Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

• the invention relates to the use of sotagliflozin for the treatment of patients with type 2 diabetes mellitus and moderate renal impairment.
• sotagliflozin is a dual inhibitor of the sodium- glucose cotransporters type 1 and 2 (SGLT1 and SGLT2).
• Sotagliflozin has the following formula:
• Sotagliflozin is being developed for use in Type 2 diabetes (T2D or type 2 diabetes mellitus), a metabolic disorder characterized by hyperglycemia that results from a combination of increased insulin resistance and beta-cell dysfunction.
• T2D Type 1 diabetes
• T1 D Type 1 diabetes
• Diabetes is among the leading causes of death by disease and is a leading cause of heart disease, stroke, blindness, kidney disease, and amputation.
• none of the current therapies is curative and the results of treatment are variable.
• Glycemic control with the currently available agents often leads to side effects, most notably weight gain and an increased frequency of hypoglycemia. These concerns emphasize the need to develop new agents that effectively and safely control glucose levels in diabetic patients.
• HbA1 c or A1 C Glycated haemoglobin (HbA1 c or A1 C) HbA1c is the gold standard measurement for the assessment of glycemic control as it reflects average plasma glucose over the previous eight to 12 weeks (Rinsho Byori. 2014 Jan;62(1):45-52.).
• diabetes is not only related with poo glycemic control but is also associated with various complications.
• micro vascular complications of diabetes are well known and can result in impaired renal function, retinopathy and neuropathy and the macrovascular complications result in coronary disease, amputations and stroke..
• diabetic nephropathy is a well-established complication of poor glycemic control in patients with diabetes.
• diabetic nephropathy represents a particular challenge to the health care providers.
• An estimated 10-36% of patients with T2DM have some degree of renal impairment and chronic kidney disease (CKD) is present in approximately 40% of patients with diabetes.
• CKD chronic kidney disease
• CKD is classified into 5 stages, depending on the eGFR (estimated glomerular filtration rate) levels:
• stage 1 corresponds to kidney damage with normal kidney function with a GFR (ml_/min/1.73 m2 ) of 90 or higher;
• stage 2 corresponds to kidney damage with a mild decrease of kidney function and a GFR from 60 to 89;
• stage 3 corresponds to a moderate decrease of kidney function with a GFR from 30 to 59; within stage 3, two stages are differentiated:
• o stage 3a corresponds to a mild to moderate decrease of kidney
• o stage 3b corresponds to a moderate to severe loss of kidney function with a GFR from 40 to 45;
• stage 4 corresponds to a severe decrease in GFR (GFR 15-29); and stage 5 corresponds to kidney failure with a GFR lower than 15.
• sotagliflozin has demonstrated an ability to significantly improve glycemic control in patients with type 2 diabetes, in particular by achieving a reduction in A1 C (Lapuerta et al., Diabetes & Vascular Disease Research2015, Vol. 12(2) 101-1 10).
• sotagliflozin improves glycaemic control in adults with type 2 diabetes mellitus and renal impairment, in particular moderate renal impairment.
• a subject matter described hereinafter thus relates to the use of sotagliflozin, in particular a dose of 400mg of sotagliflozin, to improve glycaemic control in patients with type 2 diabetes mellitus and renal impairment, in particular moderate renal impairment.
• the subject matter relates to the use of sotagliflozin, in particular a dose of 400mg of sotagliflozin, in patients with type 2 diabetes mellitus and CKD3, in particular CKD3a.
• sotagliflozin in particular a dose of 400mg of sotagliflozin, wherein said patients have failed to achieve adequate glycaemic control.
• a subject matter described here is the use of a dose of 400mg of sotagliflozin, wherein said patients have inadequate glycemic control.
• Another subject matter described here is the use of a dose of 400mg of sotagliflozin, as an adjunct to insulin or metformin therapy to improve glycaemic control in adults with type 2 diabetes mellitus and CKD3, in particular CKD3a.
• said patients have failed to achieve adequate glycaemic control despite optimal insulin therapy.
• Another subject matter described here is the use of a dose of 400mg of sotagliflozin, wherein sotagliflozin is administered once daily.
• Another subject matter described here is the use of a dose of 400mg of sotagliflozin, wherein sotagliflozin is administered before the first meal of the day.
• Another subject matter described here is a method of treating type 2 diabetes comprising administering to a patient in need thereof a daily dose of 400mg of sotagliflozin, wherein said patient has type 2 diabetes and renal impairment, in particular CKD3, more particularly CKD3a.
• Another subject matter described here is a method of improving glycemic control comprising administering to a patient in need thereof a daily dose of 400mg of sotaglilfozin, wherein said patient has type 2 diabetes and renal impairment, in particular CKD3, more particularly CKD3a.
• Another subject matter described here is a method of improving A1 C comprising administering to a patient in need thereof an effective a daily dose of 400mg of sotagliflozin, wherein said patient has type 2 diabetes and renal impairment, in particular CKD3, more particularly CKD3a.
• sotagliflozin is administered as an adjunct to insulin or metformin therapy.
• Another subject matter described here is a method according to anyone wherein sotagliflozin administration is initiated in a patient who had failed to achieve adequate glycaemic control despite optimal insulin therapy.
• Another subject matter described here is a dose of 400mg of sotagliflozin for the treatment of type 2 diabetes in patients with renal impairment, in particular CKD3, more particularly CKD3a.
• Another subject matter described here is a dose of 400mg of sotagliflozin for the treatment to improve glycaemic control in patients with type 2 diabetes renal impairment, in particular CKD3, more particularly CKD3a.
• the dosage of 400 mg of sotagliflozin is administered as twice a 200mg tablet.
• the selected patients were adult patients with T2D (drug-naive or on antidiabetic therapy) and documented moderate renal insufficiency defined by an eGFR (based on the 4 variable Modification of Diet in Renal Disease [MDRD] equation) of >30 and ⁇ 60 mL/min/1.73 m 2 (CKD 3A, 3B).
• T2D drug-naive or on antidiabetic therapy
• eGFR based on the 4 variable Modification of Diet in Renal Disease [MDRD] equation
• the patient recruitment was carried out by taking into account the following inclusion criteria:
• systemic glucocorticoids excluding topical, intra-articular, or ophthalmic application, nasal spray, or inhaled forms
• HbA1c measurement eg, genetic Hb variants
• medical conditions that affect interpretation of HbA1 c results eg, blood transfusion or severe blood loss in the last 3 months prior to randomization, any condition that shortens erythrocyte survival.
• Patient is an employee of the Sponsor, or is the Investigator or any Sub investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in conducting the study.
• Type 1 diabetes mellitus is Type 1 diabetes mellitus.
• HbA1 c ⁇ 7% or HbA1 c >11 % measured by the central laboratory at Screening.
• Oral antidiabetic agent or insulin use if dose not stable for 8 weeks before randomization
• a selective SGLT2 inhibitor eg, canagliflozin, dapagliflozin, or
• Renal disease that required treatment with immunosuppressive therapy within the last 12 months, or a history of dialysis or renal transplant or initiation of chronic dialysis within 4 weeks prior to the Screening Visit or expected to occur during the study duration.
• SMBG blood glucose
• ECG electrocardiogram
• Run-in phase (Visit 2), lasted 2 weeks. Patients were treated in a single-blind manner with two placebo tablets (identical to sotagliflozin 200 mg in appearance) administered once daily during the Run-in phase, starting from Visit 2
• Double-blind Treatment Period (Day 1 to Week 26): Eligible patients will be randomized on Day 1 (Visit 3). Following randomization, patients will be treated in a double-blind manner for 52 weeks. A total of 787 patients >18 years of age (or > legal age of the majority, whichever is greater) were randomly assigned 1 :1 :1 to the following 3 treatment groups:
• Sotagliflozin 400 mg given as two (2) 200 mg tablets, once daily, before the first meal of the day.
• the primary endpoint of this study was to demonstrate the superiority of sotagliflozin 400 mg and 200 mg versus placebo with respect to hemoglobin A1 c (HbA1 c) reduction at
• the primary efficacy endpoint was analyzed using an analysis of covariance (ANCOVA) model.
• the ANCOVA model included treatment groups (sotagliflozin 200 mg,
• randomization stratum of SBP ( ⁇ 130, >130 mmHg), randomization stratum of CKD stage (3A, 3B), and country as fixed effects, and baseline HbAl c value as a covariate.
• Table 1 shows that sotagliflozin achieved its primary endpoint by leading to statistically significant lower A1 C levels for the 400 mg dose when compared to placebo after the core treatment period.
• Missing data are imputed using control-based copy reference multiple imputation under the missing not at random framework.
• Multiple datasets are generated with each containing complete (i.e., non-missing) data.
• complete (i.e., non-missing) data For each complete dataset, the change from baseline to Week 26 is analyzed using ANCOVA model. Results from each complete dataset are combined using Rubin's rule.
• ANCOVA covariance
• PGM PRODOPS/SAR439954/EFC14837/CIR_EX_01/REPORT/PGM/eff_pchghbalc_wk26_imp_i_t.sas
• sotagliflozin especially at a daily dose of 400mg improved glycemic control in renal impaired patients, in particular patients with CKD3, and more particularly patients with CKD3a.

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• Health & Medical Sciences (AREA)
• Diabetes (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Obesity (AREA)
• Hematology (AREA)
• Endocrinology (AREA)
• Emergency Medicine (AREA)
• Epidemiology (AREA)
• Urology & Nephrology (AREA)
• Molecular Biology (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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Citations (1)

• 2019
  • 2019-07-25 EP EP19188477.4A patent/EP3769767A1/en not_active Ceased
• 2020
  • 2020-07-24 JP JP2022504622A patent/JP2022541322A/ja active Pending
  • 2020-07-24 EP EP20747477.6A patent/EP4003366A1/en not_active Withdrawn
  • 2020-07-24 WO PCT/IB2020/057016 patent/WO2021014420A1/en not_active Ceased
  • 2020-07-24 AU AU2020319164A patent/AU2020319164A1/en not_active Abandoned
  • 2020-07-24 CA CA3148400A patent/CA3148400A1/en active Pending
  • 2020-07-24 CN CN202080053637.0A patent/CN114222571A/zh not_active Withdrawn
  • 2020-07-24 US US17/629,166 patent/US20220265690A1/en not_active Abandoned

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Non-Patent Citations (6)

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