pharmaceutical combination, as well as its use in the preparation of a medication for the treatment

专利摘要:
pharmaceutical combination, as well as its use in the preparation of a drug for the treatment of diabetes. type 2". The present invention relates to a pharmaceutical combination for use in treating a patient with type 2 diabetes, which comprises (a) despro 36 exendin-4(1-39)-lys 6 -nh 2 or /and a pharmaceutically acceptable salt thereof, (b) insulin glargine or/and a pharmaceutically acceptable salt thereof, and (c) metformin or/and a pharmaceutically acceptable salt thereof The present invention further relates to the use of said combination in the treatment of type 2 diabetes.
公开号:BR112014010200A2
申请号:R112014010200-7
申请日:2012-10-26
公开日:2020-10-27
发明作者:Louise SILVESTRE；Elisabeth SOUHAMI；Xiaodan WEI
申请人:Sanofi-Aventis Deutschland Gmbh；
IPC主号:

专利说明:

[001] [001] The present invention relates to a pharmaceutical combination for use in the treatment of a patient with type 2 diabetes, in which type 2 diabetes is insufficiently controlled by at least one oral antidiabetic drug, said combination comprising (a) des- Pro Exendin-4 (1-39) -Lyss-NH> and / or a pharmaceutically acceptable salt thereof, (b) insulin gargline and / or pharmaceutically acceptable salt thereof, and (c) metformin and / or a pharmaceutically acceptable salt of same, in which the treatment of the patient with type 2 diabetes comprises the steps: (i) administration of compounds (b) and (c) for at least 4 weeks, and (ii) continuation of treatment by administration of compounds (a), (b) and (c), in which the amount of compound (b) in steps (i) and / or (ii) to be administered is adjusted so that a predetermined fasting plasma glucose level and / or a predetermined self-controlled level of plasma glucose is reached or at least approximate.
[002] [002] In a healthy person the release of insulin by the pancreas is strictly coupled with the concentration of glucose in the blood. An increased level of glucose in the blood, as it appears after meals, is quickly offset by a corresponding increase in insulin secretion. Under fasting conditions the plasma insulin level drops to a baseline value that is sufficient to ensure continuous supply of glucose to insulin-sensitive organs and tissues and to keep liver glucose production at a low level at night.
[003] [003] In contrast to type 1 diabetes, there is generally no lack of insulin in type 2 diabetes but in many cases, particularly in progressive cases, insulin treatment is considered to be the most appropriate therapy, if necessary in combination with orally administered antidiabetic drugs.
[004] [004] An increased blood glucose level for several years without initial symptoms represents a significant health risk. It can be clearly shown by the large-scale study of DCCT in the USA (The Diabetes Control and Complications Trial Research group (1993) N. Engl. J. Med. 329, 977-986) that chronically increased blood glucose levels are a reason leading to the development of diabetes complications. Examples of complications of diabetes are micro and macrovascular damage that possibly manifest in retinopathies, nephropathies or neuropathies and lead to blindness, kidney failure and loss of extremities and are accompanied by an increased risk of cardiovascular disease. Thus, it can be concluded that improved diabetes therapy primarily has to keep blood glucose in the physiological range as close as possible.
[005] [005] There is a particular risk for overweight patients suffering from type 2 diabetes, for example patients with a body mass index (BMI)> 30. In these patients, the risks of diabetes outweigh the risks of overweight, leading for example to a increased cardiovascular disease compared to patients with type 2 diabetes who are at a normal weight. Thus, it is particularly necessary to treat diabetes in these patients while reducing overweight.
[006] [006] Metformin is a hypoglycemic agent of biguanide used in the treatment of non-insulin-dependent diabetes mellitus (type 2 diabetes mellitus) that does not respond to dietary changes. Metformin improves glycemic control by improving insulin sensitivity and decreasing intestinal glucose absorption. 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 to control type 2 diabetes mellitus may be necessary.
[007] [007] Insuliha is a polypeptide having 51 amino acid residues. Insulin consists of chain A having 21 amino acid residues, and chain B having 30 amino acid residues. The chains are coupled by 2 disulfide bridges. Insulin formulations have been used for a long time for therapy of type 1 and 2 diabetes mellitus. Recently, insulin derivatives and insulin analogs have been used.
[008] [008] The desPro compound Ӽ * Exendin-4 (1-39) -Lyss-NH> (AVEOO010, lixisenatide) is a derivative of Exendin-4. lixisenatide is disclosed as SEQ ID NO: 93 in WO 01/04156: SEQ ID NO: 1: lixisenatide (44 AS) HGEGTFTSDLSKQMEEEAVRL-F-1 | -EWLKNGGP- SSGAPPSKKKKKK-NH, SEQ ID NO: 2: Exendin-4 (39 AS) HGEGTFTSDLSKQMEEEAVRL-F-1 | -EWLKNGGP- SSGAPPPS-NH,
[009] [009] Exendins are a group of peptides that can lower the concentration of glucose in the blood. The lixisenatide exendin analog is characterized by C-terminal truncation of the native Exendin-4 sequence. Lixisenatide comprises six C-terminal lysine residues not present in Exendina-4.
[0010] [0010] In the context of the present invention, lixisenatide includes its pharmaceutically acceptable salts. The person skilled in the art knows pharmaceutically acceptable salts of lixisenatide. A preferred pharmaceutically acceptable salt of lixisenatide employed in the present invention is acetate.
[0011] [0011] In the present invention, it has surprisingly been found that the effectiveness of a combination of insulin gargline, metformin and lixisenatide can be improved if treatment begins with administration of the combination of insulin gargline and metformin alone (optionally with another, such as thiazolidinedione). After such a run-in phase, the combination of insulin gargline, metformin and lixisenatide are administered (with optionally - another antidiabetic agent, such as thiazolidinedione). In the example of the present invention, during a 12-week run-in phase, insulin gargline resulted in a remarkable reduction in the mean HbArc value from 8.6% in each group to 7.56% in the lixisenatide group and 7, 60% in the placebo group. Another significant reduction in the mean HbArc value was seen in both treatment groups during the 24-week randomized treatment phase. Surprisingly, the effect was greater in the lixisenatide group (administration of insulin gargline, metformin and lixisenatide) than in the placebo group (administration of insulin gargline, metformin and placebo). In the lixisenatide group, HbAic decreased to 6.96% in the lixisenatide group and to 7.30% in the placebo group. Furthermore, under this treatment protocol, the number of patients reaching an HDAic value <7% is surprisingly higher in the lixisenatide group than in the placebo group. At week 24, 56.3% of patients in the lixisenatide group and 38.5% of patients in the placebo group reached HbA, values <7% (p = 0.0001).
[0012] [0012] The daily dose of insulin gargline in both groups gradually increased during the 24-week test period of the Example of the present invention. Surprisingly, patients in the lixisenatide group showed less increase in the daily dose of insulin gargline while achieving a greater reduction in HbA; c (mean difference LS versus placebo of 2.24 U, P value = 0.0300). Therefore, according to the treatment protocol for Patients with Type
[0013] [0013] Another surprising effect of the treatment protocol, as described here, refers to postprandial glycemic control significantly improved by treatment with lixisenatide as measured by 2-hour postprandial plasma glucose (PPG) and glucose excursion postprandial. A statistically significant reduction in PPG of 2 hours after a standard baseline meal for week 24 was achieved in the lixisenatide group compared to the placebo group. Here, correspondingly, a substantial reduction in glucose excursion was observed in patients treated with lixisenatide compared to those treated with placebo.
[0014] [0014] Furthermore, treatment with lixisenatide demonstrated a statistically significant improvement in the average 7-point self-monitored plasma glucose profile (SMPG) compared to the placebo group.
[0015] [0015] A first aspect of the present invention is the pharmaceutical combination for use in the treatment of a patient with type 2 diabetes, in which type 2 diabetes is insufficiently controlled by at least one oral antidiabetic drug, said combination comprising (a) desPro * ºExendin-4 (1-39) -Lyss-N H2 ebuum its pharmaceutically acceptable salt, (b) insulin gargline and / or its pharmaceutically acceptable salt, and (c) metformin and / or a pharmaceutically acceptable salt thereof, in which the Treatment of a type 2 diabetes patient comprises the steps: (i) administration of compounds (b) and (c) for at least 4 weeks, and (ii) continuation of treatment by administration of compounds (a), (b) and (c), in which the amount of compound (b) to be administered in steps (i) and / or (i) is adjusted so that a predetermined fasting plasma glucose level and / or a plasma glucose level predetermined self-monitoring is achieved or at least approximate.
[0016] [0016] Metformin is the non-patented international name of 1,1-dimethylbiguanide (CAS number 657-24-9). In the present invention, the term "" metformin "includes any pharmaceutically acceptable salt thereof.
[0017] [0017] In the present invention, metformin can be administered orally. The knowledgeable person knows metformin formulations suitable for the treatment of type 2 diabetes by oral administration. Metformin can be administered to an individual who needs it, in an amount sufficient to induce a therapeutic effect. Metformin can be administered in a dose of at least 1.0 g / day or at least 1.5 g / day. For oral administration, metformin can be formulated in a solid form, such as a pill or pill. Metformin can be formulated with suitable pharmaceutically acceptable carriers, auxiliaries, and / or auxiliary substances.
[0018] [0018] Insulin gargline (Lantus) is insulin from human GIy (A21) -Arg (B31) - Arg (B32). In the present invention, insulin gargline includes its pharmaceutically acceptable salts.
[0019] [0019] Insulin gargline and / or a pharmaceutically acceptable salt thereof can be administered parenterally, for example, by injection (such as by intramuscular injection or by subcutaneous injection). The person skilled in the art knows suitable liquid insulin formulations, including suitable vehicles, auxiliaries, and / or suitable pharmaceutically acceptable auxiliary substances. Suitable injection devices, for example, so-called "pens" comprising a cartridge comprising the active ingredient, and an injection needle, are known. In the present invention, insulin gargline and / or its pharmaceutically acceptable salt can be administered to an individual who needs them, in an amount sufficient to induce a therapeutic effect. Insulin gargline and / or a pharmaceutically acceptable salt thereof can be administered, for example, in an amount in the range of 15 to 80 U per dose.
[0020] [0020] In the present invention, insulin gargline and / or a pharmaceutically acceptable salt thereof can be administered in a daily dose in the range of 15 to 80 U. Insulin garglina and / or a pharmaceutically acceptable salt thereof can be administered once daily, for example, by one injection a day.
[0021] [0021] In step (i), the compounds (b) and (c) of the pharmaceutical combination of the present invention can be administered for at least 4 weeks, at least 8 weeks, at least 12 weeks, or at least 16 weeks. Preferably, step (i) comprises administration of compounds (b) and (c) for at least about 12 weeks.
[0022] [0022] Step (i) can be performed for a maximum of about 8 weeks, a maximum of about 12 weeks, a maximum of about 16 weeks, a maximum of about 20 weeks, or a maximum of 24 about weeks. Preferred is a duration of step (i) of about 12 weeks.
[0023] [0023] Step (i) can be carried out on the condition that compound (a) is not administered. As demonstrated by the Example of the present invention, a treatment with the combination of insulin garglines, metformin and lixisenatide can improve postprandial glycemic control, HDArc value, and SMPG if treatment begins with administration of insulin gargline and metformin alone. Through this treatment protocol, the dose of insulin garglina can be reduced.
[0024] [0024] Step (i) and / or step (ii) may comprise the other administration of thiazolidinedione. Thiazolidinediones (also called Glitazones) such as piogltaizone are anti-glycemic agents that reduce resistance by sensitizing muscle, liver and adipose tissue (Dormandy et al., Lancet 2005, 366: 1270-89, Yki-Jarvinen, N Engl J Med 2004, 351 : 1106-18). In the context of the present invention, "thiazolidinedione, as used herein, includes its pharmaceutically acceptable salts. Glitazone can be selected from pioglitazone, troglitazone and rosiglitazone and their pharmaceutically acceptable salts. Thiazolidinedione, in particular pioglitazone, can be administered in a dose of at least 10 mg / day, at least 20 mg / day, at least 30 mg / day, or at least 40 mg / day. The maximum daily dose of thiazolidinedione, in particular pioglitazone, can be 50 mg / day or 60 mg / day. A preferred dosage range is 10 mg / day to 50 mg / day or 30 mg / day to 40 mg / day. A more preferred dose is about 30 mg / day. Rosiglitazone can be administered at a dose of 2 mg / day to 10 mg / day, or 3 mg / day to 8 mg / day. a more preferred dose of rosiglitazone is about 4 mg / day. For oral administration, thiazolidinedione, in particular pioglitazone, can be formulated in a solid form, such as a tablet or pill. Thiazolidinedione, in particular pioglitazone, can be formulated with suitable pharmaceutically acceptable vehicles, auxiliaries and / or auxiliary substances.
[0025] [0025] The pharmaceutical combination of any of the preceding claims, wherein administration in steps (i) and / or (ii) is carried out on a daily basis. Metformin, lixisenatide and insulin gargline can be administered within 24 h. Metformin, lixisenatide and insulin gargline each can be administered in a dosage once a day. Metformin, lixisenatide and insulin gargline can be administered by different routes of administration. Metformin can be administered orally, and lixisenatide and insulin gargline can be administered parenterally.
[0026] [0026] In the present invention, desPro * ºExendin-4 (1-39) -Lyss-NH, and / or a pharmaceutically acceptable salt can be administered in a therapy added to the administration of insulin gargline and metformin. In the present invention, the terms "added", "treatment - added" and "added therapy" refer to the treatment of type 2 diabetes mellitus with metformin, lixisenatide and insulin garglins. The added treatment may include the administration of thiazolidinedione, as described herein.
[0027] [0027] The individual to be treated by the medicament of the present invention suffering from type 2 diabetes may be an individual suffering from type 2 diabetes, in which type 2 diabetes is not adequately controlled by treatment with at least one oral antidiabetic drug alone, for example with at least 1.0 g / day metformin or at least 1.5 g / day metformin, for example, for 3 months, or with thiazolinadione as described here, for example, for 3 months, or the combination of metformin and thiazolinadione. In the present invention, an individual whose type 2 diabetes is not adequately controlled can have an HbArc value in the range of 7% to 10% or even greater.
[0028] [0028] In the pharmaceutical composition of the present invention, the amount of compound (b) to be administered in steps (i) and / or (ii) is adjusted so that a predetermined fasting plasma glucose level and / or a level of glucose in the predetermined self-monitored plasma is reached or at least approximate. The amount of compound (b) to be administered in steps (i) and / or (ii) can be adjusted based on daily measurements of the plasma glucose concentration. In particular the amount of compound (b) to be administered in steps (i) and / or (ii) can be adjusted so that a fasting plasma glucose level from about 4.4 mmoles / 1 to about 5 , 6 mmoles / lI and / or a self-monitored plasma glucose (SMPG) level of about 8 mmoles / 1 (or about 140 mg / dl) is reached or at least approximate.
[0029] [0029] "Self-monitored plasma glucose (SMPG)", as used here, is in particular "7-point self-monitored plasma glucose". "7-point self-monitored plasma glucose" in particular refers to measuring plasma glucose seven times a day and calculating the average plasma glucose concentration from it. The "7-point self-monitored plasma glucose" value is in particular an average plasma glucose concentration including fasting and postprandial conditions. In particular, plasma glucose concentration measurements are performed before breakfast, after breakfast, before lunch, after lunch, before dinner, after dinner and at bedtime (see also Figure 6). Combination treatment of the present invention, as described herein, can improve self-monitored plasma glucose.
[0030] [0030] As demonstrated by the Example disclosed here, the combination as described here can be used to improve glycemic control in a patient with type 2 diabetes. In particular glycemic control is a postprandial glycemic control. More particular postprandial glycemic control is postprandial plasma glucose control and / or postprandial glucose excursion.
[0031] [0031] In the present invention, "improving glycemic control" or "glycemic control" includes improving glucose tolerance, improving glucose concentration in postprandial plasma, improving postprandial glucose excursion, improving concentration of glucose fasting plasma glucose, improving the HbA value, and / or improving fasting plasma insulin concentration.
[0032] [0032] In particular, improving glucose tolerance includes improving the concentration of glucose in the postprandial plasma, improving the excursion of postprandial glucose, and / or improving the concentration of insulin in the fasting plasma. More particularly, “improving glucose tolerance includes improving the concentration of glucose in postprandial plasma.
[0033] [0033] Improvement of glucose excursion is in particular reduction of glucose excursion. The glucose excursion can be at least 2 mmoles / L, at least 3 mmoles / L, at least 4 mmoles / L or at least 5 mmoles / L before treatment as described here.
[0034] [0034] In particular, improvement of glucose concentration in postprandial plasma is the reduction of glucose concentration in postprandial plasma. Reduction in particular means that the plasma glucose concentration reaches normoglycemic values or at least approximates those values.
[0035] [0035] In particular, improving fasting plasma glucose concentration is reducing fasting plasma glucose concentration. Reduction in particular means that the plasma glucose concentration reaches normoglycemic values or at least approximates those values.
[0036] [0036] In particular, improving the HbArc value is reducing the HbAc value. Reduction of the HbAje value in particular means that the HbArc value is reduced below 6.5% or 7%, for example after treatment by steps (i) and / or (ii), as described here, for at least two months , at least three months, at least four months, at least five months, at least six months or at least one year.
[0037] [0037] In particular, improving fasting plasma insulin concentration is reducing fasting plasma insulin concentration. In the Example of the present invention, it was surprisingly found that the dose of insulin gargline could be reduced when administered together with lixisenatide and metformin, as described herein, compared to administration of insulin gargline and metformin alone. The plasma insulin concentration is coupled with the plasma glucose concentration. Under treatment as described here, in fasted condition plasma insulin can reach or at least approximate values to ensure continuous supply of glucose to insulin sensitive organs and tissues and / or to maintain hepatic glucose production at a low level in the evening. In fasting conditions, the insulin concentration can reach or at least approximation values associated with normodglycemia or glucose concentration in the plasma that approaches normodlycemia.
[0038] [0038] The individual to be treated by the medicament of the present invention suffering from type 2 diabetes may be an obese individual. In the present invention, an obese individual can have a body mass index of at least 30 kg / m .
[0039] [0039] The individual being treated by the medicament of the present invention suffering from type 2 diabetes may have a normal body weight. In the present invention, can an individual having normal body weight have a body mass index in the range of 17 kg / m to kg / m , or 17 kg / m at <30 kg / m .
[0040] [0040] The individual to be treated by the medicament of the present invention can be an adult individual. The individual can be at least 18 years old and can be in the range 18 to 80 years old, 18 to 50 years old, or 40 to 80 years old, or 50 to 60 years old. The individual may be younger than 50 years.
[0041] [0041] The individual to be treated by the medicine of the present invention may suffer from type 2 diabetes mellitus for at least 1 year or at least 2 years. In particular, in the subject to be treated, type 2 diabetes mellitus was diagnosed at least 1 year or at least 2 years before the start of therapy by the drug of the present invention.
[0042] [0042] The individual to be treated can have an HbAc value of at least about 8% or at least about 7.5% at the beginning of step (i). The individual may also have an HbAic value of about 7 to about 10% or even more. The example of the present invention demonstrates that treatment by lixisenatide results in an HbA value. improved in patients with type 2 diabetes.
[0043] [0043] In yet another aspect of the present invention, the combination as described here can be used to improve the value of HDAc in a patient suffering from type 2 diabetes. Improvement in the value of HbArc means that the value of HDAc is reduced below 6.5% or 7%, for example, after treatment for at least two months, or at least three months.
[0044] [0044] In the present invention, normoglycemic values are blood glucose concentrations of in particular 60 - 140 mg / dl (corresponding to 3.3 to 7.8 mMM / L). This range refers in particular to blood glucose concentrations under fasting and postprandial conditions.
[0045] [0045] The individual to be treated may have a 2 hour postprandial plasma glucose concentration of at least 10 mmoles / L, at least 12 mmoles / L, or at least 14 mmoles / L at the beginning of the stage (i ). These plasma glucose concentrations exceeded normoglycemic concentrations.
[0046] [0046] The individual to be treated may have a glucose excursion of at least 2 mmoles / L, at least 3 mmoles / L, at least 4 mmoles / L or at least 5 mmoles / L at the beginning of step (i). In the present invention, the glucose excursion is in particular the difference in the glucose concentration in the 2 hour postprandial plasma and the glucose concentration in the plasma 30 minutes before the meal test.
[0047] [0047] "Postprandial" is a term that is well known by a person versed in the technique of diabetology. The term "postprandial" describes in particular the phase after eating and / or glucose exposure under experimental conditions. In a healthy person this phase is characterized by a subsequent increase and decrease in the concentration of glucose in the blood. The term "postprandial" or "postprandial phase" typically ends within 2 h after a meal and / or exposure to glucose.
[0048] [0048] The individual to be treated as disclosed here may have a fasting plasma glucose concentration of at least 8 mmoles / L, at least 8.5 mmoles / L or at least 9 mmoles / L at the beginning of the stage (i ). These plasma glucose concentrations exceed normoglycemic concentrations.
[0049] [0049] The patient to be treated as disclosed here preferably does not receive antidiabetic treatment with an insulin and / or a pharmaceutically acceptable salt thereof at the beginning of step (i).
[0050] [0050] The treatment of the present invention, as described here, can induce weight loss and / or prevent weight gain in a patient with type 2 diabetes. Surprisingly it has been found in the Example of the present invention that the treatment as described here can prevent gain of weight. During the 24-week time period, slightly increased body weight in both groups with an average change of LS of 0.28 kg for patients treated with lixisenatide and 1.16 kg for patients treated with placebo. Weight gain was statistically significantly lower in the lixisenatide group than in the placebo group.
[0051] [0051] The treatment of the present invention, as described here, can prevent hypoglycemia in a patient with type 2 diabetes. In particular, the pharmaceutical combination is used for the prevention of symptomatic hypoglycemia and / or severe symptomatic hypoglycemia and a patient with diabetes mellitus type 2.
[0052] [0052] In the present invention, hypoglycemia is a condition in which type 2 diabetes mellitus patient experiences a plasma glucose concentration of below 60 mg / dl (or below 3.3 mmoles / L), below 50 mg / d dL, below 40 mg / dL, or below 36 mg / dL.
[0053] [0053] By the method of the present invention, hypoglycemia can be reduced to below 12%, below 11%, below 10%, below 9%, below 8%, below 7%, below 6% or below of 5% of Type 2 Diabetes Patients who receive the combination of lixisenatide and / or a pharmaceutically acceptable salt thereof, insulin garglins and / or a pharmaceutically acceptable salt thereof and optionally metformin and / or a pharmaceutically acceptable salt thereof, as described herein.
[0054] [0054] In the present invention, "symptomatic hypoglycemia" is a condition associated with a clinical symptom that results from hypoglycemia, in which the plasma glucose concentration is below 60 mg / dL (or below 3.3 mmoles / L) , below 50 mg / dL, or below 40 mg / dL. Clinical symptoms can be, for example, sweating, palpitations, hunger, restlessness, anxiety, fatigue, irritability, headache, loss of concentration, drowsiness, psychiatric disorders, visual disorders, transient sensory defects,
[0055] [0055] Hypoglycemia - symptomatic may be associated with immediate recovery after carbohydrate administration.
[0056] [0056] In the present invention, "severe symptomatic hypoglycemia" is a condition with a clinical symptom, as indicated here, which results from hypoglycemia, in which the plasma glucose concentration is below 36 mg / dL (or below 2, 0 mmoles / L). Severe symptomatic hypoglycemia may be associated with an acute neurological decrease that results from the hypoglycemic event. In severe symptomatic hypoglycemia, the patient may require assistance from another person, if, for example, the patient could not treat or assist himself / herself due to acute neurological impairment. The definition of severe symptomatic hypoglycemia can include all episodes in which neurological impairment is severe enough to prevent self-treatment and which were thus thought of as putting patients at risk of injury to themselves or others. Acute neurological decrease can be at least one selected from drowsiness, psychiatric disorders, visual disorders, transient sensory defects, transient motor defects, confusion, seizures, and coma.
[0057] [0057] Severe symptomatic hypoglycemia may be associated with immediate recovery after administration of oral carbohydrate, intravenous glucose, and / or glucagon.
[0058] [0058] In the present invention, desPro ºExendin-4 (1-39) -Lyss-N H2 and / or its pharmaceutically acceptable salt can be administered to an individual who needs it, in an amount sufficient to induce a therapeutic effect .
[0059] [0059] In the present invention, desPro * ºExendin-4 (1-39) -Lyss-NH,
[0060] [0060] The desPro * ºExendin-4 (1-39) -Lys; -N H2 compound and / or a pharmaceutically acceptable salt thereof! it can be administered parenterally, for example by injection (such as by intramuscular injection or by subcutaneous injection). Suitable injection devices, for example the so-called "pens" comprising a cartridge comprising the active ingredient, and an injection needle, are known. The desPro * ºExendin-4 (1-39) -Lyss-N —H2 compound or a pharmaceutically acceptable salt thereof can be administered in an appropriate amount, for example in an amount ranging from 10 to 15 pg per dose or from 15 to 20 pg per dose.
[0061] [0061] In the present invention, desPro * ºExendin-4 (1-39) -Lyss-NH, and / or a pharmaceutically acceptable salt thereof can be administered in a daily dose in the range of 10 to 20 pg, in the range of 10 to 15 pg, or in the range of 15 to 20 pg. DesPro ºExendin-4 (1-39) -Lyss-NH2 and / or a pharmaceutically acceptable salt thereof can be administered by one injection per day.
[0062] [0062] In the present invention, desPro * Exendin-4 (1-39) -Lyss-N H2 and / or a pharmaceutically acceptable salt thereof can be provided in a liquid composition. The skilled person knows liquid lixisenatide compositions suitable for parenteral administration. A liquid composition of the present invention can have an acidic or physiological pH. An acidic pH is preferably in the pH range of 1 - 6.8, pH of 3.5 - 6.8, or pH of 3.5 - 5. A physiological pH is preferably in the pH range of 2.5 - 8.5, pH 4.0 - 8.5, or pH 6.0 - 8.5. The pH can be adjusted by a pharmaceutically acceptable diluted acid (typically HCI) or a pharmaceutically acceptable diluted base (typically NaOH).
[0063] [0063] The liquid composition comprising desPro ӼExendin- 4 (1-39) -Lyss-NH> 7 and / or a pharmaceutically acceptable salt thereof can comprise a suitable preservative. A suitable preservative can be selected from phenol, m-cresol, benzyl alcohol and p-hydroxybenzoic acid ester. A preservative effect is m-cresol.
[0064] [0064] The liquid composition comprising desPro * ºExendin- 4 (1-39) -Lyss-NH2 and / or a pharmaceutically acceptable salt thereof can comprise a tonicity agent. A tonicity agent can be selected from compounds containing glycerol, lactose, sorbitol, mannitol, glucose, NaCl, calcium or magnesium such as CaCl. The concentration of glycerol, lactose, sorbitol, mannitol and glucose can be in the range of 100 - 250 mM. The NaCl concentration can be up to 150 MM. A preferred tonicity agent is glycerol.
[0065] [0065] The liquid composition comprising desPro * ºExendin- 4 (1-39) -Lyss-NH, and / or a pharmaceutically acceptable salt thereof may comprise methionine from 0.5 pg / ml to 20 pg / ml, preferably 1 fag / ml at 5 pg / ml. Preferably, the liquid composition comprises L-methionine.
[0066] [0066] Another aspect of the present invention is a method for the treatment of type 2 diabetes patient, in which type 2 diabetes is insufficiently controlled by at least one oral antidiabetic drug, wherein the method comprises the administration of a combination, the said combination comprises (a) desPro * ººExendin-4 (1-39) -Lyss-N H2 and / or a pharmaceutically acceptable salt thereof, (b) insulin gargline and / or its pharmaceutically acceptable salt, and (c) metformin and / or a pharmaceutically acceptable salt thereof,
[0067] [0067] in which administration of the combination comprises the steps: (1) administration of compounds (b) and (c) for at least 4 weeks, and (ii) further treatment by administration of compounds (a), (b) and (c), in which the amount of compound (b) to be administered in steps (i) and / or (ii) is adjusted so that a predetermined fasting plasma glucose level and / or a glucose level in the predetermined self-monitored plasma is reached or at least approximate.
[0068] [0068] In particular, in the method of the present invention, the combination as described herein can be administered. More particularly, compounds (a), (b) and (c) are compounds as defined herein. In particular, the patient is a patient as defined here. In addition, steps (i) and (ii) are carried out in particular as defined here. Furthermore, adjustment of the compound (b) to be administered in steps (i) and (ii) is in particular carried out as disclosed here,
[0069] [0069] Yet another aspect of the present invention is the use of a combination comprising (a) desPro ºExendin-4 (1-39) -Lys; -NH2e / or a pharmaceutically acceptable salt thereof, (b) insulin gargline and / or its pharmaceutically acceptable salt, and (c) metformin and / or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a patient with type 2 diabetes, in which type 2 diabetes is insufficiently controlled by at least one drug oral antidiabetic, and where the combination treatment comprises the steps: (i) administration of compounds (b) and (c) for at least 4 weeks, and
[0070] [0070] In particular, in the use of the present invention, the combination as described herein can be administered. More particularly, compounds (a), (b) and (c) are compounds as defined herein. In particular, the patient as defined here can be treated by the drug. In addition, steps (i) and (ii) are carried out in particular as defined here. Furthermore, adjustment of the compound (b) to be administered in steps (i) and (ii) is in particular carried out as disclosed here,
[0071] [0071] The invention is further illustrated in the following examples and figures. Picture's description
[0072] [0072] Figure 1: Study design. For the run-in phase, a visit window of +3 days is acceptable using the data from visit 2 as a reference. During the double blind treatment period chosen at random from a visit window of +3 days until the visit (week 2) and +5 days after visit 15 is acceptable, using visit day 13 as a reference. a visit window of -1 day or + 3 days is acceptable for the post-treatment follow-up visit using the day of visit 22 as a reference. * Placebo combined volume.
[0073] [0073] Figure 2: Kaplan-Meier time diagram for treatment discontinuation due to any reason - Population chosen at random.
[0074] [0074] Figure 3: Diagram of average change in HbA; c (%) from the baseline by visit - mITT population. LOCF = Last observation made. Note: The measurements excluded from the diagram obtained after the introduction of rescue medication and / or after the interruption of treatment plus 14 days.
[0075] [0075] Figure 4: Diagram of average HbArc (%) per visit - mITT population. LOCF = Last observation made. Note: The measurements excluded from the diagram obtained after the introduction of recovery medication and / or after the interruption of treatment plus 14 days.
[0076] [0076] Figure 5: Diagram of mean change in mean glucose in self-monitored plasma at 7 points (SMPG) (mmoles / L) from the baseline by visit - mITT population. LOCF = Last observation made. Note: The measurements excluded from the diagram obtained after the introduction of recovery medication and / or after treatment interruption.
[0077] [0077] Figure 6: 7-point self-monitoring plasma glucose diagram (SMPG) (mmoles / L) for each time point, at baseline and Week 24 (LOCF) - mITT population. Note: The baseline value is defined as the last available value before the first injection of the double-blind investigational product. The measurements excluded from the diagram obtained after the introduction of recovery medication and / or after the interruption of treatment.
[0078] [0078] Figure 7: Diagram of average change in body weight (kg) from baseline by visit - mITT population. LOCF = Last observation made. Note: The measurements excluded from the diagram obtained after the introduction of recovery medication and / or after the interruption of treatment plus 3 days.
[0079] [0079] Figure 8: Diagram of mean change in insulin gargline (U) dose from baseline by visit - mITT population.
[0080] [0080] Figure 9: Diagram of mean fasting plasma glucose change (mmoles / L) from baseline by visit - mITT population. LOCF = Last observation made. Note: The measurements excluded from the diagram obtained after the introduction of recovery medication and / or after the interruption of treatment plus 1 day.
[0081] [0081] The Example refers to a multinational, double-blind, placebo-controlled, double-arm, randomized study that assesses the efficacy and safety of lixisenatide compared to placebo as a treatment added to insulin gargline and metformin in combination with or without TZDs in patients with type 2 diabetes. The approximately maximum study duration per patient was 39 weeks [up to a 14-week screening period (including up to a 2-week screening phase and a run-in 12 weeks) + a 24-week double-blind treatment period, placebo-controlled treatment period + a 3-day follow-up period]. The study was conducted at 140 centers in 25 countries. The primary purpose of the study was to assess the effects on glycemic control of lixisenatide compared to placebo as a treatment added to insulin gargline and metformin in terms of HbA1c change over a 24-week period.
[0082] [0082] A total of 446 patients were randomly chosen for one of the two treatment groups (223 in the lixisenatide group and 223 in the placebo group) and all patients chosen at random were exposed to the investigational product (IP). Baseline and demographic characteristics were generally similar across treatment groups. No patient was excluded from the mITT population for analysis of efficacy. During the study treatment period, 29 (13.0%) patients treated with lixisenatide prematurely discontinued | P, while 12 (5.4%) patients treated with placebo discontinued PI. For both treatment groups, the main reason for discontinuing treatment was an "adverse event" (8.5% for lixisenatide versus 4.0% for placebo) followed by "other reasons" (3.6% for lixisenatide versus 1.3% for placebo). Of observation, GI-related AEs were the main TEAEs that lead to discontinuation of PI for lixisenatide (10 patients [4.5%]).
[0083] [0083] HbAI c decreased in both treatment groups from a value of 7.56% at baseline to 6.96% at week 24 (LOCF) in the lixisenatide group and from 7.60% at 7, 30% in the placebo group. The decrease in HblIAc for lixisenatide was significantly greater compared to placebo: mean changes from least squares (LS) from baseline to Week 24 were -0.71% and -0.40%, respectively, and mean difference of LS vs. placebo was -0.32%, with a p-value <0.0001. It is worth noting that, per protocol, insulin dose adjustments to keep fasting plasma glucose in the target were left in both treatment groups throughout the study.
[0084] [0084] A total of 121 patients (56.3%) in the lixisenatide group achieved HbA, <7% at Week 24 compared to 85 patients (38.5%) in the placebo group, and 69 (32.1% ) patients treated with lixisenatide had HBA, 6.5% compared to 36 (16.3%) of patients treated with placebo. HbA respondent analysis.
[0085] [0085] Treatment with postprandial glycemic control of lixisenatide significantly improved as measured by glucose in the postprandial plasma for 2 hours (PPG) and postprandial glucose excursion. The statistically significant reduction in PPG for two hours after the standard test meal from the baseline for Week 24 was achieved in the lixisenatide group compared to the placebo group, with the mean LS difference of -3.6 mmoles / L (p value <.0001). Correspondingly, a substantial reduction in glucose excursion was observed in patients treated with lixisenatide compared to those treated with placebo (mean difference of LS = -3.09 mmoles / L, 95% CI = -3.842 to -2.331).
[0086] [0086] Furthermore, treatment with lixisenatide demonstrated a statistically significant improvement in the average glucose profile in the 7-point self-monitored plasma (SMPG) (mean difference of LS of -0.39 mmoles / L; p value 0.0071 ) compared to the placebo group.
[0087] [0087] A statistically significant weight loss was observed in the lixisenatide group than in the placebo group (mean weight change from LS from baseline to Week 24 was 0.28 kg for patients treated with lixisenatide and 1.16 kg for patients treated with placebo; mean difference of LS versus placebo = -0.89 kg, p-value = 0.0012)
[0088] [0088] During the 24-week treatment period, in both groups, the gradually increased daily insulin dose that was allowed by the protocol to maintain FPGs between 100 and 80 mg / d (5.6 and 4.4 mmmoles / L ) (mean change from LS from baseline was 3.10 U in the lixisenatide group and 5.34 in the placebo group). However, patients in the lixisenatide group showed a less significant increase in the daily insulin gargline dose while achieving a greater reduction in HbAI c (mean difference from LS versus placebo = -2.24 U; p-value = 0.0300).
[0089] [0089] For fasting plasma glucose, no statistically significant difference was observed between treatment groups (mean difference from LS versus placebo = -0.12 mmoles / L; p-value = 0.5142). A total of 2 patients (1 [0.4%] in each group) received recovery therapy.
[0090] [0090] Lixisenatide was well tolerated. The safety profile in the lixisenatide group was generally comparable with the placebo group although the number of patients with treatment-emergent adverse events (TEAEs) was slightly higher in the lixisenatide group [178 (79.8%)] than that in the placebo group [152 (68.2%)]. This disproportion in the number of patients with TEAEs was mainly driven by the AEs related to Gl (39.9% for lixisenatide versus 16.1% for placebo).
[0091] [0091] Two patients in the placebo group and the patient in the lixisenatide group had TEAEs that lead to death.
[0092] [0092] The number of patients with serious TEAEs was 17 (7.6%) in the lixisenatide group and 10 (4.5%) in the placebo group without a noticeable increased occurrence in any specific System Organ Classes (SOC) .
[0093] [0093] Fifty (22.4%) patients treated with lixisenatide and 30 (13.5%) patients in the placebo group reported symptomatic hypoglycemic events as defined in the protocol during the treatment period. One patient in the lixisenatide group (0.4%) and the patient in the placebo group experienced a severe symptomatic hypoglycemia event as defined by the protocol.
[0094] [0094] With the exception of hypoglycemia, TEAE was most often nausea (27.4%) for the lixisenatide and influenza group (6.3%) for the placebo group.
[0095] [0095] A total of 4 patients (3 [1.3%] patients treated with lixisenatide and 1 [0.4%] patients treated with placebo) reported 4 TEAESs judged as an allergic reaction by the Allergic Reaction Assessment Committee (ARAC ), and three of these events (2 urticaria events in the lixisenatide group and 1 dermatitis event in the placebo group) were judged to be possibly related to | P. Fifteen patients (6.7%) in the lixisenatide group and 5 patients (2.2%) in the injection site reaction experienced by the AEs placebo group.
[0096] [0096] In the placebo group, 1 patient reported 1 TEAE of suspected pancreatitis and 2 patients reported 2 TEAEs of increased blood calcitonin, while in patients in the lixisenatide group reported such TEAESs. 1 Objectives
[0097] [0097] The primary objective of the study was to assess the effects on glycemic control of lixisenatide compared to placebo as a treatment added to insulin gargline and metformin in terms of HbAI c change over a 24-week period.
[0098] [0098] This was a phase 3 study of the 2-arm parallel group, placebo-controlled, randomly chosen 1: 1, double-blind, multinational, multicenter. The study was doubly blinded to placebo and active ingredient treatment. The drug volume study (i.e., dose of active drug or corresponding placebo) was not blind. The study project is illustrated by Figure 1.
[0099] [0099] Patients were stratified by Al c values of glycated hemoglobin (HbAlc) collected at Visit 12, which was staggered for one week before the end of the run-in phase (<8%,> 8%), and use of Thiazolidinediones (TZD) (yes, no).
[00100] [00100] TZDs were the only additional concomitant diabetes treatment allowed for insulin gargline and metformin that could be continued during the study. At the end of the run-in phase, acceptable patients were centrally chosen at random via an interactive response system (IVRS) in a 1: 1 ratio for either lixisenatide or placebo. Forced randomization was not left.
[00101] [00101] The study consisted of 3 periods: (1) and a screening period of up to 14 weeks, which included a screening phase of up to 2 weeks and a run-in phase of 12 weeks with the introduction and titration of insulin garglina on top of metformin +/- TZDs; patients started insulin gargline once daily and titrated the insulin dose by a treatment regimen to target to reach a glycemic target of 100 -80 mg / dl FPG (5.6-4.4 mmoles / L) during run-in. (2) a randomly chosen double-blind treatment period of 24 weeks for those patients
[00102] [00102] Whose HbAI c (centralized assay) was 7% and .9% and whose mean fasting self-monitored plasma glucose (SMPG) during the 7 days before visit 12 was 140 mg / dl (7.8 mmo1 / 1); and (3) a follow-up period with a security call visit (last study visit) 3 (-1 / + 3) days after the end of the treatment visit.
[00103] [00103] Patients who prematurely discontinued study treatment were continued into the study until the staggered data at the conclusion of the study. They were followed up according to the specific study procedures in the protocol (except the meal challenge test and treatment satisfaction assessment). 3 Key Primary and Secondary Endpoints
[00104] [00104] The primary variable efficacy was the absolute change in HbAic from the baseline to Week 24, which is defined as: as HLAi value in Week 24 - HbAtc at the baseline.
[00105] [00105] If a patient permanently discontinued received recovery therapy or double blind treatment during the 24 week double blind treatment period or did not have an HbAie value at Week 24, the last post-baseline HbAle measurement period in the treatment it was used as the HbAlc value at Week 24 (last observation made of the procedure [LOCF] forward).
[00106] [00106] For secondary efficacy variables the same procedure - for the handling of early loss / discontinuation assessments was applied as for the primary efficacy variable. Continuous variables eChange in PPG in 2 hours (mmoles / L) after the standardized meal test from the baseline for Week 24; eChange in blood glucose excursion (2-hour PPG- plasma glucose 30 minutes before meal test before PI administration) (mmoles / L) after standardized meal challenge test from baseline to Week 24; e Change in the 7-point SMPG profiles (mmoles / L) (that is, the daily average and each 7-point time point) from the baseline to Week 24; eChange in FPG (mmoles / L) from baseline to Week 24; eChange body weight (kg) from baseline to week 24; eChange the mean daily insulin gargline (U) dose from baseline to week 24; eChange in the treatment satisfaction rating (sum of items 1, 4,5,6,7 and 8 of DTSQs) from the baseline to week 24; eChange in each individual item (items 1 to 8) of DTSQs from the baseline for week 24. Categorical variables. º Percentage of patients with HbAlc <7% in week 24; Percentage of patients with HbAI c 5-6.5% in the week
[00107] [00107] The safety analysis was based on reported TEAEs and other safety information including symptomatic hypoglycemia and severe symptomatic hypoglycemia, local tolerability at the injection site, allergic events (as judged by ARAC), suspected pancreatitis, increased calcitonin, signs vitals, ECG guide 12 and laboratory tests.
[00108] [00108] Major cardiovascular events were also collected and sent for adjudication by a Cardiovascular Adjudication Committee (CAC). Events judged and confirmed by
[00109] [00109] The sample size / power calculations were performed based on the primary variable, change from baseline to week 24 in HbAlc.
[00110] [00110] A sample size of 450 patients (225 patients per group) was expected to provide 98% power to detect 0.5% differences and 90% to detect 0.4% differences in change from the line baseline until week 24 in HbAlc between lixisenatide and placebo assuming the common standard deviation was 1.3% with a 2-sided test at the 5% significance level. Statistical methods
[00111] [00111] The mITT population consisted of all patients who were chosen at random, received at least one dose of the double-blind (PI) investigational product, and both had a baseline evaluation and at least a post-line evaluation. basis of any effective primary or secondary variables, without restriction of agreement with the study protocol and procedures.
[00112] [00112] The safety population was the total treated population defined as all patients chosen at random (via the central randomization system according to the protocol) and exposed to at least one dose of | double-blind | P, regardless of the amount of treatment administered.
[00113] [00113] The primary efficacy variable (change in HbA; from baseline to week 24) was analyzed using a covariance analysis template (ANCOVA) with treatment groups (lixisenatide or placebo), layers of visit randomization 12 HbAje (<8.0, 8.0%), layers of randomization of the use of TZDs (yes, no), and country as fixed effects and baseline HbAlc value as a covariate. Difference between lixisenatide and placebo and 95% two-sided confidence interval as well as p-value were estimated within the ANCOVA framework.
[00114] [00114] The baseline for the primary efficacy variable was the last available value before the first double-blind PI injection (lixisenatide or placebo).
[00115] [00115] The LOCF procedure was used for taking the last HbA measurement; in the available post-baseline treatment (before the start of the new medication in the recovery therapy event) as the HbA value, at week 24.
[00116] [00116] The primary analysis of the primary efficacy variable was performed based on the mITT population and the measurements obtained during the treatment period for the efficacy variables. The treatment period for the efficacy variables was defined as the time of the first double-blind IP dose up to 14 days for HLbAI c; 1 day for FPG through the central laboratory; The day for reaction challenge parameters, 7-point SMPG, and insulin garglins; and 3 days for body weight and treatment satisfaction rating after the last double-blind IP dose or until the introduction of recovery therapy, whichever was the previous one.
[00117] [00117] Since the primary variable was statistically significant at = 0.05, the testing procedure was performed to test the following secondary efficacy variables in the following prioritized order. The tests stop as soon as an end point has not been found statistically significant at = 0.05.
[00118] [00118] No multiplicity adjustment was made on the other secondary efficacy variables, which are not mentioned above.
[00119] [00119] Baseline for secondary efficacy variables was the last available value before the first double-blind PI injection (lixisenatide or placebo) except for the insulin gargline dose (mean daily dose at baseline was the mean daily dose for the week before visit 12 which took place in week —1).
[00120] [00120] All continuous secondary efficacy variables at week 24 were analyzed using a similar ANCOVA model as described for the primary analysis of the primary efficacy endpoint. Treatment estimates mean the difference between lixisenatide and placebo and a 95% two-sided confidence interval was provided.
[00121] [00121] The following categorical secondary efficacy variables at week 24 were analyzed using a Cochran-
[00122] [00122] Number and percentage of patients with 5% weight loss from baseline at week 24 are reported by treatment groups.
[00123] [00123] Safety analyzes were mainly based on the treatment period. The treatment period for the safety analysis was defined as the time from the first double-blind IP dose to 3 days after the last double-blind IP dose, regardless of the introduction of rescue status. The 3-day interval was chosen based on half the double-blind PI (about 5 times the half-life).
[00124] [00124] The summary of safety results (descriptive statistics or frequency tables) is presented by treatment groups. 6 Results
[00125] [00125] A total of 1470 patients were screened from 140 centers in 25 countries (Argentina, Brazil, Canada, Chile, Taiwan, Colombia, Czech Republic, Denmark, Estonia, France, Germany, Hungary, India, Israel, Italy, Malaysia, Mexico, Netherlands, Poland, Romania, Russian Federation, South Africa, Sweden, Ukraine and United
[00126] [00126] A total of 446 patients were chosen at random from one of the two treatment groups. The main reason for run-in failure was the HbAlc value at visit 12 (Week -1) was outside the range defined by the protocol (304 [20.7%] out of 1470 screened patients). All 446 patients chosen at random were exposed to PI. No patient was excluded from the mITT population for analysis of efficacy. Table 1 provides the number of patients included in each analysis population. Table 1 Analysis populations - Population chosen at random Placebo Lixisenatide All (N = 223) (N = 223) (N = 446) Population chosen at random 223 (100%) 223 (100%) 446 (100%) Effective population Intention for treat modified (mITT) 223 (100%) 223 (100%) 446 (100%) Safety population 223 223 446 Note: Patients in the safety population are tabulated according to the treatment actually received (as treated).
[00127] [00127] Table 2 provides a summary of patient disposition for each treatment group.
[00128] [00128] During the 24-week study treatment period, 29 (13.0%) patients treated with lixisenatide prematurely discontinued IP, while 12 (5.4%) patients treated with placebo discontinued IP. For both treatment groups, the main reason for discontinuing treatment was "adverse event" (19 patients [8.5%] for lixisenatide and 9 patients [4.0%] for placebo). From observation, AE related to Gl was the main TEAEs that lead to discontinuation of PI for lixisenatide (10 patients [4.5%]) The second most common reason for discontinuing treatment was "other reasons" (8 patients [3.6% ] for lixisenatide versus 3 patients [1.3%] for placebo), most of the time being personal reasons but also including withdrawals from randomly selected patients not eligible by mistake (3 patients in lixisenatide group and 1 patient in the placebo group) . Three patients died during the study: two in the placebo group died of a TEAE and u in the lixisenatide group died of a non-TEAE during the post-treatment period.
[00129] [00129] The time to start treatment discontinuation due to any reason for the 24-week treatment period is shown in Figure 2. A higher rate of discontinuation was observed for the lixisenatide group. Table 2 Patient disposition - Population randomly chosen Placebo Lixisenatide (N = 223) (N = 223) Randomly chosen and treated 223 (100%) 223 (100%) Treatment of double blind study not completed 12 (5.4%) 29 (13.0%) individual's request for treatment discontinuation 8 (3.6%) 17 (7.6%) Reason for study treatment discontinuation 12 (5.4%) 29 (13.0%) Event adverse 9 (4.0%) 19 (8.5%) Lack of effectiveness oo Low adherence to protocol o 2 (0.9%) Lost to follow-up oo Other reasons 3 (1.3%) 8 (3.6 %) State not last contact in the study 223 (100%) 223 (100%)
[00130] [00130] Baseline patient and demographic characteristics were generally similar across treatment groups for the safety population (Table 3). The average age of the study population was 57.0 years. The majority of patients were Caucasian (74.4%). Table 3 Patient and demographic characteristics at screening or baseline - Safety population Placebo Lixisenatide All (N = 223) (N = 223) (N = 446) Age (years) Number 223 223 446 Mean (SD) 56.1 (10.2) 56.4 (9.7) 56.2 (9.9) Median 57.0 56.0 57.0 Min: Max 25:81 33:80 25:81 Age group (years) [ n (%)] Number 223 223 446 <50 56 (25.1%) 53 (23.8%) 109 (24.4%)> 50a <65 124 (55.6%) 123 (55.2%) 247 (55.4%)> 65a <75 38 (17.0%) 41 (18.4%) 79 (17.7%)> 75 5 (2.2%) 6 (2.7%) 11 ( 2.5%) Gender [n (%)] Number 223 223 446 Male 113 (50.7%) 109 (48.9%) 222 (49.8%) Female 110 (49.3%) 114 (51, 1%) 224 (50.2%) Race [n (%)] Number 223 223 446 Caucasian / White 167 (74.9%) 165 (74.0%) 332 (74.4%) Black 11 (4, 9%) 9 (4.0%) 20 (4.5%) Asian / Oriental 43 (19.3%) 44 (19.7%) 87 (19.5%) Other 2 (0.9%) 5 (2.2%) 7 (1.6%) Ethnicity [n (%)] Number 223 223 446 Hispanic 49 (22.0%) 52 (23.3%) 101 (22.6%) Non-Hispanic 174 ( 78.0%) 171 (76.7%) 345 (77.4%)
[00131] [00131] Disease characteristics including diabetic history were summarized in Tables 4, 5 and 6. The average duration of diabetes was slightly higher for the lixisenatide group (8.12 years) than that for the placebo group (7, 28 years). Chronic diabetic complications including neuropathy, retinopathy and diabetic nephropathy were generally compatible with small variations in the proportion of patients in each treatment group. Of observation, eleven patients (8 for lixisenatide and 3 for placebo) took GLP-1 receptor agonists before the study.
[00132] [00132] The mean daily dose of insulin gargline at baseline (V12, week-1) (see section 5.3) was 43.44 U for the lixisenatide group and 44.24 U for the placebo group. The mean dose remained almost unchanged at randomization (V13) (44.08 U for lixisenatide and 44.95 U for placebo) in both treatment groups.
[00133] [00133] The duration of use and the average daily dose of metformin were very similar between the two treatment groups; at baseline, the average dose was 2048.7 mg for the study population. Of each of the 72 patients who used TZDs at the screening visit, 54 patients continued the TZDs at baseline with an identical proportion of use in both treatment groups (12.1%, Table 7). The discrepancy in the number of patients between the "TZD use randomization layers" (Table 3) and the "actual baseline TZD use" was due to layers of randomization errors (Table 7). Three patients in the lixisenatide group did not use TZDs at randomization, but were chosen at random with stratification “TZ / D = No. Eight patients (6 on lixisenatide and 2 on placebo) used TZDs at randomization, but were chosen at random with 'TZD = stratification. At the".
[00134] [00134] The average IP treatment exposure (lixisenatide or placebo) was 155.8 days (22.3 weeks) for the lixisenatide group and 163.4 days (23.3 weeks) for the placebo group (Table 9 ). Of the 446 patients, 143 (64.1%) patients in the lixisenatide group and 151 (67.7%) patients in the placebo group received at least 169 days (24 weeks) of treatment.
[00135] [00135] For the lixisenatide group, 196 patients (87.9%) were at the target total daily dose of 201.1, g at the end of the 24-week double-blind treatment period (Table 10). For the placebo group, 215 patients (96.4%) were on the target total daily dose of pg at the end of the 24-week double-blind treatment period (Table 10). Table 9 Exposure - Safety population Placebo Lixisenatide (N = 223) (N = 223) Cumulative duration of treatment exposure (patient years) 99.8 95.1 Duration of study treatment (days) Number 223 223 Mean (SD) 163.4 (28.9) 155.8 (41.2) Median 169.0 169.0 Min: Max 9: 211 6: 197 Duration of study treatment by category [n (%)] Lost oo 1-14 days 1 (0.4%) 4 (1.8%) 15-28 days 4 (1.8%) 6 (2.7%) 29-56 days 3 (1.3%) 8 (3.6% ) 57-84 days 2 (0.9%) 4 (1.8%) 85-168 days 62 (27.8%) 58 (26.0%)> 168 days 151 (67.7%) 143 (64 , 1%) Cumulative duration of study treatment by category [n (%)] Lost oo> 1 day 223 (100%) 223 (100%)> 15 days 222 (99.6%) 219 (98.2%)> 29 days 218 (97.8%) 213 (95.5%)> 57 days 215 (96.4%) 205 (91.9%)> 85 days 213 (95.5%) 201 (90.1%) > 169 days 151 (67.7%) 143 (64.1%)
[00136] [00136] Table 11 summarizes the results of the primary efficacy parameters, change from baseline to week 24 (LOCF) in HbArc using ANCOVA analysis,
[00137] [00137] Insulin treatment garglina = during the 12-week run-in phase resulted in a notable reduction in the mean HbAlc value of 8.68% in each group (Table 34) to 7.56% in the lixisenatide group and 7.60% in the placebo group. The mean HbAlc value was further reduced in both treatment groups during the treatment phase chosen at random from 24 weeks to 6.96% in the lixisenatide group and 7.30% in the treatment group. placebo. The mean change from the minimum squares from the baseline randomization to week 24 in HbAlI c was -0.71% for the lixisenatide group and - 0.40% for the placebo group. The pre-specified primary analysis showed that this treatment with lixisenatide resulted in a statistically significant decrease in HbAje from baseline for week 24, compared to treatment with placebo (mean difference of LS versus placebo group = -0.32%; p value <0.0001 ), Observation, per protocol, insulin dose adjustment to keep fasting plasma glucose in the target was left in both treatment groups throughout the study. Table 11 Mean change in HbA1c (%) from baseline at Week 24 - mITT population Placebo Lixisenatide HbA1c (%) (N = 223) (N = 223) Baseline Number 221 215 Mean (SD) 7.60 (0.54) 7.56 (0.54) Median 7.40 7.50 Min: Max 6.7: 9.1 6.0: 9.1 Week 24 (LOCF) Number 221 215 Average (SD) 7 , 30 (0.85) 6.96 (0.81) Median 7.10 6.80 Min: Max 5.4: 11.2 5.4: 10.4 Change from baseline at Week 24 (LOCF) Number 221 215 Mean (SD) -0.30 (0.80) -0.60 (0.77) Median -0.40 -0.70 Min: Max -3.2: 2.8 -2.9: 24 Average LS (SE) -0.40 (0.092) -0.71 (0.091) Mean difference of LS (SE) vs.
[00138] [00138] Figures 3 and 4 illustrate the mean change (+ SE) from the baseline in HbA, c and the average values of HbA, c (+ SE) per visit during the 24-week double-blind treatment period.
[00139] [00139] As shown in Figure 3, both treatments reached a glycemic plateau from Week 8 through Week 16 and a slight increase in HbA1c was observed during the last phase of the treatment period compared to the end,
[00140] [00140] Table 12 summarizes the proportion of patients with treatment response in HbA ,, 6.5% or <7% at week 24, respectively, The analysis of HbA respondents; using the HCM method showed a significant treatment difference between the lixisenatide and placebo groups (p <0.0001 and p = 0.0001, respectively) in both HbAlc categories, at week 24, 32.1% of patients treated with lixisenatide and 16.3% of patients treated with placebo achieved HbA values of 6.5%; 56.3% of patients in the lixisenatide group and 38.5% of patients in the placebo group achieved HbA values, <7%.
[00141] [00141] Tables 13-16, and Table 18,19 and 21 summarize the ANCOVA analysis of glucose in the postprandial plasma for 2 hours, glucose excursion, 7-point mean SMPG, body weight, insulin gargline dose, classifications of FPG and DTSQs, respectively. Figures 5, 7-9 illustrate the mean change (+ SE) from baseline and mean 7-point SMPG, body weight, dose of insulin gargline and FPG over time during the 24-week double-blind treatment period .
[00142] [00142] Postprandial plasma glucose results 2 hours after a standard test meal showed a statistically significant improvement from baseline to week 24 in the lixisenatide group compared to the placebo group (difference mean LS versus placebo = -3.16 mmoles / L; p value <, 0001, Table 13). Furthermore, treatment with lixisenatide substantially decreases postprandial plasma glucose excursion from baseline to week 24 compared to placebo treatment (mean difference of LS = -3.09 mmoles / L, 95% CI = -3.842 to -2.331) (Table 14). Table 13 Mean change in glucose in 2-hour postmeal plasma (mmol / L) from baseline at week 24 - mITT population “postmeall plasma glucose! —- Placebo -. Lixisenatide = 2 hours (mmol / L) (N = 223) (N = 223) “Linhadebase
[00143] [00143] For a 7-point average ParaoSMPG, a statistically significant glucose reduction from baseline for week 24 was observed in the lixisenatide group compared to the placebo group (mean difference of LS versus placebo = -0.39 mmoles / L; p-value = 0.0071) (Table 15), Total glycemia measured by 7-point SMPG with both treatments was in line with the HbAlc trend during the course of the 24-week treatment period (Figure 4) . Table 15 Mean change in self-monitored glucose at 7 midpoint in plasma (SMPG) (mmol / L) from baseline at week 24 - mITT population “7-point self-monitored glucose. - Placebo Lixisenatide | mean in plasma (SMPG) (mmol / L) (N = 223) (N = 223) “Linhadebase Number 214 210 Mean (SD) 8.29 (1.52) 8.20 (1.45) Median 8.31 8.14 Min: Max 4.4: 13.3 5.3: 12.9 Week 24 (LOCF) Number 214 210
[00144] [00144] As I show in figure 6 which illustrates the 7-point SMPG for each time point in the baseline and end point, a profound reduction in the post-breakfast and a modest decrease in the post-lunch from the basis for week 24 were observed in the lixisenatide group compared to that in the placebo group; while, it appeared that the decrease in postprandial glucose decreased in the period after dinner and at bedtime.
[00145] [00145] The average body weight change from LS from baseline to week 24 was 0.28 kg for patients treated with lixisenatide and 1.16 kg for patients treated with placebo, a minor weight gain statistically significant in the lixisenatide group than in the placebo group was observed (mean difference of LS versus placebo = -0.89 kg, p-value = 0.0012) (Table 16), Slightly more patients treated with lixisenatide (5, 1%) than placebo-treated patients (3.2%) had a weight loss of 5% or more from baseline to week 24 (Table 17). Table 16 Average change in body weight (kg) from baseline at week 24 - mITT population Placebo Lixisenatide Body weight (kg) (N = 223) (N = 223) Baseline Number 220 217 Average (SD ) 86.74 (20.54) 87.47 (21.98) Median 85.10 84.40 Min: Max 45.6: 187.3 47.5: 169.4 Week 24 (LOCF) Number 220 217 Average (SD) 87.54 (20.74) 87.45 (22.25) Median 86.75 84.00 Min: Max 45.7: 183.2 49.0: 173.0 Baseline change in the week 24 (LOCF) Number 220 217 Mean (SD) 0.80 (2.85) -0.02 (2.76) Median 0.60 0.00 Min: Max -9.5: 12.8 -8.0 : 7.9 LS Mean (SE) * 1.16 (0.330) 0.28 (0.331) Mean difference of LS (SE) vs.
[00146] [00146] During the 24-week treatment period, the daily insulin dose in both groups increased gradually, which was allowed by the protocol to maintain FPGs between 100 and 80 mg / d (5.6 and 4.4 mmmoles / L ), However, patients in the lixisenatide group showed a less considerable increase in the daily insulin gargline dose (Figure 8) while achieving a greater reduction in HbAI c, the average change in insulin dose for the lixisenatide group at the end point ( Week 24) achieved a statistically significant difference compared to the placebo group (mean difference from LS versus placebo = -2.24 U; p value = 0.0300) (Table 18).
[00147] [00147] Patients in any treatment group showed a slight increase in FPG from baseline for week 24 (mean LS 0.384 mmoles / L for lixisenatide versus 0.46 mmoles / L for placebo) with no statistical difference significant difference observed between the lixisenatide and placebo groups (mean difference of LS versus placebo = -0.12 mmoles / L; p-value = 0.5142) (Table 19). Table 19 Average change in fasting plasma glucose (mmol / L) from baseline at week 24 - mITT population Fasting plasma glucose Placebo Lixisenatide (mmol / L) (N = 223) (N = 223) Line basic Number 220 214 Mean (SD) 6.69 (1.98) 6.56 (1.74) Median 6.30 6.33 Min: Max 3.4: 16.8 3.2: 12.7 Week 24 (LOCF) Number 220 214 Mean (SD) 6.86 (1.88) 6.70 (1.79) Median 6.44 6.38 Min: Max 3.3: 134 3.4: 16.9 Change baseline at week 24 (LOCF) Number 220 214 Mean (SD) 0.17 (2.41) 0.14 (2.30) Median 0.24 0.11 Min: Max -12.2: 6, 5 -7.8: 7.1 LS Mean (SE) * 0.46 (0.214) 0.34 (0.213) Mean difference of LS (SE) vs.
[00148] [00148] “As per adjustment of the testing strategy for interferential testing, multiplicity for the percentages of patients requiring recovery therapy at week 24 were exploratory as the previous test (FPG) failed to show statistically significant group difference. A total of 2 patients (1 [0.4%] each in the placebo group and the lixisenatide group) received recovery therapy (Table 20). Table 20 Number (%) of patients requiring recovery therapy during the 24-week treatment period - mITT population “Placebo teragja requirement. Lixisenatide recovery (N = 223) (N = 223) “Number 22 28 Yes 1 (0.4%) 1 (0.4%) No 222 (99.6%) 222 (99.6%) p value vs . placebo - 1.0000
[00149] [00149] A view of the adverse events observed during the treatment period is provided in Table 22. The proportion of patients with emergent adverse treatment events (TEAEs) was 79.8% for the lixisenatide group and 68.2% for the placebo group. The disproportionate number of patients with ASDs in the lixisenatide group was mainly driven by Gl related AEs (39.9% for lixisenatide versus 16.1% for placebo). Two patients (both on placebo) had TEAEs that lead to death. The percentage of patients who experienced serious TEAEs was higher in the lixisenatide group (7.6%) than in the placebo group (4.5%), with no increased occurrence observable in any Specific System Organ Classes (SOC ). The percentage of patients with TEAEs leading to treatment discontinuation was 8.5% in the lixisenatide group compared to 3.6% in the placebo group. The most common TEAEs that lead to treatment discontinuation were nausea and vomiting in the lixisenatide group (9 patients [4.0%]), while no patient in the placebo group discontinued treatment due to nausea or vomiting. Tables 23, 24, and 25 summarize TEAEs that lead to death, serious TEAEs, and TEAEsS that lead to discontinuation of treatment by primary SOC, Term of high level group of high level group (HLGT), high level term (HLT ) and preferred term (PT).
[00150] [00150] Table 35 The annex presents the incidences of TEAES that occur in at least 1% of patients in any treatment group during the treatment period. For both treatment groups, hypoglycemia was the most frequently reported TEAE (61 [27.4%] for lixisenatide and 43 [19.3%] for placebo). Beside hypoglycemia, the most common TEAE in the lixisenatide group was nausea (61 patients [27.4%] for lixisenatide versus 11 patients [4.9%] for placebo), followed by migraine (22 patients [9.9 %] for lixisenatide versus 8 [3.6%] for placebo) and vomiting (21 patients [9.4%] for lixisenatide versus 3 [1.3%] for placebo). Table 22 Adverse event profile view: emergent adverse event in treatments during the treatment period - Safety population o Plaebo - Lixisenatide | (N = 223) (N = 223) “Patients with any ASD == 152 (682%) 178 (798%) Patients with any serious ASD 10 (4.5%) 17 (7.6%) Patients with any ASD who leads 2 (0.9%) to death Patients with any TEAE that leads 8 (3.6%) 19 (8.5%) to discontinuation of permanent treatment
[00151] [00151] Hypoglycemia was further analyzed according to the protocol definition (see section 3.2,2). During the treatment period, 50 (22.4%) patients treated with lixisenatide reported 87 symptomatic hypoglycemic events and 30 (13.5%) patients treated with placebo reported 53 symptomatic hypoglycemic events (Table 26). The incidence rate for symptomatic hypoglycemia was 89.8 per 100 patient years for lixisenatide and 52.2 per 100 patient years for placebo. The incidence rate for symptomatic hypoglycemia confirmed by a BG <60 mg / dL was 79.5 per 100 patient years for lixisenatide and 44.3 per 100 patient years for placebo.
[00152] [00152] In addition, 24 patients (11 for lixisenatide and 13 for placebo), who reported hypoglycemic TEAEs (Table 35), were not included in Table 26 because of failure to complete the protocol definition; among them, 23 reported hypoglycemia with a blood glucose value above 60 mg / dl (3.3 mmoles / L) and one patient did not test blood glucose and spontaneously recovered without any carbohydrate treatment.
[00153] [00153] During the treatment period, one patient [lixisenatide (0.4%)] in the total safety population, reported 1 severe symptomatic hypoglycemic event per protocol definition (see section 3.2,2). This 71-year-old female patient had a severe TEAE of hypoglycemic unconsciousness (Tables 24 & 27). Five days after the first IP administration, around 13:30, while walking, she experienced loss of consciousness associated with sweating and numbness on the lips. She received help from people passing by, ate chocolate and then checked her blood sugar which was 134 mg / dL at 2:00 pm. His last meal before the event was the same day at 8:50. The investigator assessed the event as possibly related to | P and suggested that the late meal may be an alternative explanation for hypoglycemia, IP was permanently discontinued due to its event. Table 27 Summary of severe symptomatic hypoglycemia during the treatment period - Safety population TT Placebo Lixisenatide- Type (N = 223) (N = 223) Total patient age 101.6 96.9 Any severe symptomatic hypoglycemia Number of patients with events , n (%) o 1 (0.4%) Number of patients with events per 100 patient years o 1.0 Number of events o 1
[00154] [00154] Fifteen patients (6.7%) from the lixisenatide group and patients (2.2%) from the placebo group experienced a reaction at the AEs injection site during the treatment period (Table 28). The reaction at the AEs injection site were identified by searching for the term "injection site" in both the investigated reported AE PTs and coded PTs of the ARAC diagnosis. None of the reactions were of severe or serious intensity. Despite this, two patients in the lixisenatide group had a TEAE-related injection site that leads to | P discontinuation. Table 28 Number (%) of patients who experience reactions at the injection site during the treatment period - Safety population
[00155] [00155] During the treatment period, 25 events from 19 patients were reported as suspected allergic events by investigators and sent to ARAC for judgment, Of these, 4 events from 4 patients (3 [1.3%] patients treated with lixisenatide and 1 [0.4%] patients treated with placebo) were judged as allergic reactions by ARAC, and 3 of these events (two events from the lixisenatide group and one event from the placebo group) were judged as possibly related to IP (Table 29): «Patient 840212004 (lixisenatide): A 51-year-old female patient with an ongoing medical history of dyslipidemia, hypothyroidism and drug allergy, related to a mild urticaria TEAE on May 30, 2010
[00156] [00156] Per protocol, any increase in amylase and / or lipase above twice the upper limit of the normal range (ULN) that had been confirmed by a repeated measurement should be monitored and documented in a pre-specified form: "event form adverse for suspected pancreatitis ”, during the treatment period, 5 (2.2%) patients treated with lixisenatide and 10 (4.5%) patients treated with placebo reported 34 TEAEs in the form of pre-specified LA (Table 30) Of these, a moderate intensity "suspected pancreatitis" TEAE was reported in the placebo group. In addition, 4 patients (2 on placebo and 2 on lixisenatide) had an unconfirmed elevation of lipase reported as TEAEs in the form of regular AE (Table 35).
[00157] [00157] Patients who had at least a 3 ULN lipase or amylase value during the treatment period are summarized in Table 31. Thirteen patients (4 [1.8%] patients in the lixisenatide group and 9 [4.1 %] in the placebo group) with elevated lipase (2 3ULN) were observed. One patient in the placebo group had elevated amylase (> 3ULN), and none in the lixisenatide group. Table 30 Number (%) of patients with TEAE reported as a specific adverse event for suspected pancreatitis during the treatment period - Safety population Placebo - Lixisenatide Preferred term (N = 223) (N = 223) Any ºIYÚÇ AH 5 (22 %)
[00158] [00158] Per protocol, any calcination value> 20 pg / ml confirmed by a repeated measurement should be monitored and reported in the form of a pre-specific adverse event for "increased calcination> 20 pg / ml", during the treatment period , 2 patients on placebo, and the patient on lixisenatide, reported 2 TEAEs of increased blood calcitonin (Table 32). In addition, 2 calcitonin-increasing TEAEs, which were <20 pg / mL, were reported in the form of regular AE (Table 35) from 2 patients in the placebo group. Table 32 Number (%) of patients with TEAE reported in the form of an adverse event specific to increased calcitonin (> 20 ng / L) during the treatment period - Safety population To Placebo Lixisenatide | Preferred term (N = 223) (N = 223) “Qualguer AP oôiiiia Bog 0 Increased blood calcitonin 2 (0.9%) on (%) = number and percentage of patients with any cases reported in the form of AE for increased calcitonin > 20ng / L.
[00159] [00159] Patients with at least one serum calcitonin measured during the treatment period are summarized in Table 33 according to the 4 categories of baseline calcitonin level, In the patients in the lixisenatide group had calcitonin values ng / L during the treatment period (Table 33). Table 33 Calcitonin in blood - Number (%) of patients by pre-defined categories during the period of treatment according to the baseline category - Safety population Laboratory criteria Baseline status Placebo Lixisenatide Post-baseline ( N = 223) (N = 223) Calcitonin (ng / L) Total <ULN 198/215 (92.1%) 185/206 (89.8%)> ULN - <20 ng / L 15/215 (7, 0%) 21/206 (10.2%)> 20 ng / L - <50 ng / L 2/215 (0.9%) 0/206> = 50 ng / L 0/215 0/206 Lost <ULN 8/8 (100%) 4/4 (100%)> ULN - <20 ng / L o / 8 0/4> 20 ng / L - <50 ng / L o / 8 0/4> 50 ng / L o / 8 o / 4 <ULN <ULN 187/194 (96.4%) 178/188 (94.7%)> ULN - <20 ng / L 7/194 (3.6%) 10/188 (5 , 3%)> 20 ng / L - <50 ng / L 0/194 0/188> 50 ng / L 0/194 0/188
Laboratory criteria Baseline status Placebo Lixisenatide Post-baseline (N = 223) (N = 223)> ULN - <20 ng / L <ULN 3/12 (25.0%) 3/14 (21.4 %)> ULN - <20 ng / L 8/12 (66.7%) 11/14 (78.6%)> 20 ng / L - <50 ng / L 1/12 (8.3%) 0 / 14> 50 ng / L 0/12 0/14> 20 ng / L - <50 ng / L <ULN o / 1 0/0> ULN - <20 ng / L o / 1 0/0> 20 ng / L - <50 ng / L 1/1 (100%) 0/0> 50 ng / L o / 1 0/0> 50 ng / L <ULN 0/0 0/0> ULN - <20 ng / L 0 / 0 0/0> 20 ng / L - <50 ng / L 0/0 0/0> 50 ng / L 0/0 0/0 ULN = Upper limit of normal * Regardless of the baseline.
Observation: Period in treatment = time from the first dose of the study medication, double blind up to 3 days after the last dose administration.
The numerator represents the number of patients who were in the categories not specified in the post-baseline in each baseline category.
The denominator for each parameter within a treatment group is the number of patients for the treatment group who had that post-baseline assessed per parameter per baseline state.
A patient is counted only in the worst category.
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LOCF = Last observation taken forward.
Note: The analysis excluded measurements obtained after the introduction of the recovery medication and / or after the interruption of treatment plus 14 days.
Table 35 Number (%) of patients experiencing common TEAE (s) (PT 2 1% in any treatment group) presented by SOC, HLGT, HLT and primary PT during the treatment period - Safety population “ORGAN CLASS OF SYSTEM - Lixisenatide placebo PRIMARY (N = 223) (N = 223) HLGT: Term of the high-level group HLT: High-level term Preferred term “Any class A52 (68.2%) - 178 (79.8%) | INFECTIONS AND INFESTATIONS 59 (26.5%) 63 (28.3%) HLGT: infections - unspecified pathogen 43 (19.3%) 44 (19.7%) HLT: abdominal and gastrointestinal infections 7 (3.1% ) 5 (2.2%) Gastroenteritis 6 (2.7%) 5 (2.2%) HLT: Lung and lower respiratory tract infections 5 (2.2%) 2 (0.9%) Bronchitis 3 ( 1.3%) 1 (0.4%) HLT: Upper respiratory tract infections 27 (12.1%) 26 (11.7%) Nasopharyngitis 12 (5.4%) 11 (4.9%) Pharyngitis 3 (1.3%) o Sinusitis 5 (2.2%) 4 (1.8%) Infection of the upper respiratory tract 4 (1.8%) 11 (4.9%) HLT: Urinary tract infections 2 (0 , 9%) 10 (4.5%) Urinary tract infection 2 (0.9%) 6 (2.7%) HLGT: Disorders from viral infections 19 (8.5%) 16 (7.2%) HLT : Viral infections by herpes 4 (1.8%) 2 (0.9%) Herpes zoster 3 (1.3%) o HLT: Viral infections by Influenza 14 (6.3%) 11 (4.9%)
“SYSTEM ORGAN CLASS - PRIMARY Lixisenatide Placebo (N = 223) (N = 223) HLGT: High-level group term HLT: High-level term Preferred term“ lnfluenzga OS “! ÊES" i | 3á802 2 “A ( 93%) 11 (49% HLT: NEC viral infections 3 (1.3%) 3 (1.3%) Viral infection 3 (1.3%) 2 (0.9%)
BLOOD AND LYMPHATIC SYSTEM DISORDERS 2 (0.9%) 11 (4.9%) HLGT: Marrow depression and non-hemolytic anemias 1 (0.4%) 6 (2.7%) HLT: NEC 1 anemias (0 , 4%) 5 (2.2%) Anemia 1 (0.4%) 5 (2.2%)
METABOLISM AND NUTRITIONAL DISORDERS 51 (22.9%) 70 (31.4%) HLGT: General nutritional disorders and appetite 2 (0.9%) 4 (1.8%) HLT: Appetite disorders 2 (0.9% ) 4 (1.8%) decreased appetite 2 (0.9%) 4 (1.8%) HLGT: Glucose metabolism disorders (incl diabetes mellitus) 45 (20.2%) 61 (27.4%) HLT: Hypoglycemic conditions NEC 44 (19.7%) 61 (27.4%) Hypoglycemia 43 (19.3%) 61 (27.4%) PSYCHIATRIC DISORDERS 10 (4.5%) 5 (2.2%) HLGT: Anxiety disorders and symptoms 5 (2.2%) 3 (1.3%) HLT: Anxiety symptoms 5 (2.2%) 3 (1.3%) Anxiety 5 (2.2%) 2 ( 0.9%) NERVOUS SYSTEM DISORDERS 26 (11.7%) 46 (20.6%) HLGT: Enchaqueca 9 (4.0%) 24 (10.8%) HLT: NEC 8 (3.6%) ) 23 (10.3%) Enchaqueca 8 (3.6%) 22 (9.9%)
“SYSTEM ORGAN CLASS - PRIMARY Lixisenatide placebo (N = 223) (N = 223) HLGT: High-level group term HLT: High-level term Preferred term“ HLGT: Movement disorders qineg NM AAcoiiioiss A parkinsonismo) 4 ( 1.8%) 13 (5.8%) HLT: Tremor (congenital excl) 4 (1.8%) 13 (5.8%) Tremor 4 (1.8%) 13 (5.8%) HLGT: NEC neurological disorders 15 (6.7%) 20 (9.0%) HLT: NEC neurological symptoms and signs 7 (3.1%) 12 (5.4%) Dizziness 6 (2.7%) 12 (5, 4%) HLT: NEC sensory abnormalities 3 (1.3%) 5 (2.2%) Hypoesthesia 2 (0.9%) 4 (1.8%) EYE DISORDERS 8 (3.6%) 7 (3, 1%) HLGT: Eye infections, irritations and inflammations 4 (1.8%) 3 (1.3%) HLT: Infections, irritations and inflammations of conjunctiva 4 (1.8%) o Conjunctivitis 4 (1.8%) O
LABYRINTH AND EAR DISORDERS 3 (1.3%) 2 (0.9%) HLGT: Disorders of the eighth cranial nerve and inner ear 3 (1.3%) 2 (0.9%) HLT: Signs and symptoms of inner ear 3 (1.3%) 2 (0.9%) Vertigo 3 (1.3%) 2 (0.9%) VASCULAR DISORDERS 10 (4.5%) 11 (4.9%) HLGT: Disorders vascular hypertension 8 (3.6%) 6 (2.7%) HLT: Hypertensive disorders NEC 7 (3.1%) 6 (2.7%) Hypertension 6 (2.7%) 6 (2.7% ) RESPIRATORY, THORAXIC AND MEDIASTINE DISORDERS 11 (4.9%) 17 (7.6%)
“SYSTEM ORGAN CLASS - PRIMARY Lixisenatide Placebo (N = 223) (N = 223) HLGT: Term of the high-level group HLT: High-level term Preferred term
“HLGT: NEC respiratory disorders ———— 8 (36%) 11 (49% HLT: Associated symptoms and cough 8 (3.6%) 6 (2.7%) Cough 8 (3.6%) 5 (2 , 2%) GASTROINTESTINAL DISORDERS 36 (16.1%) 89 (39.9%) HLGT: Dental and gum conditions 6 (2.7%) 2 (0.9%) HLT: Toothache and sensation disorders 3 (1.3%) 1 (0.4%) Toothache 3 (1.3%) 1 (0.4%) HLGT: Gastrointestinal conditions NEC 4 (1.8%) 2 (0.9%) HLT: Secretion disorders and gastrointestinal mucosa dystrophies 3 (1.3%) 1 (0.4%) Hyperchlorhydria 3 (1.3%) 1 (0.4%) HLGT: Gastrointestinal inflammatory conditions 3 (1.3% ) 5 (2.2%) HLT: Gastritis (excluding infectious) 2 (0.9%) 4 (1.8%) Gastritis 2 (0.9%) 4 (1.8%) HLGT: Defecation conditions and gastrointestinal motility 10 (4.5%) 24 (10.8%) HLT: Diarrhea (excluding infectious) 7 (3.1%) 16 (7.2%) Diarrhea 7 (3.1%) 15 (6.7 %) HLT: Hypomotility and atonic gastrointestinal disorders NEC 3 (1.3%) 8 (3.6%) Constipation 3 (1.3%) 6 (2.7%) HLGT: Gastrointestinal signs and symptoms 17 (7, 6%) 76 (34.1%) HLT: Flatulence, swelling and dys tension 3 (1.3%) 6 (2.7%) Abdominal distention 2 (0.9%) 4 (1.8%) HLT: Gastrointestinal and abdominal pains (excl oral and throat) 3 (1.3%) 14 (6.3%) Abdominal pain 2 (0.9%) 7 (3.1%) Upper abdominal pain 1 (0.4%) 7 (3.1%) HLT: Nausea and vomiting symptoms 13 (5 , 8%) 67 (30.0%)
“SYSTEM ORGAN CLASS - PRIMARY Lixisenatide placebo (N = 223) (N = 223) HLGT: High-level group term HLT: High-level term Preferred term“ Nausea 0 1149% 61 (274% Vomit 3 (1, 3%) 21 (9.4%)
SUBCUTANEOUS TISSUE AND SKIN DISORDERS 10 (4.5%) 16 (7.2%) HLGT: Epidermal and dermal conditions 8 (3.6%) 6 (2.7%) HLT: NEC 3 rashes, rashes and exanthems ( 1.3%) 1 (0.4%) Rash 3 (1.3%) 1 (0.4%) HLGT: Appendix conditions on the skin 1 (0.4%) 9 (4.0%) HLT: Disorders of the apocrine and eccrine glands 1 (0.4%) 8 (3.6%) Hyperhidrosis 1 (0.4%) 7 (3.1%)
CONNECTIVE TISSUE AND SKELETAL MUSCLE DISORDERS 21 (9.4%) 28 (12.6%) HLGT: Joint disorders 9 (4.0%) 7 (3.1%) HLT: Signs and symptoms related to the joint 7 (3.1%) 5 (2.2%) Arthralgia 6 (2.7%) 5 (2.2%) HLGT: Muscle disorders 3 (1.3%) 7 (3.1%) HLT: Muscle pain 1 (0.4%) 7 (3.1%) Myalgia 1 (0.4%) 7 (3.1%) HLGT: Connective tissue and skeletal muscle disorders NEC 9 (4.0%) 14 (6 , 3%) HLT: Discomfort and pain from connective tissue and skeletal muscle 7 (3.1%) 14 (6.3%) Back pain 2 (0.9%) 6 (2.7%) Skeletal muscle pain 2 (0.9%) 3 (1.3%) Pain in the extremity 3 (1.3%) 6 (2.7%)
GENERAL DISORDERS AND CONDITIONS OF THE ADMINISTRATION SITE 24 (10.8%) 34 (15.2%)
“SYSTEM ORGAN CLASS - PRIMARY Lixisenatide Placebo (N = 223) (N = 223) HLGT: Term of the high-level group HLT: High-level term Preferred term
- HLGT: Reactions at the administration site ——— 5 (22%) - 14 (63%) HLT: Reactions at the injection site 4 (1.8%) 14 (6.3%) Hematoma at the injection site 2 (0.9%) 5 (2.2%) Reaction at the injection site o 3 (1.3%) Swelling at the injection site o 3 (1.3%) HLGT: Body temperature conditions 4 (1, 8%) 4 (1.8%) HLT: Febrile disorders 4 (1.8%) 4 (1.8%) Pyrexia 4 (1.8%) 4 (1.8%) HLGT: Disorders of the general NEC system 15 (6.7%) 19 (8.5%) HLT: Asthenic conditions 6 (2.7%) 14 (6.3%) Asthenia 3 (1.3%) 8 (3.6%) Fatigue 3 ( 1.3%) 4 (1.8%) HLT: NEC edema 4 (1.8%) 2 (0.9%) Peripheral edema 4 (1.8%) 1 (0.4%) INVESTIGATIONS 22 (9 , 9%) 18 (8.1%) HLGT: Endocrine investigations (incl sex hormones) 5 (2.2%) o HLT: Analyzes of gastrointestinal, pancreatic hormone and APUD 4 (1.8%) o Increased blood calcitonin 4 (1.8%) o HLGT: Gastrointestinal investigations 11 (4.9%) 7 (3.1%) HLT: Digestive enzymes 11 (4.9%) 7 (3.1%) Increased blood amylase 3 ( 1.3%) 1 (0.4%) Increased lipase 9 (4.0%) 6 (2.7%) HLGT: Metabolic, nude tritional and blood gas investigations 6 (2.7%) 3 (1.3%) HLT: Carbohydrate tolerance analyzes (incl diabetes) 5 (2.2%) 3 (1.3%) Reduced blood glucose 5 ( 2.2%) 3 (1.3%)
PRIMARY (N = 223) (N = 223) HLGT: High-level group term HLT: High-level term Preferred term PROCEDURE COMPLICATIONS, | úÚU | INJURY, AND POISONING 6 (2.7%) 11 (4.9%) HLGT: NEC lesions 5 (2.2%) 8 (3.6%) HLT: NEC 3 site-specific lesions (1.3% ) 5 (2.2%) Fall 1 (0.4%) 5 (2.2%) "TEAE: Emerging adverse event in treatment, SOC: System organ class, HLGT: High-level group term, HLT : High level term, PT: Preferred term.
MEedDRA version: 14.0. n (%) = number and percentage of patients with at least one TEAE.
Observation: Period in treatment = time from the first dose of the study medication, double blind up to 3 days after the last dose administration.
Table classified by internationally combined order SOC and HLGT, HLT, PT in alphabetical order.
Only SOC with at least one PT> 1% in at least one group are shown.

权利要求:
Claims (29)
[1]
1. Pharmaceutical combination for use in the treatment of a patient with type 2 diabetes, in which type 2 diabetes is insufficiently controlled by at least one oral antidiabetic drug, characterized by the fact that it comprises: (a) —desProººExendin- 4 (1-39) -Lyss-NH> or / and a pharmaceutically acceptable salt thereof, (b) insulin glargine or / and a pharmaceutically acceptable salt thereof, and (c) metformin or / and a pharmaceutically salt acceptable treatment, in which the treatment of a patient with type 2 diabetes comprises the steps of: (i) administration of compounds (b) and (c) for at least 4 weeks, and (ii) continuation of treatment by administration of compounds (a), (b) and (c), wherein the amount of compound (b) to be administered in step (s) (i) or / and (ii) is adjusted so that a predetermined fasting plasma glucose level or / and a predetermined self-monitored plasma glucose level is / are achieved or, at least, is / are approximate.
[2]
2. Pharmaceutical combination according to claim 1, characterized by the fact that step (i) comprises the administration of compounds (b) and (c) for at least 4 weeks, at least 8 weeks, at least 12 weeks , or at least 16 weeks.
[3]
3. Pharmaceutical combination according to claim 2, characterized by the fact that step (i) comprises administration for at least about 12 weeks.
[4]
4. Pharmaceutical combination according to claim
1 or 3, characterized by the fact that step (i) is carried out on the condition that compound (a) is not administered.
[5]
Pharmaceutical combination according to any one of claims 1 to 4, characterized by the fact that step (s) (i) or / and (ii) subsequently comprise the administration of a thiazolidinedione.
[6]
6. Pharmaceutical combination according to any one of claims 1 to 5, characterized by the fact that the administration in step (s) (i) or / and (ii) is / are performed in one daily basis.
[7]
Pharmaceutical combination according to any one of claims 1 to 6, characterized in that the amount of the compound (b) to be administered in step (s) (1) or / and (ii) is / are adjusted (s) based on daily measurements of plasma glycoside concentration.
[8]
Pharmaceutical combination according to any one of claims 1 to 7, characterized in that the amount of the compound (b) to be administered in step (s) (i) or / and (ii) is / are adjusted (s) so that a fasting plasma glucose level from about 4.4 mmoles / L to about 5.6 mmoles / L or / and a self-monitored plasma glucose level of about 8 mmol / L is / are achieved or at least is / are approximate.
[9]
Pharmaceutical combination according to any one of claims 1 to 8, characterized in that the treatment of a patient with type 2 diabetes improves glycemic control in a patient with type 2 diabetes.
[10]
10. Pharmaceutical combination according to claim 9, characterized by the fact that glycemic control is postprandial glycemic control.
[11]
11. Pharmaceutical combination according to claim 10, characterized by the fact that post-glycemic control
prandial is the control of glucose in the postprandial plasma or / and postprandial glucose excursion.
[12]
Pharmaceutical combination according to any one of claims 1 to 11, characterized in that the treatment of a patient with type 2 diabetes improves self-monitored plasma glucose.
[13]
Pharmaceutical combination according to any one of claims 1 to 12, characterized in that the treatment of a patient with type 2 diabetes induces weight loss or / and prevents weight gain.
[14]
Pharmaceutical combination according to any one of claims 1 to 13, characterized in that the treatment of a patient with type 2 diabetes prevents hypoglycemia.
[15]
Pharmaceutical combination according to any one of claims 1 to 14, characterized by the fact that the patient to be treated is obese.
[16]
16. Pharmaceutical combination according to any one of claims 1 to 15, characterized by the fact that the patient to be treated has a body mass index of at least 30 kg / m ”.
[17]
Pharmaceutical combination according to any one of claims 1 to 16, characterized in that the patient to be treated is an adult patient.
[18]
18. Pharmaceutical combination according to any one of claims 1 to 17, characterized by the fact that the patient to be treated does not receive an insulin or / and pharmaceutically acceptable salt treatment at the beginning of step (i).
[19]
19. Pharmaceutical combination according to any one of claims 1 to 18, characterized by the fact that the patient to be treated is diagnosed with type 2 diabetes mellitus for at least 1 year or at least 2 years before the start of therapy.
[20]
Pharmaceutical combination according to any one of claims 1 to 19, characterized in that the patient to be treated has an HbA value. from about 7 to about 10%.
[21]
21. Pharmaceutical combination according to any one of claims 1 to 20, characterized by the fact that, at the beginning of step (i), the patient has a fasting plasma glucose concentration of at least 8 mmol / L.
[22]
22. Pharmaceutical combination according to any one of claims 1 to 21, characterized by the fact that, at the beginning of step (i), the patient has a 2-hour postprandial plasma glucose concentration of at least 10 mmoles / L, at least 12 mm / L, or at least 14 mmoles / L.
[23]
23. Pharmaceutical combination according to any of claims 1 to 22, characterized by the fact that, at the beginning of step (i), the patient has a glucose excursion of at least 2 mmoles / L, at least 3 mmoles / L , at least 4 mmoles / L or at least 5 mmoles / L, where the glucose excursion is the difference in glucose concentration in the 2-hour postmeal plasma and 30-minute plasma glucose concentration before a meal test.
[24]
24. Pharmaceutical combination according to any one of claims 1 to 23, characterized in that the des- Pro ºExendin-4 (1-39) -Lyss-NH> or / and the pharmaceutically acceptable salt thereof is / are prepared (s) for parenteral administration.
[25]
25. Pharmaceutical combination according to any one of the claims | to 24, characterized by the fact that insulin glargine or / and the pharmaceutically acceptable salt thereof is / are prepared (s) for parenteral administration.
[26]
26. Pharmaceutical combination according to any one of claims 1 to 25, characterized by the fact that the
Pro ºExendin-4 (1-39) -Lyss-NH, or / and the pharmaceutically acceptable salt thereof is / are prepared for administration in a selected daily dose in the range of 10 µg to 20 µg.
[27]
27. Pharmaceutical combination according to any one of claims 1 to 26, characterized in that metformin or / and the pharmaceutically acceptable salt thereof is / are prepared for oral administration.
[28]
28. Use of a combination, characterized by the fact that it is for the preparation of a medicine for the treatment of a patient with type 2 diabetes, in which type 2 diabetes is insufficiently controlled by at least one oral antidiabetic drug, being that said combination comprises (a) —desProºExendin-4 (1-39) -Lyss-NH> or / and a pharmaceutically acceptable salt thereof, (b) insulin glargine or / and pharmaceutically acceptable salt thereof, and (c) metformin or / and a pharmaceutically acceptable salt thereof, where the combination treatment comprises the stages of: (1) administration of the compounds (b) and (c) for at least 4 weeks, and (ii) further treatment by administering compounds (a), (b) and (c), (iii) in which 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 / are reached or, at least, nos, is / are approximate.
[29]
29. Invention, characterized by any of its concretions
claims or categories of claim encompassed by the material initially disclosed in the present patent application or in the examples presented herein.
o 27 1/5 "8a>: 32% E, from |: to E AS E. 155 at o À 223 q; En. Xs / É yu." - |). ; ass S í “; EO Ê cs: | 12Ê | sa a! S SO '8 "* Be) P Telz e ao É 1E5 | 1º à | HR to ER" s / en EElm = io À: i ÉS É 8 2 É Í E. r 8 1 o 2 à + io i Í 4 . "S á F 3 SS: Â 2 1: 1 f | £ õ í EI o É is EE 'í $ à SN | 8 i + es fan 3 |. 4 É' el 4- oao | E | º He IS 'E:: í 8 Es + | S e.' 2 O. 1) 8: es 8 Sit, 'Ê 2 | E EE 3: Â 2 ES S | " 3: | | 2/3) Ss and ês': =. | o SP v so 8 & F o «e 5 o CN e | > if 3 to DB. o Ê É: 8 «- EZEE ENE é 8). 2 5853 2 1. wool Ss ES 1 Las | A a É 18 o | zo 2 'Í E 1 "É 1" & 2 S Ss i í Ss <: H "Ss a aziaa is 4: -: Sis | l + == 2 E. Es *" iõo' Fe do o 2 <| 'Hd oo 8 3 | Ê & <> id f 8 E Ss = i '> without ã & o 8: - é' ”f ê ll é & = UA fH: sds E" ú and SS - |: 8 ES eu. = If $$ et and 8 o 8 Ê +: nm 2 E ss $ 1
Y Y: the Y IS E <1 & 7 35%, D ES is 1 & 5 8 Ev «Pr E à 85 É | : a. 8 E $ 258 E 3 2 y es IS 3: 53283 E É E ET LS ê bio S / 8 s ET É "| & Ê SS uM: 1: Ss X EE É v2 s is EE 2 ss & of”: vo E + 8 Ê EE É 3: the 2 and the E NS - Are: ES so 2 4-7 and the 2 E = Ss E. io 7 ss 7 and gs E FM 8 and Ss 23 3 Hi SE 8 É "EN C z 2 í 8% Ss f 3 êz T.- 2 Egds É F * $ o: 3" o E & - | FE ST: 2 5
E 8
ZÉ - = «
Symbol = censor = Placebo = Lixisenatide ie Ss N = 3 E 15 = 8 m and q o Ev)
C E 10
AND
E So o o o— 6 io) 5 o hi
s
s
Ê 6 T r '0 30 60 90 120 150 180 210 240 Number at risk Days since the first double-blind IP Placebo 223 218 214 213 213 211 4 1 o Lixisenatida 223 213 205 201 196 195 12 oo 0o0jam 1 011 L wu ”L FT hi to 1 sj. Í = | It's sl. The 1 FE 1. = | 4 S os) L 3 = Í. "081 to L |.". | . . 051 Y + t | . | . t 091, r - À; - —— - r Baseline * and “user Treatment Week AdáPacehbo Memliiiconatida rs”. ro &. ”Nn wu '1 O” i À F: t Í so 3 1 É í $ E 7. ”Z T A. = Healthy uses pn i 2
And if = ”.” o “s Baseline - an o a s anocr Week Treatment AAA Placebo MEM Lixisenatide os. 00 jam | ; tt] | 4 is | | À | 4th | ": N Fr Ss. Bo a |: V) E NX | E '. 8 os -. 2: | os. -S Linhadebase = s s your Treatment Week
. * ““ “X:" "*. ih a. "To R .. o." X + and x 8; ; Huh . ss of, z la 3 2. IT'S . And s: & A o SG. x and 2 to ne dd lex ... “…. os: “. ss Pre-coffee - Post-coffee Pre-lunch Post-lunch Pre-post-dinner At bedtime tomorrow morning Treatment *** Placebo, Wee Lixsisenatida, XXX Placebo, OOO week Lixisenatide, baseline week baseline 24 (LOCF ) 24 (LOCF) 1º, í 4 u. O . The . * 6 Ss. Ê 4 sz a. &.
É É Ss o E úja t 'à =. . . . . "os. Il | à U Baseline Week Treatment AAA morning. BRR ivicanatida
. a à | s 4. a à + ”&, 2] F h D. '
And there are 4. IT'S . . : / ES ES, N À ”o and Linhadebase 6 2 + s at 2100 Week Treatment 44h Placebo MEM Lixisenatida os. or. * *
It's À: | | 7, A E f 1 1 FAITH | 6th | ”And hello F. 8 "o 7 2:. + A is * | -o." *.
L os Baseline at 5 6 to 2nocr Week Treatment AAA PDliacaohn - NENMlixisenatida

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法律状态:
2021-04-20| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2021-05-11| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2021-06-01| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-12-07| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

---

申请号 | 申请日 | 专利标题

---

EP11187169.5|2011-10-28|

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EP11187169|2011-10-28|

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PCT/EP2012/071271|WO2013060850A1|2011-10-28|2012-10-26|Treatment protocol of diabetes type 2|

---