SGLT2 inhibitors and bardoxolone for the treatment of chronic kidney disease and hypertension

Abstract

The present disclosure provides a method of treating chronic kidney disease (CKD) and hypertension in a patient in need thereof, the method comprising administering to the patient a combination comprising bardoxolone or a pharmaceutically acceptable salt thereof and a sodium-glucose cotransporter 2 (SGLT2) inhibitor.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 610,570, filed December 15, 2023, the disclosure of which is incorporated herein by reference. Technical Field

[0003] This disclosure provides compounds and methods for treating chronic kidney disease and hypertension. Background Technology

[0004] Since 1990, estimates of the incidence, prevalence, and mortality of chronic kidney disease (CKD) worldwide have increased significantly; this impact is driven by population growth, aging, and the increasing prevalence of diabetes and hypertension (HTN) (Xie et al., Kidney Int. 2018; 94(3):567-81). An estimated 843,600,000 people worldwide have CKD. Chronic kidney disease was the 10th leading cause of death globally in 2019 (Kovesdy Kidney internationalsupplements. 2022; 12(1):7-11), and projections indicate that it will become the fifth leading cause of lost years of life globally by 2040 (Foreman et al., Lancet (London, England). 2018; 392(10159):2052-90).

[0005] Effective management of HTN in patients with CKD reduces the risk of cardiovascular (CV) events and delays CKD progression (Ku et al., American Journal of Kidney Diseases: the official journal of the National Kidney Foundation. 2019; 74(1):120-31). The Kidney Disease Improving Global Outcomes (KDIGO) 2021 guidelines recommend treating patients with hypertension and CKD to a target systolic blood pressure (SBP) of <120 mmHg; however, this is not achieved in many patients despite the use of currently available therapies. Renin-angiotensin system inhibitors (ACE inhibitors or ARBs) are recommended for patients with hypertension (BP) and proteinuria-related CKD. Regardless of BP control, CKD guidelines recommend the use of ACE inhibitors or ARBs for patients with CKD who have significantly increased proteinuria. There remains an unmet need for new therapies to improve BP control in patients with CKD and HTN because many CKD patients do not achieve target BP despite currently available therapies.

[0006] It has been demonstrated that sodium-glucose cotransporter-2 (SGLT2) inhibitors can reduce the risk of persistent renal decline, renal failure, and CV death in patients with CKD and diabetes (canagliflozin, CREDENCE trial; (Perkovic et al., The New England Journal of Medicine. 2019; 380(24): 2295-306), and with or without diabetes (dapagliflozin, DAPA-CKD trial (Heerspink et al., The New England Journal of Medicine. 2020; 383(15): 1436-46); empagliflozin, EMPA Kidney Trial (Herrington et al., The New England Journal of Medicine. 2023; 388(2): 117-27). The updated KDIGO guidelines provide a 1A recommendation for use in patients with eGFR ≥ 20 mL / min / 1.73 m 2Furthermore, SGLT2 inhibitors were used in CKD patients with a UACR ≥ 200 mg / g (KDIGO 2023). Additionally, SGLT2 inhibitors were associated with a reduced risk of hyperkalemia, especially when treated with agents known to increase the risk of hyperkalemia (Agarwal et al., 2022; Neuen et al., 2022; Provenzano et al., 2022). Despite the beneficial effects of SGLT2 inhibitors in renal protection, the residual risk of CKD progression to end-stage kidney disease (ESKD, also known as end-stage renal disease (ESRD)) and the risk of cardiovascular disease (CVD) and mortality remain, highlighting the need for novel therapies with complementary mechanisms of action.

[0007] In humans, persistently elevated serum aldosterone levels are detrimental to the kidneys, and mineralocorticoid receptor antagonism has been shown to be effective. Extremely high serum aldosterone levels observed in patients with primary aldosteronism are known to be associated with functional and structural kidney damage, manifested as increased proteinuria and urinary markers of kidney injury (Halimi and Mimran, Journal of hypertension. 1995; 13(12 Pt 2): 1801-2; Wu et al., Journal of hypertension. 2011; 29(9): 1778-86; Wu et al., Journal of the American Heart Association. 2023; 12(4): e028146), as well as histopathological lesions such as segmental glomerulosclerosis and interstitial fibrosis (Ogata et al., Hypertension 2021; 78(2): 411-21). Observational studies have shown increased serum aldosterone levels in patients with CKD. In addition, baseline serum aldosterone concentration was negatively correlated with renal function, and high aldosterone was associated with 50% of the eGFR decline and the composite endpoint of end-stage renal disease in the Chronic Renal Insufficiency Cohort (CRIC) study (Verma et al., European Heart Journal. 2022; 43(38): 3781-91), as well as eGFR slope (Minakuchi et al., Sci Rep. 2020; 10(1): 16626).

[0008] Bardostat is a highly selective aldosterone synthase inhibitor that can significantly reduce aldosterone levels, offering the potential to not only improve blood pressure in CKD patients but also mitigate the negative effects of elevated aldosterone on renal function.

[0009] Bardostat and dapagliflozin have different and complementary mechanisms of action, so their combination may provide particularly beneficial effects in slowing the progression of CKD in patients with CKD and HTN. Summary of the Invention

[0010] This disclosure provides a method for treating chronic kidney disease (CKD) and hypertension in patients in need, the method comprising administering to the patient a combination comprising a first amount of baxdrostat or a pharmaceutically acceptable salt thereof and a second amount of a sodium-glucose cotransporter 2 (SGLT2) inhibitor, wherein the first and second amounts together constitute a therapeutically effective amount.

[0011] Also provided are bardostat or its pharmaceutically acceptable salts for use in any of the methods described herein.

[0012] Also provided are SGLT2 inhibitors for use in any of the methods described herein.

[0013] It also provides the use of bardosstat or pharmaceutically acceptable salts thereof in the preparation of medicaments for use in any of the methods described herein.

[0014] The use of SGLT2 inhibitors in the preparation of medicaments for use in any of the methods described herein is also provided.

[0015] A kit is also provided comprising: (a) bardostat or a pharmaceutically acceptable salt thereof and / or an SGLT2 inhibitor, and (b) instructions for use of bardostat or a pharmaceutically acceptable salt thereof and / or an SGLT2 inhibitor in any of the methods described herein.

[0016] Other aspects of this disclosure will be apparent to those skilled in the art upon reading this specification. Attached Figure Description

[0017] Figure 1 The changes in UACR relative to baseline are shown in patients in Study 1 (a phase 2 trial of bardostat for the treatment of antihypertensive disease, Clinicaltrials.gov ID: NCT04519658).

[0018] Figure 2 The study design of Study 2 (a study in patients with uncontrolled hypertension and chronic kidney disease, Clinicaltrials.gov ID: NCT05432167) is shown.

[0019] Figure 3The study design of Study 3 (as described herein, a phase III, randomized, double-blind, positive-controlled study to evaluate the efficacy, safety, and tolerability of bardostat in combination with dapagliflozin compared with dapagliflozin alone in the progression of chronic kidney disease (CKD) in participants with CKD and hypertension) is shown.

[0020] Figure 4 The study design of Study 4 (as described herein, a phase III, randomized, double-blind, placebo-controlled, event-driven study to evaluate the efficacy, safety, and tolerability of bardostat in combination with dapagliflozin compared with dapagliflozin alone in renal outcomes and cardiovascular mortality in participants with chronic kidney disease and hypertension) is shown. Detailed Implementation

[0021] This disclosure can be more fully understood by referring to the following description, including the definitions and examples. Certain features of the disclosed compositions and methods described herein in the context of individual aspects may also be provided in combination within those individual aspects. Alternatively, various features of the disclosed compositions and methods described in the context of individual aspects for the sake of brevity may also be provided individually or in any sub-combination. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit this disclosure.

[0022] In this disclosure, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” include plural indicators, and references to a particular numerical value include at least that particular value.

[0023] When a value is expressed as an approximation using the descriptive term "about," it should be understood that the particular value forms another embodiment. Generally, the use of the term "about" indicates an approximation that may vary depending on the desired characteristics sought through the disclosed subject matter and is interpreted based on its function within the specific context of its use. Those skilled in the art will be able to interpret this conventionally. In some cases, the number of significant figures used for a particular value can be a non-limiting method for determining the extent of the term "about." In other cases, the rank used in a range of values ​​can be used to determine the expected range of the term "about" available for each value. Where present, all ranges are inclusive and associative. That is, references to values ​​stated in a range include every value within that range.

[0024] When a list is presented, unless otherwise stated, it should be understood that each individual element of the list and each combination of the list should be interpreted as a separate implementation. For example, a list of implementations presented as “A, B or C” should be interpreted as including implementations “A”, “B”, “C”, “A or B”, “A or C”, “B or C”, or “A, B or C”.

[0025] It should be understood that, for clarity, certain features of the invention described herein in the context of individual embodiments may also be provided in combination in a single embodiment. That is, unless obviously incompatible or excluded, each individual embodiment is considered to be combinable with any other embodiment, and such combination is considered another embodiment. Conversely, for brevity, the various features of the invention described in the context of individual embodiments may also be provided individually or in any sub-combination. It should also be noted that the claims may be drafted to exclude optional elements. Therefore, this statement is intended to serve as a premise for the use of exclusive terms such as “only” or the use of “negative” limitations in relation to the recitation of the elements of the claims.

[0026] Those skilled in the art can readily determine the effectiveness of the compounds disclosed herein in treating CKD and hypertension. Those skilled in the art can also readily determine and adjust appropriate dosing regimens (e.g., adjusting the amount of each dose of the compound and / or the number of doses and frequency of administration). A patient's health status can be monitored using one or any combination of diagnostic methods (including physical examination, assessment and monitoring of clinical symptoms, and the execution of the analytical tests and methods described herein).

[0027] "Effective amount" or "therapeutic effective amount" refers to an amount of one or more compounds of this disclosure that, when administered to a patient as a single dose or as part of a series of doses, effectively produces at least one therapeutic effect. The dose may depend on the patient's body mass, weight, and / or blood volume. Treatment effectiveness in a patient can typically be monitored using assays suitable for the disease, condition, and / or symptom being treated or prevented. The level of the compound administered to a patient can be monitored by measuring the level of the compound (or its metabolites) in biological fluids (e.g., blood, blood fractions (e.g., serum), and / or urine) and / or other biological samples from the patient. The level of the compound can be measured during a treatment regimen using any method practiced in the art for detecting the compound or its metabolites.

[0028] The dosage of the compounds described herein may depend on the patient’s condition, namely the stage of the disease, the severity of the symptoms caused by the disease, the overall health status, and age, sex, weight, and other factors that are obvious to a person of ordinary skill in the medical field.

[0029] The terms "treating," "treatment," or "to treat" refer to therapeutic measures that cure, slow, alleviate, or reduce the symptoms of a diagnosed pathological disease, symptom, or condition and / or stop its progression. Treatment does not necessarily result in a complete cure; the term encompasses partial suppression or alleviation of the treated condition.

[0030] The terms "subject" and "patient" are used interchangeably and generally refer to mammals. In some embodiments, the patient or subject is a human. In some embodiments, the subject or patient is at least 18 years old, i.e., an adult.

[0031] As used herein, the term "combination" with bardostat or its pharmaceutically acceptable salts and SGLT2 inhibitors (e.g., dapagliflozin) may include, for example, fixed and non-fixed (e.g., free) forms (including kits or other administration or dosage forms) and uses, such as simultaneous, sequential, or separate use of bardostat or its pharmaceutically acceptable salts and SGLT2 inhibitors (e.g., dapagliflozin).

[0032] This disclosure relates to a method for treating chronic kidney disease (CKD) and hypertension in patients in need, the method comprising administering to the patient a combination comprising a first amount of bardostat or a pharmaceutically acceptable salt thereof and a second amount of a sodium-glucose cotransporter 2 (SGLT2) inhibitor (e.g., dapagliflozin), wherein the first and second amounts together constitute a therapeutically effective amount.

[0033] A method for reducing the rate of renal function decline in patients with CKD and hypertension is also disclosed, comprising administering to the patient a combination of a first dose of bardostat and a second dose of an SGLT2 inhibitor, wherein the first and second doses together constitute a therapeutically effective dose. In some embodiments, the rate of renal function decline is reduced to a greater extent compared to treatment in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo. In some embodiments, the rate of eGFR decline is reduced by 0.5 mL / min / 1.73 m compared to treatment in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo. 2 / year or more, such as 0.75mL / min / 1.73 m 2 / year or more or 1.0mL / min / 1.73m 2 / year or more.

[0034] A method for reducing the estimated rate of decline in glomerular filtration rate (eGFR) in patients with CKD and hypertension is also disclosed, comprising administering to the patient a combination containing a first dose of bardostat and a second dose of an SGLT2 inhibitor, wherein the first and second doses together constitute a therapeutically effective dose. In some embodiments, the rate of decline in the patient's eGFR is reduced to a greater extent compared to treatment in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo. In some embodiments, the rate of decline in the patient's eGFR is reduced by 0.5 mL / min / 1.73 m compared to treatment in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo. 2 / year or more, such as 0.75mL / min / 1.73 m 2 / year or more or 1.0 mL / min / 1.73 m 2 / year or more.

[0035] A method for reducing the risk of a sustained eGFR decline of ≥50% relative to baseline in patients with CKD and hypertension is also disclosed, comprising administering to the patient a combination comprising a first dose of bardostat and a second dose of an SGLT2 inhibitor, wherein the first and second doses together constitute a therapeutically effective dose. In some embodiments, this method reduces the risk of a sustained eGFR decline of ≥50% relative to baseline to a greater extent (e.g., resulting in a hazard ratio < 1) compared to methods in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo.

[0036] A method for reducing the risk of a sustained eGFR decline of ≥57% relative to baseline in patients with CKD and hypertension is also disclosed, comprising administering to the patient a combination comprising a first dose of bardostat and a second dose of an SGLT2 inhibitor, wherein the first and second doses together constitute a therapeutically effective dose. In some embodiments, this method reduces the risk of a sustained eGFR decline of ≥57% relative to baseline to a greater extent (e.g., resulting in a hazard ratio < 1) compared to methods in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo.

[0037] A method for reducing the risk of end-stage renal disease (ESKD) in patients with CKD and hypertension is also disclosed, comprising administering to the patient a combination containing a first dose of bardostat and a second dose of an SGLT2 inhibitor, wherein the first and second doses together constitute a therapeutically effective dose. In some embodiments, this method reduces the risk of ESKD to a greater extent (e.g., resulting in a hazard ratio < 1) compared to methods in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo.

[0038] A method for reducing the risk of ESKD or cardiovascular (CV) death in patients with CKD and hypertension with a sustained eGFR decline of ≥50% relative to baseline is also disclosed. This method involves administering a combination to the patient comprising a first dose of bardostat and a second dose of an SGLT2 inhibitor, wherein the first and second doses together constitute a therapeutically effective dose. In some embodiments, this method reduces the risk of patients with a sustained eGFR decline of ≥50% relative to baseline, reaching ESKD or CV death (e.g., resulting in a hazard ratio <1) to a greater extent than methods in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo.

[0039] A method for reducing the risk of a sustained eGFR decline of ≥50% relative to baseline or ESKD in patients with CKD and hypertension is also disclosed, comprising administering to the patient a combination comprising a first dose of bardostat and a second dose of an SGLT2 inhibitor, wherein the first and second doses together constitute a therapeutically effective dose. In some embodiments, this method reduces the risk of a sustained eGFR decline of ≥50% relative to baseline or ESKD to a greater extent (e.g., resulting in a hazard ratio < 1) compared to methods in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo.

[0040] A method for reducing the risk of CV death, heart failure events, myocardial infarction, or stroke in patients with CKD and hypertension is also disclosed, comprising administering to the patient a combination comprising a first dose of bardostat and a second dose of an SGLT2 inhibitor, wherein the first and second doses together constitute a therapeutically effective dose. In some embodiments, this method reduces the risk of CV death, heart failure events, myocardial infarction, or stroke to a greater extent (e.g., resulting in a hazard ratio < 1) compared to methods in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo.

[0041] A method for reducing the risk of CV death or heart failure events in patients with CKD and hypertension is also disclosed, comprising administering to the patient a combination comprising a first dose of bardostat and a second dose of an SGLT2 inhibitor, wherein the first and second doses together constitute a therapeutically effective dose. In some embodiments, this method reduces the risk of CV death or heart failure events in patients to a greater extent (e.g., resulting in a hazard ratio < 1) compared to methods in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo.

[0042] A method for reducing the risk of CV death in patients with CKD and hypertension is also disclosed, comprising administering to the patient a combination comprising a first dose of bardosstat and a second dose of an SGLT2 inhibitor, wherein the first and second doses together constitute a therapeutically effective dose. In some embodiments, this method reduces the risk of CV death in patients to a greater extent (e.g., resulting in a hazard ratio <1) compared to methods in which bardosstat or a pharmaceutically acceptable salt thereof is replaced with a placebo.

[0043] A method for reducing the risk of death in patients with CKD and hypertension is also disclosed, comprising administering to the patient a combination comprising a first dose of bardostat and a second dose of an SGLT2 inhibitor, wherein the first and second doses together constitute a therapeutically effective dose. In some embodiments, this method reduces the risk of death in patients to a greater extent (e.g., resulting in a hazard ratio < 1) compared to methods in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo.

[0044] The severity of hypertension can be classified into the categories shown in the table below:

[0045]

[0046] SBP = Systolic blood pressure; DBP = Diastolic blood pressure

[0047] In some implementations, hypertension is stage 1 or stage 2 hypertension. In some implementations, hypertension is stage 1 hypertension. In some implementations, hypertension is stage 2 hypertension. In some implementations, hypertension is not a hypertensive crisis.

[0048] In some implementations, hypertension is uncontrolled hypertension (uHTN). In some implementations, uHTN is hypertension that has not been successfully treated with one or two antihypertensive agents.

[0049] In some implementations, the patient's systolic blood pressure (SBP) is ≥ 120 mmHg. In some implementations, the patient has an SBP ≥ 130 mmHg. In some implementations, the patient has an SBP ≥ 140 mmHg.

[0050] In some embodiments, the patient has a systolic blood pressure (SBP) ≤ 180 mmHg. In some embodiments, the patient's SBP is ≥ 120 mmHg and ≤ 180 mmHg. In some embodiments, the patient has an SBP ≥ 130 mmHg and ≤ 180 mmHg. In some embodiments, the patient has an SBP ≥ 140 mmHg and ≤ 180 mmHg.

[0051] In some implementations, SBP is the average seated SBP.

[0052] In some implementations, the patient's diastolic blood pressure (DBP) is ≥ 80 mmHg. In some implementations, the patient's diastolic blood pressure (DBP) is ≥ 90 mmHg. In some implementations, the patient's diastolic blood pressure (DBP) is ≤ 110 mmHg. In some implementations, the patient's diastolic blood pressure (DBP) is ≤ 120 mmHg. In some implementations, the DBP is the mean sitting DBP.

[0053] The severity of CKD can be divided into the stages described below:

[0054] Stage 1: Kidney injury, with eGFR ≥ 90 mL / min / 1.73 m 2 This can last for 3 months or longer.

[0055] Stage 2: Kidney injury, with eGFR 60 mL / min / 1.73 m 2 -89 mL / min / 1.73 m 2 This can last for 3 months or longer.

[0056] Stage 3a: Mild to moderate loss of renal function (eGFR 45 mL / min / 1.73 m) 2 -59 mL / min / 1.73 m 2 This can last for 3 months or longer.

[0057] Stage 3b: Moderate to severe loss of renal function (eGFR 30 mL / min / 1.73 m) 2 -44 mL / min / 1.73 m 2 This can last for 3 months or longer.

[0058] Stage 4: Severe loss of renal function (eGFR 15 mL / min / 1.73 m) 2 -29 mL / min / 1.73 m 2 This can last for 3 months or longer.

[0059] Stage 5: Renal failure (eGFR < 15 mL / min / 1.73 m) 2 (This may require dialysis for 3 months or longer).

[0060] As used herein, the term "end-stage renal disease (ESKD)" refers to (i) a condition characterized by <15 mL / min / 1.73 m 2 (ii) sustained eGFR, (iii) receiving chronic dialysis, or (iv) receiving a kidney transplant.

[0061] In some implementations, the CKD is a Phase 1 CKD, Phase 2 CKD, Phase 3a CKD, Phase 3b CKD, or Phase 4 CKD. (This text is repeated four times in the original.)

[0062] In some implementation schemes, the patient has ≥ 15 and < 90 mL / min / 1.73 m 2 The estimated glomerular filtration rate (eGFR). In some implementations, patients with ≥30 and <90 mL / min / 1.73 m 2 eGFR. In some implementations, patients with ≥15 and <60 mL / min / 1.73 m 2 eGFR. In some implementations, patients have ≥30 and <60 mL / min / 1.73 m 2 eGFR. In some implementations, the patient has an eGFR ≥25 mL / min / 1.73 m 2 And ≤75mL / min / 1.73m 2 eGFR.

[0063] In some implementations, the patient has CKD at risk of progression. In some implementations, the patient has CKD at high risk of progression. In some implementations, the patient has or has an eGFR >3 mL / min / 1.73 mcg. 2 There is a risk of a decline in the annual rate.

[0064] In some implementations, the patient has a urinary albumin-to-creatinine ratio (UACR) ≥100 mg / g. In some implementations, the patient has an UACR ≥200 mg / g. In some implementations, the patient has an UACR ≥200 mg / g and ≤5000 mg / g. In some implementations, the patient has an UACR >200 mg / g and <5000 mg / g. In some implementations, the patient has albuminuria.

[0065] In some embodiments, the patient has normal serum potassium. In some embodiments, the patient does not have hyperkalemia. In some embodiments, the patient has serum potassium <5.5 mmol / L. In some embodiments, the patient has serum potassium <5.0 mmol / L. In some embodiments, the patient has serum potassium ≤4.8 mmol / L. In some embodiments, the patient has serum potassium between 3.5 mmol / L and 4.8 mmol / L. In some embodiments, the patient has serum potassium between 3.5 mmol / L and 4.8 mmol / L and ≥45 mL / min / 1.73 m 2 eGFR. In some implementations, patients have serum potassium levels of 3.5 mmol / L to 4.5 mmol / L and < 45 mL / min / 1.73 m 2 eGFR.

[0066] In some implementations, the patient has a serum sodium level of <135 mmol / L.

[0067] In some implementations, the patient does not have type 1 diabetes. In some implementations, the patient does not have uncontrolled type 2 diabetes. In some implementations, the patient does not have uncontrolled type 2 diabetes with HbA1c > 10.5% (> 91 mmol / mol). In some implementations, the patient has type 2 diabetes. In some implementations, the patient has controlled type 2 diabetes.

[0068] In some implementations, the patient is a New York Heart Association functional HF class I, II, or III. In some implementations, the patient is not a New York Heart Association functional HF class IV.

[0069] In some embodiments, the methods described herein reduce the rate of renal function decline in patients. In some embodiments, the method reduces the rate of renal function decline in patients to a greater extent compared to treatment in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo.

[0070] In some embodiments, the methods described herein reduce renal function decline relative to baseline to a greater extent compared to treatment in which bardostat or its pharmaceutically acceptable salts are replaced with a placebo. In some embodiments, renal function decline is measured after approximately 2 years of treatment with the combination. In some embodiments, renal function decline is measured after approximately 26 weeks of treatment with the combination.

[0071] In some embodiments, the methods described herein reduce the rate of decline in a patient's eGFR. In some embodiments, the method reduces the rate of decline in a patient's eGFR to a greater extent compared to treatment in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo.

[0072] In some implementations, the methods described herein reduce the rate of eGFR decline in patients, and patients with ≥30 mL / min / 1.73 m 2 And <90mL / min / 1.73 m 2 eGFR. In some implementations, this method reduces the rate of eGFR decline to a greater extent in patients with eGFR ≥30 mL / min / 1.73 m 2 And <90mL / min / 1.73 m 2 eGFR.

[0073] In some implementations, the methods described herein reduce the rate of eGFR decline in patients by 0.5 mL / min / 1.73 m 2 / year or more, such as 0.75mL / min / 1.73 m 2 / year or more or 1.0 mL / min / 1.73 m 2 / year or more.

[0074] In some implementations, compared with treatment in which bardostat or its pharmaceutically acceptable salts are replaced with a placebo, the methods described herein reduced the rate of eGFR decline in patients by 0.5 mL / min / 1.73 m 2 / year or more, such as 0.75mL / min / 1.73 m 2 / year or more or 1.0 mL / min / 1.73 m 2 / year or more.

[0075] In some embodiments, the methods described herein reduce the decline in eGFR relative to baseline to a greater extent compared to treatment in which bardostat or a pharmaceutically acceptable salt is replaced with a placebo. In some embodiments, the decline in eGFR is measured after approximately 2 years of treatment with the combination. In some embodiments, the decline in eGFR is measured after approximately 26 weeks of treatment with the combination.

[0076] In some embodiments, the method described herein reduces a patient's UACR relative to baseline. In some embodiments, the method reduces a patient's UACR to a greater extent than treatment in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo. In some embodiments, UACR is measured after approximately 2 years of treatment with the combination. In some embodiments, UACR is measured after approximately 26 weeks of treatment with the combination. In some embodiments, UACR is measured after approximately 16 weeks of treatment with the combination.

[0077] In some embodiments, the methods described herein reduce a patient's UACR by 20% or more, such as 25% or more, or 30% or more, relative to baseline. In some embodiments, UACR is measured after approximately 2 years of treatment with the combination. In some embodiments, UACR is measured after approximately 26 weeks of treatment with the combination. In some embodiments, UACR is measured after approximately 16 weeks of treatment with the combination.

[0078] In some embodiments, compared to treatment in which bardostat or its pharmaceutically acceptable salts are replaced with a placebo, the methods described herein reduce a patient's UACR by 20% or more, such as 25% or more, or 30% or more, relative to baseline. In some embodiments, UACR is measured after approximately 2 years of treatment with the combination. In some embodiments, UACR is measured after approximately 26 weeks of treatment with the combination. In some embodiments, UACR is measured after approximately 16 weeks of treatment with the combination.

[0079] In some embodiments, the method described herein reduces a patient's SBP relative to baseline. In some embodiments, the method reduces a patient's SBP to a greater extent relative to baseline compared to treatment in which bardostat or a pharmaceutically acceptable salt is replaced with a placebo. In some embodiments, SBP is measured after approximately 2 years of treatment with the combination. In some embodiments, SBP is measured after approximately 26 weeks of treatment with the combination. In some embodiments, SBP is measured after approximately 16 weeks of treatment with the combination. In some embodiments, SBP is mean sitting SBP.

[0080] In some embodiments, compared to treatment in which bardostat or its pharmaceutically acceptable salts are replaced with a placebo, the methods described herein reduce a patient's SBP by 4 mmHg or more relative to baseline, such as 5 mmHg or more, or 6 mmHg or more. In some embodiments, SBP is measured after approximately 2 years of treatment with the combination. In some embodiments, SBP is measured after approximately 26 weeks of treatment with the combination. In some embodiments, SBP is measured after approximately 16 weeks of treatment with the combination. In some embodiments, SBP is the mean sitting SBP.

[0081] In some embodiments, the methods described herein reduce a patient's SBP to <120 mmHg. In some embodiments, the methods described herein reduce a patient's SBP to <130 mmHg.

[0082] In some implementations, the methods described herein reduce the risk of a patient experiencing a sustained eGFR decrease of ≥50% relative to baseline. In some implementations, the method reduces the risk of a sustained eGFR decrease of ≥50% relative to baseline to a greater extent (e.g., resulting in a hazard ratio < 1) compared to treatment in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo.

[0083] In some implementations, the methods described herein reduce the risk of a patient experiencing a sustained eGFR decrease of ≥57% relative to baseline. In some implementations, the method reduces the risk of a sustained eGFR decrease of ≥57% relative to baseline to a greater extent (e.g., resulting in a hazard ratio <1) compared to treatment in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo.

[0084] In some implementations, the methods described herein reduce the risk of ESKD in patients. In some implementations, the method reduces the risk of ESKD to a greater extent (e.g., resulting in a hazard ratio < 1) compared to treatment in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo.

[0085] In some embodiments, the methods described herein reduce the risk of a patient experiencing a sustained eGFR decline of ≥50% relative to baseline or ESKD. In some embodiments, compared with treatment in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo, the method reduces the risk of a patient experiencing a sustained eGFR decline of ≥50% relative to baseline or ESKD to a greater extent (e.g., resulting in a hazard ratio < 1).

[0086] In some implementations, the methods described herein reduce the risk of patients with a sustained eGFR decrease of ≥50% relative to baseline or ESKD, and patients with ≥30 mL / min / 1.73 m 2 And <60mL / min / 1.73 m 2 The method reduces the risk of a sustained eGFR decline of ≥50% relative to baseline or ESKD (e.g., resulting in a hazard ratio <1) to a greater extent than treatment in which bardostat or its pharmaceutically acceptable salt is replaced with a placebo, and the patient has ≥30 mL / min / 1.73 m 2 And <60mL / min / 1.73 m 2 eGFR.

[0087] In some embodiments, the methods described herein reduce the chronic eGFR slope in patients. In some embodiments, the method reduces the chronic eGFR slope to a greater extent compared to treatment in which bardostat or a pharmaceutically acceptable salt thereof is replaced with placebo. In some embodiments, the chronic eGFR slope is the rate of eGFR decline in patients during approximately 8 weeks to approximately 2 years of treatment with the combination. In some embodiments, during approximately 8 weeks to approximately 2 years of treatment with the combination, the rate of eGFR decline in patients is reduced by 0.5 mL / min / 1.73 m 2 / year or more, such as 0.75mL / min / 1.73 m 2 / year or more or 1.0mL / min / 1.73m 2 / year or more.

[0088] In some implementations, the methods described herein reduce the risk of a patient’s persistent eGFR decline, reaching ESKD, or CV death. In some implementations, compared with treatment in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo, the method reduces the risk of a patient’s persistent eGFR decline, reaching ESKD, or CV death to a greater extent (e.g., resulting in a hazard ratio < 1).

[0089] In some embodiments, the methods described herein reduce the risk of patients experiencing a sustained eGFR decline of ≥50% relative to baseline, reaching ESKD, or CV death. In some embodiments, compared to treatment in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo, the method reduces the risk of patients experiencing a sustained eGFR decline of ≥50% relative to baseline, reaching ESKD, or CV death to a greater extent (e.g., resulting in a hazard ratio < 1).

[0090] In some implementations, the methods described herein reduce the risk of CV death, heart failure events, myocardial infarction, or stroke in patients. In some implementations, the methods described herein reduce the risk of CV death, heart failure events, myocardial infarction, or stroke to a greater extent (e.g., resulting in a hazard ratio < 1) compared to treatment in which a placebo is used instead of bardostat or a pharmaceutically acceptable salt thereof.

[0091] In some implementations, the methods described herein reduce the risk of CV death or heart failure events in patients. In some implementations, the methods described herein reduce the risk of CV death or heart failure events to a greater extent (e.g., resulting in a hazard ratio <1) compared to treatment in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo.

[0092] In some implementations, the methods described herein reduce the risk of CV death in patients. In some implementations, the methods described herein reduce the risk of CV death in patients to a greater extent (e.g., resulting in a hazard ratio < 1) compared to treatment in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo.

[0093] In some implementations, “cardiovascular (CV) death” refers to death in patients whose primary cause of death is acute myocardial infarction (MI), sudden cardiac death, heart failure, stroke, cardiovascular surgery, cardiovascular bleeding, or other cardiovascular causes. “Other cardiovascular causes” refers to CV deaths not included in the above categories but with specific known causes (e.g., pulmonary embolism or peripheral artery disease). In some implementations, CV death may also include deaths in patients whose underlying cause of death is unknown.

[0094] In some implementations, a “heart failure event” (HF event) is defined as HF with or without hospitalization.

[0095] In some implementation schemes, a "HF event" is hospitalization for HF.

[0096] In some implementations, HF hospitalization includes hospitalization lasting at least 24 hours or as measured by changes in calendar dates, and the patient has objective evidence of new or worsening HF.

[0097] In some implementations, HF hospitalization meets one or more of the following criteria: (i) hospitalization with a primary cause of HF; and / or (ii) due to the patient exhibiting new or worsening symptoms of HF; and / or (iii) objective evidence of new or worsening HF; and / or (iv) initiation or intensification of specific treatment for HF. In some implementations, HF hospitalization meets all of the above criteria. In some implementations, new or worsening symptoms of HF exhibited by the patient include at least one of the following: dyspnea (such as forced dyspnea, resting dyspnea, orthopnea, and / or paroxysmal nocturnal dyspnea); decreased exercise tolerance; fatigue; and other symptoms of worsening end-organ perfusion or volume overload. In some implementations, objective evidence of new or worsening HF includes physical examination findings considered to be due to HF, laboratory evidence of new or worsening HF, and / or invasive evidence of new or worsening HF. In some implementations, physical examination findings considered to be due to HF include at least one of the following: peripheral edema; increased abdominal distension or ascites (e.g., in the absence of primary liver disease); pulmonary rales / crackling / pitching; increased jugular venous pressure and / or hepatojugular reflux; third heart sound (S3) gallop rhythm; and clinically significant or rapid weight gain associated with fluid retention. In some implementations, laboratory evidence of new or worsening HF includes at least one of the following: increased B-type natriuretic peptide (BNP) / NT-proBNP concentrations consistent with decompensated heart failure; radiographic, ultrasound, or implantable monitoring evidence of pulmonary congestion; and non-invasive or implantable diagnostic evidence of clinically significant increases in left or right ventricular filling pressure or low cardiac output. In some implementations, invasive evidence of new or worsening HF includes at least one of the following findings: right heart catheterization showing elevated pulmonary capillary wedge pressure (pulmonary occlusion pressure), elevated central venous pressure, and / or decreased cardiac index; and left heart catheterization showing elevated left ventricular end-diastolic pressure consistent with decompensation in HF. In some implementations, initiating or intensifying specific treatment for HF includes at least one of the following: initiating maintenance diuretic therapy; enhancing oral diuretic therapy (such as increasing the dose of a single diuretic, e.g., doubling it, or initiating combination diuretics); initiating intravenous diuretic administration; initiating intravenous vasoactive agents (such as catecholamines, phosphodiesterase-3 inhibitors, or other vasopressors or vasodilators); mechanical or surgical interventions (such as mechanical circulatory support); and mechanical fluid removal (such as ultrafiltration, hemofiltration, and hemodialysis).

[0098] In some implementations, non-hospitalized HF includes outpatient visits in emergency or outpatient settings where the patient has objective evidence of new or worsening HF.

[0099] In some implementations, non-hospitalized HF meets one or more of the following criteria: (i) the patient exhibits new or worsening symptoms due to HF; and / or (ii) objective evidence of new or worsening HF; and / or (iii) initiation or intensification of specific treatment for HF. In some implementations, non-hospitalized HF meets all of the above criteria. In some implementations, new or worsening symptoms due to HF exhibited by the patient include at least one of the following: dyspnea (such as forced dyspnea, resting dyspnea, orthopnea, and / or paroxysmal nocturnal dyspnea); decreased exercise tolerance; fatigue; and other symptoms of worsening end-organ perfusion or volume overload. In some implementations, objective evidence of new or worsening HF includes physical examination findings considered to be due to HF, imaging evidence of structural or functional heart disease consistent with the diagnosis of HF, laboratory evidence of new or worsening HF, and / or invasive evidence of new or worsening HF. In some implementations, physical examination findings considered to be due to HF include at least one of the following: peripheral edema; increased abdominal distension or ascites (e.g., in the absence of primary liver disease); pulmonary rales / crackling / pitching; increased jugular venous pressure and / or hepatojugular reflux; third heart sound (S3) gallop rhythm; and clinically significant or rapid weight gain associated with fluid retention. In some implementations, imaging evidence of structural or functional heart disease consistent with a diagnosis of HF includes at least one of the following: left ventricular systolic dysfunction; left atrial enlargement; left ventricular diastolic dysfunction; increased pulmonary pressure; and left ventricular hypertrophy. In some implementations, laboratory evidence of new or worsening HF includes at least one of the following: increased B-type natriuretic peptide (BNP) / NT-proBNP levels; radiological, ultrasound, or implantable monitoring evidence of pulmonary congestion; and non-invasive or implantable diagnostic evidence of clinically significant increases in left or right ventricular filling pressure or low cardiac output. In some implementations, invasive evidence of new or worsening HF includes at least one of the following findings: right heart catheterization showing elevated pulmonary capillary wedge pressure (pulmonary occlusion pressure), elevated central venous pressure, and / or decreased cardiac index; and left heart catheterization showing elevated left ventricular end-diastolic pressure consistent with decompensation in HF.In some implementations, initiating or enhancing specific treatment for HF includes at least one of the following: initiating oral administration of at least one novel oral diuretic therapy, SGLT2i therapy, renin-angiotensin system inhibitor, angiotensin receptor neprilysin inhibitor, beta-blocker, MRA, ivabradine, digoxin, vexiguanidine, or hydralazine / isosorbide receptor, prescribed as a treatment for HF; enhancing oral diuretic therapy (such as increasing the diuretic dose, e.g., doubling it, or initiating combination diuretic therapy); initiating intravenous administration of a diuretic; initiating intravenous administration of a vasoactive agent (such as catecholamines, phosphodiesterase-3 inhibitors, or other vasopressors or vasodilators); mechanical or surgical intervention (such as mechanical circulatory support); and mechanical fluid clearance (e.g., ultrafiltration, hemofiltration, and hemodialysis).

[0100] In some implementation schemes, non-hospitalized HF is considered an emergency HF medical visit.

[0101] In some implementations, an emergency HF medical visit is an emergency room visit for a new or worsening HF, but does not require hospitalization. In other implementations, an emergency HF medical visit is an emergency unplanned visit to a physician's office for a new or worsening HF.

[0102] In some implementations, an HF event is a worsening HF event with or without hospitalization, as described below: Abraham et al., Eur J Heart Fail., 2020; 22(12):2175-86.

[0103] In some implementations, an HF event is an HF hospitalization or an emergency outpatient visit for HF, as described below: Hicks et al., Circulation, 2018 137(9), 961-972.

[0104] In some implementations, the methods described herein reduce the risk of patient death. In some implementations, the methods described herein reduce the risk of patient death to a greater extent (e.g., resulting in a hazard ratio < 1) compared to treatment in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo.

[0105] The methods described herein can refer to clinical outcomes relative to treatments or methods in which bardostat or its pharmaceutically acceptable salts are replaced with a placebo. As an example of such a comparison, clinical outcomes from methods including administration of bardostat and dapagliflozin are compared with clinical outcomes obtained from the same methods including administration of placebo and dapagliflozin in other respects. As another example, clinical outcomes from methods including administration of bardostat, dapagliflozin, and standard care agents for CKD are compared with clinical outcomes obtained from the same methods including administration of placebo, dapagliflozin, and standard care agents for CKD in other respects.

[0106] The methods described herein may refer to a reduction in the risk of clinical events, such as CV death. In some embodiments, the reduction in risk is measured as a reduction in the time to the first occurrence of the clinical event. For example, a reduction in the risk of CV death may be measured as a reduction in the time to CV death. In some embodiments, the shortening of the time to the first occurrence of the clinical event may be measured relative to the time to the first occurrence of the clinical event in a treatment or method in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo.

[0107] The methods described herein may refer to a reduction in the composite risk of a clinical event (e.g., a sustained decrease in eGFR ≥50% relative to baseline, reaching ESKD, or CV death). In some embodiments, the reduction in risk is measured as a reduction in the time to first occurrence of one of the composite clinical events. For example, a reduction in the risk of a sustained decrease in eGFR ≥50% relative to baseline, reaching ESKD, or CV death may be measured as a reduction in the time to first occurrence of one of the composite clinical events relative to a sustained decrease in eGFR ≥50% relative to baseline, reaching ESKD, or CV death. In some embodiments, a reduction in the time to first occurrence of one of the composite clinical events may be measured relative to the time to first occurrence of one of the composite clinical events in a treatment or method in which placebo is used instead of bardostat or a pharmaceutically acceptable salt thereof.

[0108] In the embodiments described herein, the hazard ratio is used to indicate the risk reduction provided by the methods described herein. In some embodiments, the hazard ratio is < 1. In some embodiments, the hazard ratio is ≤ 0.9. In some embodiments, the hazard ratio is ≤ 0.85. In some embodiments, the hazard ratio is ≤ 0.8. In some embodiments, the hazard ratio is < 1, and the full range of the 95% confidence interval (CI) for the hazard ratio is < 1. In some embodiments, the hazard ratio is ≤ 0.9, and the full range of the 95% CI for the hazard ratio is < 1. In some embodiments, the hazard ratio is ≤ 0.85, and the full range of the 95% CI for the hazard ratio is < 1. In some embodiments, the hazard ratio is ≤ 0.8, and the full range of the 95% CI for the hazard ratio is < 1.

[0109] Some embodiments described herein may refer to changes in clinical outcomes, such as a reduction, or changes in clinical outcomes relative to other treatments or methods, such as a reduction. In some embodiments, the change (such as a reduction) is clinically significant. In some embodiments, the change (such as a reduction) is statistically significant. In some embodiments, the change (such as a reduction) is statistically significant. In some embodiments, the change (such as a reduction) is both clinically significant and statistically significant.

[0110] The chemical name of bardostat is N-[(8R)-4-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl]propionamide, and the chemical structure of bardostat is as follows:

[0111] .

[0112] Bardostat can be prepared by the method disclosed in International Patent Application No. WO2013 / 041591. This disclosure considers the use of pharmaceutically acceptable salts of bardostat in the methods described herein. “Pharmaceutically acceptable” means properties and / or substances that are acceptable to patients from a pharmacological / toxicological point of view and acceptable to pharmaceutical chemists from a physical / chemical point of view, in terms of composition, formulation, stability, patient acceptability and bioavailability.

[0113] Pharmaceutically acceptable salts of bardostat include salts formed with pharmaceutically acceptable acids or bases, such as inorganic acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, hydroiodic acid, nitric acid, and phosphoric acid) and organic acids (i.e., adipic acid, citric acid, fumaric acid, maleic acid, malic acid, malonic acid, mandelic acid, ascorbic acid, oxalic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, cyclohexylaminosulfonic acid (cyclohexylaminosulfonic acid), ethanedisulfonic acid, glutaric acid, or p-toluenesulfonic acid). Pharmaceutically acceptable bases include alkali metals (e.g., sodium or potassium) and alkaline earth metals (e.g., calcium or magnesium), hydroxides, and organic bases (e.g., alkylamines, arylalkylamines, and heterocyclic amines).

[0114] In some embodiments, the bardostat or a pharmaceutically acceptable salt thereof administered in the methods described herein is bardostat.

[0115] In some embodiments, bardostat or a pharmaceutically acceptable salt thereof is in a form suitable for oral administration. In some embodiments, bardostat or a pharmaceutically acceptable salt thereof is in tablet form.

[0116] In some embodiments, bardostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.5 mg / day to about 4 mg / day. In some embodiments, bardostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.5 mg / day, about 1 mg / day, or about 2 mg / day. In some embodiments, bardostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg / day or about 2 mg / day. In some embodiments, bardostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg / day. In some embodiments, bardostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 2 mg / day.

[0117] In some embodiments, bardostat or a pharmaceutically acceptable salt thereof is administered at a dose of 0.5 mg / day to 4 mg / day. In some embodiments, bardostat or a pharmaceutically acceptable salt thereof is administered at a dose of 0.5 mg / day, 1 mg / day, or 2 mg / day. In some embodiments, bardostat or a pharmaceutically acceptable salt thereof is administered at a dose of 1 mg / day or 2 mg / day. In some embodiments, bardostat or a pharmaceutically acceptable salt thereof is administered at a dose of 1 mg / day. In some embodiments, bardostat or a pharmaceutically acceptable salt thereof is administered at a dose of 2 mg / day.

[0118] In some embodiments, a dose of bardostat or a pharmaceutically acceptable salt thereof is selected such that the patient does not exhibit hyperkalemia. In some embodiments, the dose of bardostat or a pharmaceutically acceptable salt thereof is selected from about 0.5 mg / day, about 1 mg / day, and about 2 mg / day, so that the patient does not exhibit hyperkalemia. In some embodiments, the dose of bardostat or a pharmaceutically acceptable salt thereof is selected from about 1 mg / day and about 2 mg / day, so that the patient does not exhibit hyperkalemia.

[0119] In some embodiments, bardostat or a pharmaceutically acceptable salt thereof is initially administered at a dose of about 1 mg / day, then increased to about 2 mg / day. In some embodiments, bardostat or a pharmaceutically acceptable salt thereof is initially administered at a dose of about 1 mg / day, then increased to about 2 mg / day, provided the patient does not have hyperkalemia. In some embodiments, bardostat or a pharmaceutically acceptable salt thereof is initially administered at a dose of about 1 mg / day, then increased to about 2 mg / day, provided that serum potassium is ≤ 4.8 mmol / L.

[0120] In some implementations, if the patient has hyperkalemia, the dose of bardostat or a pharmaceutically acceptable salt thereof is reduced to approximately 1 mg / day. In some implementations, if serum potassium is > 5.5 mmol / L, the dose of bardostat or a pharmaceutically acceptable salt thereof is reduced to approximately 1 mg / day.

[0121] An embodiment describing the quality of bardostat or its pharmaceutically acceptable salts refers to a specified mass of bardostat or an equimolar amount of a pharmaceutically acceptable salt of bardostat. For example, a pharmaceutically acceptable salt of 2 mg / day bardostat refers to the dose of pharmaceutically acceptable salt of bardostat required to deliver 2 mg / day of bardostat.

[0122] In some embodiments, bardostat or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, bardostat or a pharmaceutically acceptable salt thereof is administered orally once daily.

[0123] In some embodiments, the SGLT2 inhibitor is selected from U.S. Patent No. 6,515,177, WO / 2003 / 099836, U.S. Patent Publication No. 2006 / 0194809, and U.S. Patent Publication No. 2006 / 0063722. A1, WO / 2002 / 083066, US Patent Publication No. 2003 / 0064935, US Patent No. 6,774,112, US Patent Publication No. 2005 / 0209166, US Patent Publication No. 2006 / 0074031, US Patent Publication No. 2006 / 0035841, US Patent Publication No. 2006 / 0009400, US Patent Publication No. 2006 / 0025349, US Patent Publication No. 2006 / 0122126, US Patent Publication No. 2006 / 0019948, US Patent Publication No. 2006 / 0194809, US Patent No. 6,908,905, US Patent No. 6,815,428, US Patent No. 6,555,519, US Patent No. 6,683,056, EP 598359 A1, JP 035988, US Patent No. 5,731,292, EP 0850948 A1, US Patent No. 6,048,842, JP 09188625 A, JP 09124685 A, JP09124684, EP 773226 A1, US Patent No. 5,767,094, JP 08027006 A, EP 684254 A1, JP10245391 (Dainippon), US Patent Publication No. 2005 / 0233982 (Boehringer Ingelheim Corp.), US Patent Publication No. 2005 / 0119192 (Kissei Pharmaceutical Co.), WO / 2006 / 035796 (Kissei Pharmaceutical Co.), JP 2006 / 117651 (Taisho Pharmaceutical Co.), JP 2004 / 4359630 (Yamanouchi Pharmaceutical Co.), WO / 2006 / 080421 (Chugai Seiyaku Kabushiki Kaishi), U.S. Patent Publication No. 2005 / 0233988 (Tanabe Seiyaku Co.), WO / 2005 / 012321 (Tanabe Seiyaku Co.), U.S. Patent No. 7,015,201 (Ajinomoto Co.Those disclosed in WO 2006 / 058597 (Merck Patent GmbH), WO 2006 / 011469 (Chugai Seiyaku Kabushiki Kaisha), U.S. Patent Publication No. 2003 / 0195235 (Johnson & Johnson), and WO 2006 / 037537 (Boehringer Ingelheim).

[0124] In some implementations, the SGLT2 inhibitor is selected from those disclosed in Tsujihara, K. et al., Chem. Pharm. Bull., 44:1174-1180 (1996); Hongu, M. et al., Chem. Pharm. Bull., 46:22-33 (1998); Hongu, M. et al., Chem. Pharm. Bull., 46:1545-1555 (1998); and Oku, A. et al., Diabetes, 48:1794-1800 (1999).

[0125] In some implementations, the SGLT2 inhibitor may be dapagliflozin, canagliflozin, empagliflozin, eoaggliflozin, soragliflozin, ioggliflozin, toggliflozin, or luggliflozin, or a pharmaceutically acceptable salt thereof.

[0126] In some embodiments, the SGLT2 inhibitor is dapagliflozin, such as that described in U.S. Patent Nos. 6,414,126 and 6,515,117, the entire contents of which are incorporated herein by reference.

[0127] The chemical name of dapagliflozin is (1S)-1,5-anhydrous-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-D-glucanol, and its chemical structure is as follows:

[0128] .

[0129] In some embodiments, dapagliflozin is in the form of a (S)-propylene glycol ((S)-PG) solvate having the following structure:

[0130] .

[0131] A method for preparing (S)-PG solvates (including crystalline (S)-PG solvates) of dapagliflozin is provided in U.S. Patent No. 7,919,598.

[0132] In some embodiments, SGLT2 inhibitors (such as dapagliflozin) are in a form suitable for oral administration. In some embodiments, SGLT2 inhibitors (such as dapagliflozin) are in tablet form.

[0133] In some implementations, dapagliflozin is administered at a dose of approximately 10 mg / day.

[0134] In some embodiments, dapagliflozin is administered once daily. In some embodiments, dapagliflozin is administered orally once daily. In some embodiments, about 0.5 mg, about 1 mg, or about 2 mg of bardostat or a pharmaceutically acceptable salt thereof is administered to the patient once daily, and about 10 mg of dapagliflozin is administered to the patient once daily. In some embodiments, about 1 mg of bardostat or a pharmaceutically acceptable salt thereof is administered to the patient once daily, and about 10 mg of dapagliflozin is administered to the patient once daily. In some embodiments, about 2 mg of bardostat or a pharmaceutically acceptable salt thereof is administered to the patient once daily, and about 10 mg of dapagliflozin is administered to the patient once daily.

[0135] In some implementations, bardostat is administered to the patient once daily at a dose of about 0.5 mg, about 1 mg, or about 2 mg, and dapagliflozin is administered to the patient once daily at a dose of about 10 mg. In some implementations, bardostat is administered to the patient once daily at a dose of about 1 mg, and dapagliflozin is administered to the patient once daily at a dose of about 10 mg. In some implementations, bardostat is administered to the patient once daily at a dose of about 2 mg, and dapagliflozin is administered to the patient once daily at a dose of about 10 mg.

[0136] In some embodiments, bardostat in tablet form (about 0.5 mg, about 1 mg, or about 2 mg) is administered orally once daily, along with dapagliflozin in tablet form (about 10 mg) once daily. In some embodiments, bardostat in tablet form (about 1 mg or about 2 mg) is administered orally once daily, along with dapagliflozin in tablet form (about 10 mg) once daily. In some embodiments, bardostat in tablet form (about 1 mg or about 1 mg) is administered orally once daily, along with dapagliflozin in tablet form (about 10 mg) once daily. In some embodiments, bardostat in tablet form (about 2 mg or about 1 mg) is administered orally once daily, along with dapagliflozin in tablet form (about 10 mg) once daily.

[0137] In some embodiments, bardostat or a pharmaceutically acceptable salt thereof is administered before, after, or concurrently with an SGLT2 inhibitor. In some embodiments, bardostat or a pharmaceutically acceptable salt thereof is administered concurrently with an SGLT2 inhibitor.

[0138] In some embodiments, bardostat in tablet form (about 0.5 mg, about 1 mg, or about 2 mg) is administered orally once daily, along with dapagliflozin in tablet form (about 10 mg) once daily, wherein bardostat and dapagliflozin are administered concurrently. In some embodiments, bardostat in tablet form (about 1 mg or about 2 mg) is administered orally once daily, along with dapagliflozin in tablet form (about 10 mg) once daily, wherein bardostat and dapagliflozin are administered concurrently. In some embodiments, bardostat in tablet form (about 2 mg) is administered orally once daily, along with dapagliflozin in tablet form (about 10 mg) once daily, wherein bardostat and dapagliflozin are administered concurrently.

[0139] In some implementations, bardostat or its pharmaceutically acceptable salts and SGLT2 inhibitors (such as dapagliflozin) are administered together with standard care agents for CKD. Exemplary standard care agents for CKD include angiotensin-converting enzyme inhibitors (ACEi or ACE inhibitors) and angiotensin receptor blockers (ARBs). Standard care agents for CKD and their dosages are well known to practicing physicians who examine and treat patients with CKD. Representative examples of ACE inhibitors include captopril, enalapril, and lisinopril. Representative examples of ARBs include valsartan, losartan, and irbesartan.

[0140] The standard care agent for CKD described herein may be used before and / or during administration of a combination comprising bardostat or a pharmaceutically acceptable saline thereof and an SGLT2 inhibitor (e.g., dapagliflozin). In some embodiments, the standard care agent for CKD and bardostat or a pharmaceutically acceptable saline thereof and an SGLT2 inhibitor (e.g., dapagliflozin) are administered together at the same or different times. In some embodiments, the patient is receiving a stable regimen of the maximum tolerated daily dose of an ACE inhibitor or ARB. In some embodiments, the ACE inhibitor or ARB, bardostat or a pharmaceutically acceptable saline thereof and an SGLT2 inhibitor (e.g., dapagliflozin) are administered together at the same or different times.

[0141] In some implementations, the patient has not received a mineralocorticoid receptor antagonist (MRA) (such as spironolactone, eplerenone, or finerenone) within four weeks prior to the first administration of the combination. In some implementations, the patient is not treated with a mineralocorticoid receptor antagonist (such as spironolactone, eplerenone, or finerenone) during treatment with the combination.

[0142] In some implementations, the patient has not received a potassium-sparing diuretic (such as triamterene or amiloride) within four weeks prior to the first administration of the combination. In some implementations, the patient is not treated with a potassium-sparing diuretic (such as triamterene or amiloride) during treatment with the combination.

[0143] In some implementations, the patient has not received a potassium binder (such as sodium zirconium cyclosilicate, partiromere, or sodium polystyrene sulfonate) within four weeks prior to the first administration of the combination. In some implementations, the patient is not treated with a potassium binder (such as sodium zirconium cyclosilicate, partiromere, or sodium polystyrene sulfonate) during treatment with the combination.

[0144] In some implementations, bardostat or its pharmaceutically acceptable salts and SGLT2 inhibitors (e.g., dapagliflozin) are administered together with a potassium binder (such as sodium zirconium cyclosilicate, partiromere, or sodium polystyrene sulfonate). In some implementations, if the patient presents with hyperkalemia, bardostat or its pharmaceutically acceptable salts and SGLT2 inhibitors (e.g., dapagliflozin) are administered together with a potassium binder (such as sodium zirconium cyclosilicate, partiromere, or sodium polystyrene sulfonate).

[0145] In some embodiments, bardostat or a pharmaceutically acceptable salt thereof is provided for use in any of the methods described herein.

[0146] In some embodiments, an SGLT2 inhibitor is provided for use in any of the methods described herein. In some embodiments, dapagliflozin is provided for use in any of the methods described herein. In some embodiments, a (S)-PG solvate of dapagliflozin is provided for use in any of the methods described herein.

[0147] In some embodiments, a combination comprising bardostat or a pharmaceutically acceptable salt thereof and an SGLT2 inhibitor is provided for use in any of the methods described herein. In some embodiments, a combination comprising bardostat and dapagliflozin is provided for use in any of the methods described herein. In some embodiments, a combination comprising bardostat and dapagliflozin (S)-PG solvates is provided for use in any of the methods described herein.

[0148] In some embodiments, use of bardostat or a pharmaceutically acceptable salt thereof is provided in the preparation of a medicament for use in any of the methods described herein.

[0149] In some embodiments, the use of SGLT2 inhibitors in the preparation of medicaments for use in any of the methods described herein is provided. In some embodiments, the use of dapagliflozin in the preparation of medicaments for use in any of the methods described herein is provided. In some embodiments, the use of dapagliflozin's (S)-PG solvate in the preparation of medicaments for use in any of the methods described herein is provided.

[0150] In some embodiments, use is provided in the preparation of a medicament comprising bardostat or a pharmaceutically acceptable salt thereof and an SGLT2 inhibitor in any of the methods described herein. In some embodiments, use is provided in the preparation of a medicament comprising bardostat and dapagliflozin in any of the methods described herein. In some embodiments, use is provided in the preparation of a medicament comprising a (S)-PG solvate of bardostat and dapagliflozin in any of the methods described herein.

[0151] In some embodiments, a kit is provided comprising: (a) bardostat or a pharmaceutically acceptable salt thereof and / or an SGLT2 inhibitor, and (b) instructions for use of bardostat or a pharmaceutically acceptable salt thereof and / or an SGLT2 inhibitor in any of the methods described herein.

[0152] In some embodiments, a kit is provided comprising: (a) bardostat and / or dapagliflozin, and (b) instructions for use of bardostat and / or dapagliflozin in any of the methods described herein.

[0153] In some embodiments, a kit is provided comprising: (a) a (S)-PG solvate of bardostat and / or dapagliflozin, and (b) instructions for use of the (S)-PG solvate of bardostat and / or dapagliflozin in any of the methods described herein.

[0154] All documents cited in this article are incorporated herein in their entirety by reference, including all data, tables, figures, and text presented in the cited documents.

[0155] Abbreviations and definitions of terms

[0156]

[0157]

[0158] The following examples are provided to illustrate some of the concepts described in this disclosure. While the examples are thought to provide specific individual embodiments of formulations, methods of preparation, and uses, they should not be considered as limiting the more general embodiments described herein.

[0159] Study 1: A Phase 2 trial of bardostat for the treatment of antihypertensive diseases

[0160] The BrigHTN study is a phase 2 trial of bardostat for the treatment of antihypertensive diseases and is described in Freeman et al., N Engl J Med 2023;388:395-405 (Clinicaltrials.gov ID: NCT04519658).

[0161] like Figure 1 As shown, at the end of the study, treatment with bardostat 2 mg / day resulted in a placebo-corrected reduction in UACR of >30%. Estimated geometric mean ratio (GMR) from ANCOVA, adjusted for logarithmic change from baseline (95% CI). Placebo: -2.8 (-20.5, 18.7); Bardostat 0.5 mg / day: -21.6 (-37.1, -2.3); Bardostat 1 mg / day: -19.9 (-35.2, -1.0); Bardostat 2 mg / day: -33.7 (-46.5, -17.9).

[0162] A total of 275 participants were randomly assigned. Some participants had eGFR and UACR outside the normal range (see Levey AS et al., Kidney Int 2005;67:2089–100). Baseline eGFR and UACR (for the treatment population) are shown in the table below:

[0163]

[0164] All bardostat groups showed a placebo-adjusted reduction in UACR from day 0 to day 85 (95% CI): bardostat 0.5 mg / day: -19.3% (-40.1, 8.9); bardostat 1 mg / day: -17.6% (-38.6, 1.1); bardostat 2 mg / day: -31.8 (-49.2, -8.4).

[0165] Bardostatin was well tolerated at all doses. Overall, there were six cases of hyperkalemia in the bardostat group (one case at 0.5 mg / day; four cases at 1 mg / day; and one case at 2 mg / day), and none in the placebo group. One case of hyperkalemia in the bardostatin 2 mg / day group was classified as severe (the investigators considered it unrelated to bardostatin).

[0166] Study 2: A study in patients with uncontrolled hypertension and chronic kidney disease

[0167] This is a randomized, double-blind, placebo-controlled, multicenter, parallel-group, dose-range study to evaluate bardostat (Clinicaltrials.gov ID: NCT05432167) for the treatment of patients with uHTN and CKD. The primary objective is to evaluate the effect of bardostat on SBP compared to placebo at week 26. Secondary objectives include evaluating the effect of bardostat on SBP compared to placebo using high- or low-dose strategies, determining the percentage of patients achieving SBP <130 mmHg, evaluating changes in urinary albumin-to-creatinine ratio (UACR) relative to baseline, evaluating changes in DBP relative to baseline for each dosing strategy, and evaluating changes in eGFR relative to baseline after 26 weeks of treatment. Safety objectives include evaluating vital signs, standing BP and heart rate, physical examination, electrocardiogram, weight measurement, and clinical laboratory assessments, including standard safety chemistry, hematology, coagulation, and urinalysis. Approximately 300 patients are planned to be enrolled at 70 clinical sites in the United States.

[0168] This study aims to enroll adult male and female patients with uHTN and mild to severe CKD. Patients with uHTN are defined as those taking a stable dose of an antihypertensive ACEI / ARB and, if diabetic, having a sitting office SBP ≥140 mmHg or ≥130 mmHg. Patients with mild to severe CKD are defined as those with a blood pressure of 25 mL / min / 1.73 m. 2 Up to 75 mL / min / 1.73 m 2eGFR (based on the CKD-EPI equation). Patients taking MRA must agree to discontinue MRA administration to meet the criteria for starting a 2-week run-in period, during which patients will take a single-blind placebo tablet once daily while continuing background antihypertensive medication. Eligible patients will be randomized to one of three treatment arms: placebo, low-dose strategy, and high-dose strategy, and begin a 26-week treatment period.

[0169] Patients assigned to the low-dose strategy arm were given bardostac 0.5 mg once daily. If, based on laboratory tests of samples drawn at week 1, patients did not experience hyperkalemia, hyponatremia, or a significant decline in renal function, and if mean sitting SBP ≥ 130 mmHg at week 3, the dose could be increased to 1 mg at week 3. If, based on laboratory tests of samples drawn at week 5, patients experienced hyperkalemia, hyponatremia, or a decline in renal function, the dose titer could be decreased 6 weeks after randomization. No further dose titration was permitted after 6 weeks. The study design was in... Figure 2 As shown in the image.

[0170] Inclusion criteria

[0171] Patients who meet all of the following criteria will be eligible to participate in this study. :

[0172] 1 is an adult male or female patient aged ≥18 years.

[0173] 2. The mean seated SBP with ≥ 140 mmHg was observed during screening (Visit 1), Visit 2 and Visit 3.

[0174] Note: If the patient is diabetic, a mean sitting SBP ≥ 130 mmHg may be eligible.

[0175] Note: Mean seated SBP is defined as the average of three seated SBP measurements taken during any single clinical site visit.

[0176] 3. Patients with a prior diagnosis of mild to severe CKD at visit 1, defined as 25 mL / min / 1.73 m 2 Up to 75 mL / min / 1.73 m 2 eGFR, including end values ​​(based on CKD-EPI equations).

[0177] Note: To ensure that the data represents patients with moderate to severe renal impairment, a flow rate of ≥ 60 mL / min / 1.73 m is required. 2 And < 75 mL / min / 1.73 m 2 The number of patients with eGFR will be capped at 45.

[0178] 4. Based on the first urine collected in the morning on several consecutive days during the screening period, the UACR has ≥ 100 mg / g (≥ 11.3 mg / mmol) in at least 2 out of 3 measurements.

[0179] 5. Based on the investigator's judgment, currently patients should take ACEi or ARB at the maximum tolerated daily dose for more than 4 weeks prior to visit 1.

[0180] 6. If an SGLT2 inhibitor is taken at screening (Visit 1), the regimen must be stable for at least 8 weeks prior to Visit 1 and a stable dose is expected to be maintained during the study.

[0181] Note: Patients who are not currently taking SGLT2 inhibitors at screening (Visit 1) are not expected to initiate treatment with this type of drug throughout the study period.

[0182] 7. Willing to comply with the following contraceptive and reproductive restrictions as studied:

[0183] - Female patients with fertility potential (i.e., ovulating, premenopausal, and non-surgically sterilized) must have a recorded negative pregnancy test at Visit 1 and randomized visit (Visit 3); and must use highly effective contraception (i.e., failure rate < 1%) from day 1 to day 30 after final administration of the study drug.

[0184] Note: For female patients of childbearing potential recruited in the study, acceptable methods of contraception include the following:

[0185] Surgical sterilization (tubal ligation)

[0186] ○ Intrauterine devices that have been in place for at least 12 weeks prior to visit 1

[0187] ○Hormonal contraception (oral, implantable, injectable, IUD, or patch) used for at least 12 weeks prior to Visit 1.

[0188] ○ Diaphragm used in combination with spermicides

[0189] - Postmenopausal women must have been free of menstrual bleeding for at least one year prior to starting medication and, at visit 1, must be >60 years old or have elevated follicle-stimulating hormone (FSH) levels >40 mIU / mL.

[0190] 8. Able and willing to provide informed consent for participation in the research.

[0191] 9. After a mandatory 2-week induction period, researchers must confirm that the patient’s BP and UACR measurements still meet the required criteria.

[0192] Exclusion criteria

[0193] Patients meeting any of the following criteria will be excluded from participation in the study. :

[0194] 1. Has a recorded diagnosis of type 1 diabetes.

[0195] 2. Unwilling or unable to discontinue mineralocorticoid receptor agonists (MRAs) or potassium-sparing diuretics as part of an existing antihypertensive regimen.

[0196] Note: Patients taking MRAs or potassium-sparing diuretics (e.g., triamterene, amiloride, etc.) as antihypertensive agents must be willing to discontinue the medication to meet study eligibility criteria. Potassium-sparing diuretics may be discontinued and replaced with non-potassium-sparing diuretics. All patients who maintain a stable antihypertensive regimen, including non-potassium-sparing diuretics, for at least 6 weeks will be eligible for single-blind enrollment. If a patient discontinues their previous MRA or potassium-sparing diuretic and / or begins a new antihypertensive study or adjusts their antihypertensive dose after visit 1, they should maintain a stable antihypertensive regimen for at least 4 weeks and will have an extended screening period of up to 9 weeks from signing informed consent to randomization (visit 3).

[0197] 3. A single instance of mean seated SBP > 180 mmHg or diastolic blood pressure (DBP) > 110 mmHg during screening (if such BP is recorded during screening, the patient may attend an ad hoc visit for additional BP measurement and reassessment of inclusion / exclusion criteria).

[0198] Note: Mean seated BP is defined as the average of three measurements taken at any clinical visit. If a patient missed their scheduled antihypertensive medication prior to the visit (Visit 1 or Visit 2), a BP retest is permitted ≥ 2 hours after medication administration, on the following day, or after re-establishing a scheduled antihypertensive regimen.

[0199] 4. During visit 1, the patient had a blood pressure > 50 kg / m². 2 Body Mass Index (BMI).

[0200] 5. Bilateral clinically relevant renal artery stenosis ≥ 70% has been documented; if imaging evidence is available, the patient should be excluded, as hypertension itself can be considered “clinically relevant.” Suspected or undocumented renal artery stenosis cannot be excluded.

[0201] 6. Undergo dialysis for acute kidney injury / acute renal failure within 12 weeks prior to the screening period, or undergo planned dialysis or kidney transplantation during the study.

[0202] 7. Within 6 months of visit 1, a known record of New York Heart Association Class III or IV chronic heart failure and / or hospitalization due to heart failure.

[0203] 8. Within 6 months of visit 1, the patient had suffered a stroke, transient ischemic attack, hypertensive encephalopathy, acute coronary syndrome, or was hospitalized due to heart failure.

[0204] 9. Has a known current severe left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy and / or severe aortic valve disease diagnosed from a previous echocardiogram or another imaging study.

[0205] 10. Having planned coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) or any major surgery during the study period.

[0206] 11. Patients who have had PCI, CABG, other major cardiac surgery (e.g., valve replacement) or peripheral artery bypass surgery within 6 months of visit 1.

[0207] 12. They had previously undergone solid organ transplantation or cell transplantation.

[0208] 13. Expected to receive or currently receiving any exclusionary medications, such as strong inducers of cytochrome P450 (CYP) 3A, nonsteroidal anti-inflammatory drugs, long-term use of spironolactone / eplerenone (more than 3 times a week for more than 3 months), and / or long-term use of systemic steroids.

[0209] 14. Has known hypersensitivity to any of the following drugs:

[0210] -CIN-107 or similar medications

[0211] -CIN-107 or similar excipients

[0212] 15. Individuals who have received immunotherapy for CKD within 6 months of visit 1, or who are expected to receive immunotherapy for CKD during participation in the study.

[0213] 16. Patients with any clinically relevant medical or surgical condition, including unstable conditions and / or conditions requiring regular blood transfusions or treatment with systemic immunosuppressants (including corticosteroids), which, in the investigator's view, would put the patient at risk by participating in the study.

[0214] 17. Evidence of any one of the following during visit 1 (one retest allowed):

[0215] - White blood cell count > 15 × 10 9 / L or absolute neutrophil count < 1 × 10 9 / L

[0216] Serum potassium < 3.5 mEq / L

[0217] Note: If researchers choose to use supplements to compensate for serum potassium levels and provide advice on managing the condition, patients with serum potassium levels below the normal range can continue the study without being retested.

[0218] Serum potassium > 5.0 mEq / L

[0219] - Serum sodium < 135 mEq / L

[0220] - Serum aspartate aminotransferase or alanine aminotransferase >3 × upper limit of normal (ULN) or

[0221] - Total bilirubin > 2 × ULN, unless due to Gilbert's syndrome.

[0222] -eGFR is < 25 or > 75 mL / min / 1.73 m 2

[0223] 18 patients had uncontrolled diabetes and glycosylated hemoglobin > 10.5% at visit 1.

[0224] The test results were positive for 19 pairs of human immunodeficiency virus (HIV) antibodies, hepatitis B surface antigen, or hepatitis C virus (HCV) ribonucleic acid (RNA).

[0225] 20 people typically consume more than 14 alcoholic beverages per week.

[0226] Note: One glass of alcohol is equivalent to ½ pint of beer (285mL), one glass of spirits (25mL), or one glass of wine (125mL).

[0227] 21. If the applicant has participated in another clinical study involving any investigational drug within 30 days prior to visit 1, or plans to participate in another clinical study within 30 days of the investigational drug being discontinued.

[0228] 22. Those who have received experimental treatment with small molecules within 30 days of the visit (whichever is longer) or experimental treatment with large molecules within 90 days of the visit (whichever is longer).

[0229] Note: Vaccination, including the vaccine for coronavirus disease 2019 (COVID-19), will not be exclusive.

[0230] 23. Those who are pregnant, breastfeeding, or planning to become pregnant during the study.

[0231] 24. If, after reviewing medical and psychiatric history, physical examination, and laboratory evaluation, the researcher deems the patient unsuitable for any other reason that could place the patient at increased risk during participation or interfere with the interpretation of the study results, then the patient is deemed unsuitable for the study. A history of COVID-19 infection is not itself an exclusion criterion unless the patient is subsequently deemed unsuitable for the study based on the criteria described above.

[0232] result

[0233] A low-dose strategy for bardostat represents 0.5 mg / day or 1 mg / day (if tolerated). A high-dose strategy for bardostat represents 2 mg / day or 4 mg / day (if tolerated).

[0234] Demographic and baseline characteristics (ITT population):

[0235]

[0236]

[0237]

[0238] a Assume all samples are in a sitting position, and the reference range is the adult reference range: standing 8:00-10:00 AM: ≤ 28 ng / dL, standing 4:00-6:00 PM: ≤ 21 ng / dL.

[0239] Median adherence was high in all intervention groups (bardostolicat low-dose strategy: 87.1%; bardostolicat high-dose strategy: 87.8%; and placebo: 87.2%), with 11 participants having a total intake >110%, 95 participants having a total intake between 80% and 100%, and 61 participants having a total intake <80%.

[0240] Security

[0241] In participants with uHTN and CKD, bardostat was well tolerated with both low- and high-dose strategies, and no new safety findings were observed. The most frequently reported treatment-associated adverse event (TEAE) was hyperkalemia, which occurred at higher rates in the low-dose and high-dose bardostat groups than in the placebo group (30.8%, 46.0%, and 4.7%, respectively).

[0242] effect

[0243] Bardostat was effective in reducing SBP in participants with uHTN and CKD. In the mITT population, treatment with bardostat (combined treatment group) resulted in a mean reduction in sitting SBP from baseline to week 26 compared to placebo (-8.08 [95% CI: -13.36, -2.79] mmHg, p = 0.003).

[0244] The primary objective of this study was to demonstrate that, in participants with uHTN and CKD, bardostat (in the combined treatment group) was superior to placebo in terms of mean change in seated SBP relative to baseline after 26 weeks of treatment.

[0245] In the mITT population, treatment with bardostat using low- or high-dose strategies resulted in a decrease in mean seated SBP from baseline to week 26 compared to placebo (-8.99 [95% CI: -15.10, -2.87] mmHg, p = 0.004 and -7.22 [95% CI: -13.24, -1.19] mmHg, p = 0.019, respectively).

[0246] The secondary objective of this study was to demonstrate that, after 26 weeks of treatment, bardostatin with both high-dose and low-dose strategies was superior to placebo in terms of mean change in seated SBP relative to baseline.

[0247] These results are consistent across the subgroups of SBP.

[0248] In the bardostabolic combined group (95% CI: 1.23, 7.23), 38 (36.2%) participants achieved SBP < 130 mmHg by week 26, compared with 8 (16.7%) participants in the placebo group (odds ratio 2.99, p = 0.015). In the bardostabolic low-dose strategy group, 21 (42.0%) participants (95% CI: 1.44, 10.15) achieved SBP < 130 mmHg by week 26 (odds ratio 3.82, p = 0.007). In the bardostabolic high-dose strategy group, 17 (30.9%) participants (95% CI: 0.88, 6.27) achieved SBP < 130 mmHg by week 26 (odds ratio 2.35, p = 0.088).

[0249] For participants in the bardostat combined group, the mean (SD) DBP change relative to baseline at week 26 was -5.64 (10.174) mmHg, and the mean (SD) DBP percentage change relative to baseline was -6.53 (12.533)%.

[0250] For participants in the low-dose bardostat strategy group, the mean (SD) DBP change from baseline at week 26 was -6.46 (11.412) mmHg, and the mean (SD) DBP percentage change from baseline was -7.59 (14.488)%. For participants in the high-dose bardostat strategy group, the mean (SD) DBP change from baseline at week 26 was -4.89 (8.945) mmHg, and the mean (SD) DBP percentage change from baseline was -5.57 (10.492)%. For the placebo group, the mean (SD) DBP change from baseline at week 26 was -0.99 (8.445) mmHg, and the mean (SD) DBP percentage change from baseline was -0.77 (10.417)%.

[0251] Compared with placebo, bardostat treatment resulted in a decrease in mean seated DBP from baseline to week 26 in the mITT population. At week 26, the mean LS difference (95% CI) in MMRM adjustment between the bardostat combined group and placebo was -4.84 (-7.92, -1.77) mmHg, p = 0.002; for participants in the low-dose bardostat strategy treatment group, it was -5.04 (-8.60, -1.48) mmHg, p = 0.006; and for participants in the high-dose bardostat strategy treatment group, it was -4.65 (-8.16, -1.14) mmHg, p = 0.010.

[0252] At week 26, compared with placebo, the percentage change (95% Ci) of UACR from baseline in participants in the bardostat combination therapy group was -55.17 (-67.41, -38.34)%, p < 0.001; the percentage change of UACR from baseline in participants in the low-dose bardostat strategy therapy group was -52.02 (-66.84, -30.56)%, p < 0.001; and the percentage change of UACR from baseline in participants in the high-dose bardostat strategy therapy group was -57.97 (-70.83, -39.43)%, p < 0.001.

[0253] A 50% reduction in UACR from baseline to month 6 reduced the relative risk of predicting clinical renal endpoints by 48% (Heerspink et al., The Lancet Diabetes & Endocrinology, 2019, 7(2), 128-139).

[0254] At week 26, compared with placebo, the change in eGFR from baseline in participants in the bardostat combined group (95% CI) (LS mean difference) was -2.3 (-5.06, 0.49) mL / min / 1.73 m 2 The p-value was 0.105 for participants in the low-dose bardostat treatment group, which was -1.8 (-4.99, 1.43) mL / min / 1.73 m 2 The p-value was 0.275, and for participants in the bardostat high-dose strategy treatment group, it was -2.8 (-6.00, 0.35) mL / min / 1.73 m 2 The p-value is 0.080.

[0255] There was an indication of a larger effect on UACR in participants with higher plasma renin activity at baseline (-22.10 [95% CI: -54.00, 31.95]% for plasma renin activity < 1 ng / mL / hr and -68.05 [95% CI: -78.30, -52.96]% for plasma renin activity ≥ 1 ng / mL / hr; p-value for interaction = 0.008).

[0256] With baseline SGLT2i use, at week 26, compared with placebo, the percentage change (95% CI) in UACR relative to baseline in participants in the combined bardostostat group was -59.88 (-76.56, -31.33)% for participants using baseline SGLT2i and -52.32 (-67.97, -29.01)% for participants not using baseline SGLT2i (interaction p=0.611).

[0257] Study 3: A phase III, randomized, double-blind, positive-control study to evaluate the efficacy of bardogliflozin compared to dapagliflozin alone. The efficacy and safety of the combination of statone and dapagliflozin in the progression of chronic kidney disease (CKD) in participants with CKD and hypertension. Safety and Tolerability

[0258] A. Research Design

[0259] This is a phase III, multicenter, randomized, double-blind, positive-control, parallel-group study (see [link]). Figure 3 This study aimed to evaluate the effect of the combination of bardostol and dapagliflozin on the change in eGFR over time in participants with CKD and HTN compared to dapagliflozin alone.

[0260] Approximately 2500 participants were randomly assigned to the study intervention. Participants aged ≥ 18 years were eligible for participation, with an eGFR ≥ 30 mL / min / 1.73 m 2 And < 90 mL / min / 1.73 m 2UACR > 200 mg / g and < 5000 mg / g, SBP ≥ 130 mmHg, having received a stable and maximally tolerated daily dose of an ACE inhibitor or ARB for at least 4 weeks prior to the screening visit, and serum potassium ≥ 3.5 mmol / L and ≤ 4.8 mmol / L at screening (for eGFR < 45 mL / min / 1.73 m 2 Participants with serum potassium ≤ 4.5 mmol / L.

[0261] Introduction Period: Participants treated with SGLT2i for at least 4 weeks after screening are eligible for randomization visits. Participants who have not received SGLT2i at Visit 1 (i.e., those who have not been exposed to SGLT2i) will receive an introduction intervention of dapagliflozin 10 mg QD (provided by the sponsor) for at least 4 weeks prior to randomization (see [link to introductory intervention]). Figure 3 These participants will undergo central laboratory creatinine assessment (at Visit 1.2) at least 72 hours after 4 weeks of dapagliflozin induction and before randomized visit (Visit 2) for eGFR calculation.

[0262] Double-blind period: Participants with SBP ≥ 120 mmHg at Visit 2 (randomization) will be randomized to one of the two treatment groups at a 1:1 ratio:

[0263] • Bardostat / Dapagliptin (n = approximately 1250)

[0264] • Bardostat (n = approximately 1250)

[0265] Participants who have received a stable dose of SGLT2i at screening visit 1 will take their last dose of prescription SGLT2i the day before randomization (day-1) and will switch to the study intervention at visit 2 (day 1) according to their randomization assignment.

[0266] Field visits were conducted at weeks 2, 4, 8, and 16 post-randomization (for safety assessments, including blood pressure and potassium). Participants were then visited at the study site every 4 months until visit 12 (EoT, day 731 ± 7 (24 months) post-randomization).

[0267] Participants randomized to the bardostol / dapagliflozin group will initially receive 1 mg bardostol and 10 mg dapagliflozin. Participants randomized to the dapagliflozin group will receive a placebo matched with 1 mg bardostol and 10 mg dapagliflozin. At visits 3, 4, and 5, for participants meeting the potassium-based upregulation criteria, the dose of bardostol or the matched placebo may be increased to 2 mg (therefore, participants may receive 2 mg bardostol / 10 mg dapagliflozin or 2 mg matched placebo / 10 mg dapagliflozin).

[0268] Open-label period: Following 24 months of double-blind treatment (EoT visit), participants continued open-label treatment with 10 mg dapagliflozin (i.e., participants randomized to the bardostostat / dapagliflozin group discontinued bardostostat, and those randomized to dapagliflozin discontinued placebo) until the EoS visit (day 787 ± 7), approximately 6 weeks later. The EoS visit consisted of two separate visits in which eGFR was measured at two time points at least 72 hours apart. The purpose of this period was to collect eGFR data after bardostostatin discontinuation to assess irreversible disease progression, independent of the hemodynamically mediated acute decrease in eGFR expected at the start of treatment.

[0269] In the event of an early interruption of the blinded study intervention, the participant will continue the study and receive open-label dapagliflozin 10 mg monotherapy unless the participant meets the specific interruption criteria for dapagliflozin, in which case all IMPs will be interrupted and the participant will enter the PTDV.

[0270] Definition of study completion: For the purpose of transparency in clinical trials, the definition of study completion differs under FDA and EU regulatory requirements:

[0271] • The EU requires that the completion of a study be defined as the last visit to the last participant in any program-related activities.

[0272] • The Food and Drug Administration requires the definition of two completion dates:

[0273] -Preliminary Completion Date- The date on which the last participant was examined or received an intervention for the final collection of data for the primary outcome measure, regardless of whether the clinical study ended or was terminated according to a pre-specified protocol. In the case of clinical studies with more than one primary outcome measure having different completion dates, this term refers to the date on which data collection for all primary outcomes was completed.

[0274] -Study Completion Date- The date on which the last participant was examined or received intervention for the final collection of data on primary and secondary outcome measures and adverse events (AEs) (e.g., the last visit of the last participant), regardless of whether the clinical study ended or was terminated according to a pre-specified protocol.

[0275] If a participant has completed all phases of the study, including the final planning process, he / she is considered to have completed the study.

[0276] The end of a study is defined as the date of the last visit of the last participant in the study or the date of the last planned procedure of the last participant in a global study, whichever occurs last.

[0277] B. Research Group

[0278] (i) Inclusion criteria

[0279] Participants are eligible for inclusion in this study only if all of the following criteria apply:

[0280] 1. Participants of any gender must be 18 years of age or older when signing the informed consent form.

[0281] 2. During screening, eGFR ≥ 30 mL / min / 1.73 m 2 And < 90mL / min / 1.73m 2

[0282] 3. At the screening stage, the urine albumin-to-creatinine ratio is > 200 mg / g (22.6 mg / mmol) and < 5000 mg / g (565 mg / mmol).

[0283] 4. Participants with a history of HTN and whose SBP was ≥ 130 mmHg at screening and ≥ 120 mmHg at randomized visits.

[0284] 5. Stable and maximum tolerated daily dose of ACE inhibitors or ARBs (not both) for at least 4 weeks prior to the screening visit.

[0285] 6. Based on eGFR screening, serum potassium levels in the central laboratory must meet the following criteria during screening visits:

[0286] ○ For screening eGFR ≥ 45 mL / min / 1.73 m 2 Participants must have potassium levels ≥3.5 mmol / L and ≤4.8 mmol / L at the screening visit.

[0287] ○ For screening eGFR < 45 mL / min / 1.73 m 2 Participants must have potassium levels ≥3.5 mmol / L and ≤4.5 mmol / L at the screening visit.

[0288] (ii) Exclusion criteria

[0289] Participants are excluded from the study if any of the following criteria apply:

[0290] 1. During screening, systolic blood pressure > 180 mmHg, or diastolic blood pressure > 110 mmHg.

[0291] 2. Known hyperkalemia, defined as potassium ≥ 5.5 mmol / L within 3 months at the time of screening.

[0292] 3. During the screening visit, serum sodium < 135 mmol / L was measured by the central laboratory.

[0293] 4. Type 1 diabetes or uncontrolled type 2 diabetes with HbA1c > 10.5% (> 91 mmol / mol) at the time of screening.

[0294] 5. New York Heart Association functional HF Class IV at screening.

[0295] 6. Within the three months prior to randomization, the individual had experienced a stroke, transient ischemic attack, valve implantation or replacement, carotid artery surgery or carotid angioplasty, acute coronary syndrome, or hospitalization due to worsening heart failure.

[0296] 7. Optionally, the baseline QTcF > 470 milliseconds.

[0297] 8. Optional location, family history of long QT syndrome.

[0298] 9. Known severe liver injury, defined as Child-Pugh Class C based on documented medical history.

[0299] 10. Record history of adrenal insufficiency.

[0300] 11. Any dialysis (including acute kidney injury) within 3 months prior to the screening visit.

[0301] 12 Any acute kidney injury within 3 months prior to the screening visit.

[0302] 13. Hypersensitivity to the investigated treatment (active substance or excipient) is known.

[0303] 14. History of organ transplantation or bone marrow transplantation within 6 months after randomization, or planned organ transplantation (including kidney transplantation).

[0304] 15. A history of allergic / hypersensitivity reactions to SGLT2 inhibitors (e.g., empagliflozin) or ASI, as determined by the investigator.

[0305] 16 Any clinical condition requiring systemic immunosuppressive therapy other than maintenance therapy (stabilized for at least 3 months prior to visit 1).

[0306] 17. Drugs or alcoholism that, in the researcher's judgment, make a participant an undesirable candidate for the study.

[0307] 18. Any use of mineralocorticoid receptor antagonists (such as spironolactone, eplerenone, or fenelitonee), potassium-sparing diuretics (such as triamterene or amiloride), or potassium binders (such as sodium zirconium cyclosilicate, partiromere, or sodium polystyrene sulfonate) within 4 weeks prior to screening.

[0308] 19. Concomitant therapy with strong inducers of cytochrome P450 (CYP) 3A (e.g., apatamide, avasimibe, carbamazepine, enzalutamide, lumacaftor, mitotane, phenytoin, rifampin, rifapentine, St. John's wort).

[0309] 20. Optionally, if possible, drugs that prolong the QT should be avoided, and if other alternatives are expected to prolong the QT in the future, these drugs should be preferred. If such QT-prolonging drugs are still necessary, the investigator must ensure that appropriate ECG and electrolyte monitoring is performed based on clinical judgment.

[0310] 21 Any other condition or treatment that, in the investigator's or sponsor's judgment, would make a participant unsuitable for the study, including conditions or treatments that the investigator anticipates would preclude participation for the entire duration of the study (e.g., active malignancy or other conditions that limit life expectancy to less than 12 months).

[0311] 22 participated in another clinical study prior to randomization and was administered the investigational product within the past 3 months.

[0312] 23. For WOCBP, the pregnancy test is positive at screening.

[0313] C. Research interventions and concomitant therapies

[0314] (i) Research interventions applied

[0315] All participants will receive bardostat and dapagliflozin, or placebo and dapagliflozin. To ensure treatment blinding, matching bardostat tablets (1 mg, 2 mg, and placebo) will be visually identical (matched and indistinguishable). The study treatments to be administered and investigated in this study are described in the table below:

[0316]

[0317] The automated IRT / RTSM centrally assigns all participants who meet all the eligibility criteria to a randomized, blinded study intervention, which assigns participants 1:1 to one of two different treatment groups (i.e., the bardostat / dapagliflozin group or the dapagliflozin group).

[0318] The number of randomized participants with UACR > 200 mg / g to < 500 mg / g and eGFR ≥ 30 mL / min / 1.73 m will be monitored. 2 Up to < 45 mL / min / 1.73 m 2The number of participants was determined as shown in the laboratory tests at the time of registration (Visit 1), and the randomization in IxRS was capped to ensure that the number of participants in each subgroup did not exceed approximately 20%.

[0319] (ii) Dosage modification

[0320] If serum potassium rises to > 5.5 mmol / L at any point during the study treatment, bardostat / matched placebo should be temporarily discontinued, see details below. All participants will begin with a lower dose (1 mg) of bardostat or a matched placebo, and the investigator may increase the dose to the target dose (2 mg).

[0321] Increase: The dose should be increased to 2 mg at Visit 3, Visit 4, or Visit 5, provided that the potassium concentration (local laboratory value) is ≤ 4.8 mmol / L. Once the above local laboratory parameters are confirmed, the increase should be made within 7 days, preferably as soon as possible. Note: Participants who experience potassium > 5.5 mmol / L or sodium < 130 mmol / L at any time during the study should not be increased and should maintain a dose of 1 mg.

[0322] Downregulation: For participants who have previously received an upregulation, downregulation may be considered at any point throughout the trial, for example, based on potassium, systolic blood pressure, or sodium, or for other safety or tolerability considerations. Where possible, these decisions should be reviewed using medical monitoring. Following a downregulation, an unplanned safety visit may be conducted within 2 weeks at the investigator's discretion. Participants who were downregulated from 2 mg to 1 mg during the trial should maintain 1 mg for the remainder of the study.

[0323] (iii) Potassium monitoring and measurement

[0324] Hyperkalemia is a common event in subjects with CKD and is one of the major risk factors identified from previous bardostostat studies. Therefore, serum potassium levels were systematically monitored throughout the study. Instructions for managing serum potassium measurements are described below:

[0325] Serum potassium ≤ 4.8 mmol / L:

[0326] If a participant was taking 1 mg of bardostat, the dose was increased to 2 mg.

[0327] If participants received 2 mg of bardostat, they continued with the same dose.

[0328] Serum potassium 4.9 mmol / L to 5.5 mmol / L: continue with the same dose.

[0329] Serum potassium > 5.5 mmol / L: Do not administer bardostat and recheck potassium within 72 hours. If subsequent samples are ≤ 5.0 mmol / L, optionally ≤ 4.8 mmol / L, restart bardostat at 1 mg. Serum potassium should be rechecked within 2 weeks (+ / - 7 days) during unplanned visits. Note: Participants experiencing serum potassium > 5.5 mmol / L should not have their levels upregulated during the study.

[0330] If subsequent samples show > 5.0 mmol / L, or optionally > 4.8 mmol / L: continue without bardostat; continue monitoring serum potassium, and restart bardostat at 1 mg when potassium ≤ 5.0 mmol / L, or optionally ≤ 4.8 mmol / L. Serum potassium should be rechecked within 2 weeks (+ / - 7 days) during unplanned visits. Note: Participants experiencing serum potassium > 5.5 mmol / L should not have their levels upregulated during the study.

[0331] (iv) Prohibited concomitant medications

[0332] The following medications and supplements are prohibited during this study.

[0333] • Potassium-sparing diuretics (e.g., amiloride, triamterene) and direct renin inhibitors (e.g., Aliskiren).

[0334] • Mineralocorticoid receptor antagonists or aldosterone antagonists (e.g., eplerenone, finerenone, spironolactone) or aldosterone synthase inhibitors.

[0335] • Strong CYP3A4 inducers (e.g., apalutamide, avasimibe, carbamazepine, enzalutamide, lumacaftor, mitotane, phenytoin, rifampin, rifapentine, St. John's wort).

[0336] • Companion therapy with open-label SGLT2 inhibitors.

[0337] • Treatment with potassium supplements is not prohibited, but should only be prescribed to individuals whom the investigator deems necessary to prevent hypokalemia.

[0338] C. Goal / Endpoint

[0339]

[0340] aThe graded composite endpoint was defined as the participant's most severe outcome, based on the severity of the following results: death, KFRT (as defined in the Clinical Events Adjudication Charter for chronic dialysis or kidney transplantation), and sustained GFR < 15 mL / min / 1.73 m. 2 ; a sustained decrease in GFR relative to baseline of ≥ 57%; ≥ 50%; or, if no outcome occurs, the individual change in eGFR from baseline to post-treatment at 24 months.

[0341] The participant eGFR used to determine eligibility, assess eligibility adjustments, and evaluate primary and applicable key secondary endpoints will be calculated based solely on serum creatinine concentration according to the CKD-EPI 2021 equation (Inker et al., N Engl J Med. 2021; 385(19): 1737-49).

[0342] UACR is calculated as follows:

[0343] UACR (mg / g = urinary albumin [mg / dL] / urinary creatinine [g / dL])

[0344] According to the HF Academic Research Consortium, a potential HF event (with and without hospitalization) is defined as either an HF event with or without hospitalization (Abraham et al., Eur J Heart Fail., 2020; 22(12): 2175-86).

[0345] Main estimation definition

[0346] The estimation is described by the following attributes:

[0347] Population: Participants with CKD and HTN, as defined by inclusion and exclusion criteria.

[0348] Endpoint: Change in eGFR relative to baseline.

[0349] Treatment criteria: Study intervention (randomized to bardostat / dapagliflozin or dapagliflozin) with or without change in background drug therapy (treatment strategy) regardless of whether it was interrupted for any reason.

[0350] Remaining concurrent events:

[0351] • KFRT or kidney death: eGFR was analyzed as 0-10 mL / min / 1.73 m after the event had occurred. 2 The composite strategy implemented based on the value

[0352] • Non-renal death: Hypothetical strategy implemented by processing eGFR after events in the missing data framework.

[0353] Population-level pooled measure: the difference in mean change from baseline to 2 years after treatment (approximately 6 weeks after EoT) between treatment groups, expressed as mean change per year.

[0354] Study 4: A phase III, randomized, double-blind, placebo-controlled, event-driven study to evaluate the efficacy of dapavrin alone. Compared to dapagliflozin, the combination of bardostal and dapagliflozin showed better renal and cardiovascular outcomes in participants with chronic kidney disease and hypertension. Efficacy, safety, and tolerability of the drug for controlling mortality.

[0355] A. Research Design

[0356] This is a phase III, multicenter, randomized, double-blind, placebo-controlled, event-driven study to evaluate whether bardosstat / dapagliflozin is superior to placebo / dapagliflozin in reducing the risk of combined renal events (a sustained 50% decline in eGFR, renal failure, or CV death) in participants with CKD and HTN when added to the standard of care. Approximately 5000 participants were randomized to the study intervention in this study. The study design... Figure 4 As shown in the image.

[0357] The aim of this study was to investigate the efficacy, safety, and tolerability of bardostat in combination with dapagliflozin compared with placebo and dapagliflozin in reducing the combined (risk) of eGFR decline > 50%, renal failure, or CV death in individuals with CKD and HTN.

[0358] The study consisted of a 4-week dapagliflozin induction period for participants who were not treated with SGLT2i at screening, and a double-blind period in which participants would receive either bardostat / dapagliflozin or placebo / dapagliflozin.

[0359] Field visits will be conducted at weeks 2, 4, 8, 16, 34, and 52 following randomization. Visits will then be conducted approximately every four months.

[0360] The study termination procedure will be initiated when the predetermined number (N = 845) of the primary endpoint events, i.e., PACD, have occurred. All randomized participants, including any who have prematurely discontinued the study intervention, will be scheduled for SCV within 6 weeks of PACD.

[0361] In the event of premature discontinuation of a blinded study intervention, the participant will continue the study and receive dapagliflozin 10 mg unless the participant meets the specific discontinuation criteria for dapagliflozin. If the study intervention is temporarily or permanently discontinued, the participant should remain in the study, and importantly, the planned study visits (including the PTDV for participants who have permanently discontinued the study intervention) and data collection should continue in accordance with the study protocol until the SCV.

[0362] Eligible participants must be ≥18 years old and have CKD and HTN. Specific inclusion criteria include eGFR ≥30 mL / min / 1.73 m 2 And ≤ 75 mL / min / 1.73 m 2 UACR ≥ 30 mg / g and ≤ 5000 mg / g, SBP ≥ 130 mmHg (the latest value within 4 weeks of screening or at the screening visit) and ≥ 120 mmHg at randomization, stable and maximum tolerated daily dose of ACEi or ARB for at least 4 weeks prior to the screening visit, and potassium ≥ 3.0 mmol / L and ≤ 4.8 mmol / L (for eGFR < 45 mL / min / 1.73 m 2 For participants with eGFR ≤ 4.5 mmol / L. Results for eGFR, potassium, and sodium used to assess inclusion / exclusion criteria should be available on the same day, should be the most recent values ​​within 4 weeks of screening or at the time of screening visit, and should be values ​​from all local or all central laboratories.

[0363] Where permitted by local regulations, the study will include an optional pre-screening period in which participants will be assessed for at least one of the following parameters: eGFR, UACR, potassium, sodium, HbA1c, and BP. This is intended to facilitate on-site identification of participants who can be considered for inclusion in the full screening assessment as described in the SoA. All participants participating in the optional pre-screening period will be required to sign an additional pre-screening ICF.

[0364] All consenting participants (after ICF signature) will be screened during a screening period of up to 2 weeks. Participants who are not treated with SGLT2i (or have been treated for less than 4 weeks) during the screening period will complete an introductory period of at least 4 weeks (but not more than 6 weeks) with dapagliflozin after the screening period and before randomization. Participants who meet the screening eligibility criteria and have received SGLT2i (regardless of the previous dose of SGLT2i) for at least 4 weeks prior to screening may proceed to the randomization visit.

[0365] Eligible participants with SBP ≥ 120 mmHg at Visit 2 (randomization) will be randomized to one of the two intervention groups at a 1:1 ratio:

[0366] • Bardostabrine 1 mg and dapagliflozin 10 mg (n = approximately 2500)

[0367] • Match bardostat placebo 1 mg and dapagliflozin 10 mg (n = approximately 2500)

[0368] Participants randomized to the bardostat / dapagliflozin group will initially receive 1 mg bardostat and 10 mg dapagliflozin. Participants randomized to the placebo / dapagliflozin group will receive a placebo matched with 1 mg bardostat and 10 mg dapagliflozin. At visit 5, for participants meeting the upregulation criteria based on potassium levels measured by a local laboratory from visits 3, 4, and 5, bardostat or the matched placebo may be upregulated to 2 mg (therefore, participants may receive 2 mg bardostat / 10 mg dapagliflozin or 2 mg of the matched placebo / 10 mg dapagliflozin).

[0369] The study visits were scheduled as follows: Visit 1 (screening / registration); Visit 2 (randomization, day 1); Visit 3 (day 15 ± 3); Visit 4 (day 29 ± 3); Visit 5 (day 57 ± 3); Visit 6 (day 113 ± 7); Visit 7 (day 240 ± 14); Visit 8 (day 365 and every 4 months ± 14).

[0370] The expected total study duration is approximately 3.5 years for any study participant, with a maximum expected duration of up to 5 years for early participants, depending on the randomization rate and event rate. Participants in the study may have a shorter or longer study duration depending on when they enroll. The study duration may change if the event rate or randomization rate differs from the expected duration.

[0371] Statistical methods

[0372] Primary Analysis: The primary endpoint of the study is the time to first occurrence of any of the following composite endpoints: ≥50% sustained decline in eGFR, renal failure, and CV death. The primary estimator for the primary endpoint is a Cox proportional hazards model of time to first event, factored with the treatment group and adjusted for covariates: baseline eGFR, baseline UACR, SGLT2i use at screening, and baseline T2DM status. Study omissions and other missing data will not be entered. HRs, 95% CIs, and p-values ​​for comparisons between the treatment and treatment groups will be presented.

[0373] Multiple testing procedure: Formal hypothesis testing of the treatment effects of bardostabolic statin / dapagliflozin versus placebo / dapagliflozin will be performed on the primary and secondary efficacy endpoints, with an overall one-sided type I error control of 2.5%. To preserve against multiple comparison fallacies, a pre-specified tiered ranking of the primary and secondary endpoints will be applied to the confirmation test procedure for assessing statistical significance.

[0374] Sample Size: Approximately 5000 participants were randomized to the study intervention. Assuming a true HR of 0.80 for the primary endpoint between treatment groups, a total of 845 events would provide 90% power for the one-sided primary test with α = 0.025. In the placebo / dapagliflozin treatment group, an event rate of gradually increasing was assumed, characterized by Weibull risk with a scale parameter of 0.029 and a shape parameter of 1.578. The estimated total sample size of 5000 participants provided the required number of events over a mean follow-up of approximately 41 months.

[0375] Goal / End Point

[0376]

[0377]

[0378] Note: Bardostat / dapagliflozin = a combination of bardostat and dapagliflozin; Placebo / dapagliflozin = a combination of placebo and dapagliflozin.

[0379] The participant eGFR used to determine eligibility and assess primary and applicable key secondary endpoints will be calculated based on serum creatinine, age, and sex according to the CKD-EPI 2021 equation (Inker et al., N Engl J Med. 2021; 385(19): 1737-49).

[0380] UACR is calculated as follows:

[0381] UACR (mg / g = urine albumin [mg / dL] / urine creatinine [g / dL]).

[0382] According to the HF Academic Research Consortium, a potential HF event (with and without hospitalization) is defined as either an HF event with or without hospitalization (Abraham et al., Eur J Heart Fail., 2020; 22(12): 2175-86).

[0383] Key measurement definition: This measurement is described by the following attributes:

[0384] • Population: Patients with CKD and HTN, as defined by the inclusion and exclusion criteria.

[0385] • Variables: ≥ 50% sustained decrease in eGFR, renal failure (defined as any of the following: sustained eGFR <15 mL / min / 1.73 m 2The timing of the first event in a composite event of chronic dialysis treatment, receiving a kidney transplant or dying from a primary cause of kidney disease (due to kidney failure when not undergoing dialysis), and CV death.

[0386] • Treatment: Bardoxetine / dapagliflozin or placebo / dapagliflozin, regardless of whether the study intervention was interrupted (treatment strategy) or whether concomitant drug therapy was started or changed (treatment strategy).

[0387] Concurrent event strategy:

[0388] • Non-CV deaths will be handled using an assumption strategy, which assumes that participants cannot die from non-CV deaths, and is achieved by reviewing data at the time of death rather than entering data after death.

[0389] Summary of the group level of the variables:

[0390] • HR between treatment groups.

[0391] All efforts will be made to track randomized participants and collect data as much as possible, regardless of study intervention adherence and the use of concomitant medications.

[0392] B. Research Group

[0393] (i) Inclusion criteria

[0394] Participants are eligible for inclusion in this study only if all of the following criteria apply:

[0395] 1. Participants of any gender must be 18 years of age or older when signing the informed consent form.

[0396] 2 participants have

[0397] (a) eGFR ≥ 30 mL / min / 1.73 m 2 And < 60 mL / min / 1.73 m 2 (Local or central laboratory values), and UACR ≥ 30 mg / g (3.39 mg / mmol) and < 500 mg / g (56.5 mg / mmol) (central laboratory values ​​only), or

[0398] (b) eGFR ≥ 30 mL / min / 1.73 m 2 And ≤ 75 mL / min / 1.73 m 2(Local or central laboratory values), and UACR ≥ 500 mg / g (56.5 mg / mmol) and ≤ 5000 mg / g (565 mg / mmol) or UPCR ≥ 700 mg / g (79 mg / mmol) and ≤ 7000 mg / g (790 mg / mmol) (Local or central laboratory values).

[0399] 3 participants had a history of HTN and SBP ≥ 130 mmHg (within 4 weeks of screening or the latest value at the screening visit) and ≥ 120 mmHg at the randomization visit.

[0400] 4. A stable and maximum tolerated dose of ACEi or ARB (not both) for at least 4 weeks prior to the screening visit.

[0401] 5 participants have:

[0402] (a) If eGFR ≥ 45 mL / min / 1.73 m 2 (Local or central laboratory values), then serum or plasma potassium ≥3.0 and ≤4.8 mmol / L, or

[0403] (b) If eGFR < 45 mL / min / 1.73 m 2 (Local or central laboratory values), then serum or plasma potassium ≥3.0 and ≤4.5 mmol / L.

[0404] 5. The use of contraceptive pills should comply with local regulations regarding contraceptive methods for individuals participating in clinical trials.

[0405] The results for eGFR, potassium, and sodium used to assess inclusion / exclusion criteria should be available on the same day, should be the most recent values ​​within 4 weeks of screening or at the time of screening visits, and should be values ​​from all local or all central laboratories.

[0406] (ii) Exclusion criteria

[0407] Participants are excluded from the study if any of the following criteria apply:

[0408] 1. During screening, systolic blood pressure > 180 mmHg, or diastolic blood pressure > 110 mmHg.

[0409] 2. Known hyperkalemia, defined as potassium ≥ 5.5 mmol / L within 3 months prior to screening.

[0410] 3. Serum sodium < 135 mmol / L (value obtained from a central or local laboratory within 4 weeks prior to screening or at the screening visit).

[0411] Type 41 diabetes:

[0412] (a) For the United States only: Patients with T1DM who have been treated with SGLT2i for at least 4 months, have no DKA during that period, and have a history of ketosis monitoring are eligible for inclusion.

[0413] (b) For Japan only: Patients with T1DM who have been treated with 10 mg dapagliflozin for at least 4 months and have no DKA during the dapagliflozin treatment period are eligible for inclusion.

[0414] 5. Uncontrolled T2DM with HbA1c > 10.5% (> 91 mmol / mol) (central or local laboratory values ​​obtained within 3 months prior to screening or at the screening visit).

[0415] 6. New York Heart Association functional HF Class IV at screening.

[0416] 7. Within the three months prior to randomization, the individual had experienced a stroke, transient ischemic attack, valve implantation or replacement, carotid artery surgery or carotid angioplasty, acute coronary syndrome, or hospitalization due to worsening heart failure.

[0417] 8. Known severe liver injury, defined as Child-Pugh Class C based on documented medical history.

[0418] 9. Historical records of adrenal insufficiency.

[0419] 10. Any dialysis (including acute kidney injury) within 3 months prior to the screening visit.

[0420] 11. Any acute kidney injury within 3 months prior to the screening visit.

[0421] 12. Hypersensitivity to the investigated treatment (active substance or excipient) is known.

[0422] 13. History of organ transplantation or bone marrow transplantation within 6 months after randomization, or planned organ transplantation (including kidney transplantation).

[0423] 14. A history of allergic / hypersensitivity reactions to SGLT2 inhibitors (e.g., empagliflozin) or ASI, as determined by the investigator.

[0424] 15 Any clinical condition requiring systemic immunosuppressive therapy other than maintenance therapy (stabilized for at least 3 months prior to visit 1).

[0425] 16. Drugs or alcoholism that, in the researcher's judgment, make a participant a poor candidate for the study.

[0426] 17. Any use of mineralocorticoid receptor antagonists (such as spironolactone, eplerenone, or fenelitonee), ASI, or potassium-sparing diuretics (such as triamterene or amiloride) within 4 weeks prior to screening.

[0427] 18. Concomitant therapy with strong inducers of cytochrome P450 (CYP) 3A (e.g., apalutamide, avasimibe, carbamazepine, enzalutamide, lumacaftor, mitotane, phenytoin, rifampin, rifapentine, St. John's wort).

[0428] 19. Any use of potassium binders (such as sodium zirconium cyclosilicate, partiromere, or sodium polystyrene sulfonate) within 4 weeks prior to screening. However, their use is permitted after randomization based on the judgment of the investigator and treating physician.

[0429] 20 Any other condition or treatment that, in the investigator's or sponsor's judgment, would make a participant unsuitable for the study, including conditions or treatments that the investigator anticipates would preclude participation for the entire duration of the study (e.g., active malignancy or other conditions that limit life expectancy to less than 12 months).

[0430] 21 had participated in another clinical study prior to randomization and had received the study intervention within the past 3 months.

[0431] 22. For WOCBP, a positive pregnancy test and / or breastfeeding.

[0432] C. Research interventions and concomitant therapies

[0433] (i) Research interventions applied

[0434] Participants will receive either bardostat / dapagliflozin or placebo / dapagliflozin. To ensure treatment blinding, matching bardostat tablets (1 mg, 2 mg, and placebo) will be visually identical (matched and indistinguishable). The study interventions to be administered and investigated in this study are described in the table below.

[0435]

[0436] The automated IRT / RTSM was used to centrally assign all participants who met all the eligibility criteria to a randomized, blinded study intervention, which assigned participants 1:1 to one of the two study intervention groups (i.e., the bardostabolic / dapagliflozin group or the placebo / dapagliflozin group).

[0437] The number of randomized participants with certain ranges of UACR and eGFR as shown in laboratory tests at enrollment (Visit 1) will be monitored, and a cap will be set for randomization in IRT / RTSM to ensure that the number of participants in these subgroups does not exceed the set percentage. The following population caps will be applied to all patients:

[0438] •eGFR ≥ 60 mL / min / 1.73 m 2 To ≤ 75 mL / min / 1.73 m 2 Set a total population cap of approximately 10%.

[0439] In addition, for patients included according to inclusion criterion 2(a), the following population caps will also be applied:

[0440] • UACR ≥ 30 mg / g to < 200 mg / g: Set an upper limit of approximately 10% of the total population.

[0441] • UACR ≥ 200 mg / g to < 500 mg / g: Set an upper limit of approximately 10% of the total population.

[0442] (ii) Dosage modification

[0443] All participants will begin with a lower dose (1 mg) of bardostat or a matched placebo, and the investigator may increase the dose to the target dose (2 mg). If local serum potassium rises to > 5.5 mmol / L at any point during the study treatment, bardostat / matched placebo should be temporarily discontinued; see details below.

[0444] Increase: The dose should be increased to 2 mg at visit 5, provided that the potassium concentration (local laboratory value) is ≤ 4.8 mmol / L at visits 3, 4, and 5. Once the above local laboratory parameters are confirmed, the increase should be made within 7 days, preferably as soon as possible. Potassium levels must be checked by local and central laboratories 14 (±5) days after the dose increase. Note: Participants experiencing symptomatic hypotension (potassium > 5.5 mmol / L, recurrent sodium < 130 mmol / L, or SBP ≤ 90 mmHg) at any time during the study should not be increased and should maintain a dose of 1 mg upon restart.

[0445] Downregulation: For participants who have previously received an upregulation, downregulation may be considered at any point throughout the study, for example, based on potassium, SBP, or sodium, or for other safety or tolerability considerations. Following a downregulation, an unplanned safety visit may be conducted within 2 weeks at the investigator's discretion. Participants who were downregulated from 2 mg to 1 mg during the study should maintain 1 mg for the remainder of the study.

[0446] (iii) Potassium monitoring and measurement

[0447] Hyperkalemia is a common event in patients with CKD and has been identified as a risk factor for bardostatin in previous studies. Therefore, potassium levels were systematically monitored throughout the study. Instructions for managing potassium measurements are described below:

[0448] Upward adjustment: If the participant was taking 1 mg bardostat / placebo at visit 5 and potassium ≤ 4.8 mmol / L at visits 3, 4 and 5, the dose was increased to 2 mg.

[0449] Serum potassium management:

[0450] Serum potassium ≤ 5.5 mmol / L: Continue with the same dose of bardostat / placebo.

[0451] Serum potassium > 5.5 mmol / L: Do not administer bardostat / placebo, control hyperkalemia (e.g., with potassium binders), and recheck potassium levels based on clinical judgment. If subsequent samples are ≤ 4.8 mmol / L, restart bardostat / placebo at 1 mg. Serum potassium should be rechecked within 2 weeks (+ / - 5 days) during unplanned visits. Note: Participants experiencing serum potassium > 5.5 mmol / L should not have their levels upregulated during the study.

[0452] If subsequent samples > 4.8 mmol / L: continue without bardostat / placebo; continue monitoring serum potassium, and restart bardostat / placebo at 1 mg when potassium ≤ 4.8 mmol / L. Serum potassium should be rechecked within 2 weeks (+ / - 5 days) during unplanned visits. Note: Participants experiencing serum potassium > 5.5 mmol / L should not have their levels upregulated during the study.

[0453] (iv) Prohibited concomitant medications

[0454] The following medications and supplements are prohibited during this study.

[0455] • Potassium-sparing diuretics (e.g., amiloride, triamterene) and direct renin inhibitors (e.g., alikram, zenjiram).

[0456] • Mineralocorticoid receptor antagonists or aldosterone antagonists (e.g., eplerenone, finerenone, spironolactone) or aldosterone synthase inhibitors.

[0457] • Strong CYP3A4 inducers (e.g., apalutamide, avasimibe, carbamazepine, enzalutamide, lumacaftor, ivacato, evacarb, mitotane, phenytoin, fosphenytoin, rifampin, and St. John's wort).

[0458] • Use SGLT2i instead of dapagliflozin provided during the study as concomitant therapy, including homeopathic preparations containing phlorizin.

[0459] • Treatment with potassium supplements is not prohibited, but should only be prescribed to individuals whom the investigator deems necessary to prevent hypokalemia.

Claims

1. A method for treating a patient with chronic kidney disease (CKD) and hypertension, the method comprising administering to the patient a combination comprising a first amount of bardostat or a pharmaceutically acceptable salt thereof and a second amount of a sodium-glucose cotransporter 2 (SGLT2) inhibitor, wherein the first amount and the second amount together constitute a therapeutically effective amount.

2. The method of claim 1, wherein the bardostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.5 mg / day, about 1 mg / day, or about 2 mg / day.

3. The method of claim 1, wherein the bardostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg / day or about 2 mg / day.

4. The method according to any one of the preceding claims, wherein the bardostat or a pharmaceutically acceptable salt thereof is administered once daily.

5. The method according to any one of the preceding claims, wherein the bardostat or a pharmaceutically acceptable salt thereof is bardostat.

6. The method according to any one of the preceding claims, wherein the SGLT2 inhibitor is selected from dapagliflozin, canagliflozin, empagliflozin, soagliflozin, ioggliflozin, eleggliflozin, toggliflozin and luggliflozin, or pharmaceutically acceptable salts thereof.

7. The method according to any one of the preceding claims, wherein the SGLT2 inhibitor is dapagliflozin.

8. The method of claim 7, wherein the dapagliflozin is administered at a dose of about 10 mg / day.

9. The method according to claim 7 or claim 8, wherein the dapagliflozin is administered once daily.

10. The method according to any one of the preceding claims, the method comprising administering to the subject once daily a combination of bardostat comprising about 1 mg or about 2 mg and dapagliflozin once daily.

11. The method according to any one of the preceding claims, wherein the bardostat or a pharmaceutically acceptable salt thereof is in a form suitable for oral administration.

12. The method according to any one of claims 7 to 11, wherein the dapagliflozin is in a form suitable for oral administration.

13. The method according to claim 11 or claim 12, wherein the form suitable for oral administration is a tablet.

14. The method according to any one of claims 7 to 13, wherein the dapagliflozin is in the form of a (S)-propylene glycol ((S)-PG) solvate having the following structure 。 15. The method according to any one of the preceding claims, wherein the bardostat or a pharmaceutically acceptable salt thereof is administered before, after, or concurrently with the SGLT2 inhibitor such as dapagliflozin.

16. The method according to any one of the preceding claims, wherein the patient has SBP ≥ 130 mmHg.

17. The method according to any one of the preceding claims, wherein the patient has SBP ≥ 140 mmHg.

18. The method according to any one of the preceding claims, wherein the patient has a concentration of ≥ 30 mL / min / 1.73 m 2 And <90mL / min / 1.73 m 2 The estimated glomerular filtration rate (eGFR).

19. The method according to any one of the preceding claims, wherein the patient has a concentration of ≥ 30 mL / min / 1.73 m 2 And <60mL / min / 1.73 m 2 eGFR.

20. The method according to any one of claims 1 to 17, wherein the patient has a blood flow rate of ≥ 25 mL / min / 1.73 m 2 And ≤75mL / min / 1.73 m 2 eGFR.

21. The method according to any one of the preceding claims, wherein the patient has a urinary albumin-to-creatinine ratio (UACR) of ≥ 100 mg / g.

22. The method according to any one of the preceding claims, wherein the patient has a UACR of ≥ 200 mg / g.

23. The method according to any one of the preceding claims, wherein the patient has a serum potassium level of 3.5 mmol / L to 4.8 mmol / L.

24. The method according to any one of the preceding claims, wherein the patient has a serum potassium level of 3.5 mmol / L to 4.8 mmol / L and a blood glucose level of ≥ 45 mL / min / 1.73 m 2 eGFR.

25. The method according to any one of claims 1 to 23, wherein the patient has a serum potassium level of 3.5 mmol / L to 4.5 mmol / L and a blood glucose level of < 45 mL / min / 1.73 m 2 eGFR.

26. The method according to any one of the preceding claims, wherein the patient is not treated with a mineralocorticoid receptor antagonist (MRA) during the combined treatment.

27. The method according to any one of the preceding claims, wherein the method comprises administering one or more standard care agents for CKD to the patient.

28. The method according to any one of the preceding claims, wherein the method reduces the rate of renal function decline in the patient.

29. The method according to any one of the preceding claims, wherein the method reduces the rate of renal function decline in the patient to a greater extent compared with treatment in which a placebo is used instead of bardostat or a pharmaceutically acceptable salt thereof.

30. The method according to any one of the preceding claims, wherein the method reduces the patient's renal function decline relative to baseline to a greater extent compared to treatment in which a placebo is used instead of bardostat or a pharmaceutically acceptable salt thereof.

31. The method according to any one of the preceding claims, wherein the method reduces the rate of decline of the patient's eGFR.

32. The method according to any one of the preceding claims, wherein the method reduces the rate of decline of eGFR in the patient to a greater extent compared with treatment in which a placebo is used instead of bardostat or a pharmaceutically acceptable salt thereof.

33. The method according to any one of the preceding claims, wherein the method reduces the decline in the patient's eGFR relative to baseline to a greater extent compared to treatment in which a placebo is used instead of bardostat or a pharmaceutically acceptable salt thereof.

34. The method according to any one of the preceding claims, wherein the method reduces the patient's UACR relative to baseline.

35. The method according to any one of the preceding claims, wherein the method reduces the patient's UACR to a greater extent relative to baseline compared to treatment in which a placebo is used instead of bardostat or a pharmaceutically acceptable salt thereof.

36. The method according to any one of the preceding claims, wherein the method reduces the patient's SBP relative to baseline.

37. The method according to any one of the preceding claims, wherein the method reduces the patient's SBP relative to baseline to a greater extent than treatment in which a placebo is used instead of bardostat or a pharmaceutically acceptable salt thereof.

38. The method according to any one of the preceding claims, wherein the method reduces the patient's SBP to <120 mmHg.

39. The method according to any one of the preceding claims, wherein the method reduces the risk of the patient having a sustained decrease in eGFR of ≥50% relative to baseline.

40. The method according to any one of the preceding claims, wherein, compared with treatment in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo, the method reduces the risk of a sustained eGFR decrease of ≥50% relative to baseline in the patient to a greater extent.

41. The method according to any one of the preceding claims, wherein the method reduces the risk of the patient having a sustained decrease in eGFR of ≥57% relative to baseline.

42. The method according to any one of the preceding claims, wherein, compared with treatment in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo, the method reduces the risk of a sustained eGFR decrease of ≥57% relative to baseline in the patient to a greater extent.

43. The method according to any one of the preceding claims, wherein the method reduces the risk of the patient developing end-stage renal disease (ESKD).

44. The method according to any one of the preceding claims, wherein the method reduces the risk of ESKD in the patient to a greater extent compared with treatment in which a placebo is used instead of bardostat or a pharmaceutically acceptable salt thereof.

45. The method according to any one of the preceding claims, wherein the method reduces the chronic eGFR slope of the patient.

46. ​​The method according to any one of the preceding claims, wherein the method reduces the chronic eGFR slope of the patient to a greater extent compared with treatment in which a placebo is used instead of bardostat or a pharmaceutically acceptable salt thereof.

47. The method of claim 45 or claim 46, wherein the chronic eGFR slope is the rate of decrease in eGFR of the patient between approximately 8 weeks and approximately 2 years of treatment with the combination.

48. The method according to any one of the preceding claims, wherein the method reduces the risk of the patient experiencing a sustained decrease in eGFR of ≥50% relative to baseline, reaching ESKD, or cardiovascular (CV) death.

49. The method according to any one of the preceding claims, wherein, compared with treatment in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo, the method reduces to a greater extent the risk of the patient experiencing a sustained eGFR decline of ≥50% relative to baseline, reaching ESKD, or CV death.

50. The method according to any one of the preceding claims, wherein the method reduces the risk of the patient having a sustained eGFR decrease of ≥50% relative to baseline or ESKD.

51. The method according to any one of the preceding claims, wherein, compared with treatment in which bardostat or a pharmaceutically acceptable salt thereof is replaced with a placebo, the method reduces the risk of the patient having a sustained eGFR decline of ≥50% relative to baseline or ESKD to a greater extent.

52. The method according to any one of the preceding claims, wherein the method reduces the risk of CV death, heart failure events, myocardial infarction, or stroke in the patient.

53. The method according to any one of the preceding claims, wherein, compared with treatment in which a placebo is used instead of bardostat or a pharmaceutically acceptable salt thereof, the method reduces the risk of CV death, heart failure events, myocardial infarction, or stroke in the patient to a greater extent.

54. The method according to any one of the preceding claims, wherein the method reduces the risk of CV death or heart failure events in the patient.

55. The method according to any one of the preceding claims, wherein the method reduces the risk of CV death or heart failure events in the patient to a greater extent compared to treatment in which a placebo is used instead of bardostat or a pharmaceutically acceptable salt thereof.

56. The method according to any one of claims 52 to 55, wherein the heart failure event is either hospitalized or outpatient heart failure.

57. The method according to any one of claims 52 to 55, wherein the heart failure event is hospitalized heart failure.

58. The method according to any one of the preceding claims, wherein the method reduces the risk of CV death in the patient.

59. The method according to any one of the preceding claims, wherein the method reduces the risk of CV death in the patient to a greater extent compared with treatment in which a placebo is used instead of bardostat or a pharmaceutically acceptable salt thereof.

60. The method according to any one of the preceding claims, wherein the method reduces the risk of death of the patient.

61. The method according to any one of the preceding claims, wherein the method reduces the risk of death of the patient to a greater extent compared with treatment in which a placebo is used instead of bardostat or a pharmaceutically acceptable salt thereof.

62. Bardostat or a pharmaceutically acceptable salt thereof, for use in the method according to any one of the preceding claims.

63. An SGLT2 inhibitor for use in the method according to any one of claims 1 to 61.

64. Use of bardostat or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in any one of claims 1 to 61.

65. Use of the SGLT2 inhibitor in the preparation of a medicament for use in any one of claims 1 to 61.

66. A kit comprising: (a) bardostat or a pharmaceutically acceptable salt thereof and / or an SGLT2 inhibitor, and (b) instructions for use of the bardostat or a pharmaceutically acceptable salt thereof and / or an SGLT2 inhibitor in the method according to any one of claims 1 to 61.

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