] Based on the studies summarized above, the combination of lorensta HBr and dapagliflozin has been shown to be effective in treating CKD and / or hypertension in subjects with chronic kidney disease (CKD) and hypertension who are being treated with maximally tolerated doses of angiotensin-converting enzyme inhibitors (ACEi) and / or angiotensin receptor blockers (ARBs).

[0437] Based on the research described above, it is determined that: (a) When used in combination with lorenstat HBr and dapagliflozin, the amount of ACEi or ARB is lower than the amount at which ACEi or ARB inhibitors are effective in treating CKD and / or hypertension when used alone. (b) When administered with lorenstat HBr and dapagliflozin, the amount of ACEi or ARB is lower than the amount at which ACEi or ARB inhibitors are effective in treating CKD and / or hypertension when administered without lorenstat HBr and / or dapagliflozin; and / or (c) When administered without the use of lorenstat HBr and / or dapagliflozin, an amount of ACEi or ARB that is effective in treating CKD and / or hypertension may cause one or more side effects in the subject, wherein such one or more side effects may not be caused by the amount of ACEi or ARB, lorenstat HBr and dapagliflozin that is effective in treating CKD and / or hypertension when administered together.

[0438] Based on the research described above, it is determined that: (a) When taken together, the amounts of lorenstat HBr and dapagliflozin can effectively achieve greater than the sum of their therapeutic effects in treated subjects; (b) The amount of dapagliflozin used was lower than the amount at which dapagliflozin is effective in treating CKD when used alone; (c) The amount of lorenstat HBr is lower than the amount at which lorenstat HBr is effective in treating CKD and / or hypertension when administered alone. (d) The amount of dapagliflozin is lower than the amount at which dapagliflozin is effective in treating CKD when administered without lorenstat HBr; and / or (e) When dapagliflozin is administered in the absence of lorenstat HBr, an amount that is effective in treating CKD causes one or more side effects in the subject, wherein the one or more side effects are not caused by the amount of dapagliflozin and lorenstat HBr that are effective in treating CKD when administered together.

[0439] Based on the research described above, it has been determined that the method is effective in treating subjects who also have type 2 diabetes (T2DM).

[0440] Based on the research described above, it has been determined that the method is effective in treating subjects who do not have type 2 diabetes (T2DM).

[0441] Based on the research described above, it has been determined that the method is effective in treating subjects who do not have type 1 diabetes.

[0442] Based on the research described above, it has been determined that the method is effective in treating subjects who do not have primary aldosteronism.

[0443] References Ando, ​​H. (2023). Inhibition of aldosterone synthase: Does this offeradvantages compared with the blockade of mineralocorticoid receptors?. Hypertension Research , 1-2. Bakris, GL, et al. (2020). Effect of finerenone on chronic kidneydisease outcomes in type 2 diabetes. New England Journal of Medicine , 383 (23), 2219-2229. Braunwald, E. (2022). Gliflozins in the management of cardiovascular disease. New England Journal of Medicine , 386 (21), 2024-2034. Brown, KD, et al. (2020). Precision medicine in kidney disease: the patient's view. Nature Reviews Nephrology , 16 (11), 625-627. Carey RM, Calhoun DA, Bakris GL, et al. Resistant hypertension:detection, evaluation, and management: a scientific statement from theAmerican Heart Association. Hypertension.2018;72(5):e53-e90。

[0444] Centers for Disease Control and Prevention. Chronic Kidney Disease inthe United States, 2021. Atlanta, GA: US Department of Health and HumanServices, Centers for Disease Control and Prevention; 2021.5 Chen, D., et al. (2013). Aldosterone stimulates fibronectin synthesisin renal fibroblasts through mineralocorticoid receptor-dependent andindependent mechanisms. Gene , 531 (1), 23-30. Chen, T. K., Knicely, D. H., & Grams, M. E. (2019). Chronic kidneydisease diagnosis and management: a review. Jama , 322 (13), 1294-1304. Eisenberg JM. Center for Clinical Decisions and CommunicationsScience. Management of Chronic Kidney Disease Stages 1–3. 2012 Oct 11. In:Comparative Effectiveness Review Summary Guides for Clinicians [Internet].Rockville (MD): Agency for Healthcare Research and Quality (US); 2007–. Epstein, M. (2021). Aldosterone and mineralocorticoid receptorsignaling as determinants of cardiovascular and renal injury: from Hans Selyeto the present. American Journal of Nephrology, 52(3), 209-216. Fay KS, Cohen DL. Resistant Hypertension in People With CKD: AReview. Am J Kidney Dis. 77(1):110-121。

[0445] Forouzanfar MH, Liu P, Roth GA, et al. Global burden of hypertensionand systolic blood pressure of at least 110 to 115 mm Hg, 1990-2015.JAMA.2017;317(2):165-182。

[0446] Garcia Sanchez, J. J., et al. (2022). Treatments for chronic kidneydisease: a systematic literature review of randomized controlled trials. Advances in Therapy , 39(1), 193-220. Mende, C. W. (2022). Chronic kidney disease and SGLT2 inhibitors: areview of the evolving treatment landscape. Advances in Therapy, 1-17. Mogi, M. (2022). Aldosterone breakthrough from a pharmacologicalperspective. Hypertension Research , 45 (6), 967-975. Mukoyama M, Kuwabara T. Role of renin-angiotensin system blockade inadvanced CKD: to use or not to use? Hypertens Res. 2022;45:1072–1075. Murray CJL, Lopez AD. Measuring the global burden of disease. N EnglJ Med.2013;369(5):448-457。

[0447] Neuen, B. L., et al. (2022). Sodium-glucose cotransporter 2inhibitors and risk of hyperkalemia in people with type 2 diabetes: A meta-analysis of individual participant data from randomized, controlled trials.Circulation, 145(19), 1460-1470. Heerspink, H. J., et al. (2020). Dapagliflozin in patients withchronic kidney disease. New England Journal of Medicine , 383(15), 1436-1446. Herrington WG, Staplin N, Wanner C, et al. Empagliflozin in patientswith chronic kidney disease. N. Engl. J. Med. 2023;388:117–127. Jongs, N., et al. (2021). Effect of dapagliflozin on urinary albuminexcretion in patients with chronic kidney disease with and without type 2diabetes: a prespecified analysis from the DAPA-CKD trial. The lancet Diabetes & endocrinology , 9 (11), 755-766. Kovesdy, C. P. (2022). Epidemiology of chronic kidney disease: anupdate 2022. Kidney International Supplements , 12 (1), 7-11. Levin, A., et al. (2013). Kidney Disease: Improving Global Outcomes(KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for theevaluation and management of chronic kidney disease. Kidney international supplements , 3 (1), 1-150. Mukoyama, M., & Kuwabara, T. (2022). Role of renin-angiotensin systemblockade in advanced CKD: to use or not to use?. Hypertension Research , 45 (6), 1072-1075. Perkovic, V., et al.(2018). Canagliflozin and renal outcomes in type2 diabetes: results from the CANVAS Program randomised clinical trials. The lancet Diabetes & endocrinology , 6 (9), 691-704. Perkovic, V., et al.(2019). Canagliflozin and renal outcomes in type2 diabetes and nephropathy. New England Journal of Medicine, 380(24), 2295-2306. Provenzano, M., et al. (2022). ROTATE-3 study group members.Albuminuria-Lowering Effect of Dapagliflozin, Eplerenone, and TheirCombination in Patients with Chronic Kidney Disease: A Randomized CrossoverClinical Trial. J Am Soc Nephrol, 33(8), 1569-1580. Pugh D, Gallacher PJ, Dhaun N. Management of Hypertension in ChronicKidney Disease. Drugs. 2019 Mar;79(4):365-379. Mineralys Therapeutics, Trial on the Safety and Efficacy of MLS-101in Patients with Uncontrolled Hypertension (Target-HTN). ClinicalTrials.govidentifier: NCT05001945. Available at: clinicaltrials.gov Tanner RM, Calhoun DA, Bell EK, et al. Prevalence of apparenttreatment-resistant hypertension among individuals with CKD. Clin J Am SocNephrol. 2013;8(9):1583-1590. Teo, Y. H., et al. (2021). Effects of sodium / glucose cotransporter 2(SGLT2) inhibitors on cardiovascular and metabolic outcomes in patientswithout diabetes mellitus: A systematic review and meta‐analysis ofrandomized‐controlled trials. Journal of the American Heart Association , 10 (5), e019463. Vaidya, A., et al. (2018).The expanding spectrum of primaryaldosteronism: implications for diagnosis, pathogenesis, and treatment.Endocrine reviews, 39(6), 1057-1088. Vejakama, P., et al. (2012). Reno-protective effects of renin–angiotensin system blockade in type 2 diabetic patients: a systematic reviewand network meta-analysis. Diabetologia, 55, 566-578. Verma, A., Vaidya, A., Subudhi, S., & Waikar, S. S. (2022).Aldosterone in chronic kidney disease and renal outcomes. European Heart Journal ,43 (38), 3781-3791. Wanner, C., et al. (2016). Empagliflozin and progression of kidneydisease in type 2 diabetes. New England Journal of Medicine , 375 (4), 323-334. Weldon, S. M., & Brown, N. F. (2019). Inhibitors of aldosteronesynthase. Vitamins and Hormones, 109, 211-239. Wiviott, S. et al. (2019). Dapagliflozin and cardiovascular outcomesin type 2 diabetes. New England Journal of Medicine, 380(4), 347-357. Xie, X., et al. (2016). Renin-angiotensin system inhibitors andkidney and cardiovascular outcomes in patients with CKD: a Bayesian networkmeta-analysis of randomized clinical trials. American Journal of KidneyDiseases, 67(5), 728-741.

Claims

1. A method for treating CKD in a subject suffering from chronic kidney disease (CKD), characterized in that, The method comprises administering a certain amount of lorenstat or a pharmaceutically acceptable salt thereof to the subject once daily, wherein the amount is effective in treating the subject's CKD.

2. A method for treating CKD in a subject suffering from chronic kidney disease (CKD), characterized in that, The method includes: The subjects were diagnosed with: CKD, in the following cases: under stable doses of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs), preferably at the maximum tolerated dose of ACEi or ARB: The urinary albumin to creatinine ratio (UACR) in 24-hour urine or the first morning urine is 200-3500 mg / g or 200-5000 mg / g; and / or The estimated glomerular filtration rate (eGFR) is at least 30 mL / min / 1.73 m. 2 Or at least 45 mL / min / 1.73m 2 And preferably less than 90 mL / min / 1.73m 2 ; Mild to moderate CKD occurs when taking a stable dose of an ACE inhibitor or ARB, preferably the maximum tolerated dose of an ACE inhibitor or ARB: The presence of albuminuria is characterized by an albumin reflux rate (UACR) of 300-3500 mg / g in the 24-hour urine or the first morning urine; and The estimated glomerular filtration rate (eGFR) is at least 45 mL / min / 1.73 m. 2 And less than 90 mL / min / 1.73m 2 ;or Moderate to severe CKD occurs when taking a stable dose of an ACE inhibitor or ARB, preferably the maximum tolerated dose of an ACE inhibitor or ARB: The presence of albuminuria is characterized by an albumin reflux rate (UACR) of 300-3500 mg / g in the 24-hour urine or the first morning urine; and The estimated glomerular filtration rate (eGFR) is at least 30 mL / min / 1.73 m. 2 And less than 45 mL / min / 1.73m 2 ;as well as The subject was given an effective amount of lorenstat or a pharmaceutically acceptable salt thereof once daily, wherein the amount was effective in treating the subject's CKD.

3. The method according to claim 2, characterized in that, Step a) includes identifying the subject: The patient has hypertension, preferably with a systolic blood pressure between 135 and 180 mmHg (inclusive). He does not have type 1 diabetes; Serum cortisol levels in the morning were between 3 µg / dL and 22 µg / dL (inclusive). It has 18-40 kg / m 2 Or 18-45 kg / m 2 Body Mass Index (BMI); Serum potassium levels less than 4.8 mmol / L; and / or The serum sodium level is greater than 135 mmol / L, preferably wherein the serum sodium measurement result needs to be corrected if hyperglycemia is present.

4. The method according to any one of claims 1 to 3, characterized in that, The subjects with CKD were being treated with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs).

5. The method according to claim 4, characterized in that, The subjects suffering from CKD were being treated with the maximum tolerated dose of ACEi or ARB.

6. The method according to claim 4 or 5, characterized in that: When administered with the aforementioned lorensta or a pharmaceutically acceptable salt thereof, the amount of the ACEi or ARB is lower than the amount at which the ACEi or ARB inhibitor is effective in treating CKD when administered alone. When administered with lorenlstat or a pharmaceutically acceptable salt thereof, the amount of the ACEi or ARB is lower than the amount at which the ACEi or ARB is effective in treating CKD when administered without lorenlstat or a pharmaceutically acceptable salt thereof; and / or When administered without the use of the ACEi or ARB or a pharmaceutically acceptable salt thereof, an amount of the ACEi or ARB that is effective in treating CKD causes one or more side effects in the subject, wherein the one or more side effects are not caused by the amount of the ACEi or ARB and the ACEi or ARB that is effective in treating CKD when administered together.

7. The method according to any one of claims 4 to 6, characterized in that, When administered in combination with the ACEi or ARB, lorenstastat or a pharmaceutically acceptable salt thereof is more effective in treating the subject than when the same amount of each agent is administered alone.

8. The method according to any one of claims 1 to 7, characterized in that, The amount of lorenstat or its pharmaceutically acceptable salt is: 10-15 mg daily, preferably 12.5 mg daily; 20-30 mg daily, preferably 25 mg daily; or 40-60 mg daily, preferably 50 mg daily.

9. The method according to any one of claims 1 to 8, characterized in that, Lorenzat or its pharmaceutically acceptable salt is administered in the morning.

10. The method according to any one of claims 1 to 9, characterized in that, Lorenzat or its pharmaceutically acceptable salts are administered daily: Lasting at least one week; Lasting at least two weeks; Lasting at least four weeks; Lasting at least eight weeks; or It will last for at least 12 weeks.

11. The method according to any one of claims 1 to 10, characterized in that, The lorenstat or its pharmaceutically acceptable salt is lorenstat hydrobromide.

12. The method according to any one of claims 1 to 11, characterized in that, The method also includes administering a sodium-glucose cotransporter 2 (SGLT2) inhibitor to the subject once daily, wherein the amount of the SGLT2 inhibitor taken together with the amount of lorensta or a pharmaceutically acceptable salt thereof is sufficient to treat the subject's CKD.

13. The method according to claim 12, characterized in that, The SGLT2 inhibitor and lorensta or a pharmaceutically acceptable salt thereof are administered as a combination pharmaceutical composition.

14. The method according to claim 12, characterized in that, The SGLT2 inhibitor and lorensta or a pharmaceutically acceptable salt thereof are administered simultaneously, concurrently, or concurrently.

15. The method according to any one of claims 12 to 14, characterized in that, The subjects with CKD were being treated with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs).

16. The method according to claim 15, characterized in that, The subjects suffering from CKD were being treated with the maximum tolerated dose of ACEi or ARB.

17. The method according to claim 15 or 16, Its characteristics are: When administered in combination with the SGLT2 inhibitor and lorensta or a pharmaceutically acceptable salt thereof, the amount of the ACEi or ARB is lower than the amount at which the ACEi or ARB inhibitor is effective in treating CKD when administered alone. When administered in combination with the SGLT2 inhibitor and lorenstat or a pharmaceutically acceptable salt thereof, the amount of the ACEi or ARB is lower than the amount at which the ACEi or ARB is effective in treating CKD when administered without the SGLT2 inhibitor and / or lorenstat or a pharmaceutically acceptable salt thereof; and / or When administered without the SGLT2 inhibitor and / or lorenstat or a pharmaceutically acceptable salt thereof, the amount of the ACEi or ARB that is effective in treating CKD in the subject causes one or more side effects, wherein the one or more side effects are not caused by the amount of the ACEi or ARB, SGLT2 inhibitor and lorenstat or a pharmaceutically acceptable salt thereof that is effective in treating CKD when administered together.

18. The method according to any one of claims 12 to 17, characterized in that: When taken together, the amounts of the SGLT2 inhibitor and lorensta or their pharmaceutically acceptable salts are effective in achieving greater than the sum of their therapeutic effects in the subjects. The amount of the SGLT2 inhibitor is lower than the amount at which the SGLT2 inhibitor is effective in treating CKD when administered alone; The amount of lorenstat or its pharmaceutically acceptable salt is lower than the amount at which lorenstat or its pharmaceutically acceptable salt is effective in treating CKD when administered alone; The amount of the SGLT2 inhibitor is lower than the amount at which the SGLT2 inhibitor is effective in treating CKD when administered without the use of lorenstat or its pharmaceutically acceptable salts; and / or When the SGLT2 inhibitor is administered in the absence of lorenlstat or a pharmaceutically acceptable salt thereof, the amount at which it is effective in treating CKD causes one or more side effects in the subject, wherein the one or more side effects are not caused by the amount at which the SGLT2 inhibitor and lorenlstat or a pharmaceutically acceptable salt thereof are effective in treating CKD when administered together.

19. The method according to any one of claims 12 to 18, characterized in that, When administered together, the amount of the SGLT2 inhibitor and lorensta or a pharmaceutically acceptable salt thereof is more effective in treating the subject than when each agent is administered alone in the same amount.

20. The method according to any one of claims 12 to 19, characterized in that, The SGLT2 inhibitors are selected from: dapagliflozin, empagliflozin, ioggliflozin, luggliflozin, canagliflozin, ertoggliflozin, and betagliflozin.

21. The method according to any one of claims 12 to 20, characterized in that, The SGLT2 inhibitor is dapagliflozin.

22. The method according to claim 21, characterized in that, The dosage of dapagliflozin is 8-12 mg per day, preferably 10 mg per day.

23. The method according to any one of claims 12 to 22, characterized in that, The SGLT2 inhibitor and the lorensta or a pharmaceutically acceptable salt thereof are administered in the morning.

24. The method according to any one of claims 12 to 23, characterized in that, The SGLT2 inhibitor and the lorenlustat or a pharmaceutically acceptable salt thereof: Apply daily for at least one week; Apply daily for at least two weeks; Apply daily for at least four weeks; or Apply daily for at least eight weeks.

25. The method according to any one of claims 1 to 24, characterized in that, The method described is effective: Treating the subject's proteinuria, preferably wherein the method is effective in treating the subject's albuminuria; and / or Slows down the progression of kidney disease.

26. The method according to any one of claims 1 to 25, characterized in that: The urinary albumin to creatinine ratio (UACR) of the subject's 24-hour urine or first morning urine was lower than the UACR of the subject's 24-hour urine or first morning urine before the subject received the lorensta or its pharmaceutically acceptable salt and SGLT2 inhibitor (as administered). The subject's 24-hour total urinary albumin (TUA) was lower than the subject's TUA prior to administration of the lorensta or its pharmaceutically acceptable salts and SGLT2 inhibitors (as administered). The subject's 24-hour urinary protein to creatinine ratio (UPCR) was lower than the subject's UPCR prior to administration of the lorenstat or its pharmaceutically acceptable salts and SGLT2 inhibitors (as administered); and / or The subject's 24-hour urinary protein was lower than the subject's 24-hour urinary protein before receiving the lorensta or its pharmaceutically acceptable salt and SGLT2 inhibitor (such as administration).

27. The method according to any one of claims 1 to 26, characterized in that: The urinary albumin to creatinine ratio (UACR) of the subject's 24-hour urine or first morning urine was reduced by at least 30%, at least 40%, between 30% and 70%, between 30% and 60%, between 30% and 50%, between 40% and 80%, between 40% and 70%, and between 40% and 60% compared to the subject's 24-hour urine or first morning urine UACR before the subject received the lorensta or its pharmaceutically acceptable salts and SGLT2 inhibitors (such as administration). The subject's 24-hour total urinary albumin (TUA) was reduced by at least 30%, at least 40%, between 30% and 70%, between 30% and 60%, between 30% and 50%, between 40% and 80%, between 40% and 70%, and between 40% and 60% compared to the subject's TUA prior to administration of the lorensta or its pharmaceutically acceptable salts and SGLT2 inhibitors (as administered). The subject's 24-hour urine protein to creatinine ratio (UPCR) was reduced by at least 30%, at least 40%, between 30% and 70%, between 30% and 60%, between 30% and 50%, between 40% and 80%, between 40% and 70%, between 40% and 60%; and / or The subject's 24-hour urinary protein was reduced by at least 30%, at least 40%, between 30% and 70%, between 30% and 60%, between 30% and 50%, between 40% and 80%, between 40% and 70%, and between 40% and 60% compared to the 24-hour urinary protein level before the subject received the lorensta or its pharmaceutically acceptable salts and SGLT2 inhibitors (such as administration).

28. The method according to any one of claims 1 to 27, characterized in that, The subjects' aldosterone levels followed a essentially normal circadian rhythm.

29. The method according to any one of claims 1 to 27, characterized in that: The amount of lorenstat or a pharmaceutically acceptable salt thereof can inhibit CYP 11β2β hydroxylase activity for a duration sufficient to maintain the subject's sodium and volume depletion state; The method does not produce persistent hyperkalemia or mild non-anion gap metabolic acidosis in the subjects. The lorenstat or its pharmaceutically acceptable salt does not accumulate substantially in the subject, preferably, wherein the lorenstat or its pharmaceutically acceptable salt does not accumulate substantially in the subject such that the subject's aldosterone level returns to the pre-administration baseline within 24-48 hours of administration of the lorenstat or its pharmaceutically acceptable salt, more preferably within 16-24 hours of administration of the lorenstat or its pharmaceutically acceptable salt; The subject's potassium level is generally maintained within the clinically normal range. Preferably, the subject's potassium level is slightly elevated relative to the subject's potassium level prior to administration of lorensta or its pharmaceutically acceptable salt. More preferably, the subject's potassium level is elevated by 0.35 mmol / L or less. More preferably, the subject's potassium level is maintained below 5.5 mmol / L. More preferably, the subject's potassium level is maintained between 3.5 mEq / L and 5.1 mEq / L; and / or The lorensta or its pharmaceutically acceptable salt was administered to the subject in the following amounts: Inhibit the production of aldosterone in the subjects; Increase the serum and / or plasma potassium levels of the subjects; and / or Increase the plasma renin activity (PRA) of the subjects; Preferably, wherein: The subject's serum and / or plasma aldosterone AUC-24 was reduced by at least 25% relative to the subject's aldosterone levels prior to administration of the lorensta or its pharmaceutically acceptable salts; The subject's serum and / or plasma potassium levels increased by at least 0.2 mMol / L relative to the subject's serum and / or plasma potassium levels prior to administration of the lorensta or its pharmaceutically acceptable salts; and / or The subject's PRA increased by at least 5 ng / ml / hr compared to the subject's PRA prior to administration of the lorensta or its pharmaceutically acceptable salt.

30. The method according to any one of claims 1 to 29, characterized in that: The subject suffers from CKD, which is characterized by one or more or all of the following: The urinary albumin to creatinine ratio (UACR) in 24-hour urine or first morning urine is 200-3500 mg / g or 200-5000 mg / g. The estimated glomerular filtration rate (eGFR) is at least 25 mL / min / 1.73 m. 2 Or at least 30 mL / min / 1.73m 2 And preferably less than 90 mL / min / 1.73m 2 ; Kidney disease; Proteinuria, such as albuminuria; Abnormal urine sediment; Abnormalities, such as electrolyte abnormalities caused by renal tubular disease; Abnormalities detected through histology; and Structural anomalies detected by imaging; or The subjects suffered from mild to moderate CKD, characterized by the following: eGFR is at least 45 mL / min / 1.73 m 2 And less than 90 mL / min / 1.73 m 2 ; as well as Albuminuria is present, with a UACR of ≥300 mg / g to 3500 mg / g; or The subjects suffered from moderate to severe CKD, characterized by the following: eGFR is at least 30 mL / min / 1.73 m 2 And less than 45 mL / min / 1.73 m 2 ; as well as The presence of albuminuria is characterized by an albuminuria rate of ≥300 mg / g to 3500 mg / g.

31. The method according to any one of claims 1 to 30, characterized in that, The subject also suffers from hypertension, preferably wherein the subject has a systolic blood pressure of at least 120 mmHg and a systolic blood pressure of at least 80 mmHg, more preferably wherein the subject has a systolic blood pressure between 135 and 180 mmHg (inclusive).

32. The method according to claim 31, characterized in that: The method described is effective: The subject's systolic blood pressure was reduced by at least 10 mmHg, 10-55 mmHg, 10-50 mmHg, 10-45 mmHg, 10-40 mmHg, 10-35 mmHg, 10-30 mmHg, 10-25 mmHg, 10-20 mmHg, or 10-15 mmHg relative to the subject's systolic blood pressure prior to the period of administration of the SGLT2 inhibitor and lorenlustat or a pharmaceutically acceptable salt thereof for at least eight weeks; and / or The subject's diastolic blood pressure was reduced by at least 5 mmHg, 5-25 mmHg, 5-20 mmHg, or 5-15 mmHg relative to the subject's diastolic blood pressure prior to a period of at least eight weeks of administration of the SGLT2 inhibitor and lorensta or a pharmaceutically acceptable salt thereof. The subjects' average systolic blood pressure during sleep was reduced relative to the following: The subjects' average systolic blood pressure during sleep prior to receiving the SGLT2 inhibitor and lorensta or a pharmaceutically acceptable salt thereof for at least eight weeks; The subject's average systolic blood pressure during sleep prior to a period of at least eight weeks of continuous administration of the lorenstat or its pharmaceutically acceptable salt; and / or The subjects' mean daytime systolic blood pressure; The subjects' average sleep-time systolic blood pressure was reduced by at least 10%, between 10% and 40%, between 10% and 30%, or between 10% and 20% relative to the subjects' average daytime systolic blood pressure; The mean systolic blood pressure during sleep of the subject was reduced by at least 8 mmHg, at least 10 mmHg, between 8 mmHg and 55 mmHg, between 10 mmHg and 45 mmHg, or between 10 mmHg and 25 mmHg, relative to the mean systolic blood pressure during sleep of the subject prior to a period of at least eight weeks of continuous administration of the SGLT2 inhibitor and lorenlustat or a pharmaceutically acceptable salt thereof; and / or The mean sleep-time systolic blood pressure of the subject was reduced by at least 8 mmHg, at least 10 mmHg, between 8 mmHg and 55 mmHg, between 10 mmHg and 45 mmHg, or between 10 mmHg and 25 mmHg, relative to the mean sleep-time systolic blood pressure of the subject prior to a period of at least eight weeks of continuous administration of lorenstat or its pharmaceutically acceptable saline; and / or When administered with the aforementioned lorensta or a pharmaceutically acceptable salt thereof, the amount of the ACEi or ARB is lower than the amount at which the ACEi or ARB inhibitor is effective in treating CKD and / or hypertension when administered alone. When administered with lorenlstat or a pharmaceutically acceptable salt thereof, the amount of the ACEi or ARB is lower than the amount at which the ACEi or ARB is effective in treating CKD and / or hypertension when administered without lorenlstat or a pharmaceutically acceptable salt thereof; and / or When administered without the use of the ACEi or ARB or a pharmaceutically acceptable salt thereof, the amount of the ACEi or ARB that is effective in treating CKD and / or hypertension in the subject causes one or more side effects, wherein the one or more side effects are not caused by the amount of the ACEi or ARB and the ACEi or ARB that is effective in treating CKD and / or hypertension when administered together. When administered in combination with the ACEi or ARB, the amount of lorensta or a pharmaceutically acceptable salt thereof is more effective in treating the subject’s CKD and / or hypertension than when the same amount of each drug is administered alone.

33. The method according to any one of claims 1 to 31, characterized in that, The subjects also had type 2 diabetes (T2DM).

34. The method according to any one of claims 1 to 31, characterized in that, The subjects: Not diagnosed with type 2 diabetes (T2DM); and / or They do not have type 1 diabetes.

35. The method according to any one of claims 1 to 34, wherein the subject does not suffer from primary aldosteronism.

36. A method for identifying subjects treated with lorenstat or a pharmaceutically acceptable salt thereof, characterized in that, The method includes: Measure the urinary albumin to creatinine ratio (UACR) and / or estimate the glomerular filtration rate (eGFR) of the subject in the 24-hour urine or first morning urine. Subjects with the following conditions were selected when taking the maximum tolerated dose of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs): Chronic kidney disease (CKD) occurs in the following situations: The urinary albumin to creatinine ratio (UACR) in 24-hour urine or the first morning urine is 200-3500 mg / g or 200-5000 mg / g; and / or The estimated glomerular filtration rate (eGFR) is at least 30 mL / min / 1.73 m. 2 Or at least 45 mL / min / 1.73m 2 And preferably less than 90 mL / min / 1.73m 2 ; Mild to moderate CKD occurs in the following situations: The presence of albuminuria is characterized by a urinary albumin-to-creatinine ratio (UACR) of 300-3500 mg / g in the 24-hour urine or the first morning urine; and The estimated glomerular filtration rate (eGFR) is at least 45 mL / min / 1.73 m. 2 And less than 90 mL / min / 1.73m 2 ;or Moderate to severe CKD is defined in the following situations: The presence of albuminuria is characterized by a urinary albumin-to-creatinine ratio (UACR) of 300-3500 mg / g in the 24-hour urine or the first morning urine; and The estimated glomerular filtration rate (eGFR) is at least 30 mL / min / 1.73 m. 2 And less than 45 mL / min / 1.73m 2 ; This allows for the identification of the subjects treated with lorenstat or its pharmaceutically acceptable salts.

37. The method according to claim 36, characterized in that, Identify the subjects who received the following treatment: Lorenzat or a pharmaceutically acceptable salt thereof, 10-15 mg daily, preferably 12.5 mg daily; Lorenzat or a pharmaceutically acceptable salt thereof, 20-30 mg daily, preferably 25 mg daily; or Lorenzat or a pharmaceutically acceptable salt thereof, 40-60 mg daily, preferably 50 mg daily.

38. A method for identifying a subject treated with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and lorenlustat or a pharmaceutically acceptable salt thereof, characterized in that, The method includes: Measure the urinary albumin to creatinine ratio (UACR) and / or estimate the glomerular filtration rate (eGFR) of the subject in the 24-hour urine or first morning urine. Subjects with the following conditions were selected when taking the maximum tolerated dose of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs): Chronic kidney disease (CKD) occurs in the following situations: The urinary albumin to creatinine ratio (UACR) in 24-hour urine or the first morning urine is 200-3500 mg / g or 200-5000 mg / g; and / or The estimated glomerular filtration rate (eGFR) is at least 30 mL / min / 1.73 m. 2 Or at least 45 mL / min / 1.73m 2 And preferably less than 90 mL / min / 1.73m 2 ;or Mild to moderate CKD occurs in the following situations: The presence of albuminuria is characterized by a urinary albumin-to-creatinine ratio (UACR) of 300-3500 mg / g in the 24-hour urine or the first morning urine; and The estimated glomerular filtration rate (eGFR) is at least 45 mL / min / 1.73 m. 2 And less than 90 mL / min / 1.73m 2 ;or Moderate to severe CKD is defined in the following situations: The presence of albuminuria is characterized by a urinary albumin-to-creatinine ratio (UACR) of 300-3500 mg / g in the 24-hour urine or the first morning urine; and The estimated glomerular filtration rate (eGFR) is at least 30 mL / min / 1.73 m. 2 And less than 45 mL / min / 1.73m 2 ; This allows for the identification of subjects treated with sodium-glucose cotransporter 2 (SGLT2) inhibitors and lorensta or pharmaceutically acceptable salts thereof.

39. The method according to claim 38, characterized in that, The SGLT2 inhibitors are selected from: dapagliflozin, empagliflozin, ioggliflozin, luggliflozin, canagliflozin, ertoggliflozin, and betagliflozin.

40. The method according to claim 39, characterized in that, The SGLT2 inhibitor is dapagliflozin.

41. The method according to claim 40, characterized in that, Identify the subjects who received the following treatment: Lorenstat or a pharmaceutically acceptable salt thereof, 10-15 mg daily, preferably 12.5 mg daily, and dapagliflozin, 8-12 mg daily, preferably 10 mg daily; Lorenzat or a pharmaceutically acceptable salt thereof, 20-30 mg daily, preferably 25 mg daily, and dapagliflozin, 8-12 mg daily, preferably 10 mg daily; Lorenzat or a pharmaceutically acceptable salt thereof, 40-60 mg daily, preferably 50 mg daily, and dapagliflozin, preferably 10 mg daily, for use in combination.

42. The method according to any one of claims 36 to 41, characterized in that, The lorenstat or its pharmaceutically acceptable salt is lorenstat hydrobromide.

43. The method according to any one of claims 36 to 42, characterized in that, Step b) also includes selecting subjects who do not have type 1 diabetes.

44. The method according to any one of claims 36 to 43, characterized in that: Step a) further includes measuring the subject’s serum cortisol in the morning, and step b) further includes selecting subjects with serum cortisol levels between 3 µg / dL and 22 µg / dL; Step a) further includes measuring the subject's body mass index (BMI), and step b) further includes selecting a BMI of 18-40 kg / m². 2 The subjects; Step a) further includes measuring the subject's serum potassium, and step b) further includes selecting subjects with serum potassium levels less than 4.8 mmol / L; Step a) further includes measuring the subject's serum sodium, and step b) further includes selecting subjects with serum sodium greater than 135 mmol / L; and / or Step a) further includes measuring the subject's systolic blood pressure, and step b) further includes selecting subjects with hypertension, preferably characterized by a systolic blood pressure of at least 135 mmHg, more preferably between 135 mmHg and 180 mmHg (including extreme values).

45. A lorensta or a pharmaceutically acceptable salt thereof, characterized in that, Used in any of the methods according to claims 1 to 35.

46. ​​A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises lorenstat or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and is used in any of the methods according to claims 1 to 35.

47. A lorensta or a pharmaceutically acceptable salt thereof, characterized in that, For the treatment of subjects with chronic kidney disease (CKD), wherein the use is in combination with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and optionally an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), wherein the SGLT2 inhibitor is preferably dapagliflozin.

48. The use of a lorensta or a pharmaceutically acceptable salt thereof, characterized in that, This treatment is intended for subjects with chronic kidney disease (CKD) in combination with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and optionally an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), preferably wherein the SGLT2 inhibitor is dapagliflozin.

49. A lorensta or a pharmaceutically acceptable salt thereof, characterized in that, This is used to treat subjects with chronic kidney disease (CKD) and hypertension, wherein the use is in combination with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and optionally an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), preferably wherein the SGLT2 inhibitor is dapagliflozin.

50. The use of a lorensta or a pharmaceutically acceptable salt thereof, characterized in that, This medication is intended for use in combination with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and optionally an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB) to treat subjects with chronic kidney disease (CKD) and hypertension, preferably wherein the SGLT2 inhibitor is dapagliflozin.

51. A type of packaging, characterized in that, Include: The first pharmaceutical composition comprises a certain amount of lorenstat or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; The second pharmaceutical composition contains a certain amount of sodium-glucose cotransporter 2 (SGLT2) inhibitor; Optionally, a third pharmaceutical composition comprising an angiotensin-converting enzyme inhibitor (ACEi). Optionally, a fourth pharmaceutical composition comprising an angiotensin receptor blocker (ARB); and Instructions for use for the treatment of subjects with CKD or CKD and hypertension, together with the first pharmaceutical composition, the second pharmaceutical composition, the third pharmaceutical composition, and the fourth pharmaceutical composition (if present).

52. A type of packaging, characterized in that, Include: A first pharmaceutical composition comprising a certain amount of lorenlustat or a pharmaceutically acceptable salt thereof, a certain amount of a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and a pharmaceutically acceptable carrier; and Optionally, a second pharmaceutical composition comprising an amount of an angiotensin-converting enzyme inhibitor (ACEi) and / or an angiotensin receptor blocker (ARB) and a pharmaceutically acceptable carrier; and Instructions for use of the pharmaceutical composition for the treatment of subjects with chronic kidney disease (CKD) or CKD and hypertension.

53. A pharmaceutical composition, characterized in that, Include: A certain amount of lorenstat or its pharmaceutically acceptable salt; A certain amount of sodium-glucose cotransporter 2 (SGLT2) inhibitor or a pharmaceutically acceptable salt thereof; Optionally, a certain amount of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) or a pharmaceutically acceptable salt thereof. The lorensta or its pharmaceutically acceptable salts, SGLT2 inhibitors and ACEi or ARB (if present) are administered simultaneously, concurrently or concurrently.

54. A pharmaceutical composition, characterized in that, Containing an amount of lorenstat or a pharmaceutically acceptable salt thereof, said lorenstat or a pharmaceutically acceptable salt thereof is used in combination with an amount of sodium-glucose cotransporter 2 (SGLT2) inhibitor and optionally an amount of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) for the treatment of subjects with chronic kidney disease (CKD) or CKD and hypertension.

55. A unit dosage form of pharmaceutical composition, characterized in that, The pharmaceutical composition may be used to treat subjects with chronic kidney disease (CKD) or CKD and hypertension, and comprises: A certain amount of lorenstat or its pharmaceutically acceptable salt; A certain amount of sodium-glucose cotransporter 2 (SGLT2) inhibitor or a pharmaceutically acceptable salt thereof; and Optionally, a certain amount of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) or a pharmaceutically acceptable salt thereof. The appropriate amounts of the lorensta or its pharmaceutically acceptable salt, the SGLT2 inhibitor, and the ACEi or ARB (if present) in the composition are effective in treating the subject when the composition in one or more of the unit dosage forms is administered concurrently.

56. A therapeutic package, characterized in that, The treatment package is intended for distribution to subjects with chronic kidney disease (CKD) or CKD and hypertension, or for use in subjects with chronic kidney disease (CKD) or CKD and hypertension, and comprises: One or more unit doses, each such unit dose containing: A certain amount of lorenstat or its pharmaceutically acceptable salt; A certain amount of sodium-glucose cotransporter 2 (SGLT2) inhibitor or a pharmaceutically acceptable salt thereof; and Optionally, a certain amount of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) or a pharmaceutically acceptable salt thereof. The corresponding amount of the lorensta or its pharmaceutically acceptable salt, the SGLT2 inhibitor, and the ACEi or ARB (if present) in the unit dose are effective in treating the subject's CKD or CKD and hypertension when administered concomitantly. A refined drug container for the treatment package, the container containing the one or more unit doses, the container also containing or including a label instructing the use of the package to treat the subject.

57. The packaging according to any one of claims 51 to 52, the pharmaceutical composition according to any one of claims 53 to 55, or the therapeutic packaging according to claim 56, characterized in that, The SGLT2 inhibitor is dapagliflozin.

58. The packaging according to any one of claims 51 to 52, the pharmaceutical composition according to any one of claims 53 to 55, or the therapeutic packaging according to claim 56, characterized in that, The lorenstat or its pharmaceutically acceptable salt is lorenstat hydrobromide.

59. The packaging, pharmaceutical composition, or therapeutic packaging according to claim 57 or 58, characterized in that, The pharmaceutical composition, unit dose or unit dosage form comprises 10-15 mg, 20-30 mg or 40-60 mg of lorenstat or a pharmaceutically acceptable salt thereof, preferably 12.5 mg, 25 mg or 50 mg of lorenstat or a pharmaceutically acceptable salt thereof, and 8-12 mg of dapagliflozin, preferably 10 mg of dapagliflozin.

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