Methods of treating diabetes

Abstract

To provide a method for delivering blood glucose control in a subject having diabetes requiring such control.SOLUTION: Doses and dosing regimens are provided, comprising determining and administering doses of 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 for treating diabetes mellitus. More specifically, the present invention relates to methods for treating diabetes mellitus with a long-acting insulin receptor agonist. The methods described herein include a dosing regimen that includes determining and administering a dose of a long-acting insulin receptor agonist suitable for once-weekly dosing, such as weekly basal insulin-Fc (BIF). [Background technology]

[0002] Diabetes mellitus is a chronic disease characterized by hyperglycemia due to defects in insulin secretion, insulin action, or both. Type 1 diabetes (T1D) is characterized by little or no insulin secretory capacity, and T1D patients require insulin for survival. 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 contributing factors. Many T2D patients require insulin therapy as the disease progresses.

[0003] Because T1D patients produce little or no insulin, effective insulin therapy generally involves the use of two types of exogenously administered insulin: rapid-acting mealtime or pre-prandial insulin, delivered via bolus injection, and long-acting basal insulin, administered once or twice daily to control blood glucose levels between meals and overnight. 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 levels, oral medications and incretin-based therapies may be required. If these medications remain insufficient, insulin treatment is considered. Patients with T2D whose disease has progressed to the point where they require insulin therapy generally begin receiving once-daily injections of long-acting basal insulin.

[0004] 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.

[0005] Existing insulin therapy regimens involving daily injections can be complex and painful to administer and can result in undesirable side effects such as hypoglycemia and weight gain. Thus, even after initiating insulin therapy, many diabetic patients are unwilling, unable, or unable to adhere to the insulin regimen necessary to maintain strict control of blood glucose levels. Research is being conducted to identify insulin products that have a longer duration of action and therefore require less frequent injections than currently available insulin products, including as frequently as once weekly. Such products could improve acceptance and compliance.

[0006] However, there are potential problems associated with the administration of products with prolonged insulin action. For example, prolonged insulin action may theoretically increase the risk of hypoglycemic events or prolong the duration of such events and / or weight gain. In addition, weekly administration of products with prolonged insulin action may require several weeks for insulin activity to reach a steady state, resulting in suboptimal hyperglycemia control during that time. Although an increased risk of hypoglycemia, weight gain, and / or suboptimal hyperglycemic control may be a potential downside of products with a longer duration of insulin action than existing insulins, such risks can be managed or eliminated by using optimized doses and dosing regimens.

[0007] WO 2014 / 009316 describes insulin derivatives that are said to have a sufficiently long duration of action that diabetic patients can administer them about once a week to obtain an adequate basal dose of insulin. Treatment regimens for these derivatives are proposed in WO 2016 / 001185.

[0008] US2016 / 0324932 describes fusion proteins, including BIF, that have a sufficient duration of action at the insulin receptor to allow dosing as frequently as once a week. No specific dosing regimen is described.

[0009] There remains a need for insulin therapies that require fewer injections than currently available insulin products. 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. There remains a need for insulin therapies that require fewer injections than currently available insulin products. There remains a need for insulin therapies that provide enhanced glycemic control compared to currently available insulin products. There also remains a need for methods of treatment using such insulin therapies with no increased or reduced risk of weight gain compared to currently available insulin products. There also remains a need for insulin therapies that are administered in a manner that allows patients to rapidly reach steady-state serum levels. Summary of the Invention

[0010] Accordingly, the present invention provides a method of providing glycemic control in a subject with diabetes in need thereof, comprising: a) To the subject, i) The subject is: a. Insulin naive or b. Have T2D and fasting glucose (FG) > 120 mg / dL, or c. If you have T1D, the initial dose is a loading dose; ii) administering an initial dose of BIF according to the following criteria: if the subject has T2D but does not meet the above criteria in a. or b., the initial dose is a weekly maintenance dose; and b) administering to the subject one or more weekly maintenance doses once a week starting one week after administration of the initial dose.

[0011] In another aspect, the present invention provides BIF for use in the treatment of diabetes, the treatment comprising: a) To the subject, i) The subject is: a. Insulin naive or b. Have T2D and FG > 120 mg / dL, or c. If you have T1D, the initial dose is a loading dose; ii) administering an initial dose of BIF according to the following criteria: if the subject has T2D but does not meet the above criteria in a. or b., the initial dose is a weekly maintenance dose; and b) administering to the subject one or more weekly maintenance doses once a week starting one week after administration of the initial dose, thereby providing glycemic control.

[0012] The present invention also provides criteria for selecting loading and maintenance doses of BIF for use in the treatment of diabetes.

[0013] In another aspect, the present invention provides a method of providing glycemic control in a subject having diabetes, comprising: a) determining a first dose of a long-acting insulin receptor agonist suitable for once-weekly dosing to be administered to a subject; b) administering to the subject a first dose of an insulin receptor agonist suitable for once-weekly dosing; c) measuring the subject's fasting glucose (FG); and d) tabulating the frequency and severity of subjects' hypoglycemia; and e) determining a second dose of insulin receptor agonist suitable for weekly dosing to be administered to the subject based on the subject's FG determined in step c) and the frequency and severity of hypoglycemia determined in step d); f) administering a second dose of an insulin receptor agonist suitable for once-weekly dosing.

[0014] The present invention also provides a method of providing glycemic control in a subject with diabetes comprising administering a loading dose of a long-acting insulin receptor agonist suitable for once-weekly dosing administered to the subject.

[0015] In certain embodiments, the loading dose is determined by first determining the subject's expected weekly maintenance dose, and then multiplying the subject's expected weekly maintenance dose by the ratio of steady-state concentration:single-dose peak concentration of a long-acting insulin receptor agonist suitable for once-weekly dosing. DETAILED DESCRIPTION OF THE INVENTION

[0016] The present application provides dosing regimens, uses and methods of treatment for long-acting insulin receptor agonists suitable for once-weekly dosing.

[0017] As used herein, the term "insulin receptor agonist" refers to a protein that binds to and activates the insulin receptor, resulting in lowered blood glucose levels and / or suppressed hepatic glucose production, characteristics that can be tested and measured using known techniques, such as those shown in the studies described below. The term "long-acting insulin receptor agonist" refers to an insulin receptor agonist that has a sustained pharmacokinetic and pharmacodynamic profile for controlling blood glucose levels between meals when administered no more frequently than once or twice daily. As used herein in reference to insulin receptor agonists, the term "suitable for once-weekly dosing" refers to a long-acting insulin receptor agonist that has a pharmacokinetic and pharmacodynamic profile that is sufficiently sustained to control blood glucose levels between meals when administered no more frequently than once weekly. Examples of such molecules include the fusion proteins described in US 2016 / 0324932, which contain BIF.

[0018] 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.

[0019] 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.

[0020] 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.

[0021] Described herein are several embodiments of dosing regimens and methods of use for long-acting insulin receptor agonists suitable for once-weekly dosing. In certain embodiments, the regimens, uses, and methods described herein include determining and administering an initial or loading dose of such insulin receptor agonists. In other embodiments, the regimens, uses, and methods described herein include determining and administering a weekly maintenance dose, including when and how to adjust the weekly maintenance dose.

[0022] Embodiments of criteria and guidelines for determining the loading dose and weekly maintenance dose are described in more detail below.

[0023] Determination and administration of loading dose. In certain embodiments, the methods, uses, and dosing regimens described herein include determining and administering a loading dose. Due to their long elimination half-life, when a once-weekly insulin receptor agonist suitable for weekly dosing is administered according to a weekly dosing regimen, pharmacokinetic steady state may not be reached for several weeks. In addition, the long elimination half-life of such products, when administered once a week for several weeks, may result in peak serum concentration levels significantly higher than those observed after administration of a single dose. Certain embodiments of the regimens, uses, and methods described herein address these issues through the administration of a single initial loading dose designed to shorten the time to reach pharmacokinetic steady state. Therefore, as used herein, the term "loading dose" refers to the first dose of a long-acting insulin receptor agonist suitable for weekly dosing administered to a given subject, which is higher than the dose expected to be used for long-term maintenance treatment.

[0024] The loading doses described herein generally include a single dose that is greater than the expected weekly maintenance dose, described in more detail below, by a factor that allows a near-steady-state concentration to be reached within the first week after administration of the single dose. The factor by which the expected weekly maintenance dose is increased to provide such a loading dose is determined based on the ratio of (a) the serum concentration of the insulin receptor agonist after administration of a sufficient number of weekly maintenance doses to reach steady state, to (b) the peak serum concentration of the insulin receptor agonist reached after administration of a single expected weekly maintenance dose. This ratio is sometimes referred to as the "steady-state concentration:single-dose peak concentration." Thus, for example, if the serum concentration of the insulin receptor agonist reached after administration of a sufficient number of expected weekly maintenance doses to reach steady state is three times higher than the peak serum concentration reached after administration of a single dose, the steady-state:single-dose peak concentration ratio is 3, and the loading dose is a single dose that is three times greater than the expected weekly maintenance dose.

[0025] As used herein, the term "anticipated weekly maintenance dose" refers to the dose of an insulin receptor agonist suitable for once-weekly dosing that is anticipated to be required to provide glycemic control in a given subject. The anticipated weekly maintenance dose is determined prior to the initiation of treatment with an insulin receptor agonist suitable for once-weekly dosing, while the weekly maintenance dose administered during the course of treatment is determined based on various criteria, which are described in more detail below. In certain embodiments of insulin-naive patients, the anticipated weekly maintenance dose may be set at a fixed level, such as 100 insulin units (also referred to herein as U or IU). In other embodiments, such as patients already treated with basal insulin, the initial weekly maintenance dose or "anticipated weekly maintenance dose" may be based on the subject's current daily basal insulin dose and / or the subject's fasting glucose (FG), and optionally other factors, such as the frequency and severity of hypoglycemia, body weight (BW), etc.

[0026] In certain embodiments, the loading dose is in the range of about 1.5 to about 5 times higher than the expected weekly maintenance dose. In certain embodiments, the loading dose is in the range of about 1.5 to about 3 times higher than the expected weekly maintenance dose. In certain embodiments, the loading dose is about 1.5, 1.6, 1.8, 2, or 3 times higher than the expected weekly maintenance dose.

[0027] For BIF, steady-state serum concentration levels after initiation of once-weekly dosing are predicted to be reached after approximately 8 to 10 or 12 weeks of weekly administration without a loading dose. Using a loading dose approximately three times higher than the initial or anticipated weekly maintenance dose allows near-steady-state concentrations to be reached within the first week of dosing. In certain preferred embodiments, the insulin receptor agonist suitable for weekly dosing is BIF, and the loading dose is approximately three times higher than the initial or anticipated weekly maintenance dose.

[0028] If a subject is already being treated with an existing basal insulin, such as insulin degludec or insulin glargine, and is switched to an insulin receptor agonist suitable for once-weekly dosing, the expected weekly maintenance dose of the insulin receptor agonist suitable for once-weekly dosing will typically be based, at least in part, on the subject's current basal insulin dose.

[0029] Because such subjects' daily basal insulin doses have been replaced with a single weekly dose, the daily dose in units must be converted to a weekly dose, referred to herein as the "weekly equivalent of the daily basal dose," which is expected to provide the same level of insulin activity every day once steady state is reached with weekly dosing. The weekly equivalent of the daily basal dose can be expressed in insulin units or mg. When expressed in insulin units, the daily dose of once-daily basal insulin units before initiating weekly insulin receptor agonist treatment is multiplied by 7 to obtain the equivalent daily basal dose of the once-daily insulin receptor agonist. For example, the weekly equivalent of the daily basal dose for a patient receiving 42 units / day of insulin degludec before initiating weekly insulin receptor agonist treatment would be 294 units.

[0030] In certain embodiments, the once-weekly insulin receptor agonist is provided in a device that allows for adjustment in 5-unit or 10-unit increments, and therefore, when determining the dose of weekly insulin to be administered, the weekly equivalent of the daily basal dose calculated above is rounded to the nearest 5 or 10 units. Thus, in certain embodiments, if the weekly insulin is provided in a device that allows for dose adjustment in 5-unit increments, the weekly equivalent of the daily basal dose of 294 units calculated above may be rounded to 295 units or 290 units.

[0031] When expressed in mg, the unit dose must be converted to mg equivalents based on the potency of the insulin receptor agonist suitable for weekly dosing using what is referred to herein as a "weekly basal conversion factor" or "daily basal conversion factor." For example, it has been determined that 1 mg of BIF provides approximately 35 units per week, so the weekly basal conversion factor for BIF is approximately 35 U / week / mg, and the daily basal conversion factor for BIF is approximately 5 U / day / mg. Thus, a patient receiving 42 units of insulin degludec per day would have a mg dose of BIF of approximately 8.4 mg (42 units / day x 7 days = 294 units / week / 35 U / week / mg).

[0032] In certain embodiments, determining the weekly equivalent of the daily basal dose may require additional adjustment for patients treated with certain basal insulins. For example, for patients treated with twice-daily neutral protamine Hagedorn (NPH) insulin, in certain embodiments, the daily basal insulin dose should be reduced by 20% before determining the weekly equivalent of the daily basal dose as described above. Similarly, for patients treated with U300 insulin glargine, in certain embodiments, the daily basal insulin dose should be reduced by 20% before determining the weekly equivalent of the daily basal dose as described above.

[0033] In certain embodiments, the dosing regimens, uses, and methods described herein are designed to minimize the time it takes for a subject to achieve acceptable glycemic control by providing a loading dose. In certain embodiments, where a T2DM patient is currently treated with a once-daily basal insulin with or without multiple daily doses of insulin (MDI) and replaces the existing basal insulin with a once-weekly insulin receptor agonist, the need for a loading dose depends on the patient's FG before starting treatment with the once-weekly insulin receptor agonist. For example, in certain embodiments, if such a patient has a baseline FG > 120 mg / dL, a loading dose is provided, but if such a patient has a baseline FG < 120 mg / dL, a loading dose may not be required.

[0034] In certain embodiments, when a loading dose of BIF is indicated for such a T2DM patient with a baseline FG > 120 mg / dL, the loading dose is three times greater than the weekly equivalent of the daily basal dose, as determined above. Thus, for example, the loading dose of BIF for a patient treated with 42 units of insulin degludec per day would be 885 units [3 × (42 units / day × 7 days = 294 units, rounded to the nearest 5 = 295 units)]. In certain embodiments, the determination of the loading dose is subject to a maximum limit. For example, in certain embodiments, the maximum loading dose is 1600 units. Thus, for example, in such an embodiment, if the calculated loading dose is > 1600 units, the loading dose would be 1600 units. In certain embodiments, if a loading dose is not indicated for such a patient with a baseline FG ≦ 120 mg / dL, the first dose of BIF administered is the weekly maintenance dose, as determined, for example, as described in more detail below.

[0035] In certain embodiments for T1D patients, a loading dose is indicated, but the amount of the loading dose depends on factors such as the patient's FG. For example, in certain embodiments, the loading dose for T1D patients with FG ≤ 140 mg / dL is three times greater than the weekly equivalent of the daily basal dose, as described above for T2DM patients. For patients with FG > 140 mg / dL, in certain embodiments, the loading dose is adjusted upward. For example, in certain embodiments, for patients with a baseline FG of 141-160 mg / dL, the loading dose is calculated by first increasing the previous daily dose by 10-20%, then multiplying the increased dose by 7 to convert to a weekly dose. For patients with a baseline FG > 160 mg / dL, the upward adjustment is increased by 20-30%. Such embodiments are shown in Table 1 below. [Table 1]

[0036] In other embodiments, determining the expected weekly maintenance dose may require further adjustment beyond calculating the weekly equivalent of the daily basal dose. For example, if a subject's FG levels are above the target level at the start of treatment, the weekly equivalent of the daily basal dose in certain embodiments should be increased to determine the expected weekly maintenance dose. While the exact amount of adjustment may vary depending on the particular insulin receptor agonist, in certain embodiments, adjustments typically include increases of about 10-70% for subjects with FG levels relatively far from the target level, requiring adjustment at the upper end of the range, compared to subjects with FG levels closer to the target level. Similarly, in certain embodiments, if a subject's FG levels are below the target level at the start of treatment, the weekly equivalent of the daily basal dose should be reduced to determine the expected weekly maintenance dose. While the exact amount of adjustment may vary depending on the particular insulin receptor agonist, adjustments in certain embodiments typically include decreases of about 10-50%.

[0037] For example, in one particular embodiment of a subject switching from daily basal insulin to BIF, projected weekly maintenance dose adjustments designed to allow the subject to remain at or quickly reach a target FG of 100 mg / dL are shown below in Table 2. [Table 2]

[0038] In embodiments following the guidelines set forth in Table 2, the need for and magnitude of any adjustment to a subject's basal insulin equivalent dose switching from an existing basal insulin to BIF is based on the subject's FG and previous basal insulin dose. For example, if a subject taking 25 U / day of insulin degludec has a basal insulin equivalent dose of 5 mg and the subject's FG is 150 mg / dL, the recommended dose adjustment would be to add 1.5 mg, resulting in an expected weekly maintenance dose of 6.5 mg. As noted above, in certain preferred embodiments, the loading dose should be increased three-fold, resulting in a recommended loading dose of 19.5 mg.

[0039] The above guidelines for determining the loading dose for a subject switching from existing basal insulin to BIF can also be expressed in the form of the following formula: Loading dose = 3*(basal insulin equivalent dose-(0.25*X)+(0.25*Y)) During the ceremony, If the subject's median FG is ≥ 80, then X = 0; If the subject's median FG was <80 and their previous daily basal insulin dose was ≤15 U, then X=1; If the subject's median FG was <80 and their previous daily basal insulin dose was 16-30 U, then X=4, or If the subject's median FG was <80 and their previous daily basal insulin dose was >30 U, then X=6; During the ceremony, If the subject's median FG is ≦100, then Y=0; or If the subject's median FG was 101-140 and the previous basal insulin dose was ≤15 U, then Y=1; Y=2 if the subject's median FG was 141-180 and their previous basal insulin dose was 16-30 U, or if the subject's median FG was 101-140 and their previous basal insulin dose was 16-30 U; Y=3 if the subject's median FG was 181-220 and their previous basal insulin dose was ≦15 U, or if the subject's median FG was 101-140 and their previous basal insulin dose was >30 U; Y=4 if subject's median FG was >220 and previous basal insulin dose was ≤15U; or Y=6 if the subject's median FG was 181-220 and their previous basal insulin dose was 16-30 U, or if the subject's median FG was 141-180 and their previous basal insulin dose was >30 U; or Y=8 if the subject's median FG was >220 and their previous basal insulin dose was 16-30 U, or if the subject's median FG was 181-220 and their previous basal insulin dose was >30 U; If the subject's median FG was >220 and their previous basal insulin dose was >30 U, then Y=12.

[0040] In other embodiments of subjects switching from daily basal insulin to BIF, the expected weekly maintenance and loading doses may be determined based on the subject's daily basal insulin dose and baseline HbA1c level prior to initiation of treatment with BIF, as shown in Table 3 below. [Table 3]

[0041] Patients not currently treated with basal insulin and initiating a once-weekly insulin receptor agonist (referred to herein as "insulin-naive" patients) do not have a pre-existing daily basal insulin dose, and therefore the basal insulin equivalent dose cannot form the basis for determining the expected weekly maintenance and / or loading dose. Thus, for such patients, in certain embodiments, the loading dose of BIF will be 300 U, since the initial weekly maintenance dose will be set at a fixed level selected to approximate the requirement, e.g., 100 U, regardless of the patient's other characteristics.

[0042] In other embodiments for such patients, the expected weekly maintenance dose and / or loading dose is determined according to other patient characteristics, including, for example, the patient's FG and BW. In certain embodiments, the loading dose for such patients is designed to allow the patient to reach target FG levels relatively quickly. In certain embodiments, guidelines for selecting a loading dose incorporate a "baseline loading dose" based on the efficacy of the insulin receptor agonist, and, for subjects with FG and BW each below a certain threshold, incorporate gradual upward adjustment of the dose corresponding to increases in FG and / or BW.

[0043] In certain embodiments, the baseline loading dose of a given insulin receptor agonist is referred to herein as the "baseline loading dose," and the amount of any necessary adjustment based on an increase in FG and / or BW is expressed as a certain number or percentage increase of the additional baseline loading dose to be added. Certain insulin receptor agonists may have a baseline loading dose expressed as a number of insulin units, while others may have a baseline loading dose expressed as mg. In certain embodiments, the amount of any necessary upward adjustment is based on a percentage or number of additional baseline loading dose to be added. For example, if insulin has a baseline loading dose of 30 IU and FG and / or BW determine a subject's loading dose that recommends a 50% increase in the baseline loading dose, the loading dose would be 45 IU.

[0044] In certain embodiments, any recommended adjustment of the loading dose is based in part on the patient's FG falling within at least three ranges of FG levels: low, mid, and high. In certain embodiments, the low range is FG≦140, the mid range is FG from 141 to 220, and the high range is FG >220, where a FG in the low range does not result in any recommended increase in the baseline loading dose, a FG in the mid range results in a recommended increase of 100-200% of the baseline loading dose, and a FG in the high range results in a recommended increase of 300% of the baseline loading dose. In certain embodiments, the mid range includes two ranges: a first mid range of FG from 141 to 180 and a second mid range of FG from 181 to 220, where the first mid range results in a recommended increase of 100% of the baseline loading dose and the second mid range results in a recommended increase of 200% of the baseline loading dose.

[0045] Similarly, in certain embodiments, the amount of any recommended dose adjustment to the loading dose is based in part on the patient's BW falling within at least three ranges of BW: low, mid, and high. In certain embodiments, the low range is BW ≤ 80 kg, the mid range is BW between 80.1 and 120 kg, and the high range is BW > 120.1 kg, where a BW in the low range does not result in any recommended increase in the baseline loading dose, a BW in the mid range results in a recommended increase of 50-100% of the baseline loading dose, and a FG in the high range results in a recommended increase of 150% of the baseline loading dose. In certain embodiments, the mid range includes two ranges: a first mid range of BW between 80.1 and 100 kg and a second mid range of BW between 100.1 and 120 kg, where the first mid range results in a recommended increase of 50% of the baseline loading dose and the second mid range results in a recommended increase of 100% of the baseline loading dose.

[0046] For example, in certain embodiments, recommended loading doses designed to enable insulin-naive patients starting on BIF to rapidly reach steady-state serum concentrations and remain at or rapidly reach a target FG of 100 mg / dL are shown below in Table 4. [Table 4]

[0047] According to the regimen shown in Table 4, the loading dose for a patient not currently treated with daily basal insulin and starting on BIF is based on the subject's FG and BW. For example, the loading dose for a subject with a FG of 150 mg / dL and a BW of 110 kg would be 15 mg.

[0048] In other embodiments, the loading dose for insulin-naive subjects is determined according to the guidelines set forth below in Table 5. [Table 5]

[0049] Determination and administration of weekly maintenance dose. In certain embodiments, this document describes the method for determining and administering the weekly maintenance dose of insulin receptor agonist suitable for weekly administration.As used herein, the term " weekly maintenance dose " refers to any weekly dose of insulin receptor agonist suitable for weekly administration other than loading dose, as defined above.

[0050] In certain embodiments, the weekly maintenance dose can be specifically specified herein according to the number of previous doses of insulin receptor agonist administered.For example, the term "first weekly maintenance dose" used herein refers to either the weekly maintenance dose administered one week after the loading dose is administered, or the initial dose if no loading dose is administered.The term "second weekly maintenance dose" used herein refers to the weekly maintenance dose administered the week after the "first weekly maintenance dose".The term "third weekly maintenance dose" used herein refers to the weekly maintenance dose administered the week after the "second weekly maintenance dose".

[0051] In certain embodiments, the regimens, uses and methods described herein provide for the determination and administration of one or more weekly maintenance doses, designed to enable patients to reach target FG levels after the administration of as few doses as possible while minimizing the risk of hypoglycemia.

[0052] The dosage regimens herein vary in complexity, with less complex regimens offering the advantage of ease of interpretation and implementation, and more complex adjustments and regimens offering potential advantages with respect to glucose control. In general, however, the regimens described herein share certain common features: when FG is low, the dose is reduced; when FG is at or near the target, there is no dose adjustment; and when FG is high, the dose is increased. Additionally, in certain embodiments, the magnitude of the dose adjustment generally depends on how far the patient's FG is from the target; for example, an FG significantly above or below the target will result in a larger adjustment than an FG slightly above or below the target.

[0053] In certain embodiments, where a patient has T2D and has not progressed to the need for MDI treatment, the initial weekly maintenance dose is 100 U for insulin-naive patients, or equal to the weekly equivalent of the above daily basal dose for patients currently treated with once-daily basal insulin (i.e., 7 times the patient's current daily dose of basal insulin). For subsequent weekly maintenance doses, the determination of whether a dose adjustment is necessary is determined based on the patient's FG levels.

[0054] In certain embodiments, weekly maintenance dose adjustments can be determined according to the guidelines set forth below in Table 6. [Table 6]

[0055] In other embodiments, particularly for T2DM patients who are switching from once-daily basal insulin but have not progressed to MDI treatment, who have a median FG ≦120 mg / dL prior to initiation of once-daily insulin treatment, and / or whose once-daily basal insulin dose is <20 units / day, weekly maintenance dose adjustments can be determined according to the guidelines set forth below in Table 7. [Table 7]

[0056] In other embodiments, particularly for patients switching from a once-daily basal insulin and whose once-daily basal insulin dose is <10 units / day, weekly maintenance dose adjustments can be determined according to the guidelines set forth below in Table 8. [Table 8]

[0057] In addition, the weekly maintenance dose adjustments typically take into account any occurrence of hypoglycemia. For example, if a patient has experienced a hypoglycemic episode in the previous week, as indicated by a blood glucose of <70 mg / dL, the patient's dose should not be increased, even if the median FG falls within one of the ranges for which a dose adjustment is recommended. Furthermore, certain criteria may lead to a recommended dose reduction. For example, in certain embodiments, a 40-unit dose reduction is recommended for patients who meet any of the criteria shown in Table 9 below. [Table 9]

[0058] In certain embodiments of a T2D patient being treated with an MDI and switching from once-daily basal insulin to once-weekly insulin, weekly maintenance dose adjustments can be determined according to the guidelines set forth below in Table 10. [Table 10]

[0059] For T1D patients, similar to the loading dose calculation above in Table 10, in certain embodiments, the determination of a patient's first weekly maintenance dose depends on the patient's baseline FG before starting treatment with weekly insulin.

[0060] For example, in certain embodiments, the first weekly maintenance dose, loading dose for T1D patients with FG≦140 mg / dL will be 7-fold higher than their daily basal dose, while for patients with a baseline FG of 141-160 or >160, the daily basal dose will be increased by about 10-20% or about 20-30%, respectively, before conversion to a weekly dose, as shown in Table 11 below. [Table 11]

[0061] In certain embodiments, the T1D patient's subsequent weekly maintenance dose adjustment is determined according to the patient's FG and current dose of weekly insulin. For example, upward dose adjustments for patients with FG above the target glucose range may be more aggressive for patients receiving doses above a certain threshold and less aggressive for patients receiving doses below a certain threshold. In certain embodiments, the T1D patient's weekly maintenance dose adjustment may be determined according to the guidelines set forth below in Table 12. [Table 12]

[0062] The dose adjustments described above in Tables 11 and 12 may be subject to caution for patients who have experienced a hypoglycemic event. While the hypoglycemia-based limits on dose adjustments described above for T2D patients not treated with MDIs may also be appropriate for T1D and T2D patients treated with MDIs, these limits may result in underdosing of weekly basal insulin in some cases, as such patients may experience hypoglycemia related to MDI treatment and / or disease characteristics, potentially leading to unnecessary basal insulin dose reduction or dose increase restrictions. Thus, in certain embodiments, for MDI-treated patients, if the patient experiences hypoglycemia that is attributed to the patient's weekly basal insulin rather than their preprandial insulin, the patient's weekly basal dose should be reduced to the previous lower dose. For example, in some embodiments, a reduction to the previous lower dose may be indicated if the patient experiences nocturnal hypoglycemia. For example, in such embodiments, even if the patient's FBG from the previous week was above 120, if the patient had hypoglycemia warranting a reduction in the basal insulin dose, a dose escalation according to the guidelines set forth above in Tables 11 or 12 is indicated, and the patient's weekly insulin dose is reduced to the previous lower dose received prior to the dose administered the previous week. In certain embodiments, if the patient had no previous dose because this was the initially assigned dose, the weekly equivalent of the daily basal dose may be reduced, for example, by about 10-20%. Similarly, if the patient had been receiving the same weekly maintenance dose since treatment initiation, the previous week's dose may be reduced by about 10-20%.

[0063] In certain embodiments that may be applicable to a wide range of patients, weekly maintenance dose adjustments may be determined according to the guidelines set forth below in Table 13. [Table 13]

[0064] Additionally, in certain embodiments, such as those set forth in the guidelines above in Table 5, dose reductions are implemented if any of the following occur: multiple episodes of documented hypoglycemia with SMBG <70 mg / dL, severe hypoglycemia (requiring assistance), or documented hypoglycemia of ≦54 mg / dL in the previous week. In certain embodiments, if an individual blood glucose measurement is documented <70 mg / dL at any time in the previous week, the dose may not be increased.

[0065] The above guidelines can also be expressed in the form of the following formula: Weekly maintenance dose = previous dose - 14*X + 14*Y During the ceremony, If FG > 71, then X = 0 or If FG is between 55 and 70, then X=1, or If FG<54, then X=2; During the ceremony, If FG≦100, then Y=0 or If FG is between 101 and 125, then Y=1, or If FG is >125, then Y=2, but However, Y does not have to be >0 if the subject's SMBG measurement was <70 mg / dL at any time in the previous week.

[0066] In another embodiment, the FG target is 120 mg / dL and the criteria for dose adjustment are shown in Table 14 below. [Table 14]

[0067] In another embodiment, the FG target is 140 mg / dL and the criteria for dose adjustment are shown in Table 15 below. [Table 15]

[0068] In certain embodiments, the determination of the weekly maintenance dose may also take into account the number of previous doses of insulin receptor agonist that the patient has received. While the complexity of such regimens may vary, generally, the magnitude of the recommended dose adjustment will be relatively larger for the first weekly maintenance dose administered to a patient with certain characteristics than for the second or subsequent weekly maintenance doses.

[0069] In certain embodiments, weekly maintenance dose adjustments can be determined according to the guidelines set forth below in Table 16. [Table 16]

[0070] In addition to the guidelines in Table 16, dose reductions will be implemented based on the occurrence of any of the following hypoglycemic events: multiple episodes of documented hypoglycemia with SMBG <70 mg / dL, severe hypoglycemia (requiring assistance), and / or documented hypoglycemia of ≦54 mg / dL in the previous week. Additionally, if any SMBG readings <70 mg / dL have been documented at any time in the previous week, the dose may not be increased.

[0071] In certain embodiments, the guidelines for weekly maintenance dose adjustments set forth in Table 16 above are implemented in the form of the following formula: Weekly maintenance dose = previous dose - 14*X + 14*Y During the ceremony, If the subject's FG is ≧101 or the subject has received at least 3 previous doses and has an FG of 81-100, then X=0; If the subject's FG is ≦80 and the subject has received at least 3 previous doses, then X=1; or If the subject's FG is 81-100 and the subject has received two previous doses, then X=2; If the subject's BW is 81-100 and the subject has received one previous dose, then X=3; or If the subject's median FG is ≦80 and the subject has received one prior dose, then X=5; During the ceremony, If the subject's FG is ≦100, or if the subject's FG is 81-100 and the subject has received at least 3 previous doses, then Y=0; Y=1 if the subject's FG is 101-140 and the subject has received at least 3 previous doses; or If the subject's FG is 141-180 and the subject has received at least 3 previous doses, Y=2; or Y=3 if the subject's FG is >180 mg / dL and the subject has received at least 3 previous doses; or If the subject's FG is 141-180 and the subject has received two previous doses, then Y=5; If the subject's FG is 141-180 and the subject has received 1 previous dose, or if the subject's FG is >180 and the subject has received 2 previous doses, then Y=8.57; or If the subject's FG is >180 and the subject has received one previous dose, then Y=15; However, Y does not have to be >0 if the subject's any SMBG measurement was <70 mg / dL at any time in the previous week.

[0072] In certain embodiments, recommended adjustments to a weekly maintenance dose administered weekly can be described by adding or subtracting a given percentage or amount of "dose adjustment units" representing the minimum dose adjustment recommended for that particular insulin. For example, if the minimum recommended dose adjustment for any patient being treated with a given insulin receptor agonist is 2 IU, an increase of 4 dose adjustment units refers to an increase of 8 IU. In certain embodiments, the dose adjustment unit is about 0.5-5 IU. In other embodiments, the dose adjustment unit is about 0.75-4 IU. In other embodiments, the dose adjustment unit is about 1-3 IU. In a preferred embodiment, the dose adjustment unit is 1.75 IU. The dose adjustment unit can also be expressed in other units of measure, such as mg.

[0073] In certain embodiments, the regimens, uses, and methods described herein are designed to achieve a FG of 100 mg / dL, including five ranges based on these patient characteristics: (1) < about 80 mg / dL, (2) about 80 to about 100 mg / dL, (3) about 101 to about 140 mg / dL, (4) about 141 to about 180 mg / dL, and (5) > about 180 mg / dL. For patients in the first range who switched from daily basal insulin, the recommended dose adjustment is a reduction in each of the first, second, and third (or subsequent) weekly maintenance doses, but the amount of dose reduction is reduced by 30% and 50% for the second and third (or subsequent) weekly maintenance doses, respectively, compared to the amount of dose reduction for the first weekly maintenance dose. For patients in the second range switched from daily basal insulin, the recommended dose adjustment is a reduction in the first and second weekly maintenance doses, with the amount by which the dose is reduced being a 50% reduction for the second weekly maintenance dose compared to the amount by which the dose is reduced for the first weekly maintenance dose, and no dose adjustment is recommended for the third (or any subsequent weekly maintenance doses). For patients in the third range switched from daily basal insulin, no adjustment is recommended for the first and second weekly maintenance doses, and an upward adjustment is recommended for the third (or any subsequent) weekly maintenance dose. For patients in the fourth range switched from daily basal insulin, the recommended dose adjustment is an increase in the first, second, and third (or any subsequent) weekly maintenance doses, with the amount of the second and third (or any subsequent) increases being a 50% reduction compared to the increase for the first weekly maintenance dose. Finally, for patients in the fifth range, the recommended dose adjustments are increases in the first, second, and third (or subsequent) weekly maintenance doses, but the second and third (or subsequent) weekly maintenance dose increases are reduced by 50% and 75%, respectively, compared to the first weekly maintenance dose increase.

[0074] For example, for patients switching from daily basal insulin to BIF, recommended dose adjustments in certain embodiments are shown in Table 17 below. [Table 17]

[0075] In certain embodiments, dose adjustments for weekly maintenance doses for insulin-naive patients targeting 100 mg / dL FG follow the same general principles as above, but there are some differences in the specific application of those principles, such as different magnitudes of adjustments, and in some cases, different recommended adjustments depending on the size of the previous dose. In certain embodiments, recommended dose adjustments for insulin-naive patients initiating basal insulin therapy with BIF are shown in Table 18 below. [Table 18]

[0076] In certain embodiments, after a dose adjustment determined according to the above criteria has been administered for a certain number of weeks, the patient reaches a level of serum glucose control at which the need for dose adjustment can be determined less frequently than once a week. For example, in certain embodiments, the patient uses the above criteria to determine dose adjustment once a week for the first 8, 9, 10, 11, or 12 weeks of treatment, but only determines whether adjustment is necessary every 2, 3, or 4 weeks thereafter. In certain preferred embodiments, the patient uses the above criteria to determine dose adjustment once a week for the first 12 weeks of treatment, but only determines whether adjustment is necessary every 4 weeks thereafter. However, even in these embodiments, the occurrence of hypoglycemia may prevent a dose increase or lead to a dose decrease according to the above criteria.

[0077] Although some of the above embodiments are described for use with particular patient populations defined by certain criteria, such as whether the patient has T1D or T2D, the patient's baseline FG, whether the patient is treated with daily basal insulin, the patient's current basal insulin dose, and whether the patient is treated with an MDI, the use of such embodiments need not be mutually exclusive with respect to the populations. Thus, in some cases, aspects of the guidelines described above for one population may be used equally well for determining and adjusting doses for other populations.

[0078] In certain embodiments, the doses described herein are administered from a reusable pen injector or a disposable pen device.

[0079] Other definitions. 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.

[0080] As used herein, the term "dose" or "doses" refers to an amount of an insulin receptor agonist suitable for weekly dosing administered to an individual in discrete amounts at specific time points. When used in connection with terms such as dose, medication, doses, etc., the term "adjustment" refers to any decrease or increase in the amount of the dose administered the previous week. When used in connection with terms such as dose, medication, doses, etc., the term "regimen" refers to a set of guidelines for determining and administering one or more doses and / or adjustments thereto.

[0081] As used herein, the term "baseline" refers to a patient's characteristics before treatment with an insulin receptor agonist suitable for weekly dosing is initiated. For example, a patient's baseline FG is the patient's FG before the initial dose of an insulin receptor agonist suitable for weekly dosing is administered.

[0082] 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.

[0083] 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.

[0084] "MDI" therapy refers to therapy with injections of basal insulin combined with bolus or prandial insulin, which are short-acting and typically administered at mealtimes. Examples of bolus or prandial insulins used in such regimens include insulin lispro, insulin aspart, insulin glulisine, and regular insulin.

[0085] "Subject" refers to a mammal, preferably a human, having a disease, disorder, or condition that would benefit from treatment with an insulin receptor agonist suitable for once-weekly dosing.

[0086] "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.

[0087] "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.

[0088] "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.

[0089] 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.

[0090] The methods of treatment and use described herein may be provided in combination, simultaneously or sequentially, with other T2D treatments, including oral T2D medications such as metformin, and / or other injectable medications, including fast-acting or basal insulin or GLP-1 receptor agonists.

[0091] Certain non-limiting embodiments of the subject matter described herein are as follows.

[0092] Embodiment 1. A method of improving glycemic control in a subject with diabetes, comprising: a) determining a first dose of a long-acting insulin receptor agonist suitable for once-weekly dosing to be administered to a subject; b) administering to the subject a first dose of an insulin receptor agonist suitable for once-weekly dosing; c) measuring the subject's fasting glucose (FG); and d) tabulating the frequency and severity of subjects' hypoglycemia; and e) determining a second dose of insulin receptor agonist suitable for weekly dosing to be administered to the subject based on the subject's FG determined in step c) and the frequency and severity of hypoglycemia determined in step d); f) administering a second dose of an insulin receptor agonist suitable for once-weekly dosing.

[0093] Embodiment 2. The method of embodiment 1, wherein the first dose is a loading dose.

[0094] Embodiment 3. A method of improving glycemic control in a subject having diabetes, comprising administering to the subject a single loading dose of a long-acting insulin receptor agonist suitable for once-weekly dosing, and administering to the subject a weekly maintenance dose of an insulin receptor agonist suitable for once-weekly dosing.

[0095] Embodiment 4. The method of embodiment 2 or 3, wherein the loading dose is determined by determining the subject's expected weekly maintenance dose and multiplying the subject's expected weekly maintenance dose by 3.

[0096] The method of any one of embodiments 1-4, wherein the long-acting insulin receptor agonist is BIF.

[0097] Embodiment 5. The method of embodiment 2 or 3, wherein the subject is switching treatment from a daily basal insulin to a long-acting insulin receptor agonist suitable for once-weekly dosing, and the expected weekly maintenance dose is determined by taking the subject's current daily basal insulin dose and multiplying the subject's current daily basal insulin dose by 7.

[0098] Embodiment 6. The method of embodiment 1, wherein the subject is switching from a daily basal insulin to an insulin receptor agonist suitable for once-weekly dosing, and the first dose is determined by multiplying the weekly equivalent of the subject's previous daily insulin dose by 3.

[0099] Embodiment 7. The method of embodiment 3, wherein the subject is insulin naive and the loading dose is from about 3 mg to about 16.5 mg.

[0100] Embodiment 8. The method of any one of embodiments 1-4, wherein the loading dose is selected from the group consisting of 3 mg, 4.5 mg, 6 mg, 7.5 mg, 9 mg, 10.5 mg, 12 mg, 13.5 mg, 15 mg, and 16.5 mg.

[0101] Embodiment 9. The load is a) obtaining the subject's FG and body weight (BW); b) calculating the loading dose according to the formula: Loading dose=3+(3*X)+(1.5*Y) During the ceremony, If the subject's FG is ≦140, then X is 0 or If the target FG is 141-180, X is 1 or If the target FG is between 181 and 200, then X is 2, or If the subject's FG is >200, then X is 3; During the ceremony, If the subject's BW is ≤ 80 kg, Y is 0 or If the subject's BW is between 80.1 and 100 kg, Y is 1; If the subject's BW is between 100.1 and 120 kg, Y is 2, or

[0102] Embodiment 10. The method of embodiment 4 or 5, wherein Y is 3 if the subject's BW is ≧120.1.

[0103] Embodiment 11. The long-acting insulin receptor agonist suitable for once-weekly dosing is BIF and the expected weekly maintenance dose is: a) obtaining the subject's FG and previous daily basal insulin dose in units; b) determining the subject's previous daily basal insulin dose divided by 5 U / mg to obtain the basal insulin equivalent dose of BIF; c) calculating the expected weekly maintenance dose according to the following formula: Expected weekly maintenance dose = Basal insulin equivalent dose of BIF - (0.25*X) + (0.25*Y) During the ceremony, If the subject's median FG is ≥ 80, then X = 0; If the subject's median FG was <80 and their previous daily basal insulin dose was ≤15 U, then X=1; If the subject's median FG was <80 and their previous daily basal insulin dose was 16-30 U, then X=4, or If the subject's median FG was <80 and their previous daily basal insulin dose was >30 U, then X=6; During the ceremony, If the subject's median FG is ≦100, then Y=0; or If the subject's median FG was 101-140 and the previous basal insulin dose was ≤15 U, then Y=1; Y=2 if the subject's median FG was 141-180 and their previous basal insulin dose was 16-30 U, or if the subject's median FG was 101-14 and their previous basal insulin dose was 16-30 U; Y=3 if the subject's median FG was 181-220 and their previous basal insulin dose was ≦15 U, or if the subject's median FG was 101-140 and their previous basal insulin dose was >30 U; Y=4 if subject's median FG was >220 and previous basal insulin dose was ≤15U; or Y=6 if the subject's median FG was 181-220 and their previous basal insulin dose was 16-30 U, or if the subject's median FG was 141-180 and their previous basal insulin dose was >30 U; Y=8 if the subject's median FG was >220 and their previous basal insulin dose was 16-30 U, or if the subject's median FG was 181-220 and their previous basal insulin dose was >30 U; or The method of embodiment 2, wherein Y=12 if the subject's median FG is >220 and their previous basal insulin dose was >30 U.

[0104] Embodiment 12. The expected weekly maintenance dose is: a) obtaining the subject's FG and previous daily basal insulin dose in units; b) determining the subject's previous daily basal insulin dose divided by 7 U / mg to obtain an equivalent dose of BIF; c) determining whether to adjust the dose of BIF, wherein the subject's dose of BIF is: i) if the subject's FG is <80, it should be reduced by an amount of 0.25 mg to 1.5 mg; or ii) if the subject's FG is >101, determining whether it should be increased by an amount of 0.25 mg to 3 mg.

[0105] Embodiment 13. The subject's FG is <80 mg / dL and the expected weekly maintenance dose reduction of BIF is: a) If the subject's previous basal insulin dose is ≦15 U, reduce the dose by 0.25 mg; or b) If the subject's previous basal insulin dose is between 16 and 30 U, decrease the dose by 1 mg; or c) If the subject's previous basal insulin dose is >30 U, reduce the dose by 1.5 mg.

[0106] Embodiment 14. The subject's FG is >101 and the expected weekly maintenance dose escalation of BIF is: a) if the subject's previous basal insulin dose is ≦15 U, increase the dose by an amount of 0.25 mg to 1 mg; or b) if the subject's previous basal insulin dose is between 16 and 30 U, increase the dose by an amount between 0.5 mg and 2 mg; or c) If the subject's previous basal insulin dose is >30 U, increase the dose by an amount of 0.75 mg to 3 mg.

[0107] Embodiment 15. The subject's previous basal insulin dose is ≦15 U and the weekly maintenance dose increase of BIF is: a) If the subject's FG is 101-140, increase the dose by 0.25 mg; b) If the subject's FG is 141-180, increase the dose by 0.5 mg; c) If the subject's FG is 181-220, increase the dose by 0.75 mg; or d) The method of embodiment 10, wherein the dose is increased by 1 mg if the subject's FG is >220.

[0108] Embodiment 16. The subject's previous basal insulin dose is 16-30 U and the weekly maintenance dose increase of BIF is: a) If the subject's FG is 101-140, increase the dose by 0.5 mg; b) If the subject's FG is 141-180, increase the dose by 1 mg or c) If the subject's FG is 181-220, increase the dose by 1.5 mg; or d) The method of embodiment 10, wherein the dose is increased by 2 mg if the subject's FG is >220.

[0109] Embodiment 17. The subject's previous basal insulin dose is >30 U and the weekly maintenance dose increase of BIF is a) If the subject's FG is 101-140, increase the dose by 0.75 mg; b) If the subject's FG is 141-180, increase the dose by 1.5 mg. c) If the subject's FG is 181-220, increase the dose by 2 mg; and d) The method of embodiment 10, wherein the dose is increased by 3 mg if the subject's FG is >220.

[0110] Embodiment 18. The subject has T2D and the weekly maintenance dose is a) To compile the incidence and timing of hypoglycemia during the week following administration of the previous dose; and b) determining the subject's FG one week after administration of the previous dose; and c) calculating a weekly maintenance dose according to the formula: Weekly maintenance dose = previous dose / X-0.5Y+0.25Z, During the ceremony, If the previous dose was a loading dose, X is 3, or If the previous dose was a weekly maintenance dose, X is 1, During the ceremony, If the subject has a median FG > 100 and has received only one previous weekly maintenance dose, or if the subject has a median FG ≥ 80 and has received more than one previous weekly maintenance dose, then Y is 0; or If the subject has a median FG of 80-100 and has received one previous weekly maintenance dose, Y is 1 or If the subject has a median FG of 80-100 and has not received a previous weekly maintenance dose, Y is 2 or Y is 3 if the subject had either a median FG < 80, any episode of nocturnal hypoglycemia, or multiple episodes of hypoglycemia in the previous week and no more than one previous weekly maintenance dose was administered, or more than one previous weekly maintenance dose was administered and the previous weekly maintenance dose was ≦5 mg; or Y is 4 if the subject had either a median FG<80, any episode of nocturnal hypoglycemia, or multiple episodes of hypoglycemia in the previous week, and more than one previous weekly maintenance dose was administered, and the previous weekly maintenance dose was >5 mg; During the ceremony, If the subject has a median FG <100 mg / dL or a median FG between 101 and 140 mg / dL and has received only one previous weekly maintenance dose, Z is 0 or If the subject had a median FG of 101-140, received more than one previous weekly maintenance dose, and the previous weekly maintenance dose was ≤5 mg, then Z was 1 or If the subject received more than one previous weekly maintenance dose and had a median FG of 101-140 and the previous weekly maintenance dose was >5 mg, or if the subject had a median FG of 141-180 and the previous weekly maintenance dose was ≦5 mg, then Z is 2; or If the subject had a median FG >180 and had received more than one previous weekly maintenance dose, and the previous weekly maintenance dose was ≤5 mg, then Z was 3 or If the subject had a median FG of 141-180, received more than one previous weekly maintenance dose, and the previous weekly maintenance dose was ≥ 5 mg, Z was 4 or If the subject has received one previous weekly maintenance dose and has an FG of 141-180, or has received more than one previous weekly maintenance dose and has an FG > 180 and the previous weekly maintenance dose was > 5 mg, then Z is 6; or If the subject has not received a previous weekly maintenance dose and has an FG of 141-180, or has received one previous weekly maintenance dose and has an FG>180, then Z is 12; or The method of any one of embodiments 1-6, wherein Z is 20 if the subject has not received a previous weekly maintenance dose and has an FG>180.

[0111] Embodiment 19. The subject's first weekly maintenance dose comprises: a) To compile the incidence and timing of hypoglycemia for 1 week after administration of the loading dose; b) determining the subject's FG one week after administration of the loading dose; and c) Dividing the loading dose by 3; d) combining the dose obtained from step c) to obtain a weekly maintenance dose; i) If the subject had one or more of the following in the previous week: median FG <80 mg / dL, an episode of nocturnal hypoglycemia, or multiple episodes of hypoglycemia, reduce the dose by 1.5 mg; ii) If the subject had a median FG of 80-100 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, the dose was reduced by 1 mg; iii) If the subject had a median FG of 101-140 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, the dose was not changed. iv) If the subject had a FG of 141-180 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, the dose was increased by 3 mg. and v) determining whether the dose needs to be adjusted according to the following conditions: if the subject has had FG>180 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, then increase the dose by 5 mg.

[0112] Embodiment 20. a) determining a second weekly maintenance dose of an insulin receptor agonist to be administered to the subject; b) administering to the subject a second weekly maintenance dose of the insulin receptor agonist one week after the first weekly maintenance dose is administered to the subject.

[0113] Embodiment 21. The subject has T2D and the second weekly maintenance dose is: a) To collect the incidence and timing of hypoglycemia for one week after administration of the first weekly maintenance dose; b) determining the subject's FG one week after administration of the first weekly maintenance dose; c) dividing the first weekly maintenance dose into two doses to obtain a second weekly maintenance dose; i) If the subject had one or more of the following in the previous week: median FG <80 mg / dL, an episode of nocturnal hypoglycemia, or multiple episodes of hypoglycemia, reduce the dose by 1.5 mg; ii) If the subject had a median FG of 80-100 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, the dose was reduced by 0.5 mg; iii) If the subject had a median FG of 101-140 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, the dose was not changed. iv) If the subject had a median FG of 141-180 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, the dose was increased by 1.5 mg. v) determining whether the dose needs to be adjusted according to the following conditions: if the subject has had FG>180 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, then increase the dose by 3 mg.

[0114] Embodiment 22. a) determining a third weekly maintenance dose of an insulin receptor agonist to be administered to the subject; b) administering to the subject a third weekly maintenance dose of the insulin receptor agonist one week after the second weekly maintenance dose is administered to the subject.

[0115] Embodiment 23. The third weekly maintenance dose comprises: a) To compile the incidence and timing of hypoglycemia for one week after administration of the second weekly maintenance dose; b) determining the subject's FG one week after administration of the second weekly maintenance dose; and c) dividing the second weekly maintenance dose into two doses to obtain a third weekly maintenance dose; i) If the previous weekly maintenance dose was ≤5 mg, a. Reduce the dose by 1.5 mg if the subject had one or more of the following in the previous week: median FG < 80 mg / dL, an episode of nocturnal hypoglycemia, or multiple episodes of hypoglycemia; b. If the subject had a median FG of 80-100 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, do not change the dose. c. If the subject had a median FG of 101-140 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, increase the dose by 0.25 mg. d. If the subject had a median FG of 141-180 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, increase the dose by 0.5 mg. e. If the subject had FG > 180 mg / dL, ≤ 1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, increase the dose by 0.75 mg; ii) if the previous weekly maintenance dose was >5 mg; a. Reduce the dose by 2 mg if the subject had one or more of the following in the previous week: median FG < 80 mg / dL, an episode of nocturnal hypoglycemia, or multiple episodes of hypoglycemia; b. If the subject had a median FG of 80-100 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, do not change the dose. c. If the subject had a median FG of 101-140 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, increase the dose by 0.5 mg. d. If the subject had a median FG of 141-180 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, increase the dose by 1 mg. e. Determining whether the dose needs to be adjusted according to the following conditions: if the subject has had FG>180 mg / dL, 1 or less hypoglycemic episodes, and no nocturnal hypoglycemic episodes in the previous week, then increase the dose by 1.5 mg.

[0116] Embodiment 24. The method of embodiment 21 or 22, further comprising administering one or more subsequent weekly maintenance doses, wherein the subsequent weekly maintenance doses are determined according to the criteria described in items i) and ii) of embodiment 22.

[0117] Embodiment 25. The weekly maintenance dose is a) To compile the incidence and timing of hypoglycemia during the week following administration of the previous dose; and b) determining the subject's FG one week after administration of the previous dose; and c) calculating a weekly maintenance dose according to the formula: Weekly maintenance dose = previous dose / X-0.5*Y+0.25*Z During the ceremony, If the previous dose was a loading dose, X is 3, or If the previous dose was a weekly maintenance dose, X is 1, During the ceremony, If the subject has a median FG of ≥ 80, then Y is 0; or Y is 1 if the subject has a median FG of 80-100 mg / dL and has received one previous weekly maintenance dose, or has received at least two previous weekly maintenance doses and has had any one of the following since the previous weekly maintenance dose: a median FG <80, any episode of nocturnal hypoglycemia, or multiple episodes of hypoglycemia; or Y is 2 if the subject has a median FG of 80-100 mg / dL and has not received a previous weekly maintenance dose, or has received one previous weekly maintenance dose and has had any one of the following since the previous weekly maintenance dose: a median FG <80, any episode of nocturnal hypoglycemia, or multiple episodes of hypoglycemia; or Y is 3 if the subject has not received a previous weekly maintenance dose and has had any one of the following since the previous weekly maintenance dose: median FG < 80, any episode of nocturnal hypoglycemia, or multiple episodes of hypoglycemia; During the ceremony, If the subject has a median FG < 100 mg / dL or a median FG between 101 and 140 and has received only one previous weekly maintenance dose, then Z is 0 or If the subject had a median FG between 101 and 180 mg / dL and had received at least two previous weekly maintenance doses, Z was 1 or If the subject has a median FG between 141 and 180 mg / dL and has received one previous weekly maintenance dose, or a median FG >180 mg / dL and has received at least two previous weekly maintenance doses, then Z is 2; If the subject has a median FG between 141 and 180 mg / dL and has not received a previous weekly maintenance dose, or if the subject has a median FG >180 and has received one previous weekly maintenance dose, then Z is 4; or The method of any one of embodiments 3 or 6-8, wherein Z is 8 if the subject has a median FG>180 and has not received a previous weekly maintenance dose.

[0118] Embodiment 26. The subject has T1D and the first weekly maintenance dose is: a) To compile the incidence and timing of hypoglycemia for 1 week after administration of the loading dose; b) determining the subject's FG one week after administration of the loading dose; and c) combining the dose obtained from step c) to obtain a first weekly maintenance dose; i) If the subject had one or more of the following in the previous week: median FG <80 mg / dL, an episode of nocturnal hypoglycemia, or multiple episodes of hypoglycemia, reduce the dose by 1.5 mg; ii) If the subject had a median FG of 80-100 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, the dose was reduced by 1 mg; iii) If the subject had a median FG of 101-140 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, the dose was not changed. iv) If the subject had a FG of 141-180 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, increase the dose by 3 mg; or and v) determining whether the dose needs to be adjusted according to the following conditions: if the subject has had FG>180 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, then increase the dose by 5 mg.

[0119] Embodiment 27. a) determining a second weekly maintenance dose of an insulin receptor agonist to be administered to the subject; 26. The method of any one of embodiments 3, 6-8, or 25, further comprising: b) administering to the subject a second weekly maintenance dose of the insulin receptor agonist one week after the first weekly maintenance dose is administered to the subject.

[0120] Embodiment 28. The second weekly maintenance dose comprises: a) To collect the incidence and timing of hypoglycemia for one week after administration of the first weekly maintenance dose; b) determining the subject's FG one week after administration of the first weekly maintenance dose; c) dividing the first weekly maintenance dose into two doses to obtain a second weekly maintenance dose; i) If the subject had one or more of the following in the previous week: median FG <80 mg / dL, an episode of nocturnal hypoglycemia, or multiple episodes of hypoglycemia, reduce the dose by 1.5 mg; ii) If the subject had a median FG of 80-100 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, the dose was reduced by 0.5 mg; iii) If the subject had a median FG of 101-140 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, the dose was not changed. iv) If the subject had a median FG of 141-180 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, increase the dose by 1.5 mg; or v) determining whether the dose needs to be adjusted according to the following conditions: if the subject has had FG>180 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, then increase the dose by 3 mg.

[0121] Embodiment 29. a) determining a third weekly maintenance dose of an insulin receptor agonist to be administered to the subject; 28. The method of embodiment 26 or 27, further comprising: b) administering to the subject a third weekly maintenance dose of the insulin receptor agonist one week after the second weekly maintenance dose is administered to the subject.

[0122] Embodiment 30. The third weekly maintenance dose comprises: a) To compile the incidence and timing of hypoglycemia for one week after administration of the second weekly maintenance dose; b) determining the subject's FG one week after administration of the second weekly maintenance dose; and c) dividing the second weekly maintenance dose into two doses to obtain a third weekly maintenance dose; i) If the previous weekly maintenance dose was ≤5 mg, a. Reduce the dose by 1.5 mg if the subject had one or more of the following in the previous week: median FG < 80 mg / dL, an episode of nocturnal hypoglycemia, or multiple episodes of hypoglycemia; b. If the subject had a median FG of 80-100 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, do not change the dose. c. If the subject had a median FG of 101-140 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, increase the dose by 0.25 mg. d. If the subject had a median FG of 141-180 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, increase the dose by 0.5 mg. e. If the subject had FG > 180 mg / dL, ≤ 1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, increase the dose by 0.75 mg; ii) if the previous weekly maintenance dose was >5 mg; a. Reduce the dose by 2 mg if the subject had one or more of the following in the previous week: median FG < 80 mg / dL, an episode of nocturnal hypoglycemia, or multiple episodes of hypoglycemia; b. If the subject had a median FG of 80-100 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, do not change the dose. c. If the subject had a median FG of 101-140 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, increase the dose by 0.5 mg. d. If the subject had a median FG of 141-180 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, increase the dose by 1 mg. e. determining whether the dose needs to be adjusted according to the following conditions: if the subject has had FG>180 mg / dL, ≤1 hypoglycemic episode, and no nocturnal hypoglycemic episodes in the previous week, then increase the dose by 1.5 mg.

[0123] Embodiment 31. The method of embodiment 28 or 29, further comprising administering one or more subsequent weekly maintenance doses, wherein the subsequent weekly maintenance doses are determined according to the criteria described in items i) and ii) of embodiment 29.

[0124] Embodiment 32. The loading dose is: a) Obtaining the target FG and BW; b) Using the target FG and BW, i) If the subject's BW is ≦80 kg and the median FG is 100-140 mg / dL, the loading dose is 120 I.U. i) If the subject's BW is 81-100 kg and FG is 100-140 mg / dL, the loading dose is 200 I.U. iii) If the subject's BW is 101-120 kg and FG is 100-140 mg / dL, the loading dose is 240 I.U. iv) If the subject's BW is ≤80 kg and the median FG is 141-180 mg / dL, the loading dose is 250 I.U. v) a. Subject's BW is >120 kg and median FG is 100-140 mg / dL, or b. If the subject's BW is 81-100 kg and the median FG is 141-180 mg / dL, the loading dose is 280 I.U. vi) If the subject's BW is ≦80 kg and the median FG is 181-220 mg / dL, the loading dose is 370 I.U. vii) a. Subjects have a BW between 81 and 100 kg and a median FG between 181 and 220 mg / dL, or b. If the subject's BW is 101-120 kg and the median FG is 141-180 mg / dL, the loading dose is 420 I.U. viii) a. Subject's BW is >120 kg and median FG is 141-180 mg / dL, or b. If BW is ≦80 kg and median FG is >200 mg / dL, loading dose = 490 I.U. ix) a. Subject's BW is ≥ 101 kg and FG is 181-220 mg / dL, or b. If subject's BW is 181-100 kg and FG is >200 mg / dL, loading dose = 560 I.U. x) If the subject's BW is 101-120 kg and FG is 181-220 mg / dL, the loading dose = 630 I.U. xi) identifying the loading dose according to the following criteria: if the subject's BW is >120 kg and FG is >220 mg / dL, then loading dose=700 I.U.

[0125] Embodiment 33. The weekly maintenance dose is a) To compile the frequency and severity of hypoglycemia during the week following administration of the previous dose; and b) determining the subject's FG one week after administration of the previous dose; and c) calculating a weekly maintenance dose according to the formula: Weekly maintenance dose = previous dose - 14*X + 14*Y During the ceremony, i) X=0 if the subject's FG is ≧101 or the subject has received at least 3 previous doses and has an FG of 81-100; ii) X=1 if the subject's FG is ≦80 and the subject has received at least 3 previous doses; or iii) X=2 if the subject's FG is 81-100 and the subject has received two previous doses; iv) X=3 if the subject's BW is 81-100 and the subject has received one previous dose; or v) if the subject's median FG is ≦80 and the subject has received one previous dose, then X=5; During the ceremony, vi) Y=0 if the subject's FG is ≦100, the subject's FG is 81-100, and the subject has received at least 3 previous doses; or vii) Y=1 if the subject's FG is 101-140 and the subject has received at least 3 previous doses; or viii) Y=2 if the subject's FG is 141-180 and the subject has received at least three previous doses; or ix) Y=3 if the subject's FG is >180 mg / dL and the subject has received at least 3 previous doses; or x) If the subject's FG is 141-180 and the subject has received two previous doses, then Y=5; or xi) if the subject's FG is 141-180 and the subject has received 1 previous dose, or if the subject's FG is >180 and the subject has received 2 previous doses, then Y=8.57; or xii) if the subject's FG is >180 and the subject has received one previous dose, then Y=15; 32. The method of any one of embodiments 1-3 or 31, with the proviso that Y may not be >0 if the subject's SMBG reading was <70 mg / dL at any time in the previous week, and the dose must be reduced if the subject experiences multiple episodes of documented hypoglycemia with FG <70 mg / dL, severe hypoglycemia requiring assistance, and / or documented hypoglycemia of ≦54 mg / dL in the previous week.

[0126] Embodiment 34 The method of embodiment 1, wherein the subject is insulin naive and the first dose is about 70 I.U.

[0127] Embodiment 35. The second dose is a) To compile the incidence and timing of hypoglycemia during the week following administration of the previous dose; and b) determining the subject's FG one week after administration of the previous dose; and c) calculating a weekly maintenance dose according to the formula: Weekly maintenance dose = previous dose - 14*X + 14*Y During the ceremony, i) If FG is > 71, then X = 0; or ii) if FG is between 55 and 70, then X=1; or iii) if FG is <54, then X=2; During the ceremony, i) if FG≦100, then Y=0; or ii) if FG is between 101 and 125, then Y=1; or iii) If FG is >125, then Y=2, but 35. The method of any one of embodiments 1 or 33-34, provided that Y does not have to be >0 if the subject had any SMBG value <70 mg / dL at any time in the previous week.

[0128] Embodiment 36. The method of any one of embodiments 1 or 33-35, further comprising administering one or more additional weekly maintenance doses, wherein each of the one or more additional weekly maintenance doses is determined by the same process described in steps (a)-(c) of embodiment 35.

[0129] Embodiment 37. A method of providing glycemic control in a subject with diabetes in need thereof, comprising: a) To the subject, i) The subject is: a. Insulin naive or b. Have type 2 diabetes (T2D) and fasting glucose (FG) > 120 mg / dL, or c. If you have type 1 diabetes (T1D), the initial dose is a loading dose; ii) administering an initial weekly dose of basal insulin Fc (BIF) according to the following criteria: if the subject has T2D but does not meet the above criteria in a. or b., then the initial dose is a weekly maintenance dose; b) administering to the subject one or more weekly maintenance doses once a week starting one week after administration of the initial dose.

[0130] Embodiment 38. The method of embodiment 37, wherein the initial dose is a loading dose that is three times greater than the expected weekly maintenance dose.

[0131] Embodiment 39. The method of embodiment 37 or 38, wherein the subject is insulin naive and the loading dose is 300 U.

[0132] Embodiment 40. The method of embodiment 38, wherein the subject has T2D and FG>120 mg / dL, and the expected weekly maintenance dose is approximately 7 times greater than the subject's daily dose of basal insulin before initiation of treatment with BIF.

[0133] Embodiment 41. Each weekly maintenance dose comprises: a) If the previous dose was a loading dose, the weekly maintenance dose is equal to the expected weekly maintenance dose adjusted, if necessary, according to items (i) through (iv) below; i) If the subject's median FG in the previous week was <80 mg / dL, it will be reduced by 20 units; ii) equal to the previous dose if the subject's median FG was 80-120 mg / dL in the previous week; iii) If the subject's median FG was 121-140 mg / dL in the previous week, increase by 20 units; or iv) If the subject's median FG was >140 mg / dL, increase by 40 units; b) If the previous dose was not a loading dose, the weekly maintenance dose is selected according to the following criteria: either the expected weekly maintenance dose if the maintenance dose is an initial dose of BIF, or the previous maintenance dose adjusted, if necessary, according to items (i) to (iv) above.

[0134] Embodiment 42 The method of any one of embodiments 37 to 41, wherein prior to initiation of treatment with BIF, the subject is being treated with >10 units / day of basal insulin.

[0135] Embodiment 43 The method of any one of embodiments 37 to 42, wherein prior to initiation of treatment with BIF, the subject is being treated with >20 units / day of basal insulin.

[0136] Embodiment 44. The subject has T2D and either has a baseline FG≦120 mg / dL and / or is being treated with <20 units / day of basal insulin prior to initiation of treatment with BIF, and each weekly maintenance dose is a) If the previous dose was a loading dose, the weekly maintenance dose is equal to the expected weekly maintenance dose adjusted, if necessary, according to items (i) through (iv) below; i) If the subject's median FG in the previous week was <80 mg / dL, it will be reduced by 20 units; ii) equal to the previous dose if the subject's median FG was 80-120 mg / dL in the previous week; iii) If the subject's median FG was 121-140 mg / dL in the previous week, increase by 10 units; or iv) If the subject's median FG in the previous week was >140 mg / dL, increase by 20 units; b) If the previous dose was not a loading dose, the weekly maintenance dose is selected according to the following criteria: equal to the previous maintenance dose, adjusted, if necessary, according to items (i) to (iv) above.

[0137] Embodiment 45. The subject has T2D and is being treated with <10 units / day of basal insulin before initiation of treatment with BIF, and each weekly maintenance dose is: a) If the previous dose was a loading dose, the weekly maintenance dose is equal to the expected weekly maintenance dose adjusted, if necessary, according to items (i) through (iv) below; i) If the subject's median FG in the previous week was <80 mg / dL, it will be reduced by 20 units; ii) equal to the previous dose if the subject's median FG was 80-120 mg / dL in the previous week; iii) If the subject's median FG was 121-140 mg / dL in the previous week, it will be increased by 5 units; or iv) Increased by 10 units if the subject's median FG was >140 mg / dL in the previous week; b) If the previous dose was not a loading dose, the weekly maintenance dose is selected according to the following criteria: equal to the previous dose, adjusted, if necessary, according to items (i) to (iv) above.

[0138] Embodiment 46. The method of any one of embodiments 41-45, wherein the weekly maintenance dose is not increased if the subject has had a glycemic episode of <70 mg / dL in the previous week.

[0139] Embodiment 47. In the previous week, the subject: a) ≥3 glycemic episodes ≤70 mg / dL; b) ≥1 nocturnal glycemic episode ≤70 mg / dL; c) ≥1 glycemic episode ≤54 mg / dL, or d) The method of any one of embodiments 37-46, wherein the weekly maintenance dose is reduced by 40 units if the patient has had any of any episodes of severe hypoglycemia.

[0140] Embodiment 48. The method of any one of embodiments 41 to 47, wherein the subject is not being treated with an MDI.

[0141] Embodiment 49. The subject has T2D and is being treated with an MDI, and each weekly maintenance dose is a) if the weekly maintenance dose is the initial dose of BIF, the weekly maintenance dose is approximately 7 times the subject's daily dose of basal insulin prior to the initiation of treatment with BIF; b) If the weekly maintenance dose is not the initial dose of BIF and the subject has either a baseline FG ≦ 120 mg / dL or a daily basal dose of BIF < 20 units before initiating treatment, the weekly maintenance dose will be, as needed: i) If the subject's median FG in the previous week was <80 mg / dL, the weekly maintenance dose will be reduced by 10–20 units; ii) if the subject's median FG was 80-120 mg / dL in the previous week, the weekly maintenance dose would not be changed; iii) if the subject's median FG was 121-140 mg / dL in the previous week, the weekly maintenance dose was increased by 10 units; iv) Equal to the previous maintenance dose adjusted according to the following criteria: if the subject's median FG in the previous week was >140 mg / dL, the weekly maintenance dose would be increased by 20 units; c) If the weekly maintenance dose is not the initial dose of BIF and the subject has a baseline FG > 120 mg / dL and a basal dose ≥ 20 units / day before initiation of treatment with BIF, the weekly maintenance dose, as needed, i) If the subject's median FG in the previous week was <80 mg / dL, the weekly maintenance dose will be reduced by 20 units; ii) if the subject's median FG was 80-120 mg / dL in the previous week, the weekly maintenance dose would not be changed; iii) if the subject's median FG was 121-140 mg / dL in the previous week, the weekly maintenance dose was increased by 20 units; iv) The method of any one of embodiments 37-40, wherein the selected dose is equal to the previous maintenance dose adjusted according to the following criteria: if the subject's median FG in the previous week was >140 mg / dL, the weekly maintenance dose is increased by 40 units.

[0142] Embodiment 50. The subject has T1D and the loading dose is: a) If the subject's baseline FG is ≦140 mg / dL, then loading dose=(subject's daily dose of basal insulin before initiation of treatment with BIF)×7×3; b) If the subject's baseline FG is 140-160 mg / dL, loading dose = (subject's daily dose of basal insulin before initiation of treatment with BIF increased by approximately 10-20%) x 7 x 3; c) The method described in embodiment 37 or 38, wherein if the subject's baseline FG is >160 mg / dL, the loading dose is determined according to the following criteria: (the subject's daily basal insulin dose before the start of treatment with BIF increased by approximately 20-30%) x 7 x 3.

[0143] Embodiment 51. The subject has T1D and the subject's first weekly maintenance dose is: a) If the subject's baseline FG is ≦140 mg / dL, then the first weekly maintenance dose=(the subject's daily dose of basal insulin before initiation of treatment with BIF)×7; b) If the subject's baseline FG is 140-160 mg / dL, the first weekly maintenance dose = (the subject's daily dose of basal insulin before the start of treatment with BIF increased by approximately 10-20%) × 7; c) If the subject's baseline FG is >160 mg / dL, the first weekly maintenance dose = (the subject's daily dose of basal insulin before initiation of treatment with BIF increased by approximately 20-30%) x 7.

[0144] Embodiment 52. The subject has T1D and the subject's second and subsequent weekly maintenance doses are: a) If the subject's median FG for the previous week was <80 mg / dL, the weekly maintenance dose will be reduced to the previous low dose; b) If the subject's median FG was 80-120 mg / dL in the previous week, the weekly maintenance dose will not be changed; c) If the subject's median FG for the previous week was 121-150 mg / dL, the weekly maintenance dose will be increased by either 5 units if the previous weekly maintenance dose was <100 U, or 10 units if the previous weekly maintenance dose was ≥100 U; d) If the subject's median FG in the previous week was 151-180 mg / dL, the weekly maintenance dose will be increased by either 10 units if the previous weekly maintenance dose was <100 U, or 20 units if the previous weekly maintenance dose was ≥100 U; e) The method of any one of embodiments 37-38 or 50-51, wherein if the subject's median FG in the previous week was >180 mg / dL, the weekly maintenance dose is increased by either 20 units if the previous weekly maintenance dose was <100 U, or 30 units if the previous weekly maintenance dose was ≥100 U.

[0145] Embodiment 53. The method of any one of embodiments 49-52, wherein the weekly maintenance dose is not increased if the subject experiences one or more episodes of hypoglycemia that are attributed to BIF and not to the subject's pre-prandial insulin.

[0146] Embodiment 54. The method of any one of embodiments 49-53, wherein the weekly maintenance dose is not increased if the subject experiences one or more episodes of nocturnal hypoglycemia.

[0147] Embodiment 55. The method of any one of embodiments 49-54, wherein the weekly maintenance dose is not increased if the subject experiences one or more episodes of severe hypoglycemia.

[0148] Embodiment 56. The method of any one of embodiments 37 to 55, wherein the need to adjust any weekly maintenance dose is determined weekly for the first 12 weeks after initiation of treatment with BIF, and every 4 weeks thereafter.

[0149] Embodiment 57. The method of any one of embodiments 37-56, wherein the method comprises improving glycemic control in the patient.

[0150] Embodiment 58. BIF for use in the treatment of diabetes, wherein the treatment comprises: a) To the subject, iii) The subject is: a. Insulin naive or b. Have T2D and FG > 120 mg / dL, or c. If you have T1D, the initial dose is a loading dose; iv) administering an initial dose of BIF according to the following criteria: if the subject has T2D but does not meet the above criteria in a. or b., the initial dose is a weekly maintenance dose; and b) administering to said subject one or more weekly maintenance doses once a week starting one week after administration of the initial dose.

[0151] Embodiment 59. BIF for use according to embodiment 58, wherein the initial dose is a loading dose three times greater than the expected weekly maintenance dose.

[0152] Embodiment 60. BIF for use according to embodiment 58 or 59, wherein the subject is insulin naive and the loading dose is 300 U.

[0153] Embodiment 61. BIF for use according to embodiment 59, wherein the subject has T2D and FG>120 mg / dL and the expected weekly maintenance dose is approximately 7 times greater than the subject's daily dose of basal insulin before initiation of treatment with BIF.

[0154] Embodiment 62. Each weekly maintenance dose comprises: a) If the previous dose was a loading dose, the weekly maintenance dose is equal to the expected weekly maintenance dose adjusted, if necessary, according to items (i) through (iv) below; i) If the subject's median FG in the previous week was <80 mg / dL, it will be reduced by 20 units; ii) equal to the previous dose if the subject's median FG was 80-120 mg / dL in the previous week; iii) If the subject's median FG was 121-140 mg / dL in the previous week, increase by 20 units; or iv) If the subject's median FG was >140 mg / dL, increase by 40 units; b) If the previous dose was not a loading dose, the weekly maintenance dose is selected according to the following criteria: either the expected weekly maintenance dose if the maintenance dose is an initial dose of BIF, or the previous maintenance dose adjusted, if necessary, according to items (i) to (iv) above.

[0155] Embodiment 63. BIF for use according to any one of embodiments 58 to 62, wherein prior to the start of treatment with BIF, the subject is treated with >10 units / day of basal insulin.

[0156] Embodiment 64. BIF for use according to any one of embodiments 58 to 63, wherein prior to the start of treatment with BIF, the subject is treated with >20 units / day of basal insulin.

[0157] Embodiment 65. The subject has T2D and, prior to initiation of treatment with BIF, either has a baseline FG≦120 mg / dL and / or is being treated with <20 units / day of basal insulin, and each weekly maintenance dose is a) If the previous dose was a loading dose, the weekly maintenance dose is equal to the expected weekly maintenance dose adjusted, if necessary, according to items (i) through (iv) below; i) If the subject's median FG in the previous week was <80 mg / dL, it will be reduced by 20 units; ii) equal to the previous dose if the subject's median FG was 80-120 mg / dL in the previous week; iii) If the subject's median FG was 121-140 mg / dL in the previous week, increase by 10 units; or iv) If the subject's median FG in the previous week was >140 mg / dL, increase by 20 units; b) If the previous dose was not a loading dose, the weekly maintenance dose is equal to the previous maintenance dose, adjusted, if necessary, according to items (i) to (iv) above.

[0158] Embodiment 66. The subject has T2D and is being treated with <10 units / day of basal insulin before initiation of treatment with BIF, and each weekly maintenance dose is: a) If the previous dose was a loading dose, the weekly maintenance dose is equal to the expected weekly maintenance dose adjusted, if necessary, according to items (i) through (iv) below; i) If the subject's median FG in the previous week was <80 mg / dL, it will be reduced by 20 units; ii) equal to the previous dose if the subject's median FG was 80-120 mg / dL in the previous week; iii) If the subject's median FG was 121-140 mg / dL in the previous week, it will be increased by 5 units; or iv) Increased by 10 units if the subject's median FG was >140 mg / dL in the previous week; BIF for use according to any one of embodiments 58 to 62, wherein the weekly maintenance dose is selected according to the following criteria: b) if the previous dose was not a loading dose, the weekly maintenance dose is equal to the previous dose, adjusted, if necessary, according to items (i) to (iv) above.

[0159] Embodiment 67. A BIF for use according to any one of embodiments 63 to 66, wherein the weekly maintenance dose is not increased if the subject has had a glycemic episode of <70 mg / dL in the previous week.

[0160] Embodiment 68. In the previous week, the subject: a) ≥3 glycemic episodes ≤70 mg / dL; b) ≥1 nocturnal glycemic episode ≤70 mg / dL; c) ≥1 glycemic episode ≤54 mg / dL, or d) BIF for use according to any one of embodiments 58 to 67, wherein the weekly maintenance dose is reduced by 40 units if the patient has had any episode of severe hypoglycemia.

[0161] Embodiment 69. A BIF for use according to any one of embodiments 62 to 68, wherein the subject is not being treated with an MDI.

[0162] Embodiment 70. The subject has T2D and is being treated with an MDI, and each weekly maintenance dose is a) if the weekly maintenance dose is the initial dose of BIF, the weekly maintenance dose is approximately 7 times the subject's daily dose of basal insulin prior to the initiation of treatment with BIF; b) If the weekly maintenance dose is not the initial dose of BIF and the subject has either a baseline FG ≦ 120 mg / dL or a daily basal dose of BIF < 20 units before initiating treatment, the weekly maintenance dose will be, as needed: i) If the subject's median FG in the previous week was <80 mg / dL, the weekly maintenance dose will be reduced by 10–20 units; ii) if the subject's median FG was 80-120 mg / dL in the previous week, the weekly maintenance dose would not be changed; iii) if the subject's median FG was 121-140 mg / dL in the previous week, the weekly maintenance dose was increased by 10 units; iv) Equal to the previous maintenance dose adjusted according to the following criteria: if the subject's median FG in the previous week was >140 mg / dL, the weekly maintenance dose would be increased by 20 units; c) If the weekly maintenance dose is not the initial dose of BIF and the subject has a baseline FG > 120 mg / dL and a basal dose ≥ 20 units / day before initiation of treatment with BIF, the weekly maintenance dose, as needed, i) If the subject's median FG in the previous week was <80 mg / dL, the weekly maintenance dose will be reduced by 20 units; ii) if the subject's median FG was 80-120 mg / dL in the previous week, the weekly maintenance dose would not be changed; iii) if the subject's median FG was 121-140 mg / dL in the previous week, the weekly maintenance dose was increased by 20 units; iv) A BIF for use according to any one of embodiments 58 to 61, selected according to the following criteria: the BIF is equal to the previous maintenance dose adjusted according to the following criteria: if the subject's median FG in the previous week was >140 mg / dL, the weekly maintenance dose is increased by 40 units.

[0163] Embodiment 71. The subject has T1D and the loading dose is: a) If the subject's baseline FG is ≦140 mg / dL, then loading dose=(subject's daily dose of basal insulin before initiation of treatment with BIF)×7×3; b) If the subject's baseline FG is 140-160 mg / dL, loading dose = (subject's daily dose of basal insulin before initiation of treatment with BIF increased by approximately 10-20%) x 7 x 3; c) BIF for use according to embodiment 58 or 59, determined according to the following criteria: if the subject's baseline FG is >160 mg / dL, then loading dose = (the subject's daily basal insulin dose before the start of treatment with BIF increased by approximately 20-30%) x 7 x 3.

[0164] Embodiment 72. The subject has T1D and the subject's first weekly maintenance dose is: a) If the subject's baseline FG is ≦140 mg / dL, then the first weekly maintenance dose=(the subject's daily dose of basal insulin before initiation of treatment with BIF)×7; b) If the subject's baseline FG is 140-160 mg / dL, the first weekly maintenance dose = (the subject's daily dose of basal insulin before the start of treatment with BIF increased by approximately 10-20%) × 7; c) If the subject's baseline FG is >160 mg / dL, the first weekly maintenance dose = (the subject's daily dose of basal insulin before initiation of treatment with BIF increased by approximately 20-30%) x 7.

[0165] Embodiment 73. The subject has T1D and the subject's second and subsequent weekly maintenance doses are: a) If the subject's median FG for the previous week was <80 mg / dL, the weekly maintenance dose will be reduced to the previous low dose; b) If the subject's median FG was 80-120 mg / dL in the previous week, the weekly maintenance dose will not be changed; c) If the subject's median FG for the previous week was 121-150 mg / dL, the weekly maintenance dose will be increased by either 5 units if the previous weekly maintenance dose was <100 U, or 10 units if the previous weekly maintenance dose was ≥100 U; d) If the subject's median FG in the previous week was 151-180 mg / dL, the weekly maintenance dose will be increased by either 10 units if the previous weekly maintenance dose was <100 U, or 20 units if the previous weekly maintenance dose was ≥100 U; e) A BIF for use according to any one of embodiments 58-59 or 61-62, selected according to the following criteria: if the subject's median FG in the previous week was >180 mg / dL, then the weekly maintenance dose is increased by either 20 units if the previous weekly maintenance dose was <100 U, or 30 units if the previous weekly maintenance dose was ≥100 U.

[0166] Embodiment 74. A BIF for use according to any one of embodiments 70 to 73, wherein the weekly maintenance dose is not increased if the subject experiences one or more episodes of hypoglycemia that are attributed to the BIF and not to the subject's pre-prandial insulin.

[0167] Embodiment 75. A BIF for use according to any one of embodiments 70 to 74, wherein the weekly maintenance dose is not increased if the subject experiences one or more episodes of nocturnal hypoglycemia.

[0168] Embodiment 76. A BIF for use according to any one of embodiments 70 to 75, wherein the weekly maintenance dose is not increased if the subject experiences one or more episodes of severe hypoglycemia.

[0169] Embodiment 77. BIF for use according to any one of embodiments 58 to 76, wherein the need to adjust any weekly maintenance dose is determined weekly for the first 12 weeks after initiation of treatment with BIF, and every 4 weeks thereafter.

[0170] Embodiment 78. BIF for use according to any one of embodiments 58 to 77, wherein treatment comprises improving glycemic control in the patient.

[0171] Embodiment 79. Use of BIF in the manufacture of a medicament for use in the treatment of diabetes according to any one of embodiments 58 to 78.

[0172] This invention is further illustrated by the following examples which should not be construed as limiting the invention. [Example]

[0173] SAD and MAD studies. The study is designed to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) effects of BIF in healthy volunteers and patients with T2DM. The single ascending dose (SAD) study is a randomized, investigator- and subject-blinded, placebo-controlled, single-dose, single-center, dose-escalation study conducted in healthy subjects and patients with T2D. Six dose levels of BIF (2, 10, 12, 17, 20, and 35 mg) will be investigated in this study. Dose escalation of BIF will be evaluated in cohorts of eight healthy subjects or eight patients with T2D (six patients per cohort receive BIF and two patients receive placebo). Staggered dosing was implemented in each cohort, with each cohort receiving a new, higher dose of BIF. Because the unit dose of BIF required to achieve glycemic control equivalent to one unit of basal insulin is unknown, BIF doses are expressed in milligrams. Blood samples will be collected pre-dose and 8 hours post-dose on day 1, and once daily on days 2-7, day 14, and at the follow-up visit (day 29).

[0174] Plasma samples obtained during this study will be analyzed for BIF using a validated enzyme-linked immunosorbent assay (ELISA) method. The lower limit of quantitation (LLOQ) is 300.00 pM, and the upper limit of quantitation is 10,000.00 pM. Inter-assay precision (percent [%] relative error) during validation ranged from -1.0% to 5.4%. Inter-assay accuracy (% coefficient of variation [CV]) during validation ranged from 4.8% to 9.6%.

[0175] Plasma samples are analyzed for insulin glargine using a validated high-performance liquid chromatography method and tandem mass spectrometry (MS / MS) detection. The LLOQ for insulin glargine is 8.25 pM. The upper limit of quantitation for insulin glargine is 1649.4 pM. Inter-assay precision during validation for insulin glargine is 3.8%-9.0%, respectively. The inter-assay precision (% relative standard deviation) during validation for insulin glargine ranges from 3.8% to 9.0%.

[0176] The complete analysis set used for PK and PK / PD analyses consisted of all enrolled patients / subjects who received at least one dose of study drug, depending on the treatment they received. BIF and PK parameter estimates for insulin glargine and metabolites were calculated by standard noncompartmental analysis methods using Phoenix WinNonlin version 6.4 (Pharsight Corporation, USA). PD data were analyzed using S-Plus for Windows version 8.2.

[0177] The main parameter of the analysis was the time to maximum BIF concentration (t max ), BIF half-life, and peak-to-trough ratio of BIF. PD analysis of T2D patients is performed based on FG (using pre-breakfast fasting blood glucose from an 8-point glucose profile) version 7.3.

[0178] 57 T2D patients and 16 healthy subjects participated in this study. All 16 healthy subjects completed the study. Of the 56 T2D patients who completed the study, 36 received BIF (6 received 2, 10, 12, 17, 20, and 35 mg, respectively), 12 received placebo, and 8 received insulin glargine. Of the 16 healthy subjects, 12 received BIF (6 received 5 and 10 mg, respectively), and 4 received placebo.

[0179] PK results from the SAD study include all 36 T2D patients and 10 healthy subjects who received BIF. The dose response was linear in healthy subjects and patients, with low day-to-day and inter-subject variability in T2D patients. On average, after administration of a single dose, BIF increased C max t in patients receiving 2 mg, 10 mg, 12 mg, 17 mg, 20 mg, and 35 mg max The median (range) values ​​were 4.5 (3.0-6.0), 4.5 (3.0-5.0), 4.0 (3.0-5.0), 4.5 (2.0-14.0), 4.0 (4.0-5.0), and 4.5 (3.0-6.0), respectively. maxThe median (range) values ​​are 3.0 (3.0-4.0) and 3.0 (1.0-6.0), respectively. Maximum concentrations appear to increase proportionally with dose in healthy subjects and T2D patients. BIF plasma concentrations decline with a mean half-life of approximately 17 days in T2D patients. The calculated half-lives range from 14.8 to 18.5 days at different BIF doses in T2D patients and from 11.8 to 15.5 days at two BIF doses in healthy subjects.

[0180] The PD results of the SAD study showed that administration of a single dose of BIF to patients with T2D reduced fasting glucose levels, which were sustained for at least 5 days after administration. BIF administration resulted in glucose reduction within the first day of administration. Increased BIF concentrations were associated with a significant reduction in fasting glucose levels.

[0181] Data from the SAD study provide clear evidence of glucose lowering in study participants with T2DM following a single dose of BIF ranging from 2 to 35 mg. The PK of BIF following a single dose demonstrated a sustained action profile supporting once-weekly dosing. BIF reached maximum concentrations approximately 4 days after dosing, followed by a mean elimination half-life of approximately 17 days (range 11 to 22 days) in study participants with T2DM.

[0182] It has a long elimination half-life and is predicted to reach PK steady state in approximately 8-10 weeks when followed on a weekly fixed-dose regimen, resulting in approximately three-fold higher concentrations due to accumulation than after a single dose. Therefore, based on PK modeling, a loading dose strategy of three times the weekly dose would achieve steady-state exposure after one dose.

[0183] A triple-loading dose strategy was used in the multiple ascending dose (MAD) study. The MAD study was a three-center, randomized, open-label, active-controlled, multiple-dose, two-part, dose-escalation, and parallel-design study conducted to evaluate the safety and tolerability of BIF in patients with T2D. Dose escalation of BIF was evaluated in a cohort of up to eight patients with T2D (six BIF and two insulin glargine [Sanofi; Paris, France]). Patients taking insulin glargine (U100) continued their usual dosing regimen prior to the Day 1 dose, and patients not previously treated with insulin glargine were converted to the appropriate insulin glargine dose at the investigator's discretion. Patients assigned to the BIF group received a loading dose three times the weekly maintenance dose during the first week of administration on Day 1, followed by weekly maintenance doses (1, 2, 5, and 10 mg) once weekly for the next five weeks to rapidly achieve steady-state concentrations. Patients are discharged from the CRU on day 8. Patients assigned to the insulin glargine control group receive daily insulin glargine injections at the same dose and timing as their usual basal insulin.

[0184] Plasma samples obtained during the study were analyzed for BIF and insulin glargine, and PK and PK / PD analyses were performed as described above for the SAD study.

[0185] Thirty-three patients with type 2 disease (T2D) enrolled in the study, and 28 completed it. Patients were 40–69 years old, and 18 were male (Table 1). Twenty-five patients received BIF on day 1 (7 received 1 mg, 6 received 2 mg, 6 received 5 mg, and 6 received 10 mg), and 22 patients received BIF on week 6 (6 received 1 mg, 5 received 2 mg, 5 received 5 mg, and 6 received 10 mg).

[0186] Data show overall mean BIF t across all doses studied after the loading dose at week 1. maxThe peak-to-trough ratio of dose-normalized BIF concentrations over a 1-week period was 4.3 days. PK after a single loading dose was comparable to the concentration profile at week 6 (delivered weekly at 1 / 3 the dose), demonstrating successful transition of patients to a PK profile similar to steady state and supporting the loading dose strategy. In patients with T2D, the peak-to-trough ratio of dose-normalized BIF concentrations over a 1-week period is approximately 1.14 at steady state.

[0187] An average 7-point glucose profile is measured on days -1, 4, and 40. The glucose profile remains consistent over time across the four BIF treatment groups. Specifically, the glucose profiles of patients receiving BIF weekly are consistent throughout the 6-week study. Furthermore, the 7-point glucose profile of BIF is similar to that of insulin glargine. Higher dose levels induce a greater glucose response. There is no significant difference between subjects receiving BIF and insulin glargine.

[0188] Hypoglycemia was the most frequent treatment-related adverse reaction. Fewer episodes were reported following BIF administration compared with insulin glargine (44.0% vs. 62.5%). Most events were treated with food or drink.

[0189] Phase 2 study. T2DM patients previously treated with oral antidiabetic drugs and basal insulin The study was designed to evaluate the safety and efficacy of BIF compared with insulin degludec over a 32-week period in patients with T2DM previously treated with oral antidiabetic agents and basal insulin. The study design included two different algorithms for determining the loading dose and weekly maintenance dose of BIF.

[0190] The loading dose and expected weekly maintenance dose will be determined according to Table 19 below. [Table 19]

[0191] The two algorithms used for patients in the BIF arm of the study utilize different fasting glucose (FG) targets and adjustment intervals: Algorithm 1, with adjustments every 2 weeks targeting an FG ≦140 mg / dL, and Algorithm 2, with adjustments every 4 weeks targeting an FG ≦120 mg / dL. Dose adjustments are shown in Table 20 below. [Table 20]

[0192] Insulin degludec will be titrated to a FG target of ≤100 mg / dL using a modified Riddle treatment-to-goal algorithm. Study participants (N=399) will be randomized in a 1:1:1 ratio to one of three parallel treatment arms. Participants' mean age was 60.2 years, baseline HbA1c was 8.1%, and diabetes duration was 14.7 years. There were no statistically significant differences in demographic or baseline characteristics across the three treatment arms.

[0193] Both BIF groups achieved noninferiority (noninferiority margin = 0.4%) for the primary endpoint of HbA1c change from baseline to week 32, with mean ± SE reductions of 0.6 ± 0.1%, 0.6 ± 0.1%, and 0.7 ± 0.1% for BIF algorithm 1, BIF algorithm 2, and insulin degludec, respectively. In line with different plasma glucose targets, insulin degludec achieved greater glucose reductions from baseline compared with the BIF group. Similarly, when evaluating events <70 mg / dL (3.9 mmol / L), both BIF groups demonstrated significantly fewer hypoglycemic events (all recorded events and nocturnal events) compared with insulin degludec. Hypoglycemic events <54 mg / dL (3.0 mmol / L—all recorded events and nocturnal events) were not significantly different among the three groups. Both BIF groups had statistically significantly smaller weight gains compared with insulin degludec from baseline to week 32.

[0194] In summary, BIF, when administered weekly according to either dosing algorithm, was non-inferior to insulin degludec with respect to glycemic control as measured by change in HbA1c after 32 weeks, with lower incidence of documented hypoglycemia and nocturnal hypoglycemia <70 mg / dL, and less weight gain. Additionally, no safety signals were detected.

[0195] The results confirm the predictive power of the PK / PD-IGI model and will be used to update the model, which will be used to develop additional dose titration schemes that were studied in clinical trials described in more detail below.

[0196] Patients previously treated with multiple daily injection regimens. This three-period, multicenter, randomized, open-label, parallel, comparator-controlled study is designed to evaluate the efficacy and safety of a BIF dosing algorithm compared with insulin degludec in patients with T1DM treated with MDI for at least 3 months without interruption. The study will last 26 weeks to ensure adequate exposure to evaluate the efficacy and safety of insulin efcitra alfa. Insulin degludec is the open-label active comparator in this study and will be used to compare the effects of BIF with daily basal insulin on glycemic control, hypoglycemia, and weight gain.

[0197] The efficacy and safety assessments included in this study are generally considered reliable and accurate for assessing efficacy and safety in individuals and populations with T1DM. The primary efficacy measure is the change in HbA1c from baseline to week 26. Secondary efficacy assessments in this study are the change in HbA1c from baseline to week 12, the change in FG from baseline to weeks 12 and 26, and the change in bolus insulin dose from baseline to weeks 12 and 26.

[0198] The following safety assessments will be evaluated as secondary objectives: number and incidence of hypoglycemia, incidence of treatment-emergent SAEs, and laboratory assessments with a particular focus on changes in hepatic aminotransferases.

[0199] Participants will be randomized in a 1:1 ratio to receive either weekly subcutaneous BIF administered according to the methods and regimens described herein, or daily subcutaneous insulin degludec administered according to the modified Riddle algorithm.

[0200] Participants who complete treatment will provide at least 80% power to demonstrate non-inferiority of change in HbA1c from baseline to 26 weeks for BIF versus insulin degludec, based on the following assumptions: ●True mean difference = 0% ●SD 1.1% NIM 0.4% Use alpha level 0.1 on both sides

[0201] All tests of treatment effect were conducted at a two-sided alpha level of 0.1 unless otherwise stated, and all confidence intervals (CIs) are given at the two-sided 90% level. The maximum total duration of study participation for each participant was up to 33 weeks over the following study periods: ● Study period 1: Screening and introduction period, approximately 2 weeks Study period 2: Treatment period, 26 weeks Study period 3: Safety follow-up period, 5 weeks

[0202] A screening procedure will be performed to establish eligibility for inclusion in the study. The inclusion criteria are shown in Table 21 below. [Table 21]

[0203] The exclusion criteria are shown in Table 22 below. [Table 22-1] [Table 22-2]

[0204] After signing the informed consent form (ICF), study participants will be trained on disease monitoring and management procedures, research diary, and study procedures at Visit 1. Participant electronic diaries and paper note sheets will be distributed at Visit 2, as specified in the activity schedule for future visits. Collection of baseline self-monitoring blood glucose (SMBG) profiles via continuous glucose monitoring (CGM) will begin at Visit 2. Participants will continue the same basal and short-acting insulin regimen during the run-in period leading up to randomization. For all study participants who meet the study inclusion criteria, a Dexcom G6® CGM device will be inserted and activated (Visit 2). Participants will record two 6-point glucose profiles (using the CGM device) on non-consecutive days between Visits 2 and 3. The profiles must include measurements before and 2 hours after each of the day's main meals (breakfast, lunch, and dinner). The standard system, Dexcom G6, will be used according to the manufacturer's instructions for CGM in open-label mode. Study participants will wear this device starting at Visit 2. Additionally, all study participants will be permitted to use a personal blood glucose (BG) meter to perform additional BG tests or SMBG measurements during the outpatient period. Treatment decisions will be made based on CGM readings. Blood glucose meters should not be used to calibrate the CGM device. CGM calibration must be performed using a code provided with each sensor. Participants must use a study-specific CGM receiver and are not permitted to connect the CGM system transmitter to their personal smartphone to ensure data can be downloaded from the receiver at each visit.

[0205] At Visit 2, study participants who meet the eligibility criteria will be trained on the use of the CGM device, CGM sensor replacement, interpretation of CGM-based BG values ​​and alarms, and CGM requirements. During the first CGM session, study participants who meet all study inclusion criteria will have a CGM sensor inserted as part of Visit 2 activities.

[0206] Participants who remain eligible for the study will be randomized to one of two treatment arms. Following randomization at Visit 3, participants will participate in a 26-week treatment period. For patients randomized to the BIF arm, the following guidance regarding IP administration applies: IP will be administered at the facility by site personnel during weeks 0-8. Participants will receive education and training on how to self-administer IP. During weeks 9-12, IP will be reconstituted and administered at the site by the participant under the supervision of trained site personnel to ensure participant self-administration. Between weeks 13 and 25, outside of titration visits, IP may be self-administered by participants at home or, optionally, administered weekly by site personnel, unless local regulations require site administration. Self-injection information may be reviewed as needed throughout the study. Additional visits to ensure correct dosing, titration, and administration of study drug may be conducted at any time during the study if deemed necessary by the investigator.

[0207] Following weekly subcutaneous (SC) administration of BIF, the time to reach steady-state glucose levels is estimated to be 4–16 weeks based on BIF's long half-life. Because the risk of hyperglycemia is low and achieving BIF treatment goals in less than 12 weeks may be desirable, a loading dose strategy may be appropriate, administering an initial first dose sufficient to achieve effective exposure, followed by individually optimized weekly dose adjustments to achieve the target response. Therefore, a BIF-specific dosing algorithm was developed to rapidly achieve glycemic targets. The dosing algorithm described below is used by investigators to initiate and adjust BIF to achieve a target FG ≤ 100 mg / dL (< 5.6 mmol / L).

[0208] Therefore, a single loading dose followed by weekly dose adjustments is recommended. The loading dose is determined based on the patient's previous basal insulin use, baseline fasting glucose, and available BIF data, informing a triple loading dose strategy. Dose adjustments are based on previous fasting glucose and hypoglycemic events. Dose changes recommended by these dose adjustment algorithms are also at the investigator's discretion, taking into account hypoglycemia and other study participant safety concerns. If there is a deviation from the algorithm-recommended dose, the medical rationale for this deviation must be documented by the principal investigator.

[0209] The initial BIF dose will be determined based on both the previous basal insulin dose and baseline fasting glucose. Participants may enter the study using insulin glargine, detemir, or degludec. Consistent with product labeling, these insulins may be transferred unit-by-unit and are considered equivalent for the purposes of this protocol. Due to the long half-life of BIF, the change in fasting glucose response may take several weeks to reach a steady-state response; therefore, a loading dose strategy will be used for only the first dose to minimize the time required to achieve the desired target glycemic response.

[0210] The starting dose, i.e., loading dose, is determined by following the instructions below for converting your current basal insulin dose (units, U) to a dose of BIF (mg).

[0211] 1. Obtain the previous daily basal insulin dose of insulin glargine, detemir, or degludec assessed during the run-in period. Calculate the "basal insulin equivalent dose" (mg) of BIF by dividing the total daily dose (U) of basal insulin by a conversion factor of 7U / mg.

[0212] 2. Adjust the dose of BIF calculated in step 1 above according to the median baseline fasting glucose and the participant's previous basal insulin dose (U) category, as shown in Table 23 below. This is the expected starting weekly dose. [Table 23]

[0213] 3. Multiply the expected starting weekly dose obtained in step 2 above by 3 to obtain the loading dose.

[0214] For example, if a participant uses 35 U of degludec daily, that dose would be converted to 5 mg of BIF per Step 1. If the participant has an FG value of 155 mg / dL, the dose adjustment for this participant per Step 2 and Table 15 would be +1.5 mg. Therefore, the participant's expected starting weekly dose of BIF would be 6.5 mg, and per Step 3, the participant's loading dose would be 19.5 mg. At each subsequent site visit, the investigator will assess the study participant's glycemic control over the previous week and, if necessary, inform the study participant of any necessary dose adjustments. Dose adjustments are based on the median FG (determined from SMBG obtained from the CGM system, hereafter referred to as SMBG) obtained over at least three days (up to seven days) in the week leading up to the visit.

[0215] To enable rapid achievement of a target FG ≤ 100 mg / dL (< 5.6 mmol / L) while minimizing the risk of hyperglycemia, a dose adjustment strategy was designed that involves a larger adjustment of the first weekly dose following the loading dose (i.e., Visit 4 in this study) than the second weekly dose following the loading dose (i.e., Visit 5 in this study), and a larger adjustment of the second weekly dose following the loading dose (i.e., Visit 5 in this study) than all subsequent weekly doses. This dose adjustment strategy was implemented according to the following instructions.

[0216] 1. Obtain the starting total weekly dose as above. (This is 1 / 3 of the loading dose administered.)

[0217] 2. Using Table 24 below, determine any necessary dose adjustments after carefully reviewing the participant's fasting glucose (3-7 days prior to the visit) and any hypoglycemia recorded since the last BIF dose. [Table 24]

[0218] For example, for a participant with a 19.5 mg loading dose above, the starting weekly dose was 6.5 mg. If the participant did not report hypoglycemia and had a median FG of 150 mg / dL after the 19.5 mg loading dose, the weekly dose should be increased by 1 mg using the Week 1 (Visit 4) column. Therefore, the patient's first weekly dose (i.e., Visit 4) following the loading dose would be 7.5 mg. For the next weekly dose (i.e., Visit 5), if the participant did not report hypoglycemia and had a median FG of 153 mg / dL after the 7.5 mg dose, the weekly dose should be increased by 0.5 mg using the Week 2 (Visit 5) column. Therefore, the next weekly dose would be 8 mg. For the next weekly dose, using the "Week 3 (Visit 6) and all subsequent weeks" column, if the participant had a median FG of 133 mg / dL but reported one nocturnal hypoglycemic episode since the last dose, the dose should be reduced by 0.5 mg. Thus, the next weekly dose would be 7.5 mg. Subsequent visits would be managed using the same approach as Visit 6 (Week 3), always verifying the BIF dose administered at the previous visit, the median fasting glucose for the week prior to the visit, and any hypoglycemic status since the last dose of study drug.

[0219] Adherence to the dosing algorithm is required from Visit 3 (randomization) through Week 25 and will be monitored regularly by the study team. Study participant safety will be closely monitored during the early stages of dose titration to determine whether conversion and adjustments to the dose adjustment algorithm are necessary. In situations where the safety of study participants is a concern, the investigator may adjust the dose recommended by the dose adjustment algorithm in Table 8.

[0220] For patients randomized to the insulin degludec group, insulin degludec will be self-administered daily by participants after training and first administration under the supervision of site personnel on Day 1. The starting dose of insulin degludec will be the same dose of basal insulin used by study participants before entering the study. For subsequent dose adjustments, the investigator will use a dosing algorithm (adapted from Riddle et al. 2003) to initiate and adjust insulin degludec to target FG ≤ 100 mg / dL (< 5.6 mmol / L) to help patients achieve their glycemic goal.

[0221] If there are concerns about patient safety or if dose adjustments do not achieve the desired treatment effect, the investigator should adjust the insulin degludec dose up or down as recommended by the dose adjustment algorithm, document the clinical basis for the deviation, and notify Lilly Medical by email.

[0222] During site or telephone visits, the investigator will assess the patient's glycemic control over the previous week and inform the patient of any necessary dose adjustments, if necessary. Dosages are based on the patient's blood glucose levels. Adherence to the dosing algorithm provided for this study is mandatory from Visit 3 (randomization) through Visit 20 (Week 26) (inclusive). Dose escalations are scheduled at weekly intervals and may occur no earlier than 5 days after the last dose increase. In some cases, patient visits may occur later than 5 days due to the permitted visit tolerance period, but doses should not be increased unless at least 5 days have passed since the previous dose increase. In contrast, the insulin degludec dose may be reduced at any time at the investigator's discretion. Any deviations from this guidance must be supported by clinical evidence and accompanied by Lilly Medical information. The insulin dosing algorithm has been reviewed by Strange (2007). The insulin degludec dose escalation algorithm was adopted from Riddle et al. (2003) and is determined based on the definition of what is referred to as "Algorithm FG." The algorithm FG is the median FG (determined from SMBG) on days 5, 6, and 7 since the last insulin dose increment. If the interval since the last dose adjustment is longer than 7 days, the dose increase will be determined by the median FG value from the last 3 days. If the patient has measured FG on only 2 of the last 3 days, the smaller of those 2 FG values ​​should be used as the algorithm FG. If there is only one FG measurement in the last 3 days, the investigator should use their discretion in determining whether to make a dose adjustment based on that single FG value.

[0223] Because it is desirable to achieve glycemic targets in as many patients as possible, contingencies are provided to accommodate pre-specified protocol visits and increase the insulin degludec dose in a timely manner. Thus, if the last dose increment was 5 days prior, the dose increment will be determined by the algorithm FG, which is the smaller of the two FG values ​​on days 4 and 5. If the dose increase was 6 days prior, the algorithm FG will be the smaller of the two FG values ​​on days 5 and 6. In either case, if only one of the two FG values ​​is available, the investigator should use their discretion in determining whether to make a dose adjustment based on that single FG value.

[0224] The dose escalation algorithm is defined as follows: ●If the algorithm FG is 101-120 mg / dL (5.6-6.7 mmol / L), increase the dose by 2 U. ●If the algorithm FG is 121-140 mg / dL (6.8-7.8 mmol / L), increase the dose by 4 U. ●If the algorithm FG is 141-180 mg / dL (7.9-10.0 mmol / L), increase the dose by 6 U. ● If algorithm FG is >180 mg / dL (10.0 mmol / L), increase dose by 8 U.

[0225] The therapeutic target FG is ≤100 mg / dL (<5.6 mmol / L). If any SMBG is recorded at <70 mg / dL (<3.9 mmol / L) at any time in the previous week, the insulin degludec dose will not be increased. If there are multiple recorded hypoglycemic episodes with SMBG <70 mg / dL (<3.9 mmol / L), if severe hypoglycemia (requiring assistance) occurs, or if any SMBG is recorded at ≤54 mg / dL (≤3.0 mmol / L) in the previous week, a dose reduction of 2–4 U per adjustment may be permitted.

[0226] Participants in all groups continued to use concomitant short-acting insulin throughout the treatment period. Discontinuation or change of regimen was not permitted unless a dose adjustment was required for medical reasons or as permitted by the study protocol.

[0227] Study participants will be instructed to record their fasting glucose (FG) daily in an electronic diary (eDiary) using the values ​​displayed on their CGM device after waking. In addition, two 6-point SMBG profiles (before and 2 hours after breakfast, lunch, and dinner) must be performed on non-consecutive days in the week prior to the required visit.

[0228] Participants who develop severe persistent hyperglycemia will receive unplanned insulin intensification based on the investigator's clinical judgment. Participants who require unplanned insulin intensification will continue on IP in the trial until all study visits are completed.

[0229] All randomized participants will undergo comprehensive efficacy and safety assessments approximately one week after their last dose of BIF and one day after their last dose of insulin degludec, and will be required to conduct safety follow-up visits approximately six weeks after their last dose of BIF and five weeks after their last dose of insulin degludec. During the safety follow-up study, participants will continue to use CGM and will be returned to their previous basal insulin regimen if necessary.

[0230] Participants who discontinue IP before completing the treatment period will be encouraged to remain in the study and complete any scheduled study procedures by Visit 20. Participants who remain in the study will receive an appropriate glucose-lowering regimen.

[0231] Participants who discontinue IP for any reason and do not wish to return for the safety follow-up visit will be asked to perform an early termination (ET) visit as their final study visit.

[0232] Results from modeling simulations of the tested titration schemes support non-inferiority in HbA1c change from baseline for BIF versus insulin degludec.

[0233] Insulin-naive patients. This multicenter, randomized, open-label, parallel, comparator-controlled study with three study periods is designed to evaluate the efficacy and safety of BIF compared with insulin degludec in patients with T2DM who have been treated with a stable dose of metformin (alone or in combination with a stable dose of a DPPIV inhibitor and / or an SGLT2 inhibitor) for at least 3 months prior to screening. The study design is nearly identical to the phase 2 study in patients with T1D described above, but with a different target patient population and several other corresponding differences.

[0234] The study population included patients with a diagnosis of T2DM who had been treated with a stable dose of metformin (alone or in combination with a stable dose of a DPPIV inhibitor and / or an SGLT2 inhibitor) for at least 3 months prior to screening; aged 18-75 years; and baseline HbA 1c a value between 7.0% and 9.5% (inclusive); treated with a stable dose of metformin (alone or in combination with a stable dose of a DPPIV inhibitor and / or SGLT2 inhibitor) for 3 months prior to screening and willing to continue stable medication throughout the study; and a body mass index (BMI) between 20 and 45 kg / m 2 (inclusive) and no significant weight gain or loss (≥5%) in the past 3 months.

[0235] The population excludes participants who: have a history of more than one episode of ketoacidosis or hyperosmolar state / coma requiring hospitalization in the 6 months prior to screening; have had any episode of severe hypoglycemia and / or hypoglycemia unawareness within the 6 months prior to screening; have had any of the following CV conditions: acute myocardial infarction, New York Heart Association class III or IV heart failure, or cerebrovascular accident (stroke); have undergone gastric bypass (bariatric) surgery or restrictive bariatric surgery (e.g., Lap-Band®) prior to screening; have acute or chronic hepatitis, or nonalcoholic fatty liver disease Patients must have clear clinical signs or symptoms of any other liver disease except nonalcoholic fatty liver disease (NAFLD) (i.e., patients with NAFLD are eligible to participate), and / or have elevated liver enzyme measurements as determined by Gilbert's syndrome, alanine aminotransferase (ALT) / serum glutamic pyruvic transaminase (SGPT) >2.0 x ULN, or total bilirubin >1.5 x upper limit of normal (ULN) in the absence of aspartate aminotransferase (AST) / serum glutamic oxaloacetic transaminase (SGOT) >2.0 x ULN; estimated glomerular filtration rate (eGFR) <30 mL / min / 1.73 m 2have fasting triglycerides >400 mg / dL or non-fasting triglycerides >600 mg / dL; have experienced a significant weight loss or gain (>5%) in the 3 months prior to screening (Visit 1); have an active or untreated malignancy or have been in remission from a clinically significant malignancy (excluding basal or squamous cell skin cancer) for less than 5 years, or are at high risk of developing cancer or cancer recurrence in the investigator's opinion; have known hypersensitivity or allergy to the investigational drug or any of its excipients; have any other serious disease or condition (e.g., known drug or alcohol abuse / regular consumption or psychiatric disorder) that, in the investigator's opinion, poses a significant risk to the patient and may prevent the patient from following and completing the protocol. have had a blood transfusion or severe blood loss within 3 months prior to screening, or have any hematologic condition that may interfere with HbA1c measurement (e.g., hemoglobinopathy, hemolytic anemia, sickle cell disease); are taking medications that may significantly affect glycemic control (e.g., niacin [permitted if <1.0 g / day], bile acid sequestrants, or pentoxifylline); are receiving chronic (>14 days) systemic glucocorticoid therapy (excluding topical, intraocular, intranasal, or inhaled preparations) or have received such therapy for more than 14 days in the month prior to screening; are currently taking, or have taken within 3 months prior to screening, any prescription or over-the-counter (OTC) medication to promote weight loss.Participating patients must agree not to start a diet and / or exercise program during the study for the purpose of weight loss other than lifestyle and dietary therapy for diabetes treatment; be treated with sulfonylureas (SUs), glitazones, alpha-glucosidase inhibitors, GLP-1 receptor agonists, or insulin within 3 months prior to screening, except for short-term use of insulin for acute conditions (≤14 days within 6 months prior to screening); are using or have used antihypertensive medications at an unstable dose for 1 month prior to screening; are pregnant or planning to become pregnant, lactating / nursing (including use of a breast pump), or do not want to maintain abstinence or use contraception; or are women of childbearing potential.

[0236] Participants taking metformin (alone or in combination with a stable dose of a DPPIV inhibitor and / or SGLT2 inhibitor) will continue on the same dose to allow reliable assessment of HbA1c at randomization. If a participant develops a condition that contraindicates the use of metformin, a DPPIV inhibitor and / or an SGLT2 inhibitor (if used at screening), or starts other prohibited medications between screening and randomization, the participant will be considered ineligible and will be discontinued from the trial before randomization.

[0237] For all participants who meet the study inclusion criteria, excluding reporting screening clinical laboratory assessments, a LibrePro sensor for flash glucose monitoring (FGM) will be inserted and activated at Visit 1 for a baseline FGM assessment. If the patient is ultimately determined to be a screening failure, the sensor can be removed and discarded, or the patient can continue to wear it for up to 14 days and return to the site for measurements and diagnosis. All confirmed eligible participants will be required to continue wearing the sensor for up to 14 days, continue wearing the sensor until removal at Visit 3, or bring the sensor to Visit 3 if this visit is more than 14 days after insertion.

[0238] Participants will undergo three FGM sessions using the LibrePro System (Abbott) 14 days before randomization, at Visit 15, and at Visit 20. Patients will remain blinded to these assessments until study completion.

[0239] (Week 0, Visit 3) BIF loading doses are based on baseline median fasting glucose and body weight at Visit 3. Similar to the T1D patient study described above, a loading dose strategy is used to minimize the time required to achieve the desired target glycemic response and to achieve steady-state concentrations within Week 1. The loading dose comprises a single dose that is approximately 3-fold increased from the expected starting week maintenance dose based on the patient's median fasting glucose and body weight at the start of the study and is determined using Table 25 below. [Table 25]

[0240] For example, if a participant weighs 83 kg and has a median FG of 185 mg / dl, the initial dose of BIF is 10.5 mg. This 10.5 mg dose represents a three-fold increase in the weekly maintenance dose expected to be needed based on the patient's median fasting glucose and weight at the start of the study, i.e., based on the participant's weight and FG, the weekly maintenance dose is expected to be 3.5 mg. However, to rapidly reach the target FG value, the actual weekly maintenance dose administered in the week following the loading dose is adjusted based on the participant's FG value and any occurrences of hypoglycemia in the subsequent week, as described in more detail below.

[0241] The therapeutic target FG is ≤100 mg / dL (<5.6 mmol / L). Dose adjustments for subsequent weekly maintenance doses of BIF will be determined based on the median FG values ​​of at least 3 days (maximum 7 days) obtained in the week leading up to the visit, according to Table 26 below. All doses should be rounded to the nearest 0.25 mg. [Table 26]

[0242] For example, for the participant above who received a 10.5 mg loading dose, the expected starting weekly dose would be 3.5 mg. In subsequent weeks, the participant reported no hypoglycemia and the median FG was 175 mg / dL. Using the Week 1 (Visit 4) column in Table 18, the participant's first weekly maintenance dose following the loading dose would be 6.5 mg. In the week following administration of the first weekly maintenance dose, the participant reported no hypoglycemia and the median FG was 163. Using the Week 2 (Visit 5) column, the second weekly maintenance dose would be 8.0 mg, as the weekly dose would need to be increased by 1.5 mg. In the week following administration of the second weekly maintenance dose, the participant's median FG was 133 mg / dL. Using the "Subsequent Weeks" column, the weekly maintenance dose would need to be increased by 0.5 mg, as the third weekly maintenance dose would be 8.5 mg. Dose adjustments for all subsequent weeks are determined using the "Subsequent Weeks" column as described above for the third weekly maintenance dose.

[0243] Additional therapeutic intervention should be considered in patients who develop severe persistent hyperglycemia after randomization based on the following criteria (FDA 2008): a) Mean FG >270 mg / dL (>15.0 mmol / L) for any 2 or more weeks during the first 6 weeks after randomization, or b) Mean FG >240 mg / dL (>13.3 mmol / L) for any 2 or more weeks between Weeks 6 and 12 after randomization, or c) Mean FG >200 mg / dL (>11.1 mmol / L) for any 2 or more weeks after week 12.

[0244] The investigator must first confirm that the patient does not have an acute illness causing severe hyperglycemia and must confirm that the patient is fully adherent to the assigned treatment regimen after the first 12 weeks of the study. After considering relevant clinical criteria, the investigator will determine the appropriate glucose-lowering intervention (rescue intervention) in consultation with the patient. See the table in Section 6.5 for permitted medications. Patients receiving a new intervention for hyperglycemia management must continue receiving IP for the remainder of the trial.

[0245] As stated in the approved product labeling, insulin degludec will be administered at a starting dose of 10 IU / day, with subsequent dose adjustments determined and administered as described above for the Phase 2 study in patients with T1D.

[0246] Results from modeling simulations of the tested titration schemes support non-inferiority in HbA1c change from baseline for BIF versus insulin degludec.

[0247] Phase 3 study. The study will be a multicenter, randomized, parallel, comparator-controlled, treatment-to-target design with three study periods, including screening / run-in, treatment, and safety follow-up periods. The planned treatment periods are 26, 52, and 78 weeks. The patient population will include patients with T2DM previously treated with daily basal insulin (not MDI), insulin-naive patients with T2DM, patients with MDI-treated T2DM, and patients with T1DM.

[0248] T2DM patients treated with daily basal insulin (not MDI) This phase 3, multicenter, randomized, open-label, comparator-controlled study evaluated the efficacy and safety of BIF compared with insulin degludec in participants with type 2 disease treated with basal insulin. The study consisted of a 3-week screening / run-in period, a 78-week treatment period, and a 5-week safety follow-up period. The primary outcome was the change from baseline in HbA1c at week 26.

[0249] Participants were eligible for inclusion in the study only if they met pre-established inclusion criteria, including: 1. At least 18 years of age (or older depending on local regulations) at the time of screening; 2. Have a diagnosis of T2D according to WHO criteria and are currently treated with basal insulin; 3. Have an HbA1c value between 6.5% and 10% (inclusive) at the time of screening. 5. Treated with a stable regimen, in the investigator's opinion, of one of the following insulin regimens used according to local product labeling, with or without non-insulin diabetes therapy, for at least 90 days prior to screening (maximum three of the following: dipeptidyl peptidase (DPP-4) IV inhibitors; SGLT2 inhibitors; metformin; alpha-glucosidase inhibitors, GLP-1 receptor agonists): once-daily U100 or U200 insulin degludec, once-daily U100 or U300 insulin glargine, once- or twice-daily U100 insulin detemir, or once- or twice-daily human insulin NPH. 6. Have a body mass index of ≤45 kg / m2 at screening.

[0250] Participants will be excluded from the study if they meet any of the following criteria: 1. In the opinion of the investigator, have had significant weight gain or loss (e.g., ≥ 5%) in the past 3 months. 2. Have a diagnosis of T1D, 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). 3. Currently receive, or have received at any time in the past 6 months, any of the following insulin therapies (other than pregnancy) prior to screening for a maximum of 4 consecutive weeks, excluding short-term treatment of acute conditions: prandial insulin, insulin mixtures, inhaled insulin, U-500 insulin, or continuous subcutaneous insulin infusion therapy. 4. Have received any of the following unauthorized diabetes medications within 90 days prior to screening: glinides, sulfonylureas, pramlintide, or thiazolidinediones. 5. Have a history of more than one episode of ketoacidosis or hyperosmolar state / coma requiring hospitalization in the 6 months prior to screening. 5. Receiving chronic (>14 days) systemic glucocorticoid therapy (excluding replacement therapy for adrenal insufficiency; topical, intraocular, intranasal, or inhaled preparations or intra-articular injections) or received such treatment for more than 14 days in the month prior to screening. 6. Cardiovascular: New York Heart Association Class IV heart failure or any of the following CV conditions in the past 3 months prior to screening: acute myocardial infarction, cerebrovascular accident (stroke), or coronary artery bypass surgery. 7. Gastrointestinal: Having undergone gastric bypass (bariatric) surgery, restrictive bariatric surgery (e.g., Lap-Band®), or sleeve gastrectomy within 1 year prior to screening. 8. Liver: Have overt clinical signs or symptoms of acute or chronic hepatitis, cirrhosis, or any other liver disease except NAFLD (i.e., study participants with NAFLD are eligible to participate) and / or have elevated liver enzyme measurements as determined by a central laboratory at screening and as indicated below: total bilirubin >2x ULN, ALT / serum glutamic pyruvic transaminase >2.5x ULN, AST / serum glutamic oxaloacetic transaminase >2.5x ULN, or ALP >2.5x ULN.9. Renal: Have a history of renal transplant, currently receiving renal dialysis, or have an eGFR < 20 mL / min / 1.73 m2 calculated by the CKD-EPI formula as determined by a central laboratory at screening. 10. Have an active or untreated malignancy, have been in remission from a clinically significant malignancy (other than basal or squamous cell skin cancer) for less than 5 years, or are at high risk for developing cancer or have had cancer recurrence in the investigator's opinion. 10. Have a known hypersensitivity or allergy to the investigational drug or any of its excipients. 11. Have any other serious disease or condition (e.g., known drug or alcohol abuse or psychiatric disorder) that, in the investigator's opinion, poses a significant risk to the study participant and prevents the study participant from following and completing the protocol. 11. Evidence of a history of any substance use disorder of any severity as defined by the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) in the opinion of the investigator, excluding disorders due to nicotine or caffeine use, in the current or last 6 months. 12. Hematology: Blood transfusion or severe blood loss within the 90 days prior to Visit 1 (Week -3), or known hemoglobinopathy, hemolytic anemia, or sickle cell anemia, or any other hemoglobin abnormality characteristic of the investigator that is known to interfere with the measurement of HbA1c.

[0251] Participants who meet the inclusion criteria will be randomly assigned in a 2:1 (BIF:insulin degludec) ratio to the following treatment groups: BIF: once-weekly administration, and insulin degludec: once-daily administration. The total duration of each participant's study participation, including screening and post-treatment follow-up periods, will be approximately 86 weeks over the following study periods: Study Period I: Screening and Run-in Period, 3 weeks; Study Period II: Treatment Period, 78 weeks; and Study Period III: Safety Follow-up Period, 5 weeks.

[0252] BIF is administered once weekly at approximately the same time and day each week using a prefilled insulin pen (5-unit increments). If a dose is missed, it should be administered as soon as possible if at least 3 days (72 hours) remain until the next scheduled dose. If less than 3 days remain until the next scheduled dose, the missed dose should be skipped and the next dose should be administered on its regularly scheduled day. In either case, participants may resume their regular weekly dosing schedule. Weekly dosing days can be changed as needed, as long as the last dose was administered at least 3 days prior.

[0253] Insulin degludec (U100) is administered daily at approximately the same time each day using a commercially available insulin prefilled pen (1 unit increments).

[0254] For BIF, the maximum number of units per injection with the BIF prefilled pen is 400 units. Doses above 400 units per week (approximately 57 units per day of basal insulin [57 x 7 days = 399]) require more than one injection. The maximum single loading dose in this study is 1600 units, and the maximum weekly dose is 1400 units.

[0255] For insulin degludec, the maximum number of units per injection of insulin degludec (U100) is 80 units. For participants requiring an 80 unit dose per day, more than one injection will be required to administer the full daily dose of insulin degludec.

[0256] For both treatments, participants will be instructed to rotate injection sites from one injection to the next, even when injecting within the same area.

[0257] Participants' initial and weekly doses of BIF or daily dose of insulin degludec will be determined based on the participant's usual daily basal insulin dose before randomization. The starting dose will take into account the pre-study basal insulin labeling with regard to the ability to convert between units across insulin types / regimens. For participants whose pre-study basal insulin regimens have typically been adjusted to more conventional once-daily (U-100) basal insulin regimens (e.g., twice-daily NPH or once-daily U-300 glargine), the total daily dose will be reduced by 20% and then multiplied by 7 to obtain the weekly dose equivalent.

[0258] The dosing and titration algorithm used will be based on the participant's treatment assignment to either BIF or insulin degludec, as described in more detail below. Participants will be instructed not to take pre-study basal insulin on the day of randomization, as they will receive their assigned study insulin at the site.

[0259] In both treatment groups, insulin adjustments will be made to achieve and maintain an FBG target of 80-120 mg / dL throughout the study. Active titration will occur in both treatment groups from Visits 3-15 (Weeks 0-12), designated as the titration period, with the goal of achieving insulin dose stabilization by Visit 15 (Week 12), with monthly adjustments during the maintenance period from Visits 15-38 (Weeks 12-78).

[0260] Participants in both treatment groups will self-monitor FBG daily. A minimum of three FBG measurements must be obtained on separate days each week so that investigators can review the data and adjust doses using a weekly or daily insulin titration algorithm. The median FBG value used to determine dose adjustments beginning at Visit 6 (Week 3) will be obtained from the three most recent FBG values ​​from the previous week. The median is the middle value when the three values ​​are ordered in ascending or descending order. For example, if a participant's FBG values ​​were 180, 202, and 190 for the past three consecutive days, the median is 190. If a participant has only two FBG measurements in a week, the lower of the two measurements should be used to determine dose adjustments. If only one FBG measurement is available, the decision to change dose using only a single FBG value is at the investigator's discretion.

[0261] When considering any dose adjustment (in either treatment group), the investigator will ascertain whether the participant has experienced any documented hypoglycemic episodes. If the participant has experienced a documented BG ≤ 70 mg / dL (≤ 3.9 mmol / L) in the previous week, the dose should not be increased. Additionally, if hypoglycemic dose reduction criteria are met, the previous week's basal dose will be reduced as described in more detail below.

[0262] This section provides BIF dosing instructions for dose initiation at Visit 3 (Week 0), and administration of the daily dose at Visit 4 (Week 1), as well as subsequent dosing / dose adjustments during the treatment period.

[0263] At the randomization visit (Week 0), determine the starting dose based on FBG from the week prior to randomization. Participants with FBG > 120 mg / dL should follow the instructions in Table 27, and participants with FBG ≤ 120 mg / dL should follow the instructions in Table 20. Note: If the participant is taking twice-daily NPH or U300 glargine, the pre-study basal insulin dose should be reduced by 20% when determining the usual daily dose of pre-study basal insulin before calculating the starting week dose. [Table 27]

[0264] The loading dose must not exceed a dose of 1600 units. If the calculated loading dose is >1600 units, a maximum loading dose of 1600 units will be given as a single dose at Visit 3 (Week 0). [Table 28]

[0265] Visit 4 (Week 1): Starting Week Dose. If the participant experienced hypoglycemia in the previous week and met any of the criteria for dose reduction listed in Table 29, subtract 40 units from the starting week dose to obtain the dose for administration at Visit 4 (Week 1). [Table 29]

[0266] If the hypoglycemic dose reduction criteria are not met, administer the starting weekly dose.

[0267] The following steps show an example calculation for Visit 4 (Week 1) of the starting weekly dose. [Table 30]

[0268] Visit 5 (Week 2): Titration through Week 77. If the participant experienced documented hypoglycemia (BG ≤ 70 mg / dL) in the previous week, the dose should not be increased. If the participant experienced hypoglycemia in the previous week and met the criteria for dose reduction listed in Table 29, subtract 40 units from the previous weekly dose.

[0269] If BG ≤ 70 mg / dL is not reported, the median FBG from the previous week will be used to obtain the appropriate dose adjustment from the titration algorithm in Tables 31, 32, or 33, taking into account the participant's median FBG from the week prior to randomization and / or pre-study basal insulin dose. If the median FBG is within the target range of 80-120 mg / dL (inclusive) as shown in Tables 31-33, the dose from the previous week will not be changed. [Table 31]

[0270] For study participants entering the study with a median FBG ≤ 120 mg / dL or a pre-study basal insulin dose ≥ 10 units / day and < 20 units / day, the investigator may adjust the BIF dose according to Table 32. [Table 32]

[0271] For study participants entering the study with a pre-study basal insulin dose <10 units / day, the investigator may adjust the BIF dose according to Table 33. [Table 33]

[0272] This section provides dosing instructions for insulin degludec for dose initiation at Visit 3 (Week 0), and administration of the daily dose at Visit 4 (Week 1), and subsequent dosing / dose adjustments during the treatment period.

[0273] Visit 3 (Week 0): Randomization Visit Insulin Degludec Dose Determination from Pre-Study Insulin Dose Equivalent. Calculate the equivalent dose of insulin degludec to be administered once daily by the participant according to the instructions in Table 34. Note: If the participant is taking twice-daily NPH or U300 glargine, the pre-study basal insulin dose should be reduced by 20% when determining the once-daily dose of insulin degludec to start in the study. [Table 34]

[0274] Visit 4 (Week 1) through Visit 38 (Week 78). If the participant experienced any documented hypoglycemia (BG ≤ 70 mg / dL) in the previous week, the dose should not be increased. If the participant experienced hypoglycemia in the previous week and met the dose reduction criteria, the daily dose will be reduced as described in Table 235. [Table 35]

[0275] If the hypoglycemic dose reduction criteria are not met, the median FBG from the previous week will be used to obtain the dose adjustment from the titration algorithm in Table 36 or 37. For participants entering the study with a pre-study basal insulin dose of ≥ 10 units / day, the investigator may adjust the degludec dose according to Table 36 below. [Table 36]

[0276] For participants entering the study with a pre-study basal insulin dose <10 units / day, the investigator may adjust the degludec dose according to Table 37 below. [Table 37]

[0277] The objectives and endpoints of the study are shown in Table 38 below. [Table 38-1] [Table 38-2]

[0278] Insulin-naive T2DM patients This phase 3, parallel-design, open-label, randomized controlled trial is designed to evaluate the efficacy and safety of BIF as a weekly basal insulin compared with degludec in insulin-naive adults with type 2 diabetes (T2D) not adequately controlled with oral antihyperglycemic agents (OAMs), with or without GLP-1RAs. Participants will continue their previous stable therapy with zero to a maximum of three approved non-insulin antidiabetic medications during the study. Based on participants' randomized treatment assignment, participants will receive a prefilled insulin pen displaying and delivering their total weekly insulin doses: either once-weekly subcutaneous administration of BIF or once-daily administration of insulin degludec. In both treatment arms, 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. The investigator will determine participants' insulin doses according to the protocol and oversee dose adjustments to achieve glycemic goals while avoiding hypoglycemia. The primary endpoint of the study is at 52 weeks. The treatment period is 52 weeks, with rescue therapy beginning after 16 weeks.

[0279] Regular periodic review of blinded safety data will be performed by the study team (in accordance with the study's trial-level safety review plan), and an external data monitoring committee will review unblinded safety data as it assesses safety across all BIF Phase 3 studies.

[0280] Key design features include those shown in Table 39 below. [Table 39-1] [Table 39-2]

[0281] Inclusion criteria for the study included: 1. At least 18 years of age (or older depending on local regulations) at screening; 2. Diagnosis of type 2 diabetes mellitus (T2D) according to WHO criteria; 3. Baseline glycated hemoglobin A1c (HbA1c) levels of 7.0% to 10.5% (inclusive) at screening; 4. Acceptable non-insulin diabetes treatments may include zero to a maximum of three of the following: sulfonylureas, thiazolidinediones (TZDs), dipeptidyl peptidase IV (DPP-4) inhibitors, sodium-glucose cotransporter (SGLT)-2 inhibitors, biguanides (e.g., metformin), alpha-glucosidase inhibitors, or glucagon-like peptide-1 (GLP-1) receptor agonists; 5. Insulin-naive. However, short-term insulin treatment is permitted for up to 14 days before the screening date, as is previous insulin treatment for gestational diabetes. 6. BMI of ≤45 kg / m2 at screening with no significant weight gain or loss (≥5%) in the past 3 months. 7. In the opinion of the investigator, be sufficiently motivated, able, and willing to learn how to self-inject treatment as required for this protocol.

[0282] Participants will be excluded from the study if they meet any of the following criteria: 1. Diagnosis of type 1 diabetes mellitus, 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. Received any of the unauthorized antidiabetic medications within the past 30 days, including glinides, pramlintide, basal insulin, prandial insulin, insulin mixtures, inhaled insulin, or continuous subcutaneous insulin infusion therapy. 3. History of more than one episode of ketoacidosis or hyperosmolar state / coma requiring hospitalization within the six months prior to screening. 4. Any episode of severe hypoglycemia within the six months prior to screening. 5. Hypoglycemia unawareness, in the opinion of the investigator. 6. Cardiovascular (CV): New York Heart Association class IV heart failure or any of the following CV conditions within the past three months prior to screening: acute myocardial infarction, cerebrovascular accident (stroke), or coronary artery bypass surgery. 7. Gastrointestinal: Has undergone gastric bypass (bariatric) surgery, limited bariatric surgery (e.g., Lap-Band®), or sleeve gastrectomy within 1 year prior to screening, or in the opinion of the investigator, has clinically significant gastroparesis. 8. Hepatic: Has overt clinical signs or symptoms of acute or chronic hepatitis, cirrhosis, or other liver disease except nonalcoholic fatty liver disease (NAFLD) (i.e., study participants with NAFLD are eligible to participate), and / or has elevated liver enzyme measurements as determined by a central laboratory at screening: total bilirubin >2x upper limit of normal (ULN), alanine aminotransferase (ALT) / serum glutamic pyruvic transaminase (SGPT) >2.5x ULN, or aspartate aminotransferase (AST) / serum glutamic oxaloacetic transaminase (SGOT) >2.5x ULN, alkaline phosphatase (ALP) >2.5x ULN. 9. Renal: Have a history of renal transplant, currently undergoing renal dialysis, or have an estimated glomerular filtration rate (eGFR) <20 mL / min / 1.73 m2 calculated by the Chronic Kidney Disease-Epidemiology Equation as determined by a central laboratory at the time of screening.10. Have an active or untreated malignancy, have been in remission from a clinically significant malignancy (other than basal or squamous cell skin cancer) for less than 5 years, or are at high risk for developing cancer or have had cancer recurrence in the investigator's opinion. 11. Have a known hypersensitivity or allergy to the investigational drug or any of its excipients. 12. Have any other serious disease or condition (e.g., known drug or alcohol abuse or psychiatric disorder) that, in the investigator's opinion, poses a significant risk to the study participant and prevents the study participant from following and completing the protocol. 13. Have evidence of a history of any substance use disorder of any severity as defined by DSM-5 in the investigator's opinion, except for disorders due to nicotine or caffeine use, currently or within the last 6 months. 14. Hematology: Blood transfusion or severe blood loss within 90 days prior to Visit 1, or known characteristics of hemoglobinopathy, hemolytic anemia, sickle cell anemia, or any other hemoglobin abnormality known to interfere with the measurement of HbA1c in the opinion of the investigator, 15. Receiving chronic (>14 days) systemic glucocorticoid therapy (excluding topical, intraocular, intranasal, or inhaled preparations) or received such treatment for more than 14 days in the month prior to screening.

[0283] The timing and instructions for administration of BIF and insulin degludec will be similar to those described above for the phase 3 study in patients with T2DM treated with daily basal insulin, except that participants in this study did not receive a pre-study basal insulin dose and therefore must use a standardized expected weekly maintenance dose that is expected to be appropriate and tolerable for this patient population.

[0284] For participants randomized to BIF, the expected weekly maintenance dose will be 100 U, and a three-fold loading dose will be used, resulting in an initial dose of 300 U at Visit 4 (Week 1). The need for subsequent weekly maintenance dose adjustments will be determined according to the hypoglycemic criteria described above for Phase 3 studies in patients with T2DM treated with daily basal insulin.

[0285] For participants randomized to insulin degludec, the initial dose administered on day 1 will be 10 U, with subsequent weekly adjustments according to the criteria described above for phase 3 studies in patients with T2DM treated with daily basal insulin.

[0286] Efficacy and safety objectives, assessments and endpoints are shown in Table 40 below. [Table 40]

[0287] T2DM patients treated with MDIs This phase 3, parallel-design, open-label, randomized controlled trial is designed to evaluate the efficacy and safety of BIF compared with glargine in patients with type 2 disease who are receiving once- or twice-daily basal insulin and at least twice-daily prandial insulin before study entry. Participants will continue prior stable therapy with zero to three approved non-insulin antidiabetic medications during the study.

[0288] Based on the participant's randomized treatment assignment, a prefilled insulin pen displaying and delivering the total weekly insulin dose will be provided for either weekly subcutaneous administration of BIF or daily administration of insulin glargine. 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. The investigator will determine the participant's insulin dose as described below and oversee dose adjustments to achieve glycemic goals while avoiding hypoglycemia.

[0289] Key design features include those shown in Table 41 below. [Table 41-1] [Table 41-2]

[0290] Inclusion criteria included: 1. At least 18 years of age (or older depending on local regulations) at screening; 2. Diagnosed with type 2 diabetes mellitus (T2D) according to WHO criteria and currently treated with basal insulin, receiving at least two preprandial insulin injections per day; 4. Total daily insulin ≤ 2 units / kg / day at screening; 5. Have a baseline glycated hemoglobin A1c (HbA1c) value of 7.0% to 10% (inclusive) at screening; 6. For at least 90 days prior to screening, have been treated with a stable regimen of one of the following basal insulins used according to local product labeling, with or without non-insulin diabetes therapy: U100 or U200 insulin degludec once daily, U100 or U300 insulin glargine once daily, U100 insulin detemir once or twice daily, or human insulin neutral protamine Hagedorn once or twice daily. 7. Have been treated with a stable regimen of at least twice-daily dosing of one of the following insulins, used according to local product labeling, for at least 90 days prior to screening (one pre-meal insulin dose must be administered before dinner): insulin lispro (U100 and U200), insulin lispro-aabc (U100 or U200), insulin aspart (including U100, Fiasp, and Novolog), insulin glulisine (U100), regular insulin (U100). Acceptable non-insulin diabetes treatments may include zero to a maximum of three of the following: dipeptidyl peptidase IV inhibitors, sodium-glucose cotransporter-2 inhibitors, biguanides (e.g., metformin), or glucagon-like peptide-1 receptor agonists. Note: All non-insulin diabetes therapies must be used according to the corresponding local product labeling at the time of screening, and participants must be willing to continue stable medication throughout the study according to the protocol. 8. BMI of ≦45 kg / m2 with no significant weight gain or loss (≧5%) in the past 3 months.

[0291] Exclusion criteria include: 1. Significant weight gain or loss (e.g., ≥ 5%) in the past 3 months, in the opinion of the investigator; 2. 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); 3. Currently receiving any of the following insulin therapy (other than pregnancy) for up to 4 consecutive weeks, excluding short-term treatment of acute conditions: insulin mixtures, Affreza (inhaled regular human insulin), continuous subcutaneous insulin infusion therapy, or regular insulin U500, at any time in the past 90 days; 4. Receipt of any of the following unauthorized diabetes medications within the past 90 days, including glinides, sulfonylureas, pramlintide, alpha-glucosidase inhibitors, or thiazolidinediones; 5. History of more than one episode of ketoacidosis or hyperosmolar state / coma requiring hospitalization in the 6 months prior to screening. 6. Has had a severe hypoglycemic episode within 6 months prior to screening. 7. In the opinion of the investigator, has hypoglycemic unawareness. 8. No intention to change CGM use during the study (e.g., start, stop, change device). 9. Cardiovascular (CV): Has had New York Heart Association Class IV heart failure or any of the following CV conditions in the past 3 months prior to screening: acute myocardial infarction, cerebrovascular accident (stroke), or coronary artery bypass surgery. 10. Gastrointestinal: Has undergone gastric bypass (bariatric) surgery, restrictive bariatric surgery (e.g., Lap-Band®), or sleeve gastrectomy within 1 year prior to screening, or has clinically significant gastroparesis in the opinion of the investigator.11. Hepatic: Have overt clinical signs or symptoms of acute or chronic hepatitis or other liver disease except nonalcoholic fatty liver disease (NAFLD) (i.e., study participants with NAFLD are eligible to participate), and / or have elevated liver enzyme measurements as determined by a central laboratory at screening and as follows: total bilirubin >2x the upper limit of normal (ULN) (excluding a previous diagnosis of Gilbert's disease), alanine aminotransferase / serum glutamic pyruvic transaminase >2.5x the ULN, or aspartate aminotransferase / serum glutamic oxaloacetic transaminase >2.5x the ULN. 12. Renal: Have a history of kidney transplant, are currently receiving renal dialysis, or have an estimated glomerular filtration rate <30 mL / min / 1.73 m2 calculated by the Chronic Kidney Disease-Epidemiology Equation, as determined by a central laboratory at screening. 13. Active or untreated malignancy, in remission from a clinically significant malignancy (other than basal or squamous cell skin cancer) for less than 5 years, or at high risk for developing cancer or cancer recurrence in the investigator's opinion. 13. Hematology: Blood transfusion or severe blood loss within 90 days prior to Visit 1, or known hemoglobinopathy, hemolytic anemia, or sickle cell anemia, or any other hemoglobin abnormality characteristic of hemoglobin known to interfere with HbA1c measurement in the investigator's opinion. 14. Receiving chronic (>14 days) systemic glucocorticoid therapy (excluding topical, intraocular, intranasal, or inhaled preparations) or received such treatment for more than 14 days in the month prior to screening.

[0292] Instructions for initiation and titration of treatment with BIF are provided as set forth in Tables 42 and 43 below. [Table 42] [Table 43]

[0293] Efficacy and safety objectives, assessments and endpoints are shown in Table 44 below. [Table 44]

[0294] T1D patient A phase 3, parallel-design, open-label, randomized controlled trial is being designed to evaluate the efficacy and safety of BIF compared with degludec in participants with T1D who were treated with basal-bolus MDI therapy prior to study entry. A more detailed study description is provided below in Table 45. The study population and insulin comparator selection are supported by available efficacy and safety data from the aforementioned phase 2 study in a similar population comparing BIF with degludec. Based on participants' randomized treatment assignment, participants will be provided with a prefilled insulin pen that displays and delivers their total weekly insulin dose, either for weekly subcutaneous administration of BIF or daily administration of insulin degludec. In both treatment arms, participants will be provided with an open-label CGM and blood glucose monitor for diabetes management, will be instructed in the recognition and treatment of hypoglycemia, and will be trained on protocol-related tasks. The investigator will determine participants' insulin doses according to the protocol and oversee dose adjustments to achieve glucose goals while avoiding hypoglycemia.

[0295] Key design features include those shown in Table 45 below. [Table 45-1] [Table 45-2]

[0296] Inclusion criteria included: 1. At least 18 years of age (or older depending on local regulations) at the time of screening; 2. Have a diagnosis of type 1 diabetes mellitus (T1D) according to WHO criteria for at least one year prior to screening; 3. Have a hemoglobin A1c (HbA1c) value of 7.0% to 10% (inclusive) at screening; 4. Have been treated with a basal-bolus insulin analog MDI regimen, including bolus insulin analogs (insulin lispro, insulin aspart, insulin glulisine, Fiasp, Lyumjev) and meal-bound basal insulin analogs (glargine U-100, glargine U-300, degludec, detemir), according to local product labeling, for at least 90 days prior to screening; 5. Have a BMI ≤ 35.0 kg / m2.

[0297] Exclusion criteria included the following: 1. Diagnosis of type 2 diabetes mellitus or latent autoimmune diabetes. 2. History of more than one episode of ketoacidosis or hyperosmolar state / coma requiring hospitalization within 6 months prior to screening. 3. More than one episode of severe hypoglycemia (defined as requiring assistance due to neurologically ineffective hypoglycemia) within 6 months prior to screening. 4. Hypoglycemia unawareness in the investigator's opinion. 5. Defined excessive insulin resistance receiving a total daily dose of insulin >1.5 units / kg at the time of screening. 6. Cardiovascular (CV): New York Heart Association class IV heart failure or any of the following CV conditions within the past 3 months prior to screening: acute myocardial infarction, cerebrovascular accident (stroke), or coronary artery bypass surgery. 7. Gastrointestinal: Gastric bypass (bariatric) surgery, limited bariatric surgery (e.g., Lap-Band®), or sleeve gastrectomy within 1 year prior to screening, or the presence of clinically significant gastroparesis in the opinion of the investigator. 8. Hepatic: Overt clinical signs or symptoms of acute or chronic hepatitis, cirrhosis, or other liver disease except nonalcoholic fatty liver disease (NAFLD) (i.e., study participants with NAFLD are eligible to participate), and / or elevated liver enzyme measurements as determined by a central laboratory at screening and as follows: total bilirubin >2x upper limit of normal (ULN), alanine aminotransferase / serum glutamic pyruvic transaminase >2.5x ULN, or aspartate aminotransferase / serum glutamic oxaloacetic transaminase >2.5x ULN, alkaline phosphatase (ALP) >2.5x ULN. 9. Renal: History of renal transplant, currently receiving renal dialysis, or have an estimated glomerular filtration rate <30 mL / min / 1.73 m2 calculated by the Chronic Kidney Disease-Epidemiology Equation as determined by a central laboratory at screening. 10. Active or untreated malignancy, in remission from a clinically significant malignancy (other than basal cell or squamous cell skin cancer) for less than 5 years, or at high risk of developing cancer or recurrent cancer in the opinion of the investigator.11. Hematology: Blood transfusion or severe blood loss within 3 months prior to Visit 1, or known hemoglobinopathy, hemolytic anemia, or sickle cell anemia, or any other hemoglobin abnormality characteristic known to interfere with HbA1c measurement in the opinion of the investigator. 12. Receiving an insulin treatment regimen including NPH insulin, U-500 insulin, regular human insulin, or any premixed insulin within 90 days prior to screening (Visit 1). 13. Use of insulin human inhalation powder (Afrezza) within 90 days prior to screening (Visit 1). 14. Use of continuous subcutaneous insulin infusion (CSII) therapy within 90 days prior to screening (Visit 1). 15. Receiving any oral or injectable medication for the treatment of diabetes mellitus other than insulin within 90 days prior to screening (Visit 1). 16. Receiving chronic (>14 days) systemic glucocorticoid therapy (excluding replacement therapy for adrenal insufficiency; topical, intraocular, intranasal, or inhaled preparations) or received such treatment for more than 14 days in the month prior to screening.

[0298] BIF initiation and titration instructions (including goal-directed treatment dosing algorithms) are set forth below in Tables 46 and 47. [Table 46] [Table 47]

[0299] Additionally, guidelines are provided for reducing the dose to a previous low dose for certain hypoglycemic events.

[0300] Insulin degludec is titrated to a FG target of 80–120 mg / dL using the modified Riddle goal-directed treatment algorithm.

[0301] Efficacy and safety objectives, assessments and endpoints are shown in Table 48 below. [Table 48]

[0302] Other studies in patients with T2DM In other studies, the main inclusion criteria included a previous diagnosis of diabetes with stable background therapy, an age of at least 18 years, a baseline HbA1c value of approximately 7-10%, and a body mass index (BMI) of 20-45 kg / m2. Inclusion criteria and background therapy varied depending on the study population.

[0303] The primary objective of these studies is to investigate the effect of BIF on glycemic control compared with commercially available basal insulins such as insulin glargine or insulin degludec. The associated primary endpoint is to demonstrate non-inferiority of BIF compared with one of these basal insulins in terms of change from baseline in HbA1c. Secondary efficacy and safety objectives may include the proportion of patients achieving HbA1c targets (with or without hypoglycemia), change in fasting glucose, incidence of hypoglycemic events during the treatment period, change in weight, development of anti-drug antibodies, and CGM-derived endpoints such as time within target, above or below the target range.

[0304] Study participants and caregivers will be trained on the signs and symptoms of hyperglycemia and hypoglycemia, if applicable, and how to perform glucose monitoring as directed by the protocol. They will also be instructed to check glucose levels frequently as needed and to contact the investigational site in the event of severe, persistent hyperglycemia or severe hypoglycemia between study visits. Pertinent information for each episode of hypoglycemia will be collected in a research diary.

[0305] Self-monitoring of blood glucose or continuous glucose monitoring (using devices approved for this purpose) will be utilized to inform dose adjustments and monitor hyperglycemia and hypoglycemia. Participants who develop severe, persistent hyperglycemia based on specific predefined thresholds will receive additional glucose-lowering interventions (or rescue therapy). Additionally, if patients meet the definition of increased risk of hypoglycemia, they will be instructed to first reduce the dose of BIF according to the respective dosing algorithm and then, if necessary, discontinue the study drug. Detailed instructions on how to manage hyperglycemia and hypoglycemia will be provided to the investigational site and study participants. The safety of study participants will be closely monitored throughout the study, including safety follow-up.

[0306] In some Phase 3 studies, the starting dose for insulin-naive participants is derived from FG and BW, similar to the approach described above in insulin-naive Phase 2 trials. An example of such an approach is provided below in Table 49. [Table 49]

[0307] For participants previously treated with basal insulin, the starting dose will be determined based on the previous basal insulin dose and FG data.

[0308] Dose adjustments are determined based on the previous week's FG. An example set of guidelines for dose adjustments is shown in Table 50 below. [Table 50]

[0309] In addition to the FG-based guidelines for dose adjustments described above, dose reductions will be implemented based on the occurrence of any of the following: multiple episodes of documented hypoglycemia with SMBG <70 mg / dL, severe hypoglycemia (requiring assistance), and / or documented hypoglycemia of ≤54 mg / dL in the previous week. Additionally, if any SMBG readings <70 mg / dL have been documented at any time in the previous week, the dose may not be increased.

[0310] Additional studies are being designed to test dosing regimens designed to provide simpler dosing guidelines, while achieving desired glycemic targets, albeit potentially more gradual, without increasing the risk of hypoglycemia.

[0311] The first dose administered in these studies differs for insulin-naive participants compared with participants previously treated with daily basal insulin. The starting dose for insulin-naive participants is approximately 70 IU. Participants previously treated with basal insulin receive a loading dose based on a one-to-one unit conversion of their previous daily insulin dose to their weekly dose multiplied by a factor of three. For example, participants taking 30 IU of glargine daily will start with a BIF loading dose of 630 IU (30 IU x 7 days x 3). This loading dose strategy is designed to achieve an effective exposure that reduces transient hyperglycemia during this transition period.

[0312] Subsequent weekly dose adjustments for all participants will be based on the FG values ​​shown in Table 51 below. [Table 51]

[0313] Additionally, dose reductions will be implemented based on the occurrence of any of the following: multiple episodes of documented hypoglycemia with SMBG < 70 mg / dL, severe hypoglycemia (requiring assistance), and / or documented hypoglycemia of ≦ 54 mg / dL in the previous week. Additionally, if any SMBG readings < 70 mg / dL have been documented at any time in the previous week, the dose may not be increased.

[0314] array SEQ ID NO: 1 [ka]

Claims

1. 1. A method of providing glycemic control in a subject having diabetes in need thereof, comprising: a) administering to the subject, i) the subject is a. Insulin naive or b. have type 2 diabetes (T2D) and fasting glucose (FG) > 120 mg / dL, or c. If the patient has type 1 diabetes (T1D), the initial dose is a loading dose; ii) administering an initial weekly dose of basal insulin-Fc (BIF) according to the following criteria: if the subject has T2D but does not meet the above criteria in a. or b., then the initial dose is a weekly maintenance dose; b) administering to the subject one or more weekly maintenance doses once a week starting one week after administration of the initial dose.

2. 10. The method of claim 1, wherein the initial dose is a loading dose that is three times greater than the expected weekly maintenance dose.

3. 3. The method of claim 1 or 2, wherein the subject is insulin naive and the loading dose is 300 U.

4. 3. The method of claim 2, wherein the subject has T2D and FG>120 mg / dL, and the expected weekly maintenance dose is approximately 7 times greater than the subject's daily dose of basal insulin before initiation of treatment with BIF.

5. Each weekly maintenance dose is a) if the previous dose was a loading dose, the weekly maintenance dose is equal to the expected weekly maintenance dose adjusted, if necessary, according to items (i) to (iv) below; i) if the subject's median FG in the previous week was <80 mg / dL, it will be reduced by 20 units; ii) Equal to the previous dose if the subject's median FG during the previous week was 80-120 mg / dL; iii) increase by 20 units if the subject's median FG during the previous week was 121-140 mg / dL; or iv) if the subject's median FG is >140 mg / dL, increase by 40 units; b) if the previous dose was not a loading dose, the weekly maintenance dose is selected according to the following criteria: either the expected weekly maintenance dose if the maintenance dose is the initial dose of BIF, or the previous maintenance dose adjusted, if necessary, according to items (i) to (iv) above.

6. The method of any one of claims 1 to 5, wherein prior to initiation of treatment with BIF, the subject is treated with >10 units / day of basal insulin.

7. The method of any one of claims 1 to 6, wherein prior to initiation of treatment with BIF, the subject is treated with >20 units / day of basal insulin.

8. The subject has T2D and either has a baseline FG≦120 mg / dL and / or is being treated with <20 units / day of basal insulin prior to initiation of treatment with BIF, and each weekly maintenance dose is a) if the previous dose was a loading dose, the weekly maintenance dose is equal to the expected weekly maintenance dose adjusted, if necessary, according to items (i) to (iv) below; i) if the subject's median FG in the previous week was <80 mg / dL, it will be reduced by 20 units; ii) Equal to the previous dose if the subject's median FG during the previous week was 80-120 mg / dL; iii) increase by 10 units if the subject's median FG during the previous week was 121-140 mg / dL; or iv) if the subject's median FG in the previous week was >140 mg / dL, increase by 20 units; b) if the previous dose was not a loading dose, the weekly maintenance dose is equal to the previous maintenance dose adjusted, if necessary, according to items (i) to (iv) above.

9. The subject has T2D and was being treated with <10 units / day of basal insulin prior to initiation of treatment with BIF, and each weekly maintenance dose is a) if the previous dose was a loading dose, the weekly maintenance dose is equal to the expected weekly maintenance dose adjusted, if necessary, according to items (i) to (iv) below; i) if the subject's median FG in the previous week was <80 mg / dL, it will be reduced by 20 units; ii) Equal to the previous dose if the subject's median FG during the previous week was 80-120 mg / dL; iii) increase by 5 units if the subject's median FG during the previous week was 121-140 mg / dL; or iv) if the subject's median FG in the previous week was >140 mg / dL, increase by 10 units; b) if the previous dose was not a loading dose, the weekly maintenance dose is equal to the previous dose adjusted, if necessary, according to items (i) to (iv) above.

10. 10. The method of any one of claims 5 to 9, wherein the weekly maintenance dose is not increased if the subject has had a glycemic episode of <70 mg / dL in the previous week.

11. During the previous week, the subject: a) 3 or more glycemic episodes ≦70 mg / dL; b) 1 or more nocturnal glycemic episodes ≦70 mg / dL; c) 1 or more glycemic episodes ≦54 mg / dL, or d) the weekly maintenance dose is reduced by 40 units if the patient has had any of the following episodes of severe hypoglycemia:

12. The method of any one of claims 5 to 11, wherein the subject is not being treated with an MDI.

13. The subject has T2D and is being treated with an MDI, and each weekly maintenance dose is a) if the weekly maintenance dose is an initial dose of BIF, the weekly maintenance dose is approximately 7 times the subject's daily dose of basal insulin prior to the initiation of treatment with BIF; b) if the weekly maintenance dose is not the initial dose of the BIF and the subject has either a baseline FG≦120 mg / dL or a daily basal dose of BIF<20 units prior to initiation of treatment, the weekly maintenance dose is, as needed, i) if the subject's median FG during the previous week was <80 mg / dL, the weekly maintenance dose is reduced by 10-20 units; ii) if the subject's median FG during the previous week was between 80 and 120 mg / dL, the weekly maintenance dose is not changed; iii) if the subject's median FG during the previous week was 121-140 mg / dL, the weekly maintenance dose is increased by 10 units; iv) equal to the previous maintenance dose adjusted according to the following criteria: if the subject's median FG in the previous week was >140 mg / dL, then the weekly maintenance dose is increased by 20 units; c) if the weekly maintenance dose is not the initial dose of the BIF and the subject has a baseline FG>120 mg / dL and a basal dose >20 units / day prior to initiation of treatment with BIF, the weekly maintenance dose is, as needed, i) if the subject's median FG during the previous week was <80 mg / dL, the weekly maintenance dose is reduced by 20 units; ii) if the subject's median FG during the previous week was between 80 and 120 mg / dL, the weekly maintenance dose is not changed; iii) if the subject's median FG during the previous week was 121-140 mg / dL, the weekly maintenance dose is increased by 20 units; iv) if the subject's median FG in the previous week was >140 mg / dL, then the weekly maintenance dose is increased by 40 units.

14. wherein the subject has T1D and the loading dose comprises: a) if the subject's baseline FG is ≦140 mg / dL, then the loading dose=(the subject's daily dose of basal insulin prior to initiation of treatment with BIF)×7×3; b) if the subject's baseline FG is 140-160 mg / dL, the loading dose = (the subject's daily dose of basal insulin prior to initiation of treatment with BIF increased by about 10-20%) x 7 x 3; c) if the subject's baseline FG is >160 mg / dL, the loading dose is determined according to the following criteria: (the subject's daily dose of basal insulin before initiation of treatment with an increased BIF of about 20-30%) x 7 x 3.

15. the subject has T1D, and the subject's first weekly maintenance dose comprises: a) if the subject's baseline FG is ≦140 mg / dL, then the first weekly maintenance dose=(the subject's daily dose of basal insulin prior to initiation of treatment with BIF)×7; b) if the subject's baseline FG is 140-160 mg / dL, then the first weekly maintenance dose = (the subject's daily dose of basal insulin prior to initiation of treatment with BIF increased by about 10-20%) x 7; 15. The method of any one of claims 1-2 or 14, wherein the first weekly maintenance dose is selected according to the following criteria: c) if the subject's baseline FG is >160 mg / dL, then the first weekly maintenance dose = (the subject's daily dose of basal insulin before initiation of treatment with an increased BIF by about 20-30%) x 7.

16. wherein the subject has T1D, and the subject's second and subsequent weekly maintenance doses comprise: a) if the subject's median FG during the previous week was <80 mg / dL, the weekly maintenance dose is reduced to the previous lower dose; b) if the subject's median FG during the previous week was between 80 and 120 mg / dL, the weekly maintenance dose is not changed; c) if the subject's median FG during the previous week was 121-150 mg / dL, the weekly maintenance dose is increased by either 5 units if the previous weekly maintenance dose was <100 U, or 10 units if the previous weekly maintenance dose was ≥100 U; d) if the subject's median FG during the previous week was 151-180 mg / dL, the weekly maintenance dose is increased by either 10 units if the previous weekly maintenance dose was <100 U, or 20 units if the previous weekly maintenance dose was ≥100 U; e) if the subject's median FG in the previous week was >180 mg / dL, then the weekly maintenance dose is increased by either 20 units if the previous weekly maintenance dose was <100 U, or 30 units if the previous weekly maintenance dose was ≥100 U.

17. 17. The method of any one of claims 13-16, wherein the weekly maintenance dose is not increased if the subject experiences one or more episodes of hypoglycemia that are attributed to BIF rather than the subject's pre-prandial insulin.

18. 18. The method of any one of claims 13 to 17, wherein the weekly maintenance dose is not increased if the subject experiences one or more episodes of nocturnal hypoglycemia.

19. 19. The method of any one of claims 13-18, wherein the weekly maintenance dose is not increased if the subject experiences one or more episodes of severe hypoglycemia.

20. 20. The method of any one of claims 1 to 19, wherein the need to adjust any weekly maintenance dose is determined weekly for the first 12 weeks after initiation of treatment with BIF, and every 4 weeks thereafter.

21. 21. The method of any one of claims 1 to 20, wherein the method comprises improving glycemic control in the patient.

22. 1. A BIF for use in the treatment of diabetes, said treatment comprising: a) administering to the subject, i) the subject is a. Insulin naive or b. Have T2D and FG > 120 mg / dL, or c. If you have T1D, the initial dose is a loading dose; ii) administering the initial dose of BIF according to the following criteria: if the subject has T2D but does not meet the above criteria in a. or b., then the initial dose is a weekly maintenance dose; b) administering to said subject one or more weekly maintenance doses once a week starting one week after administration of said initial dose, thereby providing glycemic control.

23. 23. The BIF for use according to claim 22, wherein the initial dose is a loading dose three times greater than the expected weekly maintenance dose.

24. 24. The BIF for use according to claim 22 or 23, wherein the subject is insulin naive and the loading dose is 300 U.

25. 24. A BIF for use as described in claim 23, wherein the subject has T2D and FG>120 mg / dL, and the expected weekly maintenance dose is approximately 7 times greater than the subject's daily dose of basal insulin before initiation of treatment with BIF.

26. Each weekly maintenance dose is a) if the previous dose was a loading dose, the weekly maintenance dose is equal to the expected weekly maintenance dose adjusted, if necessary, according to items (i) to (iv) below; i) if the subject's median FG in the previous week was <80 mg / dL, it will be reduced by 20 units; ii) Equal to the previous dose if the subject's median FG during the previous week was 80-120 mg / dL; iii) increase by 20 units if the subject's median FG during the previous week was 121-140 mg / dL; or iv) if the subject's median FG is >140 mg / dL, increase by 40 units; 26. A BIF for use according to any one of claims 22 to 25, selected according to the following criteria: b) if the previous dose was not a loading dose, the weekly maintenance dose is equal to either the expected weekly maintenance dose if the maintenance dose is the initial dose of BIF, or the previous maintenance dose adjusted, if necessary, according to items (i) to (iv) above.

27. A BIF for use according to any one of claims 22 to 26, wherein prior to the start of treatment with the BIF, the subject is treated with >10 units / day of basal insulin.

28. A BIF for use according to any one of claims 22 to 27, wherein prior to the start of treatment with the BIF, the subject is treated with >20 units / day of basal insulin.

29. The subject has T2D and either has a baseline FG≦120 mg / dL and / or is being treated with <20 units / day of basal insulin prior to initiation of treatment with BIF, and each weekly maintenance dose is a) if the previous dose was a loading dose, the weekly maintenance dose is equal to the expected weekly maintenance dose adjusted, as appropriate, according to items (i) to (iv) below; i) if the subject's median FG in the previous week was <80 mg / dL, it will be reduced by 20 units; ii) equal to the previous dose if the subject's median FG during the previous week was 80-120 mg / dL; iii) increase by 10 units if the subject's median FG during the previous week was 121-140 mg / dL; or iv) if the subject's median FG in the previous week was >140 mg / dL, increase by 20 units; 27. The BIF for use according to any one of claims 22 to 26, wherein the BIF is selected according to the following criteria: b) if the previous dose was not a loading dose, the weekly maintenance dose is equal to the previous maintenance dose adjusted, if necessary, according to items (i) to (iv) above.

30. The subject has T2D and was being treated with <10 units / day of basal insulin prior to initiation of treatment with BIF, and each weekly maintenance dose is a) if the previous dose was a loading dose, the weekly maintenance dose is equal to the expected weekly maintenance dose adjusted, as appropriate, according to items (i) to (iv) below; i) if the subject's median FG in the previous week was <80 mg / dL, it will be reduced by 20 units; ii) Equal to the previous dose if the subject's median FG during the previous week was 80-120 mg / dL; iii) increase by 5 units if the subject's median FG during the previous week was 121-140 mg / dL; or iv) Increased by 10 units if subject's median FG was >140 mg / dL in the previous week; 27. The BIF for use according to any one of claims 22 to 26, wherein said weekly maintenance dose is selected according to the following criteria: b) if the previous dose was not a loading dose, said weekly maintenance dose is equal to said previous dose adjusted, if necessary, according to items (i) to (iv) above.

31. 31. The BIF for use according to any one of claims 27 to 30, wherein the weekly maintenance dose is not increased if the subject has had a glycemic episode of <70 mg / dL in the previous week.

32. During the previous week, the subject: a) 3 or more glycemic episodes ≦70 mg / dL; b) 1 or more nocturnal glycemic episodes ≦70 mg / dL; c) 1 or more glycemic episodes ≦54 mg / dL, or d) The BIF for use according to any one of claims 22 to 31, wherein the weekly maintenance dose is reduced by 40 units if the patient has had any of the following episodes of severe hypoglycemia:

33. The BIF for use according to any one of claims 26 to 32, wherein the subject is not being treated with an MDI.

34. The subject has T2D and is being treated with an MDI, and each weekly maintenance dose is a) if the weekly maintenance dose is an initial dose of BIF, the weekly maintenance dose is approximately 7 times the subject's daily dose of basal insulin prior to the initiation of treatment with BIF; b) if the weekly maintenance dose is not the initial dose of the BIF and the subject has either a baseline FG≦120 mg / dL or a daily basal dose of BIF<20 units prior to initiation of treatment, the weekly maintenance dose is, as needed, i) if the subject's median FG during the previous week was <80 mg / dL, the weekly maintenance dose is reduced by 10-20 units; ii) if the subject's median FG during the previous week was between 80 and 120 mg / dL, the weekly maintenance dose is not changed; iii) if the subject's median FG during the previous week was 121-140 mg / dL, the weekly maintenance dose is increased by 10 units; iv) equal to the previous maintenance dose adjusted according to the following criteria: if the subject's median FG in the previous week was >140 mg / dL, the weekly maintenance dose will be increased by 20 units; c) if the weekly maintenance dose is not the initial dose of the BIF and the subject has a baseline FG>120 mg / dL and a basal dose >20 units / day prior to initiation of treatment with BIF, the weekly maintenance dose is, as needed, i) if the subject's median FG during the previous week was <80 mg / dL, the weekly maintenance dose is reduced by 20 units; ii) if the subject's median FG during the previous week was between 80 and 120 mg / dL, the weekly maintenance dose is not changed; iii) if the subject's median FG during the previous week was 121-140 mg / dL, the weekly maintenance dose is increased by 20 units; iv) the weekly maintenance dose is increased by 40 units if the subject's median FG in the previous week was >140 mg / dL.

35. wherein the subject has T1D and the loading dose comprises: a) if the subject's baseline FG is ≦140 mg / dL, then the loading dose=(the subject's daily dose of basal insulin prior to initiation of treatment with BIF)×7×3; b) if the subject's baseline FG is 140-160 mg / dL, the loading dose = (the subject's daily dose of basal insulin prior to initiation of treatment with BIF increased by about 10-20%) x 7 x 3; c) if the subject's baseline FG is >160 mg / dL, the loading dose = (approximately 20-30% increase in the subject's daily basal insulin dose before initiation of treatment with BIF) x 7 x 3.

36. the subject has T1D, and the subject's first weekly maintenance dose comprises: a) if the subject's baseline FG is ≦140 mg / dL, then the first weekly maintenance dose=(the subject's daily dose of basal insulin prior to initiation of treatment with BIF)×7; b) if the subject's baseline FG is 140-160 mg / dL, then the first weekly maintenance dose = (the subject's daily dose of basal insulin prior to initiation of treatment with BIF increased by about 10-20%) x 7; 36. A BIF for use according to any one of claims 22-23 or 35, selected according to the following criteria: c) if the subject's baseline FG is >160 mg / dL, then the first weekly maintenance dose = (about 20-30% increase in the subject's daily dose of basal insulin before initiation of treatment with BIF) x 7.

37. wherein the subject has T1D, and the subject's second and subsequent weekly maintenance doses comprise: a) if the subject's median FG during the previous week was <80 mg / dL, the weekly maintenance dose is reduced to the previous lower dose; b) if the subject's median FG during the previous week was between 80 and 120 mg / dL, the weekly maintenance dose is not changed; c) if the subject's median FG during the previous week was 121-150 mg / dL, the weekly maintenance dose is increased by either 5 units if the previous weekly maintenance dose was <100 U, or 10 units if the previous weekly maintenance dose was ≥100 U; d) if the subject's median FG during the previous week was 151-180 mg / dL, the weekly maintenance dose is increased by either 10 units if the previous weekly maintenance dose was <100 U, or 20 units if the previous weekly maintenance dose was ≥100 U; e) if the subject's median FG in the previous week was >180 mg / dL, then the weekly maintenance dose is increased by either 20 units if the previous weekly maintenance dose was <100 U, or 30 units if the previous weekly maintenance dose was ≥100 U.

38. 38. A BIF for use according to any one of claims 34 to 37, wherein the weekly maintenance dose is not increased if the subject experiences one or more episodes of hypoglycemia that are attributed to the BIF and not to the subject's pre-prandial insulin.

39. 39. The BIF for use according to any one of claims 34 to 38, wherein the weekly maintenance dose is not increased if the subject experiences one or more episodes of nocturnal hypoglycemia.

40. 39. The BIF for use according to any one of claims 34 to 38, wherein the weekly maintenance dose is not increased if the subject experiences one or more episodes of severe hypoglycemia.

41. A BIF for use according to any one of claims 22 to 40, wherein the need to adjust any weekly maintenance dose is determined weekly for the first 12 weeks after initiation of treatment with the BIF and every 4 weeks thereafter.

42. 42. A BIF for use according to any one of claims 22 to 41, wherein said treatment comprises improving glycemic control in said patient.

24. Use in a method according to any one of claims 1 to 21 or use of BIF in the manufacture of a medicament for use in the treatment of diabetes according to any one of claims 22 to 42.

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