KR20110052990A - Methods of treating type 2 diabetes, including additional therapies for insulin glargine and metformin - Google Patents

Abstract

PURPOSE: A method for treating type 2 diabetes, comprising an additional method for insulin glargine and metformin is provided. CONSTITUTION: A method for treating type 2 diabetes contains desPro36 exedin-4(1-39)-Lys6-NH_2 or/and pharmaceutically acceptable salt thereof; insulin glargine or/and pharmaceutically acceptable salt thereof; and metformin or/and pharmaceutically acceptable salt thereof. The insulin glargine or/and pharmaceutically acceptable salt thereof and desPro36 exedin-4(1-39)-Lys6-NH_2 or/and pharmaceutically acceptable salt thereof are subcutaneously administered. The metformin is orally administered.

Description

Method of treatment of diabetes type 2 comprising add-on therapy to insulin glargine and metformin}

The subject of the present invention is a method of treating type 2 diabetes with AVE0010 (Lixensenatide) as an additional therapy for the administration of insulin glargine and metformin.

Metformin is a biguanide hypoglycemic agent used in the treatment of type 2 diabetes mellitus that does not respond to dietary modifications. Metformin improves blood sugar control by improving insulin sensitivity. Metformin is generally administered orally.

Insulin is a polypeptide with 51 amino acid residues. Insulin consists of A chain with 21 amino acid residues and B chain with 30 amino acid residues. The chain is coupled by two disulfide bridges. Insulin preparations have long been used to treat type 1 and type 2 diabetes mellitus. Insulin derivatives and insulin analogues have recently been used.

However, inhibition of type 2 diabetes mellitus by metformin and insulin may be insufficient. Thus, additional measures may be needed to suppress type 2 diabetes mellitus in the patient.

The first aspect of the present invention,

(a) desPro ³⁶ exendin-4 (1-39) -Lys ₆ -NH ₂ (AVE0010, xixinatide) or / and a pharmaceutically acceptable salt thereof,

(b) insulin glargine or / and pharmaceutically acceptable salts thereof

(c) A method of treating type 2 diabetes mellitus comprising administering metformin or / and a pharmaceutically acceptable salt thereof to a subject in need thereof.

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

Compound desPro ³⁶ exendin-4 (1-39) -Lys ₆ -NH ₂ (AVE0010, xixinatide) is a derivative of exendin-4. AVE0010 is described as SEQ ID NO: 93 in WO 01/04156:

ㆍ SEQ ID NO 1 AVE0010 (44 AS)

HGEGTFTSDLSKQMEEEAVRL-FlEWLKNGGPSSGAPPSKKKK-KK-NH ₂

ㆍ SEQ ID NO 2 Exendin-4 (39 AS)

HGEGTFTSDLSKQMEEEAVRL-FIEWLKNGGPSSGAPPPS-NH ₂

Exendin is a group of peptides that can lower blood sugar levels. Exendin analog AVE0010 is characterized by the C-terminal truncation of the native exendin-4 sequence. AVE0010 contains six C-terminal lysine residues that are not present in exendin-4.

As used herein, AVE0010 includes its pharmaceutically acceptable salts. 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.

AVE0010 (desPro ³⁶ exendin-4 (1-39) -Lys ₆ -NH ₂ ) or / and pharmaceutically acceptable salts thereof can be administered parenterally, eg, by subcutaneous injection. Suitable injection devices such as cartridges comprising the active ingredient and so-called “pens” comprising injection needles are known. AVE0010 or / and its pharmaceutically acceptable salts may be in suitable amounts, for example, in the range of 10-15 μg or 15-20 μg per dose (gradual titration from 10 μg to 15 μg and 20 μg per day, 20 μg is the effective maintenance dose).

In the present invention, AVE0010 or / and pharmaceutically acceptable salts thereof are in the range of 10-15 μg or in the range of 15-20 μg (gradual titration from 10 μg to 15 μg and 20 μg per day, 20 μg is an effective maintenance dose May be administered in a daily dose. AVE0010 or / and its pharmaceutically acceptable salts may be administered by injection once a day.

Insulin glargine (Lantus) is Gly (A21) -Arg (B31) -Arg (B32) -human insulin. Insulin glargine herein includes pharmaceutically acceptable salts thereof.

Insulin glargine or / and pharmaceutically acceptable salts thereof may be administered by injection (subcutaneous injection). Suitable injection devices such as cartridges comprising the active ingredient and so-called "pens" comprising injection needles are known. Insulin glargine or / and its pharmaceutically acceptable salts are in suitable amounts, eg, 10 units or more per day (initial amount is 10 units; 80 units is the maximum dose possible using a pen in one injection) May be administered).

In the present invention, insulin glargine or / and pharmaceutically acceptable salts thereof may be administered in a daily dose of 10 units or more. Insulin glargine or / and a pharmaceutically acceptable salt thereof may be administered by injection once a day.

In the present invention, AVE0010 or / and pharmaceutically acceptable salts thereof may be provided in a liquid composition. Those skilled in the art are aware of liquid compositions of AVE0010 suitable for subcutaneous administration.

In the present invention, insulin glargine or / and pharmaceutically acceptable salts thereof may be provided in a liquid composition. Those skilled in the art are aware of liquid compositions of insulin glargine suitable for subcutaneous administration.

Liquid compositions as used herein 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 may be adjusted with a pharmaceutically acceptable dilute acid (typically HCl) or with a pharmaceutically acceptable dilute base (typically NaOH).

Preferred pH ranges from pH 3.5 to 5.0.

The liquid composition may contain buffers such as phosphate, citrate, acetate. Preferably, it may contain acetate buffer in an amount of up to 5 μg / ml, up to 4 μg / ml or up to 2 μg / ml.

Liquid compositions as used herein may include suitable preservatives. Suitable preservatives can be selected from phenol, m-cresol, benzyl alcohol and p-hydroxybenzoic acid esters. Preferred preservative is m-cresol. However, preferred liquid compositions do not contain a preservative.

Liquid compositions as used herein may include isotonic agents. Suitable isotonic agents may be selected from glycerol, lactose, sorbitol, mannitol, glucose, NaCl, calcium or magnesium containing compounds (eg CaCl ₂ ). Concentrations of glycerol, lactose, sorbitol, mannitol and glucose can range from 100 to 250 mM. The concentration of NaCl may be up to 150 mM. Preferred isotonic agent is glycerol.

The liquid composition may also contain L-methionine at 0.5 μg / ml to 20 μg / ml, preferably 1 μg / ml to 5 μg / ml. Preferably it contains L-methionine.

Metformin is the international generic name of 1,1-dimethylbiguanide (CAS No. 657-24-9). In the present invention, the term "methformin" includes any pharmaceutically acceptable salt thereof.

In the present invention, metformin may be administered orally. Those skilled in the art are aware of formulations of metformin suitable for the treatment of type 2 diabetes by oral administration. Metformin may be administered at a dose of at least 1.5 g per day. For oral administration, metformin may be formulated in solid dosage forms such as tablets or pills.

In the present invention, desPro ³⁶ exendin-4 (1-39) -Lys ₆ -NH ₂ or / and a pharmaceutically acceptable salt thereof is administered as an additional therapy for the administration of metformin and insulin glargine.

In the present invention, the terms "add-on", "add-on treatment" and "add-on therapy" refer to metformin, insulin glargine and AVE0010. It is associated with the treatment of type diabetes mellitus. Metformin, insulin glargine and AVE0010 can be administered within a 24 hour interval. Metformin, insulin glargine and AVE0010 may each be administered in a single dose daily. Metformin can be administered by a different route of administration than insulin glargine and AVE0010. Metformin may be administered orally, while AVE0010 and insulin glargine may be administered subcutaneously.

The subject to be treated by the method of the present invention may have a fasting blood glucose concentration of 7 mmol / L or more and / or a blood sugar of 11.1 mmol / L or more at 2 hours after meals. The subject may have a HbA1c value in the range of 7% to 10%.

The subject to be treated by the method of the invention may be an adult subject. The age of the subject may range from 18 years to 50 years.

The method of the present invention is suitably suited by treatment with metformin and insulin alone, eg, with a dose of metformin and a dose of at least 1.5 units of metformin and at least 10 units of insulin per day, preferably at an insulin dose of 15 to 80 U / day for three months. It is a method of treating a subject with type 2 diabetes that is not suppressed.

Another aspect of the invention,

(a) desPro ³⁶ exendin-4 (1-39) -Lys ₆ -NH ₂ or / and a pharmaceutically acceptable salt thereof,

(b) insulin glargine or / and pharmaceutically acceptable salts thereof, and

(c) a pharmaceutical combination comprising metformin or / and a pharmaceutically acceptable salt thereof.

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

Combinations of the invention can be administered as described herein in connection with the methods of the invention. Compounds (a), (b) and (c) of the combinations of the present invention may be formulated as described herein in connection with the methods of the present invention.

Another aspect of the invention, to prepare a medicament for treating type 2 diabetes mellitus,

(a) desPro ³⁶ exendin-4 (1-39) -Lys ₆ -NH ₂ or / and a pharmaceutically acceptable salt thereof,

(b) insulin glargine or / and pharmaceutically acceptable salts thereof, and

(c) metformin or / and pharmaceutically acceptable salts thereof

It is the use of the formulation containing.

Such agents include desPro ³⁶ exendin-4 (1-39) -Lys ₆ -NH ₂ , insulin glargine and metformin in separate formulations as described herein.

The method of the present invention is directed to subjects with type 2 diabetes that cannot be treated with metformin and insulin alone, desPro ³⁶ exendin-4 (1-39) -Lys ₆ -NH ₂ or pharmaceutically acceptable salts thereof It can be treated as an additional therapy used.

The invention is further illustrated by the following examples.

24 week treatment of type 2 diabetes with LICENSATETID (AVE0010) as an additional therapy for insulin glargine and metformin

The subject of this example is a randomized, placebo-controlled 2-cancer during a 24-week double-blind treatment period evaluating the efficacy and safety of lixisenatide in patients with type 2 diabetes who are underrestricted using insulin glargine and metformin. It is a multi-center study of parallel groups.

Primary purpose of the study

The primary objective of this study was to evaluate the effect of lyxenatide on blood glucose inhibition as compared to placebo as an additional therapy for insulin glargine and metformin over a 24 week period.

Second purpose of the study

The secondary purpose is to:

% Of patients with HbA1c <7% and below 6.5%, blood glucose (fasting, postprandial, 7-point self-monitored profile during the standardized dietary challenge test), body weight, lixisenatide for insulin glargine dose Evaluate the effect of (AVE0010).

■ As an additional therapy for insulin glargine and metformin, to evaluate the lixisenatide safety and tolerability.

■ Evaluate the effects of LICENSATETID on treatment satisfaction using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) in participating countries where treatment is approved.

Condition Intervention step Type 2 diabetes mellitus Medication: Lixenatet (AVE0010)
Medication: Placebo
Medication: Insulin Glargine (HOE901) Tier III

Study type: intervention

Study design: treatment, randomization, double blind (subject, guardian, investigator, outcome assessor), placebo control group, parallel assignment, efficacy study

Primary outcome measure:

■ Changes in glycated hemoglobin (HbA1c) (time frame: 24 weeks, designated as a safety issue: none)

Secondary Outcome Measures:

■% of patients with HbA1c below 7% or below 6.5% (time frame: 24 weeks, designated as a safety issue: none)

Post-prandial blood sugar changes (time frame: 24 weeks, designated as a safety issue: none)

Changes in fasting blood sugar (time frame: 24 weeks, designated as a safety issue: none)

■ Change in 7-point self-monitored blood glucose (SMPG) profile (time frame: 24 weeks, designated as a safety issue: none)

■ Change in body weight (time frame: 24 weeks, designated as a safety issue: none)

■ Changes in insulin glargine dose (time frame: 24 weeks, designated as a safety issue: none)

■% of patients requiring rescue treatment during the double blind period (time frame: 24 weeks, designated as a safety issue: none)

Change in treatment satisfaction score (DTSQ questionnaire, time frame: 24 weeks, designated as a safety issue: none)

Number of registered subscribers: 290

Arm Assigned intervention LixiSenateed: Experimental
24 week treatment with lyxenatinide once daily in addition to insulin glargine and metformin (at least 1.5 g / day) injected in the morning within 1 hour before breakfast Medication: Lixenatet (AVE0010)
Subcutaneous injection solution

Medication: Insulin Glargine (HOE901)
Subcutaneous injection solution Placebo: Placebo Comparator
24 week treatment with placebo once daily in addition to insulin glargine and metformin (at least 1.5 g / day) injected in the morning within 1 hour before breakfast Medication: Placebo
Subcutaneous injection solution

Medication: Insulin Glargine (HOE901)
Subcutaneous injection solution

details

The study included three periods:

■ Screening periods up to 14 weeks, including up to 2 weeks of screening and 12 weeks of performance with the introduction and titration of insulin glargine in addition to metformin +/- TZD.

■ At the end of the performance phase, the average fasting SMPG calculated from self-measurement for HbA1c (intensive analysis) is greater than 7% and less than 9% and 7 days before visit (1 week) is 126 mg / dl (7.0 mm / l). Patients under) enter a 24-week double-blind randomized treatment period comparing lixisenatide to placebo (in addition to insulin glargine + metformin +/- TZD).

■ 3 day safety tracking period.

Maximum duration: 39 weeks ± 7 days

Eligibility

Suitable age for study: 18 years and older

Suitable gender for study: Both

Acceptance of Health Applicants: None

Inclusion Criteria:

At screening

■ Type 2 diabetes mellitus, as defined by WHO, diagnosed at least one year before the screening visit (over fasting blood glucose 7 mmol / L (126 mg / dL) or at least 2 hours post-prandial blood glucose 11.1 mmol / L (200 mg / dL)) Sick

■ for at least 3 months: a stable dose of metformin of 1.5 g / day or more, or a metformin stable dose of 1.5 g / day or more, and sulfonylurea (SU) (ended on the first day of visit) and / or thiazolidinedione (TZD) Treatment with Formulations

■ glycated hemoglobin (HbA1c) 7.0 or more and 10% or less

At the end of the stage and before randomization:

■ HbA1c 7.0 or higher and 9% or lower

■ The average fasting autologous blood glucose (SMPG) calculated from self-measurement for 7 days 12 days before visit (-1 week) is 126 mg / dll (7.0 mmol / l) or less

Exclusion Criteria:

At screening:

■ Pregnancy or lactation

■ Women with pregnancy potential without effective contraceptive methods.

■ Type 1 diabetes mellitus

■ Metformin, but not a stable dose of at least 1.5 g / day for at least 3 months prior to the screening visit.

■ Use of oral or injectable antidiabetic or hypoglycemic agents other than metformin, sulfonylureas, and thiazolidinediones within 3 months prior to the screening time, use of weight loss drugs even if not in a stable dose for at least 3 months prior to the screening visit.

■ History of hypoglycemia.

■ History of unexplained pancreatitis, chronic pancreatitis, pancreatic resection, gastric / intestinal surgery, inflammatory bowel disease

■ History of metabolic acidosis including diabetic ketoacidosis within 1 year prior to screening

■ Hemochromatosis or hemolytic anemia, infusion of blood or plasma products within 3 months prior to screening

■ Within the last 6 months before screening: history of heart failure, requiring myocardial infarction, stroke or hospitalization

■ Known history of drug or alcohol abuse within 6 months before screening time

■ Hypertension not suppressed or improperly suppressed at screening, with resting systolic or diastolic blood pressure greater than 180 mmHg or greater than 110 mmHg, respectively.

■ Use of systemic glucocorticoids (except topical or inhaled forms) for at least one week within three months prior to the screening time.

■ Use of study drugs within 3 months prior to screening

Kidney damage found to be greater than 1.4 mg / dL serum creatinine in women and more than 1.5 mg / dL in men

■ Hypersensitivity to insulin glargine or any excipient

■ persistent nausea, including but not limited to gastroparesis, instability (ie, exacerbation), and uncontrolled (ie, persistent nausea and vomiting) gastroesophageal reflux disease requiring medication within 6 months before the screening time And relevant medical history of gastrointestinal diseases associated with vomiting and vomiting

■ Any previous treatment with xixinatide (eg, participating in a previous study with xixinatide)

■ Allergic reactions to any GLP-1 receptor agonist (eg exenatide, liraglutide) or metacresol in the past

Additional exclusion criteria during or at the end of prerandomization phase:

■ Revocation of Consent Form (patient who is unwilling to continue or fails to return)

■ The average fasting SMPG calculated by self-measure for 7 days 12 days prior to visit (-1 week) exceeds 126 mg / dl (7.0 mmol / l).

■ HbA1c measured on day 12 (Week 1) of less than 7% or greater than 9%.

Amylase and / or lipase greater than three times the upper limit of normal study range on day 12 (week 1) of visit

The information is not intended to include all considerations related to the potential participation of patients in clinical trials.

<110> Sanofi-Aventis Deutschland GmbH <120> Method of treatment of diabetes type 2 comprising add-on therapy       to insulin glargine and metformin <130> DE2009 / 200 <160> 2 <170> KopatentIn 1.71 <210> 1 <211> 44 <212> PRT <213> Artificial <220> <223> AVE0010 (44 AS) Position 44 (Lys) is amidated <400> 1 His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu 1 5 10 15 Glu Ala Val Arg Leu Phe Leu Glu Trp Leu Lys Asn Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys         35 40 <210> 2 <211> 39 <212> PRT <213> Artificial <220> <223> Heloderma Suspectum Position 39 (Ser) is amidated <400> 2 His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu 1 5 10 15 Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser         35  

Claims (12)

(a) desPro ³⁶ exendin-4 (1-39) -Lys ₆ -NH ₂ or / and a pharmaceutically acceptable salt thereof, (b) insulin glargine or / and pharmaceutically acceptable salts thereof (c) metformin or / and a pharmaceutically acceptable salt thereof, A method of treating type 2 diabetes mellitus, comprising administering to a subject in need thereof. The method of claim 1, wherein desPro ³⁶ exendin-4 (1-39) -Lys ₆ -NH ₂ or / and a pharmaceutically acceptable salt thereof is administered subcutaneously. The method of claim 1 or 2, wherein insulin glargine or / and a pharmaceutically acceptable salt thereof is administered subcutaneously. The method of any one of claims 1 to 3, wherein metformin is administered orally. The method of claim 1, wherein desPro ³⁶ exendin-4 (1-39) -Lys ₆ -NH ₂ or / and a pharmaceutically acceptable salt thereof is administered with metformin and insulin glargine. Administered as an adjunct therapy for. 6. The method of any one of claims 1 to 5, wherein the subject to be treated is an adult subject. The method of claim 1, wherein type 2 diabetes mellitus is not adequately inhibited with metformin and insulin alone. The method of claim 9, wherein treatment with only 1.5 g / day or more of metformin and 10 units / day or more of insulin for three months does not adequately inhibit type 2 diabetes mellitus. The method of claim 1, wherein the subject to be treated has an HbA1c value in the range of 7% to 10% and / or a fasting blood glucose level of 7 mmol / L or greater and / or 2 hours post-prandial of 11.11 mmol / L or greater. How to have blood sugar. (a) desPro ³⁶ exendin-4 (1-39) -Lys ₆ -NH ₂ or / and a pharmaceutically acceptable salt thereof, (b) insulin glargine or / and pharmaceutically acceptable salts thereof (c) metformin or / and pharmaceutically acceptable salts thereof Pharmaceutical formulations comprising a. The pharmaceutical combination of claim 10 for treating type 2 diabetes mellitus. For preparing a pharmaceutical composition for treating type 2 diabetes mellitus, (a) desPro ³⁶ exendin-4 (1-39) -Lys ₆ -NH ₂ or / and a pharmaceutically acceptable salt thereof, (b) insulin glargine or / and pharmaceutically acceptable salts thereof (c) metformin or / and pharmaceutically acceptable salts thereof Use of Formulations.