US20160287674A1 - Treatment Type 2 Diabetes Mellitus Patients - Google Patents

Treatment Type 2 Diabetes Mellitus Patients Download PDF

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Publication number
US20160287674A1
US20160287674A1 US15/068,286 US201615068286A US2016287674A1 US 20160287674 A1 US20160287674 A1 US 20160287674A1 US 201615068286 A US201615068286 A US 201615068286A US 2016287674 A1 US2016287674 A1 US 2016287674A1
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insulin
plasma glucose
patient
pharmaceutically acceptable
acceptable salt
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Christine Roy
Elisabeth SOUHAMI
Nacima Demil
Jenny Ye
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Sanofi Aventis Deutschland GmbH
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Sanofi Aventis Deutschland GmbH
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Assigned to SANOFI-AVENTIS DEUTSCHLAND GMBH reassignment SANOFI-AVENTIS DEUTSCHLAND GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ROY, CHRISTINE, SOUHAMI, ELISABETH, DEMIL, Nacima, YE, Jenny
Publication of US20160287674A1 publication Critical patent/US20160287674A1/en
Priority to US15/646,760 priority Critical patent/US10434147B2/en
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    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • Subject of the present invention is a pharmaceutical combination for use in glycemic control, for use in the reduction of the HbA1c value, the fasting plasma glucose or/and the 2 hour postprandial plasma glucose, for use in the prevention of weight gain or/and for inducing weight loss, for use in the reduction of the risk of hypoglycemia, in a type 2 diabetes mellitus patient, said combination comprising
  • type 2 diabetes mellitus In contrast to type 1 diabetes, there is not generally a lack of insulin in type 2 diabetes mellitus but in many cases, particularly in progressive cases, the treatment with insulin is regarded as the most suitable therapy, if required in combination with orally administered anti-diabetic drugs.
  • a particular risk exists for overweight patients suffering from type 2 diabetes mellitus e.g. patients with a body mass index (BMI) ⁇ 30 kg/m 2 .
  • BMI body mass index
  • the risks of diabetes overlap with the risks of overweight, leading e.g. to an increase of cardiovascular diseases compared to type 2 diabetes mellitus patients being of a normal weight.
  • the compound desPro 36 Exendin-4(1-39)-Lys 6 -NH 2 (AVE0010, lixisenatide) is a derivative of Exendin-4.
  • AVE0010 is disclosed as SEQ ID NO:93 in WO 01/04156:
  • SEQ ID NO: 1 lixisenatide (44 amino acids) H-G-E-G-T-F-T-S-D-L-S-K-Q-M-E-E-E-A-V-R-L-F-I-E- W-L-K-N-G-G-P-S-S-G-A-P-P-S-K-K-K-K-K-K-NH 2
  • SEQ ID NO: 2 exendin-4 (39 amino acids) H-G-E-G-T-F-T-S-D-L-S-K-Q-M-E-E-E-A-V-R-L-F-I-E- W-L-K-N-G-G-P-S-S-G-A-P-P-S-NH 2
  • Exendins are a group of peptides which can lower blood glucose concentration.
  • the Exendin analogue lixisenatide is characterised by C-terminal truncation of the native Exendin-4 sequence.
  • Lixisenatide comprises six C-terminal lysine residues not present in Exendin-4.
  • Lixisenatide is also termed des-38-proline-exendin-4(He/oderma suspectum)-(1-39)-peptidylpenta-L-lysyl-L-lysinamide (CAS number 320367-13-3).
  • lixisenatide includes pharmaceutically acceptable salts thereof. The person skilled in the art knows suitable pharmaceutically acceptable salts of lixisenatide.
  • Insulin glargine is an analogue of human insulin.
  • Insulin glargine is 31 B -32 B -Di-Arg human insulin with further substitution of asparagine in position A21 by glycine.
  • Insulin glargine is also termed Gly(A21)-Arg(B31)-Arg(B32) human insulin.
  • the CAS number of insulin glargine is 160337-95-1.
  • “insulin glargine” includes pharmaceutically acceptable salts thereof. The person skilled in the art knows suitable pharmaceutically acceptable salts of insulin glargine.
  • Metformin is the international nonproprietary name of 1,1-dimethylbiguanide (CAS number 657-24-9). Metformin is a biguanide hypoglycemic agent used in the treatment of non-insulin-dependent diabetes mellitus (type 2 diabetes mellitus) not responding to dietary modification. Metformin improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. Metformin is usually administered orally. However, control of type 2 diabetes mellitus in obese patients by metformin may be insufficient. Thus, in these patients, additional measures for controlling type 2 diabetes mellitus may be required. “Metformin”, as used herein, included pharmaceutically acceptable salts thereof. The person skilled in the art knows suitable pharmaceutically acceptable salts of metformin.
  • the effect of the combination of lixisenatide, insulin glargine and optionally metformin has been tested in obese type 2 diabetes mellitus patients poorly controlled with a basal insulin alone or a basal insulin in combination with one to three oral anti-diabetic drugs selected from metformin, sulfonylureas, dipeptidyl-peptidase-4 (DPP-4) inhibitors and glinides.
  • the diabetes patients still had a fasting plasma glucose concentration of about 9.2 to 9.5 mmol/L and a HbA1c value of about 8.5%.
  • the 2 hour postprandial plasma glucose was about 13.8 to 14.5 mmol/L (249 to 262 mg/dL). These values still exceed normoglycemic values.
  • insulin glargine combined with lixisenatide and optionally metformin may become a preferred option, attaining meaningful glycemic targets with less hypoglycemia and with weight loss compared with prandial insulin (such as insulin glulisine), as basal insulin plus oral anti-diabetic compounds or basal insulin plus prandial insulin (bolus administration) in difficult to control, obese, insulin-treated type 2 diabetes mellitus patients.
  • prandial insulin such as insulin glulisine
  • a first aspect of the present invention is a pharmaceutical combination for use in glycemic control in a type 2 diabetes mellitus patient, said combination comprising
  • the type 2 diabetes mellitus to be treated preferably is not adequately controlled with compound (b) and optionally compound (c) alone.
  • the combination as described herein can be used for improving glycemic control.
  • “improvement of glycemic control” or “glycemic control” in particular refers to improvement of the 2 hour postprandial plasma glucose concentration, improvement of fasting plasma glucose concentration, or/and improvement of the HbA 1c value.
  • “improvement of glycemic control” or “glycemic control” includes the improvement of the 2 hour postprandial plasma glucose concentration.
  • “improvement of glycemic control” or “glycemic control” includes the reduction of the 2 hour postprandial plasma glucose concentration. Reduction means in particular that the 2 hour postprandial plasma glucose concentration reaches normoglycemic values or at least approaches these values.
  • “improvement of glycemic control” or “glycemic control” includes the improvement of the fasting plasma glucose concentration.
  • improvement of fasting plasma glucose concentration includes the reduction of the fasting plasma glucose concentration.
  • Reduction means in particular that the fasting plasma glucose concentration reaches normoglycemic values or at least approaches these values.
  • “improvement of glycemic control” or “glycemic control” includes the improvement of the HbA 1c value.
  • improvement of the HbA 1c value includes the reduction of the HbA 1c value.
  • Reduction of the HbA 1c value in particular means that the HbA 1c value is reduced below 6.5% or 7%.
  • Yet another aspect of the present invention is a pharmaceutical combination for use in the improvement of the HbA1c value, the fasting plasma glucose or/and the 2 hour postprandial plasma glucose in a type 2 diabetes mellitus patient, said combination comprising
  • the type 2 diabetes mellitus to be treated preferably is not adequately controlled with compound (b) and optionally compound (c) alone.
  • normoglycemic values are blood glucose concentrations of in particular 60-140 mg/d 1 (corresponding to 3.3 to 7.8 mmol/L). This range refers in particular to blood glucose concentrations under fasting conditions and postprandial conditions.
  • Criteria for a type 2 diabetes mellitus diagnosis include:
  • Type 2 Diabetes should not be based on a single plasma glucose concentration. Diagnosis may require continued observation with fasting or/and postprandial blood glucose levels or/and an oral glucose tolerance test.
  • fasting plasma glucose (FPG) and post challenge (postload) glucose can be classified as follows:
  • OGTT Oral Glucose Tolerance Test
  • Impaired glucose tolerance (IGT) and impaired fasting glucose concentration (IFG) are intermediate stages in the natural history of disordered carbohydrate metabolism between normal glucose homeostasis and diabetes.
  • normoglycemic values of fasting plasma glucose are blood glucose concentrations of in particular ⁇ 5.6 mmol/L.
  • normoglycemic values of postprandial plasma glucose are blood glucose concentrations of in particular ⁇ 7.8 mmol/L.
  • not adequately controlled by a particular anti-diabetic treatment means that this treatment is not sufficient to remove the symptoms of type 2 diabetes mellitus.
  • “not adequately controlled” by this treatment means that the patient does not reach normoglycemic values in terms of, for example, 2 hour postprandial plasma glucose concentration, HbA1c value or/and fasting plasma glucose concentration.
  • the type 2 diabetes mellitus patient to be treated according to the present invention may be a subject suffering from type 2 diabetes mellitus, wherein type 2 diabetes mellitus is not adequately controlled by treatment with a basal insulin monotherapy.
  • the type 2 diabetes mellitus patient to be treated according to the present invention may be a subject suffering from type 2 diabetes mellitus, wherein type 2 diabetes mellitus is not adequately controlled by treatment with a combination of a basal insulin and metformin alone, for instance with (a) a dose of at least 1.0 g/day metformin or at least 1.5 g/day metformin for at least 3 months, or/and (b) a dose of at the maximum 2.0 g/day metformin for at least 3 months or at the maximum 3.5 g/day metformin for at least 3 months.
  • the type 2 diabetes mellitus patient to be treated according to the present invention may be a subject suffering from type 2 diabetes mellitus, wherein the type 2 diabetes mellitus to be treated is not adequately controlled with compound (b) and optionally compound (c) alone.
  • Basal insulin includes insulin glargine, insulin detemir and isophane insulin (NPH insulin).
  • the basal insulin is in particular selected from insulin glargine, insulin detemir and isophane insulin (NPH insulin).
  • “to be treated according to the present invention”, “treatment according to the present invention”, or “therapy according to the present invention” relates to the treatment of a type 2 diabetes mellitus patient by the pharmaceutical combination comprising
  • a further aspect of the present invention is a pharmaceutical combination for use in the prevention of weight gain or/and for inducing weight loss, in a type 2 diabetes mellitus patient, said combination comprising
  • the type 2 diabetes mellitus to be treated preferably is not adequately controlled with compound (b) and optionally compound (c) alone.
  • the examples of the present invention demonstrate that the claimed combination can reduce body weight in type 2 diabetes patients, as defined herein, wherein the comparative treatment (insulin glulisine once daily or three times daily) induces a significant weight gain.
  • Yet another aspect of the present invention is a pharmaceutical combination for use in the reduction of the risk of hypoglycemia, in a type 2 diabetes mellitus patient, said combination comprising
  • the type 2 diabetes mellitus to be treated preferably is not adequately controlled with compound (b) and optionally compound (c) alone.
  • the examples of the present invention demonstrate that documented hypoglycemia was numerically and significantly lower with the claimed combination in view of the comparative treatment with insulin glulisine once daily or three times daily.
  • hypoglycemia is the critical limiting factor in the glycemic management of diabetes in both the short and long term. Despite steady improvements in the glycemic management of diabetes, population-based data indicate that hypoglycemia continues to be a major problem for people with both type 1 and type 2 diabetes (American diabetes association, workgroup on hypoglycemia: Defining and Reporting Hypoglycemia in Diabetes. Diabetes Care 28(5), 2005, 1245-1249).
  • the combination of the present invention can prevent hypoglycemia when administered to a type 2 diabetes mellitus patient, as described herein.
  • Prevention of hypoglycemia includes reduction of the number of hypoglycemic events and/or the severity of hypoglycemia events.
  • the combination as described herein is suitable for use in the prevention of hypoglycemia.
  • hypoglycemia is a condition wherein a type 2 diabetes mellitus patient experiences a plasma glucose concentration of below 70 mg/dL (or below 3.9 mmol/L), below 60 mg/dL (or below 3.3 mmol/L), below 54 mg/dL (or below 3.0 mmol/L), below 50 mg/dL, below 40 mg/dL, or below 36 mg/dL.
  • symptomatic hypoglycemia or “symptomatic hypoglycemic event” is a condition associated with a clinical symptom that results from the hypoglycemia, wherein the plasma glucose concentration can be below 70 mg/dL (or below 3.9 mmol/L), below 60 mg/dL (or below 3.3 mmol/L), below 54 mg/dL (or below 3.0 mmol/L), below 50 mg/dL, or below 40 mg/dL.
  • a clinical symptom can be, for example, sweating, palpitations, hunger, restlessness, anxiety, fatigue, irritability, headache, loss of concentration, somnolence, psychiatric disorders, visual disorders, transient sensory defects, transient motor defects, confusion, convulsions, and coma.
  • one or more clinical symptoms of symptomatic hypoglycemia can be selected.
  • Symptomatic hypoglycemia may be associated with prompt recovery after oral carbohydrate administration.
  • a symptomatic hypoglycemia event preferably has a plasma glucose concentration of below 60 mg/dL (or below 3.3 mmol/L).
  • “severe symptomatic hypoglycemia” or “severe symptomatic hypoglycemic event” is a condition with a clinical symptom, as indicated herein, that results from hypoglycemia, wherein the plasma glucose concentration can be below 70 mg/dL (or below 3.9 mmol/L), below 54 mg/dL (or below 3.0 mmol/L) or below 36 mg/dL (or below 2.0 mmol/L).
  • Severe symptomatic hypoglycemia can be associated with acute neurological impairment resulting from the hypoglycemic event.
  • the patient may require the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.
  • a severe symptomatic hypoglycemia event preferably has a plasma glucose concentration of below 36 mg/dL (or below 2.0 mmol/L).
  • severe symptomatic hypoglycemia may include all episodes in which neurological impairment is severe enough to prevent self-treatment and which were thus thought to place patients at risk for injury to themselves or others.
  • the acute neurological impairment may be at least one selected from somnolence, psychiatric disorders, visual disorders, transient sensory defects, transient motor defects, confusion, convulsions, and coma.
  • “Requires assistance” means that the patient could not help himself or herself. Assisting a patient out of kindness, when assistance is not required, should not be considered a “requires assistance” incident.
  • Severe symptomatic hypoglycemia may be associated with prompt recovery after oral carbohydrate, intravenous glucose, or/and glucagon administration.
  • “documented symptomatic hypoglycemia” or “documented symptomatic hypoglycemic event” is an event during which typical symptoms of hypoglycemia accompanied by a measured plasma glucose concentration of 5. 70 mg/dL (5. 3.9 mmol/L), or less than or equal to 54 mg/dL (5 3.0 mmol/L).
  • Clinical symptoms that are considered to result from a hypoglycemic episode are, e.g., increased sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, headache, sleep disorder, confusion, seizures, unconsciousness, coma.
  • asymptomatic hypoglycemia or “asymptomatic hypoglycemic event” is an event not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose concentration less than or equal to 70 mg/dL (3.9 mmol/L), or less than or equal to 54 mg/dL (3.0 mmol/L).
  • probable symptomatic hypoglycemia or “probable symptomatic hypoglycemic event” is an event during which symptoms of hypoglycemia are not accompanied by a plasma glucose determination, but was presumably caused by a plasma glucose concentration less than or equal to 70 mg/dL (or less than or equal to 3.9 mmol/L), or less than or equal to 54 mg/dL (or less than or equal to 3.0 mmol/L); symptoms treated with oral carbohydrate without a test of plasma glucose.
  • “relative hypoglycemia” or “relative hypoglycemic event” is an event during which the person with diabetes reports any of the typical symptoms of hypoglycemia, and interprets the symptoms as indicative of hypoglycemia, but with a measured plasma glucose concentration greater than 70 mg/dL (or greater than 3.9 mmol/L).
  • the hypoglycemia can be a symptomatic hypoglycemia, a severe symptomatic hypoglycemia, a documented symptomatic hypoglycemia, a probable symptomatic hypoglycemia, a relative symptomatic hypoglycemia, or an asymptomatic hypoglycemia.
  • a symptomatic hypoglycemia more preferably a severe symptomatic hypoglycemia. “Reducing the risk of hypoglycemia”, as used herein, can include reducing the incidence of hypoglycemia.
  • the incidence of hypoglycemia per patient year can be computed per patient as: 365.25 ⁇ (number of episodes of hypoglycemia)/(number of days exposed) and summarized by type of event and treatment group. “Reducing the risk of hypoglycemia”, as used herein, can further include prevention of hypoglycemia in a patient, when the formulation described herein is administered to a type 2 diabetes mellitus patient, as described herein. “Reducing the risk of hypoglycemia”, as used herein, can further include reduction of the number of hypoglycemic events, and/or the severity of hypoglycemia events.
  • the type 2 diabetes mellitus patient suffering from type 2 diabetes mellitus to be treated according to the present invention may be obese.
  • a patient can be considered as obese if the body mass index is at least 30 kg/m 2 .
  • an obese type 2 diabetes mellitus patient may have a body mass index of at least 30 kg/m 2 .
  • the obese type 2 diabetes mellitus patient may have a body weight of at least 87 kg, at least 88 kg, at least 89 kg or at least 90 kg.
  • the type 2 diabetes mellitus patient may be obese prior to the onset of therapy with the combination according to the present invention.
  • the patient to be treated may have an age of less than 50 years.
  • the patient may also have an age of at least 50 years, or an age in the range of 50 to 64 years.
  • the patient may also have an age of at least 65 years, or an age in the range of 65 to 74 years.
  • the patient may also have an age of at least 75 years. It is preferred that the patient has an age of at least 65 years.
  • the type 2 diabetes mellitus to be treated according to the present invention may suffer from a type 2 diabetes mellitus not adequately controlled with a basal insulin monotherapy or a basal insulin and one to three oral anti-diabetics alone selected from the group consisting of metformin, a sulfonylurea, a DPP-4 inhibitor or a glinide alone.
  • the basal insulin is in particular selected from insulin glargine, insulin detemir and isophane insulin (NPH insulin).
  • this type 2 diabetes mellitus to be treated preferably is not adequately controlled with compound (b) and optionally compound (c) alone.
  • the type 2 diabetes mellitus patient to be treated according to the present invention may have a fasting plasma glucose of at least 9 mmol/L or at least 9.5 mmol/L when treated with a basal insulin monotherapy or a basal insulin and one to three oral anti-diabetics alone selected from the group consisting of metformin, a sulfonylurea, a DPP-4 inhibitor or a glinide alone.
  • the patient may have this fasting plasma glucose of at least 9 mmol/L L or at least 9.5 mmol/L prior to the onset of therapy with the combination according to the present invention.
  • the basal insulin is in particular selected from insulin glargine, insulin detemir and isophane insulin (NPH insulin).
  • this type 2 diabetes mellitus to be treated preferably is not adequately controlled with compound (b) and optionally compound (c) alone.
  • the patient may have a fasting plasma glucose in the range of 5.6 to 6.9 mmol/L when treated with compound (b) and optionally compound (c) alone. This range can be considered to be an impaired fasting plasma glucose concentration.
  • the patient may have a fasting plasma glucose of at least 6.6 mmol/L, at least 6.7 mmol/L, at least 6.8 mmol/L or at least 6.9 mmol/L, when treated with compound (b) and optionally compound (c) alone.
  • the type 2 diabetes mellitus patient to be treated according to the present invention may have a HbA1c of at least 8.5% when treated with a basal insulin monotherapy or a basal insulin and one to three oral anti-diabetics alone selected from the group consisting of metformin, a sulfonylurea, a DPP-4 inhibitor or a glinide alone.
  • the patient may have this a HbA1c of at least 8.5% prior to the onset of therapy with the combination according to the present invention.
  • the basal insulin is in particular selected from insulin glargine, insulin detemir and isophane insulin (NPH insulin).
  • this type 2 diabetes mellitus to be treated preferably is not adequately controlled with compound (b) and optionally compound (c) alone.
  • the patient may have a HbA1c of at least 7.5% or at least 7.8% when treated with compound (b) and optionally compound (c) alone.
  • the patient to be treated according to the present invention does not receive concomitant treatment with at least one of a sulfonylurea, a DPP-4 inhibitor and a glinide.
  • the type 2 diabetes mellitus has been diagnosed for at least 1 year or at least 2 years prior to the onset of a therapy according to the present invention.
  • the administration of the combination according to the present invention can comprise the steps:
  • step (i) or/and (ii) wherein the amount of compound (b) to be administered in steps (i) or/and (ii) is adjusted (titrated) so that a predetermined fasting plasma glucose level or/and a predetermined self-monitored plasma glucose level is reached or at least approximated.
  • adjustment (titration) of compound (b) is performed in steps (i).
  • step (i) the compounds (b) and (c) of the pharmaceutical combination of the present invention may be administered for at least 4 weeks, at least 8 weeks, at least 12 weeks, or at least 16 weeks.
  • step (i) comprises administration of compounds (b) and (c) for at least about 12 weeks.
  • Step (i) may be performed for at the maximum about 8 weeks, at the maximum about 12 weeks, at the maximum about 16 weeks, at the maximum about 20 weeks, or at the maximum about 24 weeks. Preferred is a duration of step (i) of about 12 weeks.
  • Step (i) may be performed with the proviso that compound (a) is not administered.
  • a treatment with a combination of insulin glargine, lixisenatide and optionally metformin can improve fasting plasma glucose concentration, HbA 1c value, body weight and the risk of hypoglycemia if the treatment starts with administration of insulin glargine and optionally metformin alone.
  • the dose of insulin glargine can be reduced.
  • the amount of compound (b) to be administered in steps (i) or/and (ii) is adjusted so that a predetermined fasting plasma glucose level or/and a predetermined self-monitored plasma glucose level is reached or at least approximated.
  • the amount of compound (b) to be administered in steps (i) or/and (ii) may be adjusted on the basis of daily measurements of plasma glucose concentration.
  • the amount of compound (b) to be administered in steps (i) or/and (ii) may adjusted so that
  • SMPG Self-monitored plasma glucose
  • 4-point Self Monitored Plasma Glucose or the “7-point Self Monitored Plasma Glucose”.
  • the 4 point and 7-point Self Monitored Plasma Glucose value are in particular average plasma glucose concentrations including fasting and postprandial conditions.
  • “4-point Self Monitored Plasma Glucose” in particular refers to the measurement of plasma glucose four times a day and calculation of the average plasma glucose concentration therefrom.
  • the 4-point Self Monitored Plasma Glucose measurements are performed pre-breakfast, post-breakfast, pre-dinner, and post-dinner.
  • 7-point Self Monitored Plasma Glucose in particular refers to the measurement of plasma glucose seven times a day and calculation of the average plasma glucose concentration therefrom.
  • the 7-point Self Monitored Plasma Glucose measurements are performed pre-breakfast, post-breakfast, pre-lunch, post-lunch, pre-dinner, post-dinner and at bed-time.
  • the “fasting self-monitored plasma glucose (SMPG)”, as used herein, is measured by the patient before breakfast, in particular before insulin glargine or/and lixisenatide injection and optional intake of metformin.
  • a type 2 diabetes mellitus patient may have a HbA1c value in the range of 7% to 10%.
  • the type 2 diabetes mellitus patient to be treated may have a HbA 1c value of at least about 7%, at least about 7.5%, at least about 7.8%, at least about 8%, at least about 8.5%, or at least about 9%.
  • the type 2 diabetes mellitus patient to be treated according to the present invention may have a 2 hours postprandial plasma glucose concentration of at least 11.1 mmol/L, at least 12 mmol/L, at least 13 mmol/L, at least 13.5 mmol/L or at least 14 mmol/L. These plasma glucose concentrations exceed normoglycemic concentrations, indicating that the type 2 diabetes mellitus is not adequately controlled if treated with an antidiabetic compound, as described herein.
  • Postprandial is a term that is well known to a person skilled in the art of diabetology.
  • the term “postprandial” describes in particular the phase after an ingestion of a meal or/and exposure to glucose under experimental conditions. In a healthy person this phase is characterised by an increase and subsequent decrease in blood glucose concentration.
  • the postprandial phase typically ends up to 2 h after a meal or/and exposure to glucose (2 h postprandial plasma glucose concentration).
  • the type 2 diabetes mellitus patient to be treated according to the invention may have a fasting plasma glucose concentration of at least 8 mmol/L, at least 8.5 mmol/L, at least 9 mmol/L, or at least 9.5 mmol/L. These plasma glucose concentrations exceed normoglycemic concentrations, indicating that the type 2 diabetes mellitus is not adequately controlled if treated with an antidiabetic compound, as described herein.
  • metformin can be administered according to commonly known administration protocols of metformin in accordance with the terms of marketing authorization.
  • metformin can be administrated once daily, twice daily or three times a day.
  • the metformin dose applied before the onset of the therapy as disclosed herein is continued in combination with (a) lixisenatide or/and a pharmaceutically acceptable salt thereof, and (b) insulin glargine or/and a pharmaceutically acceptable salt thereof, as disclosed herein.
  • metformin may be administered orally.
  • Metformin may be administered to a type 2 diabetes mellitus patient in need thereof, in an amount sufficient to induce a therapeutic effect.
  • Metformin may be administered in a dose of at least 1.0 g/day or at least 1.5 g/day.
  • Metformin may be administered in a dose of at the maximum of 2.0 g/day or at the maximum of 3.5 g/day.
  • the daily metformin dose can be divided into two or three separate doses.
  • metformin may be formulated in a solid dosage form, such as a tablet or pill.
  • Metformin may be formulated with suitable pharmaceutically acceptable carriers, adjuvants, or/and auxiliary substances.
  • lixisenatide or/and a pharmaceutically acceptable salt may be administered in an add-on therapy to administration of insulin glargine and optionally metformin.
  • the terms “add-on”, “add-on treatment” and “add-on therapy” relate to treatment according to the present invention with insulin glargine and lixisenatide, and optionally metformin.
  • Metformin, insulin glargine or/and lixisenatide each may be administered in a once-a-day-dosage.
  • Metformin, insulin glargine and lixisenatide may be administered by different administration routes.
  • Metformin may be administered orally, and lixisenatide and insulin glargine may be administered parenterally.
  • additives mean that the dose of metformin administered before the onset of the treatment according to the present invention, as disclosed herein, can be continued in the treatment of the present invention.
  • lixisenatide includes pharmaceutically acceptable salts thereof.
  • suitable pharmaceutically acceptable salts of lixisenatide is the acetate salt of lixisenatide.
  • lixisenatide or/and the pharmaceutically acceptable salt thereof may be administered to a type 2 diabetes mellitus patient in need thereof, in an amount sufficient to induce a therapeutic effect.
  • lixisenatide or/and the pharmaceutically acceptable salt thereof may be formulated with suitable pharmaceutically acceptable carriers, adjuvants, or/and auxiliary substances.
  • Lixisenatide or/and a pharmaceutically acceptable salt thereof may be administered parenterally, e.g. by injection (such as by intramuscular or by subcutaneous injection). Suitable injection devices, for instance the so-called “pens” comprising a cartridge comprising the active ingredient, and an injection needle, are known. Lixisenatide or/and a pharmaceutically acceptable salt thereof may be administered in a suitable amount, for instance in an amount in the range of 10 ⁇ g to 20 ⁇ g per dose.
  • lixisenatide or/and a pharmaceutically acceptable salt thereof may be administered in a daily dose in the range of 10 ⁇ g to 20 ⁇ g.
  • Lixisenatide or/and a pharmaceutically acceptable salt thereof may be administered by one injection per day.
  • Lixisenatide or/and a pharmaceutically acceptable salt thereof may be administered about 30 min before breakfast.
  • lixisenatide or/and a pharmaceutically acceptable salt thereof may be provided in a liquid composition, which preferably is an aqueous formulation. It is preferred that the liquid composition is suitable for parenteral administration, in particular for injection.
  • a liquid composition of the present invention may have an acidic or a physiologic pH.
  • An acidic pH preferably is in the range of pH 1-6.8, pH 3.5-6.8, or pH 3.5-5.
  • a physiologic pH preferably is in the range of pH 2.5-8.5, pH 4.0-8.5, or pH 6.0-8.5.
  • the pH may be adjusted by a pharmaceutically acceptable diluted acid (typically HCl) or pharmaceutically acceptable diluted base (typically NaOH).
  • the liquid composition comprising lixisenatide or/and a pharmaceutically acceptable salt thereof may comprise a suitable preservative.
  • a suitable preservative may be selected from phenol, m-cresol, benzyl alcohol and p-hydroxybenzoic acid ester.
  • a preferred preservative is m-cresol.
  • the liquid composition comprising lixisenatide or/and a pharmaceutically acceptable salt thereof may comprise a tonicity agent.
  • a suitable tonicity agent may be selected from glycerol, lactose, sorbitol, mannitol, glucose, NaCl, calcium or magnesium containing compounds such as CaCl 2 .
  • the concentration of glycerol, lactose, sorbitol, mannitol and glucose may be in the range of 100-250 mM.
  • the concentration of NaCl may be up to 150 mM.
  • a preferred tonicity agent is glycerol.
  • the liquid composition comprising lixisenatide or/and a pharmaceutically acceptable salt thereof may comprise methionine from 0.5 ⁇ g/mL to 20 ⁇ g/mL, preferably from 1 ⁇ g/ml to 5 ⁇ g/ml.
  • the liquid composition comprises L-methionine.
  • insulin glargine or/and a pharmaceutically acceptable salt thereof may be provided in a liquid composition, which preferably is an aqueous formulation. It is preferred that the liquid composition is suitable for parenteral administration, in particular for injection. The skilled person knows such liquid compositions of insulin glargine.
  • Surfactants can be added to pharmaceutical formulation comprising insulin glargine, for example, inter alia, non-ionic surfactants.
  • pharmaceutically customary surfactants are preferred, such as, for example: partial and fatty acid esters and ethers of polyhydric alcohols such as of glycerol, sorbitol and the like (Span®, Tween®, in particular Tween® 20 and Tween® 80, Myrj®, Brij®), Cremophor® or poloxamers.
  • the surfactants are present in the pharmaceutical composition in a concentration of 5-200 ⁇ g/ml, preferably of 5-120 ⁇ g/ml and particularly preferably of 20-75 ⁇ g/ml.
  • the formulation comprising insulin glargine or/and a pharmaceutically acceptable salt thereof can additionally contain preservatives (e.g. phenol, m-cresol, p-cresol, parabens), isotonic agents (e.g. mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, glycerol), buffer substances, salts, acids and alkalis and also further excipients. These substances can in each case be present individually or alternatively as mixtures.
  • preservatives e.g. phenol, m-cresol, p-cresol, parabens
  • isotonic agents e.g. mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, glycerol
  • buffer substances e.g. mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, g
  • Glycerol, dextrose, lactose, sorbitol and mannitol can be present in the pharmaceutical formulation comprising insulin glargine or/and a pharmaceutically acceptable salt thereof in a concentration of 100-250 mM, NaCI in a concentration of up to 150 mM.
  • Buffer substances such as, for example, phosphate, acetate, citrate, arginine, glycylglycine or TRIS (i.e. 2-amino-2-hydroxymethyl-1,3-propanediol) buffer and corresponding salts, can be present in a concentration of 5-250 mM, preferably 10-100 mM.
  • Further excipients can be, inter alia, salts or arginine.
  • the zinc concentration of the formulation comprising insulin glargine or/and a pharmaceutically acceptable salt thereof is in the range of the concentration which is reached by the presence of 0-1000 ⁇ g/mL, preferably 20-400 ⁇ g/mL zinc, most preferably 90 ⁇ g/mL.
  • the zinc may be present in form of zinc chloride, but the salt is not limited to be zinc chloride.
  • glycerol and/or mannitol can be present in a concentration of 100-250 mmol/L, and/or NaCl is preferably present in a concentration of up to 150 mmol/L.
  • a buffer substance can be present in a concentration of 5-250 mmol/L.
  • Insulin glargine or/and a pharmaceutically acceptable salt thereof can be present in the pharmaceutical formulation in a concentration of 60-6000 nmol/ml, preferably 240-3000 nmol/ml.
  • the pH of the formulation comprising insulin glargine or/and a pharmaceutically acceptable salt thereof can be in the range of pH 1-6.8, preferably pH 3.5-6.8, more preferred pH 3.5-4.5, even more preferred pH 4.0-4.5.
  • Yet another aspect of the present invention is the use of a combination comprising
  • the patient may be a patient as defined herein.
  • Yet another aspect of the present invention is the use of a combination comprising
  • the fasting plasma glucose or/and the 2 hour postprandial plasma glucose in a type 2 diabetes mellitus patient preferably is not adequately controlled with compound (b) and optionally compound (c) alone.
  • the patient may be a patient as defined herein.
  • Yet another aspect of the present invention is the use of a combination comprising
  • the patient may be a patient as defined herein.
  • Yet another aspect of the present invention is the use of a combination comprising
  • the patient may be a patient as defined herein.
  • Yet another aspect of the present invention is method for glycemic control in a type 2 diabetes mellitus patient, said method comprising administration of a combination comprising
  • the type 2 diabetes mellitus to be treated preferably is not adequately controlled with compound (b) and optionally compound (c) alone.
  • the patient may be a patient as defined herein.
  • Yet another aspect of the present invention is method for the improvement of the HbA1c value, the fasting plasma glucose or/and the 2 hour postprandial plasma glucose in a type 2 diabetes mellitus patient, said method comprising administration the use of a combination comprising
  • the type 2 diabetes mellitus to be treated preferably is not adequately controlled with compound (b) and optionally compound (c) alone.
  • the patient may be a patient as defined herein.
  • Yet another aspect of the present invention is method for the prevention of weight gain or/and for inducing weight loss in a type 2 diabetes mellitus patient, said method comprising administration the use of a combination comprising
  • the type 2 diabetes mellitus to be treated preferably is not adequately controlled with compound (b) and optionally compound (c) alone.
  • the patient may be a patient as defined herein.
  • Yet another aspect of the present invention is method for the reduction of the risk of hypoglycemia in a type 2 diabetes mellitus patient, said method comprising administration the use of a combination comprising
  • the type 2 diabetes mellitus to be treated preferably is not adequately controlled with compound (b) and optionally compound (c) alone.
  • the patient may be a patient as defined herein.
  • FIG. 1 Plot of mean change in HbA1 c(%) from baseline by visit—mITT population
  • FIG. 2 Peak of mean change in body weight (kg) from baseline by visit—mITT population
  • FIG. 3 Plot of mean insulin glargine daily dose (U) by visit—mITT population
  • FIG. 4 Plot of mean daily insulin glulisine dose (U) by visit—mITT population
  • FIG. 5 Plot of mean total insulin dose (U) by visit—mITT population
  • FIG. 6 Graphical study design. 1 Insulin glargine should be injected subcutaneously once daily at dinner or breakfast time (according to patient's/investigators' preference). Injection time (dinner or breakfast) should be fixed at V2 and remain the same throughout the study. 2 Injection of lixisenatide should be performed 30-60 minutes prior to dinner or breakfast (the one associated with the highest self-monitored 2h-PPG median value across 3 different days). Meal used for lixisenatide dosing should remain the same throughout the 26-week treatment period. 3 Injection of insulin glulisine should be done 0 to 15 minutes before dinner or breakfast (the one associated with the highest self-monitored 2h-PPG median value across 3 different days). Meal used for insulin glulisine dosing should remain the same throughout the 26-week treatment period. 4 Injection of insulin glulisine prior to breakfast, lunch and dinner.
  • ECG Electrocardiogram
  • FPG Fasting plasma glucose
  • GLP-1 Glucagon-like peptide-1
  • TID Ter in die (Three times a day)
  • LOCF Last observation carried forward.
  • a Analysis of covariance (ANCOVA) model with treatment groups lixisenatide, insulin glulisine QD, and insulin glulisine TID
  • Visit 7 Wide ⁇ 1 strata of HbA1c [ ⁇ 8.0, ⁇ 8.0%], randomization strata of metformin use, and country as fixed effects and baseline HbA1c value as a covariate.
  • the analysis included measurements obtained up to 14 days after the last injection of the investigational medicinal product. Patients with both baseline and Week 26 (LOCF) measurements are included.
  • insulin glulisine QD or lixisenatide vs. insulin glulisine TID.
  • the analysis included measurements obtained up to 3 days after the last injection of the investigational medicinal product. Patients with both baseline and Week 26 (LOCF) measurements are included.
  • FIG. 1 shows the mean change in HbA1c(%) from baseline by visit in the mITT population.
  • FIG. 2 shows the mean change in body weight (kg) from baseline by visit in the mITT population.
  • LOCF Last observation carried forward.
  • a Analysis of covariance (ANCOVA) model with treatment groups lixisenatide, insulin glulisine QD, insulin glulisine TID
  • the analysis included measurements obtained up to one day after the last injection of the investigational medicinal product. Patients with both baseline and Week 26 (LOCF) measurements are included.
  • LOCF Last observation carried forward.
  • a Analysis of covariance (ANCOVA) model with treatment groups lixisenatide, insulin glulisine QD, insulin glulisine TID
  • the analysis included measurements obtained up to the date of the last injection of the investigational medicinal product. Patients with both baseline and Week 26 (LOCF) measurements are included.
  • FIG. 3 shows the mean insulin glargine daily dose (U) by visit in the mITT population.
  • FIG. 4 shows the mean daily insulin glulisine dose (U) by visit in the mITT population.
  • FIG. 5 shows the mean total insulin dose (U) by visit in the mITT population
  • On-treatment period the time from the first injection of the investigational medicinal product up to 3 days after the last injection of the investigational medicinal product. 1 Calculated as (number of patients with events * 100 divided by total exposure + 3 days in patient years). 2 Calculated as (number of events * 100 divided by total exposure + 3 days in patient years).
  • Co-primary endpoints at 26 weeks were (1) non-inferiority (95% CI upper bound ⁇ 0.4%) in HbA 1c reduction with LIXI vs GLU-1 and (2) for LIXI vs GLU-3, either non-inferiority in HbA 1c reduction (2a) OR superiority (one-sided ⁇ 0.025) in body weight change (2b).
  • FPG, PPG, IG dose, composite outcomes, AEs, and hypoglycemia were assessed.
  • Each arm randomized 298 pts (T2DM duration 12 yrs, BI duration 3 yrs, weight ⁇ 90 kg).
  • AEs adverse events
  • BL baseline
  • CI confidence interval
  • FPG fasting plasma glucose
  • HbA 1c glycated hemoglobin
  • LOCF last observation carried forward
  • LS least squares
  • mITT modified intent-to-treat
  • PPG postprandial glucose
  • QD once daily
  • SD standard deviation
  • SE standard error
  • TID thrice daily.
  • n numbers are for the mITT population (all pts who received ⁇ 1 dose of study medication, with both a baseline assessment and ⁇ 1 post-baseline assessment).

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