阅读说明：本技术 用于治疗患有慢性肾病的糖尿病患者的卡格列净 (Canagliflozin for treating diabetic patients suffering from chronic kidney disease ) 是由 N·R·罗森塔尔 于 2020-03-25 设计创作，主要内容包括：本公开提供了用于治疗慢性肾病的方法,该方法包括向有需要的患者施用治疗有效量的卡格列净；其中患者被诊断出II型糖尿病。(The present disclosure provides a method for treating chronic kidney disease, the method comprising administering to a patient in need thereof a therapeutically effective amount of canagliflozin; wherein the patient is diagnosed with type II diabetes.)

1. A method of treating a diabetic patient suffering from chronic kidney disease, comprising:

(a) determining whether the patient has chronic kidney disease; and

(b) administering to the patient a therapeutically effective amount of canagliflozin to treat the chronic kidney disease.

2. The method of claim 1, wherein the patient is a human.

3. The method of claim 1 or 2, wherein the diabetes is type II diabetes.

4. The method of any one of the preceding claims, wherein the chronic kidney disease is determined by a blood test, a urine test, kidney imaging, or a kidney biopsy.

5. The method of any one of the preceding claims, wherein the chronic kidney disease is determined by estimating glomerular filtration rate.

6. The method of any one of the preceding claims, wherein the patient has a measured HbA in the range of ≥ 7.0% and ≤ 10.5 ≤_1c。

7. The method of any one of the preceding claims, wherein the chronic kidney disease is stage 2 and/or stage 3 chronic kidney disease.

8. The method according to any one of the preceding claims, wherein the patient has ≧ 30mL/min/1.73m²To<90mL/min/1.73m²Estimated glomerular filtration rate (eGFR).

9. The method of claim 4, wherein the patient has ≧ 30mL/min/1.73m²To<45mL/min/1.73m²The eGFR of (1).

10. The method of claim 4, wherein the patient has ≧ 45mL/min/1.73m²To<60mL/min/1.73m²The eGFR of (1).

11. The method of claim 4, wherein the patient has ≧ 60mL/min/1.73m²To<90mL/min/1.73m²The eGFR of (1).

12. The method of any one of the preceding claims, wherein the patient has substantial albuminuria.

13. The method of any one of the preceding claims, wherein the method prevents serum creatinine doubling, end stage renal disease (ESKD), renal death, or any combination thereof.

14. The method of any one of the preceding claims, wherein the method prevents cardiovascular death, hospitalized heart failure, non-fatal myocardial infarction, non-fatal stroke, or any combination thereof.

15. The method of any preceding claim, further comprising an accompanying standard of care.

16. The method of claim 15, wherein the standard of care comprises administration of an angiotensin converting enzyme inhibitor and/or an angiotensin receptor blocker.

17. The method of any one of the preceding claims, wherein the risk of serum creatinine doubling, ESKD, renal death, or cardiovascular death is reduced by at least about 25% relative to a patient receiving the same level of disease progression under a standard of care including administration of an angiotensin converting enzyme inhibitor and/or an angiotensin receptor blocker, but not including treatment with canagliflozin.

18. The method of any one of the preceding claims, wherein the risk of cardiovascular death or hospitalized heart failure is reduced by at least about 25% relative to a patient receiving the same level of disease progression for a standard of care including administration of an angiotensin converting enzyme inhibitor and/or an angiotensin receptor blocker but not treatment with canagliflozin.

19. The method of any one of the preceding claims, wherein the risk of non-fatal MI or non-fatal stroke is reduced by at least about 20% relative to a patient receiving the same level of disease progression at a standard of care that includes administration of an angiotensin converting enzyme inhibitor and/or an angiotensin receptor blocker, but does not include treatment with canagliflozin.

20. The method of any one of the preceding claims, wherein the risk of hospitalized heart failure is reduced by at least about 35% relative to a patient receiving the same level of disease progression for a standard of care including administration of an angiotensin converting enzyme inhibitor and/or an angiotensin receptor blocker, but not including treatment with canagliflozin.

21. The method of any one of the preceding claims, wherein the therapeutically effective amount of canagliflozin is about 50mg to about 500 mg.

22. The method of claim 21, wherein the therapeutically effective amount of canagliflozin is about 100mg to about 300 mg.

23. The method of claim 22, wherein the therapeutically effective amount of canagliflozin is about 100 mg.

24. A method for treating chronic kidney disease, comprising administering a therapeutically effective amount of canagliflozin to a patient in need thereof, wherein the patient is diagnosed with type II diabetes.

25. The method of claim 24, wherein the patient has a measured HbA in the range of ≥ 7.0% and ≤ 10.5 ≤_1c。

26. The method of claim 24 or 25, wherein the chronic kidney disease is stage 2 and/or stage 3 chronic kidney disease.

27. The method of claim 24 or 26, wherein the patient has ≧ 30mL/min/1.73m²To<90mL/min/1.73m²Estimated glomerular filtration rate (eGFR).

28. The method of claim 27, wherein the patient has ≧ 30ml/min/1.73m²To<45ml/min/1.73m²The eGFR of (1).

29. The method of claim 27, wherein the patient has ≧ 45mL/min/1.73m²To<60mL/min/1.73m²The eGFR of (1).

30. The method of claim 27, wherein the patient has ≧ 60mL/min/1.73m²To<90mL/min/1.73m²The eGFR of (1).

31. The method of any one of claims 24 to 30, wherein the patient is further diagnosed with substantial albuminuria.

32. A method according to one of claims 24-30, wherein the occurrence of one or more renal events is reduced or prevented.

33. The method of claim 32, wherein the one or more renal events comprise serum creatinine doubling, end stage renal disease (ESKD), renal death, or any combination thereof.

34. The method of any one of claims 24 to 33, wherein the occurrence of one or more cardiovascular events is reduced or prevented.

35. The method of claim 34, wherein the one or more cardiovascular events comprise cardiovascular death, hospitalized heart failure, non-fatal myocardial infarction, non-fatal stroke, or any combination thereof.

36. The method of claim 35, wherein the one or more cardiovascular events comprise cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke.

37. The method according to any one of claims 24 to 36, further comprising concomitant standards of care comprising administration of an angiotensin converting enzyme inhibitor and/or an angiotensin receptor blocker.

38. The method of any one of claims 32-37, wherein the occurrence of the one or more renal and/or cardiovascular events is reduced or prevented relative to a standard of care comprising administration of an angiotensin converting enzyme inhibitor and/or an angiotensin receptor blocker, but not treatment with canagliflozin.

39. The method of any one of claims 34 to 38, wherein the therapeutically effective amount of canagliflozin is about 50mg to about 500 mg.

40. The method of claim 39, wherein the therapeutically effective amount of canagliflozin is about 100mg to about 300 mg.

41. The method of claim 39, wherein the therapeutically effective amount of canagliflozin is about 100 mg.

42. A method of marketing a pharmaceutical product comprising canagliflozin, the method comprising marketing the pharmaceutical product, wherein a pharmaceutical product label of a reference marketed drug for the pharmaceutical product includes instructions for treating chronic kidney disease.

43. A method of offering for sale a pharmaceutical product comprising canagliflozin, the method comprising offering for sale such pharmaceutical product, wherein a pharmaceutical product label of a reference marketed drug for such pharmaceutical product includes instructions for treating chronic kidney disease.

44. The method of claim 42 or 43, wherein the drug product is an ANDA drug product, a complementary New drug application drug product, or a 505(b) (2) drug product.

45. The method of any one of claims 42 to 44, wherein the label provides instructions for use in patients with type II diabetes or with substantial albuminuria.

46. The method of any one of claims 42-45, wherein the drug product label comprises data that reduces one or more adverse renal events or cardiovascular events relative to standard of care.

47. The method of claim 46, wherein the standard of care comprises administration of an angiotensin converting enzyme inhibitor and/or an angiotensin receptor blocker, but does not include treatment by administration of canagliflozin.

48. The method of claim 46 or 47, wherein the one or more renal events comprise serum creatinine doubling, end stage renal disease (ESKD), renal death, or any combination thereof.

49. The method of claim 46 or 47, wherein the one or more cardiovascular events comprise cardiovascular death, hospitalized heart failure, non-fatal myocardial infarction, non-fatal stroke, or any combination thereof.

50. Canagliflozin for use in a method according to any one of claims 1 to 49.

51. Canagliflozin and an angiotensin converting enzyme inhibitor and/or an angiotensin receptor blocker for use in the method according to any one of claims 16 to 23 or 37 to 41.

52. Canagliflozin and angiotensin converting enzyme inhibitor and/or angiotensin receptor blocker according to claim 51 for use in a method according to this claim, wherein the canagliflozin and angiotensin converting enzyme inhibitor and/or angiotensin receptor blocker are administered simultaneously, separately or sequentially.

53. A pharmaceutical product comprising canagliflozin for use in a method according to any one of claims 42 to 49.

Technical Field

The present invention relates to methods for treating a subject having chronic kidney disease.

Background

Despite the current standard of care, subjects with type 2diabetes and Chronic Kidney Disease (CKD) are at high risk of developing end-stage renal disease (ESKD) and cardiovascular events and have a shortened life expectancy. Once patients with diabetic nephropathy develop end-stage renal disease, these individuals have a shortened life expectancy, with a 5-year survival rate of 36% in the united states for patients receiving dialysis treatment and an even lower percentage in developing countries. Older and longer duration and high numbers of comorbidities are typical features of a population of patients who have been identified with CKD, which population has a far-from-unmet medical need.

The kidney is a bean-shaped organ located near the center of the back. Within each kidney are about one million tiny structures called nephrons, which filter blood. These nephrons clear waste and excess water, turning it into urine. Damage to the nephron is an important form of renal disease. The injury may render the kidneys incapable of clearing waste. Some injuries, such as those associated with hyperfiltration, are generally initially asymptomatic, but can occur slowly over a period of years.

At the single nephron level, hyperfiltration is presumed to be an early link in the chain of events that leads to albuminuria from intraglomerular hypertension and subsequently to reduced Glomerular Filtration Rate (GFR). On this basis, hyperfiltration therefore represents the risk of subsequent renal injury and can be classified as an early manifestation of renal pathological phenomena, commonly referred to as the hyperfiltration stage. This hyperfiltration can cause early glomerulopathy and microalbuminuria, which in turn can cause massive albuminuria and end-stage renal disease.

Creatinine is a decomposition product of phosphocreatine in muscle tissue and is usually produced at a constant rate in the body. Serum creatinine is an important indicator of kidney health, as it is a readily detectable byproduct of muscle metabolism and is secreted constantly by the kidney. The process of creatinine clearance from the blood is primarily responsible for the kidneys, which perform this process primarily by way of glomerular filtration, as well as proximal tubular secretion. Resorption of creatinine by the renal tubules generally occurs rarely or not. Blood creatinine levels will rise if there is insufficient filtration in the kidney. Thus, creatinine levels in blood and urine can be used to calculate creatinine clearance (CrCl), a value that correlates to Glomerular Filtration Rate (GFR). Blood creatinine levels alone can also be used to estimate gfr (egfr).

Albuminuria is a condition in which albumin is present in the urine. The kidneys of healthy individuals filter albumin. When the kidneys fail to properly filter large molecules (such as albumin) from the urine, albumin is secreted into the urine and is often a sign of kidney damage or excessive salt intake. Albuminuria can also occur in patients with long-term diabetes (type I (1) or type II (2) diabetes). Urinary albumin can be measured by a dipstick, or directly as the amount of protein secreted in the total urine volume collected over a 24 hour period.

Diabetic nephropathy is one of the microvascular complications of diabetes and is characterized by the persistent presence of albuminuria and a gradual decline in renal function. Hyperglycemia is an important factor in the progression and onset of diabetic nephropathy.

The clinical progression of diabetic nephropathy in patients with T1DM (type 1 diabetes) is well understood. Initially, hyperfiltration can be observed with increased Glomerular Filtration Rate (GFR) and increased renal plasma flow. Meta-analysis found that patients with T1DM had more than doubled the risk of developing microalbuminuria or macroalbuminuria if they had an hyperfiltration disorder. After this period there is a decrease in GFR and microalbuminuria (defined as urinary albumin secretion ≥ 30 mg/day (or 20 μ g/min) and <300mg/24 h (or <200 μ g/min)), which can be accompanied by an increase in blood pressure. Later in the disease progression, as GFR continues to decline, significant proteinuria (i.e., profuse albuminuria) ensues (defined as urinary albumin secretion >300 mg/day), and this is associated with hypertension exacerbations. Finally, ESKD (end stage renal disease) progression advances, requiring renal replacement therapy.

For patients with type 2diabetes (T2DM), clinical progression is variable, primarily due to multiple renal injuries, which include not only hyperglycemia, but also vascular pathology, leading to ischemic renal injury. However, other common features may contribute to renal injury in patients with T2DM, and include single nephron level of hyperfiltration, proximal tubular glucose toxicity, and stimulation of tubular cell growth due to enhanced co-transport of sodium glucose into the tubular cells.

The degree of albuminuria is positively correlated with the occurrence of ESKD and prognosis of cardiovascular distress. When an agent that acts by a hemodynamic mechanism (i.e., ACEi and ARB) is administered to a patient with T2DM and albuminuria, the patient's phenomenon of treatment-sparing of albuminuria correlates with a decrease in the progression of diabetic nephropathy and the incidence of poor cardiovascular prognosis. Thus, agents that act through unique hemodynamic mechanisms to reduce albuminuria beyond that observed with other antihypertensive or antihyperglycemic agents and that have additive effects on agents that disrupt the renin-angiotensin system may exert nephroprotective effects and possibly reduce cardiovascular adverse prognosis in diabetic nephropathy.

Despite the current standard of care, subjects with type II diabetes and chronic kidney disease are at high risk of developing ESKD and cardiovascular events and have a shortened life expectancy. What is needed is a method of treating patients in more advanced stages of chronic kidney disease.

Disclosure of Invention

In some aspects, the disclosure relates to treating a patient suffering from type II diabetes and Chronic Kidney Disease (CKD). In a particular embodiment, the patient has stage 2-3 kidney disease. In other embodiments, the patient also has substantial albuminuria. The method comprises administering a therapeutically effective amount of canagliflozin. In other embodiments, the method further comprises a concomitant standard of care comprising administration of an angiotensin converting enzyme inhibitor and/or an angiotensin receptor blocker. The methods described herein have also proven to be clinically safe and/or clinically effective.

In other aspects, the disclosure relates to a method of treating a diabetic patient suffering from chronic kidney disease, the method comprising (a) determining whether the patient has chronic kidney disease; and (b) administering canagliflozin to the patient in a therapeutically effective amount to treat chronic kidney disease.

In a further aspect, the present disclosure relates to a method of marketing a pharmaceutical product comprising canagliflozin, the method comprising marketing the pharmaceutical product, wherein the pharmaceutical product label of a reference marketed drug for the pharmaceutical product includes instructions for treating chronic kidney disease.

In other aspects, the disclosure relates to a pharmaceutical product comprising a clinically proven safe and clinically proven effective amount of canagliflozin.

Drawings

FIG. 1 is a Kaplan-Meier plot of the first appearance of the primary composite endpoint of example 1.

FIG. 2 is a graph showing that the thickness of the eGFR layer for screening is 30mL/min/1.73m or more²To<45mL/min/1.73m²HbA of (3)_1cA line graph of the change in LS mean over time relative to baseline.

FIG. 3 shows the results of screening for eGFR layers of 45mL/min/1.73m or more²To<60mL/min/1.73m²HbA of (3)_1cA line graph of the change in LS mean over time relative to baseline.

FIG. 4 shows the results of screening for eGFR layers of ≥ 60mL/min/1.73m²To<90mL/min/1.73m²HbA of (3)_1cA line graph of the change in LS mean over time relative to baseline.

Detailed Description

In this disclosure, the singular forms "a," "an," "the," and "the" include the plural reference unless the context clearly dictates otherwise, and reference to a particular numerical value includes at least that particular value. Thus, for example, reference to "a material" is a reference to at least one of such materials, equivalents of such materials known to those skilled in the art, and so forth.

When values are expressed as approximations, by use of the antecedent "about" or "substantially," it will be understood that the particular value forms another embodiment. In general, use of the terms "about" or "substantially" refer to approximations that may vary depending on the desired properties sought to be obtained by the disclosed subject matter and will be explained based upon their function in the particular context in which the approximation is used. Those skilled in the art will be able to routinely interpret these approximations. In some cases, the number of significant digits for a particular value may be one non-limiting method of determining the range of the word "about" or "substantially". In other cases, the gradient used in a series of values may be used to determine an expected range for each value that may be used for the term "about" or "substantially". Where present, all ranges are inclusive and combinable. That is, reference to a value stated in a range includes each value in the range.

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

It is to be understood that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, each individual embodiment is considered combinable with any other embodiment unless clearly incompatible or excluded, and such combination is considered another embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination. It should also be noted that the claims may be formulated to exclude any optional elements. As such, this statement is intended to serve as antecedent basis when such specific term is used in conjunction with the recitation of claim elements "individually," "uniquely," or "restrictively," or when a "negative" limitation is employed. Finally, while embodiments may be described as part of a series of steps or part of a more general structure, each such step may itself be considered a separate embodiment.

Method

The present disclosure provides a method for treating Chronic Kidney Disease (CKD) comprising administering to a patient in need thereof a therapeutically effective amount of canagliflozin. In some aspects, the patient is diabetic. In a further aspect, the patient is a diabetic patient suffering from chronic kidney disease. In other aspects, the patient is diagnosed with type II diabetes. In other aspects, the patient is further diagnosed with a substantial amount of albuminuria.

The methods described herein reflect the effectiveness of canagliflozin in treating a particular patient subpopulation, i.e., patients with type II diabetes (T2DM) and Chronic Kidney Disease (CKD). Since ACE inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs) were the standard of care for preventing the progression of diabetic nephropathy more than 15 years ago, the methods disclosed herein (by any mechanism) produce beneficial effects on the renal outcome of these patients. The methods described herein reduce the risk of certain primary endpoints by about 25% relative to current standards of care including ACEi or ARB therapy. The inventors have also found that significant duration of efficacy and/or co-morbidity is reduced and that the efficacy provided by canagliflozin is maintained even after 1 year of treatment. The duration of efficacy is consistent across all subgroups of patients tested, thus providing a durable treatment option for patients suffering from the affliction. Notably, the discovery of the beneficial effects of the primary endpoint is not solely a matter of laboratory (i.e., blood)Creatinine doubling) and passes the "hard endpoint" of ESKD (by determining sustained eGFR)<15mL/min/1.73m²Chronic dialysis or kidney transplant).

As used herein, the term "diabetes" includes types 1 and 2. In some embodiments, diabetes is type 1 diabetes. In other embodiments, diabetes is type 2 diabetes. Those skilled in the art understand type 1 and type 2 diabetes. In patients with type 1 diabetes, the patient's immune system attacks and destroys the insulin-producing beta cells in the pancreas. Therefore, type 1 diabetic patients do not produce insulin. In patients with type 2diabetes, the body of the patient cannot use insulin effectively. Therefore, type 2 diabetic patients do not respond to insulin produced in the body.

The terms "type 2 diabetes" and "type II diabetes" are interchangeable and are defined as the following conditions: wherein the patient has a fasting (i.e., no caloric intake for about 8 hours) blood glucose or serum glucose concentration of greater than about 125mg/dL (about 6.94mmol/L), as measured on a minimum of two separate occasions. Type 2diabetes is also defined as the following conditions: wherein the patient has HbA equal to or greater than about 6.5%_1cTwo hour plasma glucose equal to or greater than about 200mg/dL (about 11.1mmol/L) during the Oral Glucose Tolerance Test (OGTT), or a random glucose concentration equal to or greater than about 200mg/dL (about 11.1mmol/L) with classic symptoms of hyperglycemia or hyperglycemic crisis. In the absence of definite hyperglycemia symptoms, as with most diagnostic tests, the test results for diagnosing diabetes should be repeated to rule out laboratory errors.

HbA can be performed using a method certified by the U.S. national glycated hemoglobin standardization program and standardized or traceable by a diabetes control and complication study reference assay_1cAnd (4) evaluating. If OGTT is performed, the blood glucose level of diabetes will exceed about 200mg glucose/dL plasma (about 11.1mmol/L) about 2 hours after about 75g glucose is taken in the fasting state. In the glucose tolerance test, the test is administered after a minimum of about 8 hours of fasting, typically after about 10 to about 12 hours of fastingThe patient(s) was administered about 75g of glucose orally and blood glucose levels were recorded about 1 hour and about 2 hours immediately before and after the glucose administration. For a healthy patient, the blood glucose level will be between about 60mg/dL and about 110mg/dL plasma prior to glucose administration, less than about 200mg/dL at about 1 hour after glucose administration, and less than about 140mg/dL at about 2 hours after glucose administration. If after about 2 hours, the value is between about 140mg and about 200mg, this is considered to be the presence of an abnormality in glucose tolerance.

In some aspects, a patient diagnosed with type II diabetes has measured HbA as defined herein_1c. The term "HbA_1c'OR' haemoglobin A_1c"refers to the product of non-enzymatic saccharification of the B chain of hemoglobin, and its determination is well known to those skilled in the art. HbA during monitoring of diabetes treatment_1cThe value is very important. Due to HbA_1cThe production of HbA is mainly dependent on blood glucose level and red blood cell life, thus the "blood glucose memory" meaning_1cReflecting the previous average blood glucose levels of about 4 to about 6 weeks. In certain embodiments, a patient treated according to the methods described herein has a measured HbA in the range of about 7% to about 10.5%, such as in the range of ≧ 7.0% and ≦ 10.5 ≦_1c. In other embodiments, the patient has a measured HbA of about 7%, about 7.1%, about 7.2%, about 7.3%, about 7.4%, about 7.5%, about 7.6%, about 7.7%, about 7.8%, about 7.9%, about 8%, about 8.1%, about 8.2%, about 8.3%, about 8.4%, about 8.5%, about 8.6%, about 8.7%, about 8.8%, about 8.9%, about 9%, about 9.1%, about 9.2%, about 9.3%, about 9.4%, about 9.5%, about 9.6%, about 9.7%, about 9.8%, about 9.9%, about 10%, about 10.1%, about 10.2%, about 10.3%, about 10.4%, or about 10.5%_1c. In other embodiments, the patient has a measured HbA of about 7% to about 10%, about 7% to about 9.5%, about 7% to about 9%, about 7% to about 8.5%, about% to about 8%, about 7.5% to about 10.5%, about 8% to about 10.5%, about 8.5% to about 10.5%, about 9% to about 10.5%, or about 9.5 to about 10.5%_1c。

As disclosed herein, the patient treated suffers from chronic kidney disease. In some embodiments, the patient has stage 2 chronic kidney disease. In other embodiments, the patient has stage 3 chronic kidney disease. In another embodiment, the patient has stage 2-3 chronic kidney disease.

The methods described herein can include determining that a patient has chronic kidney disease. Typically, this determination is made by the attending physician. Diagnosis or determination of chronic kidney disease can be determined using techniques known to those skilled in the art. In some embodiments, chronic kidney disease is determined by one or more of a blood test, a urine test, a kidney imaging, or a kidney biopsy. Preferably, chronic kidney disease is diagnosed by blood testing. More preferably, the blood test measures the estimated glomerular filtration rate.

In some aspects, a patient with chronic kidney disease has about 30mL/min/1.73m²To less than about 90mL/min/1.73m²E.g. >30 mL/min/1.73m²To<90mL/min/1.73m²The eGFR of (1). In some embodiments, the patient has about 30mL/min/1.73m²About 31mL/min/1.73m²About 32mL/min/1.73m²About 33mL/min/1.73m²About 34mL/min/1.73m²About 35mL/min/1.73m²About 36mL/min/1.73m²About 37mL/min/1.73m²About 38mL/min/1.73m²About 39mL/min/1.73m²About 40mL/min/1.73m²About 41mL/min/1.73m²About 42mL/min/1.73m²About 43mL/min/1.73m²About 44mL/min/1.73m²About 45mL/min/1.73m²About 46mL/min/1.73m²About 47mL/min/1.73m²About 48mL/min/1.73m²About 49mL/min/1.73m²About 50mL/min/1.73m²About 51mL/min/1.73m²About 52mL/min/1.73m²About 53mL/min/1.73m²About 54mL/min/1.73m²About 55mL/min/1.73m²About 56mL/min/1.73m²About 57mL/min/1.73m²About 58mL/min/1.73m²About 59mL/min/1.73m²About 60mL/min/1.73m²About 61mL/min/1.73m²About 62mL/min/1.73m²About 63mL/min/1.73m²About 64mL/min/1.73m²About 65mL/min/1.73m²About 66mL/min/1.73m²About 67mL/min/1.73m²About 68mL/min/1.73m²About 69mL/min/1.73m²About 70mL/min/1.73m²About 71mL/min/1.73m²About 72mL/min/1.73m²About 73mL/min/1.73m²About 74mL/min/1.73m²About 75mL/min/1.73m²About 76mL/min/1.73m²About 77mL/min/1.73m²About 78mL/min/1.73m²About 79mL/min/1.73m²About 80mL/min/1.73m²About 81mL/min/1.73m²About 82mL/min/1.73m²About 83mL/min/1.73m²About 84mL/min/1.73m²About 85mL/min/1.73m²About 86mL/min/1.73m²About 87mL/min/1.73m²About 88mL/min/1.73m²Or about 89mL/min/1.73m²The eGFR of (1). In a further embodiment, the patient has about 30mL/min/1.73m²To about 89mL/min/1.73m²About 30mL/min/1.73m²To about 85mL/min/1.73m²About 30mL/min/1.73m²To about 80mL/min/1.73m²About 30mL/min/1.73m²To about 75mL/min/1.73m²About 30mL/min/1.73m²To about 70mL/min/1.73m²About 30mL/min/1.73m²To about 65mL/min/1.73m²About 30mL/min/1.73m²To about 65mL/min/1.73m²About 30mL/min/1.73m²To about 60mL/min/1.73m²About 30mL/min/1.73m²To about 55mL/min/1.73m²About 30mL/min/1.73m²To about 50mL/min/1.73m²About 35mL/min/1.73m²To about 89mL/min/1.73m²About 30mL/min/1.73m²To about 85mL/min/1.73m²About 35mL/min/1.73m²To about 80mL/min/1.73m²About 35mL/min/1.73m²To about 75mL/min/1.73m²About 35mL/min/1.73m²To about 70mL/min/1.73m²About 35mL/min/1.73m²To about 65mL/min/1.73m²About 35mL/min/1.73m²To about 60mL/min/1.73m²About 35mL/min/1.73m²To about55mL/min/1.73m²About 35mL/min/1.73m²To about 50mL/min/1.73m²About 40mL/min/1.73m²To about 89mL/min/1.73m²About 40mL/min/1.73m²To about 85mL/min/1.73m²About 40mL/min/1.73m²To about 80mL/min/1.73m²About 40mL/min/1.73m²To about 75mL/min/1.73m²About 40mL/min/1.73m²To about 70mL/min/1.73m²About 40mL/min/1.73m²To about 65mL/min/1.73m²About 40mL/min/1.73m²To about 60mL/min/1.73m²About 40mL/min/1.73m²To about 55mL/min/1.73m²About 40mL/min/1.73m²To about 50mL/min/1.73m²About 40mL/min/1.73m²To about 45mL/min/1.73m²About 50mL/min/1.73m²To about 89mL/min/1.73m²About 50mL/min/1.73m²To about 85mL/min/1.73m²About 50mL/min/1.73m²To about 80mL/min/1.73m²About 50mL/min/1.73m²To about 75mL/min/1.73m²About 50mL/min/1.73m²To about 70mL/min/1.73m²About 50mL/min/1.73m²To about 65mL/min/1.73m²About 50mL/min/1.73m²To about 60mL/min/1.73m²About 50mL/min/1.73m²To about 55mL/min/1.73m²About 55mL/min/1.73m²To about 89mL/min/1.73m²About 55mL/min/1.73m²To about 85mL/min/1.73m²About 55mL/min/1.73m²To about 80mL/min/1.73m²About 55mL/min/1.73m²To about 75mL/min/1.73m²About 55mL/min/1.73m²To about 70mL/min/1.73m²About 55mL/min/1.73m²To about 65mL/min/1.73m²About 55mL/min/1.73m²To about 60mL/min/1.73m²About 60mL/min/1.73m²To about 89mL/min/1.73m²About 60mL/min/1.73m²To about 85mL/min/1.73m²About 60mL/min/1.73m²To about 80mL/min/1.73m²About 60mL/min/1.73m²To about 75mL/min/1.73m²About 60mL/min/1.73m²To about 70mL/min/1.73m²About 60mL/min/1.73m²To about65mL/min/1.73m²About 65mL/min/1.73m²To about 89mL/min/1.73m²About 65mL/min/1.73m²To about 85mL/min/1.73m²About 65mL/min/1.73m²To about 80mL/min/1.73m²About 65mL/min/1.73m²To about 75mL/min/1.73m²About 65mL/min/1.73m²To about 70mL/min/1.73m²About 70mL/min/1.73m²To about 89mL/min/1.73m²About 70mL/min/1.73m²To about 85mL/min/1.73m²About 70mL/min/1.73m²To about 80mL/min/1.73m²About 70mL/min/1.73m²To about 75mL/min/1.73m²About 75mL/min/1.73m²To about 89mL/min/1.73m²About 75mL/min/1.73m²To about 85mL/min/1.73m²About 75mL/min/1.73m²To about 80mL/min/1.73m²About 80mL/min/1.73m²To about 89mL/min/1.73m²Or about 85mL/min/1.73m²To about 89mL/min/1.73m²The eGFR of (1). In other aspects, the patient has about 30mL/min/1.73m²To about 45mL/min/1.73m²E.g. >30 mL/min/1.73m²To<45mL/min/1.73m²The eGFR of (1). In a further embodiment, the patient has about 30mL/min/1.73m²To about 40mL/min/1.73m²About 30mL/min/1.73m²To about 35mL/min/1.73m²About 35mL/min/1.73m²To about 45mL/min/1.73m²About 35mL/min/1.73m²To about 40mL/min/1.73m²Or about 40mL/min/1.73m²To about 45mL/min/1.73m²The eGFR of (1). In a further aspect, the patient has about 45mL/min/1.73m²To about 59mL/min/1.73m²E.g. > 45mL/min/1.73m²To<60mL/min/1.73m²The eGFR of (1). In certain embodiments, the eGFR is about 45mL/min/1.73m²To about 59mL/min/1.73m²About 45mL/min/1.73m²To about 55mL/min/1.73m²About 45mL/min/1.73m²To about 50mL/min/1.73m²About 50mL/min/1.73m²To about 59mL/min/1.73m²Or about 50mL/min/1.73m²To about 55mL/min/1.73m². In other aspects, the patient has an overall length of60mL/min/1.73m²To about 89mL/min/1.73m²E.g. > 60mL/min/1.73m²To<90mL/min/1.73m²The eGFR of (1). In further embodiments, the eGFR has a concentration of about 60mL/min/1.73m²To about 85mL/min/1.73m²About 60mL/min/1.73m²To about 80mL/min/1.73m²About 60mL/min/1.73m²To about 75mL/min/1.73m²About 60mL/min/1.73m²To about 70mL/min/1.73m²About 65mL/min/1.73m²To about 89mL/min/1.73m²About 65mL/min/1.73m²To about 85mL/min/1.73m²About 65mL/min/1.73m²To about 80mL/min/1.73m²About 65mL/min/1.73m²To about 75mL/min/1.73m²About 70mL/min/1.73m²To about 89mL/min/1.73m²About 70mL/min/1.73m²To about 85mL/min/1.73m²About 70mL/min/1.73m²To about 80mL/min/1.73m²About 75mL/min/1.73m²To about 89mL/min/1.73m²Or about 75mL/min/1.73m²To about 85mL/min/1.73m²The eGFR of (1).

In other aspects, the patient has stage 2 chronic kidney disease. As used herein, "stage 2 chronic kidney disease" means having a density of about 60mL/min/1.73m²To about 89mL/min/1.73m²(such as ≧ 60mL/min/1.73m²To<90mL/min/1.73m²) A patient of eGFR. Patients with stage 2 chronic kidney disease may not have symptoms. To the extent there is evidence of renal injury in these patients, they include, but are not limited to, proteins in the urine, physical injury to one or both kidneys, or any combination thereof. In certain embodiments, a patient with stage 2 chronic kidney disease has an existing kidney injury.

In other aspects, the patient has stage 3 chronic kidney disease. As used herein, "stage 3 chronic kidney disease" means having a density of about 30mL/min/1.73m²To about 59mL/min/1.73m²(such as ≧ 30mL/min/1.73m²To<60mL/min/1.73m²) A patient of eGFR. Patients with stage 3 chronic kidney disease may not have symptoms. To the extent there are signs of renal injury in these patients, they include, but are not limited to, in urineProtein, physical injury to one or both kidneys, hand and/or foot swelling, back pain, more or less than normal urination, or any combination thereof. In certain embodiments, the stage 3 chronic kidney disease patient has moderate kidney injury. In another embodiment, stage 3 chronic kidney disease can be an eGFR of about 45mL/min/1.73m²To about 59mL/min/1.73m²Stage 3a of (1). In other embodiments, stage 3 chronic kidney disease is an eGFR of about 30mL/min/1.73m²To about 44mL/min/1.73m²Phase 3b of (1).

In a further aspect, the patient has stage 2-3 chronic kidney disease. As used herein, "stage 2-3 chronic kidney disease" means having a concentration of about 30mL/min/1.73m²To about 89mL/min/1.73m²(including ≥ 30mL/min/1.73m²To<90mL/min/1.73m²) A patient of eGFR. Patients with stage 2-3 chronic kidney disease may not have symptoms. To the extent there are signs of renal injury in these patients, they include, but are not limited to, proteins in the urine, physical damage to one or both kidneys, hand and/or foot swelling, back pain, more or less than normal urination, or any combination thereof. In certain embodiments, the stage 2-3 chronic kidney disease patient has an existing renal injury that may be moderate.

The term "Glomerular Filtration Rate (GFR)" is defined as the volume of fluid filtered from the renal (kidney) glomerular capillaries into the bowman's capsule per unit time. Which is indicative of overall renal function. Glomerular Filtration Rate (GFR) can be calculated by measuring any of the following chemicals: the chemical has a steady level in the blood that is freely filtered by the kidneys but is neither reabsorbed nor secreted by the kidneys. The filtration rate thus measured is the amount of the substance in urine that results from a calculable blood volume. GFR can be determined by injection of inulin into plasma. Since inulin is neither reabsorbed by nor secreted by the kidneys after glomerular filtration, its excretion rate is proportional to the filtration rate of water and solutes through the glomerular filter. Normal GFR values were about 90mL/min/1.73m²To about 125mL/min/1.73m²Preferably, the GFR is about 100mL/min/1.73m²To about 125mL/min/1.73m². Other principles for determining GFR involveAnd measuring⁵¹Cr-EDTA、[¹²⁵I]Iophthalate or iohexol. GFR is typically recorded in units of volume per unit time (e.g., milliliters per minute) and may use the following formula:

as used herein, "estimated glomerular filtration rate" or "eGFR" is defined as being derived when screening from serum creatinine values based on, for example, the epidemiological cooperative group formula for chronic kidney disease, the Cockcroft-Gault formula, or the renal disease dietary improvement experimental formula (all of which are known in the art). A subject with normal renal function is defined as having an eGFR of about 90mL/min or greater.

In addition to suffering from chronic kidney disease and type II diabetes, patients may also have substantial albuminuria. As used herein, the term "macroalbuminuria" refers to patients having an albumin/creatinine ratio (ACR) greater than about 300 mg/g. In some embodiments, patients with substantial albuminuria have an ACR of about 300mg/g to about 5000 mg/g. In additional embodiments, patients with substantial albuminuria have an ACR of about 300mg/g, about 400mg/g, about 500mg/g, about 750mg/g, about 1000mg/g, about 1250mg/g, about 1500mg/g, about 1750mg/g, about 2000mg/g, about 2250mg/g, about 2500mg/g, about 2750mg/g, about 3000mg/g, about 3250mg/g, about 3500mg/g, about 3750mg/g, about 4000mg/g, about 4250mg/g, about 4500mg/g, about 4750mg/g, or about 5000 mg/g. In other embodiments, patients with substantial albuminuria have an ACR of about 300mg/g to about 4000mg/g, about 300mg/g to about 3000mg/g, about 300mg/g to about 2000mg/g, about 300mg/g to about 1000mg/g, about 1000mg/g to about 5000mg/g, about 1000mg/g to about 4000mg/g, about 1000mg/g to about 3000mg/g, about 1000mg/g to about 2000mg/g, about 2000mg/g to about 5000mg/g, about 2000mg/g to about 4000mg/g, about 2000mg/g to about 3000mg/g, about 3000mg/g to about 5000mg/g, about 3000mg/g to about 4000mg/g, or about 4000mg/g to about 5000 mg/g.

The method comprises administering a therapeutically effective amount of canagliflozin. The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. In some embodiments, the therapeutically effective amount of canagliflozin is about 50mg to about 500 mg. In further embodiments, the therapeutically effective amount of canagliflozin is about 50mg, about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, or about 500 mg. In other embodiments, the therapeutically effective amount of canagliflozin is about 50mg to about 450mg, about 50mg to about 400mg, about 50mg to about 300mg, about 50mg to about 250mg, about 50mg to about 200mg, about 50mg to about 150mg, about 50mg to about 100mg, about 100mg to about 500mg, about 100mg to about 450mg, about 100mg to about 400mg, about 100mg to about 350mg, about 100mg to about 300mg, about 100mg to about 250mg, about 100mg to about 200mg, about 150mg to about 500mg, about 150mg to about 450mg, about 150mg to about 400mg, about 150mg to about 350mg, about 150mg to about 300mg, about 150mg to about 250mg, about 200mg to about 500mg, about 200mg to about 450mg, about 200mg to about 400mg, about 200mg to about 350mg, about 200mg to about 300mg, about 250mg to about 500mg, about 300mg to about 450mg, about 300mg to about 400mg, about 350mg to about 500mg, about 350mg to about 450mg, or about 400mg to about 500 mg. In further embodiments, the therapeutically effective amount is from about 100mg to about 300 mg. In a further embodiment, the therapeutically effective amount is about 100 mg.

As used herein, unless otherwise indicated, the term "canagliflozin" refers to 1, 5-anhydrous-1-C- (3- { [5- (4-fluorophenyl) thiophen-2-yl ] methyl ] } -4-methylphenyl) -glucitol of formula (I).

In other embodiments, canagliflozin refers to stereoisomers of canagliflozin, such as enantiomers and diastereomers, in pure or substantially pure form. Canagliflozin also refers to its racemic mixture.

In certain embodiments, "canagliflozin" refers to 1, 5-anhydrous-1-C- (3- { [5- (4-fluorophenyl) thiophen-2-yl ] methyl ] } -4-methylphenyl) -D-glucitol. In other embodiments, "canagliflozin" refers to a compound that is (1S) -1, 5-anhydro-1-C- (3- { [5- (4-fluorophenyl) thiophen-2-yl ] methyl ] } -4-methylphenyl) -D-glucitol of formula (II):

as used herein, "canagliflozin" also refers to canagliflozin in an amorphous form or in a crystalline form. In some embodiments, canagliflozin is in a crystalline form. In other embodiments, the canagliflozin is in an amorphous form. Crystallinity can be determined by one of skill in the art using one or more techniques such as, for example, single crystal x-ray diffraction, powder x-ray diffraction, differential scanning calorimetry, melting point, and the like.

As used herein, "canagliflozin" includes its anhydrous form or hydrate. In certain embodiments, canagliflozin is in an anhydrous form. In other embodiments, canagliflozin is a hydrate thereof. In further embodiments, the canagliflozin hydrate is a hemihydrate thereof. In other embodiments, canagliflozin is a monohydrate. Thus, in some embodiments, canagliflozin comprises a hemihydrate of the compound of formula (I). In other embodiments, canagliflozin comprises a hemihydrate of the compound of formula (II). In a further embodiment, canagliflozin refers to a crystalline hemihydrate form of the compound of formula (I). In a further embodiment, canagliflozin refers to a crystalline hemihydrate form of the compound of formula (II). In certain embodiments, canagliflozin refers to the crystalline hemihydrate form of the compound described in international patent publication WO 2008/069327, the disclosure of which is hereby incorporated by reference in its entirety. In other embodiments, canagliflozin comprises a monohydrate of the compound of formula (I). In a further embodiment, canagliflozin comprises a monohydrate of the compound of formula (II).

As used herein, "canagliflozin" also refers to a solvate thereof. Such solvates include molecules of the solvent bound to one or more positions of the canagliflozin molecule by intermolecular forces or chemical bonds.

As used herein, "canagliflozin" may also refer to its polymorph. Such polymorphs of canagliflozin include crystalline forms of the molecule, each polymorph having a change in the crystal lattice.

The term "canagliflozin" can also include pharmaceutically acceptable salts thereof, which can be readily selected by a person skilled in the art. "pharmaceutically acceptable salt" is intended to mean a salt of canagliflozin that is non-toxic, biologically tolerable or otherwise biologically suitable for administration to a subject. See, e.g., Berge, "Pharmaceutical Salts", J.pharm.Sci.,1977,66:1-19 and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, eds., Wiley-VCH and VHCA, Zurich,2002, which are incorporated herein by reference. Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for administration to a patient without undue toxicity, irritation, or allergic response. Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide (such as hydrobromide), chloride (such as hydrochloride), iodide (such as hydroiodide), acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, hydrogen sulfite, hydrogen iodide, and the like, Xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.

As understood by those skilled in the art, canagliflozin is commercially availableAnd (4) obtaining. For example, canagliflozin is available under the trade nameAnd (4) obtaining. Canagliflozin exhibits inhibitory activity on sodium-dependent glucose transporters such as, for example, SGLT 2; and may be prepared according to the methods disclosed in U.S. patent application publication 2005/0233988, which is incorporated herein by reference.

As used herein, unless otherwise indicated, the terms "treating", "treatment", and the like shall include the management and care of a patient for the purpose of combating a disease, condition, or disorder. The term "treating" also includes administering a compound or pharmaceutical composition as described herein to (a) alleviate one or more symptoms or complications of a disease, condition, or disorder; (b) preventing the onset of one or more symptoms or complications of a disease, condition, or disorder; and/or (c) eliminating one or more symptoms or complications of the disease, condition or disorder.

As used herein, unless otherwise indicated, the terms "preventing", "prevention", and the like shall include (a) reducing the frequency of one or more symptoms; (b) reducing the severity of one or more symptoms; (c) delay, slow or avoid the development of additional symptoms; and/or (d) slowing or avoiding the progression of the disorder or condition to a later or more severe form.

One skilled in the art will recognize that where the present disclosure relates to a method of prevention, a patient in need thereof shall include any patient or patient who has experienced or exhibited at least one symptom of the disorder, disease or condition to be prevented. Furthermore, a patient in need thereof may also be a patient who does not exhibit any symptoms of the disorder, disease or condition to be prevented, but who is deemed by a physician, clinician or other medical professional to be at risk of developing the disorder, disease or condition. For example, a patient may be considered at risk of developing a disorder, disease, or condition (and thus in need of prophylactic or preventative treatment) due to the patient's medical history, including, but not limited to, family history, predisposition to disease, co-morbid (co-morbid) disorder or condition, genetic testing, and the like.

The terms "subject" and "patient" are used interchangeably herein to refer to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. Preferably, the patient has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.

The methods described herein reduce or prevent the occurrence of one or more renal events in a patient. Because the patients described herein have chronic kidney disease, they are at increased risk for developing renal events.

As used herein, the term "renal event" refers to a disorder associated with or affecting renal function and/or renal hyperfiltration. Renal disorders include, but are not limited to, high urinary albumin levels, high serum creatinine, high serum albumin/creatinine ratios (ACR), renal hyperfiltration injury, diabetic nephropathy (including, but not limited to, hyperfiltration diabetic nephropathy), hyperfiltration, glomerular hyperfiltration, renal allograft hyperfiltration, compensatory hyperfiltration, hyperfiltration chronic nephropathy, hyperfiltration acute renal failure, obesity, end stage renal disease (ESKD), or renal death.

In some embodiments, the one or more renal events include serum creatinine doubling, end stage renal disease, or renal death, or any combination thereof. In other embodiments, the one or more renal events comprise serum creatinine doubling. In other embodiments, the one or more renal events comprise end stage renal disease. In additional embodiments, the one or more renal events comprise renal death.

The terms "end stage renal disease" and "stage 5 renal disease" are interchangeable and mean that the eGFR is less than about 15mL/min/1.73m²The patient of (1). Patients with end stage renal disease often have severe symptoms. Symptoms of this phase may include, but are not limited to, itching, muscle cramps, nausea, vomiting, loss of appetite, swelling (which typically occurs on the hands and feet), pain such as back pain, more or less than normal urination, dyspnea, sleep difficulties, or any combination thereof. In certain embodiments, patients with end-stage chronic kidney disease have near-failure or completeA failing kidney. In other embodiments, the patients are receiving dialysis, require kidney transplantation, or any combination thereof.

The methods described herein also reduce or prevent the occurrence of one or more cardiovascular events in a patient.

As used herein, unless otherwise specified, the term "cardiovascular event" shall include, but is not limited to, cardiovascular death, non-fatal myocardial infarction, non-fatal stroke (ischemic), peripheral arterial disease, hypertensive heart disease, ischemic heart disease, coronary artery disease, peripheral vascular disease, cerebrovascular disease, cardiac arrhythmias (other than sinus tachycardia), cardiomyopathy, angina (including, but not limited to unstable angina), heart failure (including, but not limited to, heart failure requiring hospitalization, heart failure, etc.), and coronary valve disease. In some embodiments, the cardiovascular event is cardiovascular death, hospitalized heart failure, non-fatal myocardial infarction, or non-fatal stroke, or any combination thereof. In other embodiments, the cardiovascular event is cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. In additional embodiments, the cardiovascular or disease is non-fatal myocardial infarction. In additional embodiments, the cardiovascular event is a non-fatal stroke. In other embodiments, the cardiovascular event is cardiovascular death. In other embodiments, the cardiovascular event is hospitalized heart failure.

In other embodiments, the patient may also be diagnosed as having one or more cardiovascular risk factors that may lead to a cardiovascular event. Cardiovascular risk factors may include, but are not limited to, syncope, transient ischemic events or stroke (except intracranial hemorrhage), cardiovascular surgery such as heart transplantation, implantation of cardiac devices such as cardiac stimulators (pacemakers) or defibrillators ("ICDs"), cerebrovascular or peripheral intervention, pulmonary embolism or deep vein thrombosis, acute pulmonary edema or dyspnea due to cardiac causes, stable angina or atypical chest pain, supraventricular heart rhythm disorders such as atrial fibrillation, arterial pressure changes (e.g., hypotension, hypertension, except syncope), cardiovascular infection, major/blood loss (requiring two or more blood cell masses or any intracranial hemorrhage), high cholesterol (hyperlipidemia) such as high LDL, low HDL, high triglycerides, obesity, microalbuminuria, peripheral vascular disease, underlying structural heart disease, atherosclerosis, Atrial fibrillation, tachycardia, coronary artery disease, non-rheumatic heart valve disease, dilated cardiomyopathy of ischemic origin, ablation, supraventricular tachycardia other than atrial fibrillation or fibrillation, a history of heart valve surgery, non-ischemic dilated cardiomyopathy, hypertrophic cardiomyopathy, rheumatic valve disease, persistent ventricular tachycardia, congenital heart disease, ventricular fibrillation, at least one heart device (including but not limited to a cardiac stimulator, an implantable defibrillator, etc.), a current or past smoking history, male gender, or any combination thereof. See, for example, Hohnloser et al, Journal of cardiovascular electrophysiology, 2008, Vol.19, No. 1, pages 69-73, which is incorporated herein by reference.

The method also allows for the application of concomitant standards of care. The term "standard of care" generally refers to a treatment prescribed by a physician for the disease condition in question. In some embodiments, the standard of care comprises, consists of, or consists essentially of administering an additional agent that is an angiotensin converting enzyme inhibitor, an angiotensin receptor blocker, or a combination thereof. In some embodiments, the method comprises administering an angiotensin converting enzyme inhibitor. In other embodiments, the method comprises administering an angiotensin receptor blocker. In additional embodiments, the method comprises administering an angiotensin converting enzyme inhibitor and an angiotensin receptor blocker. Typically, the standard of care does not include treatment by administration of canagliflozin. The standard of care may be administered to the patient before, after, or simultaneously with canagliflozin. In some embodiments, the standard of care is applied prior to canagliflozin. In other embodiments, the standard of care is applied after canagliflozin. In further embodiments, the standard of care is administered concurrently with canagliflozin.

As used herein, the term "angiotensin converting enzyme inhibitor", "ACE inhibitor" or "ACEi" is inclusiveInterchangeably, and refers to an agent that inhibits angiotensin converting enzyme, thereby reducing vascular tone and blood volume (i.e., dilating blood vessels) and thereby lowering blood pressure. ACE inhibitors can be divided into three groups based on their molecular structure: (a) thiol-containing agents, including but not limited to alacepril, captoprilAnd zofenopril; (b) dicarboxylic acid ester-containing reagents, including but not limited to enalaprilRamiprilQuinaprilPerindoprilLisinoprilBenazeprilImidaprilZofenoprilTrandolaprilMoxiprilCilazapril, delapril, spirapril and temocapril; and (c) phosphonate containing agents, including but not limited to fosinoprilIn some embodiments, the ACE inhibitor is benazepril, captopril, enalapril, imidapril, lisinopril, or ramipril. In other embodiments, the ACE inhibitor is enalapril, imidapril, lisinopril, or ramipril. In further embodiments, the ACE inhibitor is benazepril, captopril, enalapril, imidapril, lisinopril, ramipril, or any combination thereof. One skilled in the art will readily recognize that recommended dosages and dosing regimens for ACE inhibitors may be determined by Reference to appropriate Reference materials such as package insert for drugs, FDA guidelines, Physician's Desk Reference, and the like.

As used herein, unless otherwise indicated, the terms "ARB", "angiotensin receptor blocker" and "angiotensin II receptor antagonist" are interchangeable and refer to agents that modulate the renin-angiotensin-aldosterone system. More specifically, ARBs block activation of the angiotensin II AT1 receptor, which leads to vasodilation (vasodilation), decreased vasopressin secretion, and decreased production and secretion of aldosterone. The combined effect reduces blood pressure. Suitable examples of ARBs include, but are not limited to, losartanIrbesartan Olmesartan medoxomilCandesartan ValsartanTelmisartanAzilsartanAnd eprosartanIn some embodiments, the ARB is candesartan, irbesartan, losartan, or valsartan. In other embodiments, the ARB is irbesartan or losartan. One skilled in the art will readily recognize that the recommended dosage and dosing regimen for an ARB may be determined by reference to appropriate reference data such as pharmaceutical package insert, FDA guidelines, "physician's office reference", and the like.

In other embodiments, the occurrence of one or more renal events and/or cardiovascular events is reduced or prevented relative to a standard of care comprising administration of an angiotensin converting enzyme inhibitor and/or an angiotensin receptor blocker. For example, the method reduces the risk of incidence and/or predicted severity of one or more renal and/or cardiovascular events as described herein relative to a subject treated at standard of care but not receiving the same level of disease progression as treated by administration of canagliflozin.

In certain aspects, the methods described herein are effective to reduce the relative risk of serum creatinine doubling, ESKD, renal death, or Cardiovascular (CV) death, or any combination thereof. In some aspects, the method reduces the relative risk of serum creatinine doubling, ESKD, kidney death, or CV death. In other aspects, the method reduces the relative risk of serum creatinine doubling. In a further aspect, the method reduces the relative risk of ESKD. In other aspects, the method reduces the relative risk of renal death. In a further aspect, the method reduces the relative risk of CV death.

For example, the methods described herein are effective to reduce the risk of serum creatinine doubling, ESKD, kidney death, or CV death, or any combination thereof, by about or at least about 10%, 12%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% relative to patients receiving the same level of disease progression who are standard of care (such as the maximum tolerated marker daily dose of ACEi and/or ARB) but are not receiving canagliflozin treatment. In certain aspects, the reduction is at least about 25%. In other aspects, the reduction is at least about 30%. Generally, the risk of serum creatinine doubling, ESKD, renal death or CV death, or any combination thereof, is reduced relative to patients receiving the same level of disease progression for standard of care (such as the maximum tolerated marker daily dose of ACEi and/or ARB) but not receiving canagliflozin treatment, the reduction ranges from about 10% to about 70%, from about 10% to about 60%, from about 10% to about 50%, from about 10% to about 40%, from about 10% to about 30%, from about 10% to about 20%, from about 20% to about 70%, from about 20% to about 60%, from about 20% to about 50%, from about 20% to about 40%, from about 20% to about 30%, from about 30% to about 70%, from about 30% to about 60%, from about 30% to about 50%, from about 30% to about 40%, from about 40% to about 70%, from about 40% to about 60%, from about 40% to about 50%, from about 50% to about 70%, from about 50% to about 60%, or from about 60% to about 70%.

In other embodiments, the method is effective to reduce the risk of serum creatinine doubling, ESKD or renal death, or any combination thereof, by about or at least about 10%, 12%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% relative to patients receiving the same level of disease progression who are standard of care (such as the maximum tolerance marker daily dose of ACEi and/or ARB) but are not receiving canagliflozin treatment. In certain aspects, the reduction is at least about 25%. In other aspects, the reduction is at least about 30%. Generally, the risk of doubling of serum creatinine, ESKD or renal death or any combination thereof is reduced relative to patients receiving the same level of disease progression for standard of care (such as the maximum tolerated marker daily dose of ACEi and/or ARB) but not receiving canagliflozin treatment, the reduction ranges from about 10% to about 70%, from about 10% to about 60%, from about 10% to about 50%, from about 10% to about 40%, from about 10% to about 30%, from about 10% to about 20%, from about 20% to about 70%, from about 20% to about 60%, from about 20% to about 50%, from about 20% to about 40%, from about 20% to about 30%, from about 30% to about 70%, from about 30% to about 60%, from about 30% to about 50%, from about 30% to about 40%, from about 40% to about 70%, from about 40% to about 60%, from about 40% to about 50%, from about 50% to about 70%, from about 50% to about 60%, or from about 60% to about 70%.

In other embodiments, the methods described herein are effective to reduce the risk of CV death, hospitalized heart failure, or a combination thereof by about or at least about 10%, 12%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% relative to patients receiving the same level of disease progression who received standard of care (such as the maximum tolerance marker daily dose of ACEi and/or ARB) but did not receive canagliflozin treatment. In certain aspects, the reduction is at least about 25%. In other aspects, the reduction is at least about 30%. Generally, the risk of CV death, hospitalized heart failure, or a combination thereof is reduced by a range of about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 20% to about 30%, about 30% to about 70%, about 30% to about 50%, about 30% to about 60%, about 30% to about 50%, about 40% to about 70%, about 40% to about 60%, about 40% to about 50%, about 50% to about 70%, about 50% to about 60%, or about 60% to about 70% relative to a patient of the same level of disease progression who receives standard of care (such as the maximum tolerated marker daily dose of ACEi and/or ARB) but does not receive canagliflozin treatment.

In other embodiments, the methods described herein are effective to reduce the risk of non-fatal MI, non-fatal stroke, or a combination thereof by about or at least about 10%, 12%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% relative to patients receiving the same level of disease progression for standard of care (such as the maximum tolerance marker daily dose of ACEi and/or ARB) but not receiving canagliflozin treatment. In certain aspects, the reduction is at least about 20%. Generally, the risk of a non-fatal MI, non-fatal stroke, or combination thereof is reduced by a range of about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 20% to about 30%, about 30% to about 70%, about 30% to about 50%, about 40% to about 70%, about 40% to about 60%, about 40% to about 50%, about 50% to about 70%, about 50% to about 60%, or about 60% to about 70% relative to a patient receiving the same level of disease progression who receives standard of care (such as the maximum tolerated labeled daily dose of ACEi and/or ARB) but does not receive canagliflozin treatment.

In other embodiments, the methods described herein are effective to reduce the risk of hospitalized heart failure by about or at least about 10%, 12%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% relative to patients receiving the same level of disease progression who received standard of care (such as the maximum tolerated marker daily dose of ACEi and/or ARB) but did not receive canagliflozin treatment. In certain aspects, the reduction is at least about 35%. Generally, the risk of hospitalized heart failure is reduced by a range of about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 20% to about 30%, about 30% to about 70%, about 30% to about 60%, about 30% to about 40%, about 40% to about 60%, about 40% to about 50%, about 50% to about 70%, about 50% to about 60%, or about 60% to about 70% relative to a patient receiving the same level of disease progression under standard of care (such as the maximum tolerated marker daily dose of ACEi and/or ARB) but not treated with canagliflozin.

In additional embodiments, the methods described herein are effective to prevent serum creatinine doubling, end stage renal disease (ESKD), renal death, or any combination thereof. In some aspects, the method is effective to prevent doubling of serum creatinine. In a further aspect, the method is effective to prevent ESKD. In other aspects, the method is effective to prevent renal death.

In the methods described herein, a therapeutically effective amount of canagliflozin is safe, effective, or safe and effective. As used herein, unless otherwise specified, the term "safe" shall mean free of undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit to risk ratio when used in the manner of this invention. Similarly, unless otherwise specified, the term "effective" means that the therapeutic efficacy of a treatment for a patient suffering from chronic kidney disease has been demonstrated when administered at a therapeutically effective dose. In certain embodiments, the methods described herein are safe. In other embodiments, the methods described herein are effective. In further embodiments, the methods described herein are safe and effective. In other embodiments, a therapeutically effective amount of canagliflozin is safe. In additional embodiments, a therapeutically effective amount of canagliflozin is effective. In other embodiments, a therapeutically effective amount of canagliflozin is safe and effective.

As used herein, unless otherwise indicated, the term "clinical proof" (independently using or modifying the terms "safe" and/or "effective") shall mean that evidence has been demonstrated by a phase III clinical trial sufficient to meet the approval criteria of the U.S. food and drug administration or similar studies by EMEA for market authorization. Preferably, a randomized, double-blind control study of sufficient size is used to clinically demonstrate the effect of canagliflozin compared to placebo and the condition of the patient is assessed by the techniques described herein.

As used herein, unless otherwise indicated, the term "clinically proven effective" means that the efficacy of the treatment has been proven by phase III clinical trials to be statistically significant, i.e., the results of the clinical trials are unlikely to be due to chance, where alpha levels are below 0.05, or the clinical efficacy results are sufficient to meet the approval criteria of the U.S. food and drug administration or similar studies by EMEA for market authorization. For example, for treatment of patients with chronic kidney disease, canagliflozin is clinically proven effective by slowing the progression of chronic kidney disease when administered at therapeutically effective doses, as described herein and specifically in the examples.

As used herein, unless otherwise indicated, the term "clinically proven safe" means that the safety of a treatment has been demonstrated by a phase III clinical trial, i.e., the treatment is determined by analysis of trial data and results to be free of undue adverse side effects and to be commensurate with a statistically significant clinical benefit (e.g., efficacy) sufficient to meet the approval criteria of the U.S. food and drug administration or similar studies in europe, the middle east, and africa (EMEA) for market authorization. For example, for the treatment of patients with chronic kidney disease, canagliflozin is clinically proven safe when administered at a therapeutically effective dose, as described herein and as specifically described in the examples.

In certain aspects, methods of marketing a pharmaceutical product comprising canagliflozin are also provided. As used herein, the term "sale" refers to the transfer of a pharmaceutical product, such as a pharmaceutical composition or dosage form, from a seller to a buyer. Accordingly, the method comprises selling a pharmaceutical product comprising canagliflozin, wherein the method comprises selling the pharmaceutical product. In some embodiments, the drug product label of the reference marketed drug of the drug product includes instructions for treating chronic kidney disease. The method further comprises offering for sale a pharmaceutical product comprising canagliflozin. As used herein, the term "offering for sale" refers to an offer by a seller to sell a pharmaceutical product, e.g., a pharmaceutical composition or dosage form, to a buyer. These methods include offering for sale of pharmaceutical products.

The term "pharmaceutical product" is a product containing an active pharmaceutical ingredient that has been approved for sale by a governmental agency (e.g., the U.S. food and drug administration or similar agency in another country/region). In some embodiments, the pharmaceutical product comprises canagliflozin.

Similarly, a "label" or "drug product label" refers to information provided to a patient that provides relevant information about a drug product. Such information includes, but is not limited to, one or more of the following: drug description, clinical pharmacology, indications (use of the drug product), contraindications (group not to take the drug product), warnings, precautions, adverse events (side effects), drug abuse and dependence, dosing and administration, pregnancy use, lactation use, use by children and elderly patients, drug supply means, patient safety information, or any combination thereof. In certain embodiments, the label or drug product label provides instructions for use in patients with type II diabetes or with substantial albuminuria. In other embodiments, the pharmaceutical product label includes data that reduces one or more adverse renal or cardiovascular events relative to standard of care. In further embodiments, the label or drug product label identifies canagliflozin as a regulatory approved chemical entity. In other embodiments, the label provides instructions for use in a patient suffering from chronic kidney disease. In further embodiments, the label provides a definition of chronic kidney disease and instructs the patient or physician to administer canagliflozin in the event that the patient suffers from chronic kidney disease.

As used herein, the term "reference marketed drug" or "RLD" refers to a drug product to which a new, mimetic version will be compared to show that they are bioequivalent. It is also a pharmaceutical product: marketing approval of the european union member states or the european union committee has been obtained based on the complete portfolio, i.e., the quality data, preclinical data and clinical data were submitted according to clause 8(3), 10a, 10b or 10c of directive 2001/83/EC, and marketing approval applications for counterfeit/mixed pharmaceutical products were involved by demonstrating bioequivalence, typically by submitting appropriate bioavailability studies.

In the united states, companies seeking approval to sell counterfeit equivalents must refer to RLD in their own simplified new drug application (ANDA). For example, the applicant of the ANDA relies on the FDA's discovery that a previously approved drug product, RLD, is safe and effective, and must demonstrate, among other things, that the proposed counterfeit drug product is identical to RLD in some respects. In particular, with limited exceptions, the pharmaceutical products to which the ANDA is submitted must have, among other things, the same active ingredient, conditions of use, route of administration, dosage form, strength and label (with some allowable differences) as the RLD. RLD is a drug on the market that the applicant has to show himself the proposed pharmaceutical product of ANDA is identical to it in other properties, such as active ingredient, dosage form, route of administration, strength, label and conditions of use. In the electronic orange book, there are a column for RLD and a column for a reference standard. In the printed version of the orange book, the RLD and the reference standard are identified by specific symbols.

In europe, the applicant identified reference pharmaceutical products (product name, strength, pharmaceutical form, listed licensee (MAH), first authorization, member countries/communities) in its application form of its imitation/mixed pharmaceutical product (same as the ANDA or supplemental nda (sda) pharmaceutical product), which is synonymous with RLD, as follows:

1. licensed or licensed pharmaceutical products are used in the European Economic Area (EEA) as a basis for proving that the data protection period defined in european pharmaceutical legislation has expired. The reference pharmaceutical product is determined for the purpose of calculating the expiration of the data protection period and may differ from the strength, dosage form, route of administration, or performance of the counterfeit/mixed pharmaceutical product.

2. Pharmaceutical products (product name, strength, pharmaceutical form, MAH, marketing approval number) whose archives are cross-referenced in the imitation/mixed application. For the purpose of calculating the expiration of the data protection period, the reference pharmaceutical product may have been authorized by a separate procedure and by a different name than the identified reference pharmaceutical product. The product information of the reference pharmaceutical product will in principle be used as a basis for the claimed product information for the counterfeit/hybrid pharmaceutical product.

3. Pharmaceutical products (product name, strength, pharmaceutical form, MAH, source member country) for bioequivalence studies (where applicable).

The different simplified approval routes for pharmaceutical products according to the united states food, drug and cosmetic (FD & C) act are the simplified approval routes described in sections 505(j) and 505(b) (2) of the FD & C act (21 u.s.c.355(j) and 21 u.s.c.23355 (b) (2), respectively).

NDA and ANDA can be classified into the following four categories according to the FDA ("Determining wheel to Submit an ANDA or a 505(b) (2) Application guide for Industry", U.S. department of Health and Human Services, 10 months 2017, pages 1-14, the contents of which are incorporated herein by reference):

(1) an "independent NDA" is an application filed under section 505(b) (1) of the FD & C act and approved under section 505(C), containing a complete report of safety and efficacy investigations performed by or for an applicant or to which the applicant has the right to refer or use.

(2) The section 505(b) (2) application is a complete report containing a safety and efficacy survey according to NDA filed under FD & C act section 505(b) (1) and approved under section 505(C), wherein at least some of the information required for approval is from a study that was not performed by or for the applicant and which the applicant has no right to refer to or use.

(3) The ANDA is an application that is a duplicate of a previously approved drug product submitted and approved according to section 505(j) of the FD & C Act. The ANDA relies on the discovery by the FDA that previously approved drug products, i.e., reference marketed drugs (RLDs), are safe and effective. The andea must generally contain information to indicate that the proposed imitation product is (a) identical to RLD in terms of active ingredient, conditions of use, route of administration, dosage form, strength and label (with some allowed differences), and (b) bioequivalent to RLD. The ANDA must not be submitted if research is needed to determine the safety and effectiveness of the proposed product.

(4) The applicant is a type of ana for a pharmaceutical product that differs from RLD in its dosage form, route of administration, strength or active ingredient (in products with more than one active ingredient), and that the FDA does not require research to determine the safety and effectiveness of the proposed pharmaceutical product in response to the applicant's adjudication submitted under section 505(j) (2) (C) of the FD & C act (an adaptation request).

The scientific premise of the Hatch-Waxman act is that the drug product approved in the ANDA according to section 505(j) of the FD & C act is assumed to be therapeutically equivalent to its RLD. Products classified as therapeutically equivalent may be replaced when administered to a patient according to the conditions specified on the label, and it is fully expected that the replaced product will produce the same clinical effects and safety features as the prescription product. The 505(b) (2) section application allows greater flexibility regarding the characteristics of the proposed product than the ANDA. The section 505(b) (2) application will not necessarily be rated therapeutically equivalent to the marketed drug to which it is referred upon approval.

The method can further comprise incorporating, consisting of, or consisting essentially of canagliflozin into a business process. In certain embodiments, canagliflozin includes a package insert containing instructions for using canagliflozin to safely and effectively treat chronic kidney disease.

In a further aspect, described herein is a method of marketing a pharmaceutical composition containing canagliflozin, the method comprising incorporating, consisting of, or consisting essentially of the pharmaceutical composition into a business process. In certain embodiments, the pharmaceutical composition comprises a package insert containing instructions for using canagliflozin to safely and effectively treat chronic kidney disease.

In a further aspect, described herein is a method of offering for sale of canagliflozin, the method comprising offering to incorporate, consist of, or consist essentially of canagliflozin into a business process. In certain embodiments, canagliflozin includes a package insert containing instructions for using canagliflozin to safely and effectively treat chronic kidney disease.

Formulations/compositions

Pharmaceutical compositions containing canagliflozin as an active ingredient can be prepared by intimately mixing one or more of the compounds with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques. As used herein, the terms "composition" and "formulation" are used interchangeably and encompass a product comprising the specified ingredients in the specified amounts, as well as any product, such as a pharmaceutical product, obtained directly or indirectly by combining the specified ingredients in the specified amounts. A summary of pharmaceutical compositions can be found in the following documents, for example: remington: the Science and Practice of Pharmacy, 19 th edition (Easton, Pa.: Mack Publishing Company, 1995); hoover, John e., Remington: pharmaceutical Sciences, Mack Publishing co., Easton, Pennsylvania 1975; liberman, h.a. and Lachman, l., eds., Pharmaceutical document Forms, Marcel Decker, New York, n.y., 1980; and Pharmaceutical document Forms and Drug Delivery Systems, seventh edition (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

The pharmaceutical composition or pharmaceutical drug product can be administered by a variety of routes as determined by one of skill in the art. Preferably, the pharmaceutical composition or pharmaceutical product is administered by a route suitable for canagliflozin. In some embodiments, the pharmaceutical composition or pharmaceutical product is administered orally, parenterally, or any combination thereof. In other embodiments, the pharmaceutical composition or pharmaceutical product is administered orally. In further embodiments, the pharmaceutical composition or pharmaceutical product is administered parenterally.

The pharmaceutical composition or pharmaceutical drug product may be administered in a form suitable for the chosen route of administration. Thus, the pharmaceutical composition or pharmaceutical drug product may be administered as a suspension, elixir, solution, powder, pill, such as a capsule, tablet or caplet, lozenge, granule, syrup, film, lozenge, spray, paste or injection. In some embodiments, the pharmaceutical composition or pharmaceutical drug product is administered as an injection, such as intradermal injection, subcutaneous injection, intramuscular injection, intraosseous injection, intraperitoneal injection, or intravenous injection. In other embodiments, the pharmaceutical composition or pharmaceutical drug product is administered as a suspension, elixir, solution, powder, pill, such as a capsule (hard or soft), tablet or caplet, lozenge, granule, syrup, film, troche, spray, or paste. The pill can be formulated for swallowing, chewing, sublingual use, or buccal use, or can be an effervescent agent dissolved or dispersed in water prior to administration. In some embodiments, the pharmaceutical product comprises a pill, tablet, powder, sterile parenteral solution, or liquid spray.

The carrier can take a wide variety of forms depending on the desired route of administration (e.g., oral, parenteral). Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral formulations such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral formulations may also be coated with a substance such as sugar or with an enteric coating in order to modulate the primary site of absorption. For parenteral administration, the carrier will usually consist of sterile water, and other ingredients may be added to increase solubility or preserve. Thus, for parenteral administration, the pharmaceutical composition or pharmaceutical product is a sterile parenteral solution. Injectable suspensions or solutions may also be prepared using water-based carriers along with suitable additives.

To prepare such pharmaceutical compositions, canagliflozin as an active ingredient is intimately mixed with a pharmaceutical carrier, which may take a wide variety of forms depending on the form of preparation desired for administration (e.g. oral or parenteral such as intramuscular injection), according to conventional pharmaceutical compounding techniques. In preparing the compositions for oral dosage form, any of the pharmaceutically acceptable media that can be employed. Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral formulations (such as, for example, powders, capsules, caplets, and tablets), suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral unit dosage form, in which case solid pharmaceutically acceptable carriers are obviously employed. Tablets may be sugar-coated or enteric-coated, if desired, by standard techniques. For parenteral administration, the carrier will typically comprise sterile water, but may also comprise other ingredients, for example for purposes such as to aid solubility or preservation. Suspensions for injection may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit (e.g., per tablet, per capsule, per powder, per injection, per teaspoonful, etc.), an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain from about 25mg to about 500mg canagliflozin per unit dosage unit (e.g., per tablet, per capsule, per powder, per injection, per suppository, per teaspoonful, etc.), or any amount or range therein (preferably about 50mg, about 75mg, about 100mg, about 150mg, about 200mg, or about 300mg canagliflozin). However, the dosage may vary depending on the needs of the patient, the severity of the condition being treated and the compound being employed. The use pattern of daily administration or post-cycle administration may be employed.

Preferably, the pharmaceutical composition is in unit dosage form, such as a tablet, pill, capsule, powder, granule, sterile parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, autoinjector device or suppository; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. To prepare solid compositions such as tablets, the principal active ingredient (e.g., canagliflozin) is mixed with a pharmaceutically acceptable carrier (e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums) and other pharmaceutically acceptable diluents (e.g., water) to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. In certain embodiments, the two active ingredients may be formulated together, for example, as a bilayer tablet formulation. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition can be readily subdivided into equivalent dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from about 25mg to about 500mg, or any amount or range therein, of canagliflozin. Tablets or pills of the composition can be coated or otherwise compounded to provide a dosage form with long-lasting benefits. For example, a tablet or pill may comprise an inner dosage form component and an outer dosage form component, the latter being in the form of a coating on top of the former.

The compositions of the present disclosure may be incorporated into liquid forms for oral administration or administration by injection, including aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils (such as cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as elixirs and similar pharmaceutical vehicles. Dispersing or suspending agents suitable for use in aqueous suspensions include synthetic or natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

The methods described herein can also be performed using a pharmaceutical composition comprising canagliflozin and a pharmaceutically acceptable carrier. Carriers include necessary and inert pharmaceutical excipients including, but not limited to, binders, suspending agents, lubricants, flavoring agents, sweetening agents, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (including immediate release, timed release and sustained release forms, respectively), granules and powders; and liquid forms such as solutions, syrups, elixirs, emulsions and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

Advantageously, canagliflozin can be administered in a single daily dose, or the total daily dose can be administered in divided doses of two, three or four times daily.

For example, for oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient (e.g., canagliflozin) can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier (such as ethanol, glycerol, water, and the like). In addition, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the mixture, as desired or necessary. Suitable binders include, but are not limited to, starch, gelatin, natural sugars (e.g., glucose or beta-lactose), corn sweeteners, natural and synthetic gums (e.g., gum arabic, tragacanth) or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

In liquid form in a suitably flavoured suspending or dispersing agent such as synthetic and natural gums, for example tragacanth, acacia, methyl cellulose and the like. For parenteral administration, sterile suspensions and solutions are desirable. When intravenous administration is desired, isotonic formulations, which typically contain suitable preservatives, are employed.

To prepare the pharmaceutical compositions of the present disclosure, canagliflozin as an active ingredient can be intimately admixed with a pharmaceutically acceptable carrier, which can take a wide variety of forms depending on the form of preparation desired for administration (e.g., oral or parenteral administration), according to conventional pharmaceutical compounding techniques. Suitable pharmaceutically acceptable carriers are well known in the art. Some descriptions of these pharmaceutically acceptable carriers can be found in "The Handbook of Pharmaceutical Excipients" published by The American society of pharmacy and The British society of pharmacy, The disclosures of which are hereby incorporated by reference.

Methods of formulating Pharmaceutical compositions are described in various publications, such as Pharmaceutical Dosage Forms: tables, Second Edition, reviewed and Expanded, volumes 1-3, edited by Lieberman et al; pharmaceutical document Forms, fractional pharmaceuticals, volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms, Disperse Systems, Vol.1-2, edited by Lieberman et al; published by Marcel Dekker, inc, the disclosures of which are hereby incorporated by reference.

The present disclosure also provides a pharmaceutical product comprising a clinically proven safe and clinically proven effective amount of canagliflozin. Typically, the pharmaceutical product is packaged or packaged.

In some embodiments, the package comprises a label. In certain embodiments, the tag identifies canagliflozin as a regulatory approved chemical entity. In other embodiments, the label provides instructions for use in a patient suffering from chronic kidney disease. In further embodiments, the label provides a definition of chronic kidney disease and instructs the patient or physician to administer canagliflozin in the event that the patient suffers from chronic kidney disease. In other embodiments, the label further comprises instructions for use in a patient with type II diabetes or having substantial albuminuria or both. In further embodiments, the label comprises data indicating a reduction in one or more adverse renal or cardiovascular events relative to standard of care.

The following examples are provided to illustrate some of the concepts described in this disclosure. While the examples are considered to provide embodiments, they are not to be considered as limiting the more general embodiments described herein.

In the following examples, efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for.

Example 1

I. Design of research

This is a randomized, double-blind, event-driven, placebo-controlled, parallel-group, 2-arm, multi-center study to evaluate the effect of canagliflozin relative to placebo on serum creatinine doubling, end-stage renal disease (ESKD), renal death, or Cardiovascular (CV) death progression in patients with type 2diabetes (T2DM), stage 2 or 3 Chronic Kidney Disease (CKD), and massive albuminuria who receive a standard of care including a maximum tolerance marker daily dose of Angiotensin Converting Enzyme Inhibitors (ACEi) or Angiotensin Receptor Blockers (ARBs). The primary objective was to demonstrate the superiority of canagliflozin over placebo in reducing the primary composite endpoint. The security objective is to assess the overall security and tolerability of canagliflozin.

Randomization includes a 1:1 ratio of canagliflozin 100mg or matching placebo, glomerular filtration rate (eGFR) [ >30 mL/min/1.73m estimated by screening²To less than 45mL/min/1.73m²、≥45mL/min/1.73m²To less than 60mL/min/1.73m²、≥60mL/min/1.73m²To less than 90mL/min/1.73m²]To stratify. The primary efficacy composite endpoints were serum creatinine doubling, ESKD, and time to first appearance of renal or CV death. Important secondary efficacy endpoints (tested in rank order as follows) included:

composite of omicron CV death and hospitalized heart failure

Composite of CV death, non-fatal MI and non-fatal stroke (i.e., 3 points "MACE")

Omicron in-patient heart failure

Composite of omicron creatinine doubling, ESKD and renal death

Death of CV

Omicron death

Composite of omicron CV death, non-fatal MI, non-fatal stroke, hospitalized heart failure and hospitalized unstable angina

Planned interim analysis was performed at 413 primary endpoints and IDMC subsequently suggested early discontinuation of the study for efficacy based on pre-specified stopping criteria.

Statistical methods

Preliminary analysis was performed in the intent-to-treat (ITT) analysis set (i.e., all randomized subjects by the end of the study) using a stratified Cox proportional hazards model that included treatment as an explanatory variable and was stratified by screening for eGFR. The secondary endpoints were analyzed similarly.

Hypothesis testing of primary efficacy endpoints and important secondary efficacy endpoints was conducted in a pre-specified ranking order that conditionally advanced based on the significance of previous tests, and until the endpoint failed to show significance. Due to the discontinuation at interim analysis, primary endpoints were tested at a bilateral significance level of 0.022 based on the alpha depletion function, while secondary endpoints were tested at 0.038.

The safety analysis and summary that occurred at treatment was presented using the in-treatment analysis set (i.e., all treated subjects within 30 days after the last dose), while the analysis of amputations, fractures and malignancies was performed using the in-study analysis set (i.e., all treated subjects by the end of the study).

Results III

1. Subject and treatment information

1.1. Study completion/withdrawal information

A total of 4,401 randomized subjects were included in the ITT analysis set, and a total of 4397 subjects were included in both the in-study and in-treatment analysis sets for safety assessments since only 4 subjects were not dosed. The final life state is known and the completion of the study is very high. With respect to table 1, a subject is not considered to have completed the study if the subject is followed up to the point in time between notification of the Global Trial End Date (GTED) and GTED, or until the time of death of the subject who died before GTED, regardless of whether the subject is taking or withholding study medication. The proportion of subjects discontinued in the placebo group was greater compared to the canagliflozin group, and adverse events were considered to be the most common cause of discontinuation of treatment (13% for placebo and 12% for canagliflozin, respectively).

1.2. Demographic and baseline characteristics

Both final life state (99.9%) and study completion (99.1%) were very high. The most common cause considered to be early discontinuation of study medication is adverse events (12% for the canagliflozin group and 13% for the placebo group). There were no significant differences between the two treatment groups in baseline demographic, anthropometric and diabetic characteristics. Overall, the mean age was 63 years; 66.1% of subjects were male, and the majority were white (66.6%). The mean duration of diabetes was 16 years, mean baseline HbA_1cIs 8.27%, wherein 53.2% of subjects have baseline HbA_1cNot less than 8% (average HbA)_1c8.27%) and a baseline median urinary albumin/creatinine of 927 mg/g. The most common antihyperglycemic agents (AHA) used at baseline were insulin (65.5%), biguanides (57.8%) and sulfonylureas (28.8%). Almost all subjects (99.9%) were dosed with ACEi or ARB at randomization and 95% were dosed with ACEi or ARB 2 years after randomization. About 92% of subjects received cardiovascular therapy (excluding ACEi/ARB) at baseline, with about 60% taking antithrombotic agents (including aspirin) and 69% taking statins/hypertensive drugs。

The average baseline eGFR was 56.2mL/min/1.73m²And about 60% of the population has a population size of less than 60mL/min/1.73m²Baseline eGFR. The subjects had an average duration of diabetes of about 16 years. The proportion of subjects previously having CV disease was 50.4%; 14.8% have a history of heart failure; 5.3% have a history of amputation. While the entire study population had renal disease at baseline, approximately 64% of the population had at least 2 microvascular complications (i.e., diabetic nephropathy and another microvascular complication). Clinically relevant differences between treatment groups were not noted in these baseline characteristics.

The proportion of subjects with a history of amputation was similar between the groups (5.4% for the canagliflozin group and 5.2% for the placebo group).

1.3. Degree of exposure and follow-up

The mean exposure to study drug was comparable between treatment groups (115 weeks total), as was the duration of follow-up (136 weeks total).

2. Primary endpoint analysis

Canagliflozin significantly reduced the risk of the primary composite endpoint by 30% compared to placebo [ HR: 0.70; 95% CI: 0.59, 0.82; p value <0.0001 (table 2A), thereby successfully achieving the primary goal of cost research. In addition, each individual component was consistent with the overall results for the primary composite endpoint (table 2A), and further, using the in-treatment analysis set [ HR: 0.64 of; 95% CI: 0.53,0.78] consistent with the primary efficacy analysis in the ITT analysis set.

Figure 1 shows a Kaplan-Meier plot for the time at which the primary composite endpoint first appeared and shows that the initial separation occurred at week 52 and remained throughout the study. As shown in tables 2B and 2C, the robustness of the primary composite endpoint was confirmed in all 15 subgroups. The assessment of the proportional risk hypothesis on which the above analysis is based does not yield evidence of lack of proportionality (p-0.3116).

3. Important secondary endpoint

Canagliflozin significantly reduced the risk of the following secondary endpoints (shown in bold p-values in table 3B):

a 31% reduction in the composite of CV death and hospitalized heart failure [ HR: 0.69; p is 0.0001; 95% CI: 0.57,0.83]

Decrease in MACE by 20% [ HR: 0.80; p is 0.0121; 95% CI: 0.67,0.95]

Reduction of heart failure hospitalization by 39% [ HR: 0.61; p is 0.0003; 95% CI: 0.47,0.80]

Doubling of serum creatinine, a 34% decrease in the complex of ESKD and renal death [ HR: 0.66; p < 0.0001; 95% CI: 0.53,0.81].

While the remaining secondary endpoints tend to favor canagliflozin, none are statistically significant due to the hierarchical test order. In addition, the risk of exploratory hard-compounding of ESKD, renal death and CV death is reduced due to canagliflozin [ HR: 0.73; 95% CI: 0.61,0.87], so the therapeutic effect remains consistent whether or not a serum creatinine-doubled component is included. For tables 3A and 3B, HHF ═ hospitalized heart failure; DoSC-serum creatinine doubling; NFMI ═ non-lethal MI; NF stroke is not fatal stroke; HUSA is unstable angina pectoris in hospitalization.

4. Other efficacy assays

At the end of the treatment, subjects treated with canagliflozin were on HbA_1c[ least squares mean difference: -0.13%]Body weight [ least squares mean difference: -1.72%]And systolic blood pressure [ least squares mean difference: -2.81mmHg]A statistically significant reduction minus placebo (canagliflozin minus placebo) compared to baseline was observed. Assuming that subjects have been reasonably well controlled with an average baseline systolic blood pressure of 140mmHg, the systolic blood pressure differences noted between treatment groups are unlikely to have a significant Impact on primary efficacy findings (Home, Impact of the UKPDS: an overview, Diabetes. Med.,2008,25: 2-8; Kazama, Chronic kit disease and vitality fraction, Clin. Exp. Nephrol.,2017,21 (supplement 1): S46-S52; Zoungas, Combined efficiencies of route blood pressure reduction and intense glucose control on mammogram and microvascular in tissues with 2 measures: New stresses from the heart of the individual, Diabetes mellitus, 2009, type 2078: 2074).

5. Safety feature

Safety analysis was performed using either the analysis-on-treatment set (up to the treated subjects 30 days after the last dose) or the analysis-on-study set (the subjects treated by the end of the study). As discussed herein, incidence of amputation [ HR 1.11; 95% CI: 0.79 to 1.56] and fracture determination [ HR 0.98; 95% CI: 0.70 to 1.37] was lower in this study than other studies in the field. The overall adverse events as well as the incidence of severe adverse events in the canagliflozin group were numerically smaller compared to placebo.

In summary, the incidence of overall adverse events as well as severe adverse events and adverse events leading to discontinuation in the canagliflozin group was numerically smaller compared to placebo. The rate of adverse events of hyperkalemia did not increase, and the numerical value of the rate of adverse events associated with hypovolemia increased.

5.1. Summary of all adverse events

The incidence of overall adverse events as well as severe adverse events and adverse events leading to discontinuation in the canagliflozin group was numerically smaller compared to placebo (table 4).

5.2. Selected adverse events of interest

5.2.1. Lower limb amputation

Assuming "1.00" is included in the 95% confidence interval for the risk ratio comparing canagliflozin to placebo, there was no statistical difference in the risk of atraumatic lower limb amputation between treatment groups despite the relatively high historical incidence of atraumatic lower limb amputation in this population, [ HR: 1.11; 95% CI: 0.79,1.56] (table 5).

5.2.2. Fracture of bone

There were no statistical differences between the treatment groups to determine the risk of fracture, with the placebo and canagliflozin groups having an incidence of 12.09/1000 and 11.80/1000 subjects-years, respectively, and the estimated risk ratio approaching 1.00[ HR: 0.98 of; 95% CI: 0.70,1.37] (Table 6).

5.2.3. Selected malignant tumor

The overall incidence of tumors was low and balanced between treatment groups.

5.2.3.1. Malignant tumor of kidney cell

The incidence of judged Renal Cell Carcinoma (RCC) in the placebo group [5 subjects (< 0.2%) ] was numerically greater compared to the canagliflozin group [1 subject (< 0.1%) ]. In particular, the proportion of subjects who underwent confirmed diagnosis of RCC was low, and the rate of judged RCC in subjects treated with canagliflozin decreased relative to placebo-present values (incidence in placebo and canagliflozin groups was 0.87/1000 patient-year and 0.17/1000 patient-year, respectively).

5.2.3.2. Other malignant tumors

The incidence of bladder cancer per 1,000 subjects-year was similar in both treatment groups [ difference in Incidence (IRD): 0.16; 95% CI: -1.41,1.73] the incidence of female breast cancer in the canagliflozin group was numerically greater compared to placebo (incidence in the placebo and canagliflozin groups was 1.59/1000 patient-year and 4.08/1000 patient-year, respectively), whereas the 95% confidence interval for IRDs contained "0" [ IRD: 2.49; 95% CI: -1.25,6.23]. Pheochromocytoma or testicular cell carcinoma were not reported in the study. With respect to table 7, percentages are calculated as the number of subjects in each group as denominators, the incidence is based on the number of subjects experiencing at least one adverse event rather than the number of events, the 95% CI is based on a normal approximation of the difference in Incidence (IRD), and the denominators are limited to women for breast cancer.

5.2.4. Renal related adverse events

The incidence of kidney-related adverse events was lower in the canagliflozin group compared to placebo (57.12/1,000 subject-year and 79.12/1,000 subject-year, respectively). The most commonly reported preferred term for both groups is "increased creatinine blood". This finding reassures this population as to the specific risk of renal adverse events and further enhances the role of canagliflozin in reducing the risk of renal outcome in the study population. With respect to table 8, the percentages are calculated as denominator in the number of subjects in each group, and the incidence is based on the number of subjects experiencing at least one adverse event rather than the number of events.

5.2.5. Other selected adverse events

The incidence of adverse events of hyperkalemia was lower in the canagliflozin group compared to placebo (29.74/1,000 subjects-year and 36.91/1,000 subjects-year, respectively), while the incidence of adverse events of hypovolemia was higher in the canagliflozin group compared to placebo (28.36/1,000 subjects-year and 23.45/1,000 subjects-year, respectively). The incidence of Diabetic Ketoacidosis (DKA) was higher per 1,000 subject-year in the canagliflozin group compared to placebo, where the 95% confidence interval for IRDs did not include "0" [ IRD: 1.73; 95% CI: 0.32,3.14].

6. Other effects

Although for subjects treated with canagliflozin, relative to HbA_1cBody weight and systolic blood pressure, a statistically significant reduction from baseline minus placebo was observed, but the treatment effect was minimal. The effect on blood glucose decreases as eGFR decreases. According to eGFR layer, for HbA_1cThe LS mean change from baseline minus the placebo was 0.03 (95% CI: -0.128; 0.180) (in 30-45eGFR layers), -0.18 (-0.328; -0.030) (in 45-60 layers), and-0.21 (95% CI: -0.33; -0.08) (in 60 to 60)<In the 90eGFR layer). Referring to fig. 2-4, a is shown for each of the eGFR layers_1cAt any time compared to baselineThe LS mean of the transition varied. Similar trends were observed in the effects on body weight and systolic blood pressure.

Analysis to evaluate adjusted HbA_1cAnd post-baseline measurement of systolic blood pressure in the primary efficacy analysis. Fitting a series of proportional Risk regression models, including post-Baseline HbA_1cAnd systolic blood pressure measurements as time-varying covariates. Because of HbA_1cHas a delayed effect on cardiovascular risk, several models were constructed. In each model, HbA was first estimated using a single consensus value, a single hysteresis value_1cAnd then evaluated as a running average. A single consistent systolic measurement was used for all analyses.

As shown in Table 9, HbA was changed regardless of the time used for adjustment_1cAnd the method of systolic blood pressure measurement, canagliflozin remains robust to the therapeutic effect of the primary composite endpoint. Despite the consistent HbA_1cNo significant effect was shown, but the hysteresis value and the running mean HbA_1cBoth showed a modest but significant effect on the primary efficacy endpoint, as did the consistent systolic pressure. Higher post-baseline HbA after adjustment of treatment efficacy_1cAnd systolic pressure are both associated with an increased risk of experiencing the primary composite endpoint.

These results demonstrate that treatment with canagliflozin can achieve a beneficial effect on renal function, ESKD and CV death or renal death with only modest treatment-related differences in glycemic control. Generally, treatment with canagliflozin demonstrated improved renal outcome in patients receiving standard of care treatment (which included the maximum marker dose or tolerated dose of ARB or ACE inhibitor) for diabetes and CV and renal event prophylaxis, without significant differences in achieved glycemic, blood pressure, or lipid control.

7. Summary of results

In summary, this example shows significant progress in managing subjects with T2DM and confirmed CKD. Although current standards of care are established more than 15 years ago, subjects with T2DM and CKD are still at high risk of developing ESKD and CV events and having a shortened life expectancy. Canagliflozin has been shown to significantly reduce the risk of clinically significant renal and CV events in these subjects, and has acceptable safety profiles.

It should be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the foregoing description and the following examples are intended to illustrate, but not limit the scope of the invention. It will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the scope of the invention, and further that other aspects, advantages and modifications will be apparent to those skilled in the art to which the invention pertains. In addition to the embodiments described herein, the present invention also contemplates and claims those inventions resulting from combinations of features of the invention recited herein and features of prior art references that supplement the features of the invention. Similarly, it should be understood that any of the materials, features, or articles described may be used in combination with any other material, feature, or article, and such combinations are considered to be within the scope of the present invention.

The disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated by reference in their entirety for all purposes.