Methods of Treating Diabetic Subjects with Chronic Kidney Disease - Patent application

Abstract

The present disclosure is directed to methods of treating pre-diabetes or type 1 or type 2 diabetes, wherein the subject has chronic kidney disease, comprising administering to a subject in need thereof an effective amount of imeglimin.

Description

[Technical field]

[0001] The present invention relates to the use of imeglimin for the treatment of metabolic disorders such as pre-diabetes, type 1 and type 2 diabetes in patients with impaired renal function or chronic kidney disease (CKD). [Background technology]

[0002] Metabolic disorders affect the normal metabolic processes of a patient and include prediabetes and type 1 or type 2 diabetes. Type 2 diabetes mellitus (T2DM) is a long-term metabolic disorder characterized by hyperglycemia, insulin resistance, and relative insulin deficiency. The prevalence of type 2 diabetes is increasing worldwide, with approximately 451 million adults suffering from diabetes in 2017; this number is expected to increase to 693 million by 2045. This global epidemic of diabetes imposes enormous personal, social, and economic burdens, especially in the presence of the multivascular complications of diabetes. Prediabetes is a precursor stage before diabetes, in which not all symptoms necessary to diagnose diabetes are present, and blood glucose levels are higher than normal but not high enough to be called diabetes. Prediabetes is associated with obesity (especially abdominal or visceral obesity), dyslipidemia with high triglycerides and / or low HDL cholesterol, and hypertension. It is therefore a metabolic predisposition or syndrome, usually without symptoms and with only hyperglycemia as the sole manifestation. Type 1 diabetes, formerly known as juvenile onset diabetes or insulin-dependent diabetes, is a chronic condition in which the pancreas produces little or no insulin.

[0003] Chronic kidney disease (CKD) is a condition characterized by the gradual loss of kidney function over time. It is estimated that 30-50% of all people with diabetes suffer from chronic kidney disease; more than 40% of subjects with CKD are estimated to also have T2DM. Furthermore, diabetes is the most frequent underlying cause of CKD and end-stage renal disease (ESRD), and T2DM is present in more than 50% of incident ESRD cases. See Tuttle et al., Diabetic kidney disease: a report from an ADA Consensus Conference, Diabetes Care. 2014; 37(10): 2864-2883.

[0004] Diabetic kidney disease is a chronic progressive disease with limited therapeutic options. Standard of care for this population includes therapy with inhibitors of the renin-angiotensin system (RAS) for renal protection and diabetes treatment, including management of hyperglycemia and cardiovascular risk factors, as it is generally accepted that the co-occurrence of advanced CKD and T2DM presents a greatly accelerated cardiovascular (CV) risk. Palsson R, Patel UD, Cardiovascular complications of diabetic kidney disease, Adv. Chronic. Kidney Dis. 2014; 21(3):273-80. In fact, the excess mortality among diabetic patients appears to be largely confined to the subgroup with renal disease and is likely explained by their high burden of cardiovascular disease. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] U.S. Patent No. 7,034,021 [Patent Document 2] U.S. Patent No. 7,452,883 [Patent Document 3] U.S. Patent No. 7,767,676 [Patent Document 4] U.S. Patent No. 7,501,511 [Patent Document 5] U.S. Patent No. 8,227,465 [Patent Document 6] U.S. Patent No. 8,791,115 [Patent Document 7] U.S. Patent No. 8,217,040 [Patent Document 8] U.S. Patent No. 8,461,331 [Patent Document 9] U.S. Patent No. 8,846,911 [Patent Document 10] U.S. Patent No. 9,035,048 [Patent Document 11] U.S. Patent No. 8,742,102 [Patent Document 12] U.S. Patent No. 8,592,370 [Patent Document 13] U.S. Patent No. 8,980,828 [Patent Document 14] U.S. Patent No. 8,742,103 [Patent Document 15] U.S. Patent No. 9,271,984 [Patent Document 16] U.S. Patent No. 8,937,066 [Non-patent literature]

[0006] [Non-Patent Document 1] Tuttle et al., Diabetic kidney disease: a report from an ADA Consensus Conference, Diabetes Care. 2014; 37(10): 2864~2883 [Non-Patent Document 2] Palsson R, Patel UD, Cardiovascular complications of diabetic kidney disease, Adv. Chronic. Kidney Dis. 2014; 21(3):273~80 [Non-Patent Document 3] American Diabetes Association, Standards of Medical Care in Diabetes-2018 [Non-Patent Document 4] Zhang, S. et al., Drug Discovery Today, 12(9 / 10), 373~381(2007) [Non-Patent Document 5] "Infections and Infestations" and "Gastrointestinal disorders" System Organ Classes (SOCs) Summary of the Invention [Problem to be solved by the invention]

[0007] The degree of glycemic abnormalities appears to predict the development of nephropathy, and sustained intensive glycemic control provides protection from the development of microvascular complications of diabetes. However, the long-term impact of intensive glycemic control on clinical outcomes in a population of patients with concomitant T2DM and clinically significant CKD is less clear. Despite the availability of more than 15 classes of drugs to manage hyperglycemia in T2DM patients, many of these therapeutic agents are not recommended or require significant dose reduction in the presence of concomitant moderate or severe CKD. Thus, there is a need to develop better treatment options for diabetic patients with CKD, especially those with moderate or severe CKD. [Means for solving the problem]

[0008] The present disclosure provides a method for treating diabetes in a subject with chronic kidney disease, particularly moderate and severe CKD, comprising orally administering an effective amount of imeglimin to a subject in need thereof. [Brief description of the drawings]

[0009] [Figure 1]FIG. 1 shows geometric mean plasma concentrations of imeglimin in subjects with various degrees of renal impairment following imeglimin 1000 mg QD over the course of any day in a Phase 1 study (linear scale). [Diagram 2] FIG. 1 shows the geometric mean plasma concentrations of imeglimin in subjects with various degrees of renal impairment following imeglimin 1000 mg QD on day 1 in a Phase 1 study (semi-log scale). [Diagram 3] FIG. 1 shows the geometric mean plasma concentrations of imeglimin in subjects with various degrees of renal impairment following imeglimin 1000 mg QD on day 8 in a Phase 1 study (semi-log scale). [Figure 4] FIG. 1 shows geometric mean plasma concentrations of imeglimin in subjects with normal renal function versus subjects with severe renal impairment following imeglimin 500 mg bid over the course of any day in a Phase 1 study (linear scale). [Diagram 5] FIG. 1 shows placebo-adjusted changes in HbA1c across the three dose groups in a Phase 2b study in Japanese T2DM subjects. [Figure 6] FIG. 1 shows placebo-adjusted change in HbA1c from baseline HbA1c in the three dose groups in a Phase 2b study in Japanese T2DM subjects. [Figure 7A] FIG. 1 shows the percentage of salvage therapy in a Phase 2b study in Japanese T2DM subjects. [Figure 7B] FIG. 1 shows the percentage of responders in a Phase 2b study in Japanese subjects with T2DM. [Figure 8] FIG. 1 shows placebo-adjusted reduction in fasting plasma glucose (FPG) across the three dose groups in a Phase 2b study in Japanese T2DM subjects. [Figure 9] FIG. 1 shows box plots of simulated AUCss24 following the recommended imeglimin dosing regimen in subjects with different stages of renal function. [Figure 10]FIG. 1 shows predicted daily steady-state exposures (mean and SD) for the Phase 1b study and actual daily steady-state exposures from a previous Phase 2b study. [Figure 11] FIG. 15: Maximum plasma imeglimin concentration on day 15 by treatment and CKD stage. Filled circles = arithmetic mean and x = geometric mean. Boxes represent 1st quartile (Q1), median and 3rd quartile (Q3). Whiskers represent minimum observed value within lower boundary and maximum observed value within upper boundary. Lower and upper boundaries are defined as Q1-1.5x(Q3-Q1) and Q3+1.5x(Q3-Q1), respectively. [Figure 12] Figure 15. Imeglimin area under plasma concentration-time (AUC) profiles by treatment and CKD stage at day 15. Filled circles = arithmetic mean and x = geometric mean. Boxes represent 1st quartile (Q1), median and 3rd quartile (Q3). Whiskers represent minimum observed value within lower boundary and maximum observed value within upper boundary. Lower and upper boundaries are defined as Q1-1.5 x (Q3-Q1) and Q3+1.5 x (Q3-Q1), respectively. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] In order that this disclosure may be more readily understood, certain terms are first defined. As used in this application, unless otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout this application.

[0011] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The terms "a" (or "an"), as well as "one or more" and "at least one," can be used interchangeably herein. In certain aspects, the terms "a" or "an" mean "single." In other aspects, the terms "a" or "an" include "two or more" or "multiple."

[0012] Furthermore, "and / or" as used herein is to be interpreted as a specific disclosure of each of the two specified features or components with or without the other. Thus, 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" (single), and "B" (single). Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to include each of the following embodiments: 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 (single); B (single); and C (single).

[0013] 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.

[0014] The term "about" as used in conjunction with numerical values ​​throughout this specification and claims indicates an interval of accuracy familiar and accepted by those of skill in the art. Such an interval of accuracy is ±10%.

[0015] The term "treatment period" refers to the period during which a drug is administered to a subject, and certain parameters of the subject are measured and compared to baseline values. For example, the treatment period can be from about 2 weeks to about 2 years. In some embodiments, the treatment period can be about 2, about 4, about 6, about 8, about 10, about 12, about 14, about 16, about 18, about 20, about 24, about 52, about 76, or about 104 weeks. The efficacy of a drug can be assessed by measuring certain parameters and calculating the change from baseline over the treatment period. Efficacy parameters include, but are not limited to, placebo-subtracted reduction in glycosylated hemoglobin (HbA1c) percentage and placebo-subtracted reduction in fasting plasma glucose (FPG).

[0016] As used herein, the term "AUC" refers to the area under the curve of a plot of plasma concentration versus time after drug administration.

[0017] The present disclosure also describes methods of using imeglimin to treat a subject with prediabetes or diabetes and CKD stage 3B or stage 4. The present disclosure also describes methods of using imeglimin to treat a subject with T2DM and CKD stage 3B or stage 4. The present disclosure also describes methods of using imeglimin to treat a subject with type 1 diabetes and CKD stage 3B or stage 4.

[0018] The management of hyperglycemia presents particular challenges in subjects with diabetic kidney disease. Due to the loss of renal function in these subjects, many of the approved classes of antihyperglycemic therapeutics that are cleared by the kidney require reduced doses or are not recommended. Thus, there are limited therapeutic options for diabetes management in subjects with renal disease, particularly moderate or severe CKD. Insulin and selected insulin secretagogues, such as sulfonylureas, are frequently used in this population; however, reduced clearance of insulin extends the duration of insulin action, thereby increasing the risk of hypoglycemic events, including severe hypoglycemia. Given the substantial hypoglycemic risk of intensive glycemic control in CKD patients, recent clinical guidelines recommend 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.

[0019] Most licensed antihyperglycemic therapies are approved for use in patients with an estimated glomerular filtration rate (eGFR) of 45 ml / min / 1.73 m 2 However, most therapeutic agents can be used in patients with low CKD levels (i.e., those who have progressed through CKD stage 3A). 2), which affects nearly 2 million active cases in the United States and approximately 200,000 incident cases annually. For example, metformin is used in patients with an estimated glomerular filtration rate (eGFR) of 30 mL / min / 1.73 m 2 Contraindicated in patients with eGFR below 30–44 mL / min / 1.73 m 2 CKD is not recommended for patients who are between 1 and 2 years of age. Furthermore, many of the therapeutic agents available for diabetic patients with CKD often lose efficacy as patients' renal function declines. Thus, for a significant number of patients with this degree of advanced diabetic kidney disease, the set of safe and effective patient options for glycemic control is limited.

[0020] Imeglimin is disclosed as 5,6-dihydro-4-dimethylamine-2-imino-6-methyl-1,3,5-triazine and is 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) criteria, Imeglimin is a (6R)-N 2 ,N 2 Compound I can be referred to as 1,6-trimethyl-3,6-dihydro-1,3,5-triazine-2,4-diamine. Compound I is further known as imeglimin.

[0021] [ka]

[0022] Imeglimin is the first of a novel tetrahydrotriazine-containing class of oral antidiabetic agents with a unique mechanism of action that targets mitochondrial bioenergetics and function.

[0023] Imeglimin has been studied in subjects with T2DM for up to 24 weeks as monotherapy and as add-on to metformin and sitagliptin. In each study, imeglimin was well tolerated with a safety profile comparable to placebo and placebo-subtracted reductions in glycosylated hemoglobin (HbA1c) ranging from -0.42% to -0.72% for a dose of 1500 mg twice daily (BID).

[0024] The pharmacokinetics (PK) of imeglimin is characterized by less dose-proportional exposure with increasing dose over the 250 to 2000 mg range, low protein binding (<8% bound), no appreciable metabolism in standard in vitro assays, and renal excretion as the primary route of excretion.

[0025] Treatment method The present invention relates to methods of using imeglimin in the treatment of metabolic disorders in patients with impaired renal function or chronic renal disease.

[0026] In certain embodiments, a patient amenable to the methods of the present disclosure may have or be at risk for one or more of the following diseases, disorders, or conditions: 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, nonalcoholic fatty liver disease (NAFLD), polycystic ovarian syndrome (PCOS), and / or idiopathic pulmonary disease (OPD). focal syndrome, metabolic syndrome, nephropathy, micro- or macroalbuminuria, proteinuria, retinopathy, cataracts, neuropathy, learning or memory impairment, neurodegenerative or cognitive impairment, cardiovascular disease, tissue ischemia, diabetic foot disease or ulcers, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, peripheral arterial occlusive disease, cardiomyopathy (including, for example, uremic cardiomyopathy), heart failure, cardiac hypertrophy, cardiac rhythm disorders, vascular stenosis, stroke, (kidney, heart, brain, or liver) ischemia / reperfusion injury, (kidney, heart, brain, or liver) fibrosis, (kidney, heart, brain, or liver) vascular remodeling; diabetic disease, particularly type 2 diabetes (e.g., underlying disease, etc.).

[0027] In one aspect, the disclosure relates to a method of treating pre-diabetes or type 1 or type 2 diabetes, comprising administering an effective amount of Imeglimin to a subject in need thereof, wherein the subject has chronic kidney disease. It is unexpected that Imeglimin provides similar safety and efficacy in patients with moderate to severe chronic kidney disease compared to patients with normal renal function.

[0028] In another aspect, the present disclosure provides a method of improving glycemic control in a subject with prediabetes or type 1 or type 2 diabetes and chronic kidney disease, comprising administering to a subject in need thereof an effective amount of imeglimin.

[0029] In another aspect, the present disclosure provides a method of improving glycemic control in a subject with prediabetes or type 1 or type 2 diabetes and chronic kidney disease as an adjunct to diet and exercise comprising administering an effective amount of imeglimin to a subject in need thereof.

[0030] In some embodiments, the subject has pre-diabetes. In some embodiments, the subject has type 1 or type 2 diabetes. In some embodiments, the subject has type 2 diabetes.

[0031] Patients are considered to have chronic kidney disease if they have abnormalities in renal function or structure present for more than 3 months. The definition of CKD is any individual with markers of kidney damage or a kidney function exceeding 60 ml / min / 1.73 m on at least two occasions with 90 days between them. 2 Includes all individuals (with or without markers of renal injury) with an estimated glomerular filtration rate (eGFR) less than 3 mg / mmol. Markers of renal disease may include: cysteine-C, albuminuria (albumin to creatinine ratio (ACR) >3 mg / mmol), hematuria (or presumed or confirmed renal origin), electrolyte abnormalities due to tubular damage, renal histology abnormalities, structural abnormalities detected by imaging (e.g., polycystic kidney disease, reflux nephropathy), or history of renal transplantation.

[0032] [Table 1]

[0033] In some embodiments, the subject has mild renal impairment. In some embodiments, the subject has stage 2 chronic kidney disease.

[0034] In some embodiments, the subject has mild to moderate renal impairment. In some embodiments, the subject has moderate to severe renal impairment. In some embodiments, the subject has stage 3A (or stage 3a) chronic kidney disease. In some embodiments, the subject has stage 3B (or stage 3b) chronic kidney disease. Stages 3A and 3B together are considered stage 3 chronic kidney disease.

[0035] In some embodiments, the subject has severe renal dysfunction. In some embodiments, the subject has stage 4 chronic kidney disease.

[0036] In some embodiments, the subject has stage 3B or stage 4 chronic kidney disease.

[0037] In some embodiments, the subject has a blood flow of about 45 ml / min / 1.73 m 2 Approximately 59ml / min / 1.73m 2 have an eGFR of

[0038] In some embodiments, the subject receives approximately 15 ml / min / 1.73 m 2 Approximately 44ml / min / 1.73m 2 have an eGFR of

[0039] In some embodiments, the subject receives approximately 15 ml / min / 1.73 m 2 Approximately 29ml / min / 1.73m 2 In some embodiments, the subject has an eGFR of about 30 ml / min / 1.73 m 2 Approximately 44ml / min / 1.73m 2 have an eGFR of

[0040] In some embodiments, the subject receives about 30 ml / min / 1.73 m 2 Approximately 59ml / min / 1.73m 2 have an eGFR of

[0041] In some embodiments, CKD can be classified based on the patient's albumin / creatinine ratio (ACR). Albuminuria is the increased excretion of albumin in urine and is a marker of kidney damage. Normal individuals excrete very small amounts of protein in urine. Albumin / creatinine ratio (ACR) is a method to detect high protein. ACR is calculated by dividing the albumin concentration in milligrams by the creatinine concentration in grams. Moderately increased albuminuria, known as microalbuminuria (ACR 30-300 mg / g), refers to albumin excretion that is higher than the normal range but lower than the level detected by a test for total protein. Severely increased albuminuria, known as macroalbuminuria (ACR>300), refers to a higher elevation of albumin associated with a progressive decline in glomerular filtration rate.

[0042] In some embodiments, the disclosure provides a method for treating a subject having a metabolic disorder (e.g., T2DM) and chronic kidney disease, comprising: determining the severity of chronic kidney disease in the subject; determining an effective dosing regimen of imeglimin for the subject based on the severity of the chronic kidney disease; and Administering imeglimin to the subject according to a dosing regimen The present invention provides a method comprising:

[0043] In some embodiments, the method comprises orally administering an effective amount of imeglimin to a subject in need thereof, hi some embodiments, imeglimin can be administered to the subject via injection, such as intravenous injection.

[0044] In some embodiments, treatment with imeglimin according to the methods described herein is well tolerated.

[0045] In some embodiments, a subject treated with Imeglimin, or a group of subjects treated with Imeglimin, does not experience an increase in the frequency of lactic acidosis compared to before the subject or group of subjects began Imeglimin treatment.

[0046] In some embodiments, a subject treated with Imeglimin, or a group of subjects treated with Imeglimin, does not experience an increase or elevation in plasma lactate compared to before the subject or group of subjects began Imeglimin treatment.

[0047] In some embodiments, a subject treated with Imeglimin, or a group of subjects treated with Imeglimin, does not experience an increase or rise in plasma lactate above a threshold of 3 mmol / L (27 mg / dL) compared to before the subject or group of subjects began Imeglimin treatment.

[0048] In some embodiments, a subject treated with Imeglimin, or a group of subjects treated with Imeglimin, is no more or less likely than a subject treated with a placebo or a subject treated with a second pharmaceutical agent, including an exemplary antidiabetic agent described herein, to experience an increase or elevation in plasma lactate compared to before the subject or group of subjects began Imeglimin treatment.

[0049] In some embodiments, a subject treated with imeglimin, or a group of subjects treated with imeglimin, has a similar or the same frequency of treatment-emergent adverse events as a subject or group of subjects treated with a placebo.

[0050] In some embodiments, the subject or group of subjects treated with imeglimin according to the methods described herein has a pre-existing medical condition, hi some embodiments, the pre-existing medical condition is not chronic kidney disease.

[0051] In some embodiments, one or more pre-existing conditions of a subject treated with Imeglimin, or of a group of subjects treated with Imeglimin, do not become more severe or symptomatic following treatment with Imeglimin than would be expected if the subject or group of subjects were to take a second pharmaceutical agent, including an exemplary antidiabetic agent described herein.

[0052] In some embodiments, a subject treated with Imeglimin, or a group of subjects treated with Imeglimin, does not experience an increase in one or more symptoms of the subject, or one or more pre-existing medical conditions of the subject, compared to before the subject or subjects began Imeglimin treatment.

[0053] In some embodiments, one or more pre-existing conditions of a subject treated with Imeglimin, or a group of subjects treated with Imeglimin, do not become more severe or symptomatic after treatment with Imeglimin. In some embodiments, one or more pre-existing conditions of a subject treated with Imeglimin, or a group of subjects, do not become more severe or symptomatic after treatment with Imeglimin compared to before the subject or subjects began Imeglimin treatment.

[0054] In some embodiments, the pre-existing medical condition is selected from hyperkalemia, hypertension, cardiac disorders, gastrointestinal disorders, nervous system disorders, blood and lymphatic system disorders (such as anemia), eye disorders, endocrine disorders, or combinations thereof.

[0055] In some embodiments, the pre-existing medical condition is a cardiac disorder, hi some embodiments, the cardiac disorder is selected from coronary artery disease, atrial fibrillation, congestive heart failure, myocardial infarction, or a combination thereof.

[0056] In some embodiments, the pre-existing medical condition is a gastrointestinal disorder, hi some embodiments, the gastrointestinal disorder is selected from abdominal pain, constipation, diarrhea, flatulence, gastroesophageal reflux, indigestion, nausea / vomiting, or a combination thereof.

[0057] In some embodiments, the pre-existing medical condition is a nervous system disorder, hi some embodiments, the nervous system disorder is selected from diabetic neuropathy, peripheral neuropathy, or a combination thereof.

[0058] In some embodiments, the pre-existing medical condition is a blood and lymphatic system disorder, hi 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.

[0059] In some embodiments, the pre-existing medical condition is an eye disorder, hi some embodiments, the eye disorder is selected from glaucoma, cataracts, or a combination thereof.

[0060] In some embodiments, the pre-existing medical condition is an endocrine or metabolic disorder, hi some embodiments, the endocrine or metabolic disorder is selected from diabetes, gout, hyperuricemia, elevated uric acid, secondary hypoparathyroidism, or a combination thereof.

[0061] In some embodiments, the amount of Imeglimin administered per day is about 500 mg to 3000 mg. In some embodiments, the amount of Imeglimin administered per day 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.

[0062] In some embodiments, the amount of Imeglimin administered per day is from about 500 mg to about 2750 mg, from about 500 mg to about 2500 mg, from about 500 mg to about 2250 mg, from about 500 mg to about 2000 mg, from about 500 mg to about 1750 mg, from about 500 mg to about 1500 mg, from about 500 mg to about 1250 mg, from about 500 mg to about 1000 mg, or from about 500 mg to about 750 mg.

[0063] In some embodiments, the amount of Imeglimin administered per day is about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 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, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4250 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4750 mg, about 4800 mg, about 4950 mg, about 500 mg, about 500 mg, about 5100 mg, about 5200 mg, about 5300 mg, about 5400 mg, about 550 mg, about 5600 mg, about 575 mg, about 580 mg, about 590 mg, about 6 400 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 a range between any two of the preceding values.

[0064] In some embodiments, the amount of Imeglimin administered per day is from about 500 mg to about 750 mg, from about 750 mg to about 1250 mg, from about 900 mg to about 1100 mg, from about 1000 mg to about 2000 mg, from about 1250 mg to about 1750 mg, or from about 1400 to about 1600 mg.

[0065] In some embodiments, the amount of imeglimin administered per day is about 1000 mg. In some embodiments, the amount of imeglimin administered per day is about 1500 mg. In some embodiments, the amount of imeglimin administered per day is about 2000 mg. In some embodiments, the amount of imeglimin administered per day is 1000 mg. In some embodiments, the amount of imeglimin administered per day is 1500 mg. In some embodiments, the amount of imeglimin administered per day is 2000 mg.

[0066] In some embodiments, the amount of imeglimin administered per day to a diabetic subject with CKD can be substantially the same as the amount administered to a diabetic subject with normal renal function.

[0067] In some embodiments, the amount of imeglimin administered per day to a diabetic subject with CKD is less than the amount administered to a diabetic subject with normal renal function.

[0068] In some embodiments, the amount of imeglimin administered per day to a diabetic subject 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 a diabetic subject with normal renal function, or ranges between any two of the preceding values, e.g., about 20% to about 100% of the amount administered to a diabetic subject with normal renal function.

[0069] In some embodiments, the amount of imeglimin administered per day to a diabetic subject with CKD (e.g., stage 3B CKD or stage 4 CKD) is about 20% to about 40%, about 20% to about 30%, about 30% to about 50%, about 30% to about 40%, about 40% to about 60%, about 40% to about 50%, about 50% to about 70%, about 50% to about 60%, or about 60% to about 70% of the amount administered to a diabetic subject with normal renal function.

[0070] In some embodiments, the amount of imeglimin administered per day 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 a range between any two of the preceding values.

[0071] In some embodiments, imeglimin is administered without food or before a meal. In some embodiments, imeglimin is administered 2 hours or more before a meal. In some embodiments, imeglimin is administered with a meal. In some embodiments, imeglimin is administered 2 hours or more after a meal.

[0072] In some embodiments, imeglimin is administered once per day, twice per day, or three times per day. In some embodiments, imeglimin is administered once per day. In some embodiments, imeglimin is administered twice per day.

[0073] In some embodiments, Imeglimin is administered to a subject at about 500 mg twice per day. In some embodiments, Imeglimin is administered to a subject at about 750 mg twice per day. In some embodiments, Imeglimin is administered to a subject at about 1000 mg twice per day. In some embodiments, Imeglimin is administered to a subject at about 1500 mg twice per day.

[0074] In some embodiments, Imeglimin is administered to a subject at about 750 mg once per day. In some embodiments, Imeglimin is administered to a subject at about 1000 mg once per day. In some embodiments, Imeglimin is administered to a subject at about 1500 mg once per day.

[0075] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human or animal. In some embodiments, the subject is a human.

[0076] In some embodiments, the subject is male. In some embodiments, the subject is female.

[0077] In some embodiments, the subject is older than about 18 years old. In some embodiments, the subject is younger than about 18 years old. In some embodiments, the subject is between about 6 and about 18 years old, about 6 and about 12 years old, or about 12 and about 18 years old. In some embodiments, the subject is older than about 20 years old. In some embodiments, the subject is older than about 25 years old. In some embodiments, the subject is older than about 30 years old. In some embodiments, the subject is older than about 35 years old. In some embodiments, the subject is older than 40 years old. In some embodiments, the subject is older than 45 years old. In some embodiments, the subject is older than 50 years old. In some embodiments, the subject is older than 55 years old. In some embodiments, the subject is older than 60 years old. In some embodiments, the subject is older than 65 years old. In some embodiments, the subject is older than 70 years old. In some embodiments, the subject is older than 75 years old.

[0078] In some embodiments, imeglimin is administered in the form of a free base or a pharma- ceutically acceptable salt thereof. In some embodiments, imeglimin is administered in the form of a free base. In some embodiments, imeglimin is administered in the form of a pharma- ceutically acceptable salt thereof. When imeglimin is in the form of a pharma- ceutically acceptable salt, 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.

[0079] 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.

[0080] In some embodiments, Imeglimin is administered in the form of a hydrochloride salt. The amount of Imeglimin administered to a subject described herein refers to the amount of Imeglimin free base. Examples described herein may refer to "Imeglimin" when Imeglimin hydrochloride is used.

[0081] In some embodiments, the subject has a baseline glycosylated hemoglobin (HbA1c) percentage of about 6.8% to about 12.0%.

[0082] In some embodiments, the subject has a baseline glycosylated hemoglobin (HbA1c) percentage of about 7.0%, about 8.0%, about 9.0%, about 10.0%, about 11.0%, or about 12.0%, or a range between any two of the preceding values.

[0083] The efficacy of imeglimin can be assessed by measuring the change in certain parameters in subjects over the treatment period. Placebo-subtracted or placebo-adjusted change from baseline refers to the difference between the change for subjects receiving imeglimin and the change for subjects receiving placebo. In some embodiments, the change from baseline is calculated using least squares means (LS means).

[0084] The primary efficacy assessment of Imeglimin will be based on glycosylated hemoglobin (HbA1c) levels. The main measure will be the change in HbA1c from baseline to the end of the treatment period compared to placebo.

[0085] In some embodiments, the subject experiences a placebo-netted reduction in glycosylated hemoglobin (HbA1c) percentage over the treatment period. In some embodiments, the placebo-netted reduction in HbA1c percentage over the treatment period is about -0.5% to about -1.2%. In some embodiments, the placebo-netted reduction in HbA1c percentage over the treatment period is about -0.6% to about -1.1%, about -0.7% to about -1.0%, or about -0.8% to about -0.9%.

[0086] In some embodiments, the placebo-netted reduction in HbA1c percentage over the treatment period is 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 a range between any two of the preceding values. In some embodiments, the placebo-netted reduction in HbA1c percentage over the treatment period is about -0.8%. In some embodiments, the placebo-netted reduction in HbA1c percentage over the treatment period is about -1.0%.

[0087] In some embodiments, the subject experiences a placebo-netted reduction in fasting plasma glucose (FPG). In some embodiments, the placebo-netted reduction in FPG over the treatment period is about -20 mg / dL to about -30 mg / dL. In some embodiments, the placebo-netted reduction in FPG over the treatment period is about -21 mg / dL to about -28 mg / dL, about -22 mg / dL to about -27 mg / dL, about -23 mg / dL to about -26 mg / dL, or about -24 mg / dL to about -25 mg / dL.

[0088] In some embodiments, the placebo-netted reduction in FPG over the treatment period is about -20 mg / dL, about -21 mg / dL, about -22 mg / dL, about -23 mg / dL, about -24 mg / dL, about -25 mg / dL, about -26 mg / dL, about -27 mg / dL, about -28 mg / dL, about -29 mg / dL, or about -30 mg / dL, or a range between any two of the preceding values. In some embodiments, the placebo-netted reduction in fasting plasma glucose over the treatment period is about -25 mg / dL.

[0089] In some embodiments, the subject receives a daily steady-state exposure (AUC) of imeglimin of about 10 μg·hr / mL to about 100 μg·hr / mL. 24,ss In some embodiments, the subject has a daily steady state exposure (AUC) of imeglimin that 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 a range between any two of the preceding values. 24,ss ).

[0090] In some embodiments, the subject receives a daily steady-state exposure (AUC) of imeglimin from about 10 μg·hr / mL to about 50 μg·hr / mL, from about 10 μg·hr / mL to about 40 μg·hr / mL, from about 10 μg·hr / mL to about 30 μg·hr / mL, or from about 10 μg·hr / mL to about 20 μg·hr / mL. 24,ss In some embodiments, the subject has a daily steady-state exposure (AUC) of imeglimin of 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. 24,ss ).

[0091] In some embodiments, the subject has had prior anti-diabetic therapy, for example, being treated for type 2 diabetes.

[0092] Prior treatments included acetyl-CoA carboxylase-2 (ACC-2) inhibitors, phosphodiesterase (PDE)-10 inhibitors, diacylglycerol acyltransferase (DGAT) 1 or 2 inhibitors, sulfonylureas (e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide), meglitinides, α-amylase inhibitors (e.g., dentamistat, trestatin, and rituximab), and rituximab. AL-3688), α-glucoside hydrolase inhibitors (e.g., acarbose), α-glucosidase inhibitors (e.g., adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, and salbostatin), PPARγ agonists (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone, and troglitazone), PPAR Alpha / gamma 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, hirthiosal extract, and Zhang, S. et al., Drug Discovery Today, 12(9 / 10), 373-381(2007)), SIRT-1 inhibitors (e.g., reservatrol), dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, and saxagliptin), insulin secretagogues, fatty acid oxidation inhibitors, A2 antagonists, c-jun amino terminal kinase (INK) inhibitors, insulin, insulin mimetics, glycogen phosphorylase inhibitors, VPAC2 receptor agonists, glucokinase activators, and sodium glucose transporter (SGLT2 or SGLT1 / 2) inhibitors.

[0093] In some embodiments, the subject has not received prior anti-diabetic treatment, eg, treatment for type 2 diabetes.

[0094] In some embodiments, imeglimin is administered with a second pharmaceutical agent. In some embodiments, imeglimin is administered simultaneously with the second pharmaceutical agent. In some embodiments, imeglimin is administered sequentially with the second pharmaceutical agent.

[0095] In some embodiments, the second pharmaceutical agent is selected from the group consisting of insulin, alpha-glucosidase inhibitors, biguanides, dopamine agonists, DPP-4 inhibitors, glucagon-like peptides, meglitinides, sodium glucose transporter (SGLT2 or SGLT1 / 2) inhibitors, sulfonylureas, and thiazolidinediones.

[0096] The second pharmaceutical agent can include the exemplary antidiabetic agents described herein. The second pharmaceutical agent can be: an alpha-glucosidase inhibitor, such as acarbose (Glucor®) and miglitol (Diastabol®); an insulin sensitivity enhancer, such as a thiazolidinedione (TZD), such as pioglitazone (Actos®) and rosiglitazone (Avandia®); an agent that reduces glycogen production, such as a biguanide, such as metformin (Glucophage®, Stagit®); a sulfonylurea (SU), such as These may also include, for example, carbutamide (Glucidoral®), glibenclamide / glyburide (Daonil®, Euglucan®), glibomuride (Glutril®), gliclazide (Diamicron®), glimepiride (Amarel®), glipizide (Glibenese®), chlorpropamide, and tolazamide; meglinides, such as repaglinide (NovoNorm®); dopamine agonists, such as bromocriptine; DPP-4 inhibitors, such as alogliptin, linagliptin, saxagliptin, sitagliptin, or vildagliptin; sodium glucose transporter (SGLT2 or SGLT 1 / 2) inhibitors, such as dapagliflozin, canagliflozin, empagliflozin, or sotagliflozin.

[0097] In some embodiments, the second pharmaceutical agent is a DPP-4 inhibitor. In some embodiments, the second pharmaceutical agent is sitagliptin.

[0098] In some embodiments, the second pharmaceutical agent is metformin.

[0099] In some embodiments, the prior antidiabetic treatment, e.g., treatment of type 2 diabetes, does not provide or adequately controls the metabolic disorder in the subject. In some embodiments, the metabolic disorder is type 2 diabetes. In some embodiments, the prior antidiabetic treatment does not provide or adequately controls the subject's glycemic parameters, non-glycemic parameters, or both. In some embodiments, the subject has an HbA 1c or 7.5% to 10% HbA 1c not adequately controlled by prior antidiabetic therapy, as defined by

[0100] In some embodiments, the prior antidiabetic treatment is a monotherapy. In some embodiments, the monotherapy comprises a pharmaceutical agent selected from the group consisting of insulin, alpha-glucosidase inhibitors, biguanides, dopamine agonists, DPP-4 inhibitors, glucagon-like peptides, meglitinides, sodium glucose transporter (SGLT2 or SGLT1 / 2) inhibitors, sulfonylureas, and thiazolidinediones. In some embodiments, the monotherapy comprises a pharmaceutical agent comprising the exemplary antidiabetic agents described herein. EXAMPLES

[0101] Example 1 Comparative effects of imeglimin, metformin, and phenformin on the risk of lactic acidosis in a rat model of acute renal failure (ARF) Metformin is associated with a risk of lactic acidosis in patients with renal and / or cardiac failure. The plasma accumulation of metformin in renal failure is a risk factor for the development of this lactic acidosis. Acute renal failure (ARF) can be induced in rats with gentamicin, which can directly produce tubular cell necrosis and also cause a reduction in renal blood flow.

[0102] A study has been completed investigating the risk of lactic acidose induction in rats with acute renal insufficiency following treatment with imeglimin compared to biguanidides metformin and phenformin.

[0103] Renal failure in rats developed after administration of gentamicin (200 mg / kg sc) followed by randomization: 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 by subcutaneous route once a day for 4 days (dosage volume: 1 ml / kg mass). Creatinine levels, correlated to the degree of renal insufficiency, were tested for each rat 7 days after the first injection of gentamicin. After administration of gentamicin, renal failure developed, with serum creatinine ranging from 1 to 3 mg / dL compared to 0.5 mg / dL in normal rats. Creatinine levels were determined with Monarch Chemistry Systems using the IL test creatinine in rat plasma samples. This monochromatic assay is based on the formation of a red complex between creatinine and picric acid under alkaline conditions.

[0104] Imeglimin, metformin, or phenformin dissolved in saline was administered intravenously at a constant rate of 8 ml / h / kg for 180 minutes at doses of 100 mg / h / kg (imeglimin and metformin) and 50 mg / h / kg (phenformin) for the normal group, and 25, 50, 75, 100 mg / h / kg (imeglimin and metformin) and 25, 50 mg / h / kg (phenformin) for the moderate and severe groups.

[0105] In normal rats, infusion of imeglimin at a dose of 100 mg / h / kg significantly reduced plasma glucose levels from 60 min (6.5 ± 0.4 vs. 7.6 ± 0.4 mmol / L basal tp<0.001). The same effect was observed after infusion of phenformin at 50 mg / h / kg or metformin 100 mg / kg / h. However, this reduction in plasma glucose levels was more pronounced at time (180 min), 2.9 ± 1 mmol / L after phenformin versus 5.4 ± 0.4 mmol / L after imeglimin and 4 ± 0.7 mmol / L after metformin. This hypoglycemic effect was obtained with the same plasma concentration levels of imeglimin (65.16 ± 15.8 μg / ml) and metformin (84.77 ± 12.27 μg / ml).

[0106] In rats with mild or severe ARF, the reduction in plasma glucose levels by imeglimin was significant and time-dependent. However, unlike metformin and phenformin, severe hypoglycemia was not observed with imeglimin. Phenformin and metformin slowly reduced plasma glucose levels until 120 min; then, a steep drop in plasma glucose levels occurred, 1.9±1 mmol / L for metformin and 2.4±1.1 mmol / L for phenformin.

[0107] In normal rats, metformin at 100 mg / h / kg and phenformin at 50 mg / h / kg significantly increased lactatemia. Phenformin induced higher lactate production than metformin (9.4 ± 2.1 vs. 4.6 ± 0.4 mmol / L). Imeglimin did not change plasma lactate levels. In ARF rats, metformin and phenformin treatment significantly increased plasma lactate. This effect on plasma lactate was dose- but also time-dependent. The metformin-induced increase in plasma lactate levels, as defined by creatinine levels as described above, was much greater in rats with severe ARF than in those with mild ARF. In contrast to these biguanides, imeglimin did not significantly increase plasma lactate in this ARF rat model.

[0108] In ARF rats, metformin and phenformin significantly increased plasma H + Imeglimin significantly increased the concentration of imaglimin in the nasal cavity. This effect was evident 2 hours after perfusion and was dose-dependent. This pH correction did not appear to correlate with the degree of ARF severity for either compound. No signs of metabolic acidosis with imeglimin treatment were observed.

[0109] In ARF rats, phenformin and metformin infusion increased the [HCO - ] significantly decreased plasma concentrations of [HCO3 - ] significantly decreased after phenformin 50 mg / kg, 11.8 ± 1.1 vs. 22.8 ± 0.8 mmol / L in controls (p < 0.001), and after phenformin 50 mg / kg, 17.7 ± 1.3 vs. 22.8 ± 0.8 mmol / L in controls (p < 0.001). Imeglimin also significantly decreased plasma [HCO3 - This effect was independent of the severity of ARF and the compound concentration.

[0110] From 50 mg / kg / h, phenformin induced 85% mortality, which was dependent on the plasma creatinine concentration. This effect was only present in the high plasma creatinine group. The main biochemical characteristics of this mortality were hypoglycemia, hyperlactatemia, a drop in plasma pH (<7.2), and [HCO3 - These biochemical changes are the physiological hallmarks of lactic acidosis.

[0111] In the ARF rat model, plasma accumulation of metformin and imeglimin was observed. This effect appeared to be dose-dependent, but also dependent on the degree of ARF severity. A significant direct relationship between plasma metformin and plasma lactate concentrations was observed, r=0.758, p<0.001. A similar significant correlation was observed between plasma metformin and plasma H +The correlation between plasma imeglimin concentration and plasma lactate or H was r=0.611, p<0.0156. + No significant correlation was observed between the levels.

[0112] Infusion of metformin or phenformin in this rat model of acute renal failure induced lactic acidosis, a fatal side effect that was characterized by an increase in plasma lactate and H + and a dose-dependent increase in [HCO3 - The results were characterized by a decrease in lactate levels and plasma H + A significant relationship was observed between the concentrations.

[0113] Example 2 A Phase 1 clinical study to investigate the pharmacokinetics of imeglimin in subjects with renal impairment compared to subjects with normal renal function An open-label, parallel-group, multicenter, multiple oral dose study was completed to investigate the pharmacokinetics of imeglimin in subjects with renal impairment compared to subjects with normal renal function.

[0114] In this study, a total of 51 subjects received imeglimin at a daily dose of 1000 mg, either 1000 mg QD (once a day) or 500 mg bid (twice a day) for 8 days. Of the 27 subjects with chronic renal dysfunction, 9 subjects (5 received QD and 4 received the bid regimen) had mild (decreased creatinine clearance (CL Crea ) 50-80 mL / min), 12 subjects (6 given QD and 6 given the bid regimen) had moderate (CL) Crea 30 to <50 mL / min), and 6 subjects (fed the bid regimen) had severe, impaired renal function (CL Crea Twenty-four control subjects with normal renal function were matched to subjects with mild and moderate (10 subjects received QD and 8 subjects received the bid regimen) and severe (6 subjects received the bid regimen) renal impairment. Using 24-hour urine sampling, measurements of the urine / plasma ratio of creatinine were calculated (CL Crea ).

[0115] Imeglimin was administered in the morning for 8 consecutive days to subjects receiving 1000 mg once daily, and in the morning and evening to subjects receiving 500 mg twice daily for 7 consecutive days, followed by a morning dose of 500 mg on day 8. Morning doses on days 1 and 8 were administered in the fasted state 10 hours after an overnight fast, and during the 4 hours following Imeglimin administration.

[0116] Inclusion Criteria: For subjects with normal renal function: CL based on calculation using 24-hour sampling on day -2 Crea >80 mL / min. For subjects with impaired renal function: Based on calculations using the 24-hour sampling on Day -2, CL is 0.01 for subjects with mild renal impairment. Crea 50 to 80 mL / min, 30 to <50 mL / min in subjects with moderate renal impairment, and <30 mL / min in subjects with severe renal impairment.

[0117] The mean pharmacokinetic parameters of imeglimin obtained on the 8th day of treatment are presented in Tables 1 and 2. Pharmacokinetic parameters included the apparent volume of distribution (Vz / F) during the terminal phase after extravascular administration, the area under the curve of plasma concentration as a function of time (AUC 0~t ), maximum observed concentration (C max ), time to maximum concentration (t max ), plasma half-life (t 1 / 2 ), total body clearance of drug from plasma after extravascular administration (CL / F), and other parameters were included.

[0118] Median T max Steady state of imeglimin was achieved on day 6 of repeated dosing of 1000 mg QD and 500 mg bid, which was consistent with T 1 / 2 (13 to 26 hours).

[0119] Renal impairment resulted in up to 3.6-fold accumulation of Imeglimin in subjects with severe renal impairment. The difference in exposure between subjects with renal impairment and normal subjects was up to 1.5-fold, 2.3-fold, and 3.6-fold greater on day 8 in subjects with mild, moderate, and severe renal impairment, respectively. In general, only higher exposures in the moderate and severe groups compared to the normal renal function group were statistically confirmed. The mean observed plasma profiles from days 1 to 8 in subjects with various degrees of renal impairment receiving 1000 mg Imeglimin QD are shown in Figures 1-3. The mean observed plasma profiles over all days in subjects with normal renal function and severe renal impairment receiving 500 mg Imeglimin bid are shown in Figure 4.

[0120] Total oral systemic clearance and renal clearance were decreased by up to 72% and 74%, respectively, with increasing renal impairment in subjects with severe renal impairment compared with normal subjects.

[0121] A significant proportion of the dose was excreted in the urine during the 12-hour dosing interval with the 500 mg bid regimen, estimated at 44% to 46% in normal subjects, 43% in mild, 42% in severe, and 40% in subjects with moderate renal impairment.

[0122] [Table 2]

[0123] [Table 3]

[0124] The urinary excretion parameters of imeglimin in subjects with different degrees of renal impairment after oral administration of imeglimin QD or bid on day 8 are summarized in Tables 3 and 4. The parameters measured were the amount of unchanged drug excreted in the urine as a function of time (Ae 0-t ), renal clearance (CL R), and the amount of unchanged drug excreted in the urine during one dosing interval (Ae 0- The percent of the administered dose excreted in the urine during one dosing interval (feτ) is included.

[0125] [Table 4]

[0126] [Table 5]

[0127] Biochemical and hematological parameters of subjects with normal and mild renal impairment were normal in most cases and outside the normal range in only one case. All these cases were assessed as clinically irrelevant. As expected, subjects with moderate and severe renal impairment showed values ​​outside the normal range for some parameters due to their underlying disease. Urine and creatinine values ​​were outside the normal range in all cases and assessed as clinically relevant. Hematological parameters were outside the normal range in a single case and assessed as clinically irrelevant, but were expected to be due to their underlying disease. In a single case, inorganic phosphate, ALT, GLDH, CK, triglycerides, lipase, and glucose were increased in subjects with moderate and severe renal impairment, and these cases were assessed as clinically relevant. No relevant deviations from normal values ​​were observed in sodium, potassium, and chloride levels. No significant abnormalities were observed in clinical laboratory parameters. Mean systolic and diastolic blood pressure values ​​were slightly higher, as expected in subjects with severe renal impairment. Vital signs did not show any clinically relevant changes after administration of imeglimin. Mean PR intervals did not show any relevant changes during the time course of the study. QRS-, QT-intervals, and QTc-intervals corrected according to Bazett and Fridericia did not reveal any relevant changes related to the administration of the study drug.

[0128] The safety and tolerability evaluation of multiple oral doses of 1000 mg Imeglimin QD (i.e., a total dose of 8000 mg Imeglimin) or 500 mg Imeglimin BID (i.e., a total dose of 7500 mg Imeglimin) included laboratory tests (hematology, clinical chemistry, urinalysis), determination of vital signs, ECG recording, AE questioning, and physical examination. All safety parameters did not show any relevant changes during the course of the study. The incidence of AEs observed during the course of the study was low. Overall, 54 treatment-emergent AEs were reported in 31 of 51 subjects. Of these, only 15 were judged to be likely related to the study drug. The majority (39 AEs) were assessed as unlikely related. Based on these low incidences, differences between dose regimens and between renal impairment groups cannot be drawn. The overall safety and tolerability evaluation showed that Imeglimin was well or very well tolerated. Overall, the safety and tolerability of a total daily dose of 1000 mg imeglimin or 500 mg imeglimin bid administered once daily for 8 days is considered well.

[0129] Example 3 A dose-ranging, randomized, double-blind, placebo-controlled, parallel-group, multicenter study of the efficacy and safety of three doses of imeglimin after 24 weeks of treatment in Japanese subjects with type 2 diabetes In this study, a total of 299 subjects with T2DM were given Imeglimin in one of three doses (500, 1000, and 1500 mg bid)3 or placebo. The primary objective of this study was to evaluate the dose-response of Imeglimin in three doses (500, 1000, and 1500 mg bid) compared to placebo in male and female subjects with T2DM after 24 weeks of treatment using glycosylated hemoglobin (HbA1c) as the primary endpoint. Inclusion criteria: Subjects had an eGFR ≥ 50 mL / min / 1.73 m at screening. 2 and >=45 at the pre-randomization visit. A total of 299 subjects were randomized 1:1:1:1 to one of the four study arms, and 268 subjects completed the study.

[0130] The study met its primary endpoint. There was a dose-dependent decrease in placebo-adjusted change in HbA1c vs. baseline, reaching statistical significance for the three doses (-0.52%; -0.94% and -1.0%; p<0.0001 for 500 mg, 1000 mg and 1500 mg bid, respectively). See Table 5 and Figure 5.

[0131] [Table 6]

[0132] Changes in HbA1c were analyzed according to baseline HbA1c <8% or ≧8%. Changes in HbA1c were similar at the 500 mg bid (-0.47% and -0.58%, for baseline <8% and ≧8%, respectively) and 1000 mg bid (-0.93% and -0.90%, for baseline <8% and ≧8%, respectively) doses, but were greater at the 1500 mg bid dose in patients with higher HbA1c at baseline (-0.82% and -1.2%, for baseline <8% and ≧8%, respectively). See Figure 6.

[0133] The percentage of responders was defined as the percentage of subjects who achieved an HbA1c value ≤ 7% at the end of the 24-week double-blind treatment period. Analyses were performed using the FAS for subjects with HbA1c values ​​> 7.0% at baseline.

[0134] There was a statistically significant and similar increase in responder rate at the two top doses of Imeglimin (33.3% and 32.9% in the Imeglimin 1000mg bid and 1500mg bid groups vs. 8.2% in the placebo group). During the double-blind treatment period, the percentage of subjects requiring rescue therapy due to inadequate glycemic control was higher in the placebo group (10.7%) compared to the other groups with no subjects requiring rescue therapy at the top dose of Imeglimin 1500mg bid. See Figures 7A and 7B.

[0135] A decrease in FPG was observed at the top doses of 1000 and 1500 mg bid (-24.6 mg / dL or 1.37 mmol / L p<0.001) and follows the same profile with similar effects. See Table 6 and Figure 8.

[0136] [Table 7]

[0137] The change from baseline in glycated albumin (FAS) is shown in Table 7.

[0138] [Table 8]

[0139] The overall incidence of subjects experiencing any adverse events (AEs) was similar across groups, ranging from 73% (Imeglimin 1000 mg) to 77.3% (Imeglimin 1500 mg). The incidence of subjects experiencing treatment-emergent (TE) AEs ranged from 62.2% (Imeglimin 1000 mg) to 73.3% (Imeglimin 1500 mg).

[0140] The most common adverse events were from the System Organ Class (SOC) "Infections and Infestations" and "Gastrointestinal disorders." Most of the TEAEs were of mild intensity.

[0141] A small number of patients experienced TEAEs considered related to the study drug, with similar incidence between placebo and the first two doses of Imeglimin, 5.3% (Imeglimin 500 mg), 5.4% (Imeglimin 1000 mg), and 8% (placebo), with an increase with the top dose, 24% (Imeglimin 1500 mg). This higher incidence in the latter group was driven in part by an increased incidence of TEAEs from the gastrointestinal disorders SOC, 14.7% (placebo and Imeglimin 500 mg), 18.9% (Imeglimin 1000 mg), and 32% (Imeglimin 1500 mg).

[0142] TEAEs leading to discontinuation, including both hyperglycemia requiring rescue therapy and other SOC adverse events, were increased in the imeglimin dose groups (2.7% at 500 mg, 6.8% at 1000 mg, and 6.7% at 1500 mg) versus placebo (13.3%). Among non-hyperglycemic adverse events leading to discontinuation, there were no real trends.

[0143] Six severe TEAEs occurred during the course of the study (5.4% in Imeglimin 1000 mg bid, 1.3% in Imeglimin 1500 mg bid and placebo groups, and none in Imeglimin 500 mg bid, respectively). None of them were related to the study drug. There were no real trends in unrelated severe TEAEs. One severe TEAE led to death in the 1500 mg group (metastatic pancreatic cancer discovered during the study).

[0144] In conclusion, the study met its primary endpoint of demonstrating a dose-dependent reduction in the change from baseline in placebo-adjusted HbA1c, with doses of 1000 mg and 1500 mg bid showing similar maximum effects.

[0145] In a post-hoc analysis, the efficacy and safety / tolerability profile were investigated in patients according to their renal function (CKD 1 = eGFR ≥ 90 mL / min / 1.73 m 2 , CKD2=60≦eGFR<90mL / min / 1.73m 2 , CKD3A=45≦eGFR<60mL / min / 1.73m 2 ). 299 patients were randomized. 74% of patients had CKD2, 14% had CKD1, and 12% had CKD3A. The primary endpoint met statistically significant dose-dependent placebo-subtracted reductions in HbA1c at 3 doses with the 2 top doses of 1,000 and 1,500 mg bid reaching HbA1c reductions of -0.94% and -1.00%, respectively (Table 5). Imeglimin demonstrated improved HbA1c reductions compared to placebo. There were no significant differences in the incidence of AEs, SAEs, or AEs leading to treatment discontinuation. No SAEs or AEs leading to discontinuation were observed in the CKD3a subgroup.

[0146] In subjects with T2D and stage 2 CKD, the reduction in HbA1c vs. placebo was -0.60, -1.03, and -1.11 for Imeglimin 500 mg BID, 1000 mg BID, and 1500 mg BID, respectively, at 24 weeks. Additionally, in subjects with T2D and stage 3a CKD, the reduction in HbA1c vs. placebo was -0.54, -0.44, and -1.07 for Imeglimin 500 mg BID, 1000 mg BID, and 1500 mg BID, respectively, at 24 weeks (Table 8). Unlike the reduced HbA1c efficacy observed with SGLT2i in CKD, the superiority of these data suggests that the greater HbA1c efficacy with Imeglimin in subjects with CKD is not dependent on renal function and is not diminished in CKD.

[0147] The mean percent change in HbA1c from baseline through 24 weeks for Imeglimin in subjects divided by eGFR category is listed in Table 8.

[0148] [Table 9]

[0149] Fasting plasma glucose (FPG) was consistently reduced in subjects with CKD stages 2 and 3a (Table 9). Unlike the reduced FPG efficacy in CKD observed with SGLT2i, the robustness of these data suggests greater FPG efficacy with imeglimin in subjects with CKD compared to subjects with normal renal function.

[0150] The mean change in FPG (mg / dL) from baseline to week 24 (end of treatment) on Imeglimin for subjects divided by eGFR category is listed in Table 9.

[0151] [Table 10]

[0152] Example 4 A population pharmacokinetic (popPK) modeling study of imeglimin in subjects with type 2 diabetes mellitus (T2DM) and in healthy subjects A population pharmacokinetic (popPK) model for imeglimin monotherapy after repeated oral dosing in subjects with type 2 diabetes mellitus (T2DM) and in healthy subjects was developed to support dose adjustments required in subjects with chronic kidney disease (CKD). The popPK model was constructed using PK data sets from a Phase 1 study in healthy Japanese and Caucasian subjects, a Phase 1 study in renal-impaired but otherwise healthy Caucasian subjects, a Phase 2a study, and a Phase 2b study. The popPK model was used to simulate plasma exposure at steady state after different dosing regimens and according to 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 established based on the effective doses observed in T2DM subjects. Simulations and tolerability and safety data obtained in the Phase 2b study supported the following dosing adjustments in CKD subjects: 1000mg / 1500mg bid in subjects with normal renal function and CKD2; 1000mg bid in CKD3 subjects; 750mg QD in CKD4 subjects, as shown in FIG. 9.

[0153] Additionally, predicted daily steady-state exposure (AUC ) was assessed for doses of 500 mg BID, 1500 mg QD, and 1000 mg BID in T2DM subjects with CKD stages 3B or 4 in a Phase 1b study. 24,ss ) was estimated using parameters from the population PK model; mean AUC 24,ss Values ​​and standard deviations are shown in Figure 10. For reference, the mean AUC 24,ss The mean AUC for the 1500 mg BID treatment group in that study and the standard deviation are also included in FIG. 24,ss was 36.5 μg h / mL (AUC 24,ssrange was 10.1 to 169.3 μg·h / mL). Significant overlap in exposure between T2DM subjects with CKD3B and T2DM subjects with CKD4 at each of the three dose levels was predicted as revealed by the overlap of standard deviation bars between CKD3B and CKD4 subjects at each dose level.

[0154] Medication regimens from the simulation can be used to treat diabetic subjects with various stages of CKD.

[0155] Example 5 An open-label, parallel-group study to evaluate the safety, tolerability, and pharmacokinetics of imeglimin in subjects with type 2 diabetes mellitus (T2DM) and moderate-to-severe chronic kidney disease (CKD) This Phase 1b study was designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of imeglimin in subjects with T2DM and CKD stages 3B or 4.

[0156] The doses included in this study were 15 to 29 (CKD4) or 30 to 44 (CKD3B) ml / min / 1.73 m over a 28-day treatment period, including type 2 diabetes and borderline diabetes. 2 The three treatments are 500 mg twice daily (BID), 1500 mg once daily (QD), and 1000 mg twice daily (BID) given to subjects with CKD stages 3B or 4, as reflected by mean eGFR calculated using the MDRD equation between 10 and 20 mg / kg. Subjects will be randomly assigned to receive one of the three treatments or placebo.

[0157] Inclusion criteria 1) Male or female subjects aged >40 and <75 years. 2) Subjects were diagnosed with T2DM at least 2 years prior to screening and received any background regimen of approved antihyperglycemic medication, except metformin, at a stable dose 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) Type 2 diabetes, including borderline type 2 diabetes, 15 to 29 (CKD4) or 30 to 44 (CKD3B) ml / min / 1.73m 2 Subjects with CKD stage 3B or 4 as reflected by mean eGFR calculated using the MDRD equation based on two eGFR values ​​obtained during the screening period, a minimum of 3 days apart. 4) Subjects should be receiving standard of care for their diabetic kidney disease with angiotensin-converting enzyme inhibitors (ACEi) and / or angiotensin II receptor blockers (ARB) at stable, therapeutically appropriate doses for at least 12 weeks prior to screening initiation. According to prescribing information, doses lower than the minimum tolerated dose are acceptable if stable for 12 weeks prior to screening. Subjects with documented intolerance to ACEi or ARB therapy may be enrolled. 5) HbA1c between 6.8% and 12.0% at screening, including borderline.

[0158] Primary endpoint The area under the concentration-time curve (AUC) from time 0 to 12 hours post-dose on day 15 for each of the three dose groups. 0~12 ), maximum concentration (C max ), and time to maximum concentration (t max ) can be calculated. Changes from baseline in fasting plasma glucose (FPG), glycated albumin, and glycosylated hemoglobin (HbA1c) can also be measured.

[0159] Safety can be assessed by evaluation of clinical laboratory tests, physical examinations, vital sign measurements, and ECG readings at various time points during the study, as well as by documentation of AEs.

[0160] The AE verbatim text will be coded and classified by system and preferred (coding) term using MedDRA System Organ Classes (SOCs) and Preferred Terms (PTs).

[0161] The incidence of treatment-emergent adverse events (TEAEs) will be summarized by treatment. TEAE analyses will include a summary of: 1) Overview of adverse events for subjects with at least one AE in any of the following categories: AEs, SAEs, AEs resulting in death, and AEs leading to discontinuation of study drug; 2) all TEAEs by SOC and PT; 3) all TEAEs by preferred term and investigator causality assessment (related vs. unrelated), and maximum intensity; 4) All SAEs by SOC and PT; 5) TEAEs leading to treatment discontinuation; 6) Any adverse events of special interest (AESI).

[0162] Clinical chemistry, hematology, and urinalysis values ​​will be listed for each subject and flagged as higher or lower than normal ranges where appropriate. All continuous laboratory parameters will be summarized descriptively by treatment group and absolute values ​​at each visit, along with corresponding changes from baseline. Descriptive summary statistics will be generated by treatment and visit.

[0163] Renal function is a safety parameter in this study, assessed by eGFR derived from serum creatinine using the MDRD equation. Narrative summaries will be provided for eGFR, serum creatinine, urinary albumin, creatinine and calculated urinary albumin to creatinine ratio (ACR) from spot urine samples for each treatment and visit.

[0164] Plasma lactate will be summarized descriptively by absolute values ​​at each visit by treatment group, along with the corresponding changes from baseline.

[0165] Vital signs and physical examinations will be summarized narratively for each treatment and visit. Details will be provided in the SAP.

[0166] Pharmacokinetic (PK) data can be summarized descriptively by treatment group. PK parameters are determined using noncompartmental methods. Some PK summaries can also be displayed by baseline CKD stage group. Steady state can be assessed using trough concentration data.

[0167] A descriptive pharmacodynamic (PD) summary can be presented in terms of absolute values ​​by treatment group, along with corresponding changes from baseline for FPG, glycated albumin, and HbA1c.

[0168] Following completion of the above Phase 1b study to evaluate the safety, tolerability, and pharmacokinetics (PK) of Imeglimin in subjects with T2DM and CKD stages 3B or 4, the study data support the safety and tolerability of Imeglimin in subjects with CKD stages 3B or 4.

[0169] Patients with CKD have other comorbidities that contribute to their CKD and risk of cardiovascular events and mortality. Patients with moderate to severe CKD have a high prevalence of these comorbidities as evidenced by subjects with CKD stages 3B and 4 enrolled in this study, 100% of whom had T2DM, 100% had hypertension, 41% had cardiac disorders, 63% had anemia, 41% had endocrine disorders, and 53% had eye disorders (Table 10). Despite significant underlying conditions in this patient population, imeglimin was well tolerated in the setting of increasing CKD severity (up to stage 4), with no incidence of severe adverse events, no lactic acidosis, and no confirmed cases of elevated plasma lactate. All treatment-emergent adverse events (TEAEs), whether related to the study drug or not, were mild or moderate in severity and were similar in frequency for subjects treated with Imeglimin compared to placebo for both CKD stages 3B and 4 (Table 11). Study drug-related TEAEs were almost all mild and similar in frequency between Imeglimin and placebo for CKD stages 3B and 4. Gastrointestinal disorders, the most common adverse event, were similar for Imeglimin- and placebo-treated subjects. These data suggest better gastrointestinal tolerability compared to placebo reported for metformin, with no increased risk of lactic acidosis.

[0170] Extensive blood sampling for pharmacokinetic analysis was performed on day 15. After morning administration of imeglimin on day 15, the maximum observed concentration (Cmax) increased in a dose-dependent manner (Figure 11). The area under concentration-time (AUC) profiles (AUC) were similar between the 500 mg BID and 1500 mg BID treatment groups, but increased in the 1000 mg BID treatment group (Figure 12). AUC was increased in T2DM with CKD stage 4 compared to CKD3B in the 1500 mg QD and 1000 mg BID treatment groups (Figure 12). This is likely due to reduced renal filtration rate in these subjects. Despite the significant increase in systemic exposure (AUC) in the CKD stage 4 group receiving 1000 mg BID imeglimin, the incidence of adverse events was not increased compared to the other treatment groups (Table 11). Surprisingly, the rate of gastrointestinal events tended to be lower in the 1000 mg BID treatment group than in the 1500 mg QD treatment group, despite higher systemic exposure to imeglimin in the former (Table 11).

[0171] [Table 11]

[0172] [Table 12A]

[0173] [Table 12B]

[0174] Example 6 A 24-week Phase IIb dose-ranging, randomized, double-blind, placebo-controlled, parallel-group safety and efficacy study in subjects with T2DM The five parallel arms included four imeglimin doses (500, 1000, 1500, or 2000 mg twice daily) and one placebo arm. The primary endpoint was to assess dose-responsiveness in T2D subjects, using the change in HbA1c from baseline to 24 weeks as the primary outcome measure. Subjects could be treatment-naive or treated with any oral antidiabetic monotherapy and had a mean HbA1c > 50 mL / min / 1.73 m 2 In total, 382 subjects were randomized 1:1:1:1:1 to one of the five study arms, and 315 subjects completed the study. T2D and stages 2 and 3a CKD [eGFR < 90 mL / min / 1.73 m 2 In a post-hoc analysis of subjects with ≥ 100 mg / kg / day (n=211)], imeglimin demonstrated improved HbA1c reduction compared to placebo.

[0175] The mean % change in HbA1c from baseline through 24 weeks (end of treatment) for Imeglimin in subjects with T2D and stages 2 and 3a CKD are listed in Table 12 below.

[0176] [Table 13]

[0177] Example 7 A 24-week Phase III Randomized, Double-blind, Placebo-controlled Monotherapy Study to Evaluate the Efficacy, Safety, and Tolerability of Orally Administered Imeglimin in Japanese Patients with Type 2 Diabetes Mellitus (T2DM) A total of 213 subjects were randomized in a 1:1 ratio to receive Imeglimin (1000 mg BID) or placebo BID for 24 weeks, with 194 subjects completing the study without interruption of the investigational medicinal product (IMP). The primary objective of the study was to determine the change in HbA1c from baseline after 24 weeks of Imeglimin treatment compared with placebo. Secondary study endpoints included fasting plasma glucose levels along with other standard glycemic and non-glycemic parameters. Subjects were required to have an eGFR of ≥ 50 mL / min / 1.73 m at screening. 2 and pre-randomized >45 mL / min / 1.73 m 2 T2D and stage 2 and 3a CKD [eGFR < 90 mL / min / 1.73 m 2 (n=178)], imeglimin demonstrated improved A1C reduction compared with placebo.

[0178] This study evaluated the reduction in HbA1c at 24 weeks. Patients with normal eGFR (>90 mL / min / 1.73 m) treated with Imeglimin 1000 mg BID were randomized to receive 100 mg BID. 2 In subjects with CKD, 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 the greater HbA1c efficacy with imeglimin in subjects with CKD is independent of renal function and does not decrease with CKD.

[0179] The mean percent change in HbA1c from baseline to 24 weeks (end of treatment) for Imeglimin in subjects divided by eGFR category is shown in Table 13 below.

[0180] [Table 14]

[0181] While the invention has been fully described herein, it will be understood by those skilled in the art that it can be practiced under a wide and similar range of conditions, formulations, and other parameters without affecting the scope of the invention or any embodiment thereof.

[0182] Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

[0183] All patents, patent applications, and other publications cited herein are hereby fully incorporated by reference in their entirety.

Claims

1. 1. A medicament for treating type 2 diabetes in a human subject, the human subject having stage 3B or 4 chronic kidney disease, comprising an effective amount of imeglimin.

2. 1. A medicament for improving glycemic control in a human subject with type 2 diabetes, comprising an effective amount of imeglimin, wherein the human subject has stage 3B or 4 chronic kidney disease.

3. The method of claim 2, wherein imeglimin is administered as an adjunct to diet and exercise.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein the subject has moderate to severe renal impairment or stage 3B chronic renal disease.

5. The pharmaceutical composition of any one of claims 1 to 3, wherein the subject has severe renal dysfunction or stage 4 chronic renal disease.

6. The target is 45ml / min / 1.73m 2 The pharmaceutical composition of any one of claims 1 to 5, having a lower estimated glomerular filtration rate (eGFR).

7. The target is approximately 30 ml / min / 1.73 m 2 Approximately 44ml / min / 1.73m 2 The pharmaceutical composition of claim 6, having an eGFR between 0.1 and 0.

2.

8. The target is approximately 15 ml / min / 1.73 m 2 Approximately 29ml / min / 1.73m 2 The pharmaceutical composition according to any one of claims 1 to 5, having an estimated glomerular filtration rate (eGFR) between 0.1 and 0.

2.

9. The target is approximately 15 ml / min / 1.73 m 2 Approximately 44ml / min / 1.73m 2 The pharmaceutical composition according to any one of claims 1 to 5, having an estimated glomerular filtration rate (eGFR) between 0.1 and 0.

2.

10. The pharmaceutical composition of any one of claims 1 to 9, wherein the subject has a baseline glycosylated hemoglobin (HbA1c) percentage of between about 6.8% and about 12.0%.

11. The method of any one of claims 1 to 10, wherein the subject has an existing medical condition.

12. 11. The pharmaceutical agent of any one of claims 1 to 10, wherein subjects treated with imeglimin have a similar or equal frequency of treatment-emergent adverse events as subjects treated with placebo.

13. The pharmaceutical of claim 11, wherein the subject treated with imeglimin does not experience an increase in one or more symptoms of the subject's one or more pre-existing medical conditions compared to before the subject began imeglimin treatment.

14. The pharmaceutical of claim 11, wherein one or more pre-existing conditions of the subject treated with imeglimin do not worsen in severity or symptoms after treatment with imeglimin.

15. The pharmaceutical of claim 14, wherein one or more pre-existing conditions of a subject treated with imeglimin do not become worse in severity or symptoms after treatment with imeglimin compared to before the subject began imeglimin treatment.

16. The pharmaceutical agent of claim 14, wherein one or more pre-existing conditions of a subject treated with imeglimin do not become worse in severity or symptoms after treatment with imeglimin compared to what would be expected if the subject were to take a second pharmaceutical agent.

17. 17. The pharmaceutical of any one of claims 11 to 16, wherein the existing medical condition is selected from hyperkalemia, hypertension, cardiac disorders, gastrointestinal disorders, nervous system disorders, blood and lymphatic system disorders, eye disorders, endocrine disorders, or combinations thereof.

18. 18. The method of claim 17, wherein the existing medical condition is a gastrointestinal disorder.

19. 19. The method of claim 18, wherein the gastrointestinal disorder is selected from abdominal pain, constipation, diarrhea, flatulence, gastroesophageal reflux, indigestion, nausea / vomiting, or a combination thereof.

20. The pharmaceutical agent according to any one of claims 1 to 19, wherein treatment with imeglimin is well tolerated.

21. The pharmaceutical of any one of claims 1 to 20, wherein the subject treated with imeglimin does not experience an increase in the frequency of lactic acidosis compared to before the subject began imeglimin treatment.

22. The pharmaceutical of any one of claims 1 to 21, wherein a subject treated with imeglimin does not experience an increase or elevation in plasma lactate compared to before the subject began imeglimin treatment.

23. The pharmaceutical of claim 22, wherein the subject treated with imeglimin does not experience an increase or elevation in plasma lactate above a threshold of 3 mmol / L (27 mg / dL) compared to before the subject began imeglimin treatment.

24. The pharmaceutical agent of any one of claims 1 to 23, wherein a subject treated with imeglimin is no more or less likely to experience an increase or elevation in plasma lactate compared to before the subject began imeglimin treatment than a subject treated with a placebo or a subject treated with a second pharmaceutical agent.

25. The method of any one of claims 1 to 24, wherein imeglimin is administered orally.

26. 26. The pharmaceutical agent of any one of claims 1 to 25, wherein the amount of imeglimin administered to the subject per day is about 20% to about 100% of the amount administered to a subject with prediabetes or type 1 or type 2 diabetes but normal renal function.

27. 27. The pharmaceutical composition of any one of claims 1 to 26, wherein the amount of imeglimin is from about 500 mg to about 3000 mg per day.

28. 28. The pharmaceutical composition of claim 27, wherein the amount of imeglimin is from about 1000 mg to about 3000 mg per day.

29. The pharmaceutical composition of claim 28, wherein the amount of imeglimin is from about 1000 mg to about 2000 mg per day.

30. 30. The pharmaceutical composition of any one of claims 1 to 29, wherein the amount of imeglimin is about 1000 mg, about 1500 mg, or about 2000 mg per day.

31. 31. The method of any one of claims 1 to 30, wherein imeglimin is administered once, twice, or three times daily.

32. The method of claim 31, wherein imeglimin is administered twice daily.

33. 32. The medicament of claim 31, wherein imeglimin is administered at 500 mg twice daily, 1000 mg twice daily, or 1500 mg once daily.

34. 34. The method of any one of claims 1 to 33, wherein imeglimin is administered with a meal.

35. 34. The method of any one of claims 1 to 33, wherein imeglimin is administered without food.

36. 36. The method of any one of claims 1 to 35, wherein imeglimin is administered in the form of a free base or a pharma- ceutically acceptable salt thereof.

37. The method of claim 36, wherein imeglimin is administered in the form of its hydrochloride salt.

38. 38. The pharmaceutical agent of any one of claims 1 to 37, wherein the subject experiences a placebo-subtracted reduction in glycosylated hemoglobin (HbA1c) percentage of between about -0.5% and about -1.2% over the treatment period.

39. The pharmaceutical agent of claim 38, wherein the subject experiences a placebo-subtracted reduction in glycosylated hemoglobin (HbA1c) percentage of between about -0.8% and about -1.1% over the treatment period.

40. 40. The pharmaceutical agent of any one of claims 1 to 39, wherein the subject experiences a placebo-subtracted reduction in fasting plasma glucose (FPG) of between about -20 mg / dL and about -30 mg / dL over the treatment period.

41. 41. The method of claim 40, wherein the subject experiences a placebo-subtracted reduction in fasting plasma glucose (FPG) of about -25 mg / dL over the treatment period.

42. The pharmaceutical agent according to any one of claims 38 to 41, wherein the treatment period is from 4 weeks to 52 weeks.

43. The pharmaceutical composition of claim 42, wherein the treatment period is 24 weeks.

44. The subject is administered a daily steady-state exposure (AUC 24,ss 44. The pharmaceutical composition according to any one of claims 1 to 43, wherein

45. The method of any one of claims 1 to 44, wherein the subject is undergoing prior antidiabetic treatment.

46. 46. ​​The pharmaceutical of claim 45, wherein the prior antidiabetic treatment does not provide or adequately controls prediabetes or type 1 or type 2 diabetes in the subject.

47. The method of any one of claims 1 to 44, wherein the subject has not received prior antidiabetic treatment.

48. 48. The method of any one of claims 1 to 47, wherein imeglimin is administered with a second pharmaceutical agent selected from sitagliptin and insulin.

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