Methods of treating diabetes

Abstract

To provide a method for providing blood glucose control in patients with type 2 diabetes (T2D) in need thereof.SOLUTION: Provided are fixed doses and dosing regimens for long-acting insulin receptor agonists suitable for once-weekly dosing, such as weekly basal insulin-Fc (BIF).SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] Diabetes mellitus is a chronic disease characterized by hyperglycemia due to defects in insulin secretion, insulin action, or both. Type 2 diabetes (T2D) is characterized by elevated blood glucose levels due to impaired insulin secretion, insulin resistance, excessive hepatic glucose production, and / or all of the above. Treatment for T2D patients typically begins with prescribed weight loss, exercise, and a diabetic diet; however, if these measures fail to control elevated blood glucose, oral medications and incretin-based therapies may be required. If these medications remain insufficient, insulin treatment is considered. T2D patients whose disease has progressed to the point where they require insulin therapy typically begin a once-daily injection of long-acting basal insulin.

[0003] Currently available basal insulin analogs include insulin glargine, sold under the trade names LANTUS®, TOUJEO®, BASALGLAR®, and SEMGLEE®; insulin detemir, sold under the trade name LEVEMIR®; and insulin degludec, sold under the trade name TRESIBA®. Each of these insulins is indicated for once-daily administration. Many patients with T2D are hesitant to initiate and / or adhere to insulin therapy, in part because of the need for daily injections and dosage requirements that require periodic variable dose calculations. Thus, even after initiating insulin therapy, many diabetic patients are unwilling, unable, or unable to adhere to the insulin regimen required to maintain tight control of blood glucose levels.

[0004] Research is underway to identify insulin products that have a longer duration of action and therefore require less frequent injections (including as frequently as once a week) than currently available insulin products. For example, WO 2014 / 009316 describes insulin derivatives that are said to have a sufficiently long duration of action that diabetic patients can administer them approximately once a week to obtain an adequate basal dose of insulin. Treatment regimens for these derivatives are proposed in WO 2016 / 001185. US 2016 / 0324932 describes fusion proteins, including BIF, that have an extended duration of action at the insulin receptor sufficient to allow administration as frequently as once a week. Specific dosing regimens are not described.

[0005] Despite these disclosures, there remains a need for insulin therapies that can be administered in simple and convenient dosing regimens that require fewer injections than currently available insulin products and still provide adequate glycemic control. There also remains a need to provide therapies that provide a simpler, more convenient, and / or less painful patient experience. There also remains a need for methods of treatment using such insulin therapies with no increased or reduced risk of hypoglycemia compared to currently available insulin products. Summary of the Invention

[0006] Thus, the present invention provides a method for providing glycemic control in a patient with type 2 diabetes (T2D) in need thereof, comprising administering to the patient once weekly a fixed dose of BIF selected from the group consisting of 100, 150, 250 and 400 U.

[0007] The present invention also provides a) administering to the patient an initial dose of 100 U basal insulin-Fc (BIF) once weekly; b) after at least 4 weeks at a dose of 100 U, increasing the dose to 150 U of BIF once a week; c) After at least 4 weeks at a dose of 150 U, increasing the dose to 250 U of BIF once a week; and d) after at least four weeks at a dose of 250 U, increasing the dose to 400 U of BIF once a week.

[0008] In certain embodiments, steps b) through d) are performed if the patient's fasting blood glucose (FG) is >130 mg / dL.

[0009] The present invention also provides 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 about 5-10 mM; c) glycerol at a concentration of about 15 to 35 mM; An aqueous pharmaceutical composition is provided having a pH of about 5.5 to 7.5.

[0010] The present invention also provides a single-use auto-injector for use in improving glycemic control in patients with T2D, comprising a fixed dose of BIF selected from the group consisting of 100, 150, 250 and 400 U. DETAILED DESCRIPTION OF THE INVENTION

[0011] The present application provides multiple embodiments of dosing regimens, uses, and methods of treatment for long-acting insulin receptor agonists suitable for once-weekly dosing, such as those described in U.S. Patent Application Publication No. 2016 / 0324932, including BIF. In certain embodiments, the regimens and methods described herein include administering a fixed dose of BIF. In other embodiments, the regimens and methods described herein include determining whether to change a fixed dose of BIF being used to treat a T2D patient. In other embodiments, the regimens and methods described herein include identifying a simple and convenient device for administering fixed doses of BIF. In other embodiments, the regimens and methods described herein describe non-preserved formulations for use in providing fixed doses of BIF.

[0012] BIF, also known as insulin efcitra alfa, comprises a dimer of an insulin receptor agonist fused to a human IgG Fc region, the insulin receptor agonist comprising an insulin B chain analog fused to an insulin A chain analog by use of a first peptide linker, the C-terminal residue of the insulin A chain analog being fused directly to the N-terminal residue of a second peptide linker, and the C-terminal residue of the second peptide linker being fused directly 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 [16-glutamic acid, 25-histidine, 27-glycine, 28-glycine, 29-glycine, 30-glycine] (human B chain) fusion protein with peptide (synthetic 7-amino acid linker) fusion protein with insulin [47-threonine, 51-aspartic acid, 58-glycine] (human A chain) fusion protein with peptide (synthetic 20-amino acid linker) fusion protein with immunoglobulin G2 (human Fc fragment); and (2) alpha-glycosylated tris(tetraglycylglutaminyl)pentaglycyl(59-78) homo sapiens immunoglobulin heavy chain constant γ2 {del-CH1, hinge-(7-12), CH2, CH3 [K 107 >del(300)]}(79-299), and homo sapiens insulin B chain [Y16>Y(16), F25>H(25), TPKT27-30>GGGG(27-30)](1-30) fusion protein with diglycylseryltetraglycyl(31-37) insulin A chain [I10>T(47), Y14>D(51), N21>G(58)](38-58) fusion protein with dimeric (80-80':83-83')-bisdisulfide.

[0013] Each monomer of BIF has the amino acid sequence set forth in SEQ ID NO:1. [ka] (SEQ ID NO: 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 linked to form a dimer by a disulfide bond between cysteine ​​residues at positions 80 and 83. 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" refers to any insulin receptor agonist composed of 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 that relies, in whole or in part, on data submitted by Eli Lilly and Company to a regulatory authority regarding BIF, regardless of whether the party seeking approval of such product actually identifies the insulin receptor agonist as a BIF or uses some other term.

[0015] BIF is a long-acting insulin receptor agonist with a pharmacokinetic and pharmacodynamic profile that is sufficiently sustained to control blood glucose levels between meals when administered no more frequently than once a week. Unlike existing insulin therapies, which require individualized, variable dosing tailored to a patient's needs at a given time point, BIF's relatively flat pharmacokinetic profile, with a peak-to-trough ratio close to 1, allows for its use in simple and convenient dosing regimens involving the administration of a number of individual, fixed doses. Such an approach is similar to fixed-dose drug therapy in that a limited number of dose strengths are offered, limiting the maximum available dose.

[0016] The provision of this simplified dose number is expected to facilitate the transition to insulin therapy for insulin-naive T2DM patients. Such a regimen may help alleviate the clinical inertia that limits the effective titration of basal insulin in actual practice. Thus, 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 not currently treated with basal insulin and starting on a once-weekly insulin receptor agonist (referred to herein as "insulin-naive" patients).

[0017] In certain embodiments, the patient has a glycated hemoglobin A1c (HbA1c) level of 7.0% to 10.0%. In certain embodiments, the patient is also being treated with zero to up to three additional antihyperglycemic therapies selected from the group consisting of a thiazolidinedione (TZD), a dipeptidyl peptidase IV (DPP4) inhibitor, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, a biguanide (e.g., metformin), an alpha-glucosidase inhibitor, or a glucagon-like peptide-1 (GLP-1) receptor agonist. In certain embodiments, the patient has a body mass index (BMI) of ≦45 kg / m2. In certain embodiments, patients treated with such fixed-dose regimens are insulin-naive T2DM patients with an HbA1c of 7.5% to 10.0% (inclusive) and receiving two or more oral antihyperglycemic agents, with or without a GLP-1 RA.

[0018] In certain embodiments, a patient begins treatment with an initial dose and, after treatment with the initial dose for a given period of time, titrates to the next higher dose as needed. For example, a patient may receive the same fixed dose for several weeks, e.g., 4 weeks, and then titrate to the next fixed dose level if the patient requires further glycemic control. In certain embodiments, a patient is considered to be in need of further glycemic control if their FG exceeds a certain level, typically about 120-140 mg / dL. In certain embodiments, a patient is considered to be in need of further glycemic control if their FG is >120 mg / dL. In certain embodiments, a patient is considered to be in need of further glycemic control if their FG is >140 mg / dL. In certain preferred embodiments, a patient is considered to be in need of further glycemic control if their FG is >130 mg / dL. In certain embodiments, if a patient requires further glycemic control after treatment with the highest fixed dose, the patient is transitioned to treatment with a variable dose regimen outside the scope of the present disclosure.

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

[0020] Doses of BIF for use in the methods, uses, and regimens of the present invention can be expressed as either insulin units (IU or U) or mg of BIF. In certain embodiments where the dose of BIF is expressed in U, available doses are 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, available doses are 100, 150, 250, and 400 U. Because the fixed doses described herein are intended to be provided once weekly, the units specified for a given dose refer to the total number of units of insulin activity that the dose is intended to provide over a one-week period.

[0021] A preferred dosing regimen comprising such doses is set forth in Table 1 below. [Table 1]

[0022] According to the regimen shown in Table 1, patients are started on an initial dose of 100 U and increased to a dose of 150 U after at least four weeks of treatment if their FG exceeds 130 mg / dL. Similarly, for patients being treated with a 150 U dose, the dose is increased to 250 U after at least four weeks of treatment if their FG exceeds 130 mg / dL. Similarly, for patients being treated with a 250 U dose, the dose is increased to 400 U after at least four weeks of treatment if their FG exceeds 130 mg / dL. Finally, if the patient's FG falls below 80 mg / dL, the patient can be reduced to the previous lower dose at any time. Additionally, if the patient experiences one or more nocturnal hypoglycemic episodes or two or more any hypoglycemic episodes while receiving the lowest dose, the patient can discontinue treatment.

[0023] In certain embodiments, where the dose of BIF is expressed in mg, the available doses are 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 certain embodiments, the available doses are 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 certain embodiments, 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 available in and administered from a single dosage form. The fixed dose dosage form of BIF described herein can be any dosage form that can be used for subcutaneous administration of an aqueous solution, such as a vial, cartridge, pen injector, or pump, but in a preferred embodiment, the fixed dose is provided in a single-use auto-injector, such as that described in U.S. Pat. No. 8,734,394.

[0025] As used herein, the term "fixed dose regimen" refers to a treatment regimen that includes multiple fixed doses and guidelines for determining which fixed doses should be administered at a given time. For example, a fixed dose regimen may include a set of multiple fixed doses and guidelines for determining which of the fixed doses should be administered in a given week.

[0026] An advantage of the fixed doses and regimens described herein is that they can be implemented using formulations that do not require the use of preservatives. While existing insulin therapies are typically administered using variable dose regimens with multiple-use presentations that require preserved formulations with sufficient antimicrobial efficacy to meet regulatory requirements, the fixed doses described herein can be provided in non-preserved formulations, preferably administered from single-use devices. Because phenolic preservatives used in existing insulin therapies, such as meta-cresol and phenol, are known to cause stability issues for proteins and peptides, the use of such non-preserved formulations may be advantageous over traditional preserved insulin formulations from a stability standpoint. Therefore, such formulations typically require the inclusion of additional excipients to ensure sufficient stability.

[0027] Non-preserved formulations for use in the fixed-dose regimens of the present invention comprise a fixed dose of BIF, a buffer, and an isotonicity agent. In certain embodiments, the concentration of BIF is about 5 to about 25 mg / mL. In certain embodiments, the BIF is at a concentration that allows for 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 BIF is in an amount selected from the group consisting of 100, 150, 250, and 400 insulin units (IU or U). In certain embodiments, the BIF is in an amount selected from the group consisting of 2.85, 4.3, 7.15, and 11.45 mg. In certain embodiments, the fixed-dose 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 buffering agents are phosphates such as dibasic sodium phosphate, citrate, sodium acetate, and tris(hydroxymethyl)aminomethane, or TRIS. In certain embodiments, the compositions of the present invention comprise a citrate buffer at a concentration ranging from about 5 to about 10 mM. In certain embodiments, the compositions of the present invention comprise a phosphate at a concentration ranging from about 5 to about 10 mM. In certain preferred embodiments, the compositions of the present invention comprise 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 tonicity agents include glycerol (glycerin), mannitol, and sodium chloride. When the addition of an isotonicity agent is necessary, glycerin is preferred. In certain embodiments, the glycerol concentration is about 10 to about 50 mg / mL. In certain embodiments, the glycerol concentration is about 15 to about 35 mg / mL. In certain embodiments, the glycerol concentration is selected from the group consisting of about 15, 17, 20, 21, and 35 mg / mL. In certain preferred embodiments, the glycerin concentration 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 PEG 400, PEG 3000, 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®, poly Included are 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 ester.

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

[0034] Preferred compositions have 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 loss of stability. In certain embodiments, the compositions are sufficiently stable to allow storage at 25° C. for 8 weeks. In certain embodiments, the compositions are sufficiently stable to allow storage at 25° C. for 12 weeks. In certain embodiments, the compositions are sufficiently stable to allow storage at 30° C. for 8 weeks. In certain embodiments, the compositions are sufficiently stable 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 tolerance for a given amount or quantity, given the nature or precision of the measurement. For example, the degree of tolerance can be indicated by the number of significant figures provided for a measurement, as understood in the art, and includes, but is not limited to, a variation of ±1 of the most precise significant figure reported for the amount or quantity. Typically, exemplary tolerances are within 20 percent (%), preferably within 10%, and more preferably within 5% of a given value or range of values. Numerical values ​​provided herein are approximations unless otherwise specified, and the term "about" means that they can be inferred when not explicitly stated.

[0036] As used herein, the term "dose" or "doses" refers to an amount of an insulin receptor agonist suitable for once-weekly dosing administered to an individual in discrete amounts at specific time points.

[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 weekly dosing to be administered to a patient, unless otherwise specified herein, a patient's FG is determined as the median FG over multiple days, typically within at least 3 to 7 days.

[0038] As used herein, the terms "treatment," "treat," "treating," and the like are meant to include slowing or attenuating the progression of a disease or disorder. These terms also include alleviating, ameliorating, attenuating, eliminating, or alleviating 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 slowed or reversed.

[0039] "Glycemic control" refers to a subject's blood glucose levels, e.g., as measured by blood glucose and / or HbA1c levels; "providing" glycemic control refers to maintaining or improving glycemic control; "maintaining" glycemic control refers to maintaining the time that blood glucose levels are within a target range and / or maintaining or reducing HbA1c; "improving" glycemic control refers to extending the time that blood glucose levels are within a target range and / or reducing HbA1c; and "requiring further glycemic control" refers to the need to extend the time that blood glucose levels are within a target range and / or reduce HbA1c.

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

[0041] "Hypoglycemia" refers to low blood sugar, and an "episode" of hypoglycemia refers to an instance of hypoglycemia observed, for example, in a plasma glucose test or a value from a personal blood glucose monitor (BGM) or CGM device, often below about 70 mg / dL.

[0042] A "severe" hypoglycemic episode is a severe event characterized by an altered mental and / or physical state that requires assistance to treat the hypoglycemia. For example, a subject whose mental state is altered and who is unable to assist in self-care, or who is semiconscious or unconscious, or who experiences a coma with or without seizures and requires the assistance of another person to actively administer carbohydrates, glucagon, or other therapeutic measures. Although glucose measurements may not be obtained during such an event, neurological recovery due to a return of glucose levels to normal is considered sufficient evidence that the event was induced by low glucose levels.

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

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

[0045] Embodiment 1. A method of improving glycemic control in a subject with diabetes, comprising: a) identifying a subject with diabetes; b) administering to the subject a first dose of an insulin receptor agonist suitable for one or more weeks of once-weekly dosing; c) measuring the subject's FG multiple times during the week following the most recent administration of the first dose; and d) determining whether the subject's median FG from the measurements described in step c) was >130 mg / dL; and e) selecting 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 a second dose of insulin receptor agonist suitable for once-weekly dosing, or (ii) if the subject's FG is <130 mg / dL, maintain the subject on the first dose of insulin receptor agonist suitable for once-weekly dosing; f) administering the dose selected in step e) to the subject.

[0046] Embodiment 2. The dose of insulin receptor agonist administered in step f) is a second dose of insulin receptor agonist suitable for once-weekly dosing, and the second dose of insulin receptor agonist suitable for once-weekly dosing has been administered for one or more weeks; g) measuring the subject's FG multiple times during the week following the most recent administration of the second dose; h) determining whether the subject's median FG from the measurements described in step g) was >130 mg / dL; and i) selecting 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 a third dose of insulin receptor agonist suitable for once-weekly dosing; (ii) if the subject's FG is <81-130 mg / dL, maintain the subject on a second dose of insulin receptor agonist suitable for once-weekly dosing; or (iii) if the subject's FG is <81, switch the subject to the first dose of insulin receptor agonist suitable for once-weekly dosing; 10. The method of embodiment 1, further comprising: j) administering the dose selected in step i) to the subject.

[0047] Embodiment 3. The dose of insulin receptor agonist administered in step j) is a third dose of insulin receptor agonist suitable for once-weekly dosing, and the third dose of insulin receptor agonist suitable for once-weekly dosing has been administered for one or more weeks; k) measuring the subject's FG multiple times in the week following the most recent administration of the third dose; l) determining whether the subject's median FG from the measurements described in step k) was >130 mg / dL; m) selecting 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 a fourth dose of insulin receptor agonist suitable for once-weekly dosing; (ii) if the subject's FG is 81-130 mg / dL, maintain the subject on a third dose of insulin receptor agonist suitable for once-weekly dosing; or (iii) if the subject's FG is <81, switch the subject to a second dose of insulin receptor agonist suitable for once-weekly dosing; 3. The method of embodiment 2, further comprising: n) administering the dose selected in step m) to the subject.

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

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

[0050] Embodiment 6. The method of any one of embodiments 1-5, wherein the patient has T2DM.

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

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

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

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

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

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

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

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

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

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

[0061] Embodiment 17. A method of improving glycemic control in a patient with diabetes comprising administering a fixed dose of BIF selected from the group consisting of 1.5, 3.0, 4.5 and 6.0 mg.

[0062] Embodiment 18. The method of any one of embodiments 1 to 17, wherein a dose of the 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 of providing glycemic control in a subject having diabetes and in need of further glycemic control, comprising: a) identifying subjects in need of further glycemic control; and b) administering to the subject a first dose of an insulin receptor agonist suitable for once-weekly dosing for a minimum of four weeks; c) determining whether the subject is in need of further glycemic control, and if the subject is in need of further glycemic control as determined in step c), administering to the subject a second dose of an insulin receptor agonist suitable for once-weekly administration for a minimum of four weeks.

[0064] Embodiment 20. The subject has received a second dose of an insulin receptor agonist suitable for once-weekly administration for a minimum of 4 weeks; d) determining whether the subject needs further glycemic control; and e) if the subject requires further glycemic control, administering to the subject a third dose of an insulin receptor agonist suitable for once-weekly dosing for a minimum of four weeks.

[0065] Embodiment 21. The subject is receiving a third dose of an insulin receptor agonist suitable for once-weekly administration for a minimum of 4 weeks; f) determining whether the subject needs further glycemic control; and g) if the subject requires further glycemic control, administering to the subject a fourth dose once weekly for a minimum of two weeks.

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

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

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

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

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

[0071] Embodiment 27. The subject is receiving 6.0 mg of BIF once weekly for at least 2 weeks; h) determining whether the subject needs further glycemic control; and The method of embodiment 26, further comprising: i) administering to the subject a dose of BIF determined according to the criteria of any one of claims 11 to 17, 23 to 24, 30, 32 or 36 if the subject requires further glycemic control.

[0072] Embodiment 28. A method of providing glycemic control in a type 2 diabetes (T2D) patient in need thereof, comprising administering to said patient once weekly a fixed dose of basal insulin-Fc (BIF) selected from the group consisting of 100, 150, 250 and 400 U.

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

[0074] Embodiment 30 The method of 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 glycemic control.

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

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

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

[0078] Embodiment 34. A method of improving glycemic control in a type 2 diabetes (T2D) patient in need thereof, comprising: a) administering to the patient an initial dose of 100 U basal insulin-Fc (BIF) once weekly; b) after at least 4 weeks at a dose of 100 U, increasing the dose to 150 U of BIF once a week; c) After at least 4 weeks at a dose of 150 U, increasing the dose to 250 U of BIF once a week; d) after at least 4 weeks at a dose of 250 U, increasing the dose to 400 U of BIF once a week.

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

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

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

[0082] Embodiment 38. The method of any one of embodiments 34-37, 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 of any one of embodiments 28 to 38, wherein the patient discontinues treatment if the patient experiences one or more nocturnal hypoglycemic episodes or two or more hypoglycemic episodes.

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

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

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

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

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

[0089] Embodiment 45. The method of any one of embodiments 28 to 44, wherein the BIF is administered in an aqueous composition comprising phosphate at a concentration of about 5 to 10 mM and 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 of 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 of embodiment 46, wherein the phosphate is at a concentration of about 10 mM, the glycerol is at a concentration of about 25 mM, the poloxamer 188 is at a concentration of about 0.4 mg / mL, and the pH of the composition is about 6.5.

[0092] Embodiment 48. The method of any one of embodiments 1 to 47, wherein the method comprises improving glycemic control in the patient.

[0093] Embodiment 49. An aqueous pharmaceutical composition comprising: 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 about 5-10 mM; c) glycerol at a concentration of about 15 to 35 mM; An aqueous pharmaceutical composition having a pH of about 5.5 to 7.5.

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

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

[0096] Embodiment 52. A method of improving glycemic control in a patient with type 2D in need thereof, comprising administering to the subject a composition of any one of embodiments 49-51.

[0097] Embodiment 53. The method of any one of embodiments 28 to 48, wherein the 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 according to any one of embodiments 28 to 48.

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

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

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

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

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

[0104] Embodiment 60. The composition of any one of embodiments 49-51 or 58-59, wherein the composition does not contain an additional stabilizer.

[0105] Embodiment 61. The composition of any one of embodiments 49-51 or 58-60, wherein the 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 loss of stability.

[0106] Embodiment 62. The composition of 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. The composition of 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. The composition of 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. The composition of 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] This invention is further illustrated by the following examples which should not be construed as limiting the invention. [Example]

[0111] clinical research A modeling and simulation approach utilizing Phase 1 and Phase 2 clinical data will be used to develop a fixed-dosing regimen in the form of a fixed-dose 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 using a fixed-dose regimen compared with glargine in patients with type 2 disease (T2D) who were taking background oral antihyperglycemic medications with or without GLP-1 RAs before study entry. Participants will continue their previous stable therapy with up to three permitted non-insulin antidiabetic medications during the study.

[0113] Participants will be randomly assigned to treatment in a 1:1 ratio to receive either weekly BIF administered subcutaneously using a prefilled auto-injector insulin pen or once-daily glargine administered using a KwikPen device. The auto-injector is available as a single-dose device in 100, 150, 250, and 400 U doses. In both treatment groups, participants will be provided with a blood glucose meter for self-monitoring of blood glucose, instructed on the recognition and treatment of 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 progressively transitioned to the next dose every 4 weeks if the target fasting glucose of 80-130 mg / dL is not achieved with each dose. If the target glucose is not achieved after 4 weeks using the final auto-injector administration pen (400 units / week), patients will be transitioned to a KwikPen containing BIF (which can be used for more flexible dosing).

[0114] The investigator will determine participants' daily glargine insulin doses according to the protocol and oversee dose adjustments to achieve similar glycemic targets (80-130 mg / dL) while avoiding hypoglycemia. Study participants will continue their protocol-assigned treatment for a total of 52 weeks, and the primary endpoint analysis will occur at 52 weeks.

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

[0116] Inclusion criteria included: 1. At least 18 years of age (or older depending on local regulations) at screening; 2. Have a diagnosis of type 2 diabetes (T2D) according to WHO criteria and not being treated with insulin; 3. Have a baseline glycated hemoglobin A1c (HbA1c) level of 7.0% to 10.0% (inclusive) at screening; 4. Acceptable non-insulin diabetes therapies may include zero to a maximum of three 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 screening, and participants must be willing to remain on stable medication throughout the study according to the protocol. Patients must have been on a stable dose for at least 3 months prior to screening and be willing to remain on stable medication throughout the study.) 5. Insulin naive or treated with short-term insulin therapy for up to 14 days prior to screening for gestational diabetes and / or previous insulin treatment. 6. BMI of ≤45 kg / m2 at screening with no significant weight gain or loss (≥5%) in the past 3 months.

[0117] Exclusion criteria included the following: 1. Have a diagnosis of type 1 diabetes mellitus or latent autoimmune diabetes, or a specific type of diabetes other than T2D (e.g., monogenic diabetes, disease of the exocrine pancreas, drug-induced or chemical-induced diabetes); 2. Have received any of the following unauthorized diabetes medications within 30 days prior to screening, including glinides, pramlintide, sulfonylureas, and insulin; 3. Have a diagnosis of type 1 diabetes mellitus or latent autoimmune diabetes, or a specific type of diabetes other than T2D (e.g., monogenic diabetes, disease of the exocrine pancreas, drug-induced or chemical-induced diabetes); 4. Have received any of the following unauthorized diabetes medications within 30 days prior to screening, including glinides, pramlintide, sulfonylureas, and insulin; 5. Have a medical condition that, in the opinion of the investigator, poses a significant risk to the study participant and is not conducive to the study participation. 5. Hematology: Has had a blood transfusion or severe blood loss within the 3 months prior to Visit 1, or has known hemoglobinopathy, hemolytic anemia, or sickle cell anemia, or any other hemoglobin abnormality characteristic known to interfere with the measurement of HbA1c, in the opinion of the investigator; 6. Has received 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 efficacy and safety objectives, assessments, and endpoints are shown in Table 3 below. [Table 3]

[0119] As shown in Table 3, the primary efficacy measure was HbA1c, a widely used measure of glycemic control that reflects the cumulative history of blood glucose levels over the past 2–3 months. It has been found to correlate well with the risk of long-term diabetic complications. It is a widely accepted measure for assessing the glucose-lowering efficacy of drugs. Other secondary objectives provide complementary information on glycemic control. Safety will be characterized by assessing hypoglycemia, adverse events, and immunogenicity.

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

[0121] The primary objective is to demonstrate that fixed-dose BIF is non-inferior for glycemic control compared with insulin glargine in insulin-naive patients with T2DM receiving oral antihyperglycemic agents with or without an injectable GLP-1 receptor agonist.

[0122] Patients will be randomized to receive fixed-dose BIF or individualized-dose insulin glargine. Patients randomized to fixed-dose BIF will begin treatment at the lowest dose (e.g., 1.5 mg / week) and titrate to higher doses every 4 weeks as needed. Current modeling results suggest that doses can be titrated if median FPG is >130 mg / dL. If median FPG is <80 mg / dL, patients can be reduced to their previous lower dose. If patients experience one or more nocturnal hypoglycemic episodes or two or more any hypoglycemic episodes while receiving the lowest dose, patients will discontinue treatment.

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

[0124] The results of this treatment regimen will be compared to insulin glargine treatment based on the standard-of-care, goal-directed treatment algorithm used in the product. 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 complexities associated with daily titration of insulin doses. This design also allows for the evaluation of transition from the best fixed dose to the paper algorithm for those who require additional glycemic control.

[0125] Simulation results support that in insulin-naive patients with T2DM, BIF can achieve a comparable benefit-risk profile at 3-4 dose intensities compared with once-daily basal insulin adjusted according to a standard unlimited titration regimen. As a convenient weekly basal insulin, BIF is expected to provide non-inferior efficacy and hypoglycemia rates compared with insulin glargine. 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] Formulation Research The study is designed to test the stability of unpreserved BIF drug product across the dose range described herein. Compositions 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, are prepared. Samples are prepared by filling 0.5 mL of the composition into semi-finished syringes and stored at one of four storage conditions for up to 24 months: 5°C, 25°C / 60% relative humidity (RH), 0.5°C, and 30°C / 65% RH.

[0127] Samples will be collected at 0, 1, 3, 6, 9, 12, 18, and 24 months and analyzed by various stability-indicating assays, including in vitro efficacy 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 sodium dodecyl sulfate (CE-SDS), poloxamer content, pH, microflow imaging (MFI), high precision particle counting (HIAC), and functionality testing.

[0128] The results show 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 SEQ ID NO: 1 [ka]

Claims

1. 1. A method of providing glycemic control in a type 2 diabetes (T2D) patient in need thereof, comprising administering to said patient once weekly a fixed dose of basal insulin-Fc (BIF) selected from the group consisting of 100, 150, 250 and 400 U.

2. 10. The method of claim 1, wherein the first dose of BIF administered to the patient is 100 U.

3. 3. The method of claim 1 or 2, wherein the patient is administered the same dose for at least four weeks, and the dose is increased if the patient requires additional glycemic control.

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

5. 5. The method of claim 3 or 4, wherein the patient's dose is increased only if the patient has not had an episode of blood glucose <70 mg / dL.

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

7. 1. A method for improving glycemic control in a type 2 diabetes (T2D) patient in need thereof, comprising: a) administering to said patient 100 U of BIF once a week; b) after at least 4 weeks at said 100 U dose, increasing said dose to 150 U BIF once a week; c) after at least 4 weeks on the 150 U dose, increasing the dose to 250 U of BIF once a week; d) after at least 4 weeks on said 250 U dose, increasing said dose to 400 U BIF once a week.

8. 8. The method of claim 7, wherein steps b) to d) are performed to reduce FG in the patient.

9. 8. The method of claim 7, wherein steps b) through d) are performed when the patient's FG is >130 mg / dL.

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

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

12. 12. The method of any one of claims 1 to 11, wherein the patient discontinues treatment if the patient experiences one or more nocturnal hypoglycemic episodes or two or more hypoglycemic episodes.

13. The method of any one of claims 1 to 12, wherein the patient is insulin naive.

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

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

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

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

18. 18. The method of any one of claims 1 to 17, wherein the BIF is administered in an aqueous composition comprising phosphate at a concentration of about 5 to 10 mM and glycerol at a concentration of about 15 to 35 mM, and having a pH of about 5.5 to 7.

5.

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

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

5.

21. 1. An aqueous pharmaceutical composition comprising: 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 about 5-10 mM; c) glycerol at a concentration of about 15-35 mM; An aqueous pharmaceutical composition having a pH of about 5.5 to 7.

5.

22. 22. The composition of claim 21, further comprising poloxamer 188 at a concentration of about 0.1 to about 0.5 mg / mL.

23. 23. The composition of claim 22, wherein the phosphate is at a concentration of about 10 mM, the glycerol is at a concentration of about 25 mM, the poloxamer 188 is at a concentration of about 0.4 mg / mL, and the pH of the composition is about 6.

5.

24. 24. A method of providing glycemic control in a T2D patient in need thereof, comprising administering to said subject a composition according to any one of claims 21 to 23.

25. The method of any one of claims 1 to 20, wherein the fixed dose of BIF is provided in a single-use auto-injector.

26. A single-use auto-injector for use in the method of any one of claims 1 to 25.

27. A single-use automatic injector comprising the composition of any one of claims 21 to 23.

28. 26. The method of any one of claims 1-20 or 24-25, wherein the method comprises improving glycemic control in the patient.

29. A BIF for use in the treatment of T2D, wherein the treatment comprises improving glycemic control by administering a fixed dose of BIF selected from the group consisting of 100, 150, 250 and 400 U once a week.

30. 30. The BIF for use according to claim 29, wherein the first fixed dose of BIF is 100 U.

31. 31. A BIF for use according to claim 29 or 30, wherein the same dose is administered for at least 4 weeks, and the dose is increased if additional glycemic control is required.

32. 32. The BIF for use according to any one of claims 29 to 31, wherein if the patient's FG is >130 mg / dL after at least 4 weeks of treatment with a first fixed dose, the dose is increased.

33. 31. A BIF for use according to claim 29 or 30, wherein the dose is increased only if the patient has not had any episodes of FG<70 mg / dL (0 episodes).

34. 34. The BIF for use according to any one of claims 29 to 33, wherein the dose is reduced if the patient's FG is <80 mg / dL.

35. 1. A BIF for use in the treatment of T2D, said treatment comprising: a) administering an initial dose of 100 U of BIF once weekly; b) after at least 4 weeks at said 100 U dose, increasing said dose to 150 U BIF once a week; c) after at least 4 weeks on the 150 U dose, increasing the dose to 250 U of BIF once a week; d) after at least four weeks on said 250 U dose, increasing said dose to 400 U BIF once a week, thereby improving glycemic control.

36. 36. The BIF for use according to claim 35, wherein steps b) to d) are carried out to reduce FG in said patient.

37. 36. The BIF for use according to claim 35, wherein steps b) to d) are carried out if the patient's FG is >130 mg / dL.

38. 38. A BIF for use according to any one of claims 35 to 37, wherein steps b) to d) are carried out only if the patient has not had any episodes of blood glucose < 70 mg / dL (0 episodes).

39. 39. The BIF for use according to any one of claims 35 to 38, wherein if the patient's FG is <80 mg / dL, the dose is reduced to the previous dose.

40. A BIF for use according to any one of claims 28 to 33, wherein said treatment is discontinued if said patient experiences one or more nocturnal hypoglycemic episodes or two or more hypoglycemic episodes.

41. The BIF for use according to any one of claims 28 to 40, wherein the patient is insulin naive.

42. The BIF for use according to any one of claims 28 to 41, wherein the patient has uncontrolled hyperglycemia.

43. The BIF for use according to any one of claims 28 to 42, wherein the patient has an HbA1c of 7 to 10%.

44. A BIF for use according to any one of claims 28 to 43, wherein the patient is receiving two or more oral antihyperglycemic drugs.

45. The BIF for use according to any one of claims 28 to 44, wherein the patient is receiving a GLP-1 receptor agonist.

46. 46. ​​The BIF for use according to any one of claims 28 to 45, wherein the BIF is administered in an aqueous composition comprising phosphate at a concentration of about 5 to 10 mM and glycerol at a concentration of about 15 to 35 mM, and having a pH of about 5.5 to 7.

5.

47. 47. The BIF for use according to claim 46, wherein the composition further comprises poloxamer 188 at a concentration of about 0.1 to about 0.5 mg / mL.

48. 48. A BIF for use according to claim 47, wherein the phosphate is at a concentration of about 10 mM, the glycerol is at a concentration of about 25 mM, the poloxamer 188 is at a concentration of about 0.4 mg / mL, and the pH of the composition is about 6.

5.

49. A BIF for use according to any one of claims 29 to 48, wherein said dose of BIF is administered with a single-use auto-injector.

50. A BIF for use in the treatment of T2D, wherein said treatment comprises improving glycemic control by administering a composition according to any one of claims 21 to 23.

51. Use of BIF in the manufacture of a medicament for use in the treatment of diabetes according to any one of claims 29 to 50.

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