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
  • A61K31/13—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 HbA1 c 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)
• SEQ ID NO: 2 exendin-4 (39 amino acids)
• 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)- ⁇ -39)- peptidylpenta-L-lysyl-L-lysinamide (CAS number 320367-13-3).
• lixisenatide includes pharmaceutically acceptable salts thereof.
• suitable pharmaceutically acceptable salts of lixisenatide 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 HbA1 c 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-i c value.
• “improvement of glycemic control” or “glycemic control” includes the improvement of the 2 hour postprandial plasma glucose concentration.
• improved 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.
• improved 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.
• improved of glycemic control or “glycemic control” includes the improvement of the HbA 1 c value.
• improvement of the HbA 1 c value includes the reduction of the HbAi c value.
• Reduction of the HbA 1c value in particular means that the HbAi c 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 HbAi c 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/dl (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:
• the fasting plasma glucose concentration is > 7.0 mmol/L (126 mg/dl), or
• the post challenge plasma glucose concentration is > 1 1.1 mmol/L (200 mg/dl), performed as described by the World Health Organization (Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Part 1 : Diagnosis and Classification of Diabetes Mellitus. WHO/NCD/NCS/99.2. Geneva; 1999), using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water, or symptoms of diabetes and a casual plasma glucose > 200 mg/dl (1 1 .1 mmol/L).
• 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, HbA1 c 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).
• treatment according to the present invention relates to the treatment of a type 2 diabetes mellitus patient by the pharmaceutical combination comprising
• insulin glargine or/and a pharmaceutically acceptable salt thereof (ii) insulin glargine or/and a pharmaceutically acceptable salt thereof, and (iii) optionally metformin or/and a pharmaceutically acceptable salt thereof, as described herein.
• 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.
• compound (b) and optionally compound (c) alone 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. In a severe symptomatic hypoglycemia, 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 ⁇ 70 mg/dL ( ⁇ 3.9 mmol/L), or less than or equal to 54 mg/dL ( ⁇ 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" can include reducing the incidence of hypoglycemia.
• the incidence of hypoglycemia per patient year can be computed per patient as: 365.25 x (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” 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 antidiabetics 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 HbA1 c 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 HbA1 c 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 Prior to the onset of therapy with the combination according to the present invention, the patient may have a HbA1 c 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 (ii) continuing treatment by administration of compounds (a), (b) and (c), 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, HbAi c value, body weight and the risk of hypoglycemia if the treatment starts with administration of insulin glargine and optionally metformin alone. By this treatment protocol, 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 level
• 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. In particular, 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. In particular, 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.
• SMPG fasting self-monitored plasma glucose
• a type 2 diabetes mellitus patient may have a HbA1 c value in the range of 7 % to 10%.
• the type 2 diabetes mellitus patient to be treated may have a HbA c 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 %. These values exceed normoglycemic values, indicating that the type 2 diabetes mellitus is not adequately controlled if treated with an antidiabetic compound, as described herein.
• 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 1 1.1 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 pg to 20 pg per dose.
• lixisenatide or/and a pharmaceutically acceptable salt thereof may be administered in a daily dose in the range of 10 pg to 20 pg.
• 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. The skilled person knows such liquid compositions of lixisenatide.
• 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 HCI) 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, NaCI, calcium or magnesium containing compounds such as CaCI 2 .
• the concentration of glycerol, lactose, sorbitol, mannitol and glucose may be in the range of 100 - 250 mM.
• the concentration of NaCI 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 pg/mL to 20 pg/mL, preferably from 1 pg /ml to 5 pg/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.
• a liquid composition is suitable for parenteral administration, in particular for injection.
• 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 pg/ml, preferably of 5 - 120 pg/ml and particularly preferably of 20 - 75 pg/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 pg/mL, preferably 20 - 400 pg/mL zinc, most preferably 90 pg/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 NaCI is preferably present in a concentration of up to 50 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 (a) lixisenatide or/and a pharmaceutically acceptable salt thereof, ulin glargine or/and a pharmaceutically acceptable salt thereof, and
• 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 patient may be a patient as defined herein.
• Yet another aspect of the present invention is method for the improvement of the HbA1 c 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 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 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 patient may be a patient as defined herein.
• a pharmaceutical combination for use in glycemic control for use in the reduction of the HbA1 c 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
• the pharmaceutical combination for use according to item 1 wherein the type 2 diabetes mellitus to be treated is not adequately controlled with compound (b) and optionally compound (c) alone.
• the pharmaceutical combination for use according to item 1 or 2 wherein the patient to be treated is obese.
• the pharmaceutical combination for use according to any of the preceding items, wherein the patient to be treated has a body mass index of at least 30 kg/m 2 .
• the pharmaceutical combination for use according to any of the preceding items, wherein the patient to be treated has an age of at least 65 years.
• the pharmaceutical combination for use according to any of the preceding items wherein prior to the onset of therapy with the combination according to item 1 , the patient has a fasting plasma glucose of at least 9 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 pharmaceutical combination for use according to any of the preceding items wherein prior to the onset of therapy with the combination according to item 1 , the patient has a fasting plasma glucose concentration in the range of 5.6 to 6.9 mmol/L or a fasting plasma glucose concentration of at least 6.6 mmol/L when treated with compound (b) and optionally compound (c) alone.
• the pharmaceutical combination for use according to any of the preceding items wherein prior to the onset of therapy with the combination according to item 1 , the patient has a HbA1 c 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 has a HbA1 c of at least 7.5 % when treated with compound (b) and optionally compound (c) alone.
• the pharmaceutical combination for use of any of the preceding items, wherein the administration of the combination comprises the steps:
• step (ii) continuing treatment by administration of compounds (a), (b) and (c), wherein the amount of compound (b) to be administered in step (i) 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.
• SMPG self-monitored plasma glucose level
• the pharmaceutical combination for use of any of the preceding items, wherein lixisenatide or/and the pharmaceutically acceptable salt thereof is prepared for parenteral administration.
• the pharmaceutical combination for use according to any of the preceding items, wherein lixisenatide or/and the pharmaceutically acceptable salt thereof is prepared for administration in a daily dose selected from the range of 10 g to 20 pg.
• the pharmaceutical combination for use according to any of the preceding items, wherein insulin glargine or/and or/and the pharmaceutically acceptable salt thereof is prepared for parenteral administration.
• the pharmaceutical combination for use of any of the preceding items, wherein the metformin or/and the pharmaceutically acceptable salt thereof is prepared for oral administration.
• the method of item 20 wherein the type 2 diabetes mellitus to be treated is not adequately controlled with compound (b) and optionally compound (c) alone.
• Figure 3 Plot of mean insulin glargine daily dose (U) by visit - mITT population
• Figure 4 Plot of mean daily insulin glulisine dose (U) by visit - mITT population
• FIG. 6 Graphical study design.
• 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.
• ECG Electrocardiogram
• FPG Fasting plasma glucose
• GLP-1 Glucagon-like peptide- 1
• TID Ter in die (Three times a day)
• Inclusion criteria Adult patients with type 2 diabetes mellitus diagnosed for at least 1 year, treated with basal insulin for at least 6 months prior to screening visit, and with a stable basal insulin regimen for at least 3 months prior to screening. Patients could be treated with basal insulin alone or in combination with 1 to 3 oral anti-diabetic drugs (OADs) that could be: metformin (>1.5g/day or maximal tolerated dose), a sulfonylurea (SU), a dipeptidyl-peptidase-4 (DPP-4) inhibitor, a glinide.
• OADs oral anti-diabetic drugs
• HbA1c Key exclusion criteria at screening: HbA1c ⁇ 7.5% or >10.0% for patients treated with basal insulin alone or in combination with metformin only; HbA1c ⁇ 7.0% and >10.0% for patients treated with basal insulin and a combination of OADs which included a SU and/or a DPP-4 inhibitor and/or a glinide.
• Lixisenatide was supplied as a sterile aqueous solution for subcutaneous (s.c.) injection in a 3-mL glass cartridge containing 300 g of the active ingredient (ie, 100 pg/mL), Glycerol, Sodium acetate trihydrate, Methionine, Metacresol, HCL/NaOH, water for injection.
• Insulin glulisine was supplied as Apidra® SoloSTAR®
• Lixisenatide was injected subcutaneously using Delta 14 self-injector device
• Insulin glulisine was injected subcutaneously using the disposable SoloSTAR® self-injector device. Dose regimen:
• Lixisenatide was started with QD injections of 10 g for 2 weeks then continued at the maintenance dose of 20 g QD up to the end of the treatment period. If the target maintenance dose of 20 was not tolerated, lixisenatide dose could be reduced to 10 g. Lixisenatide was administered before breakfast or before dinner and remained the same regimen throughout the 26- week treatment period.
• the starting dose was 3 to 5 U.
• the dose of insulin glulisine was then titrated to obtain a bedtime (if injected at dinner) or pre- lunch (if injected at breakfast) SMPG value >100 mg/dL (5.6 mmol/L) and ⁇ 140 mg/dL (7.8 mmol/L) while avoiding hypoglycemia.
• Insulin glulisine QD was administered before breakfast or before dinner and remained the same regimen throughout the 26-week treatment period.
• the starting dose for each meal was 3 to 5 U.
• the dose of insulin glulisine was then titrated to obtain before the next meal (pre-lunch or pre-dinner) or at bedtime (for the injection performed before dinner) a SMPG value >100 mg/dL (5.6 mmol/L) and ⁇ 140 mg/dL (7.8 mmol/L) while avoiding hypoglycemia.
• HbA1c was above 8.5% at week 12 or later on, and appropriate corrective action (including appropriate titration of insulin glargine and/or insulin glulisine) failed and if the repeated HbA1c 4 weeks later remained above 8.5%, the assessment planned at visit 19 (final assessment on-treatment visit) and post-treatment follow-up visit was to be performed and the patient was to be discontinued from IMP and from the study.
• Noninvestigational medicinal product(s) (background therapy):
• Insulin glargine (Lantus®)
• Insulin glargine was supplied as Lantus® SoloSTAR® and was started at V2 (for those patients not already receiving insulin glargine) and injected subcutaneously using the disposable SoloSTAR® self-injector device.
• Insulin glargine was injected subcutaneously once daily at breakfast or dinner time according to patients'/ Investigators' preference. The injection time was to remain the same throughout the study.
• Insulin glargine dose was titrated to achieve glycemic targets [fasting SMPG in the range of 80 to 100 mg/dL (4.4 to 5.6 mmol/L) without recurrent or severe hypoglycemia, except during the 4 weeks following randomization when a stable dose should be maintained. Doses could be reduced or modified at any time for recurrent or severe hypoglycemia.
• HbA1 c at visit V7 (week -1) was >7% but ⁇ 8.0%, the insulin glargine dose was to be reduced in order to avoid hypoglycemia when starting the IMP (lixisenatide or insulin glulisine).
• the non-inferiority was assessed using the upper bound of the 2-sided 95% CI. If the upper bound of the 95% CI was less than 0.4%, the non-inferiority of lixisenatide versus insulin glulisine QD was achieved.
• the primary endpoints were analyzed using an analysis of covariance (ANCOVA) model with treatment (lixisenatide, insulin glulisine QD and insulin glulisine TID), V7 (week -1) strata of HbA1c ( ⁇ 8%, ⁇ 8 %), randomization strata of metformin use (yes, no) and country as fixed effects and using the corresponding baseline value as a covariate. Difference between lixisenatide and insulin glulisine QD and the associated two sided 95% confidence interval were estimated. Similarly, difference between lixisenatide and insulin glulisine TID and the associated 2-sided 95% confidence interval (or 97.5% confidence interval if either 2a or 2b was not met) were estimated for HbA1c and body weight.
• ANCOVA analysis of covariance
• CSH Cochran- antel-Haenszel
• Mean daily insulin glulisine dose at Week 26 was 9.97 U in the insulin glulisine QD group and 20.24 U in the insulin glulisine TID group ( Figure 4).
• Mean total daily insulin dose at Week 26 was 73.61 U in the insulin glulisine QD group and 81.05 U in the insulin glulisine TID group ( Figure 5).
• the percentages of patients with any TEAEs were: lixisenatide 74.2%, insulin glulisine QD 73.8% and insulin glulisine TID 80.3%.
• the two most frequent TEAEs were "hypoglycemia" which were reported in 107 patients (35.9%) in the lixisenatide group, 140 patients (46.5%) in the insulin glulisine QD group, and 154 patients (52.4%) in the insulin glulisine TID group, and "blood glucose decreased” (events not accompanied by typical symptoms of hypoglycemia) which were reported in 60 patients (20.1 %) in the lixisenatide group, 67 patients (22.3%) in the insulin glulisine QD group, and 82 patients (27.9%) in the insulin glulisine TID group.
• Nausea was reported in 75 patients (25.2%) in lixisenatide group, 5 patients (1.7%) in the insulin glulisine QD group and 3 patients (1.0%) in the
• lixisenatide group metastatic pancreatic cancer. A 67 year-old male patient was diagnosed with metastatic
• pancreatic cancer 35 days after the first administration of the IMP 35 days after the first administration of the IMP.
• the patient permanently discontinued lixisenatide.
• Further evaluation showed a tumor classified T4N+M1 of the corpus part of the pancreatic gland with infiltration into the vein of the left kidney and into the left adrenal gland with multiple metastases in the liver, intraabdominal lymphadenopathy, peritoneal dissemination, and ascites.
• the patient underwent palliative care and died on study day 52.
• the event was adjudicated by PSAC as probable malignant pancreatic neoplasm unrelated to IMP.
• glulisine TID skin ulcer haemorrhage. A 75 year-old male patient died of exsanguination due to severe bleeding from a skin ulcer 155 days after the first intake of insulin glulisine.
• glulisine TID cardiac failure chronic. A 59 year-old male was found dead on study day 145. Autopsy was performed and the reason of death was reported as exacerbation of chronic heart insufficiency.
• pre- treatment AE chronic obstructive pulmonary disease
• lixisenatide 15/298 [5.0%], glulisine QD: 2/301 [0.7%] and glulisine TID: 3/294 [1.0%]
• gastrointestinal disorders 3.7% in the lixisenatide group versus none in glulisine QD or TID group
• nausea and vomiting in four patients (1.3%) each.
• Protocol defined TEAEs of symptomatic hypoglycemia (either accompanied by plasma glucose ⁇ 60 mg/dL [3.3 mmol/L] or associated with prompt recovery after countermeasures if no plasma glucose was available) were experienced by more patients in the insulin glulisine groups compared to the lixisenatide group (lixisenatide: 98/298 [32.9%]; glulisine QD: 117/301 [38.9%]; glulisine TID: 132/294 [44.9%]).
• Iixisenatide administration Four days before the onset of the event routine laboratory results revealed lipase 3.37 x ULN. The investigator reported that the event consisted of epigastric pain of mild intensity, nausea and diarrhea. Abdominal US performed on Day 90 revealed steatohepatitis, which was reported as a new TEAE; no signs consistent with pancreatitis were observed. Lipase retested on Day 90 was within the normal range. The IMP was temporarily discontinued from Day 91 and was resumed on Day 102. The subject was considered recovered from the event on Day 92 without sequelae and completed the study treatment with Iixisenatide as per protocol. Further scheduled central laboratory test showed pancreatic enzymes within normal ranges. The investigator considered the event as related to Iixisenatide.
• Meal for IMP injection as determined by 4-point SMPG, only presented for lixisenatide and insulin glulisine QD groups.
• GLP-1 Glucagon like peptide- 1.
• Compliance rate (%) ( otal number of actual IMP injections for the dosing interval / Total number of expected IMP injections for the dosing interval)xl 00
• Table 7 Mean change in body weight (kg) from baseline to Week 26 - mITT population
• ANCOVA ANCOVA model with treatment groups (lixisenatide, insulin glulisine QD, and insulin glulisme TID), Visit 7 (Week -1) strata of HbAlc [ ⁇ 8.0, >8.0%], randomization strata of metformin use, and country as fixed effects and baseline body weight as a covariate.
• Figure 1 shows the mean change in HbAl c(%) from baseline by visit in the mITT population.
• Figure 2 shows the mean change in body weight (kg) from baseline by visit in the mITT population.
• ANCOVA ANCOVA model with treatment groups (lixisenatide, insulin glulisine QD, insulin glulisme TID), Visit 7 (Week -1) strata of HbAlc [ ⁇ 8.0, >8.0%], randomization strata of metformin use, and country as fixed effects and baseline insulin glargine dose as a covariate.
• Figure 3 shows the mean insulin glargine daily dose (U) by visit in the mITT population.
• Figure 4 shows the mean daily insulin glulisine dose (U) by visit in the mITT population.
• Figure 5 shows the mean total insulin dose (U) by visit in the mITT population SAFETY
• TEAE Treatment emergent adverse event
• SAE Serious adverse event
• n (%) number and percentage of patients with at least one TEAE
• TEAE Treatment emergent adverse event
• SOC System organ class
• n (%) number and percentage of patients with at least one TEAE
• Neoplasms benign, malignant and unspecified incl cysts and polyps 3 (1.0%) 0 3 (1.0%)
• Nervous system disorders 1 3 (1.0%) 2 (0.7%)
• Angina pectoris 1 (0.3%) 0 1 (0.3%)
• Atrial fibrillation 0 1 (0.3%) 0
• Atrioventricular block complete 0 0 1 (0.3%)
• Gastrointestinal disorders 2 (0.7%) 0 0
• Diabetic bullosis 1 (0.3%) 0 0
• Renal failure 1 (0.3%) 0 0 0 0 0 0 0 0
• TEAE Treatment emergent adverse event
• SOC System organ class
• PT Preferred term
• n (%) number and percentage of patients with at least one treatment emergent SAE.
• Neoplasms benign, malignant and unspecified incl cysts and polyps 2 (0.7%) 0
• Diabetic bullosis 1 (0.3%) 0 0
• TEAE Treatment emergent adverse event
• SOC System organ class
• PT Preferred term
• n (%) number and percentage of patients with at least one TEAE leading to permanent treatment discontinuation Note: Table sorted by SOC internationally agreed order and decreasing frequency of PT in Lixisenatide group.
• Symptomatic hypoglycemia Table 14 - Summary of symptomatic hypoglycemia meeting the protocol definition during the TEAE period - Safety population
• Lixisenatide Insulin Glulisine QD TID
• Symptomatic hypoglycemia symptomatic hypoglycemia as defined per protocol (accompanied by plasma glucose ⁇ 60 mg/dL [3.3 mmol L] or associated with prompt recovery to countermeasures if no plasma glucose was available).
• On-treatment period the time fi-om the first injection of the investigational medicinal product up to 3 days after the last injection of the investigational medicinal product.
• ARAC Allergic Reaction Assessment Committee.
• IMP Investigational medicinal product.
• Co-primary endpoints at 26 weeks were (1 ) non-inferiority (95% CI upper bound ⁇ 0.4%) in HbAi c reduction with LIXI vs GLU-1 and (2) for LIXI vs GLU-3, either non-inferiority in HbA-
• FPG, PPG, IG dose, composite outcomes, AEs, and hypoglycemia were assessed.
• Each arm randomized 298 pts (T2DM duration 12 yrs, Bl 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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