Method for treating chronic kidney disease with dapagliflozin

Abstract

The present disclosure relates to methods of treating patients with chronic kidney disease (CKD) with or without type 2 diabetes using an SGLT2 inhibitor such as dapagliflozin.

Description

[0001] This application is a divisional application of a Chinese patent application with the application number 202180001003.5, the filing date of April 1, 2021, and the invention title of "Method for treating chronic kidney disease with dapagliflozin". SUMMARY OF THE INVENTION

[0002] Chronic kidney disease (CKD) affects approximately 10% of the adult population globally. (Eckardt, K-U et al., Lancet 382(9887):158-169, 2013.) The most common causes of CKD are diabetes, hypertension, and chronic glomerulonephritis. Current treatments for CKD include administering angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARB) in patients with diabetes, lipid and blood pressure control, and strict glucose control.

[0003] Sodium-glucose cotransporter 2 (SGLT2) is a sodium-dependent renal protein that is responsible for reabsorbing glucose back into the bloodstream. SGLT2 inhibitors are a class of glucose-lowering agents used to lower blood glucose in patients with type 2 diabetes (T2D) by inhibiting the renal SGLT2 protein. Thus, SGLT2 inhibitors can improve glucose control without relying on insulin secretion, with a low risk of hypoglycemia, thereby providing a reduction in blood pressure, body weight, and uric acid levels. (Inzucchi et al., Diabetes & Vascular Dis Res. 12(2):90-100, 2015.) SGLT2 inhibitors can reduce the reabsorption of glucose in the kidney, thereby increasing the excretion of glucose in the urine. (Ibid.)

[0004] This disclosure relates to compounds, compositions, and methods for treating chronic kidney disease (CKD) in patients with and without type 2 diabetes (T2D) using sodium-glucose cotransporter type 2 (SGLT2) inhibitors (such as dapagliflozin).

[0005] In some embodiments, the SGLT2 inhibitor (such as dapagliflozin) is administered together with a standard CKD care agent (such as, ACE-I and / or ARB) in the same or different compositions at the same or different times.

[0006] In some embodiments, the SGLT2 inhibitor (such as dapagliflozin) is administered together with at least one other therapeutic agent (such as, an anti-diabetic agent) in the same or different compositions at the same or different times.

[0007] In the following description, certain details are set forth in order to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the disclosed embodiments may be practiced without these details. These and other embodiments will become apparent by reference to the following detailed description and the drawings. Description of the Drawings

[0008] Figure 1 is a schematic diagram outlining the study procedure, where SED = study end date,

[0009] E = enrollment, SCV = study termination visit, and R = randomization.

[0010] Figure 2 is a summary table of the final overall enrollment details of the dapagliflozin CKD phase 3 clinical trial.

[0011] Figure 3 is a summary table of the final enrollment details of the DAPA CKD phase 3 clinical trial grouped by demographics.

[0012] Figure 4 is a summary table of the final enrollment details of the DAPA CKD phase 3 clinical trial according to baseline disease status.

[0013] Figure 5 is a summary table of the final enrollment details of the DAPA CKD phase 3 clinical trial according to baseline concomitant medications.

[0014] Figure 6 is a summary of the effects of dapagliflozin on sustained eGFR decline ≥50%, ESRD, and renal or cardiovascular ("CV") death in the DAPA CKD phase 3 clinical trial. The table shows the primary composite endpoint (which is the composite of sustained eGFR decline ≥50%, ESRD, and renal or CV death) and each of its components (a = adjudicated).

[0015] Figure 7 is a graph depicting the incidence of the primary endpoint of sustained eGFR decline ≥50%, ESRD, and renal or CV death estimated using the Kaplan-Meier method, and the hazard ratio and 95% confidence interval estimated using the Cox regression model.

[0016] Figure 8 Describes the primary composite outcomes according to pre-specified subgroups from the DAPA CKD phase 3 clinical trial (T2DM status, UACR status, eGFR status, systolic blood pressure status).

[0017] Figure 9Describes the primary composite outcome according to pre-specified subgroups from the DAPA CKD Phase 3 clinical trial (age, sex, race, geographical region).

[0018] Figure 10 Summarizes the primary and secondary endpoints from the DAPA CKD Phase 3 clinical trial, which includes describing the following secondary endpoints: dapagliflozin was superior in reducing the composite of renal events without CV death, dapagliflozin was superior in reducing hospitalization for HF and CV death, and dapagliflozin was superior in reducing overall all-cause death (compared to the placebo group or patients receiving at least one standard CKD care agent alone).

[0019] Figure 11 Summarizes the secondary endpoints of dapagliflozin from the DAPA CKD Phase 3 clinical trial, that is, superior in reducing hospitalization for HF and CV death and each of its components (compared to the placebo group or patients receiving at least one standard CKD care agent alone).

[0020] Figure 12 Is a figure that describes the incidence of secondary endpoints of the early treatment effect of dapagliflozin on hospitalization for HF and CV death estimated using the Kaplan-Meier method, and the hazard ratio and 95% confidence interval estimated using the Cox regression model.

[0021] Figure 13 Describes the effect of dapagliflozin on pre-specified primary and secondary composite outcomes in patients with and without diabetes.

[0022] Figure 14 Is a figure that describes the effect of dapagliflozin on all-cause mortality estimated using the Kaplan-Meier method, and the hazard ratio and 95% confidence interval estimated using the Cox regression model.

[0023] Figure 15 Is a figure that describes the effect of dapagliflozin on the endpoints of chronic dialysis, kidney transplantation, or renal death estimated using the Kaplan-Meier method, and the hazard ratio and 95% confidence interval estimated using the Cox regression model.

[0024] Figure 16 Summarizes the exploratory endpoints of the DAPA CKD Phase 3 clinical trial, showing that dapagliflozin was superior in reducing the time to the first, second, or third hospitalization for HF (compared to the placebo group or patients receiving at least one standard CKD care agent alone) (*Ratio used to analyze recurrent events **Number of patients with 1, 2, or 3 or more hospitalizations for HF).

[0025] Figure 17Summarizes the primary endpoint of the DAPA CKD Phase 3 trial (composite of sustained eGFR decline ≥50%, ESKD, or renal or cardiovascular death), stratified by the underlying cause of kidney disease (diabetic nephropathy, ischemic / hypertensive nephropathy, glomerulonephritis, and unknown etiology) (compared to placebo or patients receiving at least one standard CKD care agent alone).

[0026] Figure 18 Summarizes the secondary renal endpoint of the DAPA CKD Phase 3 trial (composite of sustained eGFR decline ≥50%, ESKD, or renal death), stratified by the underlying cause of kidney disease (diabetic nephropathy, ischemic / hypertensive nephropathy, glomerulonephritis, and unknown etiology) (compared to placebo or patients receiving at least one standard CKD care agent alone).

[0027] Figure 19 Summarizes the secondary endpoint of the DAPA CKD Phase 3 trial (cardiovascular death or hospitalization for heart failure), stratified by the underlying cause of kidney disease (diabetic nephropathy, ischemic / hypertensive nephropathy, glomerulonephritis, and unknown etiology) (compared to placebo or patients receiving at least one standard CKD care agent alone).

[0028] Figure 20 Summarizes the secondary endpoint of the DAPA CKD Phase 3 trial (all-cause death), stratified by the underlying cause of kidney disease (diabetic nephropathy, ischemic / hypertensive nephropathy, glomerulonephritis, and unknown etiology) (compared to placebo or patients receiving at least one standard CKD care agent alone).

[0029] Figure 21 Summarizes the primary endpoint of the DAPA CKD Phase 3 trial (composite of sustained eGFR decline ≥50%, ESKD, or renal or cardiovascular death) in patients with IgA nephropathy compared to placebo or patients receiving at least one standard CKD care agent alone.

[0030] Figure 22 Summarizes the primary endpoint of the DAPA CKD Phase 3 trial (composite of sustained eGFR decline ≥50%, ESKD, or renal or cardiovascular death) and secondary endpoints (secondary renal endpoint (composite of sustained eGFR decline ≥50%, ESKD, or renal death), secondary endpoint (cardiovascular death or hospitalization for heart failure), and all-cause death), stratified by patients with or without underlying cardiovascular disease (compared to placebo or patients receiving at least one standard CKD care agent alone).

[0031] Figure 23Summarizes exploratory results stratified by patients with or without underlying cardiovascular disease from pre-specified and post-hoc analyses of the DAPA CKD Phase 3 clinical trial compared to placebo or patients receiving at least one standard CKD care agent alone.

[0032] Figure 24 Primary and secondary endpoints of the DAPA CKD Phase 3 clinical trial in patients with IgA nephropathy compared to placebo or patients receiving at least one standard CKD care agent alone.

[0033] Figure 25 Describes the incidence of new-onset T2D (HbA1c ≥ 6.5%) measured at 2 consecutive study visits after randomization, or investigator-reported new T2D (i.e., HbA1c ≥ 6.5%) in patients with previously undiagnosed diabetes in the DAPA HF Phase 3 clinical trial relative to placebo. Detailed implementation

[0034] The present disclosure relates to methods of treating patients with chronic kidney disease by administering to a patient in need an effective amount of an SGLT2 inhibitor (e.g., dapagliflozin), wherein the patient with chronic kidney disease includes patients with or without type 2 diabetes (T2D) and / or at least one disease, disorder, or condition associated with CKD. The present disclosure also provides methods of treating patients with CKD associated with ischemia, hypertension, chronic glomerulonephritis, or IgA nephropathy.

[0035] In some embodiments, the present disclosure includes methods of treating CKD in patients without type 2 diabetes (T2D), which include administering to the patient an effective amount of an SGLT2 inhibitor for treating the patient's CKD. In some embodiments, the methods disclosed herein treat CKD associated with ischemia or hypertension. In some embodiments, the methods disclosed herein treat CKD associated with chronic glomerulonephritis. In some embodiments, the methods disclosed herein treat CKD associated with IgA nephropathy (also known as Berger's disease). In other embodiments, the present disclosure includes methods of treating CKD in patients with T2D, which include administering to the patient an effective amount of an SGLT2 inhibitor for treating the patient's CKD.

[0036] Also disclosed is a method of preventing or delaying the progression of CKD, cardiovascular (CV) death, or renal death in a patient in need thereof, comprising administering to the patient an effective amount of an SGLT2 inhibitor. In some embodiments, the present disclosure includes a method of preventing or delaying the progression of CKD, CV death, or renal death in a patient not having T2D, comprising administering to the patient an amount of an SGLT2 inhibitor effective to prevent or delay progression of CKD, CV death, or renal death in the patient. In some embodiments, the present disclosure includes a method of preventing or delaying the progression of CKD, CV death, or renal death associated with ischemia, hypertension, chronic glomerulonephritis, or IgA nephropathy in a patient not having T2D, comprising administering to the patient an amount of an SGLT2 inhibitor effective to prevent or delay progression of CKD, CV death, or renal death in the patient. In other embodiments, the present disclosure includes a method of preventing or delaying the progression of CKD, CV death, or renal death in a patient having T2D, comprising administering to the patient an amount of an SGLT2 inhibitor effective to prevent or delay progression of CKD, CV death, or renal death in the patient.

[0037] Also disclosed is a method of reducing the incidence of the composite endpoint of sustained decline in eGFR of ≥50%, reaching end-stage renal disease (ESRD), CV death, or renal death in a patient having CKD, comprising administering to the patient an effective amount of an SGLT2 inhibitor. In some embodiments, the present disclosure includes a method of reducing the incidence of the composite endpoint of sustained decline in eGFR of ≥50%, reaching ESRD, CV death, or renal death in a patient having CKD but not having T2D, comprising administering to the patient an effective amount of an SGLT2 inhibitor. In other embodiments, the present disclosure includes a method of reducing the incidence of the composite endpoint of sustained decline in eGFR of ≥50%, reaching ESRD, CV death, or renal death in a patient having CKD and T2D, comprising administering to the patient an effective amount of an SGLT2 inhibitor. In some embodiments, the method reduces the incidence of the individual endpoint of sustained decline in eGFR of ≥50% in patients having CKD. In some embodiments, the method reduces the incidence of the individual endpoint of reaching end-stage renal disease (ESRD) in patients having CKD. In some embodiments, the method reduces the incidence of the individual endpoint of CV death in patients having CKD. In some embodiments, the method reduces the incidence of the individual endpoint of renal death in patients having CKD. In some of the above embodiments, the incidence of the endpoint in the treatment group (i.e., at least one patient is treated with an effective amount of an SGLT2 inhibitor) is reduced relative to placebo. In some of the above embodiments, the incidence of the endpoint in the treatment group is reduced relative to a regimen in which the patient is administered alone at least one standard CKD care agent (i.e., not treated with an effective amount of an SGLT2 inhibitor).

[0038] In some embodiments, the present disclosure provides methods for reducing the incidence of the composite endpoint of a sustained decline in eGFR of ≥50%, reaching end-stage renal disease (ESRD), or renal death in patients with CKD, the methods comprising administering to the patient an effective amount of an SGLT2 inhibitor. In some embodiments, the present disclosure includes methods for reducing the incidence of the composite endpoint of a sustained decline in eGFR of ≥50%, reaching ESRD, or renal death in patients with CKD but without T2D, the methods comprising administering to the patient an effective amount of an SGLT2 inhibitor. In other embodiments, the present disclosure includes methods for reducing the incidence of the composite endpoint of a sustained decline in eGFR of ≥50%, reaching ESRD, or renal death in patients with CKD and T2D, the methods comprising administering to the patient an effective amount of an SGLT2 inhibitor. In some of the above embodiments, relative to placebo, the incidence of the composite endpoint of a sustained decline in eGFR of ≥50%, reaching end-stage renal disease (ESRD), or renal death is reduced in patients with CKD in the treatment group (i.e., at least one patient is treated with an effective amount of an SGLT2 inhibitor). In some of the above embodiments, relative to the administration regimen in which a patient receives at least one standard CKD care agent alone (i.e., not treated with an effective amount of an SGLT2 inhibitor), the incidence of the composite endpoint of a sustained decline in eGFR of ≥50%, reaching end-stage renal disease (ESRD), or renal death is reduced in patients with CKD in the treatment group.

[0039] In some embodiments, the present disclosure provides methods for reducing the incidence of the composite endpoint of CV death or hospitalization for heart failure (HF) in patients with CKD, the methods comprising administering to the patient an effective amount of an SGLT2 inhibitor. In some embodiments, the present disclosure includes methods for reducing the incidence of the composite endpoint of CV death or hospitalization for heart failure in patients with CKD but without T2D, the methods comprising administering to the patient an effective amount of an SGLT2 inhibitor. In other embodiments, the present disclosure includes methods for reducing the incidence of the composite endpoint of CV death or hospitalization for heart failure in patients with CKD and T2D, the methods comprising administering to the patient an effective amount of an SGLT2 inhibitor. In some embodiments, the methods reduce the incidence of hospitalization for heart failure in patients with CKD. In some of the above embodiments, relative to placebo, the incidence of the composite endpoint of CV death or hospitalization for heart failure is reduced in the treatment group (i.e., at least one patient is treated with an effective amount of an SGLT2 inhibitor). In some of the above embodiments, relative to the administration regimen in which a patient receives at least one standard CKD care agent alone (i.e., not treated with an effective amount of an SGLT2 inhibitor), the incidence of the composite endpoint of CV death or hospitalization for heart failure is reduced in the treatment group.

[0040] The present disclosure relates to methods for reducing the incidence of death in patients with CKD, the methods comprising administering to the patient an effective amount of an SGLT2 inhibitor. In some embodiments, the present disclosure includes methods for reducing the incidence of death in patients with CKD but without T2D, the methods comprising administering to the patient an effective amount of an SGLT2 inhibitor. In other embodiments, the present disclosure includes methods for reducing the incidence of death in patients with CKD and T2D, the methods comprising administering to the patient an effective amount of an SGLT2 inhibitor. In some of the above embodiments, the incidence of death in the treatment group (i.e., at least one patient treated with an effective amount of an SGLT2 inhibitor) is reduced relative to placebo. In some of the above embodiments, the incidence of death in the treatment group is reduced relative to the administration regimen in which the patient receives alone at least one standard CKD care agent (i.e., not treated with an effective amount of an SGLT2 inhibitor).

[0041] In some embodiments, the method reduces the level of glycated hemoglobin (HbA1c) in CKD patients with T2D compared to baseline.

[0042] In some embodiments, the method reduces the incidence of newly diagnosed T2D in CKD patients without diabetes.

[0043] In some embodiments, a patient is identified as having CKD when the patient has an eGFR ≥ 25 and ≤ 75 mL / min / 1.73m 2 2. In some embodiments, the patient has CKD and albuminuria. In some embodiments, a patient is identified as having albuminuria when the patient has a UACR ≥ 200 and ≤ 5000 mg / g.

[0044] In some embodiments, the method reduces the intraglomerular pressure, hypertension, proteinuria, and / or the amount of fluid / sodium overload in patients with CKD. In some embodiments, the method reduces the systolic BP of the patient compared to baseline. In some embodiments, compared to placebo (or compared to patients receiving alone at least one standard CKD care agent), the method reduces the systolic BP of the patient to a greater extent compared to baseline. In some embodiments, the systolic BP of the patient is measured at day 30 (±7), day 120 (±7), day 240 (±7), day 360 (±7), day 480 (±14), and / or day 600 (±14).

[0045] In some embodiments, compared to placebo (or compared to patients receiving alone at least one standard CKD care agent), the method reduces the number of events of doubling of serum creatinine in patients with CKD.

[0046] In some embodiments, the method reduces the incidence of hyperkalemia in patients with CKD, where the serum potassium level > 6.0 mmol / L. In some embodiments, the method reduces the incidence of hyperkalemia in patients with CKD, where the serum potassium level > 5.5 mmol / L. In some embodiments, the method reduces the incidence of hypokalemia in patients with CKD, where the serum potassium level < 3.5 mmol / L. In some embodiments, the method reduces the incidence of hypokalemia in patients with CKD, where the serum potassium level < 3.0 mmol / L.

[0047] In some embodiments, the method reduces the patient's body weight compared to baseline. In some embodiments, compared to a placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the patient's body weight to a greater extent compared to baseline. In some embodiments, the patient's body weight is measured at day 30 (±7), day 120 (±7), day 240 (±7), day 360 (±7), day 480 (±14), and / or day 600 (±14).

[0048] In some embodiments, the method reduces the patient's albuminuria level compared to baseline. In some embodiments, compared to a placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the patient's albuminuria level to a greater extent compared to baseline. In some embodiments, the patient's albuminuria level is measured at day 30 (±7), day 120 (±7), day 240 (±7), day 360 (±7), day 480 (±14), and / or day 600 (±14).

[0049] In some embodiments, compared to a placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the incidence of persistent decline in renal function in patients with CKD. In some embodiments, the method does not cause a reduction in the patient's eGFR from baseline. In some embodiments, compared to a placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the eGFR to a lesser extent compared to baseline. In some embodiments, compared to a placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the incidence of a ≥30% reduction in eGFR in patients with CKD compared to baseline. In some embodiments, compared to a placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the incidence of a ≥40% reduction in eGFR in patients with CKD compared to baseline. In some embodiments, the patient's eGFR is measured at Day 30 (±7), Day 120 (±7), Day 240 (±7), Day 360 (±7), Day 480 (±14), and / or Day 600 (±14).

[0050] In some embodiments, compared to a placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the time to first CV death in patients. In some embodiments, the time to first CV death is measured at Day 30 (±7), Day 120 (±7), Day 240 (±7), Day 360 (±7), Day 480 (±14), and / or Day 600 (±14).

[0051] In some embodiments, compared to a placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the time to first renal death in patients. In some embodiments, the time to first renal death is measured at Day 30 (±7), Day 120 (±7), Day 240 (±7), Day 360 (±7), Day 480 (±14), and / or Day 600 (±14).

[0052] In some embodiments, compared to a placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the time to first hospitalization of a patient due to heart failure. In some embodiments, the time to first hospitalization due to heart failure is measured at Day 30 (±7), Day 120 (±7), Day 240 (±7), Day 360 (±7), Day 480 (±14), and / or Day 600 (±14).

[0053] In some embodiments, compared to a placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the total number of hospitalizations for heart failure and / or CV deaths in patients.

[0054] In some embodiments, compared to a placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the incidence of CKD patients reaching CKD 4 (eGFR < 30 mL / min / 1.73m 2 ).

[0055] In some embodiments, compared to a placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the incidence of fatal myocardial infarction in patients with CKD. In some embodiments, compared to a placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the incidence of non-fatal myocardial infarction in patients with CKD.

[0056] In some embodiments, compared to a placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the incidence of ischemic stroke in patients with CKD. In some embodiments, compared to a placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the incidence of hemorrhagic stroke in patients with CKD. In some embodiments, compared to a placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the incidence of fatal stroke in patients with CKD. In some embodiments, compared to a placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the incidence of non-fatal stroke in patients with CKD.

[0057] In some embodiments, compared to a placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the proportion of patients with worsening NYHA class compared to baseline. In some embodiments, compared to a placebo (or compared to patients receiving at least one standard CKD care agent alone), the method maintains or improves the NYHA class of patients compared to baseline. In some embodiments, the NYHA class of patients is measured at day 30 (±7), day 120 (±7), day 240 (±7), day 360 (±7), day 480 (±14), and / or day 600 (±14).

[0058] In some embodiments, the method improves the health status of patients as evaluated by the EQ-5D-5L questionnaire compared to a placebo (or compared to patients receiving at least one standard CKD care agent alone). In some embodiments, the health status of patients as evaluated by the EQ-5D-5L questionnaire is measured at day 30 (±7), day 120 (±7), day 240 (±7), day 360 (±7), day 480 (±14), and / or day 600 (±14).

[0059] In some embodiments, the method improves the health status of patients as evaluated by the KDQOL 36 questionnaire compared to a placebo (or compared to patients receiving at least one standard CKD care agent alone). In some embodiments, the health status of patients as evaluated by the KDQOL 36 questionnaire is measured at day 30 (±7), day 120 (±7), day 240 (±7), day 360 (±7), day 480 (±14), and / or day 600 (±14).

[0060] Also disclosed herein is a method for preventing or delaying the incidence or onset of T2D in patients with prediabetes (i.e., having a glycated hemoglobin ≥5.7% and <6.5%). In some embodiments, the patient has prediabetes with CKD. In other embodiments, the patient has prediabetes with HF. In some embodiments, the patient has prediabetes with HFrEF. In some embodiments, the patient has prediabetes without other comorbidities (such as CKD, HF, etc.). In some embodiments, the method disclosed herein reduces the incidence or onset of T2D relative to a placebo. In some embodiments, the method disclosed herein reduces the incidence or onset of T2D relative to patients taking standard HF or CKD care agents. In some embodiments, the reduction in the incidence or onset of T2D is measured by the time to the first reported glycated hemoglobin measurement of ≥6.5%. In some embodiments, the method disclosed herein results in a hazard ratio of less than 1 for reducing the incidence or onset of T2D relative to a placebo. In some embodiments, the method disclosed herein results in a hazard ratio of less than 1 for reducing the incidence or onset of T2D relative to standard HF or CKD care agents.

[0061] In some embodiments, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the methods disclosed herein result in a hazard ratio for the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death in the patient of less than 1. In some methods, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the method results in a hazard ratio for the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death in the patient that is statistically nominally less than 1. In some embodiments, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the method results in a hazard ratio for the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death in the patient of about 0.61. In some methods, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the 95% confidence interval for the hazard ratio for the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death in the patient is from about 0.51 to 0.72. In some embodiments, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the method numerically reduces the absolute risk of the composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death in the patient. In some embodiments, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the method results in a nominally significant reduction in the risk of the composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death in the patient. In some embodiments, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the method results in a numerical reduction in the composite endpoint events of ≥50% sustained decline in eGFR, or ESRD and CV or renal death in the patient.

[0062] In some embodiments, relative to the administration regimen of at least one standard CKD care agent alone in patients with T2D, the methods disclosed herein result in a hazard ratio of less than 1 for the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death in the patients with T2D. In some methods, relative to the administration regimen of at least one standard CKD care agent alone in patients with T2D, the method results in a hazard ratio that is statistically nominally less than 1 for the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death in the patients with T2D. In some embodiments, relative to the administration regimen of at least one standard CKD care agent alone in patients with T2D, the method results in a hazard ratio of approximately 0.64 for the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death in the patients with T2D. In some methods, relative to the administration regimen of at least one standard CKD care agent alone in patients with T2D, the 95% confidence interval for the hazard ratio for the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death in the patients with T2D is approximately 0.52 to 0.79. In some embodiments, relative to the administration regimen of at least one standard CKD care agent alone in patients with T2D, the method numerically reduces the absolute risk of the composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death in the patients with T2D. In some embodiments, relative to the administration regimen of at least one standard CKD care agent alone in patients with T2D, the method results in a nominally significant reduction in the risk of the composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death in the patients with T2D. In some embodiments, relative to the administration regimen of at least one standard CKD care agent alone in patients with T2D, the method results in a numerical reduction in the composite endpoint events of ≥50% sustained decline in eGFR, or ESRD and CV or renal death in the patients with T2D.

[0063] In some embodiments, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the methods disclosed herein result in a hazard ratio of less than 1 for the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death in the patients without T2D. In some methods, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the method results in a hazard ratio that is statistically nominally less than 1 for the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death in the patients without T2D. In some embodiments, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the method results in a hazard ratio of approximately 0.50 for the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death in the patients without T2D. In some methods, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the 95% confidence interval for the hazard ratio for the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death in the patients without T2D is from approximately 0.35 to 0.72. In some embodiments, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the method numerically reduces the absolute risk of the composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death in the patients without T2D. In some embodiments, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the method results in a nominally significant reduction in the risk of the composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death in the patients without T2D. In some embodiments, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the method results in a numerical reduction in the composite endpoint events of ≥50% sustained decline in eGFR, or ESRD and CV or renal death in the patients without T2D.

[0064] In some embodiments, relative to the administration regimen in which patients with UACR ≤ 1000 mg / g receive at least one standard CKD care agent alone, the methods disclosed herein result in a hazard ratio of less than 1 for the time to a first composite endpoint of sustained eGFR decline ≥ 50%, or ESRD and CV or renal death, in patients with UACR ≤ 1000 mg / g. In some methods, relative to the administration regimen in which patients with UACR ≤ 1000 mg / g receive at least one standard CKD care agent alone, the methods result in a hazard ratio that is statistically nominally less than 1 for the time to a first composite endpoint of sustained eGFR decline ≥ 50%, or ESRD and CV or renal death, in patients with UACR ≤ 1000 mg / g. In some embodiments, relative to the administration regimen in which patients with UACR ≤ 1000 mg / g receive at least one standard CKD care agent alone, the methods result in a hazard ratio of approximately 0.54 for the time to a first composite endpoint of sustained eGFR decline ≥ 50%, or ESRD and CV or renal death, in patients with UACR ≤ 1000 mg / g. In some methods, relative to the administration regimen in which patients with UACR ≤ 1000 mg / g receive at least one standard CKD care agent alone, the 95% confidence interval for the hazard ratio for the time to a first composite endpoint of sustained eGFR decline ≥ 50%, or ESRD and CV or renal death, in patients with UACR ≤ 1000 mg / g is approximately 0.37 to 0.77. In some embodiments, relative to the administration regimen in which patients with UACR ≤ 1000 mg / g receive at least one standard CKD care agent alone, the methods numerically reduce the absolute risk of a composite endpoint of sustained eGFR decline ≥ 50%, or ESRD and CV or renal death, in patients with UACR ≤ 1000 mg / g. In some embodiments, relative to the administration regimen in which patients with UACR ≤ 1000 mg / g receive at least one standard CKD care agent alone, the methods result in a nominally significant reduction in the risk of a composite endpoint of sustained eGFR decline ≥ 50%, or ESRD and CV or renal death, in patients with UACR ≤ 1000 mg / g. In some embodiments, relative to the administration regimen in which patients with UACR ≤ 1000 mg / g receive at least one standard CKD care agent alone, the methods result in a numerical reduction in the composite endpoint events of sustained eGFR decline ≥ 50%, or ESRD and CV or renal death, in patients with UACR ≤ 1000 mg / g.

[0065] In some embodiments, relative to the administration regimen in which patients with UACR > 1000 mg / g receive at least one standard CKD care agent alone, the methods disclosed herein result in a hazard ratio of less than 1 for the time to the first composite endpoint of sustained eGFR decline ≥ 50%, or ESRD and CV or renal death, in patients with UACR > 1000 mg / g. In some methods, relative to the administration regimen in which patients with UACR > 1000 mg / g receive at least one standard CKD care agent alone, the method results in a hazard ratio that is statistically nominally less than 1 for the time to the first composite endpoint of sustained eGFR decline ≥ 50%, or ESRD and CV or renal death, in patients with UACR > 1000 mg / g. In some embodiments, relative to the administration regimen in which patients with UACR > 1000 mg / g receive at least one standard CKD care agent alone, the method results in a hazard ratio of approximately 0.62 for the time to the first composite endpoint of sustained eGFR decline ≥ 50%, or ESRD and CV or renal death, in patients with UACR > 1000 mg / g. In some methods, relative to the administration regimen in which patients with UACR > 1000 mg / g receive at least one standard CKD care agent alone, the 95% confidence interval for the hazard ratio for the time to the first composite endpoint of sustained eGFR decline ≥ 50%, or ESRD and CV or renal death, in patients with UACR > 1000 mg / g is approximately 0.50 to 0.76. In some embodiments, relative to the administration regimen in which patients with UACR > 1000 mg / g receive at least one standard CKD care agent alone, the method numerically reduces the absolute risk of the composite endpoint of sustained eGFR decline ≥ 50%, or ESRD and CV or renal death, in patients with UACR > 1000 mg / g. In some embodiments, relative to the administration regimen in which patients with UACR > 1000 mg / g receive at least one standard CKD care agent alone, the method results in a nominally significant reduction in the risk of the composite endpoint of sustained eGFR decline ≥ 50%, or ESRD and CV or renal death, in patients with UACR > 1000 mg / g. In some embodiments, relative to the administration regimen in which patients with UACR > 1000 mg / g receive at least one standard CKD care agent alone, the method results in a numerical reduction in the composite endpoint events of sustained eGFR decline ≥ 50%, or ESRD and CV or renal death, in patients with UACR > 1000 mg / g.

[0066] In some embodiments, relative to the administration regimen in which patients with eGFR < 45 mL / min / 1.73m 2 receive at least one standard CKD care agent alone, the methods disclosed herein result in the eGFR < 45 mL / min / 1.73m 2The hazard ratio for the time to the first composite endpoint of sustained decline in eGFR of ≥50%, or ESRD and CV or renal death, in patients is less than 1. In some methods, relative to patients with eGFR < 45 mL / min / 1.73m 2 who receive a regimen of administration of at least one standard CKD care agent alone, the method results in an eGFR < 45 mL / min / 1.73m 2 The hazard ratio for the time to the first composite endpoint of sustained decline in eGFR of ≥50%, or ESRD and CV or renal death, in patients is statistically nominally less than 1. In some embodiments, relative to patients with eGFR < 45 mL / min / 1.73m 2 who receive a regimen of administration of at least one standard CKD care agent alone, the method results in an eGFR < 45 mL / min / 1.73m 2 The hazard ratio for the time to the first composite endpoint of sustained decline in eGFR of ≥50%, or ESRD and CV or renal death, in patients is approximately 0.63. In some methods, relative to patients with eGFR < 45 mL / min / 1.73m 2 who receive a regimen of administration of at least one standard CKD care agent alone, the method results in an eGFR < 45 mL / min / 1.73m 2 The 95% confidence interval for the hazard ratio for the time to the first composite endpoint of sustained decline in eGFR of ≥50%, or ESRD and CV or renal death, in patients is approximately 0.51 to 0.78. In some embodiments, relative to patients with eGFR < 45 mL / min / 1.73m 2 who receive a regimen of administration of at least one standard CKD care agent alone, the method numerically reduces the absolute risk of the composite endpoint of sustained decline in eGFR of ≥50%, or ESRD and CV or renal death, in patients with an eGFR < 45 mL / min / 1.73m 2 In some embodiments, relative to patients with eGFR < 45 mL / min / 1.73m 2 who receive a regimen of administration of at least one standard CKD care agent alone, the method results in an eGFR < 45 mL / min / 1.73m 2 The method nominally significantly reduces the risk of the composite endpoint of sustained decline in eGFR of ≥50%, or ESRD and CV or renal death, in patients. In some embodiments, relative to patients with eGFR < 45 mL / min / 1.73m 2 who receive a regimen of administration of at least one standard CKD care agent alone, the method results in an eGFR < 45 mL / min / 1.73m 2 A numerical reduction in the composite endpoint events of sustained decline in eGFR of ≥50%, or ESRD and CV or renal death, in patients.

[0067] In some embodiments, relative to patients with an eGFR ≥ 45 mL / min / 1.73m 2 who receive a regimen of administration of at least one standard CKD care agent alone, the methods disclosed herein result in a hazard ratio for time to a first composite endpoint of ≥ 50% sustained decline in eGFR, or ESRD and CV or renal death, in patients with an eGFR ≥ 45 mL / min / 1.73m 2 that is less than 1. In some methods, relative to patients with an eGFR ≥ 45 mL / min / 1.73m 2 who receive a regimen of administration of at least one standard CKD care agent alone, the methods result in a hazard ratio for time to a first composite endpoint of ≥ 50% sustained decline in eGFR, or ESRD and CV or renal death, in patients with an eGFR ≥ 45 mL / min / 1.73m 2 that is statistically nominally less than 1. In some embodiments, relative to patients with an eGFR ≥ 45 mL / min / 1.73m 2 who receive a regimen of administration of at least one standard CKD care agent alone, the methods result in a hazard ratio for time to a first composite endpoint of ≥ 50% sustained decline in eGFR, or ESRD and CV or renal death, in patients with an eGFR ≥ 45 mL / min / 1.73m 2 that is about 0.49. In some methods, relative to patients with an eGFR ≥ 45 mL / min / 1.73m 2 who receive a regimen of administration of at least one standard CKD care agent alone, the methods result in a 95% confidence interval for the hazard ratio for time to a first composite endpoint of ≥ 50% sustained decline in eGFR, or ESRD and CV or renal death, in patients with an eGFR ≥ 45 mL / min / 1.73m 2 that is about 0.34 to 0.69. In some embodiments, relative to patients with an eGFR ≥ 45 mL / min / 1.73m 2 who receive a regimen of administration of at least one standard CKD care agent alone, the methods numerically reduce the absolute risk of a composite endpoint of ≥ 50% sustained decline in eGFR, or ESRD and CV or renal death, in patients with an eGFR ≥ 45 mL / min / 1.73m 2 In some embodiments, relative to patients with an eGFR ≥ 45 mL / min / 1.73m 2 who receive a regimen of administration of at least one standard CKD care agent alone, the methods result in a hazard ratio for time to a first composite endpoint of ≥ 50% sustained decline in eGFR, or ESRD and CV or renal death, in patients with an eGFR ≥ 45 mL / min / 1.73m 2In some embodiments, the risk of sustained decline in eGFR ≥ 50% or the composite endpoint of ESRD and CV or renal death is nominally significantly reduced in patients with eGFR ≥ 45 mL / min / 1.73 m 2 The method results in an eGFR of ≥45 mL / min / 1.73 m 2 A numerical reduction in the number of patients achieving a sustained decline in eGFR ≥50%, or a composite endpoint of ESRD and CV or renal death.

[0068] In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for the time to a sustained decrease in eGFR of ≥50% for the patient relative to a regimen of administration of at least one standard CKD care agent received alone. In some methods, the method results in a hazard ratio of less than 1 for the time to a sustained decrease in eGFR of ≥50% for the patient relative to a regimen of administration of at least one standard CKD care agent received alone. In some embodiments, the method results in a hazard ratio of about 0.53 for the time to a sustained decrease in eGFR of ≥50% for the patient relative to a regimen of administration of at least one standard CKD care agent received alone. In some methods, the method results in a 95% confidence interval of about 0.42 to 0.67 for the hazard ratio for the time to a sustained decrease in eGFR of ≥50% for the patient relative to a regimen of administration of at least one standard CKD care agent received alone. In some embodiments, the method numerically reduces the absolute risk of a sustained decrease in eGFR of ≥50% for the patient relative to a regimen of administration of at least one standard CKD care agent received alone. In some embodiments, the method results in a nominally significant reduction in the risk of a sustained decrease in eGFR of ≥50% in the patient relative to an administration regimen in which the patient receives at least one standard CKD care agent alone. In some embodiments, the method results in a numerical reduction in a sustained decrease in eGFR of ≥50% in the patient relative to an administration regimen in which the patient receives at least one standard CKD care agent alone.

[0069] In some embodiments, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the methods disclosed herein result in a hazard ratio for time to ESRD in the patient of less than 1. In some methods, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the method results in a hazard ratio for time to ESRD in the patient that is statistically nominally less than 1. In some embodiments, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the method results in a hazard ratio for time to ESRD in the patient of about 0.64. In some methods, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the 95% confidence interval for the hazard ratio for time to ESRD in the patient is from about 0.50 to 0.82. In some embodiments, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the method numerically reduces the absolute risk of ESRD in the patient. In some embodiments, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the method results in a nominally significant reduction in the risk of ESRD in the patient. In some embodiments, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the method results in a numerical reduction in ESRD in the patient.

[0070] In some embodiments, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the methods disclosed herein result in a hazard ratio for time to CV death in the patient of less than 1. In some methods, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the method results in a hazard ratio for time to CV death in the patient that is statistically nominally less than 1. In some embodiments, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the method results in a hazard ratio for time to CV death in the patient of about 0.81. In some methods, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the 95% confidence interval for the hazard ratio for time to CV death in the patient is from about 0.58 to 1.12. In some embodiments, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the method numerically reduces the absolute risk of CV death in the patient. In some embodiments, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the method results in a nominally significant reduction in the risk of CV death in the patient. In some embodiments, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the method results in a numerical reduction in CV death in the patient.

[0071] In some embodiments, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the methods disclosed herein result in a hazard ratio of less than 1 for the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and renal death, in the patient. In some methods, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the method results in a hazard ratio that is statistically nominally less than 1 for the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and renal death, in the patient. In some embodiments, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the method results in a hazard ratio of about 0.56 for the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and renal death, in the patient. In some methods, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the 95% confidence interval for the hazard ratio for the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and renal death, in the patient is from about 0.45 to 0.68. In some embodiments, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the method numerically reduces the absolute risk of the composite endpoint of ≥50% sustained decline in eGFR, or ESRD and renal death, in the patient. In some embodiments, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the method results in a nominally significant reduction in the risk of the composite endpoint of ≥50% sustained decline in eGFR, or ESRD and renal death, in the patient. In some embodiments, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the method results in a numerical reduction in the composite endpoint events of ≥50% sustained decline in eGFR, or ESRD and renal death, in the patient.

[0072] In some embodiments, relative to a regimen of administering at least one standard CKD care agent to a patient with T2D alone, the methods disclosed herein result in a hazard ratio of less than 1 for the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and renal death, in the patient with T2D. In some methods, relative to a regimen of administering at least one standard CKD care agent to a patient with T2D alone, the method results in a hazard ratio that is statistically nominally less than 1 for the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and renal death, in the patient with T2D. In some embodiments, relative to a regimen of administering at least one standard CKD care agent to a patient with T2D alone, the method results in a hazard ratio of about 0.57 for the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and renal death, in the patient with T2D. In some methods, relative to a regimen of administering at least one standard CKD care agent to a patient with T2D alone, the 95% confidence interval for the hazard ratio for the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and renal death, in the patient with T2D is about 0.45 to 0.73. In some embodiments, relative to a regimen of administering at least one standard CKD care agent to a patient with T2D alone, the method numerically reduces the absolute risk of the composite endpoint of ≥50% sustained decline in eGFR, or ESRD and renal death, in the patient with T2D. In some embodiments, relative to a regimen of administering at least one standard CKD care agent to a patient with T2D alone, the method results in a nominally significant reduction in the risk of the composite endpoint of ≥50% sustained decline in eGFR, or ESRD and renal death, in the patient with T2D. In some embodiments, relative to a regimen of administering at least one standard CKD care agent to a patient with T2D alone, the method results in a numerical reduction in the composite endpoint events of ≥50% sustained decline in eGFR, or ESRD and renal death, in the patient with T2D.

[0073] In some embodiments, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the methods disclosed herein result in a hazard ratio of less than 1 for the time to the first composite endpoint of sustained decline in eGFR ≥ 50%, or ESRD and renal death, in the patients without T2D. In some methods, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the method results in a hazard ratio that is statistically nominally less than 1 for the time to the first composite endpoint of sustained decline in eGFR ≥ 50%, or ESRD and renal death, in the patients without T2D. In some embodiments, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the method results in a hazard ratio of approximately 0.51 for the time to the first composite endpoint of sustained decline in eGFR ≥ 50%, or ESRD and renal death, in the patients without T2D. In some methods, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the 95% confidence interval for the hazard ratio for the time to the first composite endpoint of sustained decline in eGFR ≥ 50%, or ESRD and renal death, in the patients without T2D is from approximately 0.34 to 0.75. In some embodiments, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the method numerically reduces the absolute risk of the composite endpoint of sustained decline in eGFR ≥ 50%, or ESRD and renal death, in the patients without T2D. In some embodiments, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the method results in a nominally significant reduction in the risk of the composite endpoint of sustained decline in eGFR ≥ 50%, or ESRD and renal death, in the patients without T2D. In some embodiments, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the method results in a numerical reduction in the composite endpoint events of sustained decline in eGFR ≥ 50%, or ESRD and renal death, in the patients without T2D.

[0074] In some embodiments, relative to the administration regimen in which patients with eGFR < 30 receive at least one standard CKD care agent alone, the methods disclosed herein result in a hazard ratio of less than 1 for the time to the first composite endpoint of sustained decline in eGFR ≥ 50%, or ESRD and renal death, in patients with eGFR < 30. In some methods, relative to the administration regimen in which patients with eGFR < 30 receive at least one standard CKD care agent alone, the method results in a hazard ratio that is statistically nominally less than 1 for the time to the first composite endpoint of sustained decline in eGFR ≥ 50%, or ESRD and renal death, in patients with eGFR < 30. In some embodiments, relative to the administration regimen in which patients with eGFR < 30 receive at least one standard CKD care agent alone, the method results in a hazard ratio of approximately 0.73 for the time to the first composite endpoint of sustained decline in eGFR ≥ 50%, or ESRD and renal death, in patients with eGFR < 30. In some methods, relative to the administration regimen in which patients with eGFR < 30 receive at least one standard CKD care agent alone, the 95% confidence interval for the hazard ratio for the time to the first composite endpoint of sustained decline in eGFR ≥ 50%, or ESRD and renal death, in patients with eGFR < 30 is approximately 0.53 to 1.02. In some embodiments, relative to the administration regimen in which patients with eGFR < 30 receive at least one standard CKD care agent alone, the method numerically reduces the absolute risk of the composite endpoint of sustained decline in eGFR ≥ 50%, or ESRD and renal death, in patients with eGFR < 30. In some embodiments, relative to the administration regimen in which patients with eGFR < 30 receive at least one standard CKD care agent alone, the method results in a nominally significant reduction in the risk of the composite endpoint of sustained decline in eGFR ≥ 50%, or ESRD and renal death, in patients with eGFR < 30. In some embodiments, relative to the administration regimen in which patients with eGFR < 30 receive at least one standard CKD care agent alone, the method results in a numerical reduction in the composite endpoint events of sustained decline in eGFR ≥ 50%, or ESRD and renal death, in patients with eGFR < 30.

[0075] In some embodiments, relative to the administration regimen in which patients with eGFR ≥ 30 receive at least one standard CKD care agent alone, the methods disclosed herein result in a hazard ratio for the time to a first composite endpoint of sustained eGFR decline ≥ 50%, or ESRD and renal death, in patients with eGFR ≥ 30 that is less than 1. In some methods, relative to the administration regimen in which patients with eGFR ≥ 30 receive at least one standard CKD care agent alone, the method results in a hazard ratio for the time to a first composite endpoint of sustained eGFR decline ≥ 50%, or ESRD and renal death, in patients with eGFR ≥ 30 that is statistically nominally less than 1. In some embodiments, relative to the administration regimen in which patients with eGFR ≥ 30 receive at least one standard CKD care agent alone, the method results in a hazard ratio for the time to a first composite endpoint of sustained eGFR decline ≥ 50%, or ESRD and renal death, in patients with eGFR ≥ 30 of approximately 0.58. In some methods, relative to the administration regimen in which patients with eGFR ≥ 30 receive at least one standard CKD care agent alone, the 95% confidence interval for the hazard ratio for the time to a first composite endpoint of sustained eGFR decline ≥ 50%, or ESRD and renal death, in patients with eGFR ≥ 30 is approximately 0.47 to 0.71. In some embodiments, relative to the administration regimen in which patients with eGFR ≥ 30 receive at least one standard CKD care agent alone, the method numerically reduces the absolute risk of a composite endpoint of sustained eGFR decline ≥ 50%, or ESRD and renal death, in patients with eGFR ≥ 30. In some embodiments, relative to the administration regimen in which patients with eGFR ≥ 30 receive at least one standard CKD care agent alone, the method results in a nominally significant reduction in the risk of a composite endpoint of sustained eGFR decline ≥ 50%, or ESRD and renal death, in patients with eGFR ≥ 30. In some embodiments, relative to the administration regimen in which patients with eGFR ≥ 30 receive at least one standard CKD care agent alone, the method results in a numerical reduction in the composite endpoint events of sustained eGFR decline ≥ 50%, or ESRD and renal death, in patients with eGFR ≥ 30.

[0076] In some embodiments, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the methods disclosed herein result in a hazard ratio of less than 1 for the time to the first composite endpoint of CV death and hospitalization for heart failure in the patient. In some methods, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the method results in a hazard ratio that is statistically nominally less than 1 for the time to the first composite endpoint of CV death and hospitalization for heart failure in the patient. In some embodiments, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the method results in a hazard ratio of approximately 0.71 for the time to the first composite endpoint of CV death and hospitalization for heart failure in the patient. In some methods, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the 95% confidence interval for the hazard ratio for the time to the first composite endpoint of CV death and hospitalization for heart failure in the patient is from approximately 0.55 to 0.92. In some embodiments, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the method numerically reduces the absolute risk of the composite endpoint of CV death and hospitalization for heart failure in the patient. In some embodiments, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the method results in a nominally significant reduction in the risk of the composite endpoint of CV death and hospitalization for heart failure in the patient. In some embodiments, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the method results in a numerical reduction in the composite endpoint events of CV death and hospitalization for heart failure in the patient.

[0077] In some embodiments, relative to a regimen in which a patient with T2D receives only the administration of at least one standard CKD care agent, the methods disclosed herein result in a hazard ratio of less than 1 for the time to the first composite endpoint of CV death and hospitalization for heart failure in the patient with T2D. In some methods, relative to a regimen in which a patient with T2D receives only the administration of at least one standard CKD care agent, the method results in a hazard ratio that is statistically nominally less than 1 for the time to the first composite endpoint of CV death and hospitalization for heart failure in the patient with T2D. In some embodiments, relative to a regimen in which a patient with T2D receives only the administration of at least one standard CKD care agent, the method results in a hazard ratio of approximately 0.70 for the time to the first composite endpoint of CV death and hospitalization for heart failure in the patient with T2D. In some methods, relative to a regimen in which a patient with T2D receives only the administration of at least one standard CKD care agent, the 95% confidence interval for the hazard ratio for the time to the first composite endpoint of CV death and hospitalization for heart failure in the patient with T2D is from approximately 0.53 to 0.92. In some embodiments, relative to a regimen in which a patient with T2D receives only the administration of at least one standard CKD care agent, the method numerically reduces the absolute risk of the composite endpoint of CV death and hospitalization for heart failure in the patient with T2D. In some embodiments, relative to a regimen in which a patient with T2D receives only the administration of at least one standard CKD care agent, the method results in a nominally significant reduction in the risk of the composite endpoint of CV death and hospitalization for heart failure in the patient with T2D. In some embodiments, relative to a regimen in which a patient with T2D receives only the administration of at least one standard CKD care agent, the method results in a numerical reduction in the composite endpoint events of CV death and hospitalization for heart failure in the patient with T2D.

[0078] In some embodiments, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the methods disclosed herein result in a hazard ratio of less than 1 for the time to the first composite endpoint of CV death and hospitalization for heart failure in the patients without T2D. In some methods, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the method results in a hazard ratio that is statistically nominally less than 1 for the time to the first composite endpoint of CV death and hospitalization for heart failure in the patients without T2D. In some embodiments, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the method results in a hazard ratio of approximately 0.79 for the time to the first composite endpoint of CV death and hospitalization for heart failure in the patients without T2D. In some methods, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the 95% confidence interval for the hazard ratio for the time to the first composite endpoint of CV death and hospitalization for heart failure in the patients without T2D is from approximately 0.40 to 1.55. In some embodiments, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the method numerically reduces the absolute risk of the composite endpoint of CV death and hospitalization for heart failure in the patients without T2D. In some embodiments, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the method results in a nominally significant reduction in the risk of the composite endpoint of CV death and hospitalization for heart failure in the patients without T2D. In some embodiments, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the method results in a numerical reduction in the composite endpoint events of CV death and hospitalization for heart failure in the patients without T2D.

[0079] In some embodiments, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the methods disclosed herein result in a hazard ratio of time to all-cause death for the patient of less than 1. In some methods, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the method results in a hazard ratio of time to all-cause death for the patient that is statistically nominally less than 1. In some embodiments, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the method results in a hazard ratio of time to all-cause death for the patient of about 0.69. In some methods, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the 95% confidence interval for the hazard ratio of time to all-cause death for the patient is from about 0.53 to 0.88. In some embodiments, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the method numerically reduces the absolute risk of all-cause death for the patient. In some embodiments, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the method results in a nominally significant reduction in the risk of all-cause death for the patient. In some embodiments, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the method results in a numerical reduction in all-cause death for the patient.

[0080] In some embodiments, relative to a regimen in which a patient with T2D receives only the administration of at least one standard CKD care agent, the methods disclosed herein result in a hazard ratio of time to all-cause death for the patient with T2D that is less than 1. In some methods, relative to a regimen in which a patient with T2D receives only the administration of at least one standard CKD care agent, the method results in a hazard ratio of time to all-cause death for the patient with T2D that is statistically nominally less than 1. In some embodiments, relative to a regimen in which a patient with T2D receives only the administration of at least one standard CKD care agent, the method results in a hazard ratio of time to all-cause death for the patient with T2D of about 0.74. In some methods, relative to a regimen in which a patient with T2D receives only the administration of at least one standard CKD care agent, the 95% confidence interval for the hazard ratio of time to all-cause death for the patient with T2D is from about 0.56 to 0.98. In some embodiments, relative to a regimen in which a patient with T2D receives only the administration of at least one standard CKD care agent, the method numerically reduces the absolute risk of all-cause death for the patient with T2D. In some embodiments, relative to a regimen in which a patient with T2D receives only the administration of at least one standard CKD care agent, the method results in a nominally significant reduction in the risk of all-cause death for the patient with T2D. In some embodiments, relative to a regimen in which a patient with T2D receives only the administration of at least one standard CKD care agent, the method results in a numerical reduction in all-cause death for the patient with T2D.

[0081] In some embodiments, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the methods disclosed herein result in a hazard ratio of the time to all-cause death in the patients without T2D that is less than 1. In some methods, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the method results in a hazard ratio of the time to all-cause death in the patients without T2D that is statistically nominally less than 1. In some embodiments, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the method results in a hazard ratio of the time to all-cause death in the patients without T2D of about 0.52. In some methods, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the 95% confidence interval of the hazard ratio of the time to all-cause death in the patients without T2D is about 0.29 to 0.93. In some embodiments, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the method numerically reduces the absolute risk of all-cause death in the patients without T2D. In some embodiments, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the method results in a nominally significant reduction in the risk of all-cause death in the patients without T2D. In some embodiments, relative to the administration regimen of receiving at least one standard CKD care agent alone in patients without T2D, the method results in a numerical reduction in all-cause death in the patients without T2D.

[0082] In some embodiments, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the methods disclosed herein result in a hazard ratio of less than 1 for the time to the first composite endpoint of chronic dialysis, kidney transplantation, or renal death in the patient. In some methods, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the method results in a statistically nominally less than 1 hazard ratio for the time to the first composite endpoint of chronic dialysis, kidney transplantation, or renal death in the patient. In some embodiments, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the method results in a hazard ratio of about 0.66 for the time to the first composite endpoint of chronic dialysis, kidney transplantation, or renal death in the patient. In some methods, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the 95% confidence interval for the hazard ratio for the time to the first composite endpoint of chronic dialysis, kidney transplantation, or renal death in the patient is from about 0.49 to 0.90. In some embodiments, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the method numerically reduces the absolute risk of the composite endpoint of chronic dialysis, kidney transplantation, or renal death in the patient. In some embodiments, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the method results in a nominally significant reduction in the risk of the composite endpoint of chronic dialysis, kidney transplantation, or renal death in the patient. In some embodiments, relative to a patient receiving a regimen of at least one standard CKD care agent alone, the method results in a numerical reduction in the composite endpoint events of chronic dialysis, kidney transplantation, or renal death in the patient.

[0083] In some embodiments, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the methods disclosed herein result in a hazard ratio of the time to first hospitalization due to HF for the patient that is less than 1. In some methods, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the method results in a hazard ratio of the time to first hospitalization due to HF for the patient that is statistically nominally less than 1. In some embodiments, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the method results in a hazard ratio of the time to first hospitalization due to HF for the patient of about 0.51. In some methods, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the 95% confidence interval of the hazard ratio of the time to first hospitalization due to HF for the patient is from about 0.34 to 0.76. In some embodiments, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the method numerically reduces the risk of the time to first hospitalization due to HF for the patient. In some embodiments, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the method results in a nominally significant reduction in the risk of first hospitalization due to HF for the patient. In some embodiments, relative to a patient receiving a regimen of administration of at least one standard CKD care agent alone, the method results in a numerical reduction in the risk of the time to first hospitalization due to HF for the patient.

[0084] In some embodiments, relative to a regimen of administering at least one standard CKD care agent alone to a patient with IgA nephropathy, the methods disclosed herein result in a hazard ratio of less than 1 for the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death, in the patient with IgA nephropathy. In some methods, relative to a regimen of administering at least one standard CKD care agent alone to a patient with IgA nephropathy, the method results in a hazard ratio that is statistically nominally less than 1 for the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death, in the patient with IgA nephropathy. In some embodiments, relative to a regimen of administering at least one standard CKD care agent alone to a patient with IgA nephropathy, the method results in a hazard ratio of about 0.29 for the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death, in the patient with IgA nephropathy. In some methods, relative to a regimen of administering at least one standard CKD care agent alone to a patient with IgA nephropathy, the 95% confidence interval for the hazard ratio for the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death, in the patient with IgA nephropathy is about 0.12 to 0.73. In some embodiments, relative to a regimen of administering at least one standard CKD care agent alone to a patient with IgA nephropathy, the method numerically reduces the risk of the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death, in the patient with IgA nephropathy. In some embodiments, relative to a regimen of administering at least one standard CKD care agent alone to a patient with IgA nephropathy, the method results in a nominally significant reduction in the risk of the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death, in the patient with IgA nephropathy. In some embodiments, relative to a regimen of administering at least one standard CKD care agent alone to a patient with IgA nephropathy, the method results in a numerical reduction in the risk of the time to the first composite endpoint of ≥50% sustained decline in eGFR, or ESRD and CV or renal death, in the patient with IgA nephropathy.

[0085] Also disclosed herein is AZD9977, 2-{(3S)-7-fluoro-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}-N-methylacetamide, which is disclosed in WO 2016 / 001631 and has the following structure:

[0086]

[0087] In some embodiments, a method of treating CKD is disclosed, which comprises administering to a patient in need thereof an effective amount of AZD9977 or a pharmaceutically acceptable salt thereof; and an effective amount of an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0088] In some embodiments, AZD9977 or a pharmaceutically acceptable salt thereof for treating CKD in a patient is disclosed, wherein the treatment comprises administering AZD9977 and an SGLT2 inhibitor to the patient separately, sequentially or simultaneously. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0089] In some embodiments, an SGLT2 inhibitor for treating CKD in a patient is disclosed, wherein the treatment comprises administering the SGLT2 inhibitor and AZD9977 or a pharmaceutically acceptable salt thereof separately, sequentially or simultaneously. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0090] In some embodiments, a method of reducing the rate of progression of renal failure and / or renal death and / or CV death in a patient with CKD is disclosed, which comprises administering to a patient in need thereof an effective amount of AZD9977 or a pharmaceutically acceptable salt thereof; and an effective amount of an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof. In at least one embodiment, renal failure can be defined as, for example, a ≥40% decrease in eGFR or ESRD. In some embodiments, a patient with CKD may have, for example, an eGFR of 15 - 89 ml / min / 1.73m 2 In other embodiments, a patient with CKD may have, for example, an eGFR in the range of 15 - 59 ml / min / 1.73m 2 In some embodiments, a patient with CKD may be, for example, at high risk of hyperkalemia (i.e., having T2D and / or having an eGFR of 15 - 59 ml / min / 1.73m 2 ).

[0091] In some embodiments, AZD9977 or a pharmaceutically acceptable salt thereof for reducing the rate of progression of renal failure and / or renal death and / or CV death in patients with CKD is disclosed, wherein the treatment comprises administering AZD9977 and an SGLT2 inhibitor to the patient separately, sequentially or simultaneously. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof. In at least one embodiment, renal failure can be defined as, for example, a ≥40% decrease in eGFR or ESRD. In some embodiments, a patient with CKD may have, for example, an eGFR of 15 - 89 ml / min / 1.73m 2 In other embodiments, a patient with CKD may have, for example, an eGFR in the range of 15 - 59 ml / min / 1.73m 2 In some embodiments, a patient with CKD may be, for example, at high risk of hyperkalemia (i.e., having T2D and / or having an eGFR of 15 - 59 ml / min / 1.73m 2 ).

[0092] In some embodiments, an SGLT2 inhibitor for reducing the rate of progression of renal failure and / or renal death and / or CV death in patients with CKD is disclosed, wherein the treatment comprises administering the SGLT2 inhibitor and AZD9977 or a pharmaceutically acceptable salt thereof separately, sequentially or simultaneously. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof. In at least one embodiment, renal failure can be defined as, for example, a ≥40% decrease in eGFR or ESRD. In some embodiments, a patient with CKD may have, for example, an eGFR of 15 - 89 ml / min / 1.73m 2 In other embodiments, a patient with CKD may have, for example, an eGFR in the range of 15 - 59 ml / min / 1.73m 2 In some embodiments, a patient with CKD may be, for example, at high risk of hyperkalemia (i.e., having T2D and / or having an eGFR of 15 - 59 ml / min / 1.73m 2 ).

[0093] In some embodiments, a method for reducing the risk of hyperkalemia in a patient with CKD is disclosed, which comprises administering to a patient in need thereof an effective amount of AZD9977 or a pharmaceutically acceptable salt thereof; and an effective amount of an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0094] In some embodiments, AZD9977 or a pharmaceutically acceptable salt thereof for reducing the risk of hyperkalemia in CKD patients in a patient is disclosed, wherein the treatment comprises administering AZD9977 and an SGLT inhibitor to the patient separately, sequentially or simultaneously. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0095] In some embodiments, an SGLT2 inhibitor for reducing the risk of hyperkalemia in CKD patients in a patient is disclosed, wherein the treatment comprises administering the SGLT2 inhibitor and AZD9977 or a pharmaceutically acceptable salt thereof separately, sequentially or simultaneously. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0096] In some embodiments, a method of treating HFrEF and CKD is disclosed, which comprises administering to a patient in need an effective amount of AZD9977 or a pharmaceutically acceptable salt thereof; and an effective amount of an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0097] In some embodiments, AZD9977 or a pharmaceutically acceptable salt thereof for treating HFrEF and CKD in a patient is disclosed, wherein the treatment comprises administering AZD9977 and an SGLT inhibitor to the patient separately, sequentially or simultaneously. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0098] In some embodiments, an SGLT2 inhibitor for treating HFrEF and CKD in a patient is disclosed, wherein the treatment comprises administering the SGLT2 inhibitor and AZD9977 or a pharmaceutically acceptable salt thereof separately, sequentially or simultaneously. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0099] In some embodiments, a method of treating HFpEF and CKD is disclosed, which comprises administering to a patient in need an effective amount of AZD9977 or a pharmaceutically acceptable salt thereof; and an effective amount of an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0100] In some embodiments, AZD9977 or a pharmaceutically acceptable salt thereof for treating HFpEF and CKD in a patient is disclosed, wherein the treatment comprises administering AZD9977 and an SGLT inhibitor to the patient separately, sequentially, or simultaneously. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof.

[0101] In some embodiments, an SGLT2 inhibitor for treating HFpEF and CKD in a patient is disclosed, wherein the treatment comprises administering the SGLT2 inhibitor and AZD9977 or a pharmaceutically acceptable salt thereof separately, sequentially, or simultaneously. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof.

[0102] In some embodiments, a method of treating HF and CKD is disclosed, which comprises administering an effective amount of AZD9977 or a pharmaceutically acceptable salt thereof; and an effective amount of an SGLT2 inhibitor to a patient in need thereof having an LVEF of less than 55% and an eGFR of about 30 - 60 ml / min / 1.73 m2. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof.

[0103] In some embodiments, AZD9977 or a pharmaceutically acceptable salt thereof for treating HF and CKD in a patient having an LVEF of less than 55% and an eGFR of about 30 - 60 ml / min / 1.73 m2 is disclosed, wherein the treatment comprises administering AZD9977 and an SGLT inhibitor to the patient separately, sequentially, or simultaneously. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof.

[0104] In some embodiments, an SGLT2 inhibitor for treating HF and CKD in a patient having an LVEF of less than 55% and an eGFR of about 30 - 60 ml / min / 1.73 m2 is disclosed, wherein the treatment comprises administering the SGLT2 inhibitor and AZD9977 or a pharmaceutically acceptable salt thereof separately, sequentially, or simultaneously. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof.

[0105] In any of the above embodiments, the SGLT2 inhibitor can be, for example, dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof. In at least one embodiment, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof, administered orally once daily at a dose of 10 mg. In any of the above embodiments, AZD9977 or a pharmaceutically acceptable salt thereof can be administered orally to a patient once daily in an amount in the range of 15 - 150 mg, such as 100 mg - 150 mg orally once daily. In any of the above embodiments, AZD9977 or a pharmaceutically acceptable salt thereof can be administered orally to a patient twice daily in an amount in the range of 15 - 150 mg, such as 60 mg twice daily. In any of the above embodiments, AZD9977 or a pharmaceutically acceptable salt thereof can be administered orally to a patient once weekly in an amount in the range of 15 - 150 mg.

[0106] In any of the above embodiments, the left ventricular ejection fraction (LVEF) of the patient is less than or equal to 40%, such as less than or equal to 35%, 30%, or 25%, and in at least one embodiment, is at least 20%. In some embodiments, the LVEF of the patient is greater than or equal to 40%, such as greater than or equal to 45%, 50%, or 55%, and in at least one embodiment, is less than 55%. In some embodiments, the eGFR of the patient before administration is less than or equal to 60 ml / min / 1.73m2, such as less than or equal to 50 ml / min / 1.73m2, 45 ml / min / 1.73m2, 40 ml / min / 1.73m2, or 35 ml / min / 1.73m2. In some embodiments, the eGFR of the patient before administration is greater than or equal to 30 ml / min / 1.73m2, such as greater than or equal to 35 ml / min / 1.73m2, 40 ml / min / 1.73m2, 45 ml / min / 1.73m2, or 50 ml / min / 1.73m2. In some embodiments, the patient has T2D. In some embodiments, the patient does not have T2D. In some embodiments, hyperkalemia is understood to refer to a potassium level greater than 5.5 mmol / L. In some embodiments, hyperkalemia can be mild (serum potassium level greater than 5.5 mmol / L) or moderate / severe (serum potassium level greater than 6.0 mmol / L).

[0107] In some embodiments, the SGLT2 inhibitor is selected from those disclosed in U.S. Patent No. 6,515,177, WO / 2003 / 099836, U.S. PG Publication No. 2006 / 0194809, U.S. PG Publication No. 2006 / 0063722A1, WO / 2002 / 083066, U.S. PG Publication No. 2003 / 0064935, U.S. Patent No. 6,774,112, U.S. PG Publication No. 2005 / 0209166, U.S. PG Publication No. 2006 / 0074031, U.S. PG Publication No. 2006 / 0035841, U.S. PG Publication No. 2006 / 0009400, U.S. PG Publication No. 2006 / 0025349, U.S. PG Publication No. 2006 / 0122126, U.S. PG Publication No. 2006 / 0019948, U.S. PG Publication No. 2006 / 0194809, U.S. Patent No. 6,908,905, U.S. Patent No. 6,815,428, U.S. Patent No. 6,555,519, U.S. Patent No. 6,683,056, EP 598359A1, JP 035988, U.S. Patent No. 5,731,292, EP 0850948 A1, U.S. Patent No. 6,048,842, JP 09188625A, JP 09124685 A, JP 09124684, EP 773226A1, U.S. Patent No. 5,767,094, JP 08027006 A, EP 684254A1, JP 10245391 (Dainippon), U.S. PG Publication No. 2005 / 0233982 (Boehringer Ingelheim group), U.S. PG Publication No. 2005 / 0119192 (Kissei Pharmaceutical Co., Ltd.), WO / 2006 / 035796 (Kissei Pharmaceutical Co., Ltd.), JP 2006 / 117651 (Taisho Pharmaceutical Co., Ltd.), JP 2004 / 4359630 (Yamanouchi Pharmaceutical Co., Ltd.), WO / 2006 / 080421 (Chugai Pharmaceutical Co., Ltd.), U.S. PG Publication No. 2005 / 0233988 (Tanabe Seiyaku Co.), WO / 2005 / 012321 (Tanabe Seiyaku Co.), U.S. Patent No. 7,015,201 (Ajinomoto Co.), WO 2006 / 058597 (Merck Patent GmbH), WO2006 / 011469 (Chugai Seiyaku Kabushiki Kaisha), U.S. PG Publication No. 2003 / 0195235 (Johnson & Johnson), and WO 2006 / 037537 (Boehringer Ingelheim group).

[0108] In some embodiments, 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).

[0109] In some embodiments, the SGLT2 inhibitor can be dapagliflozin Canagliflozin Empagliflozin Ertugliflozin Sotagliflozin, ipragliflozin, togliflozin or luseogliflozin, or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug of any of the foregoing.

[0110] In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof, such as described in U.S. Patent Nos. 6,414,126 and 6,515,117, which are incorporated herein by reference in their entireties.

[0111] Dapagliflozin (Forxiga TM / Farxiga TM ) is a highly selective and reversible inhibitor of SGLT2. The mechanism of action of dapagliflozin results in the direct and insulin-independent elimination of glucose by the kidney, thereby leading to a reduction in blood glucose levels in patients with type 2 diabetes (T2D). In addition, dapagliflozin has mild diuretic and natriuretic effects. The continuous loss of glucose and associated calories in the urine leads to a continuous and sustained reduction in total body weight, which is mainly the result of a reduction in fat mass, including visceral and subcutaneous adipose tissue. In addition, dapagliflozin has also been shown to reduce BP and albuminuria, which are two prognostic risk factors for CKD progression.

[0112] The chemical structure of dapagliflozin is:

[0113]

[0114] In some embodiments, dapagliflozin is in an amorphous solid form. In some embodiments, dapagliflozin is in a crystalline solid form. In some embodiments, dapagliflozin is in the form of an (S)-propylene glycol ((S)-PG) solvate, which has the following structure:

[0115]

[0116] Methods for preparing the (S)-PG solvate of dapagliflozin, including crystalline S-PG solvate, are provided in U.S. Patent No. 7,919,598.

[0117] In some embodiments, an SGLT2 inhibitor (e.g., dapagliflozin) is administered in combination with a standard of care therapy. In some embodiments, the standard of care therapy includes treatment for controlling comorbidities and / or treatment for reducing the composite of CV death and heart failure events. In some embodiments, the standard of care therapy includes one or more drugs or drug classes other than the SGLT2 inhibitor for treating CKD.

[0118] Standard CKD care agents as described herein can be used before and / or during administration of an SGLT2 inhibitor such as dapagliflozin. In some embodiments, the standard CKD care agent and the SGLT2 inhibitor are administered together at the same or different times.

[0119] Exemplary standard CKD care agents include angiotensin-converting enzyme inhibitors (ACE-I or ACE inhibitors) and angiotensin receptor blockers (ARB). Standard CKD care agents and their dosages are well known to medical practitioners who examine and treat patients with CKD. Representative examples of ACE inhibitors include captopril, enalapril, and lisinopril. Representative examples of ARB include valsartan, losartan, and irbesartan.

[0120] Exemplary "standard HF care agents" include at least one standard HF care agent, e.g., at least two or at least three or more drugs or drug classes other than the SGLT2 inhibitor for treating HF, such as HFrEF. Standard HF care agents as described herein can be used before and / or during administration of an SGLT2 inhibitor such as dapagliflozin. Standard HF care drugs and their dosages are well known to cardiologists and other medical practitioners who examine and treat patients with HFrEF. Exemplary standard HF care agents include: angiotensin-converting enzyme (ACE) inhibitors; angiotensin receptor blockers (ARB); β-blockers; mineralocorticoid receptor agents such as mineralocorticoid receptor antagonists (MRA), and neprilysin inhibitors.

[0121] Other agents that can be considered “standard HF care agents” include diuretics and loop diuretics (e.g., furosemide, bumetanide, and torsemide), digoxin, cardiac pump drugs, selective sinoatrial node inhibitors, ivabradine (a sinoatrial (SA) node modulator), aldosterone antagonists, vasodilators, calcium channel blockers (except in patients with systolic heart failure), hydralazine / isosorbide dinitrate, or other HF drugs in practice guidelines. See Yancy C.W. et al., “ACC / AHA / HFSA focused update of the 2013 ACCF / AHA guideline for the management of heart failure: A report of the American College of Cardiology / American Heart Association task force on clinical practice guidelines and the Heart Failure Society of America [Report of the American College of Cardiology / American Heart Association task force on clinical practice guidelines and the Heart Failure Society of America], J Am Coll Cardiol [Journal of the American College of Cardiology]. 70(6):776 - 803 (2017).

[0122] The present disclosure further provides methods that include administering to a patient in need thereof an effective amount of an SGLT2 inhibitor, either alone or in combination with at least one other therapeutic agent. In some embodiments, the other therapeutic agent is administered with the SGLT2 inhibitor in the same or different pharmaceutical compositions and at the same or different times.

[0123] In some embodiments, the other therapeutic agent is an anti - diabetic agent, an anti - obesity agent, an anti - hyperlipidemic agent, an anti - atherosclerotic agent, an anti - hypertensive agent, an anti - platelet agent, an anti - thrombus agent, a mineralocorticoid antagonist, a diuretic, and / or an anticoagulant agent. For example, in at least one embodiment, the other therapeutic agent is an anti - diabetic agent, such as a biguanide and / or a DPP4 inhibitor. Exemplary biguanides are metformin or a pharmaceutically acceptable salt thereof. Exemplary DPP4 inhibitors include saxagliptin, linagliptin, sitagliptin, and pharmaceutically acceptable salts thereof.

[0124] In some embodiments, the anti - diabetic agent is selected from the biguanides. In some embodiments, the biguanide is metformin or a pharmaceutically acceptable salt thereof. In some embodiments, the biguanide is metformin hydrochloride. In some embodiments, the biguanide is phenformin.

[0125] In some embodiments, the anti-diabetic agent is selected from sulfonylureas and their pharmaceutically acceptable salts. In some embodiments, the sulfonylurea is selected from glyburide, glimepiride, glipizide, gliclazide, and chlorpropamide. In some embodiments, the sulfonylurea is glyburide. In some embodiments, the sulfonylurea is glipizide.

[0126] In some embodiments, the anti-diabetic agent is selected from glucosidase inhibitors and their pharmaceutically acceptable salts. In some embodiments, the glucosidase inhibitor is selected from acarbose and miglitol.

[0127] In some embodiments, the anti-diabetic agent is selected from PPARγ agonists. In some embodiments, the PPARγ agonist is selected from thiazolidinediones. In some embodiments, the thiazolidinedione is selected from troglitazone (e.g., disclosed in U.S. Patent No. 4,572,912), rosiglitazone (e.g., manufactured by SKB), pioglitazone (e.g., manufactured by Takeda), MCC-555 of Mitsubishi (disclosed in U.S. Patent No. 5,594,016), GL-262570 of Glaxo-Wellcome, englitazone (e.g., CP-68722, manufactured by Pfizer), darglitazone (e.g., CP-86325, manufactured by Pfizer), isaglitazone (e.g., manufactured by MIT / J&J), JTT-501 (JPNT / P&U), L-895645 (Merck), R-119702 (Sankyo / WL), N,N-2344 (Dr. Reddy / NN), or YM-440 (Yamanouchi). In some embodiments, the thiazolidinedione is selected from pioglitazone and rosiglitazone. In some embodiments, the thiazolidinedione is pioglitazone. In some embodiments, the thiazolidinedione is rosiglitazone.

[0128] In some embodiments, the thiazolidinedione is selected from pioglitazone and rosiglitazone. In some embodiments, the thiazolidinedione is pioglitazone. In some embodiments, the thiazolidinedione is rosiglitazone.

[0129] In some embodiments, the anti-diabetic agent is selected from PPARα / γ dual agonists and pharmaceutically acceptable salts thereof. In some embodiments, the PPARα / γ dual agonist is selected from AR-HO39242 (Astra / Zeneca), GW-409544 (Glaxo Wellcome), KRP297 (Kyorin Merck), Murakami et al., “A Novel Insulin Sensitizer Acts As a Coligand for Peroxisome Proliferation-Activated Receptor Alpha (PPAR alpha) and PPAR gamma. Effect on PPAR alpha Activation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats” [New insulin sensitizer acts as a ligand for peroxisome proliferator-activated receptor α (PPARα) and PPARγ. Effect of PPARα activation on abnormal lipid metabolism in the liver of Zucker obese rats], Diabetes, 47:1841-1847 (1998) and those disclosed in U.S. Patent No. 6,414,002.

[0130] In some embodiments, the anti-diabetic agent is selected from aP2 inhibitors and pharmaceutically acceptable salts thereof. In some embodiments, the aP2 inhibitor is selected from those disclosed in U.S. Patent No. 6,548,529.

[0131] In some embodiments, the anti-diabetic agent is selected from DPP4 inhibitors and pharmaceutically acceptable salts thereof. In some embodiments, the DPP4 inhibitor is selected from those disclosed in U.S. Patent No. 6,395,767, WO 99 / 38501, WO 99 / 46272, WO 99 / 67279 (PROBIODRUG), WO 99 / 67278 (PROBIODRUG), WO 99 / 61431 (PROBIODRUG), NVP-DPP728A (1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine) (Novartis), those disclosed by Hughes et al., Biochemistry, 38(36):11597-11603 (1999), TSL-225 (tryptophanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (disclosed by Yamada et al., Bioorg. & Med. Chem. Lett., 8:1537-1540 (1998)), 2-cyanopyrrolidine and 4-cyanopyrrolidine (disclosed by Ashworth et al., Bioorg. & Med. Chem. Lett., 6(22):1163-1166 and 2745-2748 (1996)).

[0132] In some embodiments, the DPP4 inhibitor is selected from saxagliptin, vildagliptin, linagliptin, alogliptin, and sitagliptin. In some embodiments, the DPP4 inhibitor is selected from saxagliptin and pharmaceutically acceptable salts thereof. In some embodiments, the DPP4 inhibitor is saxagliptin. In some embodiments, the DPP4 inhibitor is saxagliptin hydrochloride.

[0133] In some embodiments, the anti-diabetic agent is selected from meglitinides and pharmaceutically acceptable salts thereof. In some embodiments, the meglitinide is selected from repaglinide, nateglinide (Novartis), and KAD1229 (PF / Kissei). In some embodiments, the meglitinide is repaglinide.

[0134] In some embodiments, the anti-diabetic agent is selected from glucokinase activators, DGAT-1 inhibitors, and pharmaceutically acceptable salts thereof. In some embodiments, the glucokinase activator is selected from those disclosed in WO 2008 / 005964. In some embodiments, the DGAT-1 inhibitor is selected from those disclosed in US PG Publication No. 2008 / 0090876A1.

[0135] In some embodiments, the anti-diabetic agent is selected from insulin, GLP-1 receptor agonists, and pharmaceutically acceptable salts thereof. In some embodiments, the anti-diabetic agent is insulin.

[0136] In some embodiments, the at least one other therapeutic agent is selected from anti-obesity agents and pharmaceutically acceptable salts thereof. In some embodiments, the anti-obesity agent is selected from β3 adrenergic agonists, lipase inhibitors, serotonin (and dopamine) reuptake inhibitors, thyroid receptor β modulators, MCH-1 receptor antagonists, 5-HT2c receptor agonists, anorectic agents, neuropeptide Y (NPY) antagonists, leptin analogs, MC4 receptor agonists, and cannabinoid receptor antagonists.

[0137] In some embodiments, the β3 adrenergic agonist is selected from AJ9677 (Takeda / Dainippon), SB-418790, L750355 (Merck), CP331648 (Pfizer), and other known β3 agonists disclosed in U.S. Patent Nos. 5,541,204, 5,770,615, 5,491,134, 5,776,983, and 5,488,064. In some embodiments, the β3 adrenergic agonist is selected from AJ9677, L750355, and CP331648.

[0138] In some embodiments, the at least one other therapeutic agent is selected from anti-hyperlipidemic agents and pharmaceutically acceptable salts thereof. In some embodiments, the anti-hyperlipidemic agent is selected from HMG CoA reductase inhibitors. In some embodiments, the HMG-CoA reductase inhibitor is selected from mevastatin and related compounds disclosed in U.S. Patent No. 3,983,140, lovastatin (mevinolin) and related compounds disclosed in U.S. Patent No. 4,231,938, pravastatin and related compounds disclosed in U.S. Patent No. 4,346,227, simvastatin and related compounds disclosed in U.S. Patent Nos. 4,448,784 and 4,450,171, and rosuvastatin and related statin compounds disclosed in U.S. Patent No. 5,753,675.

[0139] In some embodiments, the at least one other therapeutic agent is selected from antihypertensive agents and pharmaceutically acceptable salts thereof. In some embodiments, the antihypertensive agent is selected from β-adrenergic blockers, calcium channel blockers (L-type and / or T-type), diuretics, renin inhibitors, ACE inhibitors, AT-1 receptor antagonists, ET receptor antagonists (such as those disclosed in U.S. Patent Nos. 5,612,359 and 6,043,265), dual ET / AII antagonists (such as those disclosed in WO 00 / 01389), neutral endopeptidase (NEP) inhibitors, vasopeptidase inhibitors, and nitrates.

[0140] In some embodiments, the antihypertensive agent is selected from bisoprolol, carvedilol, metaprolol succinate, diltiazem, verapamil, nifedipine, amlodipine, mibefradil, chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acidtricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone, torsemide, indapamide, metolazone, triamterene, eplerenone, captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril, perindopril, trandolapril, losartan, irbesartan, valsartan, candesartan, sitaxsentan, atrsentan, omapatrilat, gemopatrilat, hydralazine, isosorbide dinitrate, nitroglycerin, and nitroprusside.

[0141] In some embodiments, the at least one other therapeutic agent is selected from antiplatelet agents and pharmaceutically acceptable salts thereof. In some embodiments, the antiplatelet agent is selected from clopidogrel, ticlopidine, prasugrel, and aspirin.

[0142] In some embodiments, the at least one other therapeutic agent is selected from antithrombotic agents, anticoagulant agents, and pharmaceutically acceptable salts thereof. In some embodiments, the antithrombotic agent and / or anticoagulant agent is selected from thrombin inhibitors, platelet aggregation inhibitors, PAI-1 inhibitors, α-2-antiplasmin inhibitors, thromboxane receptor antagonists, prostacyclin mimetics, and phosphodiesterase (PDE) inhibitors.

[0143] In some embodiments, the antithrombotic agent and / or anticoagulant agent is selected from clopidogrel, ticlopidine, prasugrel (Eli Lilly), XR-330, T-686, anti-α-2-antiplasmin antibody, ifetroban, dipyridamole, cilostazol, aspirin, ifetroban, picotamide, and ketanserin.

[0144] In some embodiments, an SGLT2 inhibitor (e.g., dapagliflozin) is administered together with at least one other therapeutic agent in the same or different compositions at the same or different times. In some embodiments, the at least one other therapeutic agent is administered before, after, or simultaneously with the SGLT2 inhibitor (e.g., dapagliflozin).

[0145] In some embodiments, dapagliflozin is formulated with another therapeutic agent, such as another antidiabetic drug, into a fixed-dose combination pharmaceutical composition. Dapagliflozin / metformin extended release and dapagliflozin / saxagliptin and dapagliflozin / saxagliptin / metformin are examples of combination pharmaceutical compositions comprising dapagliflozin.

[0146] In some embodiments, the weight ratio of the combination of the at least one compound selected from SGLT2 inhibitors (e.g., dapagliflozin) and their prodrugs to the at least one other therapeutic agent is in the range of about 0.01:1 to about 300:1. In some embodiments, the weight ratio of the combination of the at least one compound selected from SGLT2 inhibitors (e.g., dapagliflozin) and their prodrugs to the at least one other therapeutic agent is in the range of about 0.1:1 to about 200:1. In some embodiments, the weight ratio of the combination of the at least one compound selected from SGLT2 inhibitors (e.g., dapagliflozin) and their prodrugs to the at least one other therapeutic agent is in the range of about 0.2:1 to about 100:1.

[0147] In some embodiments, the patient being treated meets at least one of the following conditions:

[0148] (a) The patient does not have autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis, or ANCA-associated vasculitis;

[0149] (b) The patient has not received cytotoxic therapy, immunosuppressive therapy, or other immunotherapy for primary or secondary kidney disease within 6 months prior to treatment with the SGLT2 inhibitor;

[0150] (c) The patient has no history of organ transplantation;

[0151] (d) The patient has no intolerance to SGLT2 inhibitors;

[0152] (e) The patient does not have type 1 diabetes (T1D);

[0153] (f) The patient does not have New York Heart Association (NYHA) class IV congestive heart failure during treatment;

[0154] (g) Within 12 weeks before treatment with SGLT2 inhibitors, the patient does not have myocardial infarction (MI), unstable angina, stroke, or transient ischemic attack (TIA);

[0155] (h) The patient has not undergone coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) or valve repair / replacement within 12 weeks before treatment and does not plan to undergo any such surgery;

[0156] (i) The patient does not have any conditions outside the areas of renal and CV diseases and has a limited life expectancy of less than 2 years;

[0157] (j) The patient does not have an active malignancy requiring treatment during treatment;

[0158] (k) During treatment, the patient has no liver injury (aspartate aminotransferase [AST] > 3 times the upper limit of normal [ULN], alanine aminotransferase [ALT] > 3 times the ULN, or total bilirubin > 2 times the ULN);

[0159] (l) The patient does not have a known blood-borne infectious disease selected from Ebola virus, Lassa fever virus, hepatitis A, B, C, D, or E virus, and type 1 or 2 HIV; and / or

[0160] (m) The patient is not a woman of childbearing potential who (1) has not undergone chemical or surgical sterilization or is unwilling to use a medically acceptable contraceptive method, (2) has a positive pregnancy test, or (3) is breastfeeding.

[0161] In some embodiments, the patient is selected when the patient meets one or more of the conditions (a) to (m) listed above. In some embodiments, the patient is selected when the patient meets each of the conditions (a) to (m) listed above.

[0162] In some embodiments, the HbA1c of the patient is in the range of about 6.0% to about 6.9%. In some embodiments, the HbA1c of the patient is in the range of about 5.7% to about 6.5%.

[0163] One of ordinary skill in the relevant art can readily determine the effectiveness of the compounds of the present disclosure in treating and / or preventing CKD and / or diseases, disorders, and / or conditions associated therewith. One of ordinary skill in the relevant art can also readily determine and adjust an appropriate dosing regimen (e.g., adjusting the amount of the compound per dose and / or the number of doses and dosing frequency). One or any combination of diagnostic methods, including physical examination, assessment and monitoring of clinical symptoms, and performance of the analytical tests and methods described herein, can be used to monitor the health status of a patient.

[0164] An effective amount or therapeutically effective amount refers to an amount of at least one compound of the present disclosure or a pharmaceutical composition comprising at least one such compound of the present disclosure that, when administered to a patient as part of a single dose or a series of doses, effectively produces at least one therapeutic effect. The dose can depend on the patient's body mass, weight, and / or blood volume. The therapeutic effectiveness of a patient can generally be monitored using assays suitable for the disease, disorder, and / or condition being treated or prevented. The level of the compound administered to the patient can be monitored by determining the level of the compound (or metabolite of the compound) in a biological fluid such as blood, blood fractions (e.g., serum), and / or urine and / or other biological samples from the patient. During the course of a treatment regimen, any method practiced in the art for detecting the compound or its metabolite can be used to measure the level of the compound.

[0165] The dose of the compounds described herein can depend on the patient's condition, i.e., the stage of the disease, the severity of the symptoms caused by the disease, the overall health status, as well as age, gender, and weight, and other factors that are apparent to one of ordinary skill in the medical art.

[0166] In some embodiments, the at least one compound selected from SGLT2 inhibitors (such as dapagliflozin) and prodrugs thereof is administered at a dapagliflozin dose equivalent of about 1 to about 500 mg / day. In some embodiments, the at least one compound selected from SGLT2 inhibitors (such as dapagliflozin) and prodrugs thereof is administered at a dapagliflozin dose equivalent of about 2 to about 400 mg / day. In some embodiments, the at least one compound selected from SGLT2 inhibitors (such as dapagliflozin) and prodrugs thereof is administered at a dapagliflozin dose equivalent of about 0.5 to about 200 mg / day. In some embodiments, the at least one compound selected from SGLT2 inhibitors (such as dapagliflozin) and prodrugs thereof is administered at a dapagliflozin dose equivalent of about 1 to about 100 mg / day. In some embodiments, the at least one compound selected from SGLT2 inhibitors (such as dapagliflozin) and prodrugs thereof is administered at a dapagliflozin dose equivalent of about 1 to about 50 mg / day. In some embodiments, the at least one compound selected from SGLT2 inhibitors (such as dapagliflozin) and prodrugs thereof is administered at a dapagliflozin dose equivalent of about 1 to about 20 mg / day. In some embodiments, the at least one compound selected from SGLT2 inhibitors (such as dapagliflozin) and prodrugs thereof is administered at a dapagliflozin dose equivalent of about 2.5 to about 20 mg / day. In some embodiments, the at least one compound selected from SGLT2 inhibitors (such as dapagliflozin) and prodrugs thereof is administered at a dapagliflozin dose equivalent of about 2.5 to about 10 mg / day. In some embodiments, the at least one compound selected from SGLT2 inhibitors (such as dapagliflozin) and prodrugs thereof is administered at a dapagliflozin dose equivalent of about 10 mg / day. In some embodiments, the at least one compound selected from SGLT2 inhibitors (such as dapagliflozin) and prodrugs thereof is administered at a dapagliflozin dose equivalent of about 5 mg / day. In some embodiments, the at least one compound selected from SGLT2 inhibitors (such as dapagliflozin) and prodrugs thereof is administered at a dapagliflozin dose equivalent of about 2.5 mg / day.

[0167] In some embodiments, the methods disclosed herein include orally administering to a patient an SGLT2 inhibitor, such as dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof, at a dose of 2.5 mg / day, 5.0 mg / day, or 10 mg / day. In at least one embodiment, the dose of dapagliflozin is 10 mg.

[0168] The term "treating" or "treatment" or "to treat" refers to therapeutic measures that cure, slow down a diagnosed pathological disease, disorder or condition, relieve the symptoms of a diagnosed pathological disease, disorder or condition, and / or stop the progression of a diagnosed pathological disease, disorder or condition. The treatment need not result in a complete cure of the condition; the term encompasses partial suppression or alleviation of the condition being treated.

[0169] As used herein, the term "about" means within 20% of a given value or given range, such as within 10%, and further such as within 5%.

[0170] Unless the context clearly indicates otherwise, the term "or" is used herein to mean the term "and / or" and may be used interchangeably with the term "and / or".

[0171] As used herein, the term "other therapeutic agent" refers to a therapeutic agent other than the SLGT2 inhibitor or its prodrug disclosed herein.

[0172] As used herein, the term "prodrug" includes esters and carbonates that can be converted to dapagliflozin, for example, under physiological conditions or by solvolysis. Accordingly, the term prodrug includes pharmaceutically acceptable metabolic precursors of dapagliflozin. The term prodrug also includes covalently bound carriers that release dapagliflozin in vivo when such prodrugs are administered to a patient. Non-limiting examples of prodrugs include esters and carbonates formed by reacting one or more hydroxyl groups of dapagliflozin with an alkyl, alkoxy, or aryl-substituted acylating agent using methods known to those of skill in the art to produce acetate, pivalate, methyl carbonate, benzoate, and the like. Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see: (1) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Volume 42, pages 309-396, edited by K. Widder et al. (Academic Press, 1985); (2) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs," pages 113-191 by H. Bundgaard (1991); (3) H. Bundgaard, Advanced Drug Delivery Reviews 8:1-38 (1992); (4) H. Bundgaard et al., Journal of Pharmaceutical Sciences 77:285 (1988); and (5) N. Kakeya et al., Chem Pharm Bull, 32, 692 (1984).

[0173] As used herein, the term "having end-stage renal disease (ESRD)" means (i) having an eGFR persistently < 15 mL / min / 1.73 m 2 , (ii) receiving chronic dialysis treatment, or (iii) receiving a kidney transplant. ESRD may also be referred to as "end-stage kidney disease" (ESKD) and may be used interchangeably herein.

[0174] The following examples provide illustrative embodiments of the present disclosure. Those of ordinary skill in the art will recognize that various modifications and variations can be made without departing from the spirit or scope of the present disclosure. Such modifications and variations are encompassed within the scope of the present disclosure. The examples provided are in no way limiting of the present disclosure.

[0175] Example

[0176] Example 1: A study evaluating the effect of dapagliflozin on renal outcomes and cardiovascular mortality in patients with chronic kidney disease (DAPA CKD)

[0177] Study Design

[0178] This was an international, multicenter, event-driven, randomized, double-blind, parallel-group, placebo-controlled study evaluating the effect of dapagliflozin 10 mg relative to placebo, administered once daily in addition to standard care, to prevent the progression of chronic kidney disease (CKD) or cardiovascular (CV) death / renal death. The study followed the Figure 1 design shown.

[0179] Table 1 below shows the schedule of study visits and assessments.

[0180]

[0181] a Optional local laboratory assessments were used to assess eligibility for eGFR and / or albuminuria (per local routine).

[0182] b Central laboratory assessments included alkaline phosphatase (ALP), ALT, AST, bilirubin, blood urea nitrogen (BUN), creatinine (including eGFR assessment), hematocrit, hemoglobin (Hb), HbA1c, phosphate, potassium, and sodium.

[0183] c Blood and urine samples for future biomarker and / or genetic studies were optional. Biomarker samples were collected at Visits 2 and 7, genetic samples were collected at Visit 2, and PK samples were collected at Visit 7.

[0184] d SAEs were collected throughout the entire study period from the time of informed consent until and including the patient's last visit. Study endpoints, DAE, AEs leading to dose reduction and temporary interruption, and AEs for other purposes were collected throughout the entire study period from randomization until and including the patient's last visit.

[0185] eComplete the PRO questionnaire as per the protocol until the 7th visit, and then every 12 months thereafter, and at the PTDV and study completion visit (SCV).

[0186] Patient-reported outcomes (PRO): PRO is an umbrella term that refers to all outcomes and symptoms directly reported by patients. The following PROs were used in the study: KDQOL TM -36 and EQ-5D-5L (see Appendices B and C). Patients were asked to complete the EQ-5D-5L and KDQOL TM -36 as shown in Table 1 at each visit.

[0187] Kidney Disease Quality of Life-36 (KDQOL TM -36): KDQOL TM -36 is an abbreviation of KDQOL, which is a self-reported questionnaire that combines generic and disease-specific components and is used to evaluate the health-related quality of life of patients with CKD (see Appendix B).

[0188] EuroQol Five-Dimension Five-Level Questionnaire (EQ-5D-5L): EQ-5D-5L is a self-reported questionnaire used to derive a standardized measure of health status, also known as the utility score. The EQ-5D-5L utility score is widely accepted by reimbursement authorities and will be used to support health economic evaluations (see Appendix C).

[0189] Patient Population:

[0190] The study population selected for this study included a wide range of patients with impaired kidney function. The target population had CKD (defined as eGFR ≥25 and ≤75 mL / min / 1.73m 2 ) with albuminuria (defined as urinary albumin creatinine ratio [UACR] ≥200 and ≤5000 mg / g), with or without type 2 diabetes (T2D). However, patients with known polycystic kidney disease, glomerulonephritis with flares (lupus or antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis), or ongoing active kidney inflammation were excluded.

[0191] T2D patients randomized in this study continued with T2D treatment. Patients were eligible to adjust their antidiabetic treatment at the discretion of their diabetes care provider.

[0192] Combined treatment with open-label SGLT2 inhibitors (such as dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, tofogliflozin, and luseogliflozin), and fixed-dose combinations containing these drugs (i.e., combination treatment with the investigational product ("IP")) was prohibited.

[0193] The final patient enrollment date for the dapagliflozin CKD Phase 3 clinical trial is described in Figures 2 - 5 .

[0194] Patients enrolled in the study met the following criteria:

[0195] · Females or males aged ≥ 18 years at consent.

[0196] · eGFR ≥ 25 and ≤ 75 mL / min / 1.73 m 2 (CKD-EPI formula) at the first visit.

[0197] · Albuminuria increase for 3 months or longer prior to the first visit, and UACR ≥ 200 and ≤ 5000 mg / g at the first visit.

[0198] · If there were no medical contraindications, stable treatment with the maximum tolerated labeled daily dose of an ACE-I or ARB for at least 4 weeks prior to the first visit.

[0199] Patients were excluded from the study if they met any of the following exclusion criteria:

[0200] · Autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis, or ANCA-associated vasculitis.

[0201] · Cytotoxic therapy, immunosuppressive therapy, or other immunotherapy for primary or secondary kidney disease within 6 months prior to enrollment.

[0202] · History of organ transplantation.

[0203] · Treatment with an SGLT2 inhibitor within 8 weeks prior to enrollment or previous intolerance to an SGLT2 inhibitor.

[0204] · Type 1 diabetes (T1D).

[0205] · New York Heart Association (NYHA) class IV congestive heart failure at enrollment (see Appendix A).

[0206] · MI, unstable angina, or transient ischemic attack (TIA) within 12 weeks prior to enrollment.

[0207] · Coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) or valve repair / replacement within 12 weeks prior to enrollment, or any such surgery planned after randomization.

[0208] · Any disease outside the renal and CV disease areas, such as but not limited to malignancy, with a limited life expectancy of less than 2 years.

[0209] · An active malignancy requiring treatment at the first visit (except successfully treated basal cell carcinoma or treated squamous cell carcinoma).

[0210] · Liver injury (at enrollment, aspartate aminotransferase [AST] > 3 times the upper limit of normal [ULN], alanine aminotransferase [ALT] > 3 times the ULN, or total bilirubin > 2 times the ULN). Isolated elevation of bilirubin in patients with known Gilbert syndrome is not a reason for exclusion.

[0211] · Known blood-borne infectious diseases such as Ebola virus, Lassa fever virus, hepatitis A, B, C, D, or E virus, and / or type 1 or 2 / HIV.

[0212] · Women of childbearing potential who are unwilling to use medically acceptable contraceptive methods throughout the study period from the time of signing the informed consent and for 4 weeks thereafter (i.e., women who have not undergone chemical or surgical sterilization or are not postmenopausal), or women with a positive pregnancy test at enrollment or randomization, or women who are breastfeeding.

[0213] · Involved in the planning and / or conduct of the study.

[0214] · Previously randomized in this study.

[0215] · Participated in a clinical study of another investigational product within the last month before enrollment.

[0216] · In the opinion of the investigator, the patient is unable to understand and / or comply with the investigational product, procedures, and / or follow-up, or any condition that in the opinion of the investigator may cause the patient to be unable to complete the study. Patients who are unable to complete the patient-reported outcome (PRO) assessment may still participate in the study.

[0217] Primary Outcome Measures and Rationale:

[0218] The primary outcome measure of this study is to determine whether dapagliflozin is superior to placebo in reducing the incidence of the primary composite endpoint of a sustained decline in eGFR ≥ 50%, reaching ESRD, CV death, or renal death when added to the current background therapy in patients with eGFR ≥ 25 and ≤ 75 mL / min / 1.73m 2 and albuminuria (UACR ≥ 200 and ≤ 5000 mg / g).

[0219] Endpoints related to eGFR decline: The eGFR baseline is defined as the mean central laboratory value at the first and second visits.

[0220] The primary outcome measure was based on the requirements outlined in the draft guidelines of the European Medicines Agency (EMA), which stated that the composite endpoint of a sustained decline in eGFR of ≥50%, end-stage renal disease (ESRD), and renal death (death due to ESRD without dialysis) was an acceptable outcome measure (EMA 2016). This endpoint was also used in several previous outcome studies.

[0221] Due to the high CV mortality rate in the study population and the risk of CV death being associated with the risk of developing ESRD, CV mortality was added as a component of the composite endpoint.

[0222] For the purpose of the efficacy analysis, death was subdivided into CV major cause and non-CV major cause, as well as renal major cause (death due to ESRD without dialysis).

[0223] Secondary Outcome Measures and Rationale:

[0224] The secondary outcome measures included (1) determining whether dapagliflozin could lead to a reduced incidence of the composite endpoint of worsening renal function (compared with placebo); (2) determining whether dapagliflozin could lead to a reduced incidence of the composite endpoint of CV death or hospitalization due to heart failure (compared with placebo); and (3) determining whether dapagliflozin could lead to a reduced incidence of all-cause death (i.e., death due to any / all causes) (compared with placebo).

[0225] Heart failure was evaluated as a secondary endpoint because it is particularly common in patients with CKD. All-cause death was evaluated as a secondary endpoint to assess the effect of dapagliflozin on non-CV (including infections (e.g., sepsis) and malignancies), as well as CV, mortality, and overall mortality.

[0226] Further outcomes included determining whether dapagliflozin could lead to a reduced incidence of the composite endpoint of chronic

[0227] dialysis, kidney transplantation, or renal death (compared with placebo).

[0228] Treatment Duration:

[0229] The study was event-driven and lasted for 40 months. Due to overwhelming efficacy, the study was terminated early (60% of the planned events).

[0230] Investigational Product (IP), Dose, and Administration Regimen:

[0231] Patients were randomized 1:1 to receive either dapagliflozin 10 mg or placebo. If clinically indicated, the 5 mg dose of dapagliflozin could also be used in the study in addition to the 10 mg dose. However, if the researchers considered the patient's condition stable, then if the dose had been reduced to 5 mg, it should be increased back to dapagliflozin 10 mg or the matching placebo as soon as possible.

[0232] Statistical Methods:

[0233] The primary objective of this study was to determine the superiority of dapagliflozin over placebo in reducing the incidence of the primary composite endpoint (i.e., compared to patients receiving at least one standard CKD care agent alone).

[0234] All patients randomized to study treatment were included in the full analysis set (FAS), regardless of their protocol compliance and whether they continued to participate in the study. The primary variable was the time to the first event included in the primary composite endpoint. The primary analysis used the FAS based on the intention-to-treat (ITT) principle. In the analysis of the primary composite endpoint, the Cox proportional hazards model was used to compare dapagliflozin with placebo, with factors for the treatment groups stratified according to the random stratification factors (T2D, UACR) and adjusted for eGFR.

[0235] A interim analysis was conducted when 75% of the pre-specified number of primary endpoints was confirmed using the Haybittle-Peto rule. The interim analysis evaluated the superiority of dapagliflozin compared to placebo.

[0236] A closed testing procedure was used, which included a pre-specified hierarchical order for the primary and secondary endpoints. No multiplicity adjustment was set for the exploratory endpoints.

[0237] Safety Assessment

[0238] Definition of serious adverse event (SAE): SAE was defined as an AE that occurred at any study phase (i.e., lead-in, treatment, screening, and follow-up) meeting one or more of the following criteria:

[0239] · Resulted in death

[0240] · Immediately life-threatening

[0241] · Required hospitalization or prolongation of hospitalization

[0242] · Resulted in persistent or significant disability / incapacity or severe disruption of the ability to perform normal life functions

[0243] · Was a congenital anomaly or birth defect

[0244] · is an important medical event that may endanger the patient or may require medical intervention to prevent one of the above outcomes

[0245] Study Results

[0246] The final results of the primary endpoint measure are shown in Figures 6 - 10 and Figure 13 . The primary objective was met, with treatment with dapagliflozin resulting in a clinically meaningful and statistically significant reduction in the composite of sustained eGFR decline ≥50%, ESRD, and renal or CV death. All components contributed to the observed treatment effect. The treatment benefit was consistent across all patient subgroups, including: diabetes status, UACR, and eGFR( Figure 8 ). The treatment benefit was consistent across all patient subgroups, including: age, sex, race, and geographic region( Figure 9 ).

[0247] The final results of the secondary endpoints are shown in Figures 10 - 13 . A significant treatment effect on the kidney-only secondary endpoint (composite of sustained eGFR decline ≥50%, ESRD, and renal death) confirmed a positive renal treatment effect( Figure 10 ). The secondary endpoint of the composite of CV death and hospitalization for HF was statistically significantly reduced, as shown in Figures 11 - 12 . Both components contributed to the treatment effect. Dapagliflozin was superior to placebo in reducing all-cause death( Figures 13 - 14 ).

[0248] A sustained eGFR decline ≥50%, ESRD, CV, or renal death (primary endpoint) occurred in 197 patients (9.2%) in the dapagliflozin group and 312 patients (14.5%) in the placebo group (hazard ratio, 0.61; 95% confidence interval [CI], 0.51 to 0.72; P<0.0001( Figure 6 ). Other specific data points for each endpoint in the primary and secondary endpoints are described in Figures 6 - 13 .

[0249] The composite endpoint of chronic dialysis, kidney transplantation, or renal death was statistically significantly reduced, as shown in Figure 15 .

[0250] The primary and secondary endpoints were also stratified by the underlying cause of kidney disease (diabetic nephropathy, ischemic / hypertensive nephropathy, glomerulonephritis, and unknown etiology)( Figures 17 - 20 ) or by patients with underlying cardiovascular disease( Figure 22 ). Exploratory results that were further pre-specified and will also be analyzed post hoc were stratified by patients with underlying cardiovascular disease( Figure 23 ). The primary endpoint was also evaluated in patients with underlying IgA nephropathy( Figure 21) and secondary endpoints ( Figure 24 ).

[0251] Safety results are presented in Table 2 below (AE = adverse event). There were fewer deaths, SAEs (serious adverse events), and DAE (discontinuation due to adverse event) in the dapagliflozin group. Adverse events leading to dose interruption were balanced between treatment groups. AEs leading to dose reduction were rare but more common in the dapagliflozin group. Overall, fewer patients reported SAEs in the dapagliflozin group. The number of patients experiencing SAEs generally remained balanced between treatment groups across SOCs.

[0252] Table 2 Safety Results

[0253]

[0254]

[0255] * Lists AEs of fractures and amputations during patient treatment and during treatment discontinuation. Lists all other safety variables during treatment

[0256] The overall safety profiles of patients with T2DM and those without diabetes were generally consistent (Table 3 below). Diabetic ketoacidosis or severe hypoglycemia was not reported in patients without diabetes. Overall, patients with T2DM reported more AEs than patients without diabetes in all categories regardless of treatment.

[0257] Table 3 Safety Results in Patients with T2DM and without T2DM

[0258]

[0259]

[0260] * Lists AEs or SAEs with death, fracture, and amputation outcomes during patient treatment and during treatment discontinuation. Lists all other safety variables during treatment

[0261] Incidence of T2D in Prediabetic Patients

[0262] A subgroup of 1,398 patients enrolled in the DAPA-CKD trial with CKD and prediabetes (HbA1c ≥ 5.7% and < 6.5% at baseline) and no prior history of diabetes was randomized to dapagliflozin 10 mg once daily or placebo. The onset of newly diagnosed T2D (confirmed HbA1c ≥ 6.5%) was determined by regular HbA1c testing and the comparison between treatment groups was evaluated by Cox proportional hazards model.

[0263] After a median follow-up of 2.4 years, the incidence of T2D in the placebo group was 33 / 701 (4.7%), and in the dapagliflozin group was 21 / 697 (3.0%). The corresponding event rates were 2.4 / 100-patient-years and 1.5 / 100-patient-years, respectively. Dapagliflozin led to a 38% reduction in the incidence of T2D (hazard ratio [HR] [95% CI] 0.62 [0.36, 1.08]). According to most key pre-specified subgroups, including age, glycemic status, blood pressure, estimated glomerular filtration rate, albuminuria, race, and region, the effect of dapagliflozin on T2D prevention was not heterogeneous, but the effect was more pronounced in women (p for interaction 0.03). More than 90% of the participants who developed T2D had prediabetes (HbA1c ≥ 5.7%-6.4%) at baseline.

[0264] In the DAPA-HF trial (heart failure with reduced ejection fraction), among 2,605 non-T2D patients (about 55% of the total patients) enrolled at baseline, 157 developed T2D during the trial, and 150 (95.5%) of them had prediabetes (HbA1c ≥ 5.7%-6.4%) (the result using the more restrictive 6.0%-6.4% criterion was 136 [86.6%]). Compared with patients who still did not have diabetes, patients who developed T2D had a higher mean baseline A1c (6.2 ± 0.3 vs. 5.7 ± 0.4%; p < 0.001), a greater BMI (28.5 ± 5.9 vs. 27.1 ± 5.7 kg / m 2 ; p = 0.003), and a lower eGFR (61.5 ± 17.4 vs. 68.2 ± 19.3 ml / min / 1.73m 2 ; p < 0.001). Dapa reduced new-onset diabetes by 32%: placebo 93 / 1,307 (7.1%) vs. dapa 64 / 1,298 (4.9%); HR 0.68 (95% CI, 0.50 - 0.94; p = 0.019) (Cox.) ( Figure 25 )

[0265] A meta-analysis of DAPA-CKD and DAPA-HF showed that dapagliflozin reduced new-onset diabetes (HR 0.67 [0.51 - 0.87]; p = 0.003), and there was no heterogeneity between studies (p for interaction 0.78).

[0266] Appendix A

[0267] New York Heart Association (NYHA) functional classification

[0268] NYHA functional class

[0269]

[0270] Appendix B

[0271] Patient-reported outcome (PRO) questionnaire: Kidney Disease Quality of Life-36 (KDQOL TM -36)

[0272]

[0273]

[0274]

[0275]

[0276]

[0277] Appendix C

[0278] Patient-reported outcome (PRO) questionnaire: Euroqol Five-Dimension Five-Level Questionnaire (EQ-5D-5L

[0279]

[0280] Embodiments of the present invention include the following.

[0281] 1. A method for treating chronic kidney disease (CKD) and / or at least one disease, disorder or condition associated therewith in a patient, the method comprising administering to a patient in need thereof an effective amount of a sodium-glucose co-transporter 2 (SGLT2) inhibitor.

[0282] 2. The method according to aspect 1, wherein the patient has an eGFR ≥ 25 and ≤ 75 mL / min / 1.73 m 2 .

[0283] 3. The method according to aspect 1 or 2, wherein the patient has type 2 diabetes.

[0284] 4. The method according to aspect 1 or 2, wherein the patient does not have type 2 diabetes.

[0285] 5. The method according to any one of aspects 1 to 4, wherein the method treats CKD.

[0286] 6. The method according to any one of aspects 1 to 5, wherein the SGLT2 inhibitor is selected from dapagliflozin, canagliflozin, empagliflozin, sotagliflozin, ipragliflozin, ertugliflozin, tofogliflozin, and luseogliflozin, or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug of any of the foregoing.

[0287] 7. The method according to any one of Technical Solutions 1 to 6, wherein the SGLT2 inhibitor is dapagliflozin, which has the following structure

[0288]

[0289] 8. The method according to Technical Solution 7, wherein the dapagliflozin is in the form of a pharmaceutically acceptable solvate, mixed solvate or complex.

[0290] 9. The method according to Technical Solution 7 or 8, wherein the dapagliflozin is in the form of an amorphous solid.

[0291] 10. The method according to Technical Solution 7 or 8, wherein the dapagliflozin is in the form of a crystalline solid.

[0292] 11. The method according to any one of Technical Solutions 7 to 10, wherein the dapagliflozin is in the form of an (S)-propylene glycol ((S)-PG) solvate, which has the following structure

[0293]

[0294] 12. The method according to any one of Technical Solutions 7 to 11, wherein the dapagliflozin is in a form suitable for oral administration.

[0295] 13. The method according to Technical Solution 12, wherein the dapagliflozin is in the form of a tablet.

[0296] 14. The method according to any one of Technical Solutions 7 to 13, wherein the dapagliflozin is administered at a dose of about 2.5 mg / day, 5 mg / day or 10 mg / day.

[0297] 15. The method according to any one of Technical Solutions 7 to 14, wherein the dapagliflozin is administered at a dose of about 10 mg / day.

[0298] 16. The method according to any one of Technical Solutions 7 to 15, wherein the dapagliflozin is administered once a day.

[0299] 17. The method according to any one of Technical Solutions 7 to 16, wherein the dapagliflozin is administered in combination with at least one other therapeutic agent.

[0300] 18. The method according to Technical Solution 17, wherein the at least one other therapeutic agent is selected from antidiabetic agents, anti-obesity agents, anti-hyperlipidemia agents, anti-atherosclerosis agents, anti-hypertensive agents, antiplatelet agents, antithrombotic agents, mineralocorticoid antagonists, diuretics, and anticoagulant agents.

[0301] 19. The method according to aspect 17, wherein the at least one other therapeutic agent is an angiotensin-converting enzyme inhibitor (ACE inhibitor).

[0302] 20. The method according to aspect 19, wherein the ACE inhibitor is selected from captopril, enalapril, and lisinopril.

[0303] 21. The method according to aspect 17, wherein the at least one other therapeutic agent is an angiotensin receptor blocker (ARB).

[0304] 22. The method according to aspect 21, wherein the ARB is selected from valsartan, losartan, and irbesartan.

[0305] 23. The method according to any one of aspects 17 to 22, wherein the at least one other therapeutic agent is administered before, after, or simultaneously with dapagliflozin.

[0306] 24. The method according to any one of aspects 1 to 23, wherein the patient meets at least one of the following conditions:

[0307] (a) The patient does not have autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis, or ANCA-associated vasculitis;

[0308] (b) The patient has not received cytotoxic therapy, immunosuppressive therapy, or other immunotherapy for primary or secondary kidney disease within 6 months prior to treatment;

[0309] (c) The patient has no history of organ transplantation;

[0310] (d) The patient does not have intolerance to SGLT2 inhibitors;

[0311] (e) The patient does not have type 1 diabetes (T1D);

[0312] (f) The patient does not have New York Heart Association (NYHA) class IV congestive heart failure at the time of treatment;

[0313] (g) The patient does not have myocardial infarction (MI), unstable angina, stroke, or transient ischemic attack (TIA) within 12 weeks prior to treatment;

[0314] (h) The patient has not undergone coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) or valve repair / replacement within 12 weeks prior to treatment and does not plan to undergo any such surgery;

[0315] (i) The patient has no conditions outside the areas of kidney and cardiovascular (CV) diseases, and has a limited life expectancy of less than 2 years;

[0316] (j) The patient has no active malignancies requiring treatment during the treatment;

[0317] (k) During the treatment, the patient has no liver damage (aspartate aminotransferase [AST] > 3 times the upper limit of normal [ULN], alanine aminotransferase [ALT] > 3 times the ULN, or total bilirubin > 2 times the ULN);

[0318] (l) The patient does not have a blood-borne infectious disease selected from Ebola virus, Lassa fever virus, hepatitis A, B, C, D or E virus, and HIV type 1 or 2; and / or

[0319] (m) The patient is not (1) a woman of childbearing potential who has not undergone chemical or surgical sterilization or is unwilling to use a medically acceptable contraceptive method, (2) has a positive pregnancy test, or (3) is breastfeeding.

[0320] 25. The method according to claim 24, wherein the patient meets each of the conditions (a) to (o) according to claim 23.

[0321] 26. The method according to any one of claims 1 to 25, wherein the patient has CKD with albuminuria.

[0322] 27. The method according to claim 26, wherein the patient has a urinary albumin creatinine ratio [UACR] ≥ 200 and ≤ 5000 mg / g.

[0323] 28. The method according to any one of claims 1 to 27, wherein the method reduces the incidence of the composite endpoint of a sustained decline in eGFR ≥ 50%, reaching end-stage renal disease (ESRD), CV death, or renal death in patients with CKD.

[0324] 29. The method according to claim 28, wherein when the method is added to the current background therapy of a patient with CKD with albuminuria, the method reduces the incidence of the primary composite endpoint of a sustained decline in eGFR ≥ 50%, reaching ESRD, CV death or renal death.

[0325] 30. The method according to any one of claims 1 to 29, wherein the method reduces the intraglomerular pressure, hypertension, proteinuria and / or the amount of body fluid / sodium overload in the patient.

[0326] 31. The method according to any one of technical solutions 1 to 30, wherein the method reduces the systolic blood pressure (BP) of the patient compared to the baseline.

[0327] 32. The method according to any one of technical solutions 1 to 31, wherein compared to a placebo, the method further reduces the systolic BP of the patient compared to the baseline.

[0328] 33. The method according to technical solution 31 or 32, wherein the systolic BP of the patient is measured on the 30 (±7)th day, the 120 (±7)th day, the 240 (±7)th day, the 360 (±7)th day, the 480 (±14)th day, and / or the 600 (±14)th day.

[0329] 34. The method according to any one of technical solutions 1 to 33, wherein the method reduces the weight of the patient compared to the baseline.

[0330] 35. The method according to any one of technical solutions 1 to 34, wherein compared to a placebo, the method further reduces the weight of the patient compared to the baseline.

[0331] 36. The method according to technical solution 34 or 35, wherein the weight of the patient is measured on the 30 (±7)th day, the 120 (±7)th day, the 240 (±7)th day, the 360 (±7)th day, the 480 (±14)th day, and / or the 600 (±14)th day.

[0332] 37. The method according to any one of technical solutions 1 to 36, wherein the method reduces the albuminuria level of the patient compared to the baseline.

[0333] 38. The method according to any one of technical solutions 1 to 37, wherein compared to a placebo, the method further reduces the albuminuria level of the patient compared to the baseline.

[0334] 39. The method according to technical solution 37 or 38, wherein the albuminuria level of the patient is measured on the 30 (±7)th day, the 120 (±7)th day, the 240 (±7)th day, the 360 (±7)th day, the 480 (±14)th day, and / or the 600 (±14)th day.

[0335] 40. The method according to any one of technical solutions 1 to 39, wherein the method does not reduce the eGFR of the patient compared to the baseline.

[0336] 41. The method according to any one of technical solutions 1 to 40, wherein compared to a placebo, the method reduces the eGFR of the patient to a lesser extent compared to the baseline.

[0337] 42. The method according to claim 40 or 41, wherein the eGFR of the patient is measured at day 30 (±7), day 120 (±7), day 240 (±7), day 360 (±7), day 480 (±14), and / or day 600 (±14).

[0338] 43. The method according to any one of claims 1 to 42, wherein the HbA1c of the patient is in the range of about 6.0% to about 6.9%.

[0339] 44. The method according to claim 43, wherein the HbA1c of the patient is in the range of about 5.7% to about 6.5%.

[0340] 45. The method according to any one of claims 1 to 44, wherein the method reduces the time to first CV death in the patient compared to placebo.

[0341] 46. The method according to claim 45, wherein the time to first CV death is measured at day 30 (±7), day 120 (±7), day 240 (±7), day 360 (±7), day 480 (±14), and / or day 600 (±14).

[0342] 47. The method according to any one of claims 1 to 44, wherein the method reduces the time to first renal death in the patient compared to placebo.

[0343] 48. The method according to claim 47, wherein the time to first renal death is measured at day 30 (±7), day 120 (±7), day 240 (±7), day 360 (±7), day 480 (±14), and / or day 600 (±14).

[0344] 49. The method according to any one of claims 1 to 48, wherein the method reduces the time to first hospitalization for heart failure in the patient compared to placebo.

[0345] 50. The method according to claim 49, wherein the time to first hospitalization for heart failure is measured at day 30 (±7), day 120 (±7), day 240 (±7), day 360 (±7), day 480 (±14), and / or day 600 (±14).

[0346] 51. The method according to any one of claims 1 to 50, wherein the method reduces the total number of hospitalizations for heart failure and / or CV deaths in the patient compared to placebo.

[0347] 52. The method according to any one of technical solutions 1 to 51, wherein compared with a placebo, the method maintains or improves the NYHA class of the patient compared to the baseline.

[0348] 53. The method according to technical solution 52, wherein the NYHA class of the patient is measured at day 30 (±7), day 120 (±7), day 240 (±7), day 360 (±7), day 480 (±14), and / or day 600 (±14).

[0349] 54. The method according to any one of technical solutions 1 to 53, wherein compared with a placebo, the method improves the health status of the patient as evaluated by the EQ-5D-5L questionnaire.

[0350] 55. The method according to technical solution 54, wherein the health status of the patient as evaluated by the EQ-5D-5L questionnaire is measured at day 30 (±7), day 120 (±7), day 240 (±7), day 360 (±7), day 480 (±14), and / or day 600 (±14).

[0351] 56. The method according to any one of technical solutions 1 to 53, wherein compared with a placebo, the method improves the health status of the patient as evaluated by the KDQOL 36 questionnaire.

[0352] 57. The method according to technical solution 56, wherein the health status of the patient as evaluated by the KDQOL 36 questionnaire is measured at day 30 (±7), day 120 (±7), day 240 (±7), day 360 (±7), day 480 (±14), and / or day 600 (±14).

[0353] 58. The method according to any one of technical solutions 1 to 57, wherein the method further comprises administering the SGLT2 inhibitor in addition to standard care therapy.

[0354] 59. The method according to technical solution 58, wherein the standard care therapy includes treatment for controlling comorbidities and / or treatment for reducing the composite of CV death and heart failure events.

Claims

1. Use of dapagliflozin in the preparation of a pharmaceutical composition for the treatment of chronic kidney disease, the pharmaceutical composition being used for preventing or delaying the progression of chronic kidney disease in patients with chronic kidney disease; wherein the patients do not have type II diabetes, and wherein the pharmaceutical composition is in tablet form.

2. Use of dapagliflozin in the preparation of a pharmaceutical composition for the treatment of chronic kidney disease, the pharmaceutical composition being used for reducing the risks of persistent decline in estimated glomerular filtration rate, end-stage kidney disease, cardiovascular death, and renal death in patients with chronic kidney disease; wherein the patients do not have type II diabetes, and wherein the pharmaceutical composition is in tablet form.

3. Use of dapagliflozin in the preparation of a pharmaceutical composition for the treatment of chronic kidney disease, the pharmaceutical composition being used for reducing the risks of persistent decline in estimated glomerular filtration rate, end-stage kidney disease, cardiovascular death, renal death, hospitalization due to heart failure, and all-cause death in patients with chronic kidney disease; the potential causes of the kidney disease are diabetic nephropathy, ischemic / hypertensive nephropathy, glomerulonephritis, and unknown etiology; wherein the patients do not have type II diabetes, and the pharmaceutical composition reduces the albuminuria level of the patients; the pharmaceutical composition can reduce new-onset diabetes; the pharmaceutical composition reduces the incidence of type II diabetes in patients with chronic kidney disease and prediabetes and without a previous history of diabetes; the pharmaceutical composition reduces the number of events of doubling of serum creatinine in patients with chronic kidney disease; wherein the pharmaceutical composition is in tablet form.

4. The use according to claim 2 or 3, wherein the persistent decline in estimated glomerular filtration rate is ≥ 50%.

5. The use according to claim 2 or 3, wherein end-stage kidney disease includes a persistent glomerular filtration rate of < 15 mL / min / 1.73 m 2 , initiation of chronic dialysis treatment, and / or renal transplantation.

6. The use according to any one of claims 1-3, wherein the glomerular filtration rate of the patients is ≥ 25 and ≤ 75 mL / min / 1.73 m 2 .

7. The use according to any one of claims 1-3, wherein the urinary albumin creatinine ratio of the patients is ≥ 200 and ≤ 5000 mg / g.

8. The use according to any one of claims 1-3, wherein at least one standard chronic kidney disease care agent is also administered to the patients.

9. Use according to claim 8, wherein the at least one standard care agent is selected from angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

10. Use according to claim 9, wherein the angiotensin-converting enzyme inhibitor is selected from captopril, enalapril, and lisinopril.

11. Use according to claim 9, wherein the angiotensin receptor blocker is selected from valsartan, losartan, and irbesartan.

12. Use of dapagliflozin in the preparation of a pharmaceutical composition for the treatment of chronic kidney disease, the pharmaceutical composition being used for reducing the risk of persistent decline in estimated glomerular filtration rate, end-stage kidney disease, cardiovascular death, and renal death in patients with chronic kidney disease; wherein the patient does not have type II diabetes; wherein at least one standard chronic kidney disease care agent is also administered to the patient; and wherein the risk of persistent decline in estimated glomerular filtration rate, end-stage kidney disease, cardiovascular death, and renal death is reduced as compared to the administration regimen of the patient receiving at least one standard chronic kidney disease care agent alone; wherein the pharmaceutical composition is in tablet form.

13. Use according to claim 12, wherein the composition meets the requirement that, as compared to the administration regimen of the patient receiving at least one standard chronic kidney disease care agent alone, the hazard ratio of the time to the first composite endpoint of persistent decline in glomerular filtration rate ≥ 50%, end-stage kidney disease, cardiovascular death, or renal death in the patient is less than 1.

14. Use according to claim 12, wherein the composition meets the requirement that, as compared to the administration regimen of the patient receiving at least one standard chronic kidney disease care agent alone, the hazard ratio of the time to the first composite endpoint of persistent decline in glomerular filtration rate ≥ 50%, end-stage kidney disease, cardiovascular death, or renal death in the patient is statistically nominally less than 1.

15. Use according to claim 12, wherein the composition meets the requirement that, as compared to the administration regimen of the patient receiving at least one standard chronic kidney disease care agent alone, the hazard ratio of the time to the first composite endpoint of persistent decline in glomerular filtration rate ≥ 50%, end-stage kidney disease, cardiovascular death, or renal death in the patient is 0.

61.

16. Use according to claim 12, wherein the composition meets the requirement that, as compared to the administration regimen of the patient receiving at least one standard chronic kidney disease care agent alone, the 95% confidence interval of the hazard ratio of the time to the first composite endpoint of persistent decline in glomerular filtration rate ≥ 50%, end-stage kidney disease, cardiovascular death, or renal death in the patient is 0.51 to 0.

72.

17. Use according to claim 12, wherein the composition meets the administration regimen of at least one standard chronic kidney disease care agent relative to the patient receiving it alone, and the composition numerically reduces the absolute risk of the composite endpoint of a sustained decline in glomerular filtration rate of ≥50%, end-stage kidney disease, cardiovascular death, or renal death in the patient.

18. Use according to claim 12, wherein the composition meets the administration regimen of at least one standard chronic kidney disease care agent relative to the patient receiving it alone, and the composition results in a nominally significant reduction in the risk of the composite endpoint of a sustained decline in glomerular filtration rate of ≥50%, end-stage kidney disease, cardiovascular death, or renal death in the patient.

19. Use according to claim 12, wherein the composition meets the administration regimen of at least one standard chronic kidney disease care agent relative to the patient receiving it alone, and the composition results in a numerical reduction in the composite endpoint events of a sustained decline in glomerular filtration rate of ≥50%, end-stage kidney disease, cardiovascular death, or renal death in the patient.

20. Use of dapagliflozin in the preparation of a pharmaceutical composition for treating chronic kidney disease, the pharmaceutical composition being used for preventing or delaying the incidence or onset of type II diabetes in pre-diabetic patients, wherein the pharmaceutical composition is in tablet form, and the pre-diabetic patients are those with glycated hemoglobin ≥5.7% and <6.5%.

21. Use according to claim 20, wherein the patient has pre-diabetes with chronic kidney disease and / or heart failure.

22. Use of dapagliflozin in the preparation of a pharmaceutical composition for treating chronic kidney disease, the pharmaceutical composition further comprising AZD9977, the pharmaceutical composition being used for treating chronic kidney disease in a patient suffering from chronic kidney disease, wherein the pharmaceutical composition is in tablet form.

23. Use according to claim 22, wherein the chronic kidney disease includes a sustained decline in estimated glomerular filtration rate, end-stage kidney disease, cardiovascular death, and / or renal death.

24. Use according to claim 22 or claim 23, wherein the patient also has heart failure.

25. Use according to claim 24, wherein the ejection fraction of the patient <55%.

26. Use according to claim 22, wherein the dosage of AZD9977 is 15 - 150 mg per day.

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