MX2009012308A - Method of treatment of diabetes type 2 comprising add-on therapy to insulin glargine and metformin. - Google Patents

Abstract

A method for the treatment of diabetes mellitus type 2 comprising administering (d) desPro36Exendin-4(1-39)-Lys6-NH2 or/and a pharmaceutically acceptable salt thereof, (e) insulin glargine or/and a pharmaceutically acceptable salt thereof, and (f) metformin or/and a pharmaceutically acceptable salt thereof, to a subject in need thereof.

Description

TYPE 2 DIABETES TREATMENT METHOD COMPRISING INSULIN GLENGIN AND METFORMIN ADDICTION THERAPY The object of the present invention is a method of treatment of type 2 diabetes with AVE0010 (lixisenatide) as addition therapy to administration of insulin glargine and metformin.

Metformin is a hypoglycemic biguanide agent used in the treatment of Type 2 diabetes mellitus that does not respond to dietary modification. Metformin improves glycemic control by improving insulin sensitivity. Metformin is usually administered orally.

Insulin is a polypeptide that has 51 amino acid residues. Insulin consists of the A chain that has 21 amino acid residues, and the B chain that has 30 amino acid residues. The chains are coupled by 2 disulfide bridges. Insulin formulations have been used for a long time for therapy of diabetes mellitus type 1 and 2. Recently, insulin derivatives and insulin analogues have been used.

However, the control of type 2 diabetes mellitus by metformin and insulin may be insufficient. Thus, in these patients, measures may be required to control type 2 diabetes mellitus.

A first aspect of the present invention is a method for the treatment of type 2 diabetes mellitus which comprises administering (a) desPro3¾xendin-4 (1-39) -Lys6-NH2 (AVE0010, lixisenatide) or / and a pharmaceutically acceptable salt of. same, (b) insulin glargine or / and a pharmaceutically acceptable salt thereof, and (c) metformin or / and a pharmaceutically acceptable salt thereof, to a subject in need of it.

The compounds of (a), (b) and (c) can be administered to a subject in need thereof, in an amount sufficient to induce a therapeutic effect.

The compound desPro * 6Exendin-4 (1-39) -Lys6-NH2 (AVE0010, lixisenatide) is a derivative of Exendin-4. AVE0010 is described as SEQ ID NO: 93 in WO 01/04156: • SEQ ID NO: 1 AVE0010 (FF 12) H-G-E-G-T-F-T-S-D-L-S-K-Q-M-E-E-E-A-V-R-L-F-I-E-W-L-K-N-G-G-P-S-S-G-A-P-P-S-K-K-K-K-K-K-K-NH2 • SEQ ID NO: 2 Exendin-4 (39 AS) H-G-E-G-T-F-T-S-D-L-S-K-Q-M-E-E-E-A-V-R-L-F-I-E-W-L-K-N-G-G-P-S-S-G-A-P-P-P-S-NH2 Exendins are a group of peptides that can reduce the concentration of glucose in the blood. The exendin analog AVEOOlO is characterized by truncated C-terminal sequence of native Exendin-4-. AVEOOlO comprises six C-terminal lysine rediuos not present in Exendin-4.

In the context of the present invention, AVEOOlO includes pharmaceutically acceptable salts thereof. The person skilled in the art knows the pharmaceutically acceptable salts of AVEOOlO. A preferred pharmaceutically acceptable salt of AVEOOlO employed in the present invention is acetate.

AVEOOlO (desPro36Exendin-4 (1-39) -Lyz6-NH2 or / and a pharmaceutically acceptable salt thereof can be administered parenterally, eg, by subcutaneous injection The appropriate injection devices, for example the so-called "pens" comprising a cartridge comprising the active ingredient, and an injection needle, are known - AVEOOlO or / and a pharmaceutically acceptable salt thereof can be administered in an appropriate amount, for example in an amount in the range of 10 to 15 ug per dose or 15 to 20 ug per dose once a day (progressive titration from 10 to 15 and at 20 ug / day, 20 ug is the effective maintenance dose).

In the present invention, AVEUU1U or / and a pharmaceutically acceptable salt thereof can be administered in a daily dose on a scale of 10 to Ib ug or on a scale of 15 to 20 ug (progressive titration of 10 to 15 and 20 ug / day, 20 ug is the effective maintenance dose). AVE0010 or / and a pharmaceutically acceptable salt thereof can be administered by one injection per day.

Insulin glargine (Lantus) is insulin Gly (A21) -Arg (B31) -Arg (B32) -human. In the context of the present invention, insulin glargine includes pharmaceutically acceptable salts thereof.

Insulin glargine or / and a pharmaceutically acceptable salt thereof can be administered by injection (by subcutaneous injection). Suitable injection devices, for example so-called "pens" comprising a cartridge comprising the active ingredient, and an injection needle, are known. Insulin glargine and / or a pharmaceutically acceptable salt thereof can be administered in an appropriate amount, for example in an amount of at least 10 units per day (the initial dose is 10 units, 80 units is the maximum possible dose with the pen with 1 injection).

In the present invention, insulin glargine or / and a pharmaceutically acceptable salt thereof can be administered in a daily dose of at least 10 units. Insulin glargine or / and a pharmaceutically acceptable salt can be administered by one injection per day.

In the present invention, AVE0010 or / and a pharmaceutically acceptable salt thereof can be provided in a liquid composition. The skilled person knows liquid compositions of AVE0010 appropriate for subcutaneous administration.

In the present invention, insulin glargine or / and a pharmaceutically acceptable salt thereof can be provided in a liquid composition. The skilled person knows liquid glargine insulin compositions suitable for subcutaneous administration.

A liquid composition employed herein may have an acidic or a physiological pH. An acid pH is preferably in the range of pH 1 - 6.8, pH 3.5 - 6.8, or pH 3.5 - 5. A physiological pH is preferably in the range of pH 2.5 - 8.5, pH 4.0 to 8.5, or pH 6.0 to 8.5. The pH can be adjusted by a pharmaceutically acceptable difluid acid (typically HC1) or a pharmaceutically acceptable dilute base (typically NaOH).

The preferred pH is in the range of 3.5 to 5.0.

The liquid composition may contain a buffer, such as a phosphate, a citrate, an acetate. Preferably, it may contain an acetate buffer, in amounts up to 56 ug / mL, up to 4 ug / mL, or up to 2 ug / mL.

The liquid composition employed herein may comprise an appropriate preservative. A suitable preservative can be selected from phenol, m-cresol, benzyl alcohol and p-hydroxybenzoic acid ester. A preferred preservative is m-cresol. However, the preferred liquid composition does not contain a preservative.

The liquid composition employed herein may comprise a tonicity agent. An appropriate tonicity agent can be selected from glycerol, lactose, sorbitol, mannitol, glucose, NaCl, calcium or magnesium containing compounds such as CaCl 2. The concentration of glycerol, lactose, sorbitol, mannitol and glucose can be in the range of 100-250 mM. The concentration of NaCl can be up to 150 mM. A preferred tonicity agent is glycerol.

In addition, the liquid composition may contain L-methionine of 0.5 ug / mL at 20 ug / mL, preferably 1 ug / mL at 5 ug / mL. Preferably it contains L-methionine.

Metformin is a non-proprietary name of l, l-dimetilbíguanida (CAS Number b57-24-y). In the present invention, the term "metformin" includes any pharmaceutically acceptable salt thereof.

In the present invention, metformin can be administered orally. The person skilled in the art knows formulations of metformin appropriate for the treatment of type 2 diabetes by oral administration. Metformin can be administered in a dose of at least 1.5 q / day. For oral administration, metformin can be formulated in solid dosage form, such as a tablet or pill.

In the present invention, desProJtoExendin-4 (1-329) -Lyz6-NH2 or / and a pharmaceutically acceptable salt is administered in an addition therapy to the administration of metformin and insulin glargine.

In the present invention, the terms "addition", "addition treatment", and "addition therapy" in relation to the treatment of type 2 diabetes mellitus with metformin, insulin glargine and AVE0010. Metforminse, insulin glargine and AVE0010 can be administered within a 24-hour time interval. Metformin, insulin glargine and AVE0010 each can be administered in a dosage of one a day. Metformin can be administered by a different administration route than insulin glargine and AVEUülü. Metformin can be administered orally, while AVE0010 and insulin glargine can be administered subcutaneously.

The subject to be treated by the method of the present invention can have a fasting plasma glucose concentration of at least 7 mmol / L or / and glucose in a 2 hour postprandial plastid of at least 11.1 mmol / L. The subject can have a HbAlc value on the scale of 7% to 10%.

The subject to be treated by the method of the present invention can be an adult subject. The subject can have an age on the scale of 18 to 50 years.

The method of the present invention is preferably a method of treating a subject suffering from type 2 diabetes, wherein type 2 diabetes is not adequately controlled by treatment with metformin and insulin alone, for example with a dose of at least 1.5 g / day of metformin and an insulin dose of at least 10 units, preferably 15 to 80u / day for 3 months.

Another aspect of the present invention is a pharmaceutical combination comprising (a) desPro36Exendin-4 (1-39) -Lys6-NH2 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.

Preferably, the combination of the present invention is for the treatment of type 2 diabetes mellitus.

The combination of the present invention can be administered as described herein in the context of the method of the present invention. The compounds (a), (b) and (c) of the combination of the present invention can be formulated as described herein in the context of the method of the present invention.

Yet another aspect of the present invention is the use of a combination comprising (a) desProbExendin-4 (1-39) -Lys6-NH2 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. for the production of a medicament for the treatment of type 2 diabetes mellitus.

The drug comprises desPro36 Exendin-4- (1-39) -Lys6-H2, insulin glargine and metformin in separate formulations, as described herein.

The invention is further illustrated by the following example.

Example Treatment of type 2 diabetes of 24 weeks with lixisenatide (AVE0010) and therapy of addition to insulin glargine and metformin.

The subject of the example is randomly selected, placebo controlled, parallel group of 2 weapons, multicenter study with a double-blind treatment of 24 weeks period that determines the efficacy and safety of Lixisenatide in patients with type 2 diabetes insufficiently controlled with insulin glargine and megormin .

Primary objects of study The primary objective of this study is to determine the effects on glycemic control of lixisenatide compared to placebo as an addition treatment to insulin glargine and metformin over a period of 24 weeks.

Secondary objectives of study The secondary objectives are: To determine the effects of lixisenatide (AVE0010) on the percentage of patients achieving HbAlc < 7% and < or =? 6.5%, in plasma glucose (fasting, postprandial during a conventional food challenge test, self-supervised profiles of 7 points), but corporal, insulin glargine dose. To evaluate lixisenatide safety and tolerance capacity as an addition treatment to insulin glargine and metformin.

To determine the impact of lixisenatide on treatment satisfaction using the Diabetes Treatment Satisfaction Questionnaire (state) (DTSQs) in the participating countries where it is validated.

Drug: placebo Drug: insulin glargine (HOE901) Type of Study: Intervention Study Design: Treatment, Randomized, Double Blind (Subject, Who Provides Care, Invetigador, Results Consultant), Placebo Control, Parallel Assignment, Efficacy Study Primary Outcome Measures: Change in glycated hemoglobin (HbAlc) (time frame: 24 weeks, designed as a safety issue: no) Secondary Outcome Measures Percentage of patients with HbAlc < 7%, < o = 6.5% (time frame: 24 weeks, designed as a safety issue: no) Change in postprandial plasma glucose (time frame: 24 weeks, designed as a safety issue: no) Change in fasting plasma glucose (time frame: 24 weeks, designed for safety issue: no) Change in Glucose profiles in 7-Way Supervised Plasma (SMPG) (time frame: 24 weeks, designed as safety issue: no) Change in body weight (time frame: 24 weeks, designed as safety issue: no ) Change in insulin glargine dose (time frame: 24 weeks, designed as a matter of security: no). percentage of patients requiring rescue therapy during the double blind period (time frame: 24 weeks, designed as a safety issue: no) Change in treatment satisfaction brand (DTSQ questionnaire, timeframe: 24 weeks, designed as a safety issue: no) Weapons Assigned interventions Lixisenatide: Drug Treatment: Lixisenatide (AVE0010) experimental 24 weeks solution for injection with lixisenatide once to the subcutaneous day on insulin glargine (both injected into the Drug: insulin glargine tomorrow within 1 hour before (HOE901) solution for breakfast) and mjetformin subcutaneous injection (at least 1.5 g / day) Placebo: 24 Drug Treatment: placebo Weeks of Solution Comparator for injection Placebo with placebo once subcutaneous daily on insulin glargine (both injected in Drug: insulin glargine the morning within 1 hour (HOE901) solution for before breakfast) subcutaneous injection metformin (at least g / day) Detailed description The study will comprise 3 periods: A sieving period of up to 14 weeks, including - a screening phase of up to 2 weeks and a 12-week trial phase with introduction and titration of insulin glargine on metformin +/- TZDS.

At the end of the testing phase, patients whose HbAlC (centralized test) is> o = 7% and < o = 9% and whose average fasting SMPG calculated from auto measurements during the 7 days before visit 12 (week -1) is less than or equal to 126 mg / dl (7.0 mmol / 1), will enter a period of randomized double-blind treatment of 24 weeks comparing lixisenatide with placebo (on insulin glargine + metformin +/- TZADs).

A security monitoring period of 3 days. Maximum duration of 39 weeks + 7 days.

Eligibility Eligible ages for Study: ltí Years or greater Eligible Genders for Study: Both Healthy Volunteers Accept: No Inclusion criteria In sieving Patients with type 2 diabetes mellitus, as defined by WHO (fasting plasma glucose> = 11.1 mmol / L (200 mg / dL), diagnosed at least 1 year before screening visit During at least 3 months: treatment with a stable dose of metformin > or = 1.5 g / day or combination of stable doses of metformin > o = 1.5 g7dia with sulfonylureas (Sus) (to be stopped at visit 1) and / or thiazolidinediones (TZDs) glycated hemoglobin (HbAlc) > 9 = 7.0 and < or 10%. At the end of the test in phase and before randomization: HbAlc > o = 7.0 and < o = 9% Self-monitored Plasma Glucose in Ayurvedic Medium (SMPG) calculated from self-measurements during the 7 days prior to visit 12 (week -1) is less than or equal to 126 mg / dll (7.0 mmol / 1) Exclusion criteria Pregnancy or lactation Women of pregnancy potential without effective contraceptive method.

Diabetes mellitus type 1 Metformin not at a stable dose of at least 1.5 g / day for at least 3 months before the screening visit.

Use of oral or injectable antidiabetic or hypoglycemic agents other than metformin, sulphonylurea and diazolidinediones within 3 months before screening time, use of weight loss drugs if not at a stable dose for at least 3 months before screening visit History of ignorance of hypoglycemia.

History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy, stomach / gastric surgery, inflammatory bowel disease.

History of metabolic acidosis, including diabetic detoacidosis within 1 year before screening Hemoglobinopathy or hemolytic anemia, transfusion of blood or plasma products within 3 months before screening time Within the last 6 months before screening: history of myocardial infarction, stroke, or heart failure requiring hospitalization Known history of drug or alcohol abuse within 6 months before the screening time Hypertension not controlled or inadequately controlled at the time of screening with a blood pressure at sotolic or diastolic rest > 180 mmHg or > 110 mmHg, respectively Use of systemic glucocorticoids (including topical application or inhaled forms) for a week or more within 3 months before screening time Use of any investigational drug within 3 months before screening Kidney damage defined with serum creatinine > 1.4 mg / dL in women and > 1.5 mg / dL in men History of hypersensitivity to insulin glargine or any of the excipients Clinically relevant history of gastrointestinal disease associated with prolonged nausea and vomiting, including (but not limited to): gastroparesis, instable (ie, worsening) and uncontrolled (ie, prolonged nausea and vomiting) gastroesophageal reflux disease requiring treatment doctor, within 6 months before screening time Any previous treatment with lixisenatide (eg, involvement in a previous study with lixisenatide) · Allergic reaction to any receptor agonist GLP-1 in the past (eg, exenatide, liraglutide) or metacresol Additional exclusion criteria during or at the end of the phase on the way before randomization: · Withdrawal informed consent (patient who is not willing to continue or fails to return) SMPG of average fasting calculated for self-measurements by 7 days before visit 12 (week -1) is > 126 mg / dl (7.0 mmol / 1) · HbAlc measured at visit 12 (week -1) is < 7% o > 9% Amylase and / or lipase > 3 times the upper limit of the normal laboratory scale at visit 12 (week -1).

The above information is not intended to contain all considerations relevant to a potential patient participation in a clinical trial.

Claims (12)

1. - A method for the treatment of diabetes mellitus type 2 which comprises administering (a) desPro36Exendin-4 (1-39) -Lys6-NH2 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, to a subject in need of it.

2. The method according to claim 1, wherein desPro36Exendin-4 (1-39) -Lys6-NH2 or / and a pharmaceutically acceptable salt thereof is administered subcutaneously.

3. - The method of compliance with the claim 1 or 2, wherein the insulin glargine or / and a pharmaceutically acceptable salt thereof is administered subcutaneously.

4. - The method according to any of claims 1 to 3, wherein metformin is administered orally.

5. The method according to any of the preceding claims, wherein desPro36Exendin-4 (1-39) -Lys6-NH2 or / and a pharmaceutically salt thereof is administered in an addition therapy to the administration of metformin and insulin glargine.

6. - The method according to any of the preceding claims, wherein the subject to be treated is an adult subject.

7. The method according to any of the preceding claims, wherein type 2 diabetes mellitus is not adequately controlled with metformin and insulin alone.

8. The method according to claim 9, wherein treatment with a dose of at least 1.5 g / day of metformin and at least 10 units / day of insulin alone for three months does not adequately control type 2 diabetes mellitus.

9. - The method according to any of the preceding claims, wherein he subject to treat has a HbAlc value on the scale of 7% to 10% o / and a plasma glucose concentration in ahyunas of at least 7 mmol / L , or / or postprandial plasma glucose of 2 hours of at least 11.1 mmol / L.

10. - A pharmaceutical combination comprising (a) desPro36Exendin-4 (1-39) -Lys6-NH2 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.

11. - The combination according to claim 10, wherein the combination is for the treatment of type 2 diabetes mellitus.

12. - Use of a combination of (a) desPro36Exendin-4 (1-39) -Lys6-NH2 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, for the production of a pharmaceutical composition for the treatment of type 2 diabetes mellitus.