HK40038946B - Methods of treating subjects having diabetes with chronic kidney disease - Google Patents

Description

Methods for treating diabetic subjects with chronic kidney disease

Technical Field

This invention relates to the use of imeglimin for the treatment of metabolic conditions, such as prediabetes, type 1 or type 2 diabetes, in patients with renal insufficiency or chronic kidney disease (CKD).

Background Technology

Metabolic disorders affect a patient's normal metabolic processes and include prediabetes and type 1 or type 2 diabetes. Type 2 diabetes (T2DM) is a long-term metabolic disorder characterized by high blood sugar, insulin resistance, and a relative lack of insulin. The prevalence of type 2 diabetes is rising globally, with approximately 451 million adults having diabetes in 2017; this number is projected to increase to 693 million adults by 2045. This global diabetes epidemic imposes a significant personal, social, and economic burden, especially in the presence of multivascular complications of diabetes. Prediabetes is a precursor stage to diabetes in which not all the symptoms required for a diagnosis of diabetes are present, and blood sugar is higher than normal but not high enough to be classified as diabetes. Prediabetes is associated with obesity (especially abdominal or visceral obesity), dyslipidemia with high triglycerides and/or low HDL cholesterol, and hypertension. Therefore, it is a metabolic predisposition or syndrome that typically does not involve any symptoms and involves only high blood sugar as the sole marker. Type 1 diabetes, formerly known as juvenile diabetes or insulin-dependent diabetes, is a chronic condition in which the pancreas produces little or no insulin.

Chronic kidney disease (CKD) is a condition characterized by the progressive loss of kidney function over time. It is estimated that 30–50% of all people with diabetes have CKD: more than 40% of CKD patients also have type 2 diabetes mellitus (T2DM). In addition, diabetes is the most common underlying cause of both CKD and end-stage renal disease (ESRD), with T2DM present in more than 50% of ESRD cases. See Tuttle et al., Diabetic kidney disease: a report from the ADA consensus conference, Diabetes Care. 2014;37(10):2864–2883.

Diabetic kidney disease is a chronic, progressive disease with limited treatment options. Standard care for this population includes renal protection with the use of renin-angiotensin system (RAS) inhibitors and diabetes care, including management of hyperglycemia and cardiovascular risk factors, as the co-occurrence of advanced CKD and T2DM is generally believed to significantly accelerate cardiovascular (CV) risk. Palsson R, Patel UD, Cardiovascular complication of diabetic kidney disease, Adv. Chronic. Kidney Dis. 2014; 21(3): 273-80. Indeed, excess mortality in diabetic patients appears to be primarily confined to the kidney disease subgroup and can be explained by their high cardiovascular burden.

Clearly, the degree of glycemic abnormality predicts the progression of kidney disease, and consistent, intensive glycemic control can prevent the development of microvascular complications in diabetes. However, the long-term impact of intensive glycemic control on clinical outcomes in patients with both type 2 diabetes mellitus (T2DM) and clinically significant chronic kidney disease (CKD) remains unclear. Although more than 15 medications are available for managing hyperglycemia in patients with T2DM, many of these therapies are either not recommended or require significant dose reduction in patients with moderate or severe CKD. Therefore, there is a need to develop better treatment options for diabetic patients with CKD, particularly those with moderate or severe CKD.

Attached Figure Description

Figure 1 depicts the geometric mean plasma concentration (linear scale) of igagleemine in subjects with varying degrees of renal insufficiency after 1000 mg QD igagleemine on all days in the Phase 1 study.

Figure 2 depicts the geometric mean plasma concentration of igagleemide in subjects with varying degrees of renal insufficiency (half-logarithmic table) following a 1000 mg QD dose of igagleemide on day 1 in the phase 1 study.

Figure 3 depicts the geometric mean plasma concentration of igagleevec (half-logarithmic table) in subjects with varying degrees of renal insufficiency following a 1000 mg QD dose of igagleevec on day 8 in the Phase 1 study.

Figure 4 depicts the geometric mean plasma concentration (linear scale) of igagleemide in subjects with normal renal function versus those with severe renal insufficiency after 500 mg bid igagleemide on all days in the Phase 1 study.

Figure 5 depicts the placebo-adjusted HbA1c changes in three dose groups during a phase 2b study of Japanese patients with type 2 diabetes mellitus (T2DM).

Figure 6 depicts placebo-adjusted HbA1c changes based on baseline HbA1c in three dose groups during a phase 2b study of Japanese patients with type 2 diabetes mellitus (T2DM).

Figures 7A and 7B depict the percentage of salvage therapy and the percentage of responders in the phase 2b study of Japanese subjects with type 2 diabetes mellitus (T2DM).

Figure 8 illustrates the placebo-adjusted decrease in fasting plasma glucose (FPG) in three dose groups during a phase 2b study of Japanese patients with type 2 diabetes mellitus (T2DM).

Figure 9 depicts a box plot of simulated AUC _ss24 after the recommended igramin dosing regimen in subjects with various stages of renal function.

Figure 10 depicts the projected daily steady-state exposure (mean and SD) from the Phase 1b study and the actual daily steady-state exposure from the previous Phase 2b study.

Figure 11 depicts the maximum plasma igagriminin concentrations on day 15, categorized by treatment and CKD period. Solid circles represent the arithmetic mean, and X represents the geometric mean. Boxes indicate the first quartile (Q1), median, and third quartile (Q3). Whiskers represent the minimum observed value within the lower enclosure and the maximum observed value within the upper enclosure. The lower and upper enclosures are defined as Q1 - 1.5*(Q3 - Q1) and Q3 + 1.5*(Q3 - Q1), respectively.

Figure 12 depicts the area under the plasma concentration-time curve (AUC) of igagrimine on day 15, categorized by treatment and CKD period. Solid circles represent the arithmetic mean, and X represents the geometric mean. Boxes indicate the first quartile (Q1), median, and third quartile (Q3). Whiskers represent the minimum observation within the lower border and the maximum observation within the upper border. The lower and upper borders are defined as Q1 - 1.5*(Q3 - Q1) and Q3 + 1.5*(Q3 - Q1), respectively.

Summary of the Invention

This disclosure provides a method for treating diabetes in subjects with chronic kidney disease, particularly moderate and severe CKD, the method comprising orally administering an effective amount of iggliamine to the subject in need.

Detailed Implementation

To facilitate a clearer understanding of this disclosure, certain terms are first defined. As used herein, each of the following terms shall have the meaning set forth below unless expressly specified herein. Further definitions are set forth throughout this application.

In this specification and the appended claims, unless the context clearly indicates otherwise, the singular form without a specific quantity includes the plural designation. The designation without a specific quantity, as well as the terms "one or more" and "at least one," are used interchangeably herein. In some aspects, the designation without a specific quantity means "single." In other aspects, the designation without a specific quantity includes "two or more" or "a plurality."

Furthermore, the term “and/or” as used herein should be considered to specifically disclose each of two designated features or components, with or without the other feature or component. Therefore, the term “and/or” as used herein in phrases such as “A and/or B” is intended to include “A and B”, “A or B”, “A” (alone), and “B” (alone). Similarly, the term “and/or” as used in phrases such as “A, B, and/or C” is intended to cover each of the following: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

Throughout the specification and claims, the term "about" used in conjunction with numerical values indicates a range of precision familiar and acceptable to those skilled in the art. This range of precision is ±10%.

The term "treatment period" refers to the time during which a subject is given a drug and certain parameters of the subject are measured and compared to baseline values. For example, a treatment period can be approximately 2 weeks to approximately 2 years. In some implementations, the treatment period can be approximately 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 52, 76, or 104 weeks. The efficacy of the drug can be assessed by measuring certain parameters and calculating the change relative to baseline over the entire treatment period. Efficacy parameters include, but are not limited to, the percentage reduction in glycosylated hemoglobin (HbA1c) minus placebo and the reduction in fasting plasma glucose (FPG) minus placebo.

As used in this article, the term “AUC” refers to the area under the curve of a graph of plasma concentration versus time after drug administration.

This disclosure also describes a method of treating subjects with prediabetes or diabetes and CKD stage 3B or 4 using igagrimidine. This disclosure further describes a method of treating subjects with type 2 diabetes mellitus (T2DM) and CKD stage 3B or 4 using igagrimidine. This disclosure also describes a method of treating subjects with type 1 diabetes and CKD stage 3B or 4 using igagrimidine.

Managing hyperglycemia presents particular challenges for subjects with diabetic nephropathy. Due to the loss of kidney function in these subjects, many approved renal clearance antihyperglycemic therapies require dose reduction or are not recommended. Therefore, treatment options for diabetes management are limited in subjects with kidney disease, particularly moderate or severe CKD. Insulin and selected insulin secretagogues, such as sulfonylureas, are frequently used in this population; however, reduced insulin clearance prolongs the duration of insulin action, increasing the risk of hypoglycemic events, including severe hypoglycemia. Given the risk of severe hypoglycemia with intensive glycemic control in patients with CKD, recent clinical guidelines recommend setting a target HbA1c of 7.0% in the presence of moderate or severe CKD. See American Diabetes Association, Standards of Medical Care in Diabetes, 2018.

Most approved antihyperglycemic therapies are available for patients with an estimated glomerular filtration rate (eGFR) as low as 45 ml/min/1.73 ^m² (i.e., up to CKD stage 3A). However, most therapies are dose-reduced or contraindicated in CKD stages 3B and 4 (eGFR 15–44 ml/min/1.73 ^m² ), affecting approximately 200,000 cases annually and representing about 2 million epidemic cases in the United States. For example, metformin is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 ^m² and is not recommended for patients with an eGFR between 30–44 mL/min/1.73 ^m² . Furthermore, many of the agents available for diabetic patients with CKD often lose their efficacy due to declining renal function. Therefore, the range of safe and effective patient options for glycemic control is limited for the large number of patients with this degree of advanced diabetic kidney disease.

Igleem is disclosed as 5,6-dihydro-4-dimethylamine-2-imino-6-methyl-1,3,5-triazine and described in U.S. Patent Nos. 7,034,021, 7,452,883, 7,767,676, 7,501,511, 8,227,465, 8,791,115, 8,217,040, 8,461,331, 8,846,911, 9,035,048, 8,742,102, 8,592,370, 8,980,828, 8,742,103, 9,271,984, and 8,937,066. According to the World Health Organization (WHO) standards, igagrimidine can be referred to as (6R) ^-N₂ , ^N₂ ,6-trimethyl-3,6-dihydro-1,3,5-triazine-2,4-diamine. Compound I is also known as igagrimidine.

Igleem is the first of a new oral antidiabetic agent containing tetrahydrotriazine, with a unique mechanism of action that targets mitochondrial bioenergy and function.

Igglitazone has been studied in subjects with type 2 diabetes mellitus (T2DM) for up to 24 weeks as a monotherapy and in combination with metformin and sitagliptin. In each study, igglitazone was well tolerated at a dose of 1500 mg twice daily (BID), with a safety profile comparable to placebo, and a reduction in glycosylated hemoglobin (HbA1c) minus placebo ranging from -0.42% to -0.72%.

The pharmacokinetics (PK) of igagrimine are characterized by less than dose-proportional exposure when the dose increases in the range of 250 to 2000 mg, low protein binding (<8% binding), no significant metabolism in standard in vitro assays, and renal elimination as the main route of excretion.

Treatment

This invention relates to a method for treating metabolic disorders in patients with renal insufficiency or chronic kidney disease using igexamine.

In some implementations, patients who may be suited to the methods of this disclosure may have or be at risk of having one or more of the following diseases, conditions, or symptoms: type 1 diabetes, type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), hyperglycemia, postprandial hyperglycemia, fasting hyperglycemia, latent autoimmune diabetes in adults (LADA), overweight, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome, metabolic syndrome, nephropathy, or microalbuminemia. Urine or massive albuminuria, proteinuria, retinopathy, cataracts, neuropathy, learning or memory impairment, neurodegenerative diseases or cognitive impairment, cardiovascular disease, tissue ischemia, diabetic foot or ulcers, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, peripheral artery occlusive disease, cardiomyopathy (including, for example, uremic cardiomyopathy), heart failure, cardiac hypertrophy, arrhythmia, restenosis, stroke, ischemia/reperfusion injury (kidney, heart, brain or liver), fibrosis (kidney, heart, brain or liver), vascular remodeling (kidney, heart, brain or liver); diabetic disease, especially type 2 diabetes (e.g., underlying disease).

In one aspect, this disclosure relates to a method of treating prediabetes or type 1 or type 2 diabetes, comprising administering an effective amount of igagrimidine to a subject in need, wherein the subject has chronic kidney disease. Surprisingly, igagrimidine provides similar safety and efficacy in patients with moderate to severe chronic kidney disease compared to patients with normal kidney function.

In another aspect, this disclosure provides a method for improving glycemic control in subjects with prediabetes or type 1 or type 2 diabetes, comprising administering an effective amount of iglemin to the subject in need, wherein the subject has chronic kidney disease.

In another aspect, this disclosure provides a method for improving glycemic control in subjects with prediabetes or type 1 or type 2 diabetes as an adjunct to diet and exercise, comprising administering an effective amount of iglemin to the subject in need, wherein the subject has chronic kidney disease.

In some embodiments, the subject has prediabetes. In some embodiments, the subject has type 1 or type 2 diabetes. In some embodiments, the subject has type 2 diabetes.

If a patient's renal function or structural abnormalities persist for more than 3 months, the patient is considered to have chronic kidney disease (CKD). The definition of CKD includes all individuals with markers of renal impairment or individuals whose estimated glomerular filtration rate (eGFR) is less than 60 ml/min/1.73 ^m² at least twice within 90 days (with or without markers of renal impairment). Markers of renal disease may include: cystatin C, albuminuria (albumin-to-creatinine ratio (ACR) > 3 mg/mmol), hematuria (or suspected or confirmed renal origin), electrolyte abnormalities due to tubular disease, renal histological abnormalities, structural abnormalities detected by imaging (e.g., polycystic kidney disease, reflux nephropathy), or a history of kidney transplantation.

In some implementation schemes, CKD can be classified based on the patient's eGFR:

Expect Kidney function status eGFR Phase 1 Normal kidney function 90 or higher Phase 2 Mild loss of kidney function 60 to 89 3A period Mild to moderate loss of kidney function 45 to 59 3B period Moderate to severe loss of kidney function 30 to 44 Phase 4 Severe loss of kidney function 15 to 29 5th period End-stage renal disease (ESRD) Less than 15

In some implementations, the subject has mild renal insufficiency. In some implementations, the subject has stage 2 chronic kidney disease.

In some implementations, the subject has mild to moderate renal insufficiency. In some implementations, the subject has moderate to severe renal insufficiency. In some implementations, the subject has stage 3A (or stage 3a) chronic kidney disease. In some implementations, the subject has stage 3B (or stage 3b) chronic kidney disease. Stages 3A and 3B are collectively considered stage 3 chronic kidney disease.

In some implementations, the subject had severe renal insufficiency. In some implementations, the subject had stage 4 chronic kidney disease.

In some implementations, the subject has stage 3B or stage 4 chronic kidney disease.

In some implementations, the subject's eGFR is approximately 45 ml/min/1.73 ^m² to approximately 59 ml/min/1.73 ^m² .

In some implementations, the subject's eGFR is from about 15 ml/min/1.73 ^m² to about 44 ml/min/1.73 ^m² .

In some embodiments, the subject's eGFR is from about 15 ml/min/1.73 ^m² to about 29 ml/min/1.73 ^m² . In some embodiments, the subject's eGFR is from about 30 ml/min/1.73 ^m² to about 44 ml/min/1.73 ^m² .

In some implementations, the subject's eGFR is from about 30 ml/min/1.73 ^m² to about 59 ml/min/1.73 ^m² .

In some implementations, CKD can be classified based on the patient's albumin-to-creatinine ratio (ACR). Albuminuria is an increased excretion of urinary albumin and a marker of kidney damage. Normally, very small amounts of protein are excreted in the urine. The albumin-to-creatinine ratio (ACR) is one method for detecting elevated protein levels. ACR is calculated by dividing the albumin concentration (mg) by the creatinine concentration (g). Moderately elevated albuminuria is called microalbuminuria (ACR 30-300 mg/g), which means albumin excretion is above the normal range but below the total protein detection level. Severely elevated albuminuria is called macroalbuminuria (ACR > 300), which means even higher albumin levels accompanied by a gradual decrease in glomerular filtration rate.

In some embodiments, this disclosure provides a method for treating a subject suffering from a metabolic disorder (e.g., type 2 diabetes mellitus) and chronic kidney disease, the method comprising:

To determine the severity of the subject's chronic kidney disease;

Determine the effective dosing regimen for iogleemide in subjects based on the severity of chronic kidney disease; and

Igleemide was administered to the subject according to the dosing regimen.

In some embodiments, the method includes orally administering an effective amount of igagrimidine to a subject in need. In some embodiments, igagrimidine can be administered to the subject by injection (e.g., intravenous injection).

In some implementations, igagrimidine treatment according to the methods described herein is well tolerated.

In some implementations, a subject treated with igagleemide or a group of subjects treated with igagleemide does not experience an increased frequency of lactic acidosis compared to before the subject or group of subjects started igagleemide treatment.

In some implementations, a subject treated with igagleemide or a group of subjects treated with igagleemide does not experience an increase or elevation in plasma lactate compared to before the subject or group of subjects started igagleemide treatment.

In some implementations, a subject treated with igagleemide or a group of subjects treated with igagleemide does not experience an increase or elevation in plasma lactate exceeding the threshold of 3 mmol/L (27 mg/dL) compared to before the subject or group of subjects started igagleemide treatment.

In some implementations, a subject treated with igagleemide or a group of subjects treated with igagleemide is no more likely to experience an increase or elevation in plasma lactate than a subject treated with placebo or a subject treated with a second agent (including the exemplary antidiabetic agent described herein) compared to before the start of igagleemide treatment.

In some implementations, a subject treated with igagleemide or a group of subjects treated with igagleemide has similar or the same frequency of treatment-emergent adverse events as a subject treated with placebo.

In some implementations, the subject or group of subjects treated with igagleemide according to the methods described herein has a pre-existing medical condition. In some implementations, the pre-existing condition is not chronic kidney disease.

In some implementations, the severity or symptoms of one or more pre-existing conditions in a subject or group of subjects treated with igagleem do not worsen after igagleem treatment compared to what would have been expected when the subject or group of subjects took a second dose (including the exemplary antidiabetic agent described herein).

In some implementations, a subject treated with igagleemide or a group of subjects treated with igagleemide does not experience an increase in one or more symptoms of one or more of the subject's pre-existing condition compared to before the subject or group of subjects began igagleemide treatment.

In some implementations, the severity or symptoms of one or more pre-existing conditions in a subject or group of subjects treated with igaglimum do not worsen after igaglimum treatment. In some implementations, the severity or symptoms of one or more pre-existing conditions in this subject or group of subjects treated with igaglimum do not worsen after igaglimum treatment compared to before the subject or subjects began igaglimum treatment.

In some implementations, the pre-existing condition is selected from hyperkalemia, hypertension, heart disease, gastrointestinal disorders, neurological disorders, blood and lymphatic disorders (e.g., anemia), eye disorders, endocrine disorders, or combinations thereof.

In some embodiments, the pre-existing condition is a heart condition. In some embodiments, the heart condition is selected from coronary artery disease, atrial fibrillation, congestive heart failure, myocardial infarction, or a combination thereof.

In some embodiments, the pre-existing condition is a gastrointestinal symptom. In some embodiments, the gastrointestinal symptom is selected from abdominal pain, constipation, diarrhea, flatulence, gastroesophageal reflux, indigestion, nausea/vomiting, or a combination thereof.

In some embodiments, the pre-existing condition is a neurological disorder. In some embodiments, the neurological disorder is selected from diabetic neuropathy, peripheral neuropathy, or a combination thereof.

In some embodiments, the pre-existing condition is a blood and lymphatic system disorder. In some embodiments, the blood and lymphatic system disorder is selected from anemia, pernicious anemia, vitamin B12-dependent anemia, vitamin B12 deficiency, or a combination thereof.

In some embodiments, the pre-existing condition is an ocular disease. In some embodiments, the ocular disease is selected from glaucoma, cataracts, or a combination thereof.

In some embodiments, the pre-existing condition is an endocrine or metabolic disorder. In some embodiments, the endocrine or metabolic disorder is selected from diabetes, gout, hyperuricemia, elevated uric acid, secondary hypoparathyroidism, or a combination thereof.

In some embodiments, the daily dose of iodamine is about 500 mg to 3000 mg. In some embodiments, the daily dose of iodamine is about 750 mg to about 3000 mg, about 1000 mg to about 3000 mg, about 1250 mg to about 3000 mg, about 1500 mg to about 3000 mg, about 1750 mg to about 3000 mg, about 2000 mg to about 3000 mg, about 2250 mg to about 3000 mg, about 2500 mg to about 3000 mg, or about 2750 mg to about 3000 mg.

In some implementations, the daily dose of igagrimidine is about 500 mg to 2750 mg, about 500 mg to about 2500 mg, about 500 mg to about 2250 mg, about 500 mg to about 2000 mg, about 500 mg to about 1750 mg, about 500 mg to about 1500 mg, about 500 mg to about 1250 mg, about 500 mg to about 1000 mg, or about 500 mg to about 750 mg.

In some implementations, the daily dose of igagrimidine is approximately 500 mg, approximately 550 mg, approximately 600 mg, approximately 650 mg, approximately 675 mg, approximately 700 mg, approximately 725 mg, approximately 750 mg, approximately 775 mg, approximately 800 mg, approximately 825 mg, approximately 850 mg, approximately 900 mg, approximately 1000 mg, approximately 1100 mg, approximately 1200 mg, approximately 1300 mg, approximately 14 mg, etc. 00 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, or within the range of any two of the foregoing values.

In some implementations, the daily dose of igagrimidine is about 500 mg to about 750 mg, about 750 mg to about 1250 mg, about 900 mg to about 1100 mg, about 1000 mg to about 2000 mg, about 1250 mg to about 1750 mg, or about 1400 mg to about 1600 mg.

In some embodiments, the daily dose of iodagleemine is approximately 1000 mg. In some embodiments, the daily dose of iodagleemine is approximately 1500 mg. In some embodiments, the daily dose of iodagleemine is approximately 2000 mg. In some embodiments, the daily dose of iodagleemine is 1000 mg. In some embodiments, the daily dose of iodagleemine is 1500 mg. In some embodiments, the daily dose of iodagleemine is 2000 mg.

In some implementations, the daily dose of iogleemide administered to diabetic subjects with CKD may be substantially the same as the dose administered to diabetic subjects with normal renal function.

In some implementations, the daily dose of iogleemide administered to diabetic subjects with CKD is lower than the dose administered to diabetic subjects with normal renal function.

In some implementations, the amount of igagrimamine administered daily to diabetic subjects with CKD (e.g., stage 3B CKD or stage 4 CKD) is about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% of the amount administered to diabetic subjects with normal renal function, or within the range of any two of the foregoing values, such as about 20% to about 100% of the amount administered to diabetic subjects with normal renal function.

In some implementations, the amount of igagrimamine administered daily to diabetic subjects with CKD (e.g., stage 3B CKD or stage 4 CKD) is approximately 20% to approximately 40%, approximately 20% to approximately 30%, approximately 30% to approximately 50%, approximately 30% to approximately 40%, approximately 40% to approximately 60%, approximately 40% to approximately 50%, approximately 50% to approximately 70%, approximately 50% to approximately 60%, or approximately 60% to approximately 70% of the amount administered to diabetic subjects with normal renal function.

In some implementations, the amount of igagrimamine administered daily to a diabetic subject with CKD (e.g., stage 3B CKD or stage 4 CKD) is about 750 mg, about 1000 mg, about 1500 mg, about 2000 mg, or within any two of the aforementioned values.

In some embodiments, igagrimidine is administered either not with meals or before meals. In some embodiments, igagrimidine is administered more than two hours before meals. In some embodiments, igagrimidine is administered with meals. In some embodiments, igagrimidine is administered more than two hours after meals.

In some implementations, iogleem is administered once, twice, or three times daily. In some implementations, iogleem is administered once daily. In some implementations, iogleem is administered twice daily.

In some implementations, the subject is given approximately 500 mg of igagrimidine twice daily. In some implementations, the subject is given approximately 750 mg of igagrimidine twice daily. In some implementations, the subject is given approximately 1000 mg of igagrimidine twice daily. In some implementations, the subject is given approximately 1500 mg of igagrimidine twice daily.

In some implementations, the subject is given approximately 750 mg of igagrimidine once daily. In some implementations, the subject is given approximately 1000 mg of igagrimidine once daily. In some implementations, the subject is given approximately 1500 mg of igagrimidine once daily.

In some embodiments, the subject is a mammal. In some embodiments, the subject is a human or an animal. In some embodiments, the subject is a human.

In some embodiments, the subject is male. In some embodiments, the subject is female.

In some embodiments, the participants are over approximately 18 years of age. In some embodiments, the participants are under approximately 18 years of age. In some embodiments, the participants are between approximately 6 and approximately 18 years of age, approximately 6 and approximately 12 years of age, or approximately 12 and approximately 18 years of age. In some embodiments, the participants are over approximately 20 years of age. In some embodiments, the participants are over approximately 25 years of age. In some embodiments, the participants are over approximately 30 years of age. In some embodiments, the participants are over approximately 35 years of age. In some embodiments, the participants are over 40 years of age. In some embodiments, the participants are over 45 years of age. In some embodiments, the participants are over 50 years of age. In some embodiments, the participants are over 55 years of age. In some embodiments, the participants are over 60 years of age. In some embodiments, the participants are over 65 years of age. In some embodiments, the participants are over 70 years of age. In some embodiments, the participants are over 75 years of age.

In some embodiments, igagrimidine is administered as a free base or a pharmaceutically acceptable salt thereof. In some embodiments, igagrimidine is administered as a free base. In some embodiments, igagrimidine is administered as a pharmaceutically acceptable salt thereof. When igagrimidine is in a pharmaceutically acceptable salt form, the salt may include salts with inorganic acids, salts with organic acids, and salts with acidic amino acids. Useful examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid.

Useful examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

In some implementations, igagrimidine is administered in the form of hydrochloride. As described herein, the amount of igagrimidine administered to a subject refers to the amount of free igagrimidine base. When igagrimidine hydrochloride is used, the examples described herein may refer to "igagrimidine".

In some implementations, the subject's baseline percentage of glycosylated hemoglobin (HbA1c) is approximately 6.8% to approximately 12.0%.

In some implementations, the subject’s baseline percentage of glycosylated hemoglobin (HbA1c) is about 7.0%, about 8.0%, about 9.0%, about 10.0%, about 11.0%, or about 12.0%, or within the range of any two of the aforementioned values.

The efficacy of igagrimidine can be assessed by measuring changes in certain parameters of the subjects during treatment. The change from baseline minus the placebo change, or the placebo-adjusted change, refers to the difference between the change in subjects receiving igagrimidine and the change in subjects receiving placebo. In some implementations, the least squares mean (LS mean) is used to calculate the change from baseline.

The primary assessment of the efficacy of igagleem is based on glycosylated hemoglobin (HbA1c) levels. The primary criterion is the change in HbA1c from baseline to the end of the treatment period compared to placebo.

In some implementations, the subject experienced a decrease in the percentage of glycosylated hemoglobin (HbA1c) minus placebo during treatment. In some implementations, the decrease in the percentage of HbA1c minus placebo during treatment was from about -0.5% to about -1.2%. In some implementations, the decrease in the percentage of HbA1c minus placebo during treatment was from about -0.6% to about -1.1%, from about -0.7% to about -1.0%, or from about -0.8% to about -0.9%.

In some embodiments, the HbA1c percentage minus placebo during treatment decreases to about -0.5%, about -0.6%, about -0.7%, about -0.8%, about -0.9%, about -1.0%, about -1.1%, or about -1.2%, or within any two of the foregoing values. In some embodiments, the HbA1c percentage minus placebo during treatment decreases to about -0.8%. In some embodiments, the HbA1c percentage minus placebo during treatment decreases to about -1.0%.

In some implementations, subjects experienced a decrease in fasting plasma glucose (FPG) after subtracting placebo. In some implementations, the decrease in FPG after subtracting placebo during treatment was approximately -20 mg/dL to approximately -30 mg/dL. In some implementations, the decrease in FPG after subtracting placebo during treatment was approximately -21 mg/dL to approximately -28 mg/dL, approximately -22 mg/dL to approximately -27 mg/dL, approximately -23 mg/dL to approximately -26 mg/dL, or approximately -24 mg/dL to approximately -25 mg/dL.

In some embodiments, the placebo-minus fasting plasma glucose (FPG) decreases during treatment to approximately -20 mg/dL, approximately -21 mg/dL, approximately -22 mg/dL, approximately -23 mg/dL, approximately -24 mg/dL, approximately -25 mg/dL, approximately -26 mg/dL, approximately -27 mg/dL, approximately -28 mg/dL, approximately -29 mg/dL, or approximately -30 mg/dL, or within any two of the foregoing values. In some embodiments, the placebo-minus fasting plasma glucose decreases during treatment to approximately -25 mg/dL.

In some implementations, the subject's daily steady-state exposure to iggliflozin (AUC _{24, ss} ) is from about 10 μg·hr/mL to about 100 μg·hr/mL. In some implementations, the subject's daily steady-state exposure to igagleemine (AUC _{24, ss} ) is about 10 μg·hr/mL, about 15 μg·hr/mL, about 20 μg·hr/mL, about 25 μg·hr/mL, about 30 μg·hr/mL, about 35 μg·hr/mL, about 40 μg·hr/mL, about 45 μg·hr/mL, about 50 μg·hr/mL, about 55 μg·hr/mL, about 60 μg·hr/mL, about 65 μg·hr/mL, about 70 μg·hr/mL, about 75 μg·hr/mL, about 80 μg·hr/mL, about 90 μg·hr/mL, about 100 μg·hr/mL, or within the range of any two of the foregoing values.

In some implementations, the subject’s daily steady-state exposure to igagleemine (AUC _{24, ss} ) is about 10 μg·hr/mL to about 50 μg·hr/mL, about 10 μg·hr/mL to about 40 μg·hr/mL, about 10 μg·hr/mL to about 30 μg·hr/mL, or about 10 μg·hr/mL to about 20 μg·hr/mL. In some implementations, the subject's daily steady-state exposure to igagleemine (AUC _{24, ss} ) is about 20 μg·hr/mL to about 80 μg·hr/mL, about 20 μg·hr/mL to about 70 μg·hr/mL, about 20 μg·hr/mL to about 60 μg·hr/mL, about 20 μg·hr/mL to about 50 μg·hr/mL, about 20 μg·hr/mL to about 40 μg·hr/mL, or about 20 μg·hr/mL to about 30 μg·hr/mL.

In some implementations, the subject has already received existing antidiabetic treatment, such as treatment for type 2 diabetes.

Existing treatments may include suitable antidiabetic agents, including but not limited to acetyl-CoA carboxylase-2 (ACC-2) inhibitors, phosphodiesterase (PDE)-10 inhibitors, diacylglycerol acyltransferase (DGAT) 1 or 2 inhibitors, sulfonylureas (such as acetobenzenesulfonylcyclohexylurea, chlorpropamide, diabinese, glibenclamide, glipizide, gliburide, glimepiride, gliclazide, glibenclamide, glibenclamide, glimepiride, tolazoline, and toluene). Sulbupropion, megglitin, α-amylase inhibitors (e.g., amylase aprotinin, trestatin, and AL-3688), α-glucosidase inhibitors (e.g., acarbose), α-glucosidase inhibitors (e.g., lipolysin, canagliflozin, ethylgliflozin, miglitol, voglibose, pranamicin-Q, and salbostatin), PPARγ agonists (e.g., bagliflozin, sitagliflozin, dapagliflozin, empagliflozin, ioglitazone, pioglitazone, rosiglitazone, and troglitazone), PPARα/γ agonists (e.g., CLX-0940) GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, and SB-219994), biguanides (e.g., metformin), glucagon-like peptide-1 (GLP-1) agonists (e.g., exendin-3 and exendin-4), protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g., trodusquemine, hyrtiosal extract), and Zhang, S. et al., Drug Discover Compounds disclosed in Today, 12(9/10), 373-381 (2007), SIRT-1 inhibitors (e.g., resveratrol), dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, and saxagliptin), insulin secretagogues, fatty acid oxidation inhibitors, A2 antagonists, c-jun N-terminal kinase (INK) inhibitors, insulin, insulin mimics, glycogen phosphorylase inhibitors, VPAC2 receptor agonists, glucokinase activators, and sodium glucose transporter (SGLT2 or SGLT1/2) inhibitors.

In some implementations, the subject has not received existing antidiabetic treatment, such as treatment for type 2 diabetes.

In some embodiments, igagrimidine is administered together with a second agent. In some embodiments, igagrimidine is administered simultaneously with the second agent. In some embodiments, igagrimidine is administered sequentially with the second agent.

In some embodiments, the second agent is selected from insulin, α-glucosidase inhibitors, biguanides, dopamine agonists, DPP-4 inhibitors, glucagon-like peptides, megglitinide, sodium glucose transporter (SGLT2 or SGLT1/2) inhibitors, sulfonylureas, and thiazolidinediones.

The second agent may include the exemplary antidiabetic agents described herein. The second agent may also include: alpha-glucosidase inhibitors, such as acarbose and miglitol; insulin sensitizers, such as thiazolidinediones (TZDs), such as pioglitazone and rosiglitazone; agents that reduce glucose production, such as biguanides, such as metformin sulfonylureas (SUs), such as amiloride, glibenclamide, gliclazide, glimepiride, glipizide, chlorpropamide, and tolatiourea; megglitinide, such as repaglinide; dopamine agonists, such as bromoergotide; DPP-4 inhibitors, such as alogliptin, linagliptin, saxagliptin, sitagliptin, or vildagliptin; and sodium glucose transporter (SGLT2 or SGLT 1/2) inhibitors, such as dapagliflozin, canagliflozin, empagliflozin, or soragliflozin.

In some embodiments, the second agent is a DPP-4 inhibitor. In some embodiments, the second agent is sitagliptin.

In some implementations, the second agent is metformin.

In some embodiments, the existing antidiabetic treatment, such as treatment for type 2 diabetes, does not provide adequate control of the subject's metabolic condition or cannot adequately control the subject's metabolic condition. In some embodiments, the metabolic condition is type 2 diabetes. In some embodiments, the existing antidiabetic treatment does not provide adequate control of the subject's glycemic parameters, non-glycemic parameters, or both _, or cannot adequately control the subject's glycemic parameters, non-glycemic parameters, or both. In some embodiments, the subject is not adequately controlled by existing antidiabetic treatment, as defined by _HbA1c of not less than about 7.5% or 7.5% to 10%.

In some embodiments, the existing antidiabetic treatment is a monotherapy. In some embodiments, the monotherapy comprises an agent selected from: insulin, alpha-glucosidase inhibitors, biguanides, dopamine agonists, DPP-4 inhibitors, glucagon-like peptide, megglitinide, sodium-glucose transporter (SGLT2 or SGLT1/2) inhibitors, sulfonylureas, and thiazolidinediones. In some embodiments, the monotherapy is an agent comprising the exemplary antidiabetic agents described herein.

Example

Example 1

Comparison of the effects of iggliflozin, metformin, and phenformin on the risk of lactic acidosis in a rat model of acute renal failure (ARF).

Metformin is associated with an increased risk of lactic acidosis in patients with renal and/or heart failure. Plasma accumulation of metformin in renal insufficiency is a risk factor for this type of lactic acidosis. Acute renal failure (ARF) can occur in rats with gentamicin, which directly causes renal tubular cell necrosis and also leads to decreased renal blood flow.

A study has been completed on the risk of lactic acidosis following iodine treatment in rats with acute renal insufficiency compared to biguanides—metformin and phenformin.

Renal failure induced in rats after administration of gentamicin (200 mg/kg s.c.), followed by randomization into four groups: normal (creatinine < 0.6 mg/dL), moderate (0.6 mg/dL < creatinine < 2 mg/dL), and severe renal failure (creatinine > 2 mg/dL). Gentamicin was administered subcutaneously (1 ml/kg body weight) once daily for 4 days. Creatinine levels were measured in each rat 7 days after the first gentamicin injection, and these levels correlated with the degree of renal failure. Renal failure following gentamicin administration resulted in serum creatinine levels ranging from 1 to 3 mg/dL, compared to 0.5 mg/dL in normal rats. Creatinine levels in rat plasma samples were determined using the IL Test Creatinine assay on Monarch Chemistry Systems. This monochromatic analysis is based on the formation of a red complex between creatinine and picric acid under alkaline conditions.

Igglitazone, metformin, or phenformin dissolved in normal saline were administered intravenously at a constant rate of 8 ml/h/kg over 180 minutes. The dose for the normal control group was 100 mg/h/kg (iogglitazone and metformin) and 50 mg/h/kg (phenformin), while the doses for the moderate and severe groups were 25, 50, 75, and 100 mg/h/kg (iogglitazone and metformin) and 25 and 50 mg/h/kg (phenformin).

In normal rats, perfusion of iogleemide at a dose of 100 mg/h/kg significantly reduced plasma glucose from 60 minutes onwards (6.5 ± 0.4 mmol/L vs. 7.6 ± 0.4 mmol/L baseline tp < 0.001). The same effect was observed after infusion of 50 mg/h/kg phenformin or 100 mg/kg/h metformin. However, this reduction in plasma glucose over time (180 minutes) was 2.9 ± 1 mmol/L after phenformin, which was more pronounced than the 5.4 ± 0.4 mmol/L after iogleemide and the 4 ± 0.7 mmol/L after metformin. This hypoglycemic effect was achieved at the same plasma concentration levels of iogleemide (65.16 ± 15.8 μg/ml) and metformin (84.77 ± 12.27 μg/ml).

In rats with mild or high ARF, iogleemide significantly and in a time-dependent manner reduced plasma glucose. However, unlike metformin and phenformin, no severe hypoglycemia was observed with iogleemide. Phenformin and metformin slowly reduced plasma glucose up to 120 minutes; then plasma glucose dropped sharply, to 1.9 ± 1 mmol/L for metformin and 2.4 ± 1.1 mmol/L for phenformin.

In normal rats, metformin at 100 mg/h/kg and phenformin at 50 mg/h/kg significantly increased lactic acidosis. Phenformin induced a higher level of lactate production than metformin (9.4 ± 2.1 mmol/L vs. 4.6 ± 0.4 mmol/L). Iggliflozin did not alter plasma lactate levels. In ARF rats, both metformin and phenformin treatments significantly increased plasma lactate. This effect on plasma lactate was dose- and time-dependent. As mentioned above, in rats with high ARF, the increase in plasma lactate levels induced by metformin was greater than in rats with mild ARF (defined by creatinine levels). In contrast to these biguanides, phenformin did not significantly increase plasma lactate in this ARF rat model.

In rats with acute renal failure (ARF), metformin and phenformin significantly increased plasma H+ concentrations. This effect occurred 2 hours after perfusion and was dose-dependent. For either compound, this pH change did not appear to be correlated with the severity of ARF. No signs of metabolic acidosis were observed in rats treated with iodine.

In rats with acute renal ^failure (ARF), perfusion of phenformin and metformin significantly reduced plasma [ _HCO3- ] concentrations, an effect dependent on the severity of ARF. In groups with high creatinine levels, [ _HCO3- ^] decreased significantly after metformin 100 mg/kg (11.8 ± 1.1 mmol/L vs. 22.8 ± 0.8 mmol/L in controls, p < 0.001), and significantly after phenformin 50 mg/kg (17.7 ± 1.3 mmol/L vs. 22.8 ± 0.8 mmol/L in controls, p ^< 0.001). Iggliflozin also significantly reduced plasma [ _HCO3- ] compared to basal levels, but not compared to controls. This effect was independent of both ARF severity and compound concentration.

Starting at 50 mg/kg/h, phenformin caused an 85% mortality rate, depending on plasma creatinine concentration. This effect occurred only in the high plasma creatinine group. The main biochemical features of this mortality were hypoglycemia, hyperlactatemia, decreased plasma pH (< ^7.2 ), and decreased [ _HCO3- ] concentration. These biochemical changes are physiological markers of lactic acidosis.

In an ARF rat model, plasma accumulation of metformin and igdextromethorphan was observed. This effect appeared to be dose-dependent and also dependent on the severity of ARF. A significant direct relationship was observed between plasma metformin and plasma lactate concentration (r = 0.758, p < 0.001). A similar significant correlation was observed between plasma metformin and plasma H ⁺ concentration (r = 0.611, p < 0.0156). No significant correlation was observed between plasma igdextromethorphan concentration and plasma lactate or H ⁺ levels.

In this rat model of acute renal failure ^, perfusion with metformin or phenformin induced lactic acidosis. This fatal side effect was characterized by a dose-dependent increase in plasma lactate and H ⁺ , and a decrease in [ _HCO3- ] levels. A significant relationship was observed between lactate levels and plasma H ⁺ concentrations.

Example 2

A phase 1 clinical trial was conducted to investigate the pharmacokinetics of iogleem in subjects with renal insufficiency compared to subjects with normal renal function.

An open-label, parallel-group, multicenter, multiple-dose oral study was completed to investigate the pharmacokinetics of igagrimidine in subjects with renal insufficiency compared with subjects with normal renal function.

In this study, 51 participants received 1000 mg of igagrimidine daily over 8 days, administered either 1000 mg QD (once daily) or 500 mg BAD (twice daily). Of the 27 participants with chronic renal impairment, 9 (5 QD and 4 BAD) had mild renal impairment (creatinine clearance (CL _Crea ) 50–80 mL/min), 12 (6 QD and 6 BAD) had moderate renal impairment (CL _Crea 30–<50 mL/min), and 6 (BAD) had severe renal impairment (CL _Crea <30 mL/min). 24 control participants with normal renal function were matched with participants with mild and moderate (10 QD and 8 BAD) and severe (6 BAD) renal impairment. The urinary plasma creatinine ratio (CL _Crea ) was calculated using 24-hour urine samples.

In the group receiving 1000 mg once daily, iogleem was administered in the morning for 8 consecutive days. In the group receiving 500 mg twice daily, iogleem was administered in the morning and evening for 7 consecutive days, followed by a 500 mg morning dose on day 8. The morning doses on days 1 and 8 were administered on a fasting basis, 10 hours after an overnight fast, and within 4 hours after the administration of iogleem.

Inclusion criteria: For subjects with normal renal function: CL _Crea > 80 mL/min, calculated based on 24-hour sampling on day -2. For subjects with impaired renal function: For subjects with mild renal impairment, CL _Crea 50 to 80 mL/min; for subjects with moderate renal impairment, 30 to < 50 mL/min; for subjects with severe renal impairment, < 30 mL/min, calculated based on 24-hour sampling on day -2.

Tables 1 and 2 list the mean pharmacokinetic parameters of igagrimidine obtained on day 8 of treatment. The pharmacokinetic parameters included the apparent volume of distribution (Vz/F) at the end of extravascular administration, the area under the curve of plasma concentration versus time (AUC _0-t ), the maximum observed concentration ( _Cmax ), the time to maximum concentration ( _tmax ), the plasma half-life (t _1/2 ), the total body clearance of the drug from plasma after extravascular administration (CL/F), and other parameters.

Median _Tmax was observed 3.5 to 5 hours after administration, with no difference observed in renal function or time. Steady state of igagrimidine was reached by day 6 of repeated administration of 1000 mg QD and 500 mg BAD, consistent with T1 _/2 (13 to 26 hours).

Renal insufficiency resulted in up to a 3.6-fold increase in iogleemide accumulation in subjects with severe renal insufficiency. On day 8, the differences in exposure between subjects with mild, moderate, and severe renal insufficiency and those with normal renal function were as high as 1.5-fold, 2.3-fold, and 3.6-fold, respectively. Overall, statistically, only the moderate and severe groups showed increased exposure compared to the normal renal function group. Figures 1-3 show the mean observed plasma distribution from day 1 to day 8 in subjects with different degrees of renal insufficiency receiving a 1000 mg iogleemide QD. Figure 4 shows the mean observed plasma distribution across all days in subjects with normal and severe renal insufficiency receiving a 500 mg iogleemide BID.

Compared with normal subjects, subjects with severe renal insufficiency had a total oral clearance rate and a renal clearance rate that decreased by up to 72% and 74%, respectively, with increasing renal insufficiency.

For the 500 mg bid regimen, a significant portion of the dose is excreted in the urine during the 12-hour dosing interval, estimated at 44% to 46% in normal subjects, 43% in subjects with mild renal impairment, 42% in subjects with severe renal impairment, and 40% in subjects with moderate renal impairment.

Table 1. Pharmacokinetic parameters in subjects with renal insufficiency following oral administration of ioglitazone at a dose of 1000 mg QD on day 8.

Geometric mean (CV%) data are presented, where N = number of subjects in the study, ^a) median (min, max); ^b) N = 8. QD = once daily or once a day, AUC = area under the concentration-time curve, Cmax = maximum plasma concentration, t1/2 = elimination half-life, CL/F = apparent oral clearance, Vz/F = apparent volume of distribution.

Table 2. Pharmacokinetic parameters in subjects with renal insufficiency following oral administration of ioglitazone at a dose of 500 mg twice daily on day 8.

Geometric mean (CV%) data are presented, where N = number of subjects in the study, ^a median (min, max); bid = twice daily or twice a day, AUC = area under the concentration-time curve, Cmax = maximum plasma concentration, t1/2 = elimination half-life, CL/F = apparent oral clearance, and Vz/F = apparent volume of distribution.

Tables 3 and 4 summarize the urinary excretion parameters of igagleemide after QD or bid-administered oral doses on day 8 in subjects with varying degrees of renal impairment. The parameters measured included the unmodified amount of drug excreted in urine over time (Ae _{_0-t} ), renal clearance ( _CLR ), the unmodified amount of drug excreted in urine over a dosing interval (Ae _{_0-τ} ), and the percentage of the administered dose excreted in urine over a dosing interval (feτ).

Table 3. Urinary excretion parameters in subjects with renal insufficiency following oral administration of iogliptin (1000 mg QD) on day 8.

Geometric mean (CV%) data are presented, N = number of subjects in the study, ^a N = 2; min, max, NC = cannot be calculated.

Table 4. Urinary excretion parameters in subjects with renal insufficiency after oral administration of iogliptin (500 mg twice daily) on day 8.

Geometric mean (CV%) data are presented, where N = number of participants in the study; min, max, and NC are presented as values that cannot be calculated.

Biochemical and hematological parameters in subjects with normal and mild renal impairment were normal in most cases, and exceeded the normal range only in a single case. All of these cases were assessed as not clinically relevant. As expected, subjects with moderate and severe renal impairment showed values exceeding the normal range on several parameters due to underlying disease. In all cases, urea and creatinine values exceeded the normal range and were assessed as clinically relevant. In a single case, hematological parameters exceeded the normal range and were assessed as not clinically relevant, but were expected due to their underlying disease. In a single case, subjects with moderate and severe renal impairment had elevated inorganic phosphate, ALT, GLDH, CK, triglycerides, lipase, and glucose, which were assessed as clinically relevant. No relevant deviations in sodium, potassium, and chloride levels compared to normal values were observed. No significant abnormalities were observed in clinical laboratory parameters. As expected, subjects with severe renal impairment had slightly elevated mean systolic and diastolic blood pressure values. No clinically relevant changes in vital signs were observed after administration of igagrimidine. The mean PR intervals did not show any relevant changes during the trial's time course. The QRS-, QT-, and corrected QTc- intervals, as determined by Bazett and Fridricia, did not show any relevant changes associated with administration of the study drug.

To evaluate the safety and tolerability of various oral doses of 1000 mg igagleem QD (i.e., a total dose of 8000 mg igagleem) or 500 mg igagleem BID (i.e., a total dose of 7500 mg igagleem), laboratory tests (hematology, clinical chemistry, urinalysis), vital sign determination, ECG recording, AE inquiry, and physical examination were performed. No relevant changes were observed in any safety parameters during the study. The incidence of AEs observed during the study was low. Of the 51 subjects, 31 reported 54 treatment-related AEs. Of these, only 15 were deemed likely to be related to the study drug. The majority (39 AEs) were assessed as unlikely to be related. Based on these low incidences, no significant differences were shown between dosage regimens or between the renal impairment group. Overall safety and tolerability assessments indicated that igagleem was well or very well tolerable. Overall, the safety and tolerability of a total daily dose of 1000 mg igagleem once daily for 8 days or 500 mg igagleem twice daily were considered good.

Example 3

A dose-variable, randomized, double-blind, placebo-controlled, parallel-group, multicenter study of the efficacy and safety of three doses of igagrimidine after 24 weeks of treatment in Japanese patients with type 2 diabetes.

In this study, a total of 299 subjects with type 2 diabetes mellitus (T2DM) received either igagrimidine at one of three doses (500, 1000, and 1500 mg bid) or placebo. The primary objective of this study was to evaluate the dose-response of igagrimidine at three doses (500, 1000, and 1500 mg bid) compared to placebo in male and female T2DM subjects after 24 weeks of treatment, using glycosylated hemoglobin (HbA1c) as the primary endpoint. Inclusion criteria: subjects had an eGFR ≥50 mL/min/1.73 ^m² at screening and ≥45 at the visit prior to randomization. A total of 299 subjects were randomized in a 1:1:1:1 ratio to one of four study groups, of whom 268 completed the study.

The study met its primary endpoint. Placebo-adjusted HbA1c changes compared to baseline were dose-dependently reduced, which was statistically significant at all three doses (-0.52%, -0.94%, and -1.0% for 500 mg, 1000 mg, and 1500 mg bid, respectively; p < 0.0001). See Table 5 and Figure 5.

Table 5. MMRM analysis of HbA1c (FAS) changes relative to baseline

Changes in HbA1c were analyzed based on baseline HbA1c <8% or ≥8%. Changes in HbA1c were similar at doses of 500 mg twice daily (-0.47% and -0.58% for baseline <8% and ≥8%, respectively) and 1000 mg twice daily (-0.93% and -0.90% for baseline <8% and ≥8%, respectively), but were greater at a dose of 1500 mg twice daily in patients with higher baseline HbA1c (-0.82% and -1.2% for baseline <8% and ≥8%, respectively). See Figure 6.

The responder percentage was defined as the percentage of subjects who achieved an HbA1c value ≤7% at the end of the 24-week double-blind treatment period. Subjects with a baseline HbA1c value >7.0% were analyzed using the FAS.

The response rates for the two high-dose igagleemide regimens showed statistically significant similar increases (33.3% and 32.9% in the 1000 mg bid and 1500 mg bid groups, respectively, compared to 8.2% in the placebo group). During the double-blind treatment period, the percentage of subjects requiring salvage therapy due to poor glycemic control was higher in the placebo group (10.7%) than in the other groups, while subjects did not require salvage therapy at the highest dose of igagleemide 1500 mg bid. See Figures 7A and 7B.

The decrease in FPG followed the same pattern, with similar effects observed at two high doses of 1000 and 1500 mg twice daily (-24.6 mg/dL or 1.37 mmol/L, p < 0.001). See Table 6 and Figure 8.

Table 6. MMRM analysis of FPG (FAS) change relative to baseline

Table 7 shows the change in glycated albumin (FAS) relative to baseline.

Table 7. MMRM analysis of FPG (FAS) change relative to baseline

The overall incidence of any adverse events (AEs) was similar across groups, ranging from 73% (iogleemide 1000 mg) to 77.3% (iogleemide 1500 mg). The incidence of treatment-emergent (TE) AEs ranged from 62.2% (iogleemide 1000 mg) to 73.3% (iogleemide 1500 mg).

The most common adverse events were from the “Infections and Invasions” and “Gastrointestinal Disorders” system organ classification (SOC). Most TEAEs were of mild intensity.

Only a small number of patients experienced TEAEs considered to be related to the study drug, with similar incidence rates between placebo and the first two doses of iogliptin: 5.3% (iogliptin 500 mg), 5.4% (iogliptin 1000 mg), and 8% (placebo), increasing to 24% (iogliptin 1500 mg) at the highest dose. The higher incidence in the latter group was partly attributed to an increased incidence of TEAEs due to gastrointestinal disorders (SOCs): 14.7% (placebo and iogliptin 500 mg), 18.9% (iogliptin 1000 mg), and 32% (iogliptin 1500 mg), respectively.

TEAEs leading to discontinuation included adverse events requiring salvage therapy such as hyperglycemia and other state-of-the-art (SOC) events, and these were increased in the placebo group (13.3%) compared to the iogleemide dosage groups (2.7% at 500 mg, 6.8% at 1000 mg, and 6.7% at 1500 mg). No true trend was observed among non-hyperglycemic adverse events leading to withdrawal.

Six serious TEAEs occurred during the study (5.4% in the 1000 mg bid group, 1.3% in the 1500 mg bid and placebo groups, and none in the 500 mg bid group). None of these were related to the study drug. There was no real trend regarding unrelated serious TEAEs. In the 1500 mg group, one serious TEAE resulted in death (metastatic pancreatic cancer was discovered during the study).

In summary, the study met its primary endpoint, demonstrating a dose-dependent decrease in placebo-adjusted HbA1c change relative to baseline, with 1000 mg and 1500 mg bid showing similar and maximum effects.

In a post-hoc analysis, efficacy and safety/tolerability were studied based on patients' renal function (CKD1 = eGFR ≥ 90 mL/min/1.73 ^m² , CKD2 = 60 ≤ eGFR < 90 mL/min/1.73 ^m² , CKD3A = 45 ≤ eGFR < 60 mL/min/1.73 ^m² ). 299 patients were randomized. 74% of patients had CKD2, 14% had CKD1, and 12% had CKD3A. The primary endpoint was met, with statistically significant dose-dependent reductions in HbA1c at all three doses (subtracting placebo), achieving -0.94% and -1.00% HbA1c reductions at the two high doses of 1,000 and 1,500 mg bid, respectively (Table 5). Iggliflozin demonstrated improved HbA1c reduction compared to placebo. There was no significant difference in the incidence of adverse events (AEs), subacute adverse events (SAEs), or AEs leading to treatment discontinuation. No SAEs or adverse events leading to drug discontinuation were observed in the CKD3a subgroup.

In patients with stage T2D and CKD, at week 24, the reductions in HbA1c compared to placebo were -0.60, -1.03, and -1.11 for 500 mg BID, 1000 mg BID, and 1500 mg BID of ioggliflozin, respectively. Additionally, in patients with stage T2D and CKD 3a, at week 24, the reductions in HbA1c compared to placebo were -0.54, -0.44, and -1.07 for 500 mg BID, 1000 mg BID, and 1500 mg BID of ioggliflozin, respectively (Table 8). The strength of these data suggests that ioggliflozin has higher HbA1c efficacy in CKD patients regardless of renal function and does not decrease in CKD.

Table 8 lists the mean change (%) of HbA1c from baseline to week 24 (end of treatment) with igagleem in subjects segmented by eGFR category.

Table 8

Fasting plasma glucose (FPG) remained persistently low in subjects with CKD stages 2 and 3a (Table 9). The strength of these data, unlike the decreased FPG efficacy observed with SGLT2i in CKD, suggests that igagrimidine has greater FPG efficacy in CKD subjects compared to subjects with normal renal function.

Table 9 lists the mean FPG change (mg/dL) from baseline to week 24 (end of treatment) for igagleem in subjects segmented by eGFR category.

Table 9

Example 4

Population pharmacokinetic (population PK) model study of igagrimidine in subjects with type 2 diabetes mellitus (T2DM) and healthy subjects

Population pharmacokinetic (popPK) models of igagrimidine monotherapy following repeated oral administration were developed in subjects with type 2 diabetes mellitus (T2DM) and healthy subjects to support dose adjustment requirements in subjects with chronic kidney disease (CKD). The popPK models were built using PK datasets from a Phase 1 study of healthy Japanese and Caucasian subjects, and Phase 1, 2a, and 2b studies of healthy Caucasian subjects with impaired renal function. The popPK models were used to simulate steady-state plasma exposure based on different dosing regimens and the degree of renal impairment. Simulations were performed to support dosing regimen selection in subjects with chronic kidney disease CKD2 (mild renal impairment), CKD3 (moderate renal impairment, including 3A and 3B), and CKD4 (severe renal impairment). Dosing regimens were defined based on the effective dose observed in T2DM subjects. The simulation results obtained from the phase 2b study, along with tolerability and safety data, support the following dose adjustments for CKD subjects: 1000 mg/1500 mg bid in subjects with normal renal function and CKD2; 1000 mg bid in subjects with CKD3; and 750 mg QD in subjects with CKD4, as shown in Figure 9.

In addition, the predicted daily steady-state exposure (AUC _{24, ss} ) at doses of 500 mg BID, 1500 mg QD, and 1000 mg BID in T2DM subjects with CKD stage 3B or 4 in the phase 1b study was estimated using parameters from a population pharmacokinetic model; the mean AUC _{24, ss} values and standard deviations are shown in Figure 10. For reference, Figure 10 also includes the mean AUC _{24, ss} and standard deviations from the phase 2b clinical study; in that study, the mean AUC _{24, ss} in the 1500 mg BID treatment group was 36.5 μg·hr/mL (AUC _{24, ss} ranged from 10.1 to 169.3 μg·hr/mL). At each of these three dose levels, there was significant overlap in the predicted exposure between T2DM subjects with CKD3B and T2DM subjects with CKD4, as evidenced by the overlap of the standard deviation bars between CKD3B and CKD4 subjects at each dose level.

The dosing regimen derived from the simulation can be used to treat diabetic subjects with CKD at various stages.

Example 5

An open-label, parallel-group study was conducted to evaluate the safety, tolerability, and pharmacokinetics of igagrimidine in subjects with type 2 diabetes mellitus (T2DM) and moderate to severe chronic kidney disease (CKD).

This phase 1b study aims to evaluate the safety, tolerability, and pharmacokinetics (PK) of igagrimidine in subjects with stage 2DM and CKD 3B or 4.

This study included doses of 500 mg twice daily (BID), 1500 mg once daily (QD), and 1000 mg twice daily (BID) administered to subjects with type 2 diabetes and CKD stage 3B or 4, as reflected by mean eGFR, calculated using the MDRD equation as between 15 and 29 (CKD4) or 30 and 44 (CKD3B) ml/min/1.73 ^m² (inclusive), for a treatment period of 28 days. Subjects were randomized to receive one of the three treatments or placebo.

Selection criteria

1) Male or female subjects aged >40 years and <75 years.

2) Subjects diagnosed with T2DM at least 2 years prior to screening and receiving a stable dose of any approved antihyperglycemic agent other than metformin as background therapy for at least 12 weeks prior to the start of screening. Subjects receiving only non-pharmacological diabetes management (diet and exercise) may also be included.

3) Subjects with type 2 diabetes and CKD stage 3B or 4, as reflected by mean eGFR, which is calculated using the MDRD equation based on two eGFR values obtained at least 3 days apart during the screening period as being between 15 and 29 (CKD4) or 30 and 44 (CKD3B) ml/min/ ^1.73m2 (inclusive).

4) Subjects should be receiving standard care for diabetic nephropathy at a stable, therapeutically appropriate dose of angiotensin-converting enzyme inhibitor (ACEi) and/or angiotensin II receptor blocker (ARB) for at least 12 weeks prior to screening. If stable for 12 weeks prior to screening according to prescribing information, doses below the minimum acceptable dose are acceptable. Subjects with documented intolerance to ACEi or ARB therapy may be included.

5) HbA1c levels were between 6.8% and 12.0% (inclusive) during screening.

Main outcome measure

The area under the concentration-time curve (AUC _0–12 ), maximum concentration ( _Cmax ), and time to reach maximum concentration ( _tmax ) on day 15 can be calculated for each of the three dosing groups from 0 to 12 hours after dosing. Changes in fasting plasma glucose (FPG), glycated albumin, and glycosylated hemoglobin (HbA1c) compared to baseline can also be measured.

Safety can be assessed by evaluating clinical laboratory tests, physical examinations, vital sign measurements, ECG readings, and adverse event (AE) records at various time points during the study.

The verbatim text of the AE will be encoded and classified according to human systems and preferred (encoded) terms using the MedDRA Systemic Organ Classification (SOC) and Preferred Terminology (PT).

The incidence of treatment-associated adverse events (TEARs) will be summarized by treatment. The TEAR analysis will include the following summary:

1) Overview of adverse events in subjects who had at least one AE from any of the following categories: AE, SAE, AE with a death outcome, and AE leading to discontinuation of the study product;

2) All TEAEs according to SOC and PT;

3) All TEAEs assessed by preferred terminology and researcher (related versus unrelated) and maximum intensity;

4) All SAEs according to SOC and PT;

5) TEAEs that lead to treatment interruption;

6) All adverse events of special interest (AESI).

Clinical chemistry, hematology, and urinalysis values for each subject will be listed, and marked as high or low relative to the normal range where appropriate. All consecutive laboratory parameters will be descriptively summarized by absolute values at each visit for the treatment group, along with the corresponding changes compared to baseline. Descriptive summary statistics will be created by treatment and visit.

Renal function was a safety parameter in this study, assessed using eGFR derived from serum creatinine using the MDRD equation. A descriptive summary of eGFR, serum creatinine, urinary albumin, creatinine, and the calculated urinary albumin/creatinine ratio (ACR) will be provided from spot urine samples by treatment and visit.

Plasma lactate levels were descriptively summarized using absolute values at each visit in the treatment group, along with the corresponding changes compared to baseline.

Vital signs and physical examinations will be summarized descriptively by treatment and visit. Detailed information will be provided in SAP.

Pharmacokinetic (PK) data can be descriptively summarized by treatment group. PK parameters will be determined using a non-regional approach. Some PK summaries can also be shown by baseline CKD period groups. Trough concentration data can be used to assess steady state.

A descriptive pharmacodynamic (PD) summary of absolute values can be shown by treatment group, along with corresponding changes in FPG, glycated albumin, and HbA1c compared to baseline.

Following the completion of the aforementioned Phase 1b study to evaluate the safety, tolerability, and pharmacokinetics (PK) of igagrimidine in subjects with T2DM and CKD stage 3B or 4, the study data support the safety and tolerability of igagrimidine in subjects with CKD stage 3B or 4.

Patients with CKD often have other comorbidities that contribute to their CKD and increase the risk of cardiovascular events and death. The prevalence of these comorbidities is increased in patients with moderate to severe CKD, as demonstrated in the CKD stages 3B and 4 included in this study, of whom 100% had T2DM, 100% had hypertension, 41% had cardiomyopathy, 63% had anemia, 41% had endocrine disorders, and 53% had ocular disorders (Table 10). Despite the significant underlying symptom presence in this patient population, igagleevec was well tolerated with increasing CKD severity (to stage 4), with no serious adverse events, no lactic acidosis, and no confirmed cases of elevated plasma lactate. Compared to placebo, for CKD stages 3B and 4, the overall treatment-emergent adverse events (TEAEs) in igagleevec-treated subjects, whether or not related to the study drug, were mild to moderate and occurred at similar frequencies (Table 11). In CKD phases 3B and 4, almost all study-related adverse events (TEAEs) with igagleemide and placebo were mild and similar in frequency. Gastrointestinal symptoms (the most common adverse events) were similar in subjects treated with igagleemide and those treated with placebo. These data suggest that gastrointestinal tolerability is superior to metformin compared to placebo, and there is no increased risk of lactic acidosis.

Extensive blood sampling was performed on day 15 for pharmacokinetic analysis. The maximum observed concentration (Cmax) increased in a dose-dependent manner following morning administration of igagleem on day 15 (Figure 11). The area under the concentration-time curve (AUC) was similar between the 500 mg BID and 1500 mg BID treatment groups, but there was a noticeable increase in the 1000 mg BID treatment group (Figure 12). In both the 1500 mg QD and 1000 mg BID treatment groups, the AUC was increased in stage 4 T2DM patients compared to CKD3B (Figure 12). This is likely due to decreased renal filtration rate in these subjects. Although the systemic exposure (AUC) was significantly increased in the CKD4 group receiving 1000 mg BID igagleem, the incidence of adverse events was not increased compared to other treatment groups (Table 11). Surprisingly, the incidence of gastrointestinal events was trending lower in the 1000 mg BID treatment group compared to the 1500 mg QD treatment group, despite the higher systemic exposure to igagrimine in the former (Table 11).

Table 10. Medical history by treatment, organ system classification, and preferred term in subjects with type 2 diabetes mellitus (T2DM) and moderate to severe chronic kidney disease (CKD) included in the 28-day igelemin study.

Example 6

A 24-week, phase IIb, dose-variable, randomized, double-blind, placebo-controlled, parallel-group safety and efficacy study in patients with type 2 diabetes mellitus (T2DM).

Five parallel groups comprised four igagleem dose groups (500, 1000, 1500, or 2000 mg twice daily) and one placebo group. The primary endpoint was dose response in subjects with type 2 diabetes (T2D), assessed using changes in HbA1c from baseline to week 24 as the primary assessment criterion. Subjects may have been treatment-naïve or had received any oral antidiabetic monotherapy and had an eGFR ≥50 mL/min/1.73 ^m² . A total of 382 subjects were randomly assigned 1:1:1:1:1 to one of the five study groups, of whom 315 completed the study. In a post-hoc analysis of subjects with T2D and stage 2 and 3a CKD [eGFR <90 mL/min/1.73 ^m² (n=211)], igagleem showed improved HbA1c reduction compared to placebo.

Table 12 below lists the mean change (%) of HbA1c from baseline to week 24 (end of treatment) in subjects with T2D and CKD stages 2 and 3a treated with igagrimidine.

Table 12

Example 7

A 24-week, phase III, randomized, double-blind, placebo-controlled, monotherapy study was conducted to evaluate the efficacy, safety, and tolerability of orally administered igagrimidine in Japanese patients with type 2 diabetes mellitus (T2DM).

A total of 213 participants were randomly assigned in a 1:1 ratio to receive either igagleevec (1000 mg BID) or placebo BID for 24 weeks, with 194 participants completing the study without interruption of the investigational drug product (IMP). The primary objective of this study was to determine the change in HbA1c relative to baseline after 24 weeks of igagleevec treatment compared to placebo. Secondary endpoints included fasting plasma glucose and other standardized blood glucose and non-blood glucose parameters. Participants' eGFR was ≥50 mL/min/1.73 ^m² at screening and ≥45 mL/min/1.73 ^m² before randomization. In a pre-specified analysis of participants with stage 2D and stage 2 and 3a CKD [eGFR <90 mL/min/1.73 ^m² (n=178)], igagleevec showed an improvement in A1C reduction compared to placebo.

In this study, the reduction in HbA1c was assessed at week 24. In subjects with normal eGFR (>90 mL/min/1.73 ^m² ) treated with igagrimidine 1000 mg BID, the placebo-corrected reduction in HbA1c was -0.59%. The placebo-corrected reduction in HbA1c was greater in subjects with CKD; -0.96% and -0.70% for stage 2 CKD and stage 3a CKD, respectively. Similar to the results in Example 3, the strength of these data suggests that igagrimidine has greater HbA1c efficacy in subjects with CKD independent of renal function and does not decrease due to CKD.

Table 13 below lists the mean change (%) of HbA1c from baseline to week 24 (end of treatment) in subjects segmented by eGFR category for igagleem.

Table 13

Now that the invention has been fully described, those skilled in the art will understand that the invention can be carried out within a wide range of equivalent conditions, formulations and other parameters without affecting the scope of the invention or any of its embodiments.

Other embodiments of the invention will be apparent to those skilled in the art upon consideration of the description and practice of the invention disclosed herein. The description and examples are to be considered exemplary only, and the true scope and spirit of the invention are indicated by the appended claims.

All patents, patent applications and other publications cited in this article are incorporated herein in their entirety through citation.

Claims (45)

1. Use of igagrimidine in the manufacture of a medicament for the treatment of a human subject suffering from type 2 diabetes, wherein the subject suffers from stage 3B or 4 chronic kidney disease, and wherein the amount of igagrimidine administered to the subject is from 500 mg to 3000 mg per day. 2. Use of igagrimidine in the manufacture of a medicament for improving glycemic control in a subject with type 2 diabetes, wherein the subject has stage 3B or 4 chronic kidney disease, and wherein the amount of igagrimidine administered to the subject is from 500 mg to 3000 mg per day. 3. The use according to claim 2, wherein igleemine is administered as an aid to diet and exercise. 4. The use according to claim 1 or 2, wherein the subject suffers from stage 3B chronic kidney disease. 5. The use according to claim 1 or 2, wherein the subject suffers from stage 4 chronic kidney disease. 6. The use according to any one of claims 1 to 3, wherein the estimated glomerular filtration rate (eGFR) of the subject is between 15 ml/min/1.73 ^m² and 29 ml/min/1.73 ^m² . 7. The use according to any one of claims 1 to 3, wherein the estimated glomerular filtration rate (eGFR) of the subject is between 15 ml/min/1.73 ^m² and 44 ml/min/1.73 ^m² . 8. The use according to any one of claims 1 to 3, wherein the baseline percentage of glycosylated hemoglobin (HbA1c) of the subject is between 6.8% and 12.0%. 9. The use according to any one of claims 1 to 3, wherein the subject has a pre-existing condition. 10. The use according to any one of claims 1 to 3, wherein the subject treated with igagmin has the same frequency of post-treatment adverse events as the subject treated with placebo. 11. The use according to claim 9, wherein the subject receiving igagrimidine treatment does not experience an increase in one or more symptoms of one or more of the subject's pre-existing conditions compared to before the subject began igagrimidine treatment. 12. The use according to claim 9, wherein the severity or symptoms of one or more pre-existing conditions in the subject treated with igagrimine do not worsen after igagrimine treatment. 13. The use according to claim 12, wherein, compared with before the subject began igleemide treatment, the severity or symptoms of one or more pre-existing conditions of the subject treated with igleemide did not worsen after igleemide treatment. 14. The use according to claim 12, wherein the severity or symptoms of one or more pre-existing conditions in the subject treated with igagleem did not worsen after treatment with igagleem compared to what was expected when the subject took the second dose. 15. The use according to claim 12, wherein the prior condition is selected from hyperkalemia, hypertension, heart disease, gastrointestinal disorders, nervous system disorders, blood and lymphatic system disorders, eye disorders, endocrine disorders, or combinations thereof. 16. The use according to claim 15, wherein the blood and lymphatic system disorder is anemia. 17. The use according to claim 15, wherein the prior condition is a gastrointestinal condition. 18. The use according to claim 17, wherein the gastrointestinal symptom is selected from abdominal pain, constipation, diarrhea, flatulence, gastroesophageal reflux, indigestion, nausea/vomiting, or a combination thereof. 19. The use according to any one of claims 1 to 3, wherein the treatment with igagrimine is well tolerated. 20. The use according to any one of claims 1 to 3, wherein the subject receiving igagmin treatment does not experience an increase in the frequency of lactic acidosis compared to before the subject began igagmin treatment. 21. The use according to any one of claims 1 to 3, wherein the subject receiving igagmin treatment does not experience an increase or elevation in plasma lactate compared to before the subject began igagmin treatment. 22. The use according to claim 21, wherein the subject receiving igagrimidine treatment does not experience an increase or elevation of plasma lactate exceeding a threshold of 3 mmol/L (27 mg/dL) compared to before the subject began igagrimidine treatment. 23. The use according to any one of claims 1 to 3, wherein the subject treated with igagrimine is no more likely to experience an increase or elevation in plasma lactate than the subject treated with placebo or the subject treated with a second agent compared to before the subject began igagrimine treatment. 24. The use according to any one of claims 1 to 3, wherein igleemine is administered orally. 25. The use according to any one of claims 1 to 3, wherein the amount of igagmin is from 1000 mg to 3000 mg per day. 26. The use according to claim 25, wherein the amount of igleemine is 1000 mg to 2000 mg per day. 27. The use according to any one of claims 1 to 3, wherein the amount of igagmin is 1000 mg, 1500 mg or 2000 mg per day. 28. The use according to any one of claims 1 to 3, wherein igleemine is applied once, twice, or three times daily. 29. The use according to claim 28, wherein iglemin is administered twice daily. 30. The use according to claim 28, wherein igagrimidine is administered at 500 mg twice daily, 1000 mg twice daily, or 1500 mg once daily. 31. The use according to any one of claims 1 to 3, wherein igleemine is administered with a meal. 32. The use according to any one of claims 1 to 3, wherein igleemine is not administered with meals. 33. The use according to any one of claims 1 to 3, wherein igleemine is administered in the form of a free base or a pharmaceutically acceptable salt thereof. 34. The use according to claim 33, wherein igleemine is administered in the form of hydrochloride. 35. The use according to any one of claims 1 to 3, wherein the percentage reduction in glycosylated hemoglobin (HbA1c) subtracted from placebo experienced by the subject during treatment is between -0.5% and -1.2%. 36. The use according to claim 35, wherein the percentage reduction in glycosylated hemoglobin (HbA1c) experienced by the subject during treatment, minus placebo, is between -0.8% and -1.1%. 37. The use according to any one of claims 1 to 3, wherein the subject experiences a decrease in fasting plasma glucose (FPG) minus placebo during treatment between -20 mg/dL and -30 mg/dL. 38. The use according to claim 37, wherein the subject experiences a decrease in fasting plasma glucose (FPG) minus placebo during treatment to -25 mg/dL. 39. The use according to claim 35, wherein the treatment period is from 4 weeks to 52 weeks. 40. The use according to claim 37, wherein the treatment period is from 4 weeks to 52 weeks. 41. The use according to claim 39 or 40, wherein the treatment period is 24 weeks. 42. The use according to any one of claims 1 to 3, wherein the daily steady-state exposure (AUC _{24, ss} ) of the subject is from 20 µg·hr/mL to 100 µg·hr/mL. 43. The use according to any one of claims 1 to 3, wherein the subject has received existing antidiabetic treatment. 44. The use according to claim 43, wherein the existing antidiabetic treatment does not provide adequate control of the subject's type 2 diabetes or cannot adequately control the subject's type 2 diabetes. 45. The use according to any one of claims 1 to 3, wherein the subject has not received existing antidiabetic treatment.