Treatment of chronic kidney disease in type 1 diabetes

Abstract

The present invention also refers to finerenone or a hydrate, solvate, pharmaceutically acceptable salt or polymorph thereof for use in the prevention or treatment of chronic kidney disease in patients with type 1 diabetes, wherein the prevention or treatment comprises administering to the patient a therapeutically effective amount of finerenone or a hydrate, solvate, pharmaceutically acceptable salt or polymorph thereof.

Description

[Technical Field]

[0001] The present invention relates to medical therapies for preventing, ameliorating, or treating chronic kidney disease in type 1 diabetes. The present invention also refers to finerenone or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof for use in the prevention or treatment of chronic kidney disease in patients with type 1 diabetes, wherein the prevention or treatment comprises administering to the patient a therapeutically effective amount of finerenone or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof. [Background technology]

[0002] Diabetes mellitus (D1D) is a chronic disorder characterized by hyperglycemia due to defects in insulin secretion, insulin action, or both. Type 1 diabetes (T1D) is characterized by little or no insulin secretory capacity, and patients with T1D require insulin to survive. Because T1D patients produce little or no insulin, effective insulin therapy for T1D patients generally involves the use of two types of exogenously administered insulin: fast-acting pre-meal insulin given by bolus injection, insulin pump, closed-loop system, or inhaled insulin, and long-acting basal insulin given once or twice daily to control blood glucose levels between meals.

[0003] Approximately 1.3 million people in the United States have been diagnosed with type 1 diabetes. T1D is one of the most common childhood diseases and requires lifelong insulin treatment. A 2019 study cited in the Diabetes in America report by the National Institute of Diabetes and Digestive and Kidney Diseases (NIH / NIDDK) of the National Institutes of Health estimated the prevalence of T1D in the U.S. population between 1999 and 2010 to be between 740,000 and 970,000, and predicted that this number could triple by 2050 due to rising incidence of T1D (Imperatore G. et al., Diabetes Care. 2012, 35(12):2515-2520). A 2016 estimate by the Centers for Disease Control and Prevention (CDC) indicated that 1.3 million adults (aged 18 years and older), or 5.8% of adults diagnosed with diabetes and 0.55% of all U.S. adults, reported T1D and insulin use. (Bullard KM et al., Morb Mortal Wkly Rep. 2018, 67(12):359-361). CDC data from 2019 indicates that 244,000 children and adolescents (under 20 years of age) in the United States were diagnosed with type 1 diabetes. (Menke A et al., Epidemiology. 2013, 24(5):773-774).

[0004] Chronic kidney disease (CKD) is a major complication of T1D. CKD is often asymptomatic until the later stages, when nonspecific symptoms such as fatigue, itching, or loss of appetite occur. Diagnosis is generally made after an incidental finding from a screening test (e.g., laboratory measurement, urine dipstick, or blood test) or in late CKD, when symptoms begin to appear.

[0005] The downstream effects of hyperglycemia are a pathophysiological driver of CKD in T1D. Chronically elevated blood glucose levels can lead to elevated albuminuria or urinary albumin-to-creatinine ratio (UACR), hypertension, microvascular and macrovascular lesions, oxidative stress, inflammation, and fibrosis in the kidney, and increased risk of cardiovascular (CV) events. (Papadopoulou-Marketou N et al., Diabetes Metab Res Rev. 2017, 33(2); Nathan DM et al., Diabetes Care. 2014, 37(1):9-16) High albuminuria and low eGFR are independent risk factors for the progression of CKD and end-stage kidney disease (ESKD) or end-stage renal failure (ESRD), as well as CV morbidity and mortality (Gansevoort RT et al., Kidney Int. 2011, 80(1):93-104; Matsushita K et al., Lancet. 2010, 375(9731):2073-2081; van der Velde M et al., Kidney Int. 2011; 79(12):1341-1352). The term end-stage kidney disease (ESKD) may be used synonymously with end-stage renal failure (ESRD). The term "kidney" may be used synonymously with "renal."

[0006] A systematic analysis for the Global Burden of Disease Study reported that the prevalence of CKD due to T1D increased by 58.2% from 1990 to 2007 and by 21.7% from 2007 to 2017. The global prevalence of CKD due to T1D in 2017 was estimated to be 32.5 cases per 100,000 people (James, SL et al., Lancet 2018, 392(10159):1789-1858). Among US adults, the incidence of CKD due to T1D is approximately 25-40%, and 25-30% of patients with T1D will develop end-stage renal disease or end-stage renal failure (Bakris GL, Diabetes Care. 2018, 41(3):389-390).

[0007] Current treatment for T1D consists of insulin therapy to control hyperglycemia. In patients with T1D, glycemic interventions targeting HbA1c levels below 7% can delay the onset and progression of kidney disease. Treatment with ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) is often required to control blood pressure and reduce albuminuria to slow the progression of established kidney disease. With medications that target the renin-angiotensin-aldosterone system, such as ACEIs and ARBs, reduced albuminuria has been shown to correspond with reduced clinical outcomes, such as progression to ESKD and ESRD, for both types of diabetes. (Brenner BM et al., N Engl J Med. 2001, 345(12):861-869; Lewis, EJ et al., N Engl J Med. 1993, 329(20):1456-1462; Bjorck S et al., BMJ. 1992, 304(6823):339-343; Lewis EJ et al., N Engl J Med. 2001; 345(12):851-860).

[0008] Sodium-glucose cotransporter 2 (SGLT2) inhibitors are prescribed as adjuvants to insulin to improve glycemic control and reduce total daily insulin doses and body weight in T1D. However, this class of drug has limited clinical use due to safety concerns regarding diabetic ketoacidosis. Furthermore, SGLT2 inhibitors are not currently approved by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA) for the treatment of T1D and CKD. Despite current guideline-recommended therapy with insulin and ACEIs or ARBs, one-quarter of CKD and T1D patients progress to ESKD or ESRD, and dialysis and CKD remain the leading causes of cardiovascular events and mortality in T1D.

[0009] Since the ACEI and ARB studies were conducted nearly 30 years ago, no new treatments for CKD and T1D have emerged. For example, the landmark captopril trial was conducted as long ago as 1993 (Lewis EJ et al., NEJM, 1993;329:1456-1462). Furthermore, once-promising renal-protective strategies for CKD and T1D, such as protein kinase C-β antagonists, selective endothelin receptor A antagonists, and the Nrf2 modulator bardoxolone, have produced disappointing clinical trial results (Cherney DZI et al., Diabetes Care. 2010, 33(6):1344-1346). More recently, in the Preventing Early Renal Loss in Diabetes Study, which investigated the effects of lowering uric acid in patients with CKD and T1D, allopurinol did not reduce albuminuria or slow the rate of renal function decline compared to placebo (Doria A et al., N Engl J Med. 2020, 382(26):2493-2503). [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Imperatore G. et al., Diabetes Care. 2012, 35(12):2515-2520 [Non-patent document 2] Bullard KM et al. Morb Mortal Wkly Rep. 2018, 67(12):359-361 [Non-patent document 3] Menke A et al., Epidemiology. 2013, 24(5):773-774 [Non-patent document 4] Papadopoulou-Marketou N et al. Diabetes Metab Res Rev. 2017, 33(2) [Non-Patent Document 5] Nathan DM et al., Diabetes Care. 2014, 37(1):9-16 [Non-patent document 6] Gansevoort RT et al., Kidney Int. 2011, 80(1):93-104 [Non-Patent Document 7] Matsushita K et al., Lancet. 2010, 375(9731):2073-2081 [Non-patent document 8] van der Velde M et al. Kidney Int. 2011;79(12):1341-1352 [Non-Patent Document 9] James, SL et al., Lancet 2018, 392(10159):1789-1858 [Non-Patent Document 10] Bakris GL, Diabetes Care.2018, 41(3):389-390 [Non-Patent Document 11] Brenner BM et al., N Engl J Med. 2001, 345(12):861-869 [Non-Patent Document 12] Lewis, EJ et al., N Engl J Med. 1993, 329(20):1456-1462 [Non-Patent Document 13] Bjorck S et al., BMJ. 1992, 304(6823):339-343 [Non-Patent Document 14] Lewis EJ et al., N Engl J Med.2001;345(12):851-860 [Non-Patent Document 15] Lewis EJ et al., NEJM, 1993;329:1456-1462 [Non-Patent Document 16] Cherney DZI et al., Diabetes Care. 2010, 33(6):1344-1346 [Non-Patent Document 17] Doria A et al., N Engl J Med.2020,382(26):2493-2503 Summary of the Invention [Problem to be solved by the invention]

[0011] The aim of the present invention is to provide new interventions to slow or prevent the progression of CKD in T1D.

[0012] A further object of the present invention is to provide new interventions to extend healthy lifespan and reduce mortality and / or morbidity in patients with CKD and T1D. [Means for solving the problem]

[0013] Finerenone, a nonsteroidal mineralocorticoid receptor antagonist (MRA), improves renal and cardiovascular function in patients with CKD in type 2 diabetes (T2D). Finerenone attenuates the effects of overactivation of the mineralocorticoid receptor by ligands such as aldosterone and cortisol. Finerenone has the chemical name (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide and the formula (I): [ka] It has the chemical structure:

[0014] The synthesis, pharmacological properties, and pharmaceutical formulations / dosage forms of finerenone are described in US Pat. No. 8,436,180, which is incorporated herein by reference in its entirety.

[0015] The effects of finerenone on various aspects of diabetic kidney disease in type 2 disease (T2D) have been studied. For example, finerenone coadministered with an ACEI or ARB has been shown to slow the progression of diabetic kidney disease and reduce the incidence of cardiovascular disease in patients with type 2 disease (Veneti S. et al., Diabetes Therapy. 2021, 12(7), 1791-1797).

[0016] The unique pharmacokinetic and pharmacodynamic properties of finerenone, such as its tissue distribution, selectivity, and mineralocorticoid receptor (MR) binding mode, have been proposed to provide the basis for an improved benefit / risk profile in patients with heart failure and diabetic kidney disease, including reduced risk of developing hyperkalemia and renal dysfunction. Studies conducted in patients with heart failure with reduced ejection fraction (HFrEF) and moderate chronic kidney disease and diabetic kidney disease have shown promising results. (Licette, CY et al., Expert Opinion on Investigational Drugs. 2015, 24(8), 1123-1135)

[0017] The effects of finerenone were investigated in a novel model of CKD in T1D using the Munich Wistar Fromter (MWF) rat model (Sanz-Gomez, M et al., Journal of Hypertension. 2022, Vol. 40, Issue Suppl. 1, p. e37).

[0018] To determine whether activation of the mineralocorticoid receptor (MR) contributes to diabetic renal injury in type 1 and type 2 diabetes, the effects of the MR antagonist eplerenone on renal injury were measured in rodent models of type 1 (streptozotocin-treated rats) and type 2 (db / db mice) diabetes. (Guo et al., Endocrinology 2006, 147(11):5363-5373) From these eplerenone studies, Guo et al. suggest that MR activation is an important factor in the early pathogenesis of renal disease in both type 1 and type 2 diabetes. [Brief explanation of the drawings]

[0019] [Figure 1] 1 is a scheme illustrating the study design and procedures with timeline and evaluations according to one embodiment disclosed herein. DETAILED DESCRIPTION OF THE INVENTION

[0020] In one embodiment, the present disclosure relates to a method for preventing or treating chronic kidney disease in a patient with type 1 diabetes, comprising administering to the patient a therapeutically effective amount of finerenone, or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof. In one embodiment, the present disclosure relates to a method for slowing the progression of chronic kidney disease in a patient with chronic kidney disease associated with type 1 diabetes, comprising administering to the patient a therapeutically effective amount of finerenone, or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof. Furthermore, the present disclosure relates to a method for reducing the risk of sustained UACR decline in a patient with chronic kidney disease associated with type 1 diabetes, comprising administering to the patient a therapeutically effective amount of finerenone, or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof. In another embodiment, the present disclosure relates to a method for decreasing the UACR in a patient with chronic kidney disease associated with type 1 diabetes, comprising administering to the patient a therapeutically effective amount of finerenone, or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof. In any of the embodiments of the present disclosure, the present disclosure further relates to reducing the risk of end stage renal disease or end stage renal failure.

[0021] The present invention relates to a method for treating, preventing, or slowing the progression of CKD in T1D or related conditions by administering finerenone or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof. The methods disclosed herein for use with finerenone may also be used with a therapeutically effective amount of a hydrate, solvate, pharmaceutically acceptable salt, or polymorph of finerenone.

[0022] The polymorphic forms of finerenone are disclosed in U.S. Patent No. 10,399,977, which is incorporated herein by reference in its entirety.In the method of the present disclosure, the administered compound may be finerenone of formula (I) in the crystalline form of polymorph I, characterized in that the X-ray diffraction pattern of this compound shows peak maxima in 2θ angles at 8.5, 14.1, 17.2, 19.0, 20.5, 25.6, and 26.5.In the method of the present disclosure, the administered compound may be finerenone of formula (I) in the crystalline form of polymorph I, characterized in that the IR spectrum (IR-ATR) of this compound shows peak maxima in 2θ angles at 3475, 2230, 1681, 1658, 1606, 1572, 1485, 1255, 1136, and 1031 cm -1 In the methods of the present disclosure, the compound administered may be finerenone of formula (I) in the crystalline form of polymorph I, the Raman spectrum of which exhibits band maxima at 3074, 2920, 2231, 1601, 1577, 1443, 1327, 1267, 827, and 155 cm -1 The experimental conditions for measuring these crystal morphology parameters are described in the Examples.

[0023] In one embodiment, finerenone of formula (I) is used in the crystalline form of polymorph I. In one embodiment, finerenone is used in the crystalline form of formula (I) of polymorph I. [ka] and the X-ray diffraction pattern of this compound exhibits peak maxima in 2θ angles at 8.5, 14.1, and 19.0. In one embodiment, finerenone is a compound of formula (I) in the crystalline form of polymorph I, and the X-ray diffraction pattern of this compound further exhibits any one of peak maxima in 2θ angles at 17.2, 20.5, 25.6, and 26.5. In one embodiment, finerenone is a compound of formula (I) in the crystalline form of polymorph I, and the IR spectrum of this compound exhibits peak maxima in 2θ angles at 3475, 2230, 1681, 1658, 1606, 1572, 1485, 1255, 1136, and 1031 cm -1In one embodiment, finerenone is the compound of formula (I) in the crystalline form of polymorph I, and the IR spectrum of this compound exhibits band maxima at 3475, 2230, 1681, 1658, 1606, 1572, 1485, 1255, 1136, and 1031 cm -1 In one embodiment, finerenone is the compound of formula (I) in the crystalline form of polymorph I, and the Raman spectrum of this compound exhibits band maxima at 3074, 2920, 2231, 1601, 1577, 1443, 1327, 1267, 827, and 155 cm -1 In one embodiment, finerenone is the compound of formula (I) in the crystalline form of polymorph I, and the Raman spectrum of this compound exhibits band maxima at 3074, 2920, 2231, 1601, 1577, 1443, 1327, 1267, 827, and 155 cm -1The band maximum is at 0°C. In one embodiment, finerenone is the compound of formula (I) in the crystalline form of polymorph I, which has a melting point of 252°C. In one embodiment, the present invention relates to a safe and effective method for preventing or treating chronic kidney disease in a patient with type 1 diabetes, comprising administering a therapeutically effective amount of finerenone to the patient. In another embodiment, the present invention relates to a safe and effective method for slowing the progression of chronic kidney disease in a patient with chronic kidney disease associated with type 1 diabetes, comprising administering a therapeutically effective amount of finerenone to the patient. In a particular embodiment, the method mitigates the decline in renal function and progression to end-stage renal disease or end-stage renal failure in a patient with chronic kidney disease associated with type 1 diabetes by administering a therapeutically effective amount of finerenone to the patient. In a further embodiment, the present invention relates to a safe and effective method for reducing the risk of sustained UACR decline in a patient with chronic kidney disease associated with type 1 diabetes by administering a therapeutically effective amount of finerenone to the patient. In a further embodiment, the present invention relates to a safe and effective method for reducing the risk of sustained UACR decline in patients with CKD associated with type 1 diabetes by administering a therapeutically effective amount of finerenone to the patient.In a further embodiment, the present invention relates to a safe and effective method for reducing albuminuria in patients with end-stage renal disease or end-stage renal failure associated with type 1 diabetes, comprising administering a therapeutically effective amount of finerenone to the patient.

[0024] In a further embodiment, the present invention relates to a safe and effective method for producing a statistically significant reduction (p-value of 0.05 or greater) in UACR in patients with CKD and T1D, comprising administering a therapeutically effective amount of finerenone to the patient. Statistical analysis can be performed using SAS software, version 9.4 or later (SAS Institute). In one embodiment, the placebo-corrected relative reduction in UACR in patients receiving finerenone (at a dose of 10 mg or 20 mg) is statistically significant with a 95% CI 6 months after finerenone administration.

[0025] The daily dosage of finerenone may be selected from the group consisting of 7.5 mg, 10 mg, 20 mg, 40 mg, a range of 10 mg to 20 mg, and a range of 10 mg to 40 mg. One embodiment of the present invention refers to administering finerenone in a daily dose of 0.25 mg to 80 mg. One embodiment of the present invention refers to administering finerenone in a daily dose of 0.25 mg to 40 mg. Other embodiments of the present invention refer to administering finerenone in a daily dose of 0.25 mg to 20 mg, 0.25 mg to 10 mg, or 0.25 mg to 5 mg. In one embodiment, the dosage of finerenone is adjusted to a target dose of 10 mg during the study. In one embodiment, the dosage of finerenone is adjusted to a target dose of 20 mg during the study. In one embodiment, the dosage of finerenone is adjusted to a target dose of 40 mg during the study.

[0026] Other embodiments according to the invention refer to administering finerenone in an amount of 5-80 mg, 5-70 mg, 5-60 mg, 5-50 mg, 5-40 mg, 10-80 mg, 10-70 mg, 10-60 mg, 10-50 mg, or 10-40 mg. Other embodiments according to the invention refer to administering a daily dose of finerenone in an amount of 10-40 mg, or 20-40 mg. In one embodiment, the method of the present invention comprises administering finerenone in an amount of 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 7.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 mg. In one embodiment, the method of the present invention comprises administering finerenone in an amount of 5 mg. In one embodiment, the method of the present invention comprises administering finerenone in an amount of 10 mg. In one embodiment, the method of the present invention comprises administering finerenone in an amount of 15 mg. In one embodiment, the method of the present invention comprises administering finerenone in an amount of 20 mg. In one embodiment, the method of the present invention comprises administering finerenone in an amount of 25 mg. In one embodiment, the method of the present invention comprises administering finerenone in an amount of 30 mg. In one embodiment, the method of the present invention comprises administering finerenone in an amount of 35 mg. In one embodiment, the method of the present invention comprises administering finerenone in an amount of 40 mg. In one embodiment, the method of the present invention comprises administering finerenone in an amount of 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg. In one embodiment, the method of the present invention comprises administering finerenone in an amount of 5 mg, 10 mg, 20 mg, 30 mg, or 40 mg.

[0027] Formulations of finerenone are known in the art, including those disclosed in U.S. Patent No. 8,436,180. Common dosage forms include pills, tablets, capsules, syrups, aerosols, injections, powders, or solid crystals. Finerenone is preferably administered orally in solid form. Formulations of finerenone may contain inactive ingredients such as lactose monohydrate, cellulose microcrystals, croscarmellose sodium, hypromellose, magnesium stearate, and sodium lauryl sulfate. The film coating of finerenone tablets may contain red iron oxide (10 mg tablets) or yellow iron oxide (20 mg tablets), as well as hypromellose, titanium dioxide, and talc.

[0028] Finerenone is commercially available. In one embodiment, finerenone is present in a film-coated tablet administered orally at a dose of 10 mg once daily or 20 mg once daily. In some embodiments, patients begin treatment with an oral dose of 10 mg once daily and are then titrated to a maintenance dose of 20 mg orally once daily. In some embodiments, patients begin treatment with an oral dose of 10 mg once daily and are then titrated to a maintenance dose of 20 mg orally once daily after one month or three to five weeks of receiving a low initial dose.

[0029] In one embodiment, finerenone is present in a film-coated tablet administered orally at a dose of 40 mg once daily. In some embodiments, patients begin treatment at an oral dose of 10 mg once daily and are then titrated to a maintenance dose of 20 mg orally once daily or 40 mg orally daily. In some embodiments, patients begin treatment at an oral dose of 10 mg once daily and are then titrated to a maintenance dose of 20 mg orally once daily or 40 mg orally daily after one month or three to five weeks of receiving a low initial dose.

[0030] Preferably, the tablet is an immediate release formulation. In one embodiment, finerenone is administered in the morning at approximately the same time each day for the effective treatment period. Finerenone can be taken with or without food.

[0031] In one embodiment, a patient with T1D may also be given insulin in addition to finerenone. In one aspect, the proposed method further includes that the patient has been receiving a stable dose of an ACEI or ARB for more than four weeks before starting finerenone therapy. ACEIs are known in the art and include, but are not limited to, captopril, enalapril, lisinopril, benazepril, fosinopril, quinapril, ramipril, perindopril, moexipril, and trandolapril. Angiotensin II receptor blockers (ARBs) are known in the art and include, but are not limited to, losartan, valsartan, telmisartan, irbesartan, azilsartan, and olmesartan. The patient may be receiving insulin and a stable dose of an ACEI or ARB. In certain embodiments, patients receiving the therapy of the present disclosure are not receiving one or more of the following treatments: combination therapy with both an ACEI and an ARB, combination therapy with an SGLT-2 / SGLT-1 inhibitor or a GLP1 receptor agonist, combination therapy with a strong CYP3A4 inhibitor, combination therapy with a moderate / strong CYP3A4 inducer, combination therapy with an MRA other than finerenone, and / or combination therapy with any renin inhibitor, sacubitril / valsartan combination, or potassium-sparing diuretic. Examples of moderate CYP3A4 inhibitors include amiodarone, aprepitant, bicalutamide, chloramphenicol, imatinib, mifepristone, norfloxacin, tacrolimus, verapamil, lapatinib, dasatinib, and nilotinib.

[0032] According to one aspect of the present invention, the proposed method further includes assessing the patient's UACR before receiving finerenone. The patient's baseline UACR can be measured before initiating administration of finerenone. The baseline UACR can be measured upon the patient's first administration of finerenone. According to the method of the present invention, the patient may have (1) albuminuria, (2) a UACR of 150, 200, 250, 300, 350, 400, 450, or 500 mg / g or greater, and / or (3) a UACR of 30-5000, 200-5000, 200-4000, 200-3000, or 200-2000 mg / g. In one embodiment, the patient has a UACR of 200-5000 mg / g prior to administration of finerenone. In one embodiment, the patient has a UACR of 30-1000, 200-1000, or 200-1000 mg / g prior to administration of finerenone, hi one embodiment, the patient has a UACR of 300-1000, 300-5000, 300-4000, 300-3000, or 300-2000 mg / g.

[0033] In one embodiment, the patient has a UACR of 200 mg / g or less before administration of finerenone. In one embodiment, the patient has a UACR of 200 mg / g or more before administration of finerenone. In one embodiment, the patient has a UACR of 300 mg / g or less before administration of finerenone. In one embodiment, the patient has a UACR of 300 mg / g or more before administration of finerenone. In one embodiment, the patient has a UACR of 200-5000 mg / g before administration of finerenone. In one embodiment, the patient has a UACR of 300-1000 mg / g before administration of finerenone. In one embodiment, the patient has a UACR of 200-1000 mg / g before administration of finerenone. In one embodiment, the patient has a UACR of 400-5000 mg / g before administration of finerenone. In one embodiment, the patient has a UACR of 1000 mg / g or less before administration of finerenone. In one embodiment, the patient has a UACR of 1000 mg / g or greater before administration of finerenone. In one embodiment, the patient has a UACR of 5000 mg / g or less before administration of finerenone. In one embodiment, the patient has a UACR of 5000 mg / g or greater before administration of finerenone.

[0034] In one embodiment, the patient has (1) albuminuria and (2) a UACR of 200 mg / g or less before administration of finerenone. In one embodiment, the patient has (1) albuminuria and (2) a UACR of 200 mg / g or more before administration of finerenone. In one embodiment, the patient has (1) albuminuria and (2) a UACR of 300 mg / g or less before administration of finerenone. In one embodiment, the patient has (1) albuminuria and (2) a UACR of 300 mg / g or more before administration of finerenone. In one embodiment, the patient has (1) albuminuria and (2) a UACR of 200-5000 mg / g before administration of finerenone. In one embodiment, the patient has (1) albuminuria and (2) a UACR of 300-1000 mg / g before administration of finerenone. In one embodiment, the patient has (1) albuminuria and (2) a UACR of 200-1000 mg / g before administration of finerenone. In one embodiment, the patient has (1) albuminuria and (2) a UACR of 400-5000 mg / g before administration of finerenone. In one embodiment, the patient has (1) albuminuria and (2) a UACR of 1000 mg / g or less before administration of finerenone. In one embodiment, the patient has (1) albuminuria and (2) a UACR of 1000 mg / g or more before administration of finerenone. In one embodiment, the patient has (1) albuminuria and (2) a UACR of 5000 mg / g or less before administration of finerenone. In one embodiment, the patient has (1) albuminuria and (2) a UACR of 5000 mg / g or more before administration of finerenone.

[0035] In one embodiment, the patient: (1) Albuminuria, and (2) UACR of 300 mg / g or less, UACR of 300 mg / g or more, UACR of 300 to 1000 mg / g, UACR of 1000 mg / g or less, or UACR of 1000 mg / g or more It has.

[0036] In one embodiment, the patient has (1) albuminuria and (2) a UACR of 300 mg / g or less before administration of finerenone. In one embodiment, the patient has (1) albuminuria and (2) a UACR of 300 mg / g or more before administration of finerenone. In one embodiment, the patient has (1) albuminuria and (2) a UACR of 300-1000 mg / g before administration of finerenone. In one embodiment, the patient has (1) albuminuria and a UACR of 1000 mg / g or less before administration of finerenone. In one embodiment, the patient has (1) albuminuria and a UACR of 1000 mg / g or less before administration of finerenone.

[0037] As used herein, UACR values ​​are average values. In other embodiments, the disclosed methods are administered to patients with CKD and T1D without pre-selection of patients according to UACR levels or the presence of albuminuria.

[0038] According to another aspect of the present invention, the proposed method further comprises assessing the patient's eGFR before receiving finerenone. The patient's baseline eGFR level may be measured before initiating administration of finerenone. The baseline eGFR may be measured upon the patient's first administration of finerenone.

[0039] A baseline eGFR can be measured upon the patient's first administration of finerenone. The eGFR level can be determined using a blood test for creatine levels. The patient can be administered: (1) 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 75 mL / min / 1.73 m 2 or (2) eGFR of 15 to 90, 20 to 90, 25 to 90, 60 to 90, 25 to 75, or 25 to 60 mL / min / 1.73 m 2 may have an eGFR of

[0040] In one embodiment, the patient receives a blood glucose level of 25-90 mL / min / 1.73 m 2In another embodiment, prior to receiving finerenone or concurrently with the initiation of finerenone therapy, patients with type 1 diabetes have an eGFR of 200-5000 mg / g, an UACR of 25-90 mL / min / 1.73 m 2 have an eGFR of less than 0.01 and have been receiving a stable dose of an ACEI or ARB for more than 4 weeks.

[0041] The eGFR level can be determined using a blood test for creatine levels. In some embodiments, the patient has a blood glucose level of 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 75 mL / min / 1.73 m 2 have an eGFR of ≥ 90 mL / min / 1.73 m 2 In further embodiments, the patient receives less than 15-90, 20-90, 25-90, 30-90, 60-90, 25-75, or 25-60 mL / min / 1.73 m 2 In one embodiment, the patient has an eGFR of 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 75 mL / min / 1.73 m 2 In one embodiment, the patient has an eGFR of 25-90 mL / min / 1.73 m 2 have an eGFR of less than

[0042] In one embodiment, before receiving finerenone, the patient is administered a blood glucose level of 15 to 60 mL / min / 1.73 m 2 In one embodiment, before receiving finerenone, the patient has an eGFR of 20-60 mL / min / 1.73 m 2 In one embodiment, before receiving finerenone, the patient has an eGFR of 25-60 mL / min / 1.73 m 2 In one embodiment, before receiving finerenone, the patient has an eGFR of 30-60 mL / min / 1.73 m 2 In one embodiment, before receiving finerenone, the patient has an eGFR of 45-60 mL / min / 1.73 m 2 In one embodiment, the patient has an eGFR of 60-75 mL / min / 1.73 m2 In one embodiment, before receiving finerenone, the patient has an eGFR of 60-90 mL / min / 1.73 m 2 In one embodiment, before receiving finerenone, the patient has an eGFR of 15 to 90 mL / min / 1.73 m 2 In one embodiment, before receiving finerenone, the patient has an eGFR of 20-90 mL / min / 1.73 m 2 In one embodiment, before receiving finerenone, the patient has an eGFR of 25-90 mL / min / 1.73 m 2 In one embodiment, before receiving finerenone, the patient has an eGFR of 30-90 mL / min / 1.73 m 2 In one embodiment, before receiving finerenone, the patient has an eGFR of 45 to 90 mL / min / 1.73 m 2 have an eGFR of

[0043] In one embodiment, the patient receives a blood glucose level of 45 mL / min / 1.73 m 2 In one embodiment, the patient has an eGFR of 45 mL / min / 1.73 m 2 In one embodiment, the patient has an eGFR of 45-60 mL / min / 1.73 m 2 In one embodiment, the patient has an eGFR of 60 mL / min / 1.73 m 2 In one embodiment, the patient has an eGFR of 60 mL / min / 1.73 m 2 Have an eGFR of ≥ 100 mg / kg.

[0044] In another embodiment, prior to receiving finerenone or concurrently with the initiation of finerenone therapy, patients with T1D are administered a UACR of 200-5000 mg / g, a BP of 25-90 mL / min / 1.73 m 2 have an eGFR of less than 0.01 and have been receiving a stable dose of an ACEI or ARB for at least 4 weeks, at least 3 weeks, at least 2 weeks, or approximately 2-4 weeks prior to initiating finerenone therapy.

[0045] In one embodiment, the patient receives a blood pressure of 90 mL / min / 1.73 m 2have an eGFR of less than

[0046] In another embodiment, prior to receiving finerenone or concurrently with the initiation of finerenone therapy, patients with T1D are administered a UACR of 200-5000 mg / g, a BP of 25-90 mL / min / 1.73 m 2 have an eGFR of less than 0.01 and have been receiving a stable dose of an ACEI or ARB for at least 4 weeks.

[0047] One embodiment is a method of preventing or treating CKD in a patient with T1D, comprising administering to the patient a therapeutically effective amount of finerenone or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof, wherein prior to receiving finerenone, the patient: (1) 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 75 mL / min / 1.73 m 2 eGFR below or (2) 15-90, 20-90, 25-90, 30-90, 60-90, 25-75, or 25-60 mL / min / 1.73 m 2 eGFR The method has the following features:

[0048] In one embodiment, the patient before receiving finerenone: (1) 200 mg / g or less, or 200 mg / g or more, or 300 mg / g or less, or 300 mg / g or more, or 300-1000 mg / g, or 1000 mg / g or less, or 1000 mg / g or more, or 200 to 5000 mg / g, or 200-1000 mg / g, or UACR of 5000 mg / g or less, and (2)25mL / min / 1.73m 2 The following, or 25mL / min / 1.73m2 Greater than or equal to, or 45mL / min / 1.73m 2 The following, or 45mL / min / 1.73m 2 Greater than or equal to, or 45~60mL / min / 1.73m 2 ,or 45~90mL / min / 1.73m 2 ,or 25~60mL / min / 1.73m 2 ,or 25~90mL / min / 1.73m 2 ,or 60mL / min / 1.73m 2 The following, or 60mL / min / 1.73m 2 Greater than or equal to, or 90mL / min / 1.73m 2 eGFR below It has.

[0049] In further embodiments, finerenone may be administered to patients for at least three months or at least six months. In one embodiment, after administration of finerenone for at least three months or at least six months, the patient experiences a substantial decrease in UACR from baseline. In other embodiments, after administration of finerenone, after administration of finerenone for at least three months, or after administration of finerenone for at least six months, the patient experiences a decrease in UACR from baseline of at least 20%, 25%, 30%, 35%, 40%, or 50%.

[0050] The methods of the present invention may be used in T1D patients who have or are at risk of developing CKD, particularly patients who have one or more biomarkers that correlate with T1D.

[0051] Because T1D can be an autoimmune disease, autoimmune markers can be used to identify patients with T1D. Autoimmune markers for T1D include pancreatic islet cell autoantibodies, as well as autoantibodies against GAD (GAD65), insulin, tyrosine phosphatases IA-2 and IA-2β, and ZnT8. Type 1 diabetes can be defined by the presence of one or more of these autoimmune markers. (Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes, Diabetes Care 2019, 42(Suppl. 1):S13-S28). In one embodiment, the methods disclosed herein are used with T1D patients who have one or more of these markers.

[0052] The methods of the present invention can be used with adult T1D patients aged 18 years or older, adolescent T1D patients aged 12 to under 18 years, or 12 to 17 years or younger, and children, for example, children aged 2 to 11 years.

[0053] In treating cardiovascular and renal disorders, the authors have mentioned many possible combination therapies. In some embodiments, the methods do not involve specific drug combinations. For example, in some embodiments, the methods of the present invention involve administering finerenone to a patient who is not concurrently receiving one or more additional therapeutic agents selected from the group consisting of an SGLT2 inhibitor, a GLP1 receptor agonist, and a mineralocorticoid receptor antagonist other than finerenone. SGLT2 inhibitors are known and include, but are not limited to, canagliflozin, dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, ipragliflozin, remogliflozin, sergliflozin, sotagliflozin, and tofogliflozin. SGLT2 inhibitors, i.e., gliflozins, act by inhibiting sodium-glucose transporter protein 2 (SGLT2), thereby inhibiting glucose reabsorption in the kidney and resulting in lower blood glucose levels. SGLT2 inhibitors are used in the treatment of T2D. Glucagon-like peptide 1 (GLP-1) receptor agonists are known in the art and include, but are not limited to, dulaglutide (Trulicity®), exenatide extended-release (Bydureon®), exenatide (Byetta®), semaglutide (Ozempic®, Wegovy®), and liraglutide (Victoza®, Saxenda®), tirzepatide (Mounjaro®). Mineralocorticoid receptor antagonists other than finerenone include, but are not limited to, spironolactone, canrenone / canrenoic acid K+, eplerenone, esaxerenone (Minnebro®), LY3437943, KBP-5074, AZD9977, and aparalenone. In one embodiment, an SGLT2 inhibitor is not administered. In one embodiment, SGLT2 inhibitors are excluded from the treatment.

[0054] In some embodiments, the disclosed methods do not involve the co-administration of finerenone or the simultaneous administration of both an ACEI and an ARB. In another embodiment, the disclosed methods of treatment with finerenone do not involve co-treatment with a strong CYP3A4 inhibitor, a moderate / strong CYP3A4 inducer, any renin inhibitor, a combination of sacubitril / valsartan, or a potassium-sparing diuretic. Examples of moderate CYP3A4 inhibitors include amiodarone, aprepitant, bicalutamide, chloramphenicol, imatinib, mifepristone, norfloxacin, tacrolimus, verapamil, lapatinib, dasatinib, and nilotinib.

[0055] In one aspect, the present disclosure refers to a method of preventing or treating chronic kidney disease in a patient with type 1 diabetes, comprising administering to the patient a therapeutically effective amount of finerenone or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof.

[0056] In one aspect, the present invention refers to finerenone or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof for use in a method for preventing or treating chronic kidney disease in a patient with type 1 diabetes, the method comprising administering to the patient a therapeutically effective amount of finerenone or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof.

[0057] In a further aspect, the present invention refers to a method of slowing the progression of chronic kidney disease in a patient with chronic kidney disease associated with type 1 diabetes, comprising administering to the patient a therapeutically effective amount of finerenone or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof.

[0058] In a further aspect, the present invention refers to finerenone or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof for use in a method for slowing the progression of chronic kidney disease in a patient with chronic kidney disease associated with type 1 diabetes, the method comprising administering to the patient a therapeutically effective amount of finerenone or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof. In one embodiment, the method slows the decline in kidney function and the progression to end-stage renal disease or end-stage renal failure.

[0059] In another aspect, the present invention refers to a method for reducing the risk of sustained UACR decline in patients with chronic kidney disease associated with type 1 diabetes, comprising administering to the patient a therapeutically effective amount of finerenone or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof.

[0060] In another aspect, the present invention refers to finerenone or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof for use in a method for reducing the risk of sustained UACR decline in patients with chronic kidney disease associated with type 1 diabetes, the method comprising administering a therapeutically effective amount of finerenone or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof to the patient. In one embodiment, the method reduces the risk of end-stage renal disease or end-stage renal failure in the patient.

[0061] In a further embodiment, the present invention refers to a method for reducing UACR in a patient with chronic kidney disease associated with type 1 diabetes, comprising administering to the patient a therapeutically effective amount of finerenone or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof.

[0062] In one embodiment, the patient has a reduction in UACR of 30% or more from baseline after 6 months of finerenone treatment, where the baseline UACR is measured before or at the time of the patient's first administration of finerenone.

[0063] In one embodiment, before receiving finerenone, the patient receives 45 mL / min / 1.73 m 2 Below, 45mL / min / 1.73m 2 Above, 45~60mL / min / 1.73m 2 , 60mL / min / 1.73m 2 or less, or 60 mL / min / 1.73 m 2 In one embodiment, before receiving finerenone, the patient has an eGFR of 45 mL / min / 1.73 m 2 In one embodiment, before receiving finerenone, the patient has a baseline eGFR of 45-60 mL / min / 1.73 m 2 In one embodiment, before receiving finerenone, the patient has a baseline eGFR of less than 60 mL / min / 1.73 m 2 Have a baseline eGFR of ≥ 1.

[0064] In one embodiment, before receiving finerenone, the patient has a serum potassium of 4.5 mmol / L or less or 4.5 mmol / L or more.

[0065] In one embodiment, before receiving finerenone, the patient Less than 45, 45 to 60, or 60 mL / min / 1.73 m 2 baseline eGFR of ≥ 1, and / or a baseline UACR of <300 mg / g, 300-1000 mg / g, or >1000 mg / g, and / or Baseline serum potassium <4.5 or >4.5 mmol / L It has.

[0066] In one embodiment, the patient with type 1 diabetes is male or female.

[0067] In one embodiment, the patient with type 1 diabetes is under 65 years of age or over 65 years of age.

[0068] In one embodiment, the type 1 patient has no or no history of cardiovascular disease.

[0069] In one embodiment, prior to receiving finerenone, the patient with type 1 diabetes is Less than 45, 45 to 60, or 60 mL / min / 1.73 m 2 have a baseline eGFR of ≥ 100 mg / kg and / or had a baseline UACR of <300 mg / g, 300-1000 mg / g, or >1000 mg / g; and / or Have a baseline serum potassium of ≤4.5 or >4.5 mmol / L, and / or Male or female, and / or are under 65 or over 65 years old, and / or No or a history of cardiovascular disease.

[0070] In one embodiment, before receiving finerenone, the patient has a UACR of 200-5000 mg / g, a BP of 25-90 mL / min / 1.73 m 2 have an eGFR of less than 0.01 and have been receiving a stable dose of an ACEI or ARB for more than 4 weeks.

[0071] In one embodiment, the patient is receiving a stable dose of an ACEI or ARB prior to initiation of finerenone therapy.

[0072] In one embodiment, the patient is not concurrently administered one or more additional therapeutic agents selected from the group consisting of an SGLT2 inhibitor, a GLP1 receptor agonist, and a mineralocorticoid receptor antagonist other than finerenone.

[0073] In one embodiment, the patient is given finerenone at a daily dosage selected from the group consisting of 7.5 mg, 10 mg, 20 mg, and the range of 10 mg to 20 mg.

[0074] In one embodiment, the patient is given finerenone at a daily dosage selected from the group consisting of 7.5 mg, 10 mg, 20 mg, 40 mg, and the range of 10 mg to 40 mg.

[0075] In one embodiment, the treatment and / or prevention comprises slowing the progression of kidney disease in CKD associated with T1D. [Example]

[0076] 1. Studying finerenone in patients with T1D and CKD Study objectives and evaluation items The objective of this study was to evaluate the efficacy and safety of finerenone (10 mg and 20 mg, orally disintegrating tablets) compared with placebo in participants with T1D and CKD. The primary variable was the ratio of UACR over 6 months to UACR at baseline. The primary endpoint was to demonstrate that finerenone, added to existing standard of care, is superior to placebo in reducing UACR over 6 months in participants with CKD and T1D.

[0077] Study details include a seven-month study period per participant, a six-month treatment period per participant, and a clinic visit frequency of approximately once every one to three months.

[0078] The primary clinical question of interest is whether finerenone administration and placebo administration show differences, including differences in the effects of death and end-stage renal disease (ESRD).ESRD is defined as the development of renal disease leading to the initiation of chronic dialysis (hemodialysis or peritoneal dialysis) for at least 30 days or leading to kidney transplantation.In one embodiment, this primary clinical question includes examining differences in effects regardless of the discontinuation of treatment.

[0079] The most important intercurrent events (ICEs) measured are death and ESRD. These events are considered clinically significant and are addressed using a combined strategy. Therefore, the observed treatment effect is evaluated for the primary outcome and ICE. To address ICE from the perspective of the combined strategy, a "worst-case" approach is implemented. For participants experiencing ICE, subsequent UACR values ​​are set to the "worst-case" value. Assuming no upper limit for post-baseline UACR measurements, values ​​are drawn from the distribution of maximum UACR values ​​observed during the study (e.g., the worst 10% of UACR values). To avoid underestimation of standard errors, multiple imputation methods are adapted.

[0080] The population-level summary is the geometric mean ratio of the "ratio to baseline" for the treatment groups over the study period (i.e., the mean of the geometric means of the treatment effects at the 3- and 6-month visits).

[0081] The study will also evaluate the safety of finerenone added to standard of care compared with placebo. Safety endpoints include treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), and / or the number of participants with hyperkalemia. The study also has exploratory endpoints. The study will demonstrate these exploratory endpoints: the percentage of participants with a 30% or greater decrease in UACR from baseline at 6 months; the percentage of participants with a 50% or greater decrease in UACR from baseline at 6 months; the change in UACR from baseline to 3 months; and the change in UACR from baseline to 6 months. Another exploratory endpoint is the use of biomarkers to further investigate the study intervention, such as efficacy and safety related to mechanisms of action and pathological mechanisms associated with renal and cardiovascular disease, including diabetes, and associated health problems.

[0082] research design This study is a double-blind, parallel-group intervention study in patients with CKD type 1 disease (further eligibility characteristics are described below) with two treatment arms, including a placebo arm. Participants who meet all eligibility criteria will be randomized in a 1:1 ratio to receive finerenone or placebo in addition to standard of care. Approximately 440 participants will be screened to obtain 220 participants randomly assigned to the study intervention (110 evaluable participants per intervention arm), with 90% power to detect a treatment difference of at least 30%.

[0083] All participants will receive the blinded study intervention of finerenone 10 mg, finerenone 20 mg, or placebo once daily in addition to either an ACEI or an ARB.

[0084] The starting dose was determined by the participant's eGFR level at the screening visit; i.e., eGFR ≤ 25–60 mL / min / 1.73 m 2 Lower dose of 10 mg once daily if < CKD (CKD-EPI) or eGFR 60 mL / min / 1.73 m 2 If the CKD-EPI is above 5.5 mmol / L, the high dose (target dose) is 20 mg once daily. Participants starting on the low dose of 10 mg will be titrated to the target dose of 20 mg after month 1, provided that potassium is below 4.8 mmol / L and the eGFR has declined less than 30% since the last measurement. Titration and tapering of the study intervention will be based on local potassium and eGFR values. For safety reasons, tapering or discontinuation of the study intervention is permitted at any time during the study, and the study intervention will be discontinued if potassium exceeds 5.5 mmol / L.

[0085] Visits will occur at screening, baseline, months 1, 3, and 6 (end of planned treatment), and month 7. Further details are provided in the schedule of activities in Table 1 and in the scheme showing the study timeline in Figure 1.

[0086] [Table 1A] [Table 1B]

[0087] The planned treatment duration for participants is 6 months, and the planned follow-up period is 7 months. Additional visits will occur 4 weeks after titration and after resuming the study intervention after a treatment break of more than 7 days.

[0088] The UACR as the primary endpoint and serum potassium as the primary safety parameter will be assessed according to the scheduled visits. UACR will be collected at screening, baseline, month 3, and month 6 at the end of treatment. eGFR will be collected at all designated UACR collection time points, plus at month 1 to assess accrual and at month 7 to assess renal function 4 weeks after treatment discontinuation.

[0089] UACR is a measure of albuminuria, a predictor of long-term adverse renal and cardiovascular outcomes in patients with type 2 diabetes. (Fox et al., Lancet. 2012 Nov 10;380(9854):1662-73; Heerspink et al., Lancet Diabetes Endocrinol. 2019;7(2):128-39) Post-hoc analyses of randomized clinical trials suggest that significant reductions in albuminuria may lead to protection from declines in renal function and cardiovascular events in patients with diabetic kidney disease. (Heerspink et al., Eur J Prev Cardiol. 2014 Mar;21(3):299-309; Levey et al., Am J Kidney Dis. 2020 Jan;75(1):84-104) For every 30% decrease in albuminuria, a 23.7% decrease in risk of ESRD can be expected (95% confidence interval 11.4%-34.2%; p=0.001). (Heerspink and Gansevoort Clin J Am Soc Nephrol. 2015 Jun 5;10(6):1079-88). Changes in UACR can be detected early in response to treatment.

[0090] Eligibility Participant selection criteria: 1. Age: Participants must be 18 years of age or older. 2. Participants have been diagnosed with T1D (ADA 2020 definition), i.e., initiated insulin treatment for T1D within one year of diagnosis and are continuously receiving insulin therapy. If onset occurs after age 35, participants have one or more of the following: Circulating T1D-associated autoantibodies - History of hospitalization for diabetic ketoacidosis · Plasma C-peptide below the limit of detection in standard assays (current blood glucose >100 mg / dl). 3. Participants must have an HbA1c <10% (central assessment) at the screening visit. 4. K at screening visit + is 4.8mmol / L or less (local evaluation) 5. Participant has a clinical diagnosis of CKD and meets both of the following criteria (centrally assessed): - eGFR ≥ 25 and 90 mL / min / 1.73 m at screening visit 2 less than - UACR at the time of screening visit is 200 mg / g (22.6 mg / mmol) or more but less than 5000 mg / g (565 mg / mmol) 6. Participants are treated with a stable (preferably no change in dosage for at least 4 weeks prior to the screening visit) dose of an ACEI or ARB (but not both) at the time of the screening visit. Preferably, the stable dose of ACEI or ARB will not change throughout the study. Table 2 details the patient population.

[0091] [Table 2]

[0092] Participants were excluded from the study if they had any of the following medical conditions: type 2 disease (T2D), other known causes of CKD other than type 1 disease (T1D), kidney transplant, symptomatic heart failure with reduced ejection fraction with a class 1A indication for magnetic resonance imaging (MRA), Addison's disease, hospitalization for a CV event (decompensated heart failure, acute coronary syndrome, stroke, transient ischemic attack, acute limb ischemia) within 4 weeks prior to the screening visit, acute kidney injury requiring dialysis within 24 weeks prior to the screening visit, active cancer, liver disease (Child-Pugh C, determined using the Child-Pugh score, which grades the severity of liver disease, adapted from Pugh et al., Br J Surg. 1973 Aug;60(8):646-9), and a mean blood pressure (BP) >160 / 100 mmHg or a mean systolic BP (SBP) <90 mmHg at the time of the screening visit. Participants will also be excluded from the study if they are receiving any of the following prior / concomitant therapy: (1) concomitant dual therapy with both an ACEI and an ARB that has not been discontinued at least 8 weeks prior to the screening visit; (2) current or previous (within 8 weeks prior to the screening visit) treatment with an SGLT2 / 1 inhibitor, a GLP-1 receptor agonist, or an MRA other than finerenone (e.g., eplerenone, spironolactone, canrenone, esaxerenone, AZD9977, and KBP-5074 (osedurenone)); (3) concomitant treatment with a strong CYP3A4 inhibitor that has not been discontinued at least 7 days prior to randomization; (4) concomitant treatment with a moderate / strong CYP3A4 inducer that has not been discontinued at least 7 days prior to randomization; and (5) concomitant treatment with any renin inhibitor, sacubitril / valsartan combination, or potassium-sparing diuretic that has not been discontinued at least 8 weeks prior to the screening visit.

[0093] Statistical methods and sample size UACR was analyzed assuming a log-normal distribution. The UACR ratio at 6 months relative to baseline was assumed to be ≥200 mg / g and eGFR 25–90 mL / min / 1.73 m 2 Based on the FIDELITY UACR mixture model restricted to patients.

[0094] Since the placebo is assumed to have no effect on UACR, for sample size calculations, the UACR ratio to baseline at 6 months is assumed to be 1.00 for the placebo group.

[0095] In the FIDELITY limited population, the UACR ratio relative to baseline in the finerenone group was 0.61 at 4 months and 0.53 at 12 months. Using interpolation, this value was estimated to be 0.59 at 6 months. As a conservative approach, we assumed a treatment ratio (finerenone / placebo) of 0.7 over 6 months (i.e., a 30% difference in the UACR ratio relative to baseline between finerenone and placebo). The standard deviation was calculated to range from 0.75 to 1.0 between months 4 and 12. Using linear interpolation, the standard deviation was assumed to be approximately 0.8 at 6 months.

[0096] A sample size of 214 participants [107 per group] provides 90% power at a 5% two-sided significance level to reject the null hypothesis of a treatment rate equal to 1, assuming a true treatment rate of 0.7 with an SD of 0.8. To account for the potential loss of information when applying a "worst-case" approach to the primary estimate, the sample size is increased by 2.6% (the calculated cumulative incidence of death and renal failure from the pool of FIDELIO-DKD and FIGARO-DKD patients) to ensure the desired power is achieved. Thus, the sample size is increased to 220 participants [110 per group].

[0097] safety The methods and products of the present invention involve doses that have been clinically proven to be safe and effective in T2D. Adverse events that affect whether the therapy of the present invention is safe include hyperkalemia, symptomatic hypotension, hyponatremia, acute kidney injury, and severe hypoglycemia. Complications include death and eGFR of 15 mL / min / 1.73 m 2 Renal failure, defined as less than 18 months of age, or renal replacement therapy (peritoneal dialysis or kidney transplantation) were included. Key safety endpoints are listed in Table 3.

[0098] [Table 3]

[0099] Other analyses Further subgroup analyses Exploratory subgroup analyses will be performed on the primary efficacy variable. A list of the primary and other subgroups to be analyzed is specified below. Analyses will include descriptive statistics, estimated ratios relative to baseline with 95% CI.

[0100] The subgroups can be: Baseline eGFR categories (eGFR <45, 45-60, 60 mL / min / 1.73 m 2 (End) Baseline UACR category (<300 mg / g, 300-1000 mg / g, >1000 mg / g) Baseline serum potassium (≤4.5, >4.5 mmol / L) Race (White, Black, Asian, Other) ·Gender (male, female) Age group (under 65, over 65) History of CV disease (no, yes)

[0101] 2. Measurement of Finerenone Polymorphism Lattice parameters of the compound of formula (I) in the crystalline form of polymorph I Polymorph I Crystal system Orthorhombic system Space group P2(1)2(1)2(1) Number of molecules per unit Cell 4 Length of axis a [Å] 7.8610(3) Length of axis b [Å] 11.7797(6) Length of axis c [Å] 20.1792(8) α[°]90 β[°]90 γ[°]90 Calculated density at 100K [g cm-3] 1.345

[0102] [Table 4A] [Table 4B]

[0103] [Table 5A] [Table 5B]

Claims

1. Finerenone or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof for use in a method for preventing or treating chronic kidney disease in a patient with type 1 diabetes, said method comprising administering a therapeutically effective amount thereof to said patient.

2. Prior to receiving finerenone, said patient with type 1 diabetes: (1) Albuminuria, (2) a UACR of 150, 200, 250, 300, 350, 400, 450, or 500 mg / g or greater; and / or (3) UACR of 30 to 5000, 200 to 5000, 200 to 4000, 200 to 3000, or 200 to 2000 mg / g 2. Finerenone or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof for use according to claim 1, having the formula:

3. Prior to receiving finerenone, said patient with type 1 diabetes: (1) 200 mg / g or less, or (2) 200 mg / g or more, or (3) 300 mg / g or less, or (4) 300 mg / g or more, or (5) 300 to 1000 mg / g, or (6) 1000 mg / g or less, or (7) 1000 mg / g or more, or (8) 200 to 5000 mg / g, or (9) 200 to 1000 mg / g, or (10) 5000mg / g or less 3. Finerenone or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof for use according to claim 1 or 2, having a UACR of:

4. Prior to receiving finerenone, said patient with type 1 diabetes: (1) 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 75 mL / min / 1.73 m 2 eGFR of ≥ 100 mg / kg, or (2) 15-90, 20-90, 25-90, 30-90, 60-90, 25-75, or 25-60 mL / min / 1.73 m 2 eGFR 4. Finerenone or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof for use according to any one of claims 1 to 3, having the formula:

5. Prior to receiving finerenone, said patient with type 1 diabetes: (1) 25mL / min / 1.73m 2 The following, or (2) 25mL / min / 1.73m 2 Greater than or equal to, or (3) 45mL / min / 1.73m 2 The following, or (4) 45mL / min / 1.73m 2 Greater than or equal to, or (5) 45-60mL / min / 1.73m 2 ,or (6) 45-90mL / min / 1.73m 2 ,or (7) 25-60mL / min / 1.73m 2 ,or (8) 25-90mL / min / 1.73m 2 ,or (9) 60mL / min / 1.73m 2 The following, or (10) 60mL / min / 1.73m 2 Greater than or equal to, or (11) 90 mL / min / 1.73 m 2 the following 5. Finerenone or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof for use in accordance with any one of claims 1 to 4, having an eGFR of

6. Before receiving finerenone, the patient with type 1 diabetes had a UACR of 200-5000 mg / g, a blood glucose level of 25-90 mL / min / 1.73 m 2 6. Finerenone or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof for use in accordance with any one of claims 1 to 5, in patients with an eGFR of less than 100 mg / kg and who have been receiving a stable dose of an ACEI or ARB for more than 4 weeks.

7. Finerenone or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof for use in accordance with any one of claims 1 to 6, wherein the patient is receiving a stable dose of an ACEI or ARB prior to initiation of finerenone therapy.

8. Finerenone or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof for use according to any one of claims 1 to 7, wherein the patient is not concurrently administered one or more additional therapeutic agents selected from the group consisting of SGLT2 inhibitors, GLP1 receptor agonists, and mineralocorticoid receptor antagonists other than finerenone.

9. 9. Finerenone or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof for use according to any one of claims 1 to 8, wherein the patient is given finerenone at a daily dosage selected from the group consisting of 7.5 mg, 10 mg, 20 mg, 40 mg, a range of 10 mg to 20 mg, and a range of 10 mg to 40 mg.

10. 10. Finerenone or a hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof for use according to any one of claims 1 to 9, wherein the patient is given a daily dose of 0.25 mg to 80 mg of finerenone.

11. Finerenone or a hydrate, solvate, pharmaceutically acceptable salt or polymorph thereof for use in a method for slowing the progression of chronic kidney disease in a patient with chronic kidney disease associated with type 1 diabetes, said method comprising the step of administering a therapeutically effective amount thereof to said patient, said use being defined according to any one of claims 2 to 10.

12. Finerenone or a hydrate, solvate, pharmaceutically acceptable salt or polymorph thereof for use in a method for reducing the risk of sustained UACR decline in patients with chronic kidney disease associated with type 1 diabetes, said method comprising the step of administering a therapeutically effective amount thereof to said patient, optionally before administering finerenone, said use being defined according to any one of claims 2 to 10.

13. Finerenone is a compound of formula (I) in the crystalline form of polymorph I 【Chemistry 1】 13. Finerenone for use according to any one of claims 1 to 12, wherein the X-ray diffraction pattern of said compound exhibits peak maxima in 2θ angles at 8.5, 14.1 and 19.

0.

14. Finerenone for use in accordance with any one of claims 1 to 12, wherein the finerenone is a compound of formula (I) in a polymorphic crystalline form, and the X-ray diffraction pattern of the compound further exhibits any one of peak maxima in 2θ angle at 17.2, 20.5, 25.6, and 26.

5.

15. 15. Finerenone is the compound of formula (I) in the crystalline form of polymorph I according to claim 14, wherein the IR spectrum of said compound has the following peaks: 3475, 2230, 1681, 1658, 1606, 1572, 1485, 1255, 1136, and 1031 cm －1 13. Finerenone for use according to any one of claims 1 to 12, which exhibits any one of the band maxima at

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