WO2022255760A1 - Pharmaceutical composition for preventing or treating diabetic hypertension-accompanied nephropathy - Google Patents

Abstract

The pharmaceutical composition of the present invention can effectively prevent or treat hypertension-accompanied diabetic nephropathy by blocking, suppressing, or delaying the onset of hypertension-accompanied diabetic nephropathy in advance or by alleviating hypertension-accompanied diabetic nephropathy or suppressing the progression of hypertension-accompanied diabetic nephropathy.

Description

Pharmaceutical composition for preventing or treating diabetic kidney disease accompanied by hypertension

The present invention relates to a pharmaceutical composition for preventing or treating diabetic kidney disease, comprising fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof. More specifically, the present invention relates to a pharmaceutical composition capable of preventing or inhibiting the progression of diabetic kidney disease and effectively improving various symptoms associated with diabetic kidney disease accompanied by hypertension.

Diabetes mellitus is a type of metabolic disease, such as lack of insulin secretion or normal function, and is characterized by hyperglycemia in which the concentration of glucose in the blood increases. Hyperglycemia causes various symptoms and signs and excretes glucose through urine. .

Peripheral neuropathy, autonomic neuropathy, macrovascular complications, microvascular complications, and other chronic complications can result if diabetic patients are exposed to hyperglycemia for a long time.

Diabetic kidney disease is one of the complications caused by diabetes, and is the most important cause of chronic renal failure, and occupies a large proportion of the causative diseases of all dialysis patients.

Diabetic kidney disease is mostly asymptomatic in the early stages, and as it progresses, there are no obvious symptoms other than proteinuria appearing in urine tests. Thus, the onset of diabetic kidney disease is diagnosed by the finding of microalbuminuria (excretion of albumin in urine 30 mg - 300 mg/24h).

However, as described above, it is not easy to diagnose diabetic kidney disease at an early stage because the time point at which microalbuminuria symptoms are discovered is also after the diabetic kidney disease has progressed considerably, and in most cases, it is discovered after the kidney disease has already progressed significantly.

Another clinical significance of diabetic kidney disease is the significant increase in mortality. The mortality rate of type 1 diabetic patients with overt proteinuria compared to normal people is significantly higher than that of type 1 diabetic patients with normoalbuminuria and normal people. That is, among diabetic patients, in the case of patients having kidney disease due to diabetes, the mortality rate is significantly increased.

Such diabetic kidney disease tends to increase its share in kidney disease with the increase in diabetic patients, and in particular, kidney disease patients caused by type 2 diabetes continues to increase.

However, until now, there are still few drugs with effective preventive or therapeutic effects on diabetic kidney disease, and conventionally used drugs have many side effects when used long-term, that is, hyperkalemia, even functional or organ stenosis due to renal artery stenosis. May cause acute renal failure.

Therefore, the development of new drugs for safe and effective prevention and treatment of diabetic kidney disease is very important.

[Prior art literature]

[Patent Literature]

(Patent Document 1) Korean Patent Registration No. 0354654

An object of the present invention is to provide a pharmaceutical composition for preventing or treating diabetic kidney disease accompanied by hypertension, comprising fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof. .

An object of the present invention is to provide a use of fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof for preventing or treating diabetic kidney disease accompanied by hypertension.

An object of the present invention is to provide a method for preventing or treating diabetic kidney disease accompanied by hypertension, comprising administering fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof. will be.

The present invention provides a pharmaceutical composition for preventing or treating diabetic kidney disease accompanied by hypertension, comprising fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof.

(1) More specifically, the pharmaceutical composition according to the present invention may prevent diabetic kidney disease accompanied by hypertension, including fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof. Or a pharmaceutical composition for treatment, wherein the pharmaceutical composition has a systolic blood pressure of 140 mmHg or more and less than 180 mmHg and a diastolic blood pressure of less than 110 mmHg; Estimated Glomerular Filtration Rate (eGFR) greater than or equal to 30 ml/min/1.73 m ² ; and to subjects with albuminuria of 30 mg/g or greater.

(2) In the above (1), the diabetes may be type 2 diabetes.

(3) In the above (1) or (2), the pharmaceutically acceptable salt may be a fimasartan potassium salt.

(4) In the above (1), (2) or (3), the hydrate may be fimasartan potassium salt trihydrate.

(5) The fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof according to any one of (1) to (4) above may be for oral administration.

(6) The fimasartan, pharmaceutically acceptable salt thereof, stereoisomer thereof, or hydrate or solvate thereof according to any one of (1) to (5) above may be administered once a day.

(7) The fimasartan, pharmaceutically acceptable salt thereof, stereoisomer thereof, or hydrate or solvate thereof according to any one of (1) to (6) above is administered once a day for about 24 weeks. It can be.

(8) The daily dose of the fimasartan, pharmaceutically acceptable salt thereof, stereoisomer thereof, or hydrate or solvate thereof according to any one of (1) to (7) above is about 60 mg to It may be about 120 mg.

(9) The fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof according to any one of (1) to (8) above can reduce albuminuria in the subject. .

(10) The method according to any one of (1) to (9) above, wherein the fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof reduces albuminuria in the subject by about 30% or more. can reduce

(11) The fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof according to any one of (1) to (10) above has an estimated glomerular filtration rate within about 24 weeks of administration ( eGFR) can be reduced.

(12) The fimasartan according to any one of (1) to (11) above, wherein the fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof lowers the systolic and diastolic blood pressure of the subject. can make it

(13) The fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof according to any one of (1) to (12) above lowers the systolic blood pressure of the subject to less than 140 mmHg. can be lowered to

(14) The fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof according to any one of (1) to (13) above lowers the systolic blood pressure of the subject to less than 130 mmHg. can be lowered to

(15) The method of any one of (1) to (14) above, wherein the fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof is a cardiovascular complex evaluation variable within about 24 weeks of administration. and without generating a renal composite endpoint, the cardiovascular composite endpoint was selected from the group consisting of myocardial infarction (MI), stroke, hospitalization due to heart failure and unstable angina, coronary artery revascularization, peripheral vascular revascularization, and death. At least one is selected, and the renal composite evaluation variable may be at least one selected from the group consisting of a decrease of about 50% or more in estimated glomerular filtration rate (eGFR) compared to baseline, progression to end-stage renal failure, and death.

In the present invention, the systolic blood pressure (SBP) may be sitting systolic blood pressure (SiSBP), and the diastolic blood pressure (DBP) may be sitting diastolic blood pressure (SiDBP) ) can be.

In the present invention, the diabetic nephropathy accompanied by hypertension refers to renal failure in patients with diabetes accompanied by hypertension, and is a representative complication caused by diabetes. In a diabetic patient accompanied by high blood pressure, the glomeruli inside the kidney is damaged due to hyperglycemia caused by diabetes, and kidney function is deteriorated, resulting in kidney disease.

Diabetic kidney disease accompanied by hypertension does not show any special symptoms other than the detection of fine albumin in the urine, so treatment is generally delayed, and as a result, it leads to chronic renal failure, requiring kidney transplantation or death. do.

Therefore, it is important to prevent diabetic kidney disease from occurring in a subject with diabetes accompanied by hypertension, or to delay the occurrence of diabetic kidney disease as much as possible. In addition, when diabetic kidney disease accompanied by hypertension develops, it is important to improve the symptoms or prevent the symptoms from worsening, thereby suppressing the progression of diabetic kidney disease accompanied by hypertension or delaying the progression of the disease. .

Fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof can effectively prevent or treat kidney disease caused by diabetes accompanied by hypertension. As a result, it is possible to prevent, suppress, or delay the onset of kidney disease in a subject suffering from diabetes accompanied by hypertension. In addition, it is possible to improve the symptoms of diabetic kidney disease accompanied by hypertension in a subject with diabetic kidney disease accompanied by hypertension, and to inhibit the progression of the kidney disease or to delay the progression of the disease to prevent aggravation of the disease. have.

Therefore, the composition according to the present invention can prevent diabetic kidney disease accompanied by hypertension from reaching chronic renal failure, thereby significantly reducing the patient's mortality. In addition, when diabetic kidney disease accompanied by hypertension leads to chronic renal failure, it eventually leads to dialysis. It is possible to delay or delay the start of dialysis.

In the present invention, the prevention refers to any action that prevents or suppresses the occurrence of diabetic kidney disease accompanied by hypertension or symptoms thereof by administering the pharmaceutical composition according to the present invention, or delays the onset of the disease. . For example, when the composition of the present invention is administered to a subject who develops diabetes accompanied by hypertension but does not have diabetic kidney disease accompanied by hypertension, the occurrence of diabetic kidney disease accompanied by hypertension or symptoms thereof is prevented. can be prevented or delayed.

In the present invention, the treatment improves and ameliorates diabetic kidney disease accompanied by hypertension or its symptoms by administering the pharmaceutical composition according to the present invention, or inhibits the progression of diabetic kidney disease accompanied by hypertension. It also refers to all actions that delay or delay the deterioration of diabetic kidney disease accompanied by hypertension. For example, when the composition of the present invention is administered to a subject suffering from diabetic kidney disease accompanied by high blood pressure, diabetic kidney disease accompanied by high blood pressure or symptoms thereof can be alleviated or improved. Alternatively, when the composition of the present invention is administered to a subject suffering from diabetic kidney disease accompanied by hypertension, the progression of diabetic kidney disease accompanied by hypertension or its symptoms is inhibited or delayed, thereby diabetic kidney disease accompanied by hypertension. As a result, the death rate due to diabetic kidney disease accompanied by hypertension can be significantly reduced by preventing chronic renal failure, and the start of dialysis can be delayed.

In the present invention, the treatment includes reducing mortality due to diabetic kidney disease accompanied by hypertension or delaying the start of dialysis.

The composition of the present invention prevents the occurrence of albuminuria and / or proteinuria, reduces the amount of albuminuria and / or proteinuria, when administered to a subject with diabetes with hypertension or a subject with diabetic kidney disease with hypertension , may delay the increase in albuminuria and/or proteinuria. In addition, the composition of the present invention can delay the decrease in estimated glomerular filtration rate when administered to a subject with diabetes accompanied by hypertension or a subject with diabetic kidney disease accompanied by hypertension.

In this specification, “and/or” is used as a term referring to all combinations that can be derived from a plurality of components.

In the present specification, “albuminuria” is a type of proteinuria in which albumin is not filtered by the kidneys and is excreted out of the body through urine. Gastric albuminuria is measured as the albumin-creatinine ratio in urine by collecting the first morning urine.

When the composition of the present invention is administered to a subject with diabetes accompanied by hypertension or a subject with diabetic kidney disease accompanied by hypertension, it can prevent albuminuria from increasing or reduce the level, or the level is increased can delay

When the composition of the present invention is administered, albuminuria in the subject is reduced.

When administering the composition of the present invention, the reduction rate of albuminuria may be about 30% or more.

When the composition of the present invention is administered, albuminuria excretion can be reduced to about 300 mg/g or less in a subject whose albuminuria excretion is greater than about 300 mg/g.

When the composition of the present invention is administered, albuminuria excretion can be reduced to less than about 30 mg/g in a subject with albuminuria excretion of about 300 mg/g or less.

When administering the composition of the present invention, the reduction of albuminuria may be about 300 mg/g or more, about 400 mg/g or more, or about 500 mg/g or more. At about 24 weeks of administration, the reduction in albuminuria may be about 500 mg/g or more.

When administering the composition of the present invention, the estimated glomerular filtration rate (eGFR) may decrease within about 24 weeks of administration.

When administering the composition of the present invention, systolic and diastolic blood pressure are reduced.

When administering the composition of the present invention, the subject's systolic blood pressure may drop to less than 140 mmHg, or less than 130 mmHg.

When the composition of the present invention is administered to a subject with diabetes accompanied by hypertension or a subject with diabetic kidney disease accompanied by hypertension, it can prevent glomerular sclerosis and fibrosis, thickening of the basement membrane in the glomerulus, and improve the above symptoms. or to prevent worsening of the symptoms by suppressing the symptoms or delaying their progression.

When the composition of the present invention is administered to a subject with diabetic kidney disease accompanied by hypertension, it can prevent or delay chronic renal failure by preventing or slowing the progression of diabetic kidney disease accompanied by hypertension, and as a result, the subject It can significantly reduce mortality or delay the start of dialysis.

The composition of the present invention can sufficiently and effectively prevent or treat diabetic kidney disease accompanied by hypertension even when only fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof is used as an active ingredient. .

The compositions of the present invention exhibit sufficient safety in the subject. For example, even if the composition of the present invention is administered to a subject with diabetes accompanied by hypertension or a subject with diabetic kidney disease accompanied by hypertension, hyperkalemia and resulting irregular heartbeat or cardiac arrest occur within about 24 weeks of administration. does not cause myocardial infarction or cerebral infarction, does not result in hospitalization for heart failure and unstable angina, does not result in the possibility of coronary revascularization and peripheral revascularization, and does not result in functional or tracheal renal artery stenosis It does not cause renal impairment such as acute renal failure. There is little or no toxicity, including other side effects. Therefore, fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof according to the present invention can be safely administered to subjects with diabetes accompanied by hypertension or diabetic kidney disease accompanied by hypertension. .

Specifically, the composition according to the present invention hardly generates a cardiovascular composite endpoint and/or a renal composite endpoint within an administration period of about 24 weeks.

Here, the cardiovascular composite evaluation variable is at least one selected from the group consisting of myocardial infarction (MI), stroke, hospitalization due to heart failure and unstable angina, coronary artery revascularization, peripheral vascular revascularization, and death, and renal composite The evaluation variable is one or more selected from the group consisting of a decrease of about 50% or more in estimated glomerular filtration rate (eGFR) compared to baseline, progression to end-stage renal failure, and death.

In the present invention, the subject refers to animals including humans, and includes, for example, mice, rats, other rodents, rabbits, dogs, pigs, cats, cows, sheep, horses, primates and humans. It may be a mammal, preferably a primate or a human, more preferably a human.

In the present invention, the diabetes may be insulin-dependent type 1 diabetes or non-insulin-dependent type 2 diabetes. Preferably, it may be non-insulin dependent type 2 diabetes.

In the present invention, the fimasartan may be a compound represented by Formula 1 below.

[Formula 1]

In the present invention, the pharmaceutically acceptable salt refers to inorganic acid salts, organic acid salts, and metal salts commonly used by pharmaceutical manufacturers to prepare pharmaceuticals, and examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid. organic acids include citric acid, acetic acid, lactic acid, tartaric acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, benzoic acid, gluconic acid, glycolic acid, succinic acid, 4-morpholineethanesulfonic acid , Camphorsulfonic acid, 4-nitrobenzenesulfonic acid, hydroxy-O-sulfonic acid, 4-toluenesulfonic acid, calacturonic acid, emboic acid, glutamic acid, aspartic acid, adipic acid, or camsylic acid may be used, and the metal is sodium, Potassium, calcium or magnesium may be used.

In the present invention, the fimasartan salt may preferably be a fimasartan potassium salt, hydrochloride, calcium salt, sulfate, adipate salt, camsylate salt or besylate salt, more preferably a potassium salt. These can be purchased commercially, and can be prepared by a known method (eg, Republic of Korea Patent Registration No. 0354654).

In the present invention, the hydrate may include a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

In the present invention, the solvate may include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvent refers to a common organic solvent used in the production of organic compounds, for example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-acetate, acetone, acetic acid, no Sol, tetrahydrofuran, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate, dimethyl sulfoxide, pentane, heptane, etc., but examples thereof are limited to the solvates of the present invention. It is not.

In the present invention, the hydrate and solvate may contain water or solvent in a ratio of about 0.25 to about 10 moles, for example, about 0.5 mole, about 1 mole, about 1 mole of fimasartan potassium. 1.5 mol, about 2 mol, about 2.5 mol, about 3 mol, about 5 mol, etc., more preferably about 1 mol or about 3 mol of water per 1 mol of fimasartan potassium. For example, the pharmaceutical composition may include fimasartan potassium salt monohydrate or fimasartan potassium salt trihydrate.

In the present invention, the pharmaceutical composition may contain fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof in an amount of about 5% to about 60% by weight based on the total weight of the composition. It may be included, preferably about 10% by weight to about 50% by weight.

In the present invention, the pharmaceutical composition may further include a pharmaceutically acceptable additive. The term "pharmaceutically acceptable" means physiologically acceptable and, when administered to humans, usually does not cause allergic reactions such as gastrointestinal disorders, dizziness, or similar reactions. As for commonly used, reference may be made to Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton PA.

The additives may be carriers, excipients, extenders, antioxidants, buffers, fillers, anti-agglomerating agents, lubricants, wetting agents, flavoring agents, emulsifiers, suspending agents, surfactants and preservatives. For example, the additives include lactose, dextrose, calcium silicate, corn starch, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, Methyl Cellulose, Polyvinylpyrrolidone, Water, Methylhydroxybenzoate, Propylhydroxybenzoate, Talc, Stearic Acid, Magnesium Stearate, Calcium Stearate, Mineral Oil, Saline, Glucose Solution, Pseudosugar Solution, Alcohol, Glycol , ether (eg polyethylene glycol 400), oil, fatty acid, fatty acid ester, glyceride, or a mixture thereof. However, the additives that may be included in the composition according to the present invention are not limited to the materials listed above, and these are only examples.

The pharmaceutical composition of the present invention may be formulated according to a conventional method, and may be prepared as a preparation for oral administration or a preparation for parenteral administration. For example, the pharmaceutical composition of the present invention may be formulated for oral administration.

In the present invention, the preparation for oral administration may be a solid preparation such as tablets, pills, powders, granules, capsules, etc., or liquid preparations such as suspensions, solutions for internal use, emulsions, syrups, etc., preferably solid preparations. It can be one, more preferably it can be a tablet.

When the pharmaceutical composition of the present invention is formulated as an oral solid preparation, examples of additives used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate , gelatin, talc, and the like.

When the pharmaceutical composition is formulated as a liquid formulation for oral administration, various additives such as simple diluents such as water, liquid, and paraffin, wetting agents, sweeteners, fragrances, preservatives, preservatives, and coloring agents may be added to the pharmaceutical composition to be formulated. can

When the pharmaceutical composition of the present invention is prepared in the form of an injection, the additives include water, saline, aqueous glucose solution, similar aqueous sugar solution, alcohol, glycol, ether (eg polyethylene glycol 400), oil, fatty acid, fatty acid ester, glycerine Ride etc. are mentioned.

In the present invention, the content of the additives included in the pharmaceutical composition is not particularly limited and may be appropriately adjusted within the range of content used in conventional formulations.

In the present invention, the pharmaceutical composition contains fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof in an amount of about 1 mg to about 240 mg, or about 1 mg to about 240 mg of fimasartan. about 120 mg, about 30 mg to about 180 mg, about 60 mg to about 120 mg, about 60 mg or about 120 mg.

In the present invention, the pharmaceutical composition may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically applied), and the dosage is the patient's weight, age, sex, health The range may vary depending on the condition, diet, administration time, administration method, administration period or interval, excretion rate, constitutional specificity, nature of the preparation, severity of the disease, and the like. For example, based on a general adult weighing about 60 kg, fimasartan can be administered orally so that the dosage is about 1 mg to about 240 mg per day, preferably about 30 mg to about 180 mg per day. may be applied once a day or divided into several times.

In the present invention, the daily dosage of the fimasartan, its pharmaceutically acceptable salt, its stereoisomer or its hydrate or solvate in the pharmaceutical composition is about 1 mg to about 240 mg, about 1 mg to about 120 mg, about 30 mg to about 180 mg, about 60 mg to about 120 mg, about 60 mg or about 120 mg.

In the present invention, in the pharmaceutical composition, the fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a hydrate or solvate thereof is about 1 mg to about 240 mg, or about 1 mg to about It may be administered once a day at a dose of 120 mg, about 30 mg to about 180 mg, about 60 mg to about 120 mg, about 60 mg or about 120 mg.

In the present invention, in the pharmaceutical composition, the fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a hydrate or solvate thereof is about 1 mg to about 240 mg, or about 1 mg to about 120 mg, about 30 to about 180 mg, about 60 mg to about 120 mg, about 60 mg or about 120 mg may be administered once a day for about 24 weeks.

In the present invention, the pharmaceutical composition may further contain active ingredients having other pharmacological activities in addition to the fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof.

In addition to the fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof, the composition of the present invention may further include an antihypertensive agent, a diuretic agent, a therapeutic agent for hyperlipidemia, an antiobesity agent, or a therapeutic agent for diabetes. For example, the composition of the present invention contains amlodipine, nifedipine, verapamil, diltiazem, nicardipine, Lercardipine, atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, simvastatin, rosuvastatin, nicotinic acid, theophylline, caffeine, theobromine, aminophylline, hydrochlorothiazide, bendroflumethiazide, alogl liptin, saxagliptin, sitagliptin, metformin, exenatide, rosiglitazone, pioglitazone, tolbutamide, troglitazone, leptin, ephedrine, fenfluramine, fluoxetine, and the like.

The pharmaceutical composition of the present invention can be used alone or in combination with methods using surgery, hormone therapy, drug therapy, and biological response modifiers for the improvement, alleviation, treatment, or prevention of diabetic kidney disease.

(16) The present invention prevents or prevents diabetic kidney disease accompanied by hypertension by administering a pharmaceutical composition containing fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof to a subject. provides a way to treat The subject has a systolic blood pressure of 140 mmHg or more and less than 180 mmHg and a diastolic blood pressure of less than 110 mmHg; an estimated glomerular filtration rate (eGFR) greater than or equal to 30 ml/min/1.73 m ² ; and albuminuria greater than or equal to 30 mg/g.

(17) The present invention provides a use of fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof for preventing or treating diabetic kidney disease accompanied by hypertension. At this time, fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a hydrate or solvate thereof has a systolic blood pressure of 140 mmHg or more and less than 180 mmHg and a diastolic blood pressure of less than 110 mmHg; an estimated glomerular filtration rate (eGFR) greater than or equal to 30 ml/min/1.73 m ² ; and albuminuria of 30 mg/g or greater;

(18) The present invention relates to the use of fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof for the preparation of a medicament for preventing or treating diabetic kidney disease accompanied by hypertension. to provide. At this time, fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a hydrate or solvate thereof has a systolic blood pressure of 140 mmHg or more and less than 180 mmHg and a diastolic blood pressure of less than 110 mmHg; an estimated glomerular filtration rate (eGFR) greater than or equal to 30 ml/min/1.73 m ² ; and albuminuria of 30 mg/g or greater;

In each of (2) to (15), the contents of (1) above may be equally applied to any one of (16) to (18) above.

The pharmaceutical composition according to the present invention, comprising fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof, can effectively prevent or treat diabetic kidney disease accompanied by hypertension. have. The pharmaceutical composition according to the present invention can prevent or inhibit the onset of diabetic kidney disease accompanied by hypertension, and also improve diabetic kidney disease accompanied by hypertension or diabetic kidney disease accompanied by hypertension. The progression or worsening of the disease can be inhibited.

Hereinafter, examples will be described in detail to aid understanding of the present invention. However, the following examples are merely illustrative of the contents of the present invention, but the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

Example

1. Subject selection and distribution

Considering the dropout rate of about 20%, the subjects were divided into groups as follows. Test group A : Test group B = 1:1 (95 patients in each group).

Test group A is a standard blood pressure control group with a target systolic blood pressure of less than 140 mmHg, and test group B is a strict blood pressure control group with a target systolic blood pressure of less than 130 mmHg.

The actual number of test subjects is shown in the table below.

Inclusion Criteria

Subjects had to satisfy all of the following selection criteria to participate in this clinical trial unless otherwise specified.

(1) Adult men and women between the ages of 19 and 70

(2) Satisfy the following conditions at the time of screening (Visit 1)

- Blood pressure: Patients with the average blood pressure of the reference arm measured three times as follows (however, the average blood pressure is rounded to the first decimal place)

① Patients who have not taken antihypertensive medications within 3 months or are taking antihypertensive medications other than ACEI/ARB (Angiotensin Converting Enzyme Inhibitor/Angiotensin Receptor Blocker) at the time of screening: 140 mmHg ≤ SBP < 180 mmHg, and DBP < 110 mmHg

② Patients taking antihypertensive drugs including ACEI/ARB: 130 mmHg ≤ SBP < 180 mmHg, and DBP < 110 mmHg

- eGFR: 30 ml/min/1.73m ² (Modification of Diet in Renal Disease, MDRD) or more within 6 months

- Urine protein: satisfies one or more of the following conditions

① Patients with chronic kidney disease (CKD) whose albuminuria (ACR) excretion exceeds 300 mg/g (or mg/day) or proteinuria (PCR) excretion exceeds 500 mg/g (or mg/day) within 12 months

② At least 2 results of albuminuria (ACR) excretion of 30 mg/g to 300 mg/g (or mg/day) or proteinuria (PCR) excretion of 150 mg/g to 500 mg/g (or mg/day) within 12 months Patients with chronic kidney disease (CKD) with more than 12 weeks between two examinations

- Diabetes patients: Patients who have been diagnosed with type 2 diabetes at least 12 weeks ago and are currently receiving medication (provided that there is no change in the dosage and dosage of oral or injectable hypoglycemic agents for the past 12 weeks)

(3) Satisfy the following conditions at the baseline (Visit 3)

- Blood pressure: Patients whose average blood pressure of the reference arm measured 3 times is 140 mmHg ≤ SBP < 180 mmHg and DBP < 110 mmHg (however, average blood pressure is rounded off to the first decimal place)

- Patients with eGFR: 30 ml/min/1.73m ² (MDRD) or higher

- Urine protein: Patients with chronic kidney disease (CKD) whose albuminuria excretion is 30 mg/g or more as a result of spot urine ACR test

- Diabetic patients: If there is no change in the type of hypoglycemic agent during the placebo run-in period

(4) Those who voluntarily gave written consent to participate in the clinical trial after hearing the explanation about this clinical trial

(5) A person who understands the contents of the clinical trial, is cooperative with the progress of the trial, and is judged to be able to participate until the end of the clinical trial

Exclusion Criteria

If any of the following criteria were met, they were excluded from this clinical trial.

(1) Severely hypertensive patients with average SBP ≥ 180 mmHg or DBP ≥ 110 mmHg measured at screening (Visit 1) and baseline (Visit 3)

(However, at the screening visit, the blood pressure of both arms is used as the standard, and cases where even one arm is applicable are excluded. Average blood pressure is rounded off from the first decimal place)

(2) Patients with SBP ≥ 20 mmHg and DBP ≥ 10 mmHg in the selected arm blood pressure difference at the time of screening (Visit 1)

(3) Patients with less than 70% compliance with placebo in the placebo introduction period confirmed at baseline (Visit 3)

(4) Orthostatic hypotension patients with symptoms

(5) Insulin-dependent diabetes or uncontrolled diabetes [Those who have changed the type of oral or injection hypoglycemic agent within 12 weeks prior to screening (Visit 1), or those whose HbA1c exceeds 10% at screening (Visit 1) ]

(6) Patients with uncorrected sodium or body fluid depletion

(7) Patients with a history of or ongoing autoimmune diseases or connective tissue diseases such as all chronic inflammatory conditions or wasting diseases requiring chronic anti-inflammatory treatment, rheumatoid arthritis, systemic lupus erythematosus, etc.

(8) Those with a history of hypersensitivity to renin angiotensin system inhibitors

(9) Patients on dialysis, patients with clinically significant renal or liver diseases such as liver cirrhosis, biliary obstruction, bile secretion arrest, or liver failure, or those who show the following test findings at the screening visit (Visit 1)

① eGFR (MDRD) less than 30 ml/min/1.73m ²

② ALT or AST is more than 3 times the upper limit of normal (ULN)

③ Hypokalemia (less than 3.5 mmol/L) or hyperkalemia (more than 5.5 mmol/L)

(10) Patients who have been diagnosed with or treated for any of the following diseases within the last 6 months and are judged by the investigator to be clinically meaningful

① Patients with severe heart disease [heart failure (NYHA class III and IV), ischemic heart disease (angina pectoris, myocardial infarction), peripheral vascular disease, patients who have undergone percutaneous transvascular coronary angioplasty or coronary artery bypass grafting]

② Hypertrophic obstructive cardiomyopathy, severe obstructive coronary artery disease, aortic stenosis, hemodynamically significant aortic valve or mitral valve stenosis

③ Clinically significant ventricular tachycardia, atrial fibrillation, atrial flutter, arrhythmia, etc.

④ Patients with severe cerebrovascular disorders (stroke, cerebral infarction, cerebral hemorrhage, etc.)

⑤ Patients with known severity or malignant retinopathy, such as retinal effusion, hemorrhage, visual impairment, or retinal microaneurysm

(11) Patients with primary aldosteronism or pheochromocytoma

(12) Patients with a history of drug or alcohol abuse within the past 2 years

(13) Pregnant or lactating women

(14) Surgical or medical diseases that may affect drug absorption, distribution, metabolism, and excretion, and any of the following (but not limited to): gastrectomy, gastro-enterostomy ) or history of major gastrointestinal surgery, such as small bowel resection, gastrointestinal bypass, or gastrointestinal stapling, current active gastritis, gastrointestinal/rectal bleeding, active inflammatory bowel syndrome within the past 12 months, etc.

(15) Patients with unilateral or bilateral renal artery stenosis and severe congestive heart failure

(16) Patients with a history of malignant tumors within the past 5 years, or those currently undergoing treatment or in the process of malignant tumors

(17) Patients with genetic problems such as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption

(18) Those who have a history of hypersensitivity to the main ingredient or component of clinical trial drugs or clinically significant hypersensitivity to other drugs or additives (Yellow No. 4: Tartrazine, Yellow No. 5: Sunset Yellow FCF)

(19) If you are planning to become pregnant or have a possibility of becoming pregnant during the test period, but do not use an approved method of contraception (except for women who have undergone surgical sterilization. Women of childbearing age who have not been sterilized will be tested negative for pregnancy) Only cases judged to be eligible can participate in clinical trials, and effective contraceptive methods must be maintained throughout the entire clinical trial Periodic abstinence (e.g., basal body temperature method, natural cycle method, etc.) and abstinence are not considered acceptable contraceptive methods, and hormonal contraceptives use is not allowed)

(20) Those who are currently participating in other clinical trials under research and development other than this clinical trial, or those who have taken clinical drugs from other clinical trials within 3 months of the screening visit date

(21) Other investigators judge that participation in clinical trials is not appropriate

2. Clinical Trial Design

1) Drugs for clinical trials

This clinical trial drug was used within the expiration date.

(1) Test drug - Fimasartan

Ingredient Name and Active Ingredient Dosage: Fimasartan 60 mg, 120 mg

Product Name: Kanarb® Tablets

(2) Placebo : Placebo of Kanarb® tablets 60 mg

2) Dosage and administration method

This clinical trial is conducted with a screening and placebo introduction period of 6 weeks and a double-blind trial period of 24 weeks. In this application, the contents and results corresponding to the double-blind clinical trial period are presented in Table 1 below.

[Table 1]

3. Duration of treatment

Wash-out / Placebo run-in period: 4-6 weeks

Double blind period: 24 weeks

4. Test method

This phase 3 clinical trial was planned to compare and evaluate the efficacy of fimasartan (test group) on the change in albuminuria (ACR) in patients with diabetic kidney disease accompanied by hypertension, and to confirm the safety.

After the subject voluntarily agreed to participate in the clinical trial, the investigator conducted a screening test and medical history investigation to evaluate the suitability of the subject. As a result of the screening test, subjects who met the selection criteria and did not meet the exclusion criteria proceeded with a single blind placebo introduction period of at least 4 weeks. During this period, ACEI/ARB antihypertensive medication was discontinued, and other antihypertensive medications were continued without any change in dosage regimen. However, if the subject's safety is concerned due to blood pressure rise or if the subject's blood pressure is measured by themselves with the provided blood pressure monitor and SBP ≥ 180 mmHg or symptoms suspected of hypertension occur during the placebo introduction period, the subject visits the clinical trial institution and receives an ACEI / Antihypertensive drugs other than ARB were added or existing drugs were increased. In the pre-baseline visit (Pre-baseline Visit, Visit 2), a test for suitability evaluation was conducted, and the final selection was made in the baseline visit (Baseline Visit, Visit 3), and suitable subjects were randomized into one of the two groups. They were assigned (Fimasartan group A: Fimasartan group B = 1:1). Group A was a standard blood pressure control group (SBP < 140 mmHg), and group B was a strict blood pressure control group (SBP < 130 mmHg). Randomly assigned subjects took the clinical trial drug (fimasartan) corresponding to each administration group for 24 weeks, and then for an additional 120 weeks, while all subjects took fimasartan, disclosed into two groups according to blood pressure control criteria, group 2 , parallel trials are underway. For patients who were not controlled to the target blood pressure at each visit during the clinical trial period, the dose increase of the investigational drug and concomitant administration of other blood pressure lowering drugs were performed according to the prescribed dose titration criteria. Since the tester had to check the blood pressure control (titration) standard of the test subject, the blood pressure control group was conducted with a single blinding so that group A and group B could be identified, and from Visit 4 (Week 4), the target blood pressure for each group was To control, under the judgment of the previous investigator, the clinical trial drug was doubled or an additional antihypertensive agent other than ACEI/ARB was administered. During the double-blind, 4-group parallel test, subjects had a total of 7 visits [screening visit, pre-baseline visit, baseline visit, Visit 4 (4W), Visit 5 (8W), Visit 6 (12W), Visit 7 (24W)], and prescribed tests and evaluations were conducted at each visit.

After Visit 7, an open, group 2, parallel test is conducted for 120 weeks to confirm the efficacy and safety of the standard blood pressure control group and the strict blood pressure control group, and every 12 weeks (36W, 48W, 60W, 72W, 84W, 96W , 108W, 120W, 132W, 144W) are conducting efficacy and safety evaluation visits.

In this clinical trial, one re-screening was allowed, and written informed consent was obtained with the latest consent form approved by the IRB of each institution at the time of re-screening.

This clinical trial was conducted with a screening and placebo run-in period of 6 weeks, a double blind period of 24 weeks, and an open label period of 120 weeks (Table 2).

[Table 2]

5. Evaluation Criteria

Efficacy evaluation

1) Primary evaluation variable

Albuminuria at Week 24 from Baseline in Fimasartan Group ^* Change Rate

* Albuminuria measurement: spot urine ACR (albumin / creatinine ratio) measurement by collecting urine in the first morning

2) Main secondary evaluation variables

(1) Time to first occurrence of cardiovascular composite evaluation variable ^* according to blood pressure control criteria

* Cardiovascular composite endpoint: occurrence of myocardial infarction (MI) and stroke, hospitalization due to heart failure and unstable angina, coronary revascularization and peripheral vascular revascularization revascularization), death (all caused death)

(2) Time to first occurrence of height composite evaluation variable ^* according to blood pressure control criteria

* Renal complex evaluation variables: when eGFR decreases by 50% or more from baseline, when progression to ESRD is confirmed (initiation of long-term dialysis or kidney transplantation), and death (all caused death)

(3) Time to the first occurrence of cardiovascular and renal integrated composite evaluation variables according to blood pressure control criteria

3) Other secondary endpoints

(1) Change in albuminuria at 4, 8, and 12 weeks compared to the baseline of the fimasartan group

(2) Albuminuria change at 4, 8, 12, and 24 weeks compared to the baseline of the fimasartan group

(3) eGFR change rate and change amount at 4, 8, 12, and 24 weeks from baseline in the fimasartan group

(4) Among the subjects whose baseline albuminuria excretion exceeds 300 mg/g, the ratio of subjects whose albuminuria excretion has changed to less than 300 mg/g in the 4, 8, 12, and 24-week tests compared to baseline in the fimasartan group

(5) Among the subjects whose baseline albuminuria excretion was 300 mg/g or less, the ratio of subjects whose albuminuria excretion changed to less than 30 mg/g in the 4, 8, 12, and 24-week tests compared to baseline in the fimasartan group

(6) Proportion of subjects whose albuminuria decreased by 30% or more at 4, 8, 12, and 24 weeks compared to baseline in the fimasartan group

(7) Proportion of subjects whose eGFR decreased by 50% or more at 4, 8, 12, and 24 weeks from baseline in the fimasartan group

The evaluation variables (8) to (13) below were planned to be evaluated at 4, 8, 12, 24, 36, 48, 72, 96, 120, and 144 weeks from baseline, but in this application, the double-blind clinical trial period The corresponding results were presented.

(8) Albuminuria change rate/change amount at 4, 8, 12, and 24 weeks compared to baseline according to blood pressure control criteria

(9) eGFR change rate/change amount at 4, 8, 12, and 24 weeks from baseline according to blood pressure control criteria

(10) Among the subjects whose baseline albuminuria excretion exceeds 300 mg/g, the ratio of subjects whose albuminuria excretion has changed to less than 300 mg/g at 4, 8, 12, and 24 weeks from the baseline according to blood pressure control criteria

(11) Among the subjects whose baseline albuminuria excretion was 300 mg/g or less, the ratio of subjects whose albuminuria excretion changed to less than 30 mg/g at 4, 8, 12, and 24 weeks from the baseline according to blood pressure control criteria

(12) Proportion of subjects whose albuminuria decreased by 30% or more at 4, 8, 12, and 24 weeks compared to baseline according to blood pressure control criteria

(13) Proportion of subjects whose eGFR decreased by 50% or more at 4, 8, 12, and 24 weeks from baseline according to blood pressure control criteria

4) Exploratory endpoints

(1) SiSBP change at 4, 8, 12, and 24 weeks from baseline

(2) SiDBP change at 4, 8, 12, and 24 weeks from baseline

safety assessment

Adverse events, laboratory tests (hematological/biochemical/urinalysis), electrocardiogram and chest X-ray examination, physical examination, orthostatic hypotension test, abnormal changes in vital signs (pulse, weight)

6. STATISTICAL METHODS

Basic demographic data and baseline characteristics

Demographic data and baseline characteristics of all subjects included in this clinical trial were summarized for each administration group using the Full Analysis Set (FAS). For continuous type data, descriptive statistics (number of subjects, mean, standard deviation, median, minimum value, maximum value) were presented, and categorical data were summarized by frequency (N) and ratio (%). For comparison between administration groups, two sample t-test or Wilcoxon rank sum test was performed for continuous variables, and chi-square test or Fisher's exact test was performed for categorical variables to confirm statistical significance.

Efficacy evaluation

In the evaluation of efficacy, the main analysis target group was PPS (Per Protocol Set), but the FAS (Full Analysis Set) was also analyzed and evaluated together.

1) Primary efficacy evaluation variable

Change in albuminuria at 24 weeks compared to baseline in the fimasartan group

Descriptive statistics (number of subjects, mean, standard deviation, median value, minimum value, maximum value) were presented for each administration group for albuminuria levels and change rates at baseline (Visit 2) and week 24 (Visit 7). A one-sample t-test was conducted for the change rate within the administration group, and a two-sample t-test was performed for the difference between the two groups. If the data did not satisfy normality according to the normality test (Shapiro-Wilk statistic), the Wilcoxon signed rank test was used to test the change rate within the treatment group, and the Wilcoxon rank sum test was used to measure the difference between the two groups.

2) Key secondary efficacy endpoints

(1) Time to first occurrence of cardiovascular complex evaluation variables according to blood pressure control criteria

(2) Time to first occurrence of height composite evaluation variable according to blood pressure control criteria

(3) Time to the first occurrence of cardiovascular and renal integrated composite evaluation variables according to blood pressure control criteria

The incidence of cardiovascular, renal, combined cardiovascular and renal composite endpoints was estimated using Kaplan-Meier curves, and median values and 95% confidence intervals were presented. In addition, differences between groups were tested using the Log-rank test. In addition, descriptive statistics (number of subjects, average, standard deviation, median, minimum, maximum) of SBP values at baseline and 24 weeks from baseline for each group were presented.

3) Other secondary efficacy endpoints

(1) Change in albuminuria at 4, 8, and 12 weeks compared to the baseline of the fimasartan group

(2) Albuminuria change at 4, 8, 12, and 24 weeks compared to the baseline of the fimasartan group

(3) eGFR change rate and change amount at 4, 8, 12, and 24 weeks from baseline in the fimasartan group

(4) Proportion of subjects whose albuminuria excretion exceeded 300 mg/g at baseline and whose albuminuria excretion changed to less than about 300 mg/g at 4, 8, 12, and 24 weeks from baseline in the fimasartan group

(5) Ratio of subjects whose albuminuria excretion was less than about 30 mg/g at 4, 8, 12, and 24 weeks compared to the baseline in the fimasartan group among subjects with baseline albuminuria excretion of about 300 mg/g or less

(6) Proportion of subjects whose albuminuria decreased by about 30% or more at 4, 8, 12, and 24 weeks compared to baseline in the fimasartan group

(7) Ratio of subjects whose eGFR decreased by 50% or more at 4, 8, 12, and 24 weeks compared to baseline in the fimasartan group

(8) Albuminuria change rate/change amount at 4, 8, 12, and 24 weeks compared to baseline according to blood pressure control criteria

(9) eGFR change rate/change amount at 4, 8, 12, and 24 weeks from baseline according to blood pressure control criteria

(10) Among the subjects whose baseline albuminuria excretion exceeds 300 mg/g, the ratio of subjects whose albuminuria excretion has changed to less than 300 mg/g at 4, 8, 12, and 24 weeks from the baseline according to blood pressure control criteria

(11) Among the subjects whose baseline albuminuria excretion was 300 mg/g or less, the ratio of subjects whose albuminuria excretion changed to less than 30 mg/g at 4, 8, 12, and 24 weeks from the baseline according to blood pressure control criteria

(12) Proportion of subjects whose albuminuria decreased by 30% or more at 4, 8, 12, and 24 weeks compared to baseline according to blood pressure control criteria

(13) Proportion of subjects whose eGFR decreased by 50% or more at 4, 8, 12, and 24 weeks from baseline according to blood pressure control criteria

For continuous variables such as evaluation variables (1), (2), (3), (8), and (9), descriptive statistics (number of subjects, average, standard deviation, Median, minimum, and maximum values) were presented, and a one-sample t-test was conducted for the change rate within the administration group, and a two-sample t-test was performed for the difference between the two groups. If the data did not satisfy normality according to the normality test (Shapiro-Wilk statistic), the Wilcoxon signed rank test was used to test the change rate within the treatment group, and the Wilcoxon rank sum test was used to measure the difference between the two groups.

For the amount of change, a one-sample t-test or Wilcoxon signed rank test was performed according to the results of the normality test (Shapiro-Wilk statistic) to conduct a within-group test, and the difference between groups was analyzed using covariance analysis with the baseline value as a covariate and the administration group as a factor. was tested, and the least squared mean (Least Squared Mean) and standard error (standard error) of each group and between groups were presented.

For categorical variables such as variables (4), (5), (6), (7), (10), (11), (12), and (13), at each time point according to each administration group or blood pressure control standard The frequency and ratio of were presented, the Chi-square test or Fisher's exact test was conducted, and the Cochran-Mantel-Haenszel test with the test institution as a correction factor was conducted to test the difference between groups.

4) Exploratory analysis

As an exploratory analysis, descriptive statistics (number of subjects, mean, standard deviation, median value, minimum value, maximum value) of SiSBP and SiDBP at 4, 8, 12, and 24 weeks from baseline in the fimasartan group were presented, and within the administration group for the change One sample t-test or Wilcoxon signed rank test was performed for the test, and differences between groups were tested using analysis of covariance with the baseline value as a covariate and the administration group as a factor, and the least square mean of each group and between groups (Least Squared Mean) and standard error were presented.

safety assessment

The results of the safety evaluation were presented as a safety set.

1) Adverse reactions

Adverse reactions were standardized and presented as SOC (System Organ Class) and PT (Preferred Term) using MedDRA (Medical Dictionary for Regulatory Activities) version 22.1, and the proportion of subjects with adverse reactions in each administration group and 95% of them Confidence intervals are presented. All adverse events were organized according to severity, causality, action, treatment, and outcome, and adverse events and serious adverse events that were related to investigational drugs were also organized separately. Chi-square test or Fisher's exact test was performed to test whether there was a difference in the incidence of adverse events between groups.

2) Laboratory test, physical examination, vital signs, orthostatic hypotension test, electrocardiogram, chest x-ray

For laboratory test and vital sign (pulse, weight) results, descriptive statistics (number of subjects, mean, standard deviation, median value, minimum value, maximum value, etc.) were presented for each administration group and evaluation time point, and to test the difference between administration groups. Two sample t-test or Wilcoxon rank sum test, ANOVA or Kruskal-Wallis test was performed.

In addition, in the case of laboratory tests, physical examinations, electrocardiograms, and chest x-rays, normal or clinically meaningless abnormal (Normal or Abnormal NCS) and It was classified as clinically meaningful abnormal (Abnormal CS) and presented in the form of a shift table for each administration group, and McNemar's test was performed to compare before and after administration within the administration group.

The frequency (N) and ratio (%) of abnormal changes compared to baseline in orthostatic hypotension were presented, and differences between administration groups were tested using the Chi-square test or Fisher's exact test.

7. Evaluation results

Clinical trial participation status of subjects

Subjects from a total of 34 institutions participated in this clinical trial and underwent screening tests and medical history investigations. Among them, subjects who were judged to be suitable for the inclusion/exclusion criteria were placed in a placebo run-in period of at least 4 weeks. period) was carried out. In the pre-baseline visit (Visit 2), tests for suitability evaluation were conducted, and in the baseline visit (Visit 3), the selection/exclusion criteria were reconfirmed through the final suitability evaluation, and screening was eliminated, [Fimasartan group (test group) : 177 (Group A: 92, Group B: 85)] subjects were randomly assigned. Except for one (fimasartan group A) out of 177 randomly assigned subjects, the study drug was administered. In addition, 14 of the randomly assigned subjects [Fimasartan group 14 (Group A: 7, Group B 7)] dropped out after randomization and [163 Fimasartan group (Group A: 85, Group B: 78)] subjects completed the double-blind clinical trial period until Visit 7 (24W).

Efficacy evaluation result

1) Primary efficacy evaluation variable

Referring to Table 3 below, in the PPS of the fimasartan group, the mean (±SD) of the change in albuminuria after 24 weeks of administration of the investigational drug compared to the baseline was -37.59 (±61.22)%, and it was statistically significantly reduced (all p <0.0001).

[Table 3]

2) Key secondary efficacy evaluation variables

In PPS, up to 24 weeks after taking the investigational drug, both group A (Standard blood pressure control group; SBP < 140 mmHg) and B group (Strict blood pressure control group; SBP < 130 mmHg), which are blood pressure control criteria, cardiovascular composite endpoint, kidney composite None of the endpoints occurred individually, nor did the composite cardiovascular and renal composite endpoints.

3) Other secondary efficacy evaluation variables

(1) Change in albuminuria at 4, 8, and 12 weeks compared to the baseline of the fimasartan group

Referring to Table 4 below, the change in albuminuria at 4, 8, and 12 weeks from baseline in the fimasartan group in PPS was -25.60 (±36.28)% at 4 weeks and -35.39 (±31.33)% at 8 weeks. , -37.51 (±35.58)% at 12 weeks, all statistically significant decreases at 4, 8, and 12 weeks from baseline.

[Table 4]

(2) Albuminuria change at 4, 8, 12, and 24 weeks compared to the baseline of the fimasartan group

Referring to Table 4, the LS (Least Square) Mean (±SE) of the change in albuminuria (mg/g) at 4, 8, 12, and 24 weeks from baseline in the fimasartan-administered group in PPS was at 4 weeks -313.62 (±47.73)mg/g, Fimasartan group at 8 weeks -422.77 (±48.03)mg/g, -523.33 (±55.46)mg/g at 12 weeks, -575.51 (±60.76 at 24 weeks) ) mg/g. All showed statistically significant decreases at 4, 8, 12, and 24 weeks from baseline.

(3) eGFR change amount and change rate at 4, 8, 12, and 24 weeks from baseline in the fimasartan group

Referring to Table 5 below, the LS mean (±SE) of the fimasartan group for the change in eGFR at 4, 8, 12, and 24 weeks from baseline in PPS was -0.88 (±0.72) mL/min at 4 weeks. /1.73m², -2.19 (±0.69)mL/min/1.73m² at 8 weeks, -2.91 (±0.74)mL/min/1.73m² at 12 weeks, -4.66 (±0.72)mL/ at 24 weeks At min/1.73m², there was a statistically significant decrease in eGFR change in all of the administration groups at 8, 12, and 24 weeks from the baseline, except for the 4th week.

Referring to Table 5 below, in PPS, the average (±SD) eGFR change rate (%) at 4, 8, 12, and 24 weeks from baseline in the fimasartan-administered group was -1.15 (±14.16)% at 4 weeks, 8 -4.05 (±11.99)% at week, -5.56 (±14.19)% at 12 weeks, and -8.49 (±13.55)% at 24 weeks. Statistically significant eGFR reduction rates (%) were shown at 8, 12, and 24 weeks from the baseline, excluding the 4th week.

[Table 5]

(4) Proportion of subjects whose albuminuria excretion was less than 300 mg/g at 4, 8, 12, and 24 weeks compared to the baseline of the fimasartan group among subjects whose baseline albuminuria excretion was greater than 300 mg/g

Referring to Table 6 below, among the subjects whose albuminuria excretion was greater than 300 mg/g at baseline in PPS, the albuminuria excretion was 300 mg/g at 4, 8, 12, and 24 weeks compared to baseline in the fimasartan group. The percentage of subjects who changed below was 11.29% (14/124) at 4 weeks, 20.16% (25/124) at 8 weeks, 17.74% (22/124) at 12 weeks, and 17.74% (22/124) at 24 weeks The time point appeared in 26.61% (33/124 people).

[Table 6]

(5) Ratio of subjects whose albuminuria excretion was less than 30 mg/g at 4, 8, 12, and 24 weeks compared to the baseline of the fimasartan group among subjects whose albuminuria excretion was 300 mg/g or less at baseline

Referring to Table 7 below, among the subjects with an albuminuria excretion of 300 mg/g or less at baseline in PPS, the albuminuria excretion was less than 30 mg/g at 4, 8, 12, and 24 weeks compared to baseline in the fimasartan group. The percentage of subjects who changed was 3.85% (1/26 patients) at 4 weeks, 11.54% (3/26 patients) at 8 weeks, 11.54% (3/26 patients) at 12 weeks, and 11.54% (3/26 patients) at 24 weeks. 30.77% (8/26).

[Table 7]

(6) Proportion of subjects whose albuminuria decreased by 30% or more at 4, 8, 12, and 24 weeks compared to baseline in the fimasartan group

Referring to Table 8 below, the proportion of subjects whose albuminuria decreased by 30% or more at 4, 8, 12, and 24 weeks compared to the baseline of the fimasartan group in PPS was 50.67% (76/150 patients) at 4 weeks, 57.33% (86/150 patients) at 8 weeks, 65.33% (98/150 patients) at 12 weeks, and 70.67% (106/150 patients) at 24 weeks.

[Table 8]

(7) Ratio of subjects whose eGFR decreased by 50% or more at 4, 8, 12, and 24 weeks compared to baseline in the fimasartan group

Referring to Table 9 below, there were no subjects whose eGFR decreased by 50% or more at 4, 8, and 12 weeks from baseline in PPS.

[Table 9]

(8) Change in albuminuria and rate of change at 4, 8, 12, and 24 weeks compared to baseline according to blood pressure control criteria

According to blood pressure control criteria, they were classified into group A (standard blood pressure control group; SBP <140 mmHg) and group B (strict blood pressure control group; SBP <130 mmHg).

As a result of comparing group A and group B with respect to change in albuminuria (LS Mean (±SE)) at 4, 8, 12, and 24 weeks from baseline, group A at 4 weeks -209.49 (±47.04) mg/g , Group B -296.72 (±48.35)mg/g, at 8 weeks, Group A -301.44 (±48.26)mg/g, Group B -378.06 (±48.61)mg/g, at 12 weeks, Group A -382.48 ( ±56.74) mg/g, group B -409.07 (±57.98) mg/g, at 24 weeks, group A -394.94 (±60.60) mg/g, group B -530.56 (±61.62) mg/g. All treatment groups showed a statistically significant decrease in albuminuria at all time points (all p<0.0001).

The LS Mean Difference (±SE) for the change in albuminuria between the administration groups (group A - group B) was 87.24 (±67.46) mg/g at 4 weeks, 76.62 (±68.51) mg/g at 8 weeks, 12 weeks 26.59 (±81.16)mg/g at the time point and 135.62 (±86.47)mg/g at the 24th week. There was no statistically significant difference between the administration groups at 4, 8, 12, and 24 weeks.

The average (±SD) change in albuminuria at 4, 8, 12, and 24 weeks from baseline was -16.35 (±45.46)% in group A at 4 weeks, -18.99 (±39.03)% in group B, and -18.99 (±39.03)% in group A at 8 weeks from baseline. Group -18.18 (±56.01)%, Group B -25.54 (±35.81)%, Group A at 12 weeks -27.14 (±48.77)%, Group B -28.68 (±39.57)%, Group A at 24 weeks - 25.60 (±54.54)% and -32.69 (±64.55)% in group B, showing a statistically significant reduction (%) of albuminuria compared to baseline at all time points (all p<0.0001).

The mean difference (±SE) for the change in albuminuria between the administration groups was 2.64 (±4.99)% at 4 weeks, 7.36 (±5.61)% at 8 weeks, 1.55 (±5.34)% at 12 weeks, and 24 weeks was 7.09 (±6.88)%. At 4, 8, and 12 weeks, there was no statistically significant difference between the administration groups, but at 24 weeks, group B (Strict BP Control) compared to group A (Standard BP Control) showed a statistically significant reduction in albuminuria (%). (p=0.0306).

The above results are summarized in Table 10 below.

[Table 10]

(9) eGFR change amount and change rate at 4, 8, 12, and 24 weeks compared to baseline according to blood pressure control criteria

In PPS, the eGFR change (LS Mean (±SE)) at 4, 8, 12, and 24 weeks from the baseline according to the blood pressure control criteria was -0.55 (±0.71)mL/min/1.73m² in group A at 4 weeks. , Group B -0.57 (±0.73) mL/min/1.73m², at 8 weeks, Group A -1.71 (±0.69)mL/min/1.73m², Group B -2.16 (±0.70)mL/min/ 1.73m², at 12 weeks, group A -2.83 (±0.74)mL/min/1.73m², group B -2.34 (±0.76)mL/min/1.73m², at 24 weeks, group A -4.77 (± 0.71)mL/min/1.73m², group B was -4.49 (±0.72)mL/min/1.73m². At all time points except for the 4-week time point, both groups A and B showed a statistically significant decrease in eGFR compared to the baseline. In addition, the LS Mean Difference (±SE) for the difference in eGFR change between blood pressure control standards was 0.01 (±1.02) mL/min/1.73m² at 4 weeks and 0.46 (±0.99) mL/min/1.73m² at 8 weeks. , -0.49 (±1.06)mL/min/1.73m² at 12 weeks and -0.28 (±1.02)mL/min/1.73m² at 24 weeks, there was no significant difference between the administration groups at all time points.

In PPS, the mean (±SD) eGFR change rate at 4, 8, 12, and 24 weeks from baseline was -1.25 (±13.04)% in group A at 4 weeks, -0.34 (±12.78)% in group B, and -0.34 (±12.78)% in group B at 8 weeks. -3.25 (±13.61)% in group A, -2.94 (±12.67)% in group B, -5.26 (±14.94)% in group A at 12 weeks, -4.04 (±12.65)% in group B, -4.04 (±12.65)% in group B at 24 weeks -8.24 (±14.29)% in group B and -7.82 (±14.24)% in group B, similar to the eGFR change results, at 8, 12, and 24 weeks, except for the 4th week, both groups A and B were statistically different from the baseline A significant eGFR reduction rate (%) was shown.

The mean difference (±SE) for the eGFR change rate between the administration groups was -0.91(±1.52)% at 4 weeks, -0.31(±1.57)% at 8 weeks, and -1.23(±1.66)% at 12 weeks, 24 The main time point was -0.42 (±1.64)%, and the difference in change rate between the administration groups was not statistically significant at all time points.

The above results are summarized in Table 11 below.

[Table 11]

(10) Among the subjects whose baseline albuminuria excretion exceeds 300 mg/g, the ratio of subjects whose albuminuria excretion has changed to 300 mg/g or less at 4, 8, 12, and 24 weeks from the baseline according to blood pressure control criteria

Referring to Table 12 below, among the subjects whose albuminuria excretion was greater than 300 mg/g at baseline in PPS, albuminuria excretion was 300 mg/g at 4, 8, 12, and 24 weeks compared to the baseline according to blood pressure control criteria. The percentage of subjects who changed below was 12.10% (15/124) in group A at 4 weeks, 7.32% (9/123) in group B, 16.13% (20/124) in group A at 8 weeks, 12.20% (15/123) in group B, 16.94% (21/124) in group A at 12 weeks, 11.38% (14/123) in group B and 21.77% (27/124) in group A at 24 weeks ), 23.58% (29/123) in group B, and there was no statistically significant difference between the administration groups at any time point.

[Table 12]

(11) Among the subjects whose baseline albuminuria excretion is 300 mg/g or less, the ratio of subjects whose albuminuria excretion has changed to less than 30 mg/g at 4, 8, 12, and 24 weeks from the baseline according to blood pressure control criteria

Referring to Table 12, the ratio of subjects whose albuminuria excretion changed to less than 30 mg/g at 4, 8, 12, and 24 weeks from baseline was 6.90% (2/29) in group A at 4 weeks, Group B 4.00% (1/25 patients), at 8 weeks, group A 6.90% (2/29 patients), group B 12.00% (3/25 patients), at 12 weeks, group A 6.90% (2/29 patients) ), group B 16.00% (4/25 patients), at 24 weeks, group A 20.69% (6/29 patients), group B 20.00% (5/25 patients). Although the proportion of subjects whose albuminuria excretion changed to less than 30 mg/g was high, there was no statistically significant difference between the two administration groups at all time points.

(12) Proportion of subjects whose albuminuria decreased by 30% or more at 4, 8, 12, and 24 weeks compared to baseline according to blood pressure control criteria

Referring to Table 13 below, the ratio of subjects whose albuminuria decreased by 30% or more at 4, 8, 12, and 24 weeks compared to the baseline according to the blood pressure control criteria in PPS was 40.52% (62/153) in group A at 4 weeks persons), Group B 42.57% (63/148 persons), Group A 47.06% (72/153 persons) at 8 weeks, Group B 47.30% (70/148 persons), Group A 53.59% (82 persons) at 12 weeks /153 patients), 55.41% (82/148 patients) in group B, and 53.59% (82/153 patients) in group A and 68.92% (102/148 patients) in group B at 24 weeks.

At 24 weeks, group B showed a statistically significant decrease compared to group A (p=0.0069), and there were no statistically significant differences between the administration groups at 4, 8, and 12 weeks.

[Table 13]

(13) Proportion of subjects whose eGFR decreased by 50% or more at 4, 8, 12, and 24 weeks from baseline according to blood pressure control criteria

Referring to Table 14 below, the proportion of subjects whose eGFR decreased by 50% or more at weeks 4, 8, 12, and 24 compared to the baseline according to the blood pressure control criteria in PPS was 50% or more at 4 and 12 weeks. There were no subjects who decreased, and 0.65% (each 1/153) occurred in group A at 8 weeks and 24 weeks, but there was no statistically significant difference between the administration groups.

[Table 14]

4) Results of Exploratory Analysis

(1) SiSBP change at 4, 8, 12, and 24 weeks from baseline

Referring to Table 15 below, as a result of measuring the change in SiSBP (LS Mean (±SE)) of the fimasartan group at 4, 8, 12, and 24 weeks from baseline in PPS, the 4-week time point was -13.51 (± 1.20) mmHg, -16.96 (±1.23) mmHg at 8 weeks, -19.12 (±1.18) mmHg in the fimasartan group at 12 weeks, and -16.53 (±1.23) mmHg at 24 weeks. The fimasartan group showed a statistically significant decrease from baseline at 4, 8, 12, and 24 weeks (all p<0.0001).

[Table 15]

(2) SiDBP change at 4, 8, 12, and 24 weeks from baseline

Referring to Table 15, the result of measuring the change in SiDBP of the fimasartan group at 4, 8, 12, and 24 weeks from baseline in PPS (LS Mean (±SE)), 4 weeks at -5.33 (± 0.67) mmHg, -7.19 (±0.68) mmHg at 8 weeks, -8.88 (±0.63) mmHg at 12 weeks, and -7.82 (±0.66) mmHg at 24 weeks. All of the administration groups showed statistically significant decreases from baseline at 4, 8, 12, and 24 weeks (all p<0.0001).

Safety evaluation result

(1) Adverse reactions

Safety analysis was conducted on subjects who were administered clinical trial drugs at least once after randomization and were evaluated for safety at least once.

Adverse reactions were 175 cases in 88 patients (50.00%), and dizziness occurred in 15 cases in 14 cases (7.95%), nasopharyngitis in 9 cases (5.11%), and hyperkalemia in 7 cases (3.98%). 7 cases and so on. However, the severity of adverse reactions was mostly mild and recovered.

No serious adverse drug reactions (SADRs) or adverse events leading to death were reported during this clinical trial period.

The adverse reaction that led to discontinuation of the investigational drug was cerebral infarction in 1 patient (0.57%, 1 case), and the subject discontinued administration of the investigational drug after Visit 6, but there was no causal relationship with the investigational drug. Definitely not recovered.

(2) Laboratory tests (hematology, blood biochemistry, urine test), physical examination, vital signs (pulse, weight), orthostatic hypotension test, electrocardiogram, chest X-ray

Subjects who were normal or clinically insignificant abnormalities in laboratory tests, physical examinations, vital signs (pulse, weight), electrocardiograms, and chest X-rays, but who changed to clinically meaningful abnormalities after administration of investigational drugs, are currently Adverse reactions were reported except for one case in which the platelet value increased due to the medical history, and most of them recovered without separate treatment.

conclusion

The purpose of this clinical trial was to evaluate the efficacy and safety of fimasartan and blood pressure control criteria when administered orally for 24 weeks in patients with diabetic kidney disease accompanied by hypertension.

Compared to the baseline of the fimasartan group, the change rate and amount of change in albuminuria (ACR) in each administration group at 4, 8, 12, and 24 weeks were statistically significantly decreased at all time points.

The eGFR change amount and change rate at 4, 8, 12, and 24 weeks compared to the baseline showed a significant decrease in eGFR at 8, 12, and 24 weeks, except for the 4-week time point.

As a result of examining the incidence of cardiovascular, renal, and cardiovascular and renal complex diseases according to blood pressure control criteria, blood pressure control criteria in group A (standard blood pressure control group; SBP < 140 mmHg) and group B until 24 weeks after taking the investigational drug in PPS (Strict blood pressure control group; SBP < 130 mmHg) There were no cardiovascular, renal, cardiovascular and renal composite endpoints. At 4, 8, 12, and 24 weeks from baseline, albuminuria (ACR) according to blood pressure control criteria showed a significant decrease at all time points, but there was no difference according to blood pressure control criteria. In the case of eGFR, the eGFR level decreased in group B (strict blood pressure control group) compared to group A (standard blood pressure control group), but it was not significant. Only at 8 weeks, both groups A and B showed a significant decrease in eGFR, but there was no difference between the administration groups.

Exploratory blood pressure reductions were significant at all time points for SiSBP and SiDBP of the fimasartan group at 4, 8, 12, and 24 weeks from baseline.

In terms of safety, the incidence of adverse reactions and adverse drug reactions was predictable, and most were mild, and serious adverse reactions, adverse reactions that led to discontinuation of administration of investigational drugs, clinical laboratory tests, physical examinations, and vital signs (pulse, weight, etc.) ), orthostatic hypotension test, electrocardiogram test, and chest X-ray test, no clinically significant adverse reactions were reported.

Taken together, the results of this clinical trial suggest that administration of fimasartan is an effective and safe drug for reducing albuminuria in patients with diabetic kidney disease accompanied by hypertension. Accordingly, the pharmaceutical composition according to the present invention can have a systolic blood pressure of 140 mmHg or more and less than 180 mmHg and a diastolic blood pressure of less than 110 mmHg; an estimated glomerular filtration rate (eGFR) greater than or equal to 30 ml/min/1.73 m ² ; And it can be administered to a subject having albuminuria of 30 mg/g or more to prevent or treat diabetic kidney disease accompanied by hypertension.

Claims (18)

1. A pharmaceutical composition for preventing or treating diabetic kidney disease accompanied by hypertension, comprising fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a hydrate or solvate thereof,

   The composition

   systolic blood pressure greater than or equal to 140 mmHg but less than 180 mmHg and diastolic blood pressure less than 110 mmHg;

   an estimated glomerular filtration rate (eGFR) greater than or equal to 30 ml/min/1.73 m ² ; and

   albuminuria greater than or equal to 30 mg/g;

   To be administered to a subject having a, pharmaceutical composition.
2. According to claim 1,

   Wherein the diabetes is type 2 diabetes, the pharmaceutical composition.
3. According to claim 1,

   The pharmaceutical composition, wherein the pharmaceutically acceptable salt is a fimasartan potassium salt.
4. According to claim 1,

   The pharmaceutical composition, wherein the hydrate is fimasartan potassium salt trihydrate.
5. According to claim 1,

   The composition is for oral administration, a pharmaceutical composition.
6. According to claim 1,

   Wherein the composition is administered once a day, a pharmaceutical composition.
7. According to claim 1,

   Wherein the composition is administered once a day for about 24 weeks, a pharmaceutical composition.
8. According to claim 1,

   The pharmaceutical composition of claim 1, wherein the daily dose of the fimasartan, pharmaceutically acceptable salt thereof, stereoisomer thereof, or hydrate or solvate thereof is about 60 mg to about 120 mg.
9. According to any one of claims 1 to 8,

   Wherein the composition reduces albuminuria in the subject, a pharmaceutical composition.
10. According to claim 9,

    The pharmaceutical composition, wherein the composition reduces albuminuria of the subject by about 30% or more.
11. According to any one of claims 1 to 8,

    Wherein the composition reduces the estimated glomerular filtration rate (eGFR) within about 24 weeks of administration, the pharmaceutical composition.
12. According to any one of claims 1 to 8,

    To lower the systolic and diastolic blood pressure of the subject, the pharmaceutical composition.
13. According to claim 12,

    To lower the systolic blood pressure of the subject to less than 140 mmHg, the pharmaceutical composition.
14. According to claim 12,

    To lower the systolic blood pressure of the subject to less than 130 mmHg, the pharmaceutical composition.
15. According to any one of claims 1 to 8,

    The composition does not generate cardiovascular composite evaluation variables and renal composite evaluation variables within about 24 weeks of administration,

    The cardiovascular composite evaluation variable is one or more selected from the group consisting of myocardial infarction (MI), stroke, hospitalization due to heart failure and unstable angina, coronary artery revascularization, peripheral vascular revascularization, and death,

    The renal composite evaluation variable is at least one selected from the group consisting of about 50% or more reduction in estimated glomerular filtration rate (eGFR) compared to baseline, progression to end-stage renal failure, and death, the pharmaceutical composition.
16. A method for preventing or treating diabetic kidney disease accompanied by hypertension, comprising administering fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof to a subject,

    Fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a hydrate or solvate thereof

    systolic blood pressure greater than or equal to 140 mmHg but less than 180 mmHg and diastolic blood pressure less than 110 mmHg;

    an estimated glomerular filtration rate (eGFR) greater than or equal to 30 ml/min/1.73 m ² ; and

    albuminuria greater than or equal to 30 mg/g;

    Which is administered to a subject having

    A method for preventing or treating diabetic kidney disease with hypertension.
17. As a use of fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a hydrate or solvate thereof for the prevention or treatment of diabetic kidney disease accompanied by hypertension,

    Fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a hydrate or solvate thereof

    systolic blood pressure greater than or equal to 140 mmHg but less than 180 mmHg and diastolic blood pressure less than 110 mmHg;

    an estimated glomerular filtration rate (eGFR) greater than or equal to 30 ml/min/1.73 m ² ; and

    albuminuria greater than or equal to 30 mg/g;

    To be administered to a subject having a, use.
18. As a use of fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a hydrate or solvate thereof for the preparation of a medicament for preventing or treating diabetic kidney disease accompanied by hypertension,

    Fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a hydrate or solvate thereof

    systolic blood pressure greater than or equal to 140 mmHg but less than 180 mmHg and diastolic blood pressure less than 110 mmHg;

    an estimated glomerular filtration rate (eGFR) greater than or equal to 30 ml/min/1.73 m ² ; and

    albuminuria greater than or equal to 30 mg/g;

    To be administered to a subject having a, use.