JP5980466B2 - Method for treating type 2 diabetes including addition therapy to insulin glargine and metformin - Google Patents

Description

  The subject of the present invention is a method for the treatment of type 2 diabetes with AVE0010 (lixisenatide) as an add-on therapy for insulin glargine and metformin administration.

  Metformin is a biguanide hypoglycemic agent used to treat type 2 diabetes that does not respond to dietary improvement. Metformin improves glycemic control by improving insulin sensitivity. Metformin is usually administered orally.

  Insulin is a polypeptide having 51 amino acid residues. Insulin consists of an A chain having 21 amino acid residues and a B chain having 30 amino acid residues. These chains are connected by two disulfide bridges. Insulin preparations have long been used to treat type 1 and type 2 diabetes. Recently, insulin derivatives and insulin analogues have been used.

  However, control of type 2 diabetes with metformin and insulin may be inadequate. Therefore, in these patients, additional treatment for control of type 2 diabetes may be necessary.

A first aspect of the present invention is a method for treating type 2 diabetes,
(A) Death Pro ³⁶ exendin -4 (1-39) -Lys ₆ -NH ₂ or / and a pharmaceutically acceptable salt;
(B) insulin glargine or / and a pharmaceutically acceptable salt thereof; and (c) metformin or / and a pharmaceutically acceptable salt thereof;
Administering to a subject in need thereof.

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

This compound, DesPro ³⁶ exendin-4 (1-39) -Lys ₆ -NH ₂ (AVE0010, lixisenatide) is a derivative of exendin-4. AVE0010 is described as SEQ ID NO: 93 in International Publication No. 01/04156.
-SEQ ID NO: 1 AVE0010 (44AS)
H-G-E-G-T-F-T-S-D-L-S-K-Q-M-E-E-E-A-V-V-R-L-F-I-E-W- L-K-N-G-G-P-S-S-S-G-A-P-P-P-S-K-K-K-K-K-K-NH ₂ ;
-SEQ ID NO: 2 Exendin-4 (39AS)
H-G-E-G-T-F-T-S-D-L-S-K-Q-M-E-E-E-A-V-V-R-L-F-I-E-W- L—K—N—G—G—P—S—S—G—A—P—P—P—S—NH ₂ .

Exendins are a group of peptides that can reduce blood glucose levels. Its exendin analog AVE0010 is a C of the sequence of natural exendin-4.
Characterized by truncation at the ends. AVE0010 contains six C-terminal lysines that are not present in exendin-4.

  In the context of the present invention, AVE0010 includes pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts of AVE0010 are known to those skilled in the art. A preferred pharmaceutically acceptable salt of AVE0010 for use in the present invention is acetate.

AVE0010 (Des Pro ³⁶ Exendin-4 (1-39) -Lys ₆ —NH ₂ ) or / and a pharmaceutically acceptable salt thereof can be administered parenterally, for example, by subcutaneous injection. As a suitable injection device, for example, a so-called “pen” including a cartridge containing an active ingredient and an injection needle is known. AVE0010 or / and a pharmaceutically acceptable salt thereof in a suitable amount, for example 10-15 μg or 15-20 μg per dose (10-15 μg and progressive titration to 20 μg progressive titration, 20 μg once a day). Is an effective maintenance dose).

  In the present invention, AVE0010 or / and a pharmaceutically acceptable salt thereof is 10 to 15 μg or 15 to 20 μg (incrementally increasing dose from 10 to 15 μg and 20 μg, 20 μg is an effective maintenance amount) once a day. A range of daily doses can be administered. AVE0010 or / and a pharmaceutically acceptable salt thereof can be administered as a single daily injection.

  Insulin glargine (Lantas) is Gly (A21) -Arg (B31) -Arg (B32) -human insulin. 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). As a suitable injection device, for example, a so-called “pen” including a cartridge containing an active ingredient and an injection needle is known. Insulin glargine or / and a pharmaceutically acceptable salt thereof in a suitable amount, eg at least 10 units per day (starting dose is 10 units, 80 units being the maximum possible with a single injection with the pen Dose).

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

  In the present invention, AVE0010 or / and a pharmaceutically acceptable salt thereof can be provided in a liquid composition. AVE0010 liquid compositions suitable for subcutaneous administration are known to those skilled in the art.

  In the present invention, insulin glargine or / and a pharmaceutically acceptable salt thereof can provide a liquid composition. Liquid compositions of insulin glargine suitable for subcutaneous administration are known to those skilled in the art.

  The liquid composition used in the present invention may have an acidic or physiological pH. The acidic pH is preferably in the range of pH 1 to 6.8, pH 3.5 to 6.8, or pH 3.5 to 5. The physiological pH is preferably in the range of pH 2.5 to 8.5, pH 4.0 to 8.5, or pH 6.0 to 8.5. The pH can be adjusted with a pharmaceutically acceptable diluted acid (typically HCl) or a pharmaceutically acceptable diluted base (typically NaOH).

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

  The liquid composition can contain a buffer solution such as phosphate, citrate, and acetate. Preferably, it can contain acetate buffer in an amount of up to 5 μg / mL, up to 4 μg / mL, or up to 2 μg / mL.

  The liquid composition used in the present invention may contain a suitable preservative. Suitable preservatives can be selected from phenol, m-cresol, benzyl alcohol and p-hydroxybenzoate. A preferred preservative is m-cresol. However, preferred liquid compositions do not contain preservatives.

  The liquid composition used in the present invention may contain an isotonic agent. Suitable tonicity agents can be selected from calcium or magnesium containing compounds such as glycerin, lactose, sorbitol, mannitol, glucose, sodium chloride, calcium chloride. The concentration of glycerin, lactose, sorbitol, mannitol and glucose may be in the range of 100-250 mM. The concentration of sodium chloride may be up to 150 mM. A preferred tonicity agent is glycerin.

  Furthermore, the liquid composition may contain L-methionine from 0.5 μg / mL to 20 μg / mL, preferably from 1 μg / mL to 5 μg / mL. Preferably, the liquid composition contains L-methionine.

  Metformin is the international general name for 1,1-dimethylbiguanide (CAS number 657-24-9). In the present invention, the term “metformin” also includes any pharmaceutically acceptable salt thereof.

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

In the present invention, des Pro ³⁶ exendin-4 (1-39) -Lys ₆ -NH ₂ or / and a pharmaceutically acceptable salt is administered in an add-on therapy of metformin and insulin glargine administration. The

  In the present invention, the terms “addition”, “add-on treatment” and “additional therapy” relate to the treatment of type 2 diabetes with metformin, insulin glargine and AVE0010. Metformin, insulin glargine and AVE0010 can be administered within a 24-hour time interval. Metformin, insulin glargine and AVE0010 can each be administered in a once daily dose. 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.

  A subject to be treated with the methods of the invention can have a fasting plasma glucose concentration of at least 7 mmol / L or / and a plasma glucose concentration of at least 11.1 mmol / L for 2 hours after a meal. Subjects can have HbA1c values in the range of 7% to 10%.

  A subject to be treated with the methods of the present invention can be an adult subject. The subject may have an age in the range of 18-50 years.

  The method of the present invention is preferably a method for treating a subject suffering from type 2 diabetes, wherein type 2 diabetes is treated with metformin and insulin alone, eg at least 1.0 g / day dose of metformin and at least 10 A method of treating a subject who is not adequately controlled by treatment for 3 months with insulin at a dose of units, preferably 15-80 units / day.

Another aspect of the present invention is:
(A) Death Pro ³⁶ exendin -4 (1-39) -Lys ₆ -NH ₂ or / and a pharmaceutically acceptable salt;
(B) insulin glargine or / and a pharmaceutically acceptable salt thereof; and (c) metformin or / and a pharmaceutically acceptable salt thereof;
A pharmaceutical combination comprising

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

  The combinations of the invention can be administered as described herein in the context of the methods of the 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 provides a medicament for treating type 2 diabetes.
(A) Death Pro ³⁶ exendin -4 (1-39) -Lys ₆ -NH ₂ or / and a pharmaceutically acceptable salt;
(B) insulin glargine or / and a pharmaceutically acceptable salt thereof; and (c) metformin or / and a pharmaceutically acceptable salt thereof;
Use of a combination including

The drug comprises separate formulations of Des Pro ³⁶ exendin-4 (1-39) -Lys ₆ -NH ₂ , insulin glargine and metformin as described herein.

  The invention is further illustrated by the following examples.

[Example 1]
Treatment of type 2 diabetic patients with lixisenatide (AVE0010) as an add-on therapy of insulin glargine and metformin for 24 weeks The subject of this example is the efficacy of lixisenatide Randomized, placebo-controlled, two-treatment group parallel group, multicenter study, 24-week double-blind treatment period to assess safety.

The primary objective of the study The primary objective of this study is to evaluate the efficacy of lixisenatide as an add-on treatment of insulin glargine and metformin in terms of glycemic control compared to placebo over a period of 24 weeks.

Second purpose of research The second purpose is:
Lixisenatide (AVE0010), the percentage of patients with HbA1c less than 7% and less than 6.5%, plasma glucose (fasting, 7 meal self-measuring profile during the standard diet tolerance test), body weight, Assessing the effect on insulin glargine dose;
Assess the safety and tolerability of lixisenatide as an additional treatment with insulin glargine and metformin;
• assessing the impact of lixisenatide on treatment satisfaction in participating countries with approved diabetes treatment satisfaction questionnaires (states) (DTSQs);
It is.

Study Type: Intervention Research Plan: Treatment, Randomization, Double Blind (Subject, Caregiver, Investigator, Outcome Analyst), Placebo Control, Parallel Intergroup Assignment, Efficacy Study

First outcome measures:
・ Change in glycated hemoglobin (HbA1c) (treatment period: 24 weeks, designation as safety issue: none)

Second outcome measures:
The percentage of patients with HbA1c less than 7% and 6.5% or less (evaluation period: 24 weeks, designated as safety issue: none);
-Postprandial plasma glucose change (treatment period: 24 weeks, designated as safety issue: none);
7 points of change in plasma glucose self-measurement (SMPG) profile (treatment period: 24 weeks, designated as safety issue: none);
-Change in body weight (treatment period: 24 weeks, designation as safety issue: none)
-Change in insulin glargine dose (treatment period: 24 weeks, designated as safety issue: none);
• Percentage of patients who needed relief therapy during the double-blind period (duration: 24 weeks, designated as safety issue: none);
The amount of change in the treatment satisfaction score (DTSQ questionnaire, treatment period: 24 weeks, designated as safety issue: none).

Scheduled to include 290 people.

Detailed description The study has three periods:
A screening period of up to 14 weeks, including an introductory period with a screening phase of up to 2 weeks and a dose determination of insulin glargine in addition to 12 weeks of metformin +/− TZD;
• At the end of this introductory period, HbA1c (value from centralized intensive examination) is 7% or more and 9% or less, and average hunger calculated from self-measured values for 7 days before 12 visit (week 1) Patients with an hourly SMPG of 126 mg / dL (7.0 mmol / L) or less should be compared to placebo for lixisenatide (in addition to insulin glargine + metformin +/- TZD agent) Entering a blinded / randomized treatment period;
-3 days safety follow-up period;
including.
The longest duration is 39 weeks ± 7 days.

Patient eligibility Age eligible for the study: 18 years or older Gender eligible for the study: both Acceptance of healthy individuals: No

Inclusion criteria:
During screening,
• Defined by WHO (fasting plasma glucose 7 mmol / L (126 mg / dL) or higher or postprandial plasma glucose 11.1 mmol / L (200 mg / dL) or higher) diagnosed at least one year before the screening visit) Patients with type 2 diabetes;
At least 3 months: Metformin stable dose of 1.5 g / day or more, or metformin 1.5 g / day or more and sulfonylurea (SU agent) (to be discontinued at Visit 1) and / or thiazolidinedione agent (TZD agent) Being treated with a combination of stable doses of
-Glycated hemoglobin (HbA1c) is 7.0 or more and 10% or less;

At the end of the introduction period, before randomization,
-HbA1c is 7.0 or more and 9% or less;
-Average self-measured fasting plasma glucose (SMPG) calculated from self-measured values for 7 days before Visit 12 (Week 1) is not more than 126 mg / dL (7.0 mmol / L);
It is to be.

Exclusion criteria:
At the time of screening,
・ Pregnancy or breastfeeding;
・ Women who have not had effective contraceptives and are likely to become pregnant;
・ Type 1 diabetes;
• Metformin is not a stable dose of at least 1.5 g / day for at least 3 months before the screening visit;
-Use of oral or injectable antidiabetics or hypoglycemic agents other than metformin, sulfonylurea and thiazolidinedione within 3 months before screening, weight loss agents that are not stable doses within at least 3 months prior to screening visit use;
・ History without hypoglycemia awareness;
-History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy, abdominal / gastric surgery, inflammatory bowel disease;
-History of metabolic acidosis including diabetic ketoacidosis within 1 year before screening;
-Abnormal hemochromatosis or hemolytic anemia, acceptance of blood or plasma products within 3 months prior to screening;
A history of myocardial infarction, stroke, or heart failure requiring hospitalization within at least 6 months prior to screening;
A clear history of drug or alcohol abuse within 6 months prior to screening;
• Hypertension with resting systolic or diastolic blood pressure exceeding 180 mmHg or exceeding 110 mmHg, respectively, not controlled at screening or inappropriately controlled;
-Systemic use of glucocorticoids for a week or more within 3 months before screening (excluding topical application or inhalation);
• Use of any clinical trial drug within 3 months prior to screening;
• Renal disorder defined by serum creatinine greater than 1.4 mg / dL in women and greater than 1.5 mg / dL in men;
A history of hypersensitivity to insulin glargine or any of its additives;
• Gastroesophageal reflux disease within 6 months prior to screening, with gastric failure and unstable (ie, exacerbated) and poorly controlled (ie, prolonged nausea and vomiting) requiring medical treatment A clinically relevant history of gastrointestinal disorders associated with prolonged nausea and vomiting, including but not limited to;
Any previous treatment with lixisenatide (eg, participation in previous clinical studies with lixisenatide);
An allergic reaction to any GLP-1 receptor agonist (eg exenatide, liraglutide) or metacresol in the past.

Additional exclusion criteria during the introductory period or at the end before randomization:
Withdrawal of informed consent (patients who do not wish to continue or do not return);
-Average self-measured fasting plasma glucose (SMPG) calculated from self-measurement values for 7 days before Visit 12 (Week 1) exceeds 126 mg / dL (7.0 mmol / L);
HbA1c measured at Visit 12 (Week 1) is less than 7% or greater than 9%;
-Amylase and / or lipase at Visit 12 (Week 1) exceeds 3 times the upper limit of normal laboratory values.

  The above information is not intended to include all considerations regarding the patient's potential participation in clinical trials.

Claims (9)

A combination for use in the treatment of type 2 diabetes, the combination comprising:
(A) Death Pro ³⁶ exendin -4 (1-39) -Lys ₆ -NH ₂ or / and a pharmaceutically acceptable salt;
(B) insulin glargine or / and a pharmaceutically acceptable salt thereof; and (c) metformin or / and a pharmaceutically acceptable salt thereof;
Only including,
Here, the subject to be treated is a person who has a HbA1c value in the range of 7% to 9% by treatment with metformin and insulin alone,
The above combination. Death Pro ³⁶ exendin -4 (1-39) -Lys ₆ -NH ₂ or / and a pharmaceutically acceptable salt thereof is administered by subcutaneous, Combination according to claim 1.   The combination according to claim 1 or 2, wherein insulin glargine or / and a pharmaceutically acceptable salt thereof is administered subcutaneously.   4. A combination according to any one of claims 1 to 3, wherein metformin is administered orally. Death Pro ³⁶ exendin -4 (1-39) -Lys ₆ -NH ₂ or / and a pharmaceutically acceptable salt thereof is administered as adjunctive therapy to administration of metformin and insulin glargine, any of claims 1 to 4 A combination according to item 1.   The combination according to any one of claims 1 to 5, wherein the subject to be treated is an adult subject.   The combination according to any one of claims 1 to 6, wherein type 2 diabetes is not adequately controlled with metformin and insulin alone.   8. A combination according to claim 7, wherein treatment for 3 months with at least 1.5 g / day dose of metformin and at least 10 units / day dose of insulin alone does not adequately control type 2 diabetes. Fasting plasma glucose concentration even without the least subject 7 mmol / L to be treated, or / and a plasma glucose postprandial 2 hours of at least 11.1 mmol / L, to any one of claims 1-8 Combination described.