Methods of treating diabetes

Abstract

Described herein are fixed doses and dosing regimens of long-acting insulin receptor agonists suitable for once-weekly dosing, such as weekly basal insulin-Fc (BIF).

Description

Technical Field

[0001] The present invention relates to methods, uses, dosage regimens and products for treating diabetes. More specifically, the present invention relates to methods for treating diabetes using compositions and products comprising a long-acting insulin receptor agonist. The methods described herein include fixed doses and dosage regimens of long-acting insulin receptor agonists suitable for once-weekly dosing such as weekly basal insulin-Fc (BIF), and product presentations for use in such regimens.

Background Art

[0002] Diabetes is a chronic disorder characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Type 2 diabetes (T2D) is characterized by elevated blood glucose resulting from insulin secretion deficiency, insulin resistance, excessive hepatic glucose production, and / or contributions of all of the foregoing. Treatment of patients with T2D typically begins with prescribed weight loss, exercise, and a diabetic diet, but when these measures fail to control elevated blood glucose, oral agents and incretin-based therapies may be required. When these agents remain insufficient, treatment with insulin is considered. Patients with T2D whose disease has progressed to the point where insulin therapy is required generally begin with once-daily injection of long-acting basal insulin.

[0003] Currently available basal insulin analogs include insulin glargine, marketed under the trade names LANTUS®, TOUJEO®, BASALGLAR®, and SEMGLEE®; insulin detemir, marketed under the trade name LEVEMIR®; and insulin degludec, marketed under the trade name TRESIBA®. Each of these insulins is indicated for once-daily administration. Many T2D patients hesitate to initiate and / or adhere to insulin therapy, partly due to the need for daily injections and the dose requirements that necessitate regular variable dose calculations. Therefore, even after initiating insulin therapy, many diabetic patients are unwilling, unable, or incapable of adhering to the insulin therapy necessary to maintain strict control of blood glucose levels.

[0004] Research is underway to identify insulin products with a longer duration of action, and therefore requiring less frequent injections than currently available insulin products (including approximately once a week). For example, WO2014 / 009316 describes insulin derivatives that have a sufficiently long duration of action to allow diabetic patients to administer them approximately once a week to obtain a sufficient basal dose of insulin. Treatment regimens for these derivatives are proposed in WO2016 / 001185. US2016 / 0324932 describes fusion proteins, including BIF, with an extended duration of action at the insulin receptor sufficient to be administered approximately once a week. Specific dosing regimens are not described.

[0005] Despite these disclosures, there is still a need for insulin therapies that can be administered in a simple and convenient dosing regimen with fewer injections than currently available insulin products, while still providing adequate glycemic control. There is also still a need to present therapies that offer a simpler, more convenient, and / or less painful patient experience. There remains a need for therapies that use such insulin therapies without increasing or reducing the risk of hypoglycemia compared to currently available insulin products. [Overview of the project]

[0006] Accordingly, the present invention provides a method for providing blood glucose control to a patient with type 2 diabetes (T2D) requiring such control, comprising administering to the patient a fixed dose of BIF selected from the group consisting of 100, 150, 250, and 400 U once a week.

[0007] The present invention also, a) The patient shall be administered an initial dose of 100 U of basal insulin-Fc (BIF) once a week, b) After at least 4 weeks with a dose of 100U, increase the dose to 150U BIF once a week, c) After at least 4 weeks with a dose of 150U, increase the dose to 250U BIF once a week, d) A method for providing glycemic control in patients with type 2 diabetes (T2D), comprising increasing the dose to 400U BIF once a week after at least 4 weeks at a dose of 250U.

[0008] In a particular embodiment, steps b) to d) are performed when the patient's fasting blood glucose (FG) is >130 mg / dL.

[0009] The present invention also, a) A fixed dose of BIF in an amount selected from the group consisting of 100, 150, 250, and 400 U, b) Phosphate at a concentration of approximately 5-10 mM, c) Contains glycerol at a concentration of approximately 15-35 mM, The present invention provides an aqueous pharmaceutical composition having a pH of approximately 5.5 to 7.5.

[0010] The present invention also provides a single-use auto-injector for use in improving blood glucose control in T2D patients, comprising a fixed dose of BIF selected from the group consisting of 100, 150, 250, and 400 U. [Modes for carrying out the invention]

[0011] This application provides multiple embodiments of drug regimens, uses, and treatment methods for long-acting insulin receptor agonists suitable for once-weekly administration, including BIF, as described in U.S. Patent Application Publication No. 2016 / 0324932. In certain embodiments, the regimens and methods described herein include the administration of a fixed dose of BIF. In other embodiments, the regimens and methods described herein include determining whether the fixed dose of BIF used to treat T2D patients should be changed. In other embodiments, the regimens and methods described herein include the identification of a simple and convenient device for administering a fixed dose of BIF. In other embodiments, the regimens and methods described herein describe a non-preserved formulation for use when providing a fixed dose of BIF.

[0012] BIF, also known as insulin efcitra alfa, contains a dimer of an insulin receptor agonist fused to the human IgG Fc region, the insulin receptor agonist containing an insulin B chain analog fused to an insulin A chain analog via the use of a first peptide linker, the C-terminal residue of the insulin A chain analog directly fused to the N-terminal residue of a second peptide linker, and the C-terminal residue of the second peptide linker directly fused to the N-terminal residue of the human IgG Fc region. BIF is identified by CAS registry number 2131038-11-2 and has the following chemical names: (1) Immunoglobulin G2 (human Fc fragment), insulin [47-threonine, 51-aspartic acid, 58-glycine] (human A chain) fusion protein with a dimerized peptide (synthetic 20-amino acid linker) fusion protein, insulin [16-glutamic acid, 25-histidine, 27-glycine, 28-glycine, 29-glycine, 30-glycine] (human B chain) fusion protein with a peptide (synthetic 7-amino acid linker); and (2) Tris(tetraglycylglutaminyl)pentaglysyl(59-78) homosapiens immunoglobulin heavy chain constant γ2{del-CH1, hinge-(7-12), CH2, CH3[K 107 >del(300)]}(79-299), Homo sapiens insulin B chain [Y16>Y(16), F25>H(25), TPKT27-30>GGGG(27-30)](1-30) fusion protein having diglycylceryltetraglycyl(31-37) insulin A chain [I10>T(47), Y14>D(51), N21>G(58)](38-58) fusion protein having dimer (80-80':83-83')-bisdisulfide.

[0013] Each monomer of BIF has the amino acid sequence described in SEQ ID NO: 1. [ka] (Sequence ID 1). Each monomer contains intrachain disulfide bonds between cysteine ​​residues at positions 7 and 44, 19 and 57, 43 and 48, 114 and 174, and 220 and 278. Two monomers are joined by a disulfide bond between cysteine ​​residues at positions 80 and 83 to form a dimer. The structure, function, and production of BIF are described in more detail in U.S. Patent Application Publication No. 2016 / 0324932.

[0014] As used herein, the term "BIF" means any insulin receptor agonist comprising two monomers having the amino acid sequence of SEQ ID NO: 1, and includes any protein that is the subject of a regulatory submission seeking approval of an insulin receptor agonist product, relying on all or partial data submitted to the regulatory authority by Eli Lilly and Company with respect to BIF, regardless of whether the party seeking approval of the product actually identifies the insulin receptor agonist as BIF or uses some other terminology.

[0015] BIF is a long-acting insulin receptor agonist with a pharmacokinetic and pharmacodynamic profile that, when administered at a frequency of once a week or less, is sufficiently sustained to control intermeal blood glucose levels. Unlike existing insulin therapies that require individualized variable dose determination to suit the patient's needs at a given time, BIF's relatively flat pharmacokinetic profile, with a peak-to-trough ratio close to 1, allows for use in simple and convenient dosing regimens, including the administration of a fixed number of individual doses. Such an approach is similar to fixed-dose pharmacotherapy in that a limited number of dose intensities are offered and the maximum available dose is restricted.

[0016] The provision of these simplified doses is expected to facilitate the transition to insulin therapy in T2DM patients who have not received insulin therapy. Such regimens may help alleviate the clinical inertia that limits the effective titration of basal insulin in actual clinical practice. Therefore, while the methods, uses, and regimens of the present invention can be used to provide glycemic control in a wide range of T2D patients, they are particularly suitable for patients who are not currently being treated with basal insulin and have started with a once-weekly insulin receptor agonist (referred to herein as “insulin-naïve” patients).

[0017] In certain embodiments, the patient has a glycated hemoglobin A1c (HbA1c) value of 7.0% to 10.0%. In certain embodiments, the patient is also treated with 0 to up to 3 additional antihyperglycemic therapies selected from the group consisting of thiazolidinediones (TZDs), dipeptidyl peptidase IV (DPP4) inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, biguanides (e.g., metformin), alpha-glucosidase inhibitors, or glucagon-like peptide-1 (GLP-1) receptor agonists. In certain embodiments, the patient has a body mass index (BMI) ≤ 45 kg / m2. In certain embodiments, the patient treated with such a fixed-dose regimen is an insulin-naive T2DM patient with an HbA1c of 7.5% to 10.0% (including both extremes) and is receiving two or more oral antihyperglycemic agents, with or without GLP-1 RAs.

[0018] In certain embodiments, the patient begins treatment with an initial dose and, after treatment with the initial dose for a given period, is escalated to the next higher dose as needed. For example, the patient may be administered the same fixed dose for several weeks, e.g., four weeks, and then the dose may be escalated to the next fixed dose level if the patient requires further glycemic control. In certain embodiments, the patient is considered to require further glycemic control if the patient's FG exceeds a certain level, typically about 120–140 mg / dL. In certain embodiments, the patient is considered to require further glycemic control if the patient's FG is >120 mg / dL. In certain embodiments, the patient is considered to require further glycemic control if the patient's FG is >140 mg / dL. In certain preferred embodiments, the patient is considered to require further glycemic control if the patient's FG is >130 mg / dL. In certain embodiments, if the patient requires further glycemic control after treatment with the highest fixed dose, the patient transitions to treatment with a variable dose regimen outside the scope of this disclosure.

[0019] In certain embodiments, if a patient's FG falls below a certain level, the patient may be reduced to a previously lower dose. In certain embodiments, if a patient's FG falls below a certain level (e.g., <80 mg / dL), the patient may be reduced to a previously lower dose. In certain embodiments, if a patient experiences one or more episodes of nocturnal hypoglycemia or two or more episodes of any kind of hypoglycemia while receiving the lowest dose, the patient may discontinue treatment.

[0020] The dose of BIF for use in the methods, uses and regimens of the present invention can be expressed either in insulin units (IU or U) or in mg of BIF. In certain embodiments where the dose of BIF is expressed in U, the available dose is from about 50 to about 1050 U. In certain embodiments, the dose is from about 100 to 500 U. In certain embodiments, the dose is selected from the group consisting of 100, 150, 200, 250, 300, 350, 400, 450 and 500 U. In certain preferred embodiments, the available doses are 100, 150, 250 and 400 U. The fixed doses described herein are intended to be administered once weekly, so the unit specified for a given dose indicates the total number of units of insulin activity that the dose is intended to provide over one week.

[0021] Preferred dosing regimens consisting of such doses are set forth in Table 1 below.

Table 1

[0022] According to the regimen shown in Table 1, the patient starts with an initial dose of 100 U, and if the patient's FG exceeds 130 mg / dL, the dose is increased to 150 U after at least 4 weeks of treatment. Similarly, the dose of a patient being treated with a 150 U dose is increased to 250 U after at least 4 weeks of treatment at the 150 U dose if the patient's FG exceeds 130 mg / dL. Similarly, the dose of a patient being treated with a 250 U dose is increased to 400 U after at least 4 weeks of treatment at the 250 U dose if the patient's FG exceeds 130 mg / dL. Finally, if the patient's FG is below 80 mg / dL, the patient can always reduce the dose to the previous lower dose. In addition, if the patient experiences one or more episodes of nocturnal hypoglycemia or two or more episodes of any hypoglycemia while receiving the lowest dose, the patient may discontinue treatment.

[0023] In a specific embodiment wherein the dose of BIF is expressed in mg, the available dose is selected from the group consisting of 1, 1.5, 2, 2.5, 2.85, 3, 3.5, 4, 4.3, 4.5, 5, 5.5, 5.7, 6.5, 7, 7.15, 8, 8.6, 9, 10, 11, 11.45, 12, 12.85, 13, 14, 14.3, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 mg. In a specific embodiment, the available dose is selected from the group consisting of 1, 1.5, 2, 2.85, 3, 4.3, 4.5, 6, 7.15, 10, 11.45, 12, 12.85 and 14.3 mg. In a specific embodiment, the available doses are 2.85, 4.3, 7.15 and 11.45 mg.

[0024] As used herein, the term "fixed dose" refers to a specific dose that is available in and administered from a single dosage form. The fixed-dose dosage form of BIF described herein may be any dosage form usable for subcutaneous administration of an aqueous solution, such as a vial, cartridge, pen-type injector or pump, but in a preferred embodiment, the fixed dose is provided in a single-use automatic injector such as those described in U.S. Patent No. 8,734,394.

[0025] As used herein, the term "fixed-dose regimen" refers to a therapeutic regimen comprising a plurality of fixed doses, and guidelines for determining which fixed dose should be administered at a given time point. For example, a fixed-dose regimen may comprise a plurality of sets of fixed doses and guidelines for determining which of said fixed doses should be administered in a given week.

[0026] The advantage of the fixed-dose and regimens described herein is that they can be implemented using formulations that do not require the use of preservatives. Existing insulin therapies are typically administered using variable-dose regimens with multiple-use presentations that require conserved formulations with sufficient antimicrobial efficacy to meet regulatory requirements, whereas the fixed-dose formulations described herein can be provided in non-conserved formulations, preferably administered from single-use devices. Since phenolic preservatives used in existing insulin therapies, such as metacresol and phenol, are known to cause stability problems in proteins and peptides, the use of such non-conserved formulations may be advantageous over conventional conserved insulin formulations from a stability standpoint. Accordingly, such formulations typically require the inclusion of additional excipients to ensure sufficient stability.

[0027] The non-preserved formulation for use in the fixed-dose regimen of the present invention comprises a fixed dose of BIF, a buffer, and an isotonic agent. In certain embodiments, the concentration of BIF is about 5 to about 25 mg / mL. In certain embodiments, the concentration of BIF is such that it enables the administration of a fixed dose selected from the group consisting of 100, 150, 250, and 400 insulin units (IU or U). In certain embodiments, the amount of BIF is selected from the group consisting of 100, 150, 250, and 400 insulin units (IU or U). In certain embodiments, the amount of BIF is selected from the group consisting of 2.85, 4.3, 7.15, and 11.45 mg. In certain embodiments, the fixed dose of BIF is provided in a 0.5 mL solution having a BIF concentration selected from the group consisting of 5.7, 8.6, 14.3, and 22.9 mg / mL.

[0028] Examples of buffers include dibasic sodium phosphate, citrate, sodium acetate, and phosphates such as tris(hydroxymethyl)aminomethane or TRIS. In certain embodiments, the composition of the present invention comprises a citrate buffer at a concentration in the range of about 5 to about 10 mM. In certain embodiments, the composition of the present invention comprises a phosphate at a concentration in the range of about 5 to about 10 mM. In certain preferred embodiments, the composition of the present invention comprises a phosphate at a concentration of about 5, 6, 7, 8, 9, or 10 mM. In certain embodiments, the buffer is about 10 mM.

[0029] Typical isotonic agents include glycerol (glycerin), mannitol, and sodium chloride. When the addition of an isotonic agent is necessary, glycerin is preferred. In certain embodiments, the concentration of glycerol is about 10 to about 50 mg / mL. In certain embodiments, the concentration of glycerol is about 15 to about 35 mg / mL. In certain embodiments, the concentration of glycerol is selected from the group consisting of about 15, 17, 20, 21, and 35 mg / mL. In certain preferred embodiments, the concentration of glycerin is about 25 mg / mL.

[0030] In certain embodiments, the composition has a pH of about 5.5 to about 7.5, preferably at least about 6.1. In certain embodiments, the pH is in the range of about 6.2 to about 7.4. In certain embodiments, the pH is in the range of about 6.3 to about 6.9. In particularly preferred embodiments, the pH is about 6.5.

[0031] The composition may also contain other excipients, including stabilizers such as surfactants. Examples of surfactants disclosed for use in parenteral pharmaceutical compositions include polysorbates such as polysorbate 20 (TWEEN® 20) and polysorbate 80 (TWEEN 80), polyethylene glycols such as PEG400, PEG3000, and TRITON® X-100, polyethylene glycols such as polyoxyethylene (23) lauryl ether (CAS number: 9002-92-0, sold under the trade name BRIJ®), alkoxylated fatty acids such as MYRJ®, and poly This includes propylene glycol, block copolymers such as poloxamer 188 (CAS number 9003-11-6, sold under the trade name PLURONIC® F-68) and poloxamer 407 (PLURONIC® F127), sorbitan alkyl esters (e.g., SPAN®), polyethoxylated castor oil (e.g., KOLLIPHOR®, CREMOPHOR®), and derivatives thereof such as trehalose and trehalose laurate esters.

[0032] In certain preferred embodiments, the composition comprises a surfactant selected from the group consisting of polysorbate 20, polysorbate 80, and poloxamer 188. Poloxamer 188 is most preferred. In certain embodiments, the concentration of the surfactant is in the range of about 0.01 to about 10 mg / mL or about 0.1 to about 0.5 mg / mL. In preferred embodiments where the surfactant is poloxamer 188, the concentration of poloxamer 188 is about 0.4 mg / mL.

[0033] In certain embodiments, the composition comprises BIF at a concentration of 2.5 to 25 mg / mL, a buffer, and an isotonic agent, and has a pH of 5.5 to 7.5. In certain embodiments, the composition contains BIF in an amount of 100 to 400 U. In certain embodiments, the composition contains BIF in an amount selected from the group consisting of about 100, 150, 250, or 400 U. In certain embodiments, the buffer is a phosphate buffer at a concentration of 5 to 10 mM, the isotonic agent is glycerol at a concentration of 15 to 35 mg / mL, and the pH is 6.3 to 6.9. In certain embodiments, the composition further comprises a surfactant. In certain embodiments, the surfactant is poloxamer 188 at a concentration of 0.01 to 10 mg / mL. In certain embodiments, the composition comprises an amount of BIF selected from the group consisting of about 100, 150, 250, or 400 U, a phosphate at a concentration of about 10 mM, glycerol at a concentration of about 25 mg / mL, poloxamer 188 at a concentration of about 0.4 mg / mL, and has a pH of about 6.5. In certain embodiments, the composition does not contain preservatives. In certain embodiments, the composition does not contain zinc as a stabilizer.

[0034] A preferred composition has sufficient chemical and physical stability to allow storage at 5°C for at least 24 months and at temperatures up to 30°C for at least 2 weeks without losing stability. In certain embodiments, the composition is stable enough to allow storage at 25°C for 8 weeks. In certain embodiments, the composition is stable enough to allow storage at 25°C for 12 weeks. In certain embodiments, the composition is stable enough to allow storage at 30°C for 8 weeks. In certain embodiments, the composition is stable enough to allow storage at 30°C for 12 weeks.

[0035] As used herein, the terms “approximately” and “about” are intended to refer to the degree of error of an amount or quantity given, taking into account the nature or precision of the measurement. For example, the degree of error may be indicated by the number of significant figures provided for the measurement, as understood in the art, and may include, but is not limited to, a variation of ±1 of the most accurate significant figures reported for the amount or quantity. Typically, an exemplary degree of error is within 20 percent (%) of a given value or range of values, preferably within 10 percent, and more preferably within 5 percent. The numerical values ​​given herein are approximations unless otherwise stated, and the term “about” means that they can be inferred unless explicitly stated.

[0036] As used herein, the terms “dose” or “dose (plural)” refer to the amount of insulin receptor agonist suitable for a once-weekly dose administered to an individual at a specific time.

[0037] As used herein, the terms “fasting glucose,” “FG,” “fasting blood glucose,” “FBG,” “fasting plasma glucose,” or “FPG” refer to plasma glucose levels from a blood sample taken or obtained by continuous glucose monitoring (CGM) after a patient has fasted overnight. When used in the context of determining a suitable dose of insulin receptor agonist for a once-weekly administration to a patient, unless otherwise specified herein, the patient’s FG is determined as the median FG over multiple days, typically at least 3 to 7 days.

[0038] As used herein, terms such as “treatment,” “to treat,” and “to treat” include delaying or reducing the progression of a disease or disorder. These terms also include alleviating, relieving, reducing, eliminating, or reducing one or more symptoms of a disorder or condition, even if the disorder or condition is not actually eliminated and the progression of the disorder or condition itself is not delayed or reversed.

[0039] "Blood glucose control" refers to the blood glucose level in question, as measured by, for example, blood glucose levels and / or HbA1c levels; "to provide" blood glucose control means to maintain or improve blood glucose control; "to maintain" blood glucose control means to maintain the time that blood glucose levels are within the target range and / or to maintain or reduce HbA1c; "to improve" blood glucose control means to extend the time that blood glucose levels are within the target range and / or to reduce HbA1c; and "to require further blood glucose control" means the need to extend the time that blood glucose levels are within the target range and / or to reduce HbA1c.

[0040] HbA1c refers to the level of glycated hemoglobin, which is produced when hemoglobin binds with glucose in the blood. HbA1c levels are a commonly used measure of blood glucose control in patients with diabetes.

[0041] "Hypoglycemia" refers to low blood glucose levels, and a hypoglycemic "episode" refers to a case of hypoglycemia observed, for example, in a plasma glucose test or from a personal glucose monitor (BGM) or continuous glucose monitoring (CGM) device, which is often below approximately 70 mg / dL.

[0042] A “severe” hypoglycemic episode is a severe event characterized by altered mental and / or physical conditions requiring assistance in treating hypoglycemia. For example, a subject whose mental state was altered and who was unable to help care for themselves, or was semi-conscious or unconscious, or who experienced a seizure- or non-seizure-associated coma and required assistance from another person to actively administer carbohydrates, glucagon, or other compositional measures. Glucose measurements may not be available during such an event, but neurological recovery resulting from a return to normal glucose levels is considered sufficient evidence that the event was induced by low glucose levels.

[0043] The treatment methods, regimens, and uses described herein may be provided concurrently or sequentially in combination with other T2D treatments, including oral T2D drugs such as metformin, incretins, and / or other injectable agents. Examples of incretins include GLP-1 receptor agonists such as dulaglutide or semaglutide, GIP / GLP-1 coagonists such as tilzepatide, and GIP / GLP-1 / glucagon triple agonists. In certain embodiments, the treatment methods, regimens, and uses described herein may be provided concurrently or sequentially in combination with other basal insulins and / or rapid-acting insulins.

[0044] Certain embodiments of the methods, uses, and treatments described herein are as follows:

[0045] Embodiment 1. A method for improving blood glucose control in a person with diabetes, a) Identify subjects with diabetes, b) Administer to the subject a first dose of an insulin receptor agonist suitable for weekly administration for at least one week, c) Measure the target FG multiple times in the week following the most recent administration of the first dose, d) Determine whether the median FG value of the subject from the measurements described in step c) was >130 mg / dL, e) (i) If the subject's FG is >130 mg / dL, switch the subject to the second dose of an insulin receptor agonist suitable for once-weekly administration, or (ii) If the subject's FG is <130 mg / dL, maintain the subject at the first dose of an insulin receptor agonist suitable for once-weekly administration, and select the next dose of the insulin receptor agonist to be administered according to these criteria. f) A method comprising administering the dose selected in step e).

[0046] Embodiment 2. The dose of the insulin receptor agonist administered in step f) is a second dose of the insulin receptor agonist suitable for once-weekly administration, and the second dose of the insulin receptor agonist suitable for once-weekly administration has been administered for one week or more. g) Measure the target FG multiple times in the week following the most recent administration of the second dose, h) Determine whether the median FG value for the subject from the measurements described in step g) was >130 mg / dL, i) Select the next dose of insulin receptor agonist to be administered according to the following criteria: (i) if the subject's FG is >130 mg / dL, switch the subject to the third dose of insulin receptor agonist suitable for once-weekly administration; (ii) if the subject's FG is <81 to 130 mg / dL, maintain the subject at the second dose of insulin receptor agonist suitable for once-weekly administration; or (iii) if the subject's FG is <81, switch the subject to the first dose of insulin receptor agonist suitable for once-weekly administration. j) The method according to Embodiment 1, further comprising administering the dose selected in step i).

[0047] Embodiment 3. The dose of the insulin receptor agonist administered in step j) is a third dose of the insulin receptor agonist suitable for once-weekly administration, and the third dose of the insulin receptor agonist suitable for once-weekly administration has been administered for one week or more. k) Measure the target FG multiple times in the week following the most recent administration of the third dose, l) Determine whether the median FG value of the subject from the measurements described in step k) was >130 mg / dL, m) Select the next dose of insulin receptor agonist to be administered according to the following criteria: (i) if the subject's FG is >130 mg / dL, switch the subject to the fourth dose of insulin receptor agonist suitable for once-weekly administration; (ii) if the subject's FG is between 81 and 130 mg / dL, maintain the subject at the third dose of insulin receptor agonist suitable for once-weekly administration; or (iii) if the subject's FG is <81, switch the subject to the second dose of insulin receptor agonist suitable for once-weekly administration. The method of Embodiment 2, further comprising administering the dose selected in step m) to the target.

[0048] Embodiment 4. The dose of the insulin receptor agonist administered in step n) is a fourth dose of the insulin receptor agonist suitable for once-weekly administration, and the fourth dose has been administered for one week or more. o) After the most recent administration of the fourth dose, measure the target FG multiple times, p) Determine whether the median FG value of the subject from the measurements described in step o) was >140 mg / dL for at least two consecutive weeks, q) (i) If the subject's FG has been >140 mg / dL for two consecutive weeks, determine the next dose to be administered according to the criteria described in any one of claims 11-17, 23-24, 30, 32, or 36; (ii) If the subject's FG has been <81 after administration of the latest dose, switch the subject to a third dose of an insulin receptor agonist suitable for once-weekly administration; or (iii) If the subject's FG has been >81 after administration of the latest dose and has not been >140 mg / dL for two consecutive weeks, select the next dose of an insulin receptor agonist to be administered according to the criteria of maintaining the subject at a fourth dose of an insulin receptor agonist suitable for once-weekly administration. The method according to Embodiment 3, further comprising administering the dose selected in step q) to the target.

[0049] Embodiment 5. The method according to any one of Embodiments 1 to 4, wherein if the patient experiences one or more episodes of nocturnal hypoglycemia or two or more episodes of hypoglycemia while receiving the first dose, the patient discontinues treatment.

[0050] Embodiment 6. The method according to any one of Embodiments 1 to 5, wherein the patient has T2DM.

[0051] Embodiment 7. The method according to any one of Embodiments 1 to 6, wherein the patient is insulin-naive.

[0052] Embodiment 8. The method according to any one of Embodiments 1 to 7, wherein the patient has uncontrolled hyperglycemia.

[0053] Embodiment 9. The method according to any one of Embodiments 1 to 8, wherein the patient has an HbA1c of 7.5-10.0%.

[0054] Embodiment 10. The method according to any one of Embodiments 1 to 9, wherein the patient is receiving two or more oral antihyperglycemic agents.

[0055] Embodiment 11. The method according to any one of Embodiments 1 to 10, wherein the patient is receiving a GLP-1 receptor agonist.

[0056] Embodiment 12. The method according to any one of Embodiments 1 to 11, wherein the insulin receptor agonist suitable for once-weekly administration is BIF.

[0057] Embodiment 13. The method according to Embodiment 12, wherein the first dose of BIF is 1.5 mg.

[0058] Embodiment 14. The method according to any one of Embodiments 1 to 13, wherein the second dose of BIF is 3.0 mg.

[0059] Embodiment 15. The method according to any one of Embodiments 1 to 14, wherein the third dose of BIF is 4.5 mg.

[0060] Embodiment 16. The method according to any one of Embodiments 1 to 15, wherein the fourth dose of BIF is 6.0 mg.

[0061] A method for improving blood glucose control in a patient with diabetes, comprising administering a fixed dose of BIF selected from the group consisting of Embodiment 17.1.5, 3.0, 4.5, and 6.0 mg.

[0062] Embodiment 18. The method according to any one of Embodiments 1 to 17, wherein a dose of insulin receptor agonist has been administered for at least 4 weeks before selecting the next dose of insulin receptor agonist to be administered.

[0063] Embodiment 19. A method for providing blood glucose control in a person with diabetes who requires further blood glucose control, a) Identify individuals who require further blood glucose control, b) The subject shall be administered a first dose of an insulin receptor agonist suitable for weekly administration for a minimum of four weeks, c) a method comprising determining whether the subject requires further blood glucose control, and if the subject requires further blood glucose control as determined in step c), administering to the subject a second dose of an insulin receptor agonist suitable for weekly administration for a minimum of four weeks.

[0064] Embodiment 20. The subject is administered a second dose of an insulin receptor agonist suitable for weekly administration for a minimum of 4 weeks. d) To determine whether the subject requires further blood glucose control, e) The method according to Embodiment 19, further comprising administering to the subject a third dose of an insulin receptor agonist suitable for weekly administration for a minimum of four weeks if the subject requires further blood glucose control.

[0065] Embodiment 21. The subject is administered a third dose of an insulin receptor agonist suitable for weekly administration for a minimum of four weeks. f) To determine whether the subject requires further blood glucose control, g) If the subject requires further blood glucose control, the method according to Embodiment 20, further comprising administering a fourth dose to the subject once a week for at least two weeks.

[0066] Embodiment 22. The method according to any one of Embodiments 19 to 21, wherein the insulin receptor agonist is BIF.

[0067] Embodiment 23. The method according to Embodiment 22, wherein the first dose is 1.5 mg.

[0068] Embodiment 24. The method according to Embodiment 23, wherein the second dose is 3.0 mg.

[0069] Embodiment 25. The method according to Embodiment 24, wherein the third dose is 4.5 mg.

[0070] Embodiment 26. The method according to Embodiment 25, wherein the fourth dose is 6.0 mg.

[0071] Embodiment 27. The subject is administered 6.0 mg of BIF once a week for at least two weeks. h) To determine whether the subject requires further blood glucose control, i) If the subject requires further blood glucose control, administer to the subject a dose of BIF determined according to any one of the criteria described in claims 11-17, 23-24, 30, 32, or 36, the method according to Embodiment 26.

[0072] Embodiment 28. A method for providing blood glucose control to a patient with type 2 diabetes (T2D) requiring such control, comprising administering to the patient a fixed dose of basal insulin-Fc (BIF) once a week, selected from the group consisting of 100, 150, 250, and 400 U.

[0073] Embodiment 29. The method according to Embodiment 28, wherein the first dose of BIF administered to the patient is 100 U.

[0074] Embodiment 30. The method according to Embodiment 28 or 29, wherein the patient is administered the same dose for at least 4 weeks, and the dose is increased if the patient requires additional blood glucose control.

[0075] Embodiment 31. The method according to any one of Embodiments 28-30, wherein the patient's dose is increased if the patient's FG is >130 mg / dL after treatment with a first fixed dose for at least 4 weeks.

[0076] Embodiment 32. The method according to Embodiment 30 or 31, wherein the patient's dose is increased only if the patient has not had an episode in which blood glucose < 70 mg / dL.

[0077] Embodiment 33. The method according to any one of Embodiments 28 to 32, wherein the patient's dose is reduced if the patient's FG is <80 mg / dL.

[0078] Embodiment 34. A method for improving blood glucose control in patients with type 2 diabetes (T2D), a) The patient shall be administered an initial dose of 100 U of basal insulin-Fc (BIF) once a week, b) After at least 4 weeks with a dose of 100U, increase the dose to 150U BIF once a week, c) After at least 4 weeks with a dose of 150U, increase the dose to 250U BIF once a week, d) A method comprising increasing the dose to 400 U BIF once weekly after at least 4 weeks at a dose of 250 U.

[0079] Embodiment 35. The method according to Embodiment 34, wherein steps b) to d) are performed to reduce the patient's fasting blood glucose (FG).

[0080] Embodiment 36. The method according to Embodiment 34, wherein steps b) to d) are performed when the patient's FG is >130 mg / dL.

[0081] Embodiment 37. The method according to any one of Embodiments 34 to 36, wherein steps b) to d) are performed only if the patient has not had an episode in which FG < 70 mg / dL.

[0082] Embodiment 38. The method according to any one of Embodiments 34 to 37, wherein if the patient's FG is <80 mg / dL, the patient's dose is reduced to the previous dose.

[0083] Embodiment 39. The method according to any one of Embodiments 28 to 38, wherein the patient discontinues treatment if the patient experiences one or more episodes of nocturnal hypoglycemia or two or more episodes of hypoglycemia.

[0084] Embodiment 40. The method according to any one of Embodiments 28 to 39, wherein the patient is insulin-naive.

[0085] Embodiment 41. The method according to any one of Embodiments 28 to 40, wherein the patient has uncontrolled hyperglycemia.

[0086] Embodiment 42. The method according to any one of Embodiments 28 to 41, wherein the patient has an HbA1c of 7-10%.

[0087] Embodiment 43. The method according to any one of Embodiments 28 to 42, wherein the patient is receiving two or more oral antihyperglycemic agents.

[0088] Embodiment 44. The method according to any one of Embodiments 28 to 43, wherein the patient is receiving a GLP-1 receptor agonist.

[0089] Embodiment 45. The method according to any one of Embodiments 28 to 44, wherein BIF is administered in an aqueous composition comprising a phosphate at a concentration of about 5 to 10 mM and a glycerol at a concentration of about 15 to 35 mM, and having a pH of about 5.5 to 7.5.

[0090] Embodiment 46. The method according to Embodiment 45, wherein the composition further comprises poloxamer 188 at a concentration of about 0.1 to about 0.5 mg / mL.

[0091] Embodiment 47. The method according to Embodiment 46, wherein the phosphate is concentrated at a concentration of about 10 mM, the glycerol at a concentration of about 25 mM, the poloxamer 188 at a concentration of about 0.4 mg / mL, and the pH of the composition is about 6.5.

[0092] Embodiment 48. A method according to any one of Embodiments 1 to 47, wherein the method includes improving a patient's blood glucose control.

[0093] Embodiment 49. An aqueous pharmaceutical composition, a) A fixed dose of BIF in an amount selected from the group consisting of 100, 150, 250, and 400 U, b) Phosphate at a concentration of approximately 5-10 mM, c) Contains glycerol at a concentration of approximately 15-35 mM, An aqueous pharmaceutical composition having a pH of approximately 5.5 to 7.5.

[0094] Embodiment 50. The composition according to Embodiment 49, further comprising poloxamer 188 at a concentration of about 0.1 to about 0.5 mg / mL.

[0095] Embodiment 51. The composition according to Embodiment 50, wherein the phosphate is concentrated at a concentration of about 10 mM, the glycerol at a concentration of about 25 mM, the poloxamer 188 at a concentration of about 0.4 mg / mL, and the pH of the composition is about 6.5.

[0096] Embodiment 52. A method for improving blood glucose control in a patient with type 2 T2D, comprising administering to the subject a composition described in any one of Embodiments 49 to 51.

[0097] Embodiment 53. The method according to any one of Embodiments 28 to 48, wherein a fixed dose of BIF is provided in a single-use auto-injector.

[0098] Embodiment 54. A single-use auto-injector for use in the method described in any one of Embodiments 28 to 48.

[0099] Embodiment 55. A single-use auto-injector comprising the composition described in any one of Embodiments 49 to 51.

[0100] Embodiment 56. BIF for use in treating diabetes according to the method described in any one of the above embodiments.

[0101] Embodiment 57. Use of BIF in the manufacture of a drug for use in the treatment of diabetes according to any one of the embodiments described above.

[0102] Embodiment 58. The composition according to any one of Embodiments 49 to 51, wherein the composition does not contain a preservative.

[0103] Embodiment 59. The composition according to any one of Embodiments 49 to 51 or 58, wherein the composition does not contain zinc.

[0104] Embodiment 60. The composition according to any one of Embodiments 49-51 or 58-59, wherein the composition does not contain additional stabilizers.

[0105] Embodiment 61. A composition according to any one of Embodiments 49-51 or 58-60, wherein the composition has sufficient chemical and physical stability to allow storage for at least 24 months at 5°C and at least 2 weeks at temperatures up to 30°C without losing stability.

[0106] Embodiment 62. A composition according to any one of Embodiments 49-51 or 58-61, wherein the composition is sufficiently stable to allow storage at 25°C for 8 weeks.

[0107] Embodiment 63. A composition according to any one of Embodiments 49-51 or 58-62, wherein the composition is sufficiently stable to allow storage at 25°C for 12 weeks.

[0108] Embodiment 64. A composition according to any one of Embodiments 49-51 or 58-63, wherein the composition is sufficiently stable to allow storage at 30°C for 8 weeks.

[0109] Embodiment 65. A composition according to any one of Embodiments 49-51 or 58-64, wherein the composition is sufficiently stable to allow storage at 30°C for 12 weeks.

[0110] The present invention will be further illustrated by the following embodiments, but these embodiments should not be construed as limiting the present invention. [Examples]

[0111] clinical research Using modeling and simulation approaches based on Phase 1 and Phase 2 clinical data, we will develop a fixed-dose dosing regimen in the form of an auto-injector for Phase 3 clinical evaluation.

[0112] This Phase 3, parallel-design, open-label, randomized controlled trial is designed to evaluate the efficacy and safety of BIF (biosinus fertilizer) using a fixed-dose regimen compared to glargine in patients with T2D (times 2-day diabetes) who have been taking background oral antihyperglycemic agents, with or without GLP-1 RAs, prior to entering the study. Participants will continue their prior stable treatment with up to three approved non-insulin diabetes medications during the study.

[0113] Participants will be randomly assigned in a 1:1 ratio to receive either weekly subcutaneous administration of BIF using a pre-filled auto-injector insulin pen, or once daily glargine administered using a KwikPen device. Auto-injectors are available as single-dose devices of 100U, 150U, 250U, and 400U. In both treatment groups, participants will be provided with a blood glucose meter for self-monitoring of blood glucose, instructed on recognizing and treating hypoglycemia, and trained on protocol-related tasks. Participants randomized to BIF will begin with an initial dose of 100 units / week for 4 weeks, and will be sequentially moved to the next dose every 4 weeks if the target fasting blood glucose of 80–130 mg / dL is not achieved at each dose. If the target glucose is not achieved after 4 weeks using the final auto-injector pen (400 units / week), the patient will be switched to a KwikPen containing BIF (which can be used to administer more flexible doses).

[0114] The principal investigator will determine the participant's daily glargine insulin dose according to the protocol and supervise dose adjustments to achieve similar blood glucose targets (80-130 mg / dL) while avoiding hypoglycemia. Study participants will continue the protocol-assigned treatment for a total of 52 weeks, and the primary endpoint analysis will be conducted over 52 weeks.

[0115] The main design features are shown in Table 2 below. [Table 2-1] [Table 2-2]

[0116] Inclusion criteria include: 1. Being at least 18 years of age (or older, depending on local regulations) at the time of screening. 2. Having a diagnosis of type 2 diabetes mellitus (T2D) according to WHO criteria and not being treated with insulin. 3. Having a baseline glycated hemoglobin A1c (HbA1c) value of 7.0%–10.0% (including both extremes) at the time of screening. 4. Acceptable non-insulin diabetes therapies may include 0 to a maximum of 3 of the following: thiazolidinediones (TZDs), dipeptidyl peptidase IV inhibitors, sodium-glucose cotransporter-2 inhibitors, biguanides (e.g., metformin), alpha-glucosidase inhibitors, or glucagon-like peptide-1 receptor agonists. (Note: All non-insulin diabetes therapies must be used according to the corresponding local product label at the time of screening, and participants must be willing to continue stable medication throughout the study according to the protocol. Patients must have been taking a stable dose at least 3 months prior to screening and must be willing to continue stable medication throughout the study.) 5. Either the patient is new to insulin treatment or has been treated with short-term insulin therapy for up to 14 days prior to gestational diabetes screening and / or previous insulin treatment. 6. The patient has a BMI of ≤45 kg / m2 at screening and has not experienced significant weight gain or loss in the past 3 months (≥5%).

[0117] Exclusion criteria include: 1. Having a diagnosis of type 1 diabetes mellitus or latent autoimmune diabetes mellitus, or a specific type of diabetes other than T2D (e.g., monogenic diabetes mellitus, exocrine pancreatic disease, drug-induced or chemical-induced diabetes mellitus); 2. Having received any of the following unapproved diabetes medications, including glinides, pramulintide, sulfonylurea, or insulin, within 30 days prior to screening; 3. Having a diagnosis of type 1 diabetes mellitus or latent autoimmune diabetes mellitus, or a specific type of diabetes other than T2D (e.g., monogenic diabetes mellitus, exocrine pancreatic disease, drug-induced or chemical-induced diabetes mellitus); 4. Having received any of the following unapproved diabetes medications, including glinides, pramulintide, sulfonylurea, or insulin, within 30 days prior to screening; 5. In the opinion of the principal investigator, the participant poses a significant risk to the study participant. 7. The participant has any other serious illness or condition (e.g., known drug or alcohol abuse or mental disorder) that would prevent them from following and completing the protocol; 6. Hematology: A transfusion or severe blood loss within three months prior to visit 1, or, in the opinion of the principal investigator, a characteristic of abnormal hemoglobinopathy, hemolytic anemia or sickle cell anemia, or any other hemoglobin abnormality known to interfere with HbA1c measurement; 7. The participant is receiving chronic (>14 days) systemic glucocorticoid therapy (excluding topical, intraocular, intranasal, or inhaled formulations), or has received such therapy for more than 14 days in the month prior to screening.

[0118] The objectives, evaluation, and evaluation items for efficacy and safety are shown in Table 3 below. [Table 3]

[0119] As shown in Table 3, the primary efficacy measure is HbA1c, a widely used glycemic control measure that reflects the cumulative history of blood glucose levels over the past 2-3 months. It has been shown to correlate well with the risk of long-term diabetic complications. It is a widely accepted measure when evaluating the glucose-lowering effect of a drug. Other secondary objectives include providing supplemental information regarding glycemic control. Safety is characterized by evaluating hypoglycemia, adverse events, and immunogenicity.

[0120] A study similar to the one described above is designed to investigate another exemplary regimen, including four fixed doses in mg units (e.g., 1.5, 3.0, 4.5, and 6.0 mg). Such a presentation is designed for insulin-naive patients with T2DM who are being treated with orally or injectably administered antidiabetic drugs. A Phase 3 study is designed to evaluate these fixed doses. The study population includes insulin-naive T2DM patients with uncontrolled hyperglycemia (e.g., HbA1c between 7.5% and 10.0% (both extremes)) who are receiving two or more oral antihyperglycemic agents, with or without injectable GLP-1 RAs.

[0121] The primary objective is to demonstrate that fixed-dose biglycerides (BIF) are non-inferior to insulin glargine in terms of glycemic control in insulin-naive T2DM patients receiving oral antihyperglycemic agents, with or without injectable GLP-1 receptor agonists.

[0122] Patients are randomized to receive either a fixed-dose BIF or an individualized-dose insulin glargine. Patients randomized to a fixed-dose BIF start treatment with the lowest dose (e.g., 1.5 mg / week) and escalate to a higher dose every four weeks as needed. Current modeling results suggest that dose escalation is possible when the median FPG is >130 mg / dL. If the median FPG is <80 mg / dL, patients may be reduced to a lower dose than before. If a patient experiences one or more episodes of nocturnal hypoglycemia or two or more episodes of any kind of hypoglycemia while receiving the lowest dose, the patient should discontinue treatment.

[0123] Patients who still require additional glycemic control while receiving the highest fixed dose (e.g., 6 mg / week) can transition to a variable-dose paper algorithm. For example, participants who have FG > 140 mg / dL for two consecutive weeks while receiving the highest fixed dose can transition to the variable-dose algorithm described above. Safety measures are similar to those described in the variable-dose algorithm studies described above.

[0124] The results of this treatment regimen will be compared to insulin glargine therapy based on the standard treatment used with the product and the treatment algorithm for achieving the goal. This design allows for the evaluation of a simplified weekly fixed-dose option for T2DM patients who need to initiate basal insulin, while limiting the complexity associated with daily titration of insulin doses. This design also allows for the evaluation of transitioning from the best fixed dose to a paper algorithm for individuals who require additional glycemic control.

[0125] The simulation results support that in insulin-naive T2DM patients, BIF can achieve a comparable benefit-risk profile at 3-4 dose intensities compared to once-daily basal insulin adjusted according to a standard, unrestricted titration regimen. BIF is expected to provide non-inferior efficacy and hypoglycemia rates compared to insulin glargine as an easily initiated weekly basal insulin. The four selected dose levels for the fixed-dose approach reasonably approximate the corresponding glargine doses used by the majority of patients in this population.

[0126] Pharmaceutical research The study is designed to test the stability of unstored BIF medicinal products over the dose range described herein. Compositions are prepared containing BIF at concentrations of 2.5 mg / mL and 25 mg / mL, phosphate buffer at a concentration of 10 mM, glycerin at a concentration of 25 mg / mL, and poloxamer 188 at a concentration of 0.4 mg / mL, with a pH of 6.5 ± 0.2. Samples are prepared by filling 0.5 mL of the composition into a semi-finished syringe and stored for up to 24 months under one of four storage conditions: 5°C, 25°C / 60% relative humidity (RH), 0.5°C, 30°C / 65% RH.

[0127] Samples were collected at 0, 1, 3, 6, 9, 12, 18, and 24 months and analyzed by various stability indicator assays, including in vitro effectiveness size exclusion chromatography (SEC) (purity, aggregates, fragments), RP-HPLC (main peak purity, related substances), anion exchange chromatography (AEX) (charge heterogeneity, main peak, total acidic variants, total basic variants), non-reducing capillary electrophoresis of sodium dodecyl sulfate (CE-SDS), poloxamer content, pH, microflow imaging (MFI), high-precision liquid particle counting (HIAC), and functional tests.

[0128] The results indicate that the chemical and physical stability is sufficient to allow storage at 5°C for at least 24 months and at temperatures up to 30°C for at least 2 weeks without loss of stability.

[0129] array Sequence ID 1 [ka]

Claims

1. A pharmaceutical composition for the treatment of type 2 diabetes (T2D), comprising insulin efcitra alfa, wherein the treatment provides blood glucose control by administering a fixed dose of insulin efcitra alfa once weekly, selected from the group consisting of 100, 150, 250, and 400 U.

2. The pharmaceutical composition according to claim 1, wherein the first fixed dose of insulin efcitra alfa is 100 U.

3. The pharmaceutical composition according to claim 1 or 2, wherein the same dose is administered for at least four weeks, and the dose is increased if additional blood glucose control is required.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein if the patient's fasting blood glucose (FG) is >130 mg / dL after treatment with a first fixed dose for at least four weeks, the dose is increased.

5. The pharmaceutical composition according to claim 1 or 2, wherein the dose is increased only if the patient has not had an episode in which blood glucose < 70 mg / dL.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the dose is reduced if the patient's FG is <80 mg / dL.

7. A pharmaceutical composition for the treatment of T2D, comprising insulin efcitra alfa, a) Administer the initial dose of 100 U of insulin efcitra alfa once a week, b) After at least four weeks of the 100U dose, the dose may be increased to 150U of insulin efcitra alfa once a week, c) After at least four weeks of the 150U dose, the dose may be increased to 250U of insulin efcitra alfa once a week, d) A pharmaceutical composition comprising, as appropriate, improving blood glucose control by increasing the dose to 400 U of insulin efcitra alfa once a week after at least four weeks of the dose of 250 U.

8. The pharmaceutical composition according to claim 7, wherein steps b) to d) are performed to reduce the patient's FG.

9. The pharmaceutical composition according to claim 7, wherein steps b) to d) are performed when the patient's FG is > 130 mg / dL.

10. The pharmaceutical composition according to any one of claims 7 to 9, wherein steps b) to d) are performed only if the patient has not had an episode in which blood glucose < 70 mg / dL.

11. The pharmaceutical composition according to any one of claims 7 to 10, wherein if the patient's FG is <80 mg / dL, the dose is reduced to the previous dose.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the treatment is discontinued if the patient experiences one or more episodes of nocturnal hypoglycemia or two or more episodes of hypoglycemia.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the patient is insulin-naive.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the patient has uncontrolled hyperglycemia.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the patient has an HbA1c of 7 to 10%.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the patient is receiving two or more oral antihyperglycemic agents.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the patient is receiving a GLP-1 receptor agonist.

18. A pharmaceutical composition according to any one of claims 1 to 17, comprising a formulation in an aqueous composition, further comprising a phosphate at a concentration of about 5 to 10 mM and glycerol at a concentration of about 15 to 35 mg / mL, and having a pH of about 5.5 to 7.

5.

19. The pharmaceutical composition according to claim 18, wherein the aqueous composition further comprises poloxamer 188 at a concentration of about 0.1 to about 0.5 mg / mL.

20. The pharmaceutical composition according to claim 19, wherein the phosphate is concentrated at a concentration of about 10 mM, the glycerol is concentrated at a concentration of about 25 mg / mL, the poloxamer 188 is concentrated at a concentration of about 0.4 mg / mL, and the pH of the composition is about 6.

5.

21. A composition according to any one of claims 1 to 20 for improving blood glucose control.

22. The composition according to any one of claims 1 to 21, wherein the aforementioned dose of insulin efcitra alfa is administered by a single-use auto-injector.

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