TW201311271A - Pharmaceutical combination for use in glycemic control in diabetes type 2 patients - Google Patents

Abstract

The present invention refers to a pharmaceutical combination for use in glycemic control in diabetes type 2 patients.

Description

Pharmaceutical composition for blood sugar control in type 2 diabetic patients

The subject of the invention is a pharmaceutical composition for glycemic control in a type 2 diabetic patient, the composition comprising (a) desPro ³⁶ Exendin-4(1-39)-Lys ₆ -NH ₂ (AVE0010, lixisenatide) or/and its pharmaceutically acceptable salts, and (b) metformin or/and its pharmaceutically acceptable salts. Another aspect is a pharmaceutical composition for reducing a glycemic concentration in a type 2 diabetic patient, the composition comprising desPro ³⁶ Exendin-4 (1-39)-Lys ₆ -NH ₂ or/and A pharmaceutically acceptable salt thereof, and (b) metformin or/and a pharmaceutically acceptable salt thereof.

In a healthy person, the insulin released by the pancreas is precisely linked to the blood sugar concentration. An increase in blood glucose concentration (as occurs after a meal) is quickly offset by an individual increase in insulin secretion. In the fasted state, the plasma insulin concentration drops sufficiently to ensure continuous supply of glucose to insulin-sensitive organs and tissues, and maintains liver glucose at a low concentration base at night.

Type 2 diabetes is usually not insulin-deficient compared to type 1 diabetes, but in some cases (especially in progressive cases), insulin therapy is considered the most appropriate treatment, if necessary, with oral administration. Anti-diabetic combination.

The concentration of glucose in the blood increased within a few years but there were no initial symptoms, indicating a significant health risk. Large-scale DCCT in the USA The study (The Diabetes Control and Complications Trial Research Group (1993) N. Engl. J. Med. 329, 977-986) has clearly shown that a long-term increase in blood glucose concentration is a major cause of diabetic complications. Examples of diabetic complications are microvascular and macrovascular damage, which may themselves be manifested as retinopathy, nephropathy or neuropathy and result in blindness, renal failure and loss of limbs, with an increased risk of cardiovascular disease. It can therefore be inferred that the improved treatment of diabetes must first focus on maintaining blood glucose as close as possible to the physiological range.

It is particularly risky for overweight type 2 diabetic patients (especially those with a body mass index (BMI) ≧ 30). In these patients, the risk of diabetes partially overlaps with the risk of overweight, resulting in, for example, increased cardiovascular disease compared to normal weight type 2 diabetic patients. Therefore, it is particularly necessary to treat diabetes for these patients while reducing excessive weight.

Methotrexate is a biguanide hypoglycemic agent for the treatment of non-insulin dependent diabetes (type 2 diabetes) that does not respond to dietary changes. Methotrexate improves glycemic control by increasing insulin sensitivity and reducing intestinal absorption of glucose. Afufu is usually administered orally. However, it is not enough to control type 2 diabetes with metformin in obese patients. Therefore, other methods for controlling type 2 diabetes are needed for these patients.

Compound desPro ³⁶ Exendin-4 (1-39)-Lys ₆ -NH ₂ (AVE0010, lixisenatide) is a derivative of Exenatide-4. AVE0010 is disclosed in WO 01/04156 as SEQ ID NO: 93: SEQ ID NO: 1: AVE0010 (44 AS) HGEGTFTSDLSKQMEEEAVRL-FIEWLKNGGPSSGAPPSKKKK-KK-NH ₂

SEQ ID NO: 2: Exenatide-4 (39 AS) HGEGTFTSDLSKQMEEEAVRL-FIEWLKNGGPSSGAPPPS-NH ₂

Exenatide is a group of peptides that lower blood sugar levels. The Exenatide analog AVE0010 is characterized by a C-terminal truncation of the original Exenatide-4 sequence. AVE0010 contains six C-terminal lysine residues that are not found in Exenatide-4.

In the context of the present invention, AVE0010 comprises a pharmaceutically acceptable salt thereof. Those skilled in the art are aware of the pharmaceutically acceptable salts of AVE0010. A preferred pharmaceutically acceptable salt of AVE0010 for use in the present invention is acetate.

In Example 1 of the present invention, it has been confirmed that in type 2 diabetes patients, lixisenatide (AVE0010) with add-on therapy of metformin significantly improves glycemic control;

̇ lixisenatide (AVE0010) significantly reduced corrected plasma glucose AUC _{0:30-4:30 h} (h ^* mg/dL): -227.25 relative to baseline, compared to liraglutide -72.83.

利 After regular breakfast, lixiserad reduced the increase in plasma glucose to a greater extent than liraglutide.

̇ In the lixisenatide group, there was a substantial change in PPG fluctuations on day 28, which had a significant effect on the maximum PPG concentration (mg/dL): compared to -24.93 in the liraglutide group, Lisi The Lailai group was -70.43, with an estimated mean difference in treatment difference of -45.50 compared to liraglutide. This difference was statistically significant (p < 0.0001).

̇ After 4 weeks of treatment (Day 28), the number of patients with a plasma glucose concentration of less than 140 mg/dL after two hours of postprandial administration was higher in the lixisenatide group.

̇ About 24 hours of plasma glucose pattern on day 28 of lixisenatide and liraglutide treatment showed an overall decrease in plasma glucose compared to day -1, where the peak glucose concentration decreased during the feeding response .

̇ The mean HbA1C concentration was reduced in both treatment groups.

̇ In terms of plasma glycemic concentration, the decrease in AUC was more pronounced in the lixisenatide group than in the liraglutide group.

Example 2 of the present invention relates to glycemic control in type 2 diabetic patients in Asian countries (China, Malaysia, Thailand, and Hong Kong). These patients were not adequately controlled when using metformin alone. It has been found that in these Asian or/or Eastern ethnic groups, at week 24 of the study, compared to placebo (methampamine alone), it was possible to achieve significant exposure with metformin by combining lixisenatide. Improve blood sugar control:

The efficacy of lixiserazide versus placebo was confirmed by a significant reduction (-0.83%) in HbA _1c in the lixisenatide group compared to the placebo group (-0.47%). The LS mean difference was -0.36% relative to placebo (Table 10 in Example 2). Table 28 demonstrates a similar utility in a subgroup of Chinese patients.

Analysis of the HbA _1c responder confirmed a statistically significant difference in treatment between the lixisenatide group and the placebo group. 32.4% of patients in the Lixila group reached HbA _1c 6.5%, and only 18.1% of the placebo group reached this value. In the lixisenatide group, 53% of patients achieved HbA _1c <7%, compared with 38.8% in the placebo group (Table 11 of Example 2).

̇ About 2 hours postprandial plasma glucose (PPG) after regular diet, the lixisenatide group showed statistically significant improvement over the placebo group, with a LS mean difference of -4.28 mmol/L (Examples) Table 12 of 2). Glucose fluctuation analysis showed that the LS mean difference of the lixisenatide group was -3.99 mmol/L compared to placebo (Table 17 of Example 2).

组 The difference in fasting plasma glucose (FPG) between the lixisenatide groups was also statistically significant compared to placebo, with a LS mean difference of -0.48 mmol/L (Table 13 of Example 2). .

The overall safety of the compositions of lixiseradine and metformin is also satisfactory in Asian/eastern patients.

A first aspect of the invention is a pharmaceutical composition for glycemic control in a type 2 diabetic patient, the composition comprising: (a) desPro ³⁶ Exenatide-4(1-39)-Lys ₆ -NH ₂ or / and its pharmaceutically acceptable salts, and (b) metformin or / and its pharmaceutically acceptable salts.

As demonstrated by embodiments of the invention, the compositions described herein can be used to improve glycemic control. In the present invention, "improving blood sugar control" or "blood sugar control" specifically means improving postprandial plasma glucose concentration, improving fasting plasma glucose concentration, or/and improving HbA _1c value.

A second aspect of the invention is a pharmaceutical composition for reducing plasma glucagon concentration in a type 2 diabetic patient, the composition comprising: (a) desPro ³⁶ Exenatide-4 (1-39)- Lys ₆ -NH ₂ or/and its pharmaceutically acceptable salts, and (b) metformin or/and its pharmaceutically acceptable salts.

As demonstrated by Example 1 of the present invention, the compositions described herein can be used to reduce plasma glycosidin concentrations.

Methotrex is an international generic drug name (CAS number 657-24-9) for 1,1-dimethylbiguanide. In the present invention, the term "metafoam" includes any pharmaceutically acceptable salt thereof.

In the present invention, metformin can be administered orally. The skilled artisan is aware of a metformin formulation suitable for the treatment of type 2 diabetes by oral administration. Meflurane can be administered to an individual in need in an amount sufficient to elicit therapeutic utility. Methotrex can be administered at a dose of at least 1.0 g/day or at least 1.5 g/day. For oral administration, metformin can be formulated into a solid dosage form such as a lozenge or a pill. The metformin can be formulated with a suitable pharmaceutically acceptable carrier, adjuvant or/and auxiliary substance.

In the present invention, desPro ³⁶ Exendin-4 (1-39)-Lys ₆ -NH ₂ or/and a pharmaceutically acceptable salt can be administered in the form of an addative therapy for the administration of metformin.

In the present invention, the terms "addition", "addition therapy" and "addition therapy" are related to the treatment of type 2 diabetes with metformin and AVE0010. Affluent and AVE0010 can be administered at intervals of 24 hours. Both metformin and AVE0010 can be administered in a once-a-day dose. Methotrex and AVE0010 can be administered via different routes of administration. Affluent can be administered orally, while AVE0010 can be administered parenterally.

The composition of the present invention may further comprise a sulfonyl urea. In the composition, the sulfonyl urea can be administered orally. Those skilled in the art are aware of suitable formulations of sulfhydryl urea. As described herein, the sulfonyl urea can be administered in the form of an added treatment of a composition of desPro ³⁶ Exendin-4 (1-39)-Lys ₆ -NH ₂ and metformin.

The sulfonyl urea can be selected from the group consisting of Glibenclamide, Glibenclamide MR, Gliclazide, Gliclazide LM, Glimepridie, Glipizide , glipizide XL, Gliquidone and Tolbutamide. In a particular embodiment, any of the specific sulfonyl ureas disclosed herein can be combined with desPro ³⁶ exenatide-4(1-39)-Lys ₆ -NH ₂ and metformin as described herein. A combination of specific aspects.

The preferred dose of glibenclamide is ≦10 mg/day, 10-20 mg/day, or 20 mg / day.

The preferred dose of glibenclamide MR is 6 mg/day, 6-12 mg/day, or 12 mg / day.

The preferred dose of gliclazide is 160 mg/day, 160-320 mg/day, or 320 mg / day.

The preferred dose of gliclazide LM is 60 mg/day, 60-120 mg/day, or 120 mg / day.

The preferred dose of glimepiride is 4 mg/day, 4-8 mg/day, or 8 mg / day.

The preferred dose of glipizide is 20 mg/day, 20-40 mg/day, or 40 mg / day.

The preferred dose of glipizide XL is 10 mg/day, 10-20 mg/day, or 20 mg / day.

The preferred dose of gliclazone is 60 mg/day, 60-90 mg/day, or 90 mg / day.

The preferred dose of tolbutamide is 1500 mg / day, or 1500 mg / day.

The individual to be treated by the composition of the invention may be an individual of Asian or/and Oriental ethnicity. In Example 2 of the present invention, it has been found that in Asian or/and Oriental ethnic groups, a significant improvement can be achieved by the combination of lixisenatide and metformin compared to placebo (methampamine alone). Blood sugar control.

The individual to be treated by the agent or composition of the invention may be an individual having type 2 diabetes. Example of implementation In these patients, AVE0010 in combination with metformin provides a favorable therapy.

The individual having type 2 diabetes treated by the agent or composition of the invention may be an individual having type 2 diabetes, wherein type 2 diabetes is not adequately controlled using metformin alone, for example at least 1.0 g/ The dose of Nippon Fuming or at least 1.5 g/day of metformin persists 3 months. In the present invention, an individual whose type 2 diabetes is not sufficiently controlled may have a HbA1c value ranging from 7% to 10%.

The individual having type 2 diabetes treated by the agent or composition of the invention may be an obese individual. In the present invention, an obese individual has a body mass index of at least 30 kg/m ² .

An individual having type 2 diabetes treated by an agent or composition of the invention may have a normal body weight. In the present invention, an individual having a normal body weight has a body mass index ranging from 17 kg/m ² to 25 kg/m ² , or 17 kg/m ² to <30 kg/m ² .

The individual to be treated by the agent or composition of the invention may be an adult individual. The individual can have any age of at least 18 years of age and can have an age range of 18 to 80 years, 18 to 50 years, or 40 to 80 years, or 50 to 60 years. The individual may be younger than 50 years old.

Preferably, the individual to be treated by the agent or composition of the invention preferably does not receive an anti-diabetic treatment, such as insulin or/and related compounds.

The individual to be treated by the agent or composition of the invention may have type 2 diabetes for at least 1 year or at least 2 years. In particular, in an individual to be treated, Type 2 diabetes has been diagnosed for at least 1 year or at least 2 years prior to initiation of therapy of the agent or composition of the invention.

The individual to be treated can have an HbA _1c value of at least about 8% or at least about 7.5%. The individual may also have a HbA _1c value of from about 7 to about 10%. The practice of the present invention demonstrates that treatment with AVE0010 results in a decrease in HbA _1c values in type 2 diabetic patients.

In yet another aspect of the invention, a composition as described herein can be used to improve HbA _1c values in patients with type 2 diabetes. Improving the HbA _1c value means, for example, that the HbA _1c value falls below 6.5% or 7% after treatment for at least 1 month, at least 2 months, or at least 3 months.

In another aspect of the invention, a composition as described herein can be used to improve glucose tolerance in a patient with type 2 diabetes. Improving glucose tolerance indicates that the postprandial plasma glucose concentration is reduced by the active agent of the invention. The decrease specifically means that the plasma glucose concentration reaches or is at least close to the normal blood glucose level.

In the present invention, the normal blood glucose level is specifically a blood glucose concentration of 60-140 mg/dl (corresponding to 3.3 to 7.8 mM/L). This range specifically means the blood glucose concentration in the fasted state and the postprandial state.

The individual to be treated may have a plasma glucose concentration of at least 10 mmol/L, at least 12 mmol/L or at least 14 mmol/L at 2 hours postprandial. These plasma glucose concentrations exceed normal blood glucose concentrations.

The individual to be treated has a glucose fluctuation of at least 2 mmol/L, at least 3 mmol/L, at least 4 mmol/L or at least 5 mmol/L. In the present invention, the glucose fluctuation is specifically the difference between the plasma glucose concentration at 2 hours after a meal and the plasma glucose concentration 30 minutes before the dietary test.

"Post-meal" is a term known to those skilled in the art of diabetes. The term "post-meal" specifically describes the period of time after the diet or/and exposure to glucose under experimental conditions. In a healthy human body, this period is characterized by an increase in blood glucose concentration and a gradual decrease. The term "post-meal" or "post-meal" usually lasts up to 2 after eating or/and exposure to glucose. The end of the hour.

The individual to be treated as described herein can have a fasting plasma glucose concentration of at least 8 mmol/L, at least 8.5 mmol/L, or at least 9 mmol/L. These plasma glucose concentrations exceed normal blood glucose concentrations.

In another aspect of the invention, a composition as described herein can be used to ameliorate (i.e., reduce) fasted plasma glucose in a type 2 diabetic patient. The decrease specifically means that the plasma glucose concentration reaches or is at least close to the normal blood glucose level.

The compositions of the present invention are useful for treating one or more medical indications described herein, such as treating a type 2 diabetic patient, or a condition associated with type 2 diabetes, such as improving glycemic control, reducing fasting plasma glucose concentration, Improve glucose fluctuations, reduce postprandial plasma glucose concentration, improve glucose tolerance, improve HbA1 _c value, decrease plasma glycemic concentration, reduce weight or/and prevent weight gain.

In the present invention, desPro ³⁶ Exenatide-4(1-39)-Lys ₆ -NH ₂ or/and a pharmaceutically acceptable salt thereof can be administered to an individual in need in an amount sufficient to cause therapeutic effects.

In the present invention, desPro ³⁶ Exendin-4 (1-39)-Lys ₆ -NH ₂ or/and a pharmaceutically acceptable salt thereof may be combined with a suitable pharmaceutically acceptable carrier, adjuvant or/and The auxiliary substances are blended together.

The compound desPro ³⁶ exenatide-4(1-39)-Lys ₆ -NH ₂ or/and its pharmaceutically acceptable salt can be administered orally, for example by injection (such as by intramuscular or by means of intramuscular or by injection) Subcutaneous injection). Suitable injection devices, such as "pens" containing drug sputum (with active ingredients) and injection needles are known. Compound desPro ³⁶ Exenatide-4(1-39)-Lys ₆ -NH ₂ or/and its pharmaceutically acceptable salt can be administered in an appropriate amount, for example, 10 to 15 μg per dose or 15 to dose per dose. The number in the range of 20 μg.

In the present invention, desPro ³⁶ Exenatide-4(1-39)-Lys ₆ -NH ₂ or/and its pharmaceutically acceptable salt may be in the range of 10 to 20 μg, 10 to 15 μg or A daily dose in the range of 15 to 20 μg is administered. desPro ³⁶ Exenatide-4(1-39)-Lys ₆ -NH ₂ or/and its pharmaceutically acceptable salt can be administered once daily for administration.

In the present invention, desPro ³⁶ Exendin-4 (1-39)-Lys ₆ -NH ₂ or/and a pharmaceutically acceptable salt thereof can be provided in a liquid composition. Those skilled in the art are aware of AVE0010 liquid compositions suitable for parenteral administration. The liquid compositions of the invention may have an acidic or physiological pH. The acidic pH is preferably in the range of pH 1-6.8, pH 3.5-6.8 or pH 3.5-5. The physiological pH is preferably in the range of pH 2.5-8.5, pH 4.0-8.5 or pH 6.0-8.5. The pH can be adjusted by a pharmaceutically acceptable dilute acid (usually HCl) or a pharmaceutically acceptable dilute base (usually NaOH).

Liquid compositions comprising desPro ³⁶ Exendin-4 (1-39)-Lys ₆ -NH ₂ or/and pharmaceutically acceptable salts thereof may contain suitable preservatives. Suitable preservatives may be selected from the group consisting of phenol, m-cresol, benzyl alcohol and p-hydroxybenzoate. A preferred preservative is m-cresol.

A liquid composition comprising desPro ³⁶ Exenatide-4(1-39)-Lys ₆ -NH ₂ or/and a pharmaceutically acceptable salt thereof may contain a tonicity agent. Suitable permeability agent selected from glycerol, lactose, sorbitol, mannitol, glucose, NaCl, calcium or magnesium compounds (such as CaCl _2). The concentration of glycerol lactose, sorbitol, mannitol and glucose is in the range of 100-250 mM. The NaCl concentration is at most 150 mM. A preferred osmotic agent is glycerin.

A liquid composition comprising desPro ³⁶ Exenatide-4(1-39)-Lys ₆ -NH ₂ or/and a pharmaceutically acceptable salt thereof may contain from 0.5 μg/mL to 20 μg/mL of methionine It is preferably from 1 μg/mL to 5 μg/mL. Preferably, the liquid composition contains L-methionine.

Another aspect of the invention is a method for improving glycemic control in a type 2 diabetic patient, the method comprising: desPro ³⁶ Exendin-4 (1-39)-Lys ₆ -NH ₂ or/medicine thereof The acceptable salt combination, metformin, is administered to individuals in need. In particular, a composition as described herein can be administered. In the methods of the invention, the individual can be an individual as defined herein.

Another aspect of the invention is a method of lowering plasma glycosidin concentration in a type 2 diabetic patient, the method comprising: desPro ³⁶ Exendin-4 (1-39)-Lys ₆ -NH ₂ or / And its pharmaceutically acceptable salt combination, metformin, is administered to individuals in need. In particular, a composition as described herein can be administered. In the methods of the invention, the individual can be an individual as defined herein.

In another aspect of the invention is meant the use of a composition as described herein for the manufacture of a medicament for the treatment of a medical indication as described herein. For example, the compositions of the present invention can be used in the manufacture of a medicament for treating a type 2 diabetic patient, or for treating a condition associated with type 2 diabetes, such as improving glycemic control, reducing fasting plasma glucose concentration, improving glucose fluctuations, and reducing meals. Post plasma glucose concentration, improved HbA _1c value or / and improved glucose tolerance. The compositions of the invention may also be used in the manufacture of a medicament for lowering the concentration of plasma glycosidin in a type 2 diabetic patient. The agent can be formulated as described herein. For example, the agent may contain a parenteral formulation of AVE0010 or/and its pharmaceutically acceptable salts, and an oral formulation of metformin or/and a pharmaceutically acceptable salt thereof. The agent may further comprise a sulfonyl urea as described herein. In particular, the formulation of the sulfonyl urea is an oral formulation.

The invention will be further illustrated by the following examples and figures.

Example 1

Example 2 Summary

This example describes a randomized, double-blind, placebo-controlled, dual-arm parallel-group equilibrium study, multi-country study, type 2 that is not adequately controlled by metformin with or without sulfonylurea Patients with diabetes mellitus (T2DM) were treated with lixisenatide and placebo. The study was conducted in 37 centers in 4 countries or regions (China, Malaysia, Thailand and Hong Kong). The primary objective of this study was to evaluate the efficacy of lixisenatide as an added treatment for metformin versus placebo for glycemic control with or without sulfonylurea, for type 2 diabetes (T2DM) patients at 24 For the week, the HbA _1c is lowered.

A total of 391 patients were randomized to one of two treatment groups (196 in the lixisenatide group and 195 in the placebo group). In the placebo group, one randomized group was not exposed to study treatment for personal reasons. In total, 390 patients were exposed to double-blind treatment. Demographics and patient baseline characteristics were generally similar between treatment groups. Of the 390 patients, 363 (93.1%) completed 24-week double-blind treatment (179 patients (91.3%) in the lixisenatide group and 184 patients (94.8%) in the placebo group). Two patients (1 in each group (0.5%)) were excluded from the efficacy analysis of the modified intention-to-treat (mITT) population because of lack of post-baseline efficacy data.

Regarding the primary assessment of HbA _1c , the efficacy of lixisenatide versus placebo was based on a pre-specified primary analysis of the mean change in HbA _1c from baseline to Week 24 (LS) (in Lisila The group and the placebo group were -0.83% and -0.47%, respectively; the LS mean difference was compared with placebo = -0.36%; the 95% confidence interval (CI): -0.551, -0.162; p-value was 0.0004).

Analysis of HbA _1c responders using the Cochran-Mantel Haenszel (CMH) method (eg with HbA _1c at week 24) 6.5 or <7% of patients also showed statistically significant treatment differences between the lixisenatide group and the placebo group (in the case of HbA _1c) 6.5%, 32.4% in the lixisenatide group, 18.1% in the placebo group, p-value = 0.001; HbA _1c < 7%, 53% in the lixisenatide group versus placebo 38.8% in the group, p-value = 0.003).

Regarding plasma glucose (PPG) 2 hours postprandial after regular diet, the lixisenatide group showed statistically superior improvement over the placebo group, with a LS mean difference of 4.28 mmol/L (p-value) <0.0001). Glucose fluctuation analysis showed similar results. In fasting plasma glucose (FPG), the difference between the lixisenatide group and the placebo group was also statistically significant, with a mean LS difference of 0.48 mmol/L (p-value = 0.0109). With regard to body weight, a similar reduction of up to 1.5 kg was observed in the treatment group and no statistically significant difference was observed (LS mean difference lixisenatide versus placebo = 0.27 kg; p-value = 0.2960). The percentage of patients requiring rescue therapy was 3.6% for the lixisenatide group and 6.7% for the placebo group.

In the group treated with lixisenatide, the incidence of treatment for adverse events (TEAE) was higher than that of the placebo-treated group (64.3% and 47.4%, respectively). No patient has SAE in the treatment of death. The number of patients with critical TEAE was similar in the treatment group (3 (1.5%) and 4 (2.1%) in the lixisenatide and placebo groups, respectively). In the lixisenatide group, patients who discontinued treatment mainly because of TEAE (gastrointestinal systemic organ (SOC)) were more likely to receive treatment than the placebo group (3 patients) (1.5%)) more (11 patients (5.6%)). In the lixisenatide group, the most frequently reported TEAE is nausea, consistent with the known safety profile of the glyphosate peptide-1 (GLP-1) receptor agonist. A higher percentage of patients in the lixisenatide-treated group had nausea compared with the placebo-treated group (32 patients (16.3%) and 5 patients (2.6%), respectively). These events occur more often at the beginning of the study. In the Leishila group, the second frequently reported TEAE was hypoglycemia (18 (9.2%) lixisenatide vs. 9 (4.6%) placebo). A total of 16 patients (4.1%) had symptomatic hypoglycemia events as defined in the regulations. There were 11 patients (5.6%) in the lixisenatide group and 5 patients (2.6%) in the placebo group. The incidence of symptomatic hypoglycemia with blood glucose <60 mg/dL was identical in both treatment groups (3 patients (1.5%) in each group). The absence of a symptomatic hypoglycemia event is critical or severe. Compared with the placebo group, a higher percentage of patients in the lixisenatide group had dizziness and vomiting (for dizziness, 17 patients (8.7%) and 8 patients (4.1%) Regarding vomiting, there were 15 patients (7.7%) and 2 patients (1.0%). According to the Allergic Response Assessment Committee (ARAC), a total of 3 patients (2 (10%) and 1 placebo (0.5%) were allergic reactions, including 2 from the lixisenatide group. Two events (anaphylactic shock and injection site reactions) were thought to be related to the study product (IP). No patients suspected of having pancreatitis or increased calcitonin were reported in the treatment group.

In summary, the results of the study confirmed that the use of lixisenatide for glycemic control was superior to placebo, as HbA _1c , 2-hour PPG, and FPG decreased from baseline to week 24, and HbA _1c response at week 24 The ratio is confirmed. During the 24-week treatment period, lixisenatide was well tolerated. The incidence of critical TEAE was similar in the lixisenatide versus placebo groups. A higher percentage of patients treated with lixisenatide experienced symptomatic hypoglycemia compared to the placebo group. However, the incidence of symptomatic hypoglycemia with blood glucose <60 mg/dL was identical in both treatment groups. Nausea, dizziness, and vomiting are more often reported in lixisenatide than placebo. No specific safety considerations were observed during the trial. Overall, T2DM patients who were not adequately controlled by metformin had good and effective tolerance to lixisenatide versus placebo therapy with or without sulfonylurea.

1 goal 1.1 main objectives

The primary objective of this study was to evaluate the efficacy of lixisenatide as an add-on treatment for metformin versus blood glucose control in the presence or absence of sulfonylurea, and to reduce HbA in T2DM patients over a 24-week period. ^1c .

1.2 secondary goals

The secondary objectives of the present invention are:

̇ Evaluate the following effects of lixisenatide for the following 24 weeks: - Percentage of patients achieving HbA _1c <7% or HbA _1c ≦ 6.5%, -FPG, - 2 hours PPG and glucose fluctuations during routine dietary testing (about 50% of all randomized patients), - weight

̇ Assessing the safety and tolerability of Lisila

̇ Assess lixisenatide pharmacokinetics (PK) and anti-lixilalate

Physical development 2 test design

The study was a double-blind, randomized, placebo-controlled, two-arm parallel group balance study (1:1 ratio) with a multinational study of 190 patients in each arm. This study was double-blind in the treatment of active agents and placebo. The amount of study drug (ie, the dose of the active drug or matching placebo during the drip period and the maintenance period) was not blinded.

Patients were stratified by screening according to HbA _1c (<8%, ≧8%) and using sulfonyl urea (with, without). The number of patients in each sulfonyl urea layer (with sulfonyl urea, no sulfhydryl urea) was considered to be balanced.

The study consisted of three periods: 1) up to 3 weeks of screening, including up to 2 weeks of initial screening and 1 week of single-blind placebo preparation; 2) 24 weeks of double-blind, placebo-controlled treatment; 3) 3 days The safety tracking period is for all patients after the IP is permanently discontinued (except for patients who discontinue the study treatment early).

A one-step dose response regimen was used in the trial. During the double-blind period, the initial dose per injection for 1 hour (eg, from 0 to 60 minutes) before breakfast is 10 μg of lixisenatide or volume-matched placebo, once a day (QD). After 2 weeks, the dose was increased to 20 μg per dose, provided that all patients were safe from the 5th visit (week 2) to the entire study. The tolerated uncontrolled dose was increased to a target therapeutic concentration or volume-matched placebo up to 20 μg/injection.

Regarding background therapy, the metformin dose was stably maintained at its baseline dose (at least 1.0 g/day) and not exceeding 1.5 g/day throughout the study period. In patients given sulforamidazole on metformin, the dose of sulfocylurea was reduced by 25% to 50% at randomization, so that the risk of hypoglycemia was reduced in patients with HbA _1c <8% at screening. In patients with HbA _1c ≧ 8% at screening, the dose of sulfocyl urea was stabilized at a baseline dose of at least the maximum effective dose (ie, half of the maximum recommended dose according to local label).

Patients who discontinued the study treatment in advance continued the study until the end of the study. They were followed according to the research procedure specified in the regulations (except for 3-day safety treatment follow-up, diet testing and PK assessment).

The duration of study for each patient was 27 weeks ± 10 days (up to 2 weeks screening + 1 week preparation + 24 weeks double-blind treatment + 3 days follow-up). See Figure 7 for details.

3 main and key secondary assessment indicators 3.1 Main evaluation indicators

The primary efficacy variable is the absolute change in HbA _1c from baseline to Week 24, defined as: HbA _1c value at week 24 - HbA _1c value at baseline.

If the patient is permanently discontinued or receives rescue therapy during the 24-week double-blind treatment period or does not have HbA _1c at week 24, the last baseline post hazard treatment period during the 24-week double-blind treatment period is used as the HbA _1c measurement. The HbA _1c value at week 24, or the last value obtained before the rescue in the case of rescue (Last Observation Carry Forward (LOCF) program).

3.2 Secondary assessment indicators 3.2.1 Effectiveness evaluation indicators

Regarding the secondary efficacy variable, as with the primary efficacy variable, the same procedure for dealing with missing assessment values/early suspension is employed.

Continuous variable

FP FPG change from baseline to week 24 (mmo/L)

2 2 hours PPG change (mmo/L) from baseline to week 24 after regular diet

葡萄糖 Changes in glucose fluctuations (2 hours PPG-plasma glucose before the study drug 30 minutes before the study drug administration) from baseline to week 24 after regularized dietary stimulation test (mmo/L)

体重 Weight change from baseline to week 24 (kg)

Absolute variable

百分比 Percentage of patients with HbA _1c <7% at week 24

百分比 Percentage of patients with HbA _1c ≦ 6.5% at week 24

% Percentage of patients requiring rescue therapy during the 24-week double-blind treatment period

百分比 Percentage of patients with weight loss (kg) ≧ 5% from baseline to week 24

3.2.2 Safety assessment indicators

Safety analysis is based on reported TEAE and other safety information, including symptomatic hypoglycemia and severe symptomatic hypoglycemia, local tolerance at the injection site, allergic events (as determined by ARAC), suspected pancreas Dampitis, hypocalcemic reduction, vital signs, 12-electrocardiogram (ECG) and safety laboratory tests.

The Cardiovascular Judging Committee (CAC) also collects and identifies serious cardiovascular events. Based on the statistical analysis of the overall cardiovascular assessment values from Lisila, the CAC was selected from the study and other events identified and confirmed by the Phase 3 Institute of Lisila for analysis and summary in separate reports.

4 sample size calculation assumption

The sample size calculation was based on the primary efficacy variable of the absolute change in HbA _1c from baseline to week 24.

A total of 380 patients (190 arms per arm) are expected to provide 96% efficacy to find a 0.5% difference in absolute change in HbA _1c from baseline to week 24 between the lixisenatide-treated and placebo groups, assuming 5 The common SD in the 2-sided assay at % significant level was 1.3%. Sample size calculations were based on 2 sample t-tests and were made using nQuery® Advisor 6.01.

5 statistical methods 5.1 Analysis of ethnic groups

The mITT population consists of all randomized patients who received double-blind IP at least 1 dose and had a baseline estimate of efficacy variables and at least 1 post-baseline assessment, regardless of compliance with study protocols and procedures. sequence.

The safety population was defined as all randomized patients who received double-blind IP at least 1 dose.

5.2 main effectiveness analysis

Using the covariate analysis (ANCOVA) model for the treatment group (lixilax versus placebo), screening for random stratification of HbA _1c (<8.0, ≧ 8.0%), screening for random use of sulfonyl urea (with, without) The stratification and the country were used as fixed effects, and the primary efficacy variable (HbA _{1c change} from baseline to week 24) was analyzed using the baseline HbA _1c value as a covariate. The difference between lixisenatide and placebo was estimated with bilateral 95% CI and p-values within the framework of ANCOVA.

The primary analysis of the primary efficacy variables was based on the mITT population and the measurements obtained on the efficacy variables during the double-blind treatment period. In addition to the efficacy variables of the dietary stimulation test, the efficacy variable for the double-blind treatment period was defined as the time from the first dose of double-blind IP to the last dose of double-blind IP injection up to 3 days (except for FPG based on central experiment) Room, which is for up to 1 day), or up to the introduction of rescue therapy, whichever is the earliest. The LOCF program was used as the HbA _1c value for Week 24 by taking the last available baseline post-treatment HbA _1c measurement (in the case of rescue therapy, prior to the initial new drug).

5.3 secondary efficacy analysis

Efficacy variables (including PPG and glucose fluctuations) from the dietary stimulation test during the double-blind treatment period were defined as the date from the first dose of double-blind IP to the last dose of double-blind IP injection, or at most to the introduction of rescue treatment The time of the law, whichever is the earliest.

Once the major variables were statistically significant at a = 0.05, the following secondary efficacy variables were tested by performing the test procedure in the following order of precedence. As long as it is found that the evaluation index is not statistically significant at α=0.05, the assay is stopped.

1. PPG change (mmol/L) from baseline to week 24 after regular diet test

2. FPG change from baseline to week 24 (mmol/L)

3. Body weight change from baseline to week 24 (kg)

4. Percentage of patients requiring rescue therapy during the 24-week double-blind treatment period

All consecutive secondary efficacy variables as described in paragraph 24, paragraph 2.2.1, were analyzed using a similar method as described above for the primary analysis of primary efficacy assessment indicators and the ANCOVA model. The adjusted adjustment of treatment means the difference between lixisenatide and placebo and provides bilateral 95% CI.

The following absolute secondary efficacy variables at week 24 were analyzed by CMH method according to random stratification (screening HbA _1c [<8.0, ≧ 8.0%] and sulfonyl urea [yes, no] at screening) :

百分比 Percentage of patients with HbA _1c <7% at week 24

百分比 Percentage of patients with HbA _1c ≦ 6.5% at week 24

% Percentage of patients requiring rescue therapy during the 24-week double-blind treatment period

The number and percentage of patients with weight loss 5% at week 24 are Expressed according to the treatment group.

5.4 Security Analysis

Safety analysis is based primarily on the treatment period. The treatment period was defined as the time from the first dose of double-blind IP to the third day after the last administration of IP administration, regardless of the rescue status. The 3-day interval is selected based on the half-life of lixisela (approximately five times the half-life).

A summary of the safety results (narrative statistics and frequency tables) is expressed in terms of treatment groups.

6 results 6.1 Research patients 6.1.1 Patient Responsibilities

The study was conducted in 37 centers in 4 countries or regions (China, Malaysia, Thailand and Hong Kong). A total of 655 patients were screened and 391 were randomized to one of the two treatment groups. The main reason for the screening failure was that the HbA _1c value at the screening visit fell outside the scope of the defined procedure (147 patients (22.4%)).

Table 1 provides the number of patients in each of the analysis populations. One randomized group (placebo group) did not receive study treatment because the patient withdrew from the study. The other 390 randomized groups were exposed to study treatment. Two patients (1 (0.5%) in each group) were excluded from the mITT population of efficacy analysis because there was no post-baseline efficacy data.

6.1.2 Research and disposal

Table 2 provides a summary of patient treatment for each treatment group. During the treatment period, 27 patients discontinued the study treatment forever. In the lixisenatide group, the percentage of patients who discontinued treatment was higher than in the placebo group (8.7% vs. 5.1%, respectively). The main cause of treatment discontinuation was "adverse events" (14 patients), with more patients in the lixisenatide group than in the placebo group (11 patients (5.6%) and 3 patients, respectively) (1.5%)), mainly due to AE of gastrointestinal disorders (Table 20). The time-to-onset of treatment discontinuation is shown in Figure 8 for any reason for the treatment period, showing more frequent discontinuation at the start of the study. On day 181, there were 2 patients in the Lixi Lailai group, and 1 of 2 patients discontinued treatment and this was recorded by the investigator as discontinuation of the study treatment.

6.1.3 Demographics and baseline characteristics

Demographics and patient baseline characteristics for the safety population in the two treatment groups were generally similar (Table 3). In summary, the median age of the study population was 56 years, the median screening for HbA _1c was 7.90%, and the median body mass index (BMI) was 26.30 kg/m ² .

Table 3 Demographic and Patient Characteristics at Screening or Baseline - Safety Groups

Disease characteristics, including a history of diabetes, were generally comparable between the two treatment groups (Table 4). In summary, the mean (SD) duration of T2DM was 6.64 (4.72) years, while the mean (SD) age of T2DM was 48.1. (9.8) years old. Two patients from the same location (one in each treatment group) reported previous GLP-1 receptor agonists because they participated in at least a clinical trial of recombinant human GLP-1 (rhGLP-1) prior to screening visits. 8 months.

For the safety population, the use of background treatment (methodamine and/or sulfhydryl urea) between the two treatment groups was generally similar (Tables 5 and 6).

In summary, about half of the patients (174 patients (44.6%)) were screened On the interview, the sulfonyl urea was received on top of the metformin (Table 6). The percentage of Table 6 "Use of sulfonyl urea in screening" as recorded in the Case Report Form (CRF) is different from that recorded in Table 3 Interactive Voice Response System/Interactive Network System (IVRS/IWRS). A random stratification of sulfonyl urea was used. However, the two treatment groups were generally balanced.

The baseline efficacy variables for the safety population between the 2 treatment groups were comparable (Table 7). The study population in the two groups adequately matched baseline blood glucose parameters (including HbA _1c , 2-hour PPG, FPG, and body weight).

6.1.4 Dosage and duration

Mean treatment exposure was similar between the two treatment groups (159.4 days (22.8 weeks) and 165.5 days (23.6 weeks) in the lixisenatide and placebo groups, respectively) (Table 8). Of the 390 patients, 325 (83.3%) had prescribed 168 +/- 5 days of study treatment (164 patients (83.7%) and 161 in the lixisenatide and placebo groups, respectively) A patient (83.0%)). One placebo patient did not record the last dosing date on the CRF page "End of Treatment", so according to statistical analysis methods (SAP) data processing convention, contact duration is defined as missing.

In both treatment groups, more than 90% of patients had a target total daily dose of 20 μg at the end of the double-blind treatment period (Table 9).

6.2 effectiveness 6.2.1 Main effectiveness evaluation indicators Main analysis

The primary analysis indicated in advance confirmed that treatment with lixisenatide resulted in a statistically significant decrease in HbA _1c from baseline to week 24 compared to the placebo group (Table 10). The mean LS change for HbA _1c was 0.83% for the lixisenatide group and 0.47% for the placebo group; the mean LS difference for the placebo was -0.36%, 95% CI: -0.551%, -0.162%; p-value = 0.0004 . Chinese patients confirmed the same tendency (Table 28).

As shown in Figure 9, HbA _1c in the treatment group had decreased at week 8 and remained reduced throughout the treatment period.

Secondary analysis

Analysis of HbA _1c responders using the CMH method also showed statistically significant treatment differences between the lixisenatide and placebo groups (Table 11). At week 24, more than half of the patients in the lixisenatide group (53.0%) achieved HbA _1c <7%, compared with 38.8% of patients in the placebo group (p-value = 0.0030).

6.2.2 Secondary effectiveness assessment indicators

The 2-hour PPG assessment confirmed a statistically significant improvement from baseline to week 24 in the lixisenatide group compared with the placebo group (LS mean difference versus placebo = -4.28 mmol/L; p-value <0.001) (Table 12). Glucose fluctuation analysis showed similar results (Table 17).

Regarding FPG, a statistically significant improvement from baseline to week 24 was observed in the lixisenatide group compared with the placebo group (LS mean difference versus placebo = -0.48 mmol/L; p-value = 0.0109) (Table 13, Figure 10).

Table 13 Mean changes in fasting plasma glucose from baseline to week 24 (mmol/L) - mITT population

The LS mean weight loss relative to baseline at week 24 was 1.50 kg for patients with lixisenatide and 1.24 kg for placebo patients (Table 14, Figure 11). No statistically significant differences were observed between the two treatment groups (LS mean difference versus placebo = -0.27 kg; p-value = 0.296). In Lee In the Syrah group, the number of patients who lost 5% or more from baseline to Week 24 was slightly higher than those in the placebo group (19.7% vs. 14.7%, respectively) (Table 15).

The number of patients requiring rescue therapy at week 24 was 7 patients (3.6%) in the lixisenatide group compared with 13 patients (6.7%) in the placebo group (Table 16). .

Compared with placebo treatment, lixisenatide treatment from baseline to week 24 significantly reduced postprandial plasma glucose fluctuations (LS mean difference vs. placebo = -3.99 mmol/L, 95% CI = -4.969, -3.010) .

All in all, the results of the study confirmed that the use of lixisenatide at the 24th week had superior therapeutic efficacy in glycemic control compared to placebo, as was not adequately controlled by metformin with or without sulfonylurea. The changes in HbA _1c , HbA _1c responders, 2-hour PPG, and FPG reduction in T2DM patients were as follows.

6.3 Security

Table 18 shows an overview summary of patients with TEAE. Table 19 and Table 20 summarize the critical TEAE based on the primary SOC, High Level Group Term (HLGT), High Level Term (HLT), and Preferred Term (PT), and the TEAE that caused the treatment to be discontinued. .

As shown in Table 18, the incidence of TEAE was higher in the lixisenatide group than in the placebo group (64.3% and 47.4%, respectively). Seven patients with critically ill TEAE had a similar incidence in the lixisenatide group compared with the placebo group (3 patients (1.5%) and 4 patients (2.1%), respectively). There is no critical TEAE that is dying of the disease. The percentage of patients with TEAE who had discontinuation of treatment in the lixisenatide group was higher than in the placebo group (11 patients (5.6%) and 3 patients (1.5%), respectively), mainly with the gastrointestinal tract The SOC imbalance was associated (8 patients in the lixisenatide group (4.1%) and 0 patients in the placebo group) (Table 20).

Table 26 is an annex showing the incidence of TEAE occurring in at least 1% of patients in both treatment groups during the treatment period. In the placebo group (5 patients, (2.6%)), nausea was the most frequently reported TEAE in the lixisenatide group (32 patients (16.3%)). Among patients treated with lixisenatide, the second frequently reported TEAE was hypoglycemia (18 patients (9.2%)), followed by dizziness (17 patients (8.7%)) and vomiting ( 15 patients (7.7%)). The number of patients (%) in the placebo group was 9 patients with hypoglycemia (4.6%), 8 patients with dizziness (4.1%), and 2 patients with vomiting (1.0%).

During the treatment period, no patients in the treatment group reported at least one value of suspected pancreatitis or lipase or amylase, the upper limit 3 (ULN) of the normal range.

During the treatment period, 3 patients in the lixisenatide group experienced at least 1 critical adverse event (SAE) (Table 19), of which 1 patient was After one injection of lixisenatide, three events (anaphylactic shock, acute myocardial infarction, and diverticulum infarction) were reported and treatment was discontinued forever; one patient experienced cerebral infarction (80th day of treatment) and the treatment was discontinued; The patient went to the hospital for abdominal pain (the 13th day of treatment) and did not stop the treatment. During the treatment period, a total of 4 patients in the placebo group reported 4 SAEs (hypertension, abnormal liver function, prostatitis, and benign prostatic hyperplasia). The four events were not related to IP and caused the study treatment to be suspended forever.

Anaphylactic shock, acute myocardial infarction, and infarction (156029017):

The 66-year-old male T2DM patient has a history of hypertension and dyslipidemia but no history of allergies. He experienced allergic symptoms, itchy skin, rash and redness throughout the body after 10 minutes of IP administration. After 10 minutes, the blood pressure dropped to 60/40 mmHg (glucose value 10.2 mmol/L), and anaphylactic shock occurred when the patient was unconscious and the breathing became short. The patient was referred to the doctor and treated with dexamethasone, promethazine and dopamine: he recovered from anaphylactic shock after about 1 hour and recovered from an allergic reaction after about 6 hours. Based on ECG and cardiac enzymes tested on the same day, he was diagnosed with acute myocardial infarction but no ischemic symptoms. After receiving improved treatment with clopidogrel, aspirin, low molecular weight heparin, metoprolol and phosphocreatine, his condition stabilized. Because of anaphylactic shock and acute myocardial infarction, study treatment was discontinued. Six days after the IP was permanently discontinued, a brain magnetic resonance imaging (MRI) scan revealed a cerebral infarction (not determined to be non-stroke according to CAC). After 2 weeks, the patient recovered and was discharged. There is no residual effect after the infarction of the dimple. The case was not blinded by Sanofi (Pharmacovigilance) Suffering from receiving Lisila. The researchers assessed that anaphylactic shock and myocardial infarction events were related to the study product, and that the infarct was not associated with IP.

Cerebral infarction (156015018):

A 63-year-old male T2DM patient with a history of hypertension and dyslipidemia was randomized to a lixisenatide-treated group and underwent a mild multiple cerebral infarction at the time of study (day 80). Suspension of study treatment. Four days later, he went to the hospital because of the weakness on the right side. MRI scans of the brain showed acute cerebral infarction, multiple cerebral infarction, abnormal signals in the right anterior temporal region, leukoaraiosis, and atherosclerosis. Ten days later, after improvement of treatment (not illustrated), he was discharged from the hospital with stable condition. But after 9 days, the patient was treated again because of weakness on the right side of the body. The second brain MRI showed bridge cerebral infarction, multiple cerebral infarction, mild brain atrophy, leukoaraiosis and left anterior leaf abnormality signal (considered atherosclerosis). After 12 days, the patients were assessed to have recovered substantially and were discharged after receiving improved treatment with antiplatelet and antihypertensive therapy. This event was positively determined as a non-fatal ischemic stroke based on CAC. The researchers assessed that cerebral infarction was not related to the study product.

Abdominal pain (156008020):

A 65-year-old female T2DM disease with a history of medical history of breast cancer, uterine fibroids, hypertension, dyslipidemia, angina pectoris, obesity, hyperuricemia, and a history of penicillin and food allergy were randomly assigned to the lixisenatide treatment group. Moderate bloating occurred 7 days after the first dose of IP. After 5 days, I went to the doctor for further evaluation and diagnosed as abdominal pain. Continue to study treatment. After about 11 days, the patient recovered and did not improve treatment. hospital. No further information available. The admission diagnosis was still abdominal pain. The researchers assessed that abdominal pain events were related to the study product.

High blood pressure (156007024):

A 63-year-old female T2DM disease with obesity, hypertension, dyslipidemia, myocardial ischemia, and gallstone history was randomized to placebo treatment. At the time of study treatment (Day 106), she underwent moderate hypertension with an increase in blood pressure to 200/100 mmHg. Continue to study treatment. She was admitted to hospital and received improved treatment with felodipine, losartan, metoprolol and simvastatin. Her blood pressure returned to normal within 3 days and was discharged after 8 days. The researchers assessed that this event was not related to the study product.

Abnormal liver function (156030011):

A 55-year-old male T2DM disease with a history of fatty liver and dyslipidemia was randomized to placebo treatment. At the time of study treatment (Day 86), he developed severe, medically significant liver dysfunction. Liver function test (LFT) at the 9th visit showed serum glutamate pyruvate transaminase (SGPT) 571 U/L (normal: 6-41 U/L), glutamic acid acetic acid transaminase (SGOT) 218 U/L (normal 9-34 U/L), and γ-glutaminyl transferase (GGT) 291 U/L (normal: 11 52 U/L). The patient only felt sleepy and did not have nausea or vomiting. He only occasionally drinks alcohol and traditional Chinese medicine for periodontitis, which is used when liver function is abnormal. The study treatment was temporarily stopped for 1 week and the patient received an improved treatment with diammonium glycyrrhizinate. The patient's monitoring LFT was normal. At random group visits, the SGPT climbed to 94 U/L, the SGOT was 41 U/L, and the GGT was 298 U/L. After 21 days, the patient's LFT was approximately normal. Research treatment at 6 Continue in the days. The researchers assessed that this event was not related to the study product.

Prostatitis (156015007):

A 62-year-old male T2DM disease with a history of hypertension and prostatitis was randomized to placebo treatment. He was hospitalized on the 97th day of the treatment study because mild bloating had lasted for half a year. Research treatment continues. Improvements in treatment include aztreonam and traditional Chinese medicine. In the case of diagnosis of chronic prostatitis, the patient's symptoms improved and he was discharged after 11 days. The researchers assessed that this event was not related to the study product.

Benign Prostatic Proliferation (156008016):

A 60-year-old male T2DM disease with a history of hypertension and dyslipidemia was randomized to placebo treatment. Moderate prostate proliferation was experienced at the time of study treatment (Day 52). Symptoms are characterized by frequent urination, urinary retention (lasting 3 days), and difficulty urinating, which has worsened for 1 year. Research treatment continues. He was hospitalized and underwent urethral dilatation and transurethral resection of the prostate after 8 days. After the operation, he received anti-inflammatory medication. After 11 days, the patient was discharged from the hospital under stable conditions. The researchers assessed that this event was not related to the study product.

In the lixisenatide group, the most common TEAE causing treatment discontinuation is a gastrointestinal disorder. Eleven (5.6%) patients treated with lixisenatide were discontinued for treatment with TEAE, and 8 patients (4.1%) discontinued treatment for gastrointestinal disorders TEAE (Table 20), while in the placebo group None of the gastrointestinal adverse events caused the treatment to stop. The most frequently reported events that caused discontinuation of treatment were nausea and vomiting (3 patients (1.5%) and 2 patients (1.0%), respectively).

In summary, 16 (4.1%) patients met the prescribed definition of symptomatic hypoglycemia during the treatment period (11 (5.6%) and 5 (2.65) in the lixisenatide and placebo groups, respectively) ) (Table 21). None of these incidents is considered serious or critical. The number of symptomatic hypoglycemia with blood glucose <60 mg/dL was the same in both treatment groups (3 (1.5%) in each group). In addition, in patients treated with sulforaphane on metformin, the number of blood glucose <60 mg/dL was not observed between the two treatment groups (3 in the lixisenatide and placebo groups, respectively). Patients (3.3%) and 3 patients (3.7%) (Table 29).

The injection site reaction event is confirmed by the PT encoded by the term reported by the investigator after the determination of the allergic reaction or the term "injection site" of the PT encoded by the ARAC diagnostic term. In summary, there were 7 patients (1.8%) who experienced an injection site reaction during the treatment period (5 in lixisenatide and 2 in placebo), none of which was endangered or severe or caused a treatment discontinuation (Table 22). ).

During the treatment period, the researchers reported a total of 15 cases of suspected allergic events and sent them to the ARAC for decision. Three of these cases (two patients (1.0%) with lixisenatide and one patient (0.5%) with placebo) were judged to be allergic by ARAC (Table 23). Both events in the lixisenatide group were determined by ARAC to be potentially related to IP, and one of the events (anaphylactic shock) occurred after the first IP administration (156029017, see page 50) and caused the treatment to be permanently suspended. And one event (injection site reaction) occurred 15 days after treatment (which did not cause treatment discontinuation) and recovered when the patient continued treatment.

The increase in serum-free calcitonin was reported as TEAE (Table 24). In the Lixiraha group, one patient was found to have a calcitonin (23.6 pg/mL) higher than 20 ng/ml at the 12th visit (end of treatment visit), but hemolysin was The retest value returned to normal (15.7 pg/mL) within 1 week. No AE was reported in this case.

Finally, Lisila was well tolerated during the 24-week treatment period. In the lixisenatide group, the incidence of TEAE that caused the study treatment to be permanently discontinued was higher than in the placebo group, which was mainly due to gastrointestinal TEAE. The incidence of critical TEAE was similar in both treatment groups. Compared with the placebo group, patients treated with lixisenatide experienced a higher percentage of patients who experienced symptomatic hypoglycemia and patients with symptomatic hypoglycemia with blood glucose <60 mg/dL in both treatment groups. The number is actually the same. Nausea, dizziness, and vomiting are more often reported in Lisila than in placebo. No new specific safety considerations were observed during the trial.

Figure 1: Mean post-prandial plasma glucose patterns on day -1 and day 28 were averaged (± SEM) depending on treatment.

Figure 2: Study design in Example 1.

Figure 3: Diet challenge test - plasma insulin values (μIU/ml) on days -1 and 28.

Figure 4: Diet Challenge Test - Changes in plasma insulin data (μIU/ml) on days -1 and 28 relative to pre-meal.

Figure 5: Diet challenge test - glycemic (pg/mL) values on days -1 and 28.

Figure 6: Plasma glucose values (mg/dL) on days -1 and 28.

Figure 7: Study design in Example 2.

Figure 8: Kaplan-Meier plot of time-sustained treatment for any reason - random population.

Figure 9: HbA _1c mean change pattern (%) vs. baseline at week 24 vs. baseline - mITT population. LOCF = last observation estimate. Note: The analysis excludes measurements obtained after the introduction of rescue medication and/or after treatment interruption plus 3 days.

Figure 10: Mean change in fasting plasma glucose (mmol/L)-mITT population at baseline and at week 24 vs. baseline. LOCF = last observation estimate. Note: The analysis excludes measurements obtained after the introduction of rescue medication and/or after treatment interruption plus 3 days.

Figure 11: Average change in body weight (kg) versus mITT population at baseline and at week 24 vs. baseline. LOCF = last observation estimate. Note: points The measurements obtained after the introduction of the rescue drug and/or after the treatment interruption plus 3 days were excluded.

<110> Sanofi-Aventis Deutschland GmbH

<120> Pharmaceutical composition for blood sugar control in type 2 diabetic patients

<130> 50547PEP-1

<140> EP12163637.7

<141> 2012-04-10

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<170> PatentIn version 3.5

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<212> PRT

<213> Artificial sequence

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<223> AVE0010

<220>

<221> MOD_RES

<222> (44)..(44)

<223> Amination

<400> 1

<210> 2

<211> 39

<212> PRT

<213> Artificial sequence

<220>

<223> Exenatide-4

<220>

<221> MOD_RES

<222> (39)..(39)

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Claims (21)

A pharmaceutical composition for glycemic control in a type 2 diabetic patient, the composition comprising: (a) desPro ³⁶ exenatide-4(1-39)-Lys ₆ -NH ₂ or/and its medicinal An acceptable salt, and (b) metformin or/and its pharmaceutically acceptable salts. A pharmaceutical composition for lowering plasma glucagon concentration in a type 2 diabetic patient, the composition comprising: (a) desPro ³⁶ Exendin-4 (1-39)-Lys ₆ -NH ₂ or / And a pharmaceutically acceptable salt thereof, and (b) metformin or/and a pharmaceutically acceptable salt thereof. The pharmaceutical composition of claim 1 or 2, wherein the subject to be treated is obese. A pharmaceutical composition according to any one of the preceding claims, wherein the subject to be treated has a body mass index of at least 30 kg/m ² . A pharmaceutical composition according to any one of the preceding claims, wherein the individual to be treated is an adult individual. A pharmaceutical composition according to any one of the preceding claims, wherein the subject to be treated does not receive anti-diabetic treatment. A pharmaceutical composition according to any one of the preceding claims, wherein in the subject to be treated, type 2 diabetes has been diagnosed for at least 1 year or at least 2 years prior to the start of therapy. A pharmaceutical composition according to any one of the preceding claims, wherein the subject to be treated has a HbA _1c value of from about 7 to about 10%. A pharmaceutical composition according to any one of the preceding claims, wherein the subject to be treated has a fasting plasma glucose concentration of at least 8 mmol/L. A pharmaceutical composition according to any one of the preceding claims, wherein the subject to be treated has a postprandial 2 hour plasma grape concentration of at least 10 mmol/L, at least 12 mmol/L or at least 14 mmol/L. A pharmaceutical composition according to any one of the preceding claims, wherein the subject to be treated has a glucose fluctuation of at least 2 mmol/L, at least 3 mmol/L, at least 4 mmol/L or at least 5 mmol/L, wherein glucose fluctuations It is the difference between the plasma glucose concentration at 2 hours postprandial and the plasma glucose concentration 30 minutes before the dietary test. The pharmaceutical composition according to any one of the preceding claims, wherein the subject to be treated is an oriental and/or Asian race. A pharmaceutical composition according to any one of the preceding claims, wherein desPro ³⁶ Exenatide-4(1-39)-Lys ₆ -NH ₂ or/and a pharmaceutically acceptable salt thereof are prepared for parenteral use Cast. A pharmaceutical composition according to any one of the preceding claims, wherein desPro ³⁶ Exendin-4(1-39)-Lys ₆ -NH ₂ or/and a pharmaceutically acceptable salt thereof are prepared from 10 μg Daily doses up to 20 μg are available for administration. A pharmaceutical composition according to any one of the preceding claims, wherein metformin or/and a pharmaceutically acceptable salt thereof are prepared for oral administration. A pharmaceutical composition according to any one of the preceding claims further comprising a sulfonyl urea. A pharmaceutical composition according to claim 16, wherein the sulfhydryl urea is prepared for oral administration. A method for improving glycemic control in a type 2 diabetic patient, comprising administering a composition according to any one of claims 1 and 3 to 17 to an individual in need thereof. The method of claim 18, wherein the individual is an individual as defined in any one of claims 3 to 12. A method for lowering plasma glycosidin concentration in a type 2 diabetic patient, comprising administering a composition according to any one of claims 2 to 17 to an individual in need thereof. The method of claim 20, wherein the individual is an individual as defined in any one of claims 3 to 12.