Methods of treating diabetes

Abstract

This invention describes dosage and administration regimens, which include determining and administering a long-acting insulin receptor agonist suitable for once-weekly administration, such as a weekly dose of basal insulin-Fc (BIF).

Description

[Technical Field]

[0001] This invention relates to a method for treating diabetes. More specifically, this invention relates to a method for treating diabetes with a long-acting insulin receptor agonist. The method described herein includes a dosing regimen comprising determining and administering a dose suitable for once-weekly administration of a long-acting insulin receptor agonist, such as weekly basal insulin-Fc (BIF). [Previous Technology]

[0002] Diabetes mellitus is a chronic disease characterized by hyperglycemia caused by defects in insulin secretion, insulin action, or both. Type 1 diabetes mellitus (T1D) is characterized by very little or no insulin secretion, and patients with T1D require insulin to maintain survival. Type 2 diabetes mellitus (T2D) is characterized by elevated blood glucose levels caused by impaired insulin secretion, insulin resistance, excessive hepatic glucose output, and / or all of the above factors. In many patients with T2D, the disease progresses to the point where insulin therapy is required.

[0003] Because patients with type 1 diabetes (T1D) produce very little or no insulin, effective insulin therapy generally involves using two types of exogenous insulin: a rapid-acting, mealtime or prandial insulin administered by bolus injection, and a long-acting basal insulin administered once or twice daily to control blood glucose levels between meals and overnight. Treatment for patients with type 2 diabetes (T2D) usually begins with prescribed weight loss, exercise, and a diabetic diet, but when these measures fail to control elevated blood glucose, oral medications and incretin-based therapy may be necessary. When these medications are still insufficient, insulin therapy is considered. Patients with T2D whose disease has progressed to the point where insulin therapy is required typically begin with a single daily injection of long-acting basal insulin.

[0004] Currently available basal insulin analogs include: insulin glargine sold under the brand names LANTUS®, TOUJEO®, BASALGLAR® and SEMGLEE®; insulin detemir sold under the brand name LEVEMIR®; and insulin degludec sold under the brand name TRESIBA®. Each of these insulins is directed for once-daily administration.

[0005] Treatment regimens involving daily insulin injections can be complex and painful, and may lead to unwanted side effects such as hypoglycemia and weight gain. Therefore, even after insulin therapy is initiated, many diabetic patients are unwilling, unable, or unable to adhere to the insulin regimen required to maintain tight control of their blood glucose levels. Research is underway to identify insulin products with a longer duration of action; thus, fewer injections are required compared to currently available insulin products, including infrequent weekly injections. Such products have the potential to improve acceptability and compliance.

[0006] However, there are potential problems associated with administering products that have prolonged insulin activity. For example, prolonged insulin activity may theoretically lead to a higher risk of hypoglycemic events or a longer duration of such events and / or weight gain. Furthermore, once-weekly administration of products with prolonged insulin activity may require several weeks to reach a stable insulin activity state, resulting in suboptimal hyperglycemic control during this period. While the increased risk of hypoglycemia, weight gain, and / or suboptimal hyperglycemic control may be a potential disadvantage of products with a longer duration of insulin action compared to existing insulins, such risks can be controlled or eliminated by using optimized dosage and dosing regimens.

[0007] WO2014 / 009316 describes insulin derivatives, stating that they have a sufficiently long duration of action to allow for administration at a frequency of approximately once a week to provide adequate basal insulin to patients with diabetes. Treatment regimens for these derivatives are proposed in WO2016 / 001185.

[0008] US2016 / 0324932 describes a fusion protein having a prolonged duration of action at the insulin receptor, sufficient for infrequent administration, including once-weekly dosing, including BIF. No specific dosing regimen is described.

[0009] There remains a need for insulin therapies that require fewer injections compared to currently available insulin products. There also remains a need for treatment methods that do not increase the risk of hypoglycemia or are accompanied by methods to reduce the risk of hypoglycemia compared to currently available insulin products. There remains a need for insulin therapies that require fewer injections compared to currently available insulin products. There also remains a need for insulin therapies that provide enhanced glycemic control compared to currently available insulin products. There also remains a need for treatment methods that do not increase the risk of weight gain or are accompanied by methods to reduce the risk of weight gain compared to currently available insulin products. Furthermore, there remains a need for insulin therapy that allows patients to quickly achieve steady-state serum levels. [Summary of the Invention]

[0010] Therefore, the present invention provides a method for providing glycemic control in an individual in need of diabetes, comprising: a) administering an initial dose of BIF to the individual according to the following criteria: i) the initial dose is a loading dose if the individual meets the following conditions: a. has not previously received insulin therapy; b. has type 2 diabetes and fasting glucose (FG) > 120 mg / dL; or c. has type 1 diabetes; ii) if the individual has type 2 diabetes but does not meet the criteria set forth in a. or b. above, the initial dose is a weekly maintenance dose; and b) starting one week after administering the initial dose, administering one or more weekly maintenance doses to the individual once a week.

[0011] In another embodiment, the present invention provides a BIF for treating diabetes, wherein the treatment comprises providing glycemic control by: a) administering an initial dose of BIF to the individual according to the following criteria: i) the initial dose is a loading dose if the individual has: a. never been treated with insulin; b. has T2D and FG > 120 mg / dL; or c. has T1D; ii) if the individual has T2D but does not meet the criteria set forth in a. or b. above, the initial dose is a weekly maintenance dose; and b) starting one week after administering the initial dose, administering one or more weekly maintenance doses to the individual once a week.

[0012] The present invention also provides guidelines for selecting the loading dose and maintenance dose of BIF for the treatment of diabetes.

[0013] In another embodiment, the present invention provides a method for providing blood glucose control in an individual with diabetes, comprising: a) determining a first dose of a long-acting insulin receptor agonist suitable for once-weekly administration to the individual; b) administering the first dose of the insulin receptor agonist suitable for once-weekly administration to the individual; c) measuring the individual's fasting glucose (FG); d) recording the frequency and severity of hypoglycemia in the individual; e) determining a second dose of the insulin receptor agonist suitable for once-weekly administration to the individual based on the individual's FG determined in step c) and the frequency and severity of hypoglycemia determined in step d); and f) administering the second dose of the insulin receptor agonist suitable for once-weekly administration.

[0014] The present invention also provides a method for providing blood glucose control in an individual with diabetes, comprising administering a loading dose of a long-acting insulin receptor agonist suitable for once-weekly administration to the individual.

[0015] In some embodiments, the load dose is determined by first determining the individual’s expected weekly maintenance dose; and then multiplying the individual’s expected weekly maintenance dose by the ratio of the steady-state concentration of the long-acting insulin receptor agonist suitable for once-weekly administration to the peak concentration of a single dose.

Implementation Method

[0016] This application claims the benefit of U.S. Provisional Application No. 63 / 125,165, filed December 14, 2020, pursuant to 35 USC §119(e), the disclosure of which is incorporated herein by reference.

[0017] This application provides a dosing regimen, use and treatment method for a long-acting insulin receptor agonist suitable for once-weekly administration.

[0018] When used herein, the term "insulin receptor agonist" refers to a protein that binds to and activates the insulin receptor, causing a decrease in blood glucose levels and / or inhibition of hepatic glucose output, and whose characteristics 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, when administered no more than once or twice daily, has prolonged pharmacokinetic and pharmacodynamic characteristics for controlling inter-meal blood glucose levels. When used herein in conjunction with "insulin receptor agonist," the term "suitable for once-weekly administration" refers to a long-acting insulin receptor agonist that, when administered no more than once weekly, has sufficiently prolonged pharmacokinetic and pharmacodynamic characteristics for controlling inter-meal blood glucose levels. Examples of such molecules include fusion proteins, including BIF, as described in US2016 / 0324932.

[0019] Also known as insulin efsitora alfa, the BIF contains a dimer of an insulin receptor agonist fused to the human IgG Fc region, wherein the insulin receptor agonist contains an insulin B chain analog fused to an insulin A chain analog via a first peptide linker, wherein the C-terminal residue of the insulin chain analog is directly fused to the N-terminal residue of a second peptide linker, and the C-terminal residue of the second peptide linker is directly fused to the N-terminal residue of the human IgG Fc region. BIF identification is CAS Registry No. 2131038-11-2, which provides the following chemical names: (1) Insulin [16-glutamic acid, 25-histamine, 27-glycine, 28-glycine, 29-glycine, 30-glycine] (human B chain) fusion protein and peptide (synthetic 7-amino acid linker) fusion protein and insulin [47-threonine, 51-aspartic acid, 58-glycine] (human A chain) fusion protein and peptide (synthetic 20-amino acid linker) fusion protein and immunoglobulin G2 (human Fc fragment), dimer; and (2) Homo sapiens insulin B chain [Y16>Y(16), F25>H(25), TPKT27-30>GGGG(27-30)] (1-30) Fusion protein and di(glycinyl)serinyltetra(glycinyl) (31-37) Insulin A chain [I10>T(47), Y14>D(51), N21>G(58)] (38-58) Fusion protein and tris(tetraglycinylglutamineyl)pentaglycinyl (59-78) Homo sapiens immunoglobulin heavy chain constant γ2 {del-CH1, hinge-(7-12), CH2, CH3[K107>del(300)]} (79-299), dimer (80-80':83-83')-disulfide, expressed in CHO cells, α-glycosylated. Each monomer of BIF has the amino acid sequence described in SEQ ID NO:1: (SEQ ID NO:1). Each monomer comprises an intrachain disulfide bond 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 at positions 80 and 83 by a disulfide bond between cysteine ​​residues to form a dimer. The structure, function, and formation of the BIF are described in more detail in U.S. Patent Application Publication No. 2016 / 0324932.

[0020] When used herein, the term “BIF” means any insulin receptor agonist consisting of two monomers having the amino acid sequence of SEQ ID NO:1, including any protein that is the subject of a regulatory filing seeking approval for an insulin receptor agonist product that relies in whole or in part on information relating to BIF submitted by Eli Lilly to a regulatory authority, whether or not the party seeking approval for the product actually identifies the insulin receptor agonist as BIF or uses other terms.

[0021] This document describes several variants of dosing regimens and methods for using long-acting insulin receptor agonists suitable for once-weekly administration. In some variants, the regimens, uses, and methods described herein include determining and administering an initial or loading dose of such insulin receptor agonists. In other variants, 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] Examples of criteria and guidelines for determining loading dose and weekly maintenance dose are described in more detail below.

[0023] Determining and Administering a Loading Dose. In some embodiments, the methods, uses, and dosing regimens described herein include determining and administering a loading dose. Administering a once-weekly insulin receptor agonist suitable for once-weekly dosing at a long elimination half-life can result in pharmacokinetic steady state not being reached for several weeks. Furthermore, the long elimination half-life of such products administered once weekly for several weeks can result in peak concentration levels significantly higher than the peak serum concentration levels that would be observed after a single dose. Some embodiments of the regimens, uses, and methods described herein address these problems by administering a single initial, single-dose loading dose designed to reduce the time to reach pharmacokinetic steady state. Therefore, when used herein, the term "loading dose" refers to a first dose of a long-acting insulin receptor agonist suitable for once-weekly dosing administered to a given individual that is greater than the dose intended for long-term maintenance therapy.

[0024] The loading dose described herein typically comprises a single dose greater than the anticipated weekly maintenance dose, as described in more detail below, which is a factor that allows for the attainment of near-steady-state concentrations within the first week following the administration of the single dose. The factor that increases the anticipated weekly maintenance dose to produce a loading dose that will provide such effects is determined based on the ratio of (a) the serum concentration of insulin receptor agonists after a sufficient number of weekly maintenance doses have been administered to achieve steady state; and (b) the ratio of the peak serum concentration of insulin receptor agonists achieved after the administration of the anticipated weekly maintenance dose. This ratio may be referred to as the "steady-state concentration: single-dose peak concentration". Thus, for example, if the serum concentration of insulin receptor agonists achieved after a sufficient number of anticipated weekly maintenance doses have been administered to achieve steady state is 3 times greater than the peak serum concentration achieved after the administration of the single dose, then the steady-state concentration: single-dose peak concentration ratio is 3 times, and the loading dose will be a single dose that is 3 times greater than the anticipated weekly maintenance dose.

[0025] When used herein, the term "expected weekly maintenance dose" refers to a dose of an insulin receptor agonist suitable for once-weekly administration, which is expected to provide the glycemic control required in a given individual. The expected weekly maintenance dose is determined before initiation of treatment with an insulin receptor agonist suitable for once-weekly administration, and the weekly maintenance dose administered during treatment is determined based on various guidelines described in more detail below. In some embodiments, for patients who have not previously received insulin therapy, the expected 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 for patients already treated with basal insulin, the initial weekly maintenance dose or "expected weekly maintenance dose" may be based on factors such as the individual's current daily basal insulin dose and / or the individual's fasting glucose (FG) and, where appropriate, other factors such as the frequency and severity of hypoglycemia and body weight (BW).

[0026] In some embodiments, the loading dose ranges from about 1.5 times to about 5 times the expected weekly maintenance dose. In some embodiments, the loading dose ranges from about 1.5 times to about 3 times the expected weekly maintenance dose. In some embodiments, the loading dose is about 1.5, 1.6, 1.8, 2, or 3 times the expected weekly maintenance dose.

[0027] For BIF, it is predicted that steady-state serum concentrations will be reached approximately 8 to 10 or 12 weeks after weekly dosing without a loading dose. When a loading dose approximately three times higher than the initial or expected weekly maintenance dose is used, near-steady-state concentrations can be reached within the first week of dosing. In some preferred embodiments, the insulin receptor agonist suitable for weekly dosing is BIF, and the loading dose is approximately three times the initial or expected weekly maintenance dose.

[0028] In cases where an individual has been treated with existing basal insulin such as insulin degludec or insulin glargine and has switched to an insulin receptor agonist suitable for once-weekly administration, the expected weekly maintenance dose of the insulin receptor agonist suitable for once-weekly administration is generally based at least in part on the individual’s current basal insulin dose.

[0029] Because the daily basal insulin dose for such individuals is replaced by weekly single doses, the daily dose in units must be converted to a weekly dose, referred to herein as the "daily basal dose weekly equivalent," which is intended to provide the same level of insulin activity daily after steady-state administration via once-weekly dosing. The daily basal dose weekly equivalent can be expressed in insulin units or mg. If expressed in insulin units, the daily dose of once-daily basal insulin prior to initiation of once-weekly insulin receptor agonist therapy will be multiplied by 7 to obtain the daily basal dose weekly equivalent of the once-weekly insulin receptor agonist. For example, a patient who has received 42 units / day of tendeg insulin prior to initiation of once-weekly insulin receptor agonist therapy will have a daily basal dose weekly equivalent of 294 units.

[0030] In some embodiments, the once-weekly insulin receptor agonist is provided in a device that allows adjustments in increments of 5 or 10 units. Therefore, when determining the dose of once-weekly insulin to be administered, the weekly equivalent of the daily basal dose calculated as described above will be rounded to the nearest 5 or 10 units. Thus, in some embodiments, when once-weekly insulin is provided in a device that allows dose adjustments in increments of 5 units, the weekly equivalent of the daily basal dose of 294 units calculated as described above may be rounded to 295 units or 290 units.

[0031] If expressed in mg, the dose in units must be converted to mg equivalents based on the efficacy of an insulin receptor agonist suitable for once-weekly administration, using a factor referred to herein as the "weekly basal conversion factor" or "daily basal conversion factor". For example, it has been determined that one mg BIF provides approximately 35 units over a week, therefore the weekly basal conversion factor for BIF is determined to be approximately 35 U / week / mg and the daily basal conversion factor for BIF is determined to be approximately 5 U / day / mg. Therefore, for a patient receiving 42 units of insulin degludec daily, the mg dose of BIF would be approximately 8.4 mg (42 units / day × 7 days = 294 units / week / 35 U / week / mg).

[0032] In some embodiments, the determination of the weekly equivalent of the daily basal dose may require additional adjustments for patients treated with certain basal insulins. For example, for patients treated twice daily with NPH insulin, in some embodiments, their daily basal insulin dose should be reduced by 20% before determining their weekly equivalent of the daily basal dose as described above. Similarly, for patients being treated with U300 glargine insulin, in some embodiments, their daily basal insulin dose should be reduced by 20% before determining their weekly equivalent of the daily basal dose as described above.

[0033] In some embodiments, the dosing regimens, uses, and methods described herein are designed to minimize the time until an individual achieves acceptable glycemic control by providing a loading dose. In some embodiments where a patient with T2DM is currently being treated with once-daily basal insulin (in the presence or absence of multiple daily insulin doses (MDIs)) and whose existing basal insulin is being replaced with a once-weekly insulin receptor agonist, the need for a loading dose depends on the patient's baseline fat level (FG) prior to starting treatment with the once-weekly insulin receptor agonist. For example, in some embodiments, a loading dose will be provided if such a patient has a baseline FG > 120 mg / dL, while a loading dose may not be required if such a patient has a baseline FG ≤ 120 mg / dL.

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

[0035] In some embodiments for T1D patients, a loading dose is indicated, but the amount of the loading dose depends on factors such as the patient's free radical saturation (FG). For example, in some embodiments, for T1D patients with FG ≤ 140 mg / dL, the loading dose will be 3 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 some embodiments, the loading dose will be adjusted upwards. For example, in some embodiments, for patients with baseline FG between 141 and 160 mg / dL, the loading dose will be calculated by first increasing their previous daily dose by a factor of 10-20% and then converting the increased dose to a weekly dose by multiplying by 7. For patients with baseline FG > 160 mg / dL, the upward adjustment will increase by a factor of 20-30%. Such embodiments are illustrated in Table 1 below: Baseline FBG Loading dose ≤ 140 mg / dL Previous daily dose (U) × 7 × 3 141 - 160 mg / dL [Previous daily dose × 1.1 to 1.2; increase dose by 10% to 20%] × 7 × 3 >160 mg / dL [Previous daily dose × 1.2 to 1.3; increase dose by 20% to 30%] × 7 × 3 Table 1. Determination of loading dose for patients with T1D.

[0036] In other embodiments, determining the expected weekly maintenance dose may require further adjustments beyond calculating the weekly equivalent of the daily basal dose. For example, if an individual's FG level is higher than the target level at the start of treatment, the weekly equivalent of the daily basal dose in some embodiments should be increased to determine the expected weekly maintenance dose. While the precise amount of adjustment may vary depending on the specific insulin receptor agonist, adjustments in some embodiments will typically involve an increase of approximately 10-70%, with individuals whose FG levels are relatively further away from the target level requiring adjustments at the upper end of this range compared to individuals whose FG levels are closer to the target level. Similarly, in some embodiments, if an individual's FG level is lower than the target level at the start of treatment, the weekly equivalent of the daily basal dose should be decreased to determine the expected weekly maintenance dose. While the precise amount of adjustment may vary depending on the specific insulin receptor agonist, adjustments in some embodiments will typically involve a decrease of approximately 10-50%.

[0037] For example, in some embodiments, for individuals switching from daily basal insulin to BIF, the expected weekly maintenance dose adjustments designed to enable the individual to maintain or rapidly reach a target FG of 100 mg / dL are described in Table 2 below: Median baseline FG (mg / dL) Median baseline FG (mmol / L) BIF (basal insulin equivalent dose adjustment) (mg) Previous basal insulin dose ≤ 15 U Previous basal insulin dose 16 - 30 U Previous basal insulin dose > 30 U < 80 < 4.4 - 0.25 - 1 - 1.5 80 - 100 4.4 - 5.5 No change No change No change 101 - 140 5.6 - 7.7 + 0.25 + 0.5 + 0.75 141 - 180 7.8 - 10.0 + 0.5 +1 +1.5 181 - 220 10.1 - 12.2 + 0.75 +1.5 +2 >220 >12.2 +1 +2 +3 Table 2. Dosage adjustments for the expected weekly maintenance dose, which will be used to calculate the loading dose for patients transitioning from daily basal insulin to BIF.

[0038] In the embodiments, the required and magnitude of any adjustment to the basal insulin equivalent dose for an individual switching from existing basal insulin to BIF, in accordance with the guidelines set forth in Table 2, is based on the individual's FG and previous basal insulin dose. For example, an individual taking 25 U / tendgludec insulin would have a basal insulin equivalent dose of 5 mg, and if the individual's FG is 150 mg / dL, the recommended dose adjustment would be an addition of 1.5 mg, thus the expected weekly maintenance dose would be 6.5 mg. As mentioned above, in some preferred embodiments, the loading dose should be increased by 3 times, therefore the recommended loading dose would be 19.5 mg.

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

[0040] In other embodiments, for individuals switching from daily basal insulin to BIF, the expected weekly maintenance dose and loading dose can be determined based on the individual's daily basal insulin dose and baseline HbA1c level before starting BIF treatment, as illustrated in Table 3 below: Daily basal insulin dose before randomization Baseline HbA1c (%) Loading dose (mg) Expected weekly maintenance dose (mg) 10 IU - 19 IU <8.5 8 6 20 IU - 29 IU <8.5 14 8 30 IU - 39 IU <8.5 17 11 40 IU - 50 IU <8.5 25 14 >50 IU <8.5 34 17 10 IU - 19 IU ≥8.5 17 6 20 IU - 29 IU ≥8.5 25 8 30 IU - 39 IU ≥8.5 34 11 40 IU - 50 IU ≥8.5 42 14 >50 IU ≥8.5 50 17 Table 3.

[0041] Patients who are not currently on basal insulin therapy and have started with a once-weekly insulin receptor agonist (referred to herein as "patients who have never received insulin therapy") do not have an existing daily basal insulin dose, and therefore the basal insulin equivalent dose cannot form the basis for a defined expected weekly maintenance dose and / or load. Therefore, for such patients, in some embodiments, regardless of other patient characteristics, the initial weekly maintenance dose is set at a fixed level selected to be close to, for example, the required 100 U, so the load of BIF will be 300 U.

[0042] In other embodiments for such patients, the anticipated weekly maintenance dose and / or loading dose are determined based on other patient characteristics, including, for example, the patient's FG and BW. In some embodiments, the loading dose for such patients is designed to enable the patient to achieve the target FG level relatively quickly. In some embodiments, the guidelines for selecting the loading dose are incorporated for individuals with FG and BW each below certain thresholds into a "baseline loading dose"—based on the efficacy of the insulin receptor agonist—and the incorporated dose is progressively increased as FG and / or BW increase.

[0043] In some embodiments, the baseline loading dose of a given insulin receptor agonist is referred to herein as the "baseline loading dose," and any required adjustment based on an increase in FG and / or BW is expressed as a number or percentage of additional baseline loading doses to be added. Some insulin receptor agonists may have a baseline loading dose expressed as a number of insulin units, and others may have a baseline loading dose expressed as mg. In some embodiments, any required upward adjustment is based on a fraction or number of additional baseline loading doses to be added. For example, when determining the loading dose for an individual with a baseline loading dose of 30 IU of insulin and FG and / or BW that warrants a recommended increase to a 50% increase in the baseline loading dose, the loading dose would be 45 IU.

[0044] In some embodiments, any recommended adjustment to the loading dose is based in part on the patient's FG levels within at least three ranges: a low range, an intermediate range, and a high range. In some embodiments, the low range is FG ≤ 140, the intermediate range is FG between 141 and 220, and the high range is FG > 220, wherein FG in the low range does not cause any recommended increase in the baseline loading dose, FG in the intermediate range causes a 100-200% recommended increase in the baseline loading dose, and FG in the high range causes a 300% recommended increase in the baseline loading dose. In some embodiments, the intermediate range comprises two ranges: a first intermediate range of FG between 141 and 180 and a second intermediate range of FG between 181 and 220, wherein the first intermediate range causes a 100% recommended increase in the baseline loading dose and the second intermediate range causes a 200% recommended increase in the baseline loading dose.

[0045] Similarly, in some embodiments, the adjustment amount for any recommended dose of the loading dose is partly based on the patient's body weight (BW) within at least three ranges: a low range, a middle range, and a high range. In some embodiments, the low range is BW ≤ 80 kg, the middle range is BW between 80.1 and 120 kg, and the high range is BW > 120.1 kg, wherein BW in the low range does not cause any recommended increase in the baseline loading dose, BW in the middle range causes a 50-100% recommended increase in the baseline loading dose, and FG in the high range causes a 150% recommended increase in the baseline loading dose. In some embodiments, the middle range comprises two ranges: a first middle range with BW between 80.1 and 100 kg and a second middle range with BW between 100.1 and 120 kg, wherein the first middle range causes a 50% recommended increase in the baseline loading dose and the second middle range causes a 100% recommended increase in the baseline loading dose.

[0046] For example, in some embodiments, recommended loading doses designed to enable previously insulin-naïve patients who can initiate BIF to rapidly reach steady-state serum concentrations and maintain or rapidly reach a target FG of 100 mg / dL are described in Table 4 below: Median baseline FG (mg / dL) Median baseline FG (mmol / L) Baseline weight (kg) ≤ 80 80.1 - 100 100.1 - 120 ≥ 120.1 ≤ 140 ≤ 7.7 4 mg 6 mg 8 mg 11 mg 141 - 180 7.8 - 10.0 8 mg 11 mg 15 mg 17 mg 181 - 220 10.1 - 12.2 13 mg 15 mg 17 mg 19 mg > 220 > 12.2 17 mg 19 mg 21 mg 23 mg Table 4.

[0047] According to the protocol described in Table 4, the loading dose for patients who are not currently receiving daily basal insulin therapy and who are starting with BIF is based on the individual's FG and BW. For example, the loading dose for an individual with an FG of 150 mg / dL and a BW of 110 kg would be 15 mg.

[0048] In other embodiments, the loading dose for individuals who have not previously received insulin therapy is determined in accordance with the guidelines set forth in Table 5 below. Median FG value over 3 days (mg / DL) Weight(KG) ≤80 81-100 101-120 >120 100-140 120 IU 200 IU 240 IU 280 IU 141-180 250 IU 280 IU 420 IU 490 IU 181-220 370 IU 420 IU 560 IU 560 IU >220 490 IU 560 IU 630 IU 700 IU Table 5.

[0049] Determination and administration of weekly maintenance dose. In some embodiments, this specification describes a method for determining and administering a weekly maintenance dose of a once-weekly insulin receptor agonist suitable for once-weekly administration. As used herein, the term "weekly maintenance dose" means any single weekly dose of an insulin receptor agonist suitable for once-weekly administration other than the loading dose as defined above.

[0050] In some embodiments, the weekly maintenance dose may be specifically identified herein based on the number of previous doses to which the insulin receptor agonist has been administered. For example, as used herein, the term "first weekly maintenance dose" refers to the weekly maintenance dose administered one week after the loading dose or the initial dose administered without the loading dose. As used herein, the term "second weekly maintenance dose" refers to the weekly maintenance dose administered one week after the "first weekly maintenance dose". As used herein, the term "third weekly maintenance dose" refers to the weekly maintenance dose administered one week after the "second weekly maintenance dose".

[0051] In some embodiments, the schemes, uses and methods described herein provide for the determination and administration of one or more weekly maintenance doses, and are designed to enable patients to achieve target FG levels after administering the least amount of dose while minimizing the risk of hypoglycemia.

[0052] The dosing regimens described herein vary in complexity, with less complex regimens offering advantages in terms of ease of interpretation and implementation, while more complex adjustments and regimens offer potential advantages in glucose control. However, in general, the regimens described herein share certain common characteristics: 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. Furthermore, in some 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 higher or lower than the target will result in a larger adjustment than an FG slightly higher or lower than the target.

[0053] In some embodiments where the patient has T2D but has not progressed to the point requiring MDI treatment, the initial weekly maintenance dose is 100 U for patients who have never received insulin therapy, or, for patients currently receiving once-daily basal insulin therapy, equal to the weekly equivalent of the daily basal dose described above (i.e., 7 times the patient's current daily basal insulin dose). For subsequent weekly maintenance doses, the determination of whether dose adjustment is needed will be based on the patient's FG level.

[0054] In some embodiments, adjustments to the weekly maintenance dose may be determined according to the guidelines set forth in Table 6 below: Median FG value (mg / dL) Dosage adjustment (units) <80 -20 80-120 No change 121-140 +20 >140 +40 Table 6.

[0055] In other embodiments, particularly for patients with type 2 diabetes mellitus who have switched from once-daily basal insulin but have not progressed to MDI treatment and who have a median FG ≤ 120 mg / dL before starting treatment with once-weekly insulin and / or once-daily basal insulin at a dose of <20 units / day, the adjustment of the weekly maintenance dose may be determined according to the guidelines set forth in Table 7 below. Median FG value (mg / dL) Dosage adjustment (units) <80 -20 80-120 No change 121-140 +10 >140 +20 Table 7.

[0056] In other embodiments, particularly for patients who have switched from once-daily basal insulin and have a once-daily basal insulin dose of <10 units / day, the adjustment of the weekly maintenance dose can be determined according to the guidelines set forth in Table 8 below. Median FBG BIF dosage adjustment mg / dL Mmol / L unit <80 <4.4 (-) 20 units (decrease) 80-120 4.4-6.6 No change in dosage 121-140 6.7-7.7 (+) 5 units (increase) >140 >7.7 (+) 10 units (increase) Table 8.

[0057] Furthermore, any adjustments to the weekly maintenance dose described above should generally take into account any incidental hypoglycemic events. For example, if a patient experiences any episode of hypoglycemia as indicated by a blood glucose level of <70 mg / dL in the previous week, the dose should not be increased, even if the median FG falls within one of the recommended dose adjustment ranges. Additionally, certain criteria may lead to a recommended dose reduction. For example, in some embodiments, a dose reduction of 40 units is recommended for patients who meet any of the criteria set forth in Table 9 below. Guidelines for reducing hypoglycemic doses based on BG values Unit dose reduction ≤ 70 mg / dL for ≥ 3 episodes 40 units ≤ 70 mg / dL for ≥ 1 nocturnal attack ≤ 54 mg / dL for ≥ 1 attack Any confirmed severe hypoglycemia Table 9. Illustrative dose reductions based on hypoglycemia.

[0058] In some embodiments of T2D patients treated with MDI and who have switched from once-daily basal insulin to once-weekly insulin, adjustments to the weekly maintenance dose may be determined in accordance with the guidelines set forth in Table 10 below. Median FBG (mg / dL) BIF Adjustment (Unit) Baseline FG ≤ 120 mg / dL and / or daily basal dose < 20 units Baseline FG > 120 and daily basal dose ≥ 20 units <80 -10 to 20 -20 80-120 No change No change 121-140 +10 +20 >140 +20 +40 Table 10.

[0059] For patients with T1D, similar to the loading dose calculation described above in Table 10, in some embodiments, the determination of the patient’s first weekly maintenance dose depends on the patient’s baseline FG before starting once-weekly insulin therapy.

[0060] For example, in some embodiments, the first weekly maintenance dose for T1D patients with FG ≤ 140 mg / dL will be 7 times larger than their daily basal dose, but for patients with a baseline FG of 141-160 or > 160, their daily basal dose will be increased by about 10-20% or about 20-30% respectively before being converted to a weekly dose, as depicted in Table 11 below. Baseline FBG First weekly maintenance dose ≤ 140 mg / dL Previous daily dose (U) × 7 141 - 160 mg / dL [Previous daily dose × 1.1 to 1.2; increase dose by 10% to 20%] × 7 >160 mg / dL [Previous daily dose × 1.2 to 1.3; increase dose by 20% to 30%] × 7 Table 11. Dosage adjustments for the first weekly maintenance dose in patients with T1D.

[0061] In some embodiments, adjustments to the subsequent weekly maintenance dose for patients with T1D are determined based on the patient's free glucose level (FG) and the current weekly insulin dose. For example, an upward adjustment of the dose for a patient with an FG above the target glucose range may be more invasive for a patient receiving doses above a certain threshold and less invasive for a patient receiving doses below a certain threshold. In some embodiments, adjustments to the weekly maintenance dose for patients with T1D may be determined according to the guidelines set forth in Table 12 below. Median FPG (mg / dL) Adjustment Current dose < 100 U Current dose ≥100 U < 80 Previous lower dose Previous lower dose 80-120 No change No change 121-150 + 5 U +10 U 151-180 +10 U +20 U >180 +20 U +30 U Table 12. Dosage adjustments for subsequent weekly maintenance doses in patients with T1D.

[0062] The dose adjustments described above in Tables 11 and 12 may also serve as a reminder for patients experiencing hypoglycemic events. While the hypoglycemic-based dose adjustment restrictions described above for T2D patients not treated with MDI may also apply in some cases to T1D and T2D patients treated with MDI, these restrictions may lead to insufficient weekly basal insulin doses in some situations because such patients may experience hypoglycemia associated with their MDI treatment and / or disease characteristics, which would unnecessarily trigger dose reduction or increase restrictions on their basal insulin. Therefore, in some embodiments, for patients treated with MDI, if the patient experiences hypoglycemia that is considered attributable to once-weekly basal insulin rather than the patient's mealtime insulin, their once-weekly basal dose should be reduced to the previously lower dose. For example, in some embodiments, a reduction of the previously lower dose may be indicated if the patient has any unexpected events of nocturnal hypoglycemia. For example, in such embodiments, even if the patient's FBG has been greater than 120 since the previous week and the dose increase is directed according to the guidelines set out in Table 11 or 12 above, if the patient has hypoglycemia that justifies a reduction in the basal insulin dose, their once-weekly insulin dose will be reduced to the lower dose they were previously receiving before the dose was administered the previous week. In some embodiments, if the patient does not have a previous dose because this is the first dispensing dose, the weekly equivalent of the daily basal dose may be reduced, for example, by about 10-20%. Similarly, if the patient has been receiving the same weekly maintenance dose since the start of treatment, the dose from the previous week may be reduced by about 10-20%.

[0063] In some embodiments applicable to a wide range of patients, adjustments to the weekly maintenance dose may be determined according to the guidelines set forth in Table 13 below: FG value (mg / dL) Dosage adjustment (units) <54 -28 55-70 -14 71-100 No change 101-125 14 >125 28 Table 13.

[0064] Additionally, in some embodiments, such as those described in the criteria in Table 5 above, a dose reduction is implemented if any of the following occurs: multiple recorded episodes of hypoglycemia with SMBG < 70 mg / dL in the previous week; severe hypoglycemia (requiring assistance); or recorded hypoglycemia ≤ 54 mg / dL. In some embodiments, the dose may not be increased if any individual blood glucose reading is recorded as < 70 mg / dL at any time in the previous week.

[0065] The criteria described above can also be expressed in the form of the following equation: Weekly maintenance dose = Previous dose - 14*X + 14*Y Where: If FG > 71, then X = 0; If FG is 55-70, then X = 1; or if FG < 54, then X = 2; and Where: If FG ≤ 100, then Y = 0; If FG is 101-125, then Y = 1; or if FG > 125, then Y = 2; The limitation is that if the individual has any SMBG reading < 70 mg / dL at any time in the previous week, then Y may not be > 0.

[0066] In other embodiments, the target FG is 120 mg / dL and the dose adjustment criteria are described in Table 14 below: Criteria for determining dosage Dosage adjustment guidelines < 70 mg / dL - 2 mg 71 to 99 mg / dL - 1.4 mg 100 to 119 mg / dL 0 mg 120 to 139 mg / dL 0 mg 140-180 mg / dL + 1.4 mg >180 mg / dL + 2 mg Number of hypoglycemic episodes triggered by dose reduction 1 dose reduction - 1.4 mg Dosage adjustment interval 14 days Table 14.

[0067] In other embodiments, the target FG is 140 mg / dL and the dose adjustment criteria are described in Table 15 below: Criteria for determining dosage Dosage adjustment guidelines for target FG 140 mg / dL < 70 mg / dL - 2 mg 71 to 99 mg / dL - 1.4 mg 100 to 119 mg / dL 0 mg 120 to 139 mg / dL + 1 mg 140-180 mg / dL + 1.4 mg >180 mg / dL + 3 mg Number of hypoglycemic episodes triggered by dose reduction 1 dose reduction - 1.4 mg Dosage adjustment interval 30 days Table 15.

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

[0069] In some embodiments, adjustments to the weekly maintenance dose may be determined according to the guidelines set forth in Table 16 below: Median FG value over 3 days (mg / DL) Dosage adjustment based on previous weeks' insulin dosage (units) Week 2 Week 3 Week 4 and beyond ≤80 -70 -70 -14 81-100 -42 -28 No change 101-140 No change No change 14 141-180 120 70 28 >180 210 120 42 Table 16.

[0070] In addition to the guidelines in Table 16, dose reduction will be implemented based on any of the following hypoglycemic conditions: multiple recorded episodes of hypoglycemia with SMBG < 70 mg / dL; severe hypoglycemia (requiring support); and / or hypoglycemia ≤ 54 mg / dL recorded in the previous week. Furthermore, if any SMBG reading was recorded as < 70 mg / dL at any time in the previous week, the dose may not be increased.

[0071] In some embodiments, the guidelines for adjusting the weekly maintenance dose set forth in Table 16 above are implemented in the form of the following equation: Weekly maintenance dose = Previous dose - 14*X + 14*Y Where: If: the individual's FG ≥ 101; or the individual has been given at least 3 previous doses and has an FG of 81-100, then X = 0; If the individual's FG ≤ 80 and the individual has been given at least 3 previous doses, then X = 1; If the individual's FG is 81-100 and the individual has been given two previous doses, then X = 2; If the individual's BW is 81-100 and the individual has been given one previous dose, then X = 3; or If the individual's median FG ≤ 80 and the individual has been given one previous dose, then X = 5; and Where: If: the individual's FG ≤ Y = 0 if the individual's FG is 100; or if the individual's FG is 81-100 and the individual has received at least 3 prior doses; Y = 1 if the individual's FG is 101-140 and the individual has received at least 3 prior doses; Y = 2 if the individual's FG is >180 mg / dL and the individual has received at least 3 prior doses; Y = 3 if the individual's FG is 141-180 and the individual has received 2 prior doses; Y = 5 if the individual's FG is 141-180 and the individual has received 1 prior dose; or if the individual's FG is >180 and the individual has received 2 prior doses; or if the individual's FG is >180 and the individual has received 1 prior dose. = 15; The limitation is that if the individual has any SMBG reading of <70 mg / dL at any time in the previous week, then Y may not be >0.

[0072] In some embodiments, the recommended adjustment to the weekly maintenance dose for each week can be described by adding or subtracting a specified fraction or amount of "dose adjustment unit," which represents the minimum dose adjustment recommended for that particular insulin. For example, if the minimum dose adjustment recommended for any patient treated with a specified insulin receptor agonist is 2 IU, then an increase of 4 dose adjustment units would refer to an increase of 8 IU. In some embodiments, the dose adjustment unit is between about 0.5 and 5 IU. In other embodiments, the dose adjustment unit is between about 0.75 and 4 IU. In other embodiments, the dose adjustment unit is between about 1 and 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 measurement, such as mg.

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

[0074] For example, for patients switching from daily basal insulin to BIF, in some embodiments, recommended dose adjustments are described in Table 17 below: Median fasting glucose (mg / dL) a Median fasting glucose (mmol / L) Week 1 (4th consultation) (Second dose) Week 2 (5th consultation) (Third dose) Week 3 (6th consultation) and all subsequent weeks <80 mg / dL or any nocturnal hypoglycemia or multiple (≥3) episodes of hypoglycemia <4.4 mmol / L or having any nocturnal hypoglycemia or multiple (≥3) episodes of hypoglycemia. D - 2 mg D - 1.4 mg D - 1 mg 80 - 100 mg / dL 4.4 - 5.5 D - 1.5 mg D - 1 mg D 101 - 140 mg / dL 5.6 - 7.7 D D D + 0.5 mg 141 - 180 mg / dL 7.8 - 10.0 D + 1.5 mg D + 1 mg D + 0.5 mg >180 mg / dL >10.0 D + 3 mg D + 1.5 mg D + 1 mg Table 17. D = Previous dose.

[0075] In some embodiments, dose adjustments for weekly maintenance doses in insulin-naïve patients targeting 100 mg / dL of FG follow the same general principles as described above. However, in some cases, depending on the size of the previous dose, the specific application of these principles may differ, such as the different values ​​of adjustment and the distinction between recommended adjustments. In some embodiments, recommended dose adjustments for insulin-naïve patients initiating basal insulin therapy based on BIF are illustrated in Table 18 below: Median FG (mg / dL) Median FG (mmol / L) Week 1 (4th consultation) (Second dose) Week 2 (5th consultation) (Third dose) Subsequent Weeks Dosage ≤5 mg Dosage > 5 mg <80 mg / dL or any nocturnal hypoglycemia or multiple episodes of hypoglycemia. <4.4 mmol / L or with any nocturnal hypoglycemia or multiple episodes of hypoglycemia. D - 2 mg D - 2 mg D - 2 mg D - 3 mg 80 - 100 mg / dL 4.4 - 5.5 D - 1.5 mg D - 1 mg No change No change 101 - 140 mg / dL 5.6 - 7.7 No change No change D + 0.5 mg D + 1 mg 141 - 180 mg / dL 7.8 - 10.0 D + 4 mg D + 2 mg D + 1 mg D + 1.5 mg >180 mg / dL > 10.0 D + 7 mg D + 4 mg D + 1.5 mg D + 2 mg Table 18. D = Previous dose.

[0076] In some embodiments, after a certain number of weeks of administration of dose adjustments determined according to the criteria described above, the patient will reach a serum glucose control level for which dose adjustments may be determined less frequently than once a week. For example, in some embodiments, the patient will use the criteria described above to determine dose adjustments once a week for the first 8, 9, 10, 11, or 12 weeks of treatment, but thereafter only determine whether adjustments are needed every 2, 3, or 4 weeks. In some preferred embodiments, the patient will use the criteria described above to determine dose adjustments once a week for the first 12 weeks of treatment, but thereafter only determine whether adjustments are needed every 4 weeks. However, even in these embodiments, occasional hypoglycemic events may exclude dose increases or dose reductions according to the criteria described above.

[0077] Although some of the embodiments described above are applicable to a specific patient population 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 MDI, the use of such embodiments is not necessarily mutually exclusive with that population. Therefore, in some cases, the guidelines described above for one population may also be applied to determine the dosage and dosage adjustments for other populations.

[0078] In some embodiments, the dosage described herein is administered from a reusable pen syringe or a disposable pen device.

[0079] Other Definitions When used herein, the terms "approximately" and "about" mean the acceptable degree of error in a quantity or number indicated, taking into account the nature or precision of the measurement. For example, the degree of error may be indicated by the number of significant figures provided for the measurement, as understood in this art, and includes, but is not limited to, variations of + / -1 in the most accurate significant figures reported for the quantity or number. Typical illustrative degrees of error are within 20 percent (%) of a specified value or range of values, preferably within 10%, and more preferably within 5%. Unless otherwise stated, the numerical quantities given herein are approximate, meaning that the term "about" can be inferred when not explicitly stated.

[0080] When used herein, the term "dose / doses" means an amount of insulin receptor agonist suitable for once-weekly administration, delivered to an individual in discrete amounts at specific time points. When used in conjunction with the terms dose, administration, dosage, and the like, the term "adjustment" means any reduction or increase in the amount of dose administered in the previous week. When used in conjunction with the terms dose, administration, dosage, and the like, the term "regimen" means a set of guidelines for determining and administering one or more doses and / or adjusting them.

[0081] When used herein, the term "baseline" refers to the characteristics of a patient prior to initiation of treatment with an insulin receptor agonist suitable for once-weekly administration. For example, a patient's baseline FG is the FG prior to initiation of the initial dose of an insulin receptor agonist suitable for once-weekly administration.

[0082] When used herein, the terms “fasting glucose,” “FG,” “fasting blood glucose,” “FBG,” “fasting plasma glucose,” or “FPG” refer to the plasma glucose level obtained or acquired from a blood sample taken after a patient has fasted overnight via continuous glucose monitoring (CGM). When used in the context of determining the appropriate dose of an insulin receptor agonist to be administered to a patient for once-weekly administration, unless otherwise stated herein, the patient’s FG is determined as the median FG over multiple days, typically at least 3 days and no more than 7 days.

[0083] When used herein, the terms “treatment” and similar terms are intended to include slowing or reducing the progression of a disease or condition. Such terms also include relieving, improving, reducing, eliminating or alleviating one or more symptoms of a condition or condition (even if the condition or condition is not actually eliminated and even if the progression of the condition or condition itself is not slowed or reversed).

[0084] "MDI" treatment refers to treatment using a combination of basal insulin injections and bolus or mealtime insulin. Mealtime or mealtime insulin is short-acting and is usually administered at mealtimes. Examples of mealtime or mealtime insulin used in such regimens include lispro insulin, aspart insulin, glutathione insulin, and regular insulin.

[0085] "Subject" means a mammal, preferably a human being who has a disease, condition or illness and will benefit from treatment with an insulin receptor agonist suitable for once-weekly administration.

[0086] "Blood glucose control" refers to an individual's blood glucose level, such as that measured by blood glucose and / or HbA1c levels; "providing" blood glucose control means maintaining or improving blood glucose control; "maintaining" blood glucose control means maintaining blood glucose levels within the target range for a period of time and / or maintaining or reducing HbA1c; "improving" blood glucose control means increasing the time blood glucose levels within the target range and / or reducing HbA1c; and "requiring further" blood glucose control means requiring an increase in the time blood glucose levels within the target range and / or a reduction in HbA1c.

[0087] "HbA1c" refers to the glycated heme content, which is produced when heme combines with glucose in the blood. HbA1c content is a commonly used measure for blood glucose control in diabetic patients.

[0088] "Hypoglycemia" refers to low blood sugar, and an "attack" of hypoglycemia refers to an instance of low blood sugar, such as that observed in a plasma glucose test or from a personal blood glucose meter (BGM) or CGM device, in many cases less than about 70 mg / dL.

[0089] A “severe” hypoglycemic event is a serious event characterized by altered mental and / or physiological states requiring assistance in treating hypoglycemia. For example, an individual may have an altered mental state and be unable to participate in their own care, or may be semi-conscious or unconscious, or experience a coma with or without seizures, and require assistance from another person to actively administer carbohydrates, glucagon, or other first aid actions. Glucose measurements may be unavailable during this event, but there is sufficient evidence to suggest that the event was induced by hypoglycemia if neurological recovery attributable to a return to normal glucose levels is considered.

[0090] The treatment methods and uses described herein may be provided concurrently or in combination with other T2D treatments, including oral T2D drugs (such as metformin) and / or other injectable drugs (including rapid-acting or basal insulin or GLP-1 receptor agonists).

[0091] Certain non-limiting embodiments of the subject matter described herein are as follows: Example 1. A method for improving glycemic control in an individual with diabetes, comprising: a) determining a first dose to be administered to the individual of a long-acting insulin receptor agonist suitable for once-weekly administration; b) administering the first dose of the insulin receptor agonist suitable for once-weekly administration to the individual; c) measuring the individual's fasting glucose (FG); d) recording the frequency and severity of hypoglycemia in the individual; e) determining a second dose of the insulin receptor agonist suitable for once-weekly administration to the individual based on the individual's FG determined in step c) and the frequency and severity of hypoglycemia determined in step d); and f) administering the second dose of the insulin receptor agonist suitable for once-weekly administration. Example 2. The method of Example 1, wherein the first dose is a loading dose. Example 3. A method for improving glycemic control in an individual with diabetes, comprising: administering to the individual a single loading dose of a long-acting insulin receptor agonist suitable for once-weekly administration; and administering to the individual a weekly maintenance dose of the insulin receptor agonist suitable for once-weekly administration. Example 4. The method of any of Examples 2 or 3, wherein the loading dose is determined by: determining the individual's expected weekly maintenance dose; and multiplying the individual's expected weekly maintenance dose by 3. The method of any of Examples 1 to 4, wherein the long-acting insulin receptor agonist is a BIF. Example 5. The method of any of Examples 2 to 3, wherein the individual switches treatment from daily basal insulin to the long-acting insulin receptor agonist suitable for once-weekly administration, and wherein the expected weekly maintenance dose is determined by: obtaining the individual's current daily dose of daily basal insulin; and multiplying the individual's current daily dose of daily basal insulin by 7. Example 6. The method of Example 1, wherein the individual is switched from daily basal insulin to an insulin receptor agonist suitable for once-weekly administration, and wherein the first dose is determined by multiplying the weekly equivalent of the individual's previous daily insulin dose by 3. Example 7. The method of Example 3, wherein the individual has not previously received insulin treatment, and wherein the loading dose is between about 3 mg and about 16.5 mg. Example 8. The method of any one of Examples 1 to 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. Example 9. The method of any one of Examples 4 to 5, wherein the loading dose is determined by comprising: a) obtaining the individual's FG and BW; b) calculating the loading dose according to the following equation: Loading dose = 3 + (3*X) + (1.5*Y) Where: If the individual's FG ≤ 140, then X is 0; If the individual's FG is 141-180, then X is 1; If the individual's FG is 181-200, then X is 2; or If the individual's FG > 200, then X is 3; And where: If the individual's BW ≤ 80 kg, then Y is 0; If the individual's BW is 80.1-100 kg, then Y is 1; If the individual's BW is 100.1-120 kg, then Y is 2; or Example 10. If the individual's BW ≥ 120.1, then Y is 3. Example 11. The method of Example 2, wherein the long-acting insulin receptor agonist suitable for once-weekly administration is a BIF, and wherein the expected weekly maintenance dose is determined by: a) obtaining the individual's FG and previous daily basal insulin dose in units; b) dividing the identified individual's previous daily basal insulin dose by 5 U / mg to obtain the basal insulin equivalent dose of the BIF; c) calculating the expected weekly maintenance dose according to the following equation: Expected weekly maintenance dose = basal insulin equivalent dose of BIF - (0.25*X) + (0.25*Y) Where: If the median FG ≥ 80, then X = 0; If the median FG < 80 and the previous daily basal insulin dose ≤ 15 U, then X = 1; If the median FG < 80 and the previous daily basal insulin dose was 16-30 U, then X = 4; or if the median FG < 80 and the previous daily basal insulin dose was > 30 U, then X = 6; And where: If the median FG ≤ 100, then Y = 0; If the median FG is between 101 and 140 and the previous basal insulin dose ≤ 15 U, then Y = 1; If the median FG is between 141 and 180 and the previous basal insulin dose was 16-30 U, or if the median FG is between 101 and 140 and the previous basal insulin dose was 16-30 U, then Y = 2; If the median FG of an individual is 181-220 and the previous basal insulin dose is ≤ 15 U, or if the median FG of an individual is 101-140 and the previous basal insulin dose is > 30 U, then Y = 3; if the median FG of an individual is > 220 and the previous basal insulin dose is ≤ 15 U, then Y = 4; if the median FG of an individual is 181-220 and the previous basal insulin dose is 16-30 U, or if the median FG of an individual is 141-180 and the previous basal insulin dose is > 30 U, then Y = 6; if the median FG of an individual is > 220 and the previous basal insulin dose is 16-30 U, or if the median FG of an individual is 181-220 and the previous basal insulin dose is > 30 U, then Y = 8; or if the median FG of an individual is > 220 and the previous basal insulin dose is > 30 U, then Y = 12. Example 12. The method of Example 3, wherein the expected weekly maintenance dose is determined by: a) obtaining the individual's FG and previous daily basal insulin dose in units; b) dividing the identified individual's previous daily basal insulin dose by 7 U / mg to obtain the equivalent dose of BIF; and c) determining whether the dose of BIF should be adjusted, wherein the individual's BIF dose should be: i) if the individual's FG < 80, then reduce by an amount between 0.25 mg and 1.5 mg; or ii) if the individual's FG > 101, then increase by an amount between 0.25 mg and 3 mg. Example 13. The method of Example 10, wherein the individual's FG < 80 mg / dL and wherein the reduction in the expected weekly maintenance dose of BIF is determined according to the following criteria: a) if the individual's previous basal insulin dose ≤ 15 U, then reduce the dose by 0.25 mg; b) If the individual's previous basal insulin dose was 16-30 U, then reduce the dose by 1 mg; or c) If the individual's previous basal insulin dose was > 30 U, then reduce the dose by 1.5 mg. Example 14. The method of Example 10, wherein the individual's FG > 101 and wherein the expected weekly maintenance dose increase of BIF is determined according to the following criteria: a) If the individual's previous basal insulin dose was ≤ 15 U, then increase the dose by an amount between 0.25 mg and 1 mg; b) If the individual's previous basal insulin dose was 16-30 U, then increase the dose by an amount between 0.5 mg and 2 mg; or c) If the individual's previous basal insulin dose was > 30 U, then increase the dose by an amount between 0.75 mg and 3 mg. Example 15. The method of Example 10, wherein the individual’s previous basal insulin dose is ≤ 15 U and wherein the increase in the weekly maintenance dose of BIF is determined according to the following criteria: a) if the individual’s FG is between 101 and 140, the dose is increased by 0.25 mg; b) if the individual’s FG is between 141 and 180, the dose is increased by 0.5 mg; c) if the individual’s FG is between 181 and 220, the dose is increased by 0.75 mg; or d) if the individual’s FG is > 220, the dose is increased by 1 mg. Example 16. The method of Example 10, wherein the individual’s previous basal insulin dose was 16-30 U and wherein the increase in the weekly maintenance dose of BIF was determined according to the following criteria: a) if the individual’s FG was between 101 and 140, the dose was increased by 0.5 mg; b) if the individual’s FG was between 141 and 180, the dose was increased by 1 mg; c) if the individual’s FG was between 181 and 220, the dose was increased by 1.5 mg; or d) if the individual’s FG was > 220, the dose was increased by 2 mg. Example 17. The method of Example 10, wherein the individual's previous basal insulin dose is >30 U and wherein the increase in the weekly maintenance dose of BIF is determined according to the following criteria: a) if the individual's FG is between 101 and 140, the dose is increased by 0.75 mg; b) if the individual's FG is between 141 and 180, the dose is increased by 1.5 mg; c) if the individual's FG is between 181 and 220, the dose is increased by 2 mg; and d) if the individual's FG is >220, the dose is increased by 3 mg. Example 18.The method of any one of Examples 1 to 6, wherein the individual has T2D and wherein the weekly maintenance dose is determined by a method comprising: a) recording the incidence and timing of hypoglycemia one week after the administration of the prior dose; b) measuring the individual's FG in the week after the administration of the prior dose; and c) calculating the weekly maintenance dose according to the following equation: Weekly maintenance dose = Prior dose / X - 0.5Y + 0.25Z; Where: X is 3 if the previous dose is the loading dose; or X is 1 if the previous dose is a weekly maintenance dose; and where: Y is 0 if the individual has a median FG > 100 and has not been given more than one previous weekly maintenance dose, or the individual has a median FG ≥ 80 and has been given more than one previous weekly maintenance dose; Y is 1 if the individual has a median FG of 80-100 and has been given one previous weekly maintenance dose; Y is 2 if the individual had a median FG < 80, any episode of nocturnal hypoglycemia, or multiple episodes of hypoglycemia during the previous week and has not been given more than one previous weekly maintenance dose, or has been given more than one previous weekly maintenance dose and has a previous weekly maintenance dose ≤ 5 mg; or Y is 3 if the individual had a median FG < 80 during the previous week. 80. Any episode of nocturnal hypoglycemia or any of multiple episodes of hypoglycemia; and having received more than one previous weekly maintenance dose with a previous weekly maintenance dose > 5 mg, then Y is 4; and wherein: if the individual 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, then Z is 0; if the individual has a median FG between 101 and 140 and has received more than one previous weekly maintenance dose with a previous weekly maintenance dose ≤ 5 mg, then Z is 1; if the individual has received more than one previous weekly maintenance dose and has a median FG between 101 and 140 with a previous weekly maintenance dose > 5 mg, or has a median FG between 141 and 180 with a previous weekly maintenance dose ≤ 5 mg, then Z is 2; if the individual has a median FG > 180 and has received more than one previous weekly maintenance dose with a previous weekly maintenance dose ≤ 5 mg... Z is 3 if the individual has a median FG between 141 and 180 and has been given more than one previous weekly maintenance dose with a previous weekly maintenance dose of ≥ 5 mg; Z is 4 if the individual has been given one previous weekly maintenance dose with an FG between 141 and 180, or has been given more than one previous weekly maintenance dose with an FG > 180 and a previous weekly maintenance dose > 5 mg; Z is 6 if the individual has not been given any previous weekly maintenance dose and has an FG between 141 and 180, or has been given one previous weekly maintenance dose with an FG > 180; or Z is 20 if the individual has not been given any previous weekly maintenance dose and has an FG > 180. Example 19.As in any of Examples 1 to 6, the first weekly maintenance dose for the individual is determined by a method comprising: a) recording the incidence and timing of hypoglycemia one week after administering the loading dose; b) measuring the individual's free glucose (FG) in the week following the administration of the loading dose; c) dividing the loading dose by 3; and d) determining whether the dose obtained in step c) should be adjusted to obtain the weekly maintenance dose according to the following criteria: i) if the individual had one or more of the following during the previous week: median FG < 80 mg / dL, nocturnal hypoglycemia episodes, or multiple episodes of hypoglycemia, the dose is reduced by 1.5 mg; ii) if the individual had each of the following during the previous week: median FG 80-100 mg / dL, only one episode of hypoglycemia without nocturnal hypoglycemia episodes, the dose is reduced by 1 mg; iii) if the individual had each of the following during the previous week: 101-140 mg / dL... If the individual has a median FG of 141-180 mg / dL, a single episode of hypoglycemia, and no nocturnal hypoglycemia, the dose is not changed; iv) if the individual has any of the following during the previous week: an FG of 141-180 mg / dL, a single episode of hypoglycemia, and no nocturnal hypoglycemia, the dose is increased by 3 mg; and v) if the individual has an FG > 180 mg / dL during the previous week, a single episode of hypoglycemia, and no nocturnal hypoglycemia, the dose is increased by 5 mg. Example 20. The method of any one of Examples 1 to 7 further comprises: a) determining a second weekly maintenance dose of the insulin receptor agonist to be administered to the individual; and b) administering the second weekly maintenance dose of the insulin receptor agonist to the individual one week after the first weekly maintenance dose. Example 21. The method of Example 19, wherein the individual has T2D and wherein the second weekly maintenance dose is determined by a method comprising: a) recording the incidence and timing of hypoglycemia one week after administration of the first weekly maintenance dose; b) measuring the individual's free glucose (FG) in the week following administration of the first weekly maintenance dose; and c) determining whether the first weekly maintenance dose should be adjusted to obtain the second weekly maintenance dose according to the following criteria: i) if the individual had one or more of the following during the previous week: median FG < 80 mg / dL, episodes of nocturnal hypoglycemia, or multiple episodes of hypoglycemia, the dose is reduced by 1.5 mg; ii) if the individual had each of the following during the previous week: median FG 80-100 mg / dL, only one episode of hypoglycemia, and no episodes of nocturnal hypoglycemia, the dose is reduced by 0.5 mg; iii) If the individual had any of the following during the previous week: median FG of 101-140 mg / dL, only one episode of hypoglycemia and no nocturnal hypoglycemia, the dose is not changed; iv) If the individual had any of the following during the previous week: median FG of 141-180 mg / dL, only one episode of hypoglycemia and no nocturnal hypoglycemia, the dose is increased by 1.5 mg; and v) If the individual had any of the following during the previous week: median FG > 180 mg / dL, only one episode of hypoglycemia and no nocturnal hypoglycemia, the dose is increased by 3 mg. Example 22. The method of any of Examples 19 to 20, further comprising: a) determining a third weekly maintenance dose of the insulin receptor agonist to be administered to the individual; and b) administering the third weekly maintenance dose of the insulin receptor agonist to the individual one week after administering the second weekly maintenance dose. Example 23. The method of Example 21, wherein the third weekly maintenance dose is determined by a method comprising: a) recording the incidence and timing of hypoglycemia one week after administration of the second weekly maintenance dose; b) measuring the individual's free glucose (FG) in the week following administration of the second weekly maintenance dose; c) determining whether the second weekly maintenance dose should be adjusted to obtain the third weekly maintenance dose according to the following criteria: i) if the previous weekly maintenance dose is ≤ 5 mg: a. if the individual had one or more of the following during the previous week: median FG < 80 mg / dL, nocturnal hypoglycemia episodes, or multiple episodes of hypoglycemia, then the dose is reduced by 1.5 mg; b. if the individual had each of the following during the previous week: median FG 80-100 mg / dL, only one episode of hypoglycemia without nocturnal hypoglycemia episodes, then the dose is not changed; c. if the individual had each of the following during the previous week: 101-140 mg / dL... If the median FG is 141-180 mg / dL, and there is only one episode of hypoglycemia without nocturnal hypoglycemia, the dose is increased by 0.25 mg; d. If the individual had any of the following in the previous week: median FG of 141-180 mg / dL, only one episode of hypoglycemia without nocturnal hypoglycemia, the dose is increased by 0.5 mg; or e. If the individual had any of the following in the previous week: median FG > 180 mg / dL, only one episode of hypoglycemia without nocturnal hypoglycemia, the dose is increased by 0.75 mg. ii) If the previous weekly maintenance dose was > 5 mg: a. If the individual had one or more of the following in the previous week: median FG < 80 mg / dL, episode of nocturnal hypoglycemia or multiple episodes of hypoglycemia, the dose is reduced by 2 mg; b.If the individual had any of the following in the previous week: median FG of 80-100 mg / dL, only one episode of hypoglycemia and no nocturnal hypoglycemia, the dose remains unchanged; c. If the individual had any of the following in the previous week: median FG of 101-140 mg / dL, only one episode of hypoglycemia and no nocturnal hypoglycemia, the dose is increased by 0.5 mg; d. If the individual had any of the following in the previous week: median FG of 141-180 mg / dL, only one episode of hypoglycemia and no nocturnal hypoglycemia, the dose is increased by 1 mg; or e. If the individual had any of the following in the previous week: median FG > 180 mg / dL, only one episode of hypoglycemia and no nocturnal hypoglycemia, the dose is increased by 1.5 mg. Example 24. The method of any of Examples 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 set forth in items i) and ii) of Example 22. Example 25. The method of any of Examples 3 or 6 to 8, wherein the weekly maintenance dose is determined by comprising: a) recording the incidence and timing of hypoglycemia one week after administering the prior dose; b) measuring the individual's free glucose (FG) in the week after administering the prior dose; and c) calculating the weekly maintenance dose according to the following equation: Weekly maintenance dose = Prior dose / X - 0.5*Y + 0.25*Z; Where: X is 3 if the previous dose is the loading dose; or X is 1 if the previous dose is a weekly maintenance dose; Where: Y is 0 if the individual has a median FG ≥ 80; Y is 1 if the individual has a median FG of 80-100 mg / dL and has been given one previous weekly maintenance dose or has received at least two previous weekly maintenance doses, and has a median FG < 80, any episode of nocturnal hypoglycemia, or multiple episodes of hypoglycemia due to the previous weekly maintenance dose; Y is 2 if the individual has a median FG of 80-100 mg / dL and has not yet received any previous weekly maintenance dose or has received one previous weekly maintenance dose, and has a median FG < 80, any episode of nocturnal hypoglycemia, or multiple episodes of hypoglycemia due to the previous weekly maintenance dose; or Y is 2 if the individual has not yet received any previous weekly maintenance dose, and has a median FG < 80 due to the previous weekly maintenance dose. 80. Any episode of nocturnal hypoglycemia or any of multiple episodes of hypoglycemia, then Y is 3; and wherein: if the individual has a median FG ≤ 100 mg / dL or a median FG between 101 and 140 and has not received more than one previous weekly maintenance dose, then Z is 0; if the individual has a median FG between 101 and 180 mg / dL and has received at least two previous weekly maintenance doses, then Z is 1; if the individual has a median FG between 141 and 180 mg / dL and has received one previous weekly maintenance dose or has a median FG > 180 mg / dL and has received at least two previous weekly maintenance doses, then Z is 2; if the individual has a median FG between 141 and 180 mg / dL and has not received any previous weekly maintenance dose or has a median FG > 180 and has received one previous weekly maintenance dose, then Z is 4; or if the individual has a median FG > If 180 and no prior weekly maintenance dose has been received, then Z is 8. Example 26. The method of any of Examples 3 or 6 to 8, wherein the individual has T1D and wherein the first weekly maintenance dose is determined by means of: a) recording the incidence and timing of hypoglycemia one week after administering the loading dose; b) measuring the individual's FG in the week after administering the loading dose; c) determining whether the dose obtained in step c) should be adjusted to obtain the first weekly maintenance dose according to the following criteria: i) if the individual has one or more of the following during the previous week: median FG < 80 mg / dL, nocturnal hypoglycemia, or multiple episodes of hypoglycemia, then the dose is reduced by 1.ii) If the individual had any of the following during the previous week: median FG of 80-100 mg / dL, only one episode of hypoglycemia and no nocturnal hypoglycemia, reduce the dose by 1 mg; iii) If the individual had any of the following during the previous week: median FG of 101-140 mg / dL, only one episode of hypoglycemia and no nocturnal hypoglycemia, do not change the dose; iv) If the individual had any of the following during the previous week: FG of 141-180 mg / dL, only one episode of hypoglycemia and no nocturnal hypoglycemia, increase the dose by 3 mg; or v) If the individual had FG > 180 mg / dL during the previous week, only one episode of hypoglycemia and no nocturnal hypoglycemia, increase the dose by 5 mg. Example 27. The method of any one of Examples 3, 6 to 8 or 25, further comprising: a) determining a second weekly maintenance dose of the insulin receptor agonist to be administered to the individual; and b) administering the second weekly maintenance dose of the insulin receptor agonist to the individual one week after the first weekly maintenance dose. Example 28. The method of Example 26, wherein the second weekly maintenance dose is determined by a method comprising: a) recording the incidence and timing of hypoglycemia one week after administration of the first weekly maintenance dose; b) measuring the individual's free glucose (FG) in the week following administration of the first weekly maintenance dose; and c) determining whether the first weekly maintenance dose should be adjusted to obtain the second weekly maintenance dose according to the following criteria: i) if the individual had one or more of the following during the previous week: median FG < 80 mg / dL, nocturnal hypoglycemia episodes, or multiple episodes of hypoglycemia, the dose is reduced by 1.5 mg; ii) if the individual had each of the following during the previous week: median FG 80-100 mg / dL, only one episode of hypoglycemia without nocturnal hypoglycemia episodes, the dose is reduced by 0.5 mg; iii) if the individual had each of the following during the previous week: 101-140 mg / dL... If the individual has a median FG of 141-180 mg / dL, a single episode of hypoglycemia, and no nocturnal hypoglycemia, the dose remains unchanged; iv) if the individual had any of the following during the previous week: a median FG of 141-180 mg / dL, a single episode of hypoglycemia, and no nocturnal hypoglycemia, the dose is increased by 1.5 mg; or v) if the individual had any of the following during the previous week: a median FG > 180 mg / dL, a single episode of hypoglycemia, and no nocturnal hypoglycemia, the dose is increased by 3 mg. Example 29.The method of any of Examples 26 or 27 further comprises: a) determining a third weekly maintenance dose of the insulin receptor agonist to be administered to the individual; and b) administering the third weekly maintenance dose of the insulin receptor agonist to the individual one week after the second weekly maintenance dose. Example 30. The method of Example 18, wherein the third weekly maintenance dose is determined by a method comprising: a) recording the incidence and timing of hypoglycemia one week after administration of the second weekly maintenance dose; b) measuring the individual's free glucose (FG) in the week following administration of the second weekly maintenance dose; c) determining whether the second weekly maintenance dose should be adjusted to obtain the third weekly maintenance dose according to the following criteria: i) if the previous weekly maintenance dose is ≤ 5 mg: a. if the individual had one or more of the following during the previous week: median FG < 80 mg / dL, nocturnal hypoglycemia episodes, or multiple episodes of hypoglycemia, then the dose is reduced by 1.5 mg; b. if the individual had each of the following during the previous week: median FG 80-100 mg / dL, only one episode of hypoglycemia without nocturnal hypoglycemia episodes, then the dose is not changed; c. if the individual had each of the following during the previous week: 101-140 mg / dL... If the individual has a median FG of 141-180 mg / dL, a single episode of hypoglycemia, and no nocturnal hypoglycemia, the dose shall be increased by 0.25 mg; or if the individual has any of the following in the previous week: a median FG of 141-180 mg / dL, a single episode of hypoglycemia, and no nocturnal hypoglycemia, the dose shall be increased by 0.5 mg; or if the individual has any of the following in the previous week: a median FG > 180 mg / dL, a single episode of hypoglycemia, and no nocturnal hypoglycemia, the dose shall be increased by 0.75 mg. ii) If the previous weekly maintenance dose was > 5 mg: a. If the individual had one or more of the following during the previous week: median FG < 80 mg / dL, episodes of nocturnal hypoglycemia, or multiple episodes of hypoglycemia, reduce the dose by 2 mg; b. If the individual had each of the following during the previous week: median FG of 80-100 mg / dL, one episode of hypoglycemia, and no nocturnal hypoglycemia, do not change the dose; c. If the individual had each of the following during the previous week: median FG of 101-140 mg / dL, one episode of hypoglycemia, and no nocturnal hypoglycemia, increase the dose by 0.5 mg; d. If the individual had each of the following during the previous week: median FG of 141-180 mg / dL, one episode of hypoglycemia, and no nocturnal hypoglycemia, increase the dose by 1 mg; or e.If the individual had any of the following during the previous week: median FG > 180 mg / dL, only one episode of hypoglycemia and no nocturnal hypoglycemia, the dose is increased by 1.5 mg. Example 31. The method of any of Examples 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 set forth in items i) and ii) of Example 29. Example 32. The method of any one of Examples 2 to 3, wherein the loading dose is determined by a method comprising: a) obtaining the individual's FG and BW; and b) using the individual's FG and BW to identify the loading dose according to the following criteria: i) if the individual's BW ≤ 80 kg and median FG is 100-140 mg / dL, then the loading dose = 120 IU; ii) if the individual's BW is 81-100 kg and FG is 100-140 mg / dL, then the loading dose = 200 IU; iii) if the individual's BW is 101-120 kg and FG is 100-140 mg / dL, then the loading dose = 240 IU; iv) if the individual's BW ≤ 80 kg and median FG is 141-180 mg / dL, then the loading dose = 250 IU; v) Loading dose = 280 IU if: a. Individual's body weight (BW) > 120 kg and median fat glucose (FG) is 100-140 mg / dL; or b. Individual's BW is 81-100 kg and median FG is 141-180 mg / dL; vi) Loading dose = 370 IU if individual's BW ≤ 80 kg and median FG is 181-220 mg / dL; vii) Loading dose = 420 IU if: a. Individual's BW is 81-100 kg and median FG is 181-220 mg / dL; or b. Individual's BW is 101-120 kg and median FG is 141-180 mg / dL; viii) Loading dose = 490 IU if: a. Individual's BW > 120 kg; or b. Individual's body weight (BW) is 101-120 kg and median FG is 141-180 mg / dL; a. Body weight (BW) ≤ 80 kg and median FG > 200 mg / dL; b. Body weight (BW) ≤ 80 kg and median FG > 200 mg / dL; ix) Loading dose = 560 IU if: a. The individual's BW ≥ 101 kg and FG 181-220 mg / dL; or b. The individual's BW 181-100 kg and FG > 200 mg / dL; x) Loading dose = 630 IU if the individual's BW 101-120 kg and FG 181-220 mg / dL.; or xi) if the individual’s BW > 120 kg and FG > 220 mg / dL, then the loading dose = 700 IU. Example 33. A method as described in any one of Examples 1 to 3 or 31, wherein the weekly maintenance dose is determined by a method comprising: a) recording the frequency and severity of hypoglycemia one week after administering the prior dose; b) measuring the individual's FG in the week following the administration of the prior dose; and c) calculating the weekly maintenance dose according to the following equation: Weekly maintenance dose = Prior dose - 14*X + 14*Y Where: i) If the individual's FG ≥ 101; or the individual has been administered at least 3 prior doses and has an FG of 81-100, then X = 0; ii) If the individual's FG ≤ 80 and the individual has been administered at least 3 prior doses, then X = 1; iii) If the individual's FG is 81-100 and the individual has been administered two prior doses, then X = 2; iv) If the individual's BW is 81-100 and the individual has been administered one prior dose, then X = 3; or v) If the median FG of the individual is ≤80 and the individual has already received a previous dose, then X = 5; and where: vi) If the individual's FG is ≤100; or if the individual's FG is 81-100 and the individual has already received at least 3 previous doses, then Y = 0; vii) If the individual's FG is 101-140 and the individual has already received at least 3 previous doses, then Y = 1; viii) If the individual's FG is 141-180 and the individual has already received at least 3 previous doses, then Y = 2; ix) If the individual's FG is >180 mg / dL and the individual has already received at least 3 previous doses, then Y = 3; x) If the individual's FG is 141-180 and the individual has already received 2 previous doses, then Y = 5; xi) If: the individual's FG is 141-180 and the individual has already received one previous dose; or the individual's FG > 180 and the individual has already received two previous doses, then Y = 8.57; or xii) if the individual's FG > 180 and the individual has already received one previous dose, then Y = 15; The limitation is that if the individual had any SMBG reading < 70 mg / dL at any time during the previous week, then Y may not be > 0; and if the individual experienced: multiple recorded episodes of hypoglycemia with FG < 70 mg / dL during the previous week; severe hypoglycemia requiring support; and / or recorded hypoglycemia ≤ 54 mg / dL, then the dose must be reduced. Example 34. The method of Example 1, wherein the individual has not previously received insulin treatment and wherein the first dose is approximately 70 IU. Example 35.The method of Example 1 or any of 33 to 34, wherein the second dose is determined by a method comprising: a) recording the incidence and timing of hypoglycemia one week after administration of the prior dose; b) measuring the individual's FG in the week after administration of the prior dose; and c) calculating the weekly maintenance dose according to the following equation: Weekly maintenance dose = Prior dose - 14*X + 14*Y Where: i) if FG > 71, then X = 0; ii) if FG is 55-70, then X = 1; or iii) if FG < 54, then X = 2; and wherein: i) if FG ≤ 100, then Y = 0; and ii) if FG is 101-125, then Y = 1; or iii) if FG > 125, then Y = 2; and the limitation is that if the individual has any SMBG reading < 70 mg / dL at any time in the previous week, then Y may not be > 70 mg / dL. 0. Example 36. The method of any of Examples 1 or 33 to 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 Example 35. Example 37. A method for providing glycemic control in an individual with diabetes in need, comprising: a) administering an initial dose of weekly basal insulin-Fc (BIF) to the individual according to the following criteria: i) the initial dose is a loading dose if the individual meets the following criteria: a. has never been treated with insulin; b. has type 2 diabetes (T2D) and fasting glucose (FG) > 120 mg / dL; or c. has type 1 diabetes (T1D); ii) if the individual has T2D but does not meet the criteria set forth in a. or b. above, the initial dose is a weekly maintenance dose; and b) starting one week after administering the initial dose, administering one or more weekly maintenance doses to the individual once a week. Example 38. The method of Example 37, wherein the initial dose is a loading dose that is three times larger than the intended weekly maintenance dose. Example 39. The method of any of Examples 37 or 38, wherein the individual has never been treated with insulin and the loading dose is 300 U. Example 40. The method of Example 38, wherein the individual has type 2 diabetes (T2D) and fulminant glucose (FG) > 120 mg / dL, and wherein the expected weekly maintenance dose is approximately 7 times higher than the individual's daily basal insulin dose before starting BIF treatment. Example 41.The method of any of Examples 37 to 40, wherein each weekly maintenance dose is selected according to the following criteria: a) If the previous dose was a loading dose, the weekly maintenance dose is equal to the expected weekly maintenance dose adjusted as necessary according to the following items (i)-(iv): i) if the individual's median FG during the previous week is <80 mg / dL, then reduce by 20 units; ii) if the individual's median FG during the previous week is 80-120 mg / dL, then equal to the previous dose; iii) if the individual's median FG during the previous week is 121-140 mg / dL, then increase by 20 units; or iv) if the individual's median FG is >140 mg / dL, then increase by 40 units; b) If the previous dose was not a loading dose, the weekly maintenance dose is equal to: if the maintenance dose is the initial dose of BIF, then equal to the expected weekly maintenance dose; or equal to the previous maintenance dose adjusted as necessary according to the above items (i)-(iv). Example 42. The method of any one of Examples 37 to 41, wherein the individual is being treated with >10 units / day of basal insulin before starting BIF treatment. Example 43. The method of any one of Examples 37 to 42, wherein the individual is being treated with >20 units / day of basal insulin before starting BIF treatment. Example 44. The method of any one of Examples 37 to 40, wherein the individual has T2D and has a baseline FG ≤ 120 mg / dL and / or is on basal insulin therapy of < 20 units / day before starting BIF treatment, and wherein the weekly maintenance dose is selected according to the following criteria: a) if the previous dose is a loading dose, the weekly maintenance dose is equal to the expected weekly maintenance dose adjusted as necessary according to the following items (i)-(iv): i) if the individual's median FG during the previous week is < 80 mg / dL, then reduce by 20 units; ii) if the individual's median FG during the previous week is 80-120 mg / dL, then equal to the previous dose; iii) if the individual's median FG during the previous week is 121-140 mg / dL, then increase by 10 units; or iv) if the individual's median FG during the previous week is > 140 mg / dL, then increase by 20 units; b) If the previous dose was not a loading dose, then the weekly maintenance dose is equal to the previous maintenance dose adjusted as necessary according to items (i)-(iv) above. Example 45.The method of any of Examples 37 to 40, wherein the individual has T2D and is being treated with <10 units / day of basal insulin before starting BIF treatment, and wherein the weekly maintenance dose is selected according to the following criteria: a) if the previous dose is a loading dose, the weekly maintenance dose is equal to the expected weekly maintenance dose adjusted as necessary according to the following items (i)-(iv): i) if the individual's median FG during the previous week is <80 mg / dL, then reduce by 20 units; ii) if the individual's median FG during the previous week is 80-120 mg / dL, then equal to the previous dose; iii) if the individual's median FG during the previous week is 121-140 mg / dL, then increase by 5 units; or iv) if the individual's median FG during the previous week is >140 mg / dL, then increase by 10 units; b) If the prior dose was not a loading dose, the weekly maintenance dose is equal to the prior dose adjusted as necessary according to items (i)-(iv) above. Example 46. The method of any of Examples 41 to 45, wherein if the individual had a blood glucose episode of < 70 mg / dL in the previous week, the weekly maintenance dose is not increased. Example 47. The method of any of Examples 37 to 46, wherein if the individual had any of the following in the previous week, the weekly maintenance dose is reduced by 40 units: a) ≥ 3 blood glucose episodes ≤ 70 mg / dL; b) ≥ 1 nocturnal blood glucose episode ≤ 70 mg / dL; c) ≥ 1 blood glucose episode ≤ 54 mg / dL; or d) any episode of severe hypoglycemia. Example 48. The method of any of Examples 41 to 47, wherein the individual has not been treated with MDI. Example 49.As in any of Examples 37 to 40, where the individual has T2D and is being treated with MDI, the weekly maintenance dose is selected according to the following criteria: a) If the weekly maintenance dose is the initial dose of BIF, the weekly maintenance dose is approximately 7 times higher than the individual's daily basal insulin dose before starting BIF treatment; b) If the weekly maintenance dose is not the initial dose of BIF and the individual had a baseline FG ≤ 120 mg / dL or a daily basal dose before starting < 20 units of BIF treatment, the weekly maintenance dose is equal to the previous maintenance dose adjusted as necessary according to the following criteria: i) If the individual's median FG during the previous week is < 80 mg / dL, the weekly maintenance dose is reduced by 10-20 units; ii) If the individual's median FG during the previous week is 80-120 mg / dL, the weekly maintenance dose remains unchanged; iii) If the individual's median FG during the previous week is 121-140 mg / dL... If the median FG in the previous week is >140 mg / dL, the weekly maintenance dose is increased by 10 units; iv) If the individual's median FG in the previous week is >140 mg / dL, the weekly maintenance dose is increased by 20 units; c) If the weekly maintenance dose is not the initial dose of the BIF and if the individual had a baseline FG >120 mg / dL and a basal dose ≥20 units / day before starting BIF treatment, the weekly maintenance dose is equal to the previous maintenance dose adjusted as necessary according to the following criteria: i) If the individual's median FG in the previous week is <80 mg / dL, the weekly maintenance dose is reduced by 20 units; ii) If the individual's median FG in the previous week is 80-120 mg / dL, the weekly maintenance dose remains unchanged; iii) If the individual's median FG in the previous week is 121-140 mg / dL, the weekly maintenance dose is increased by 20 units; iv) If the individual's median FG in the previous week is >140 mg / dL, the weekly maintenance dose is increased by 20 units; If the baseline FG is 140 mg / dL, the weekly maintenance dose is increased by 40 units. Example 50. The method of any of Examples 37 or 38, wherein the individual has T1D and wherein the loading dose is determined according to the following criteria: a) If the individual's baseline FG is ≤ 140 mg / dL, the loading dose = (the individual's daily basal insulin dose before starting BIF treatment) × 7 × 3; b) If the individual's baseline FG is 140-160 mg / dL, the loading dose = (the individual's daily basal insulin dose before starting BIF treatment increased by approximately 10-20%) × 7 × 3; c) If the individual's baseline FG is > 160 mg / dL, the loading dose = (the individual's daily basal insulin dose before starting BIF treatment increased by approximately 20-30%) × 7 × 3. Example 51.As in any of Examples 37 to 38 or 50, wherein the individual has T1D and wherein the individual’s first weekly maintenance dose is selected according to the following criteria: a) if the individual’s baseline FG ≤ 140 mg / dL, the first weekly maintenance dose = (the individual’s daily basal insulin dose before starting BIF treatment) × 7; b) if the individual’s baseline FG is 140-160 mg / dL, the first weekly maintenance dose = (the individual’s daily basal insulin dose increased by about 10-20% before starting BIF treatment) × 7; c) if the individual’s baseline FG > 160 mg / dL, the first weekly maintenance dose = (the individual’s daily basal insulin dose increased by about 20-30% before starting BIF treatment) × 7. Example 52. The method of any one of Examples 37 to 38 or 50 to 51, wherein the individual has T1D and wherein the individual's second and subsequent weekly maintenance dose is selected according to the following criteria: a) If the individual's median FG during the previous week is <80 mg / dL, the weekly maintenance dose is reduced to the previous lower dose; b) If the individual's median FG during the previous week is 80-120 mg / dL, the weekly maintenance dose remains unchanged; c) If the individual's median FG during the previous week is 121-150 mg / dL, the weekly maintenance dose is increased as follows: if the previous weekly maintenance dose is <100 U, increase by 5 units; or if the previous weekly maintenance dose is ≥100 U, increase by 10 units; d) If the individual's median FG during the previous week is 151-180 mg / dL, the weekly maintenance dose is increased as follows: if the previous weekly maintenance dose is <100 U, increase by 5 units; or if the previous weekly maintenance dose is ≥100 U, increase by 10 units; If the individual's median FG > 180 mg / dL during the previous week, the weekly maintenance dose is increased as follows: if the previous weekly maintenance dose < 100 U, the dose is increased by 20 units; or if the previous weekly maintenance dose ≥ 100 U, the dose is increased by 30 units. Example 53. The method of any of Examples 49 to 52, wherein if the individual has one or more incidents of hypoglycemia attributed to BIF rather than the individual's mealtime insulin, the weekly maintenance dose is not increased. Example 54. The method of any of Examples 49 to 53, wherein if the individual has one or more incidents of nocturnal hypoglycemia, the weekly maintenance dose is not increased. Example 55. The method of any of Examples 49 to 54, wherein if the individual has one or more incidents of severe hypoglycemia, the weekly maintenance dose is not increased. Example 56.The method of any of Examples 37 to 55, wherein the need for any weekly maintenance dose adjustment is determined at the following times: weekly during the first 12 weeks after starting BIF treatment; and every 4 weeks thereafter. Example 57. The method of any of Examples 37 to 56, wherein the method comprises improving glycemic control in the patient. Example 58. A BIF for the treatment of diabetes, wherein the treatment comprises providing glycemic control by: a) administering an initial dose of BIF to the individual according to the following criteria: iii) the initial dose is a loading dose if the individual has: a. never been treated with insulin; b. has T2D and FG > 120 mg / dL; or c. has T1D; iv) if the individual has T2D but does not meet the criteria set forth in a. or b. above, the initial dose is a weekly maintenance dose; and b) starting one week after administering the initial dose, administering one or more weekly maintenance doses to the individual once a week. Example 59. A BIF as described in Example 58, wherein the initial dose is a loading dose that is three times greater than the intended weekly maintenance dose. Example 60. A BIF as described in either Example 58 or 59, wherein the individual has not previously received insulin therapy, and the loading dose is 300 U. Example 61. A BIF as described in Example 59, wherein the individual has type 2 diabetes (T2D) and fat grafting glucose (FG) > 120 mg / dL, and wherein the intended weekly maintenance dose is approximately seven times greater than the individual's daily basal insulin dose prior to starting BIF treatment. Example 62. A BIF provided as in any of Examples 58 to 61, wherein each weekly maintenance dose is selected according to the following criteria: a) if the previous dose was a loading dose, the weekly maintenance dose is equal to the expected weekly maintenance dose adjusted as necessary according to the following items (i)-(iv): i) if the individual's median FG during the previous week is <80 mg / dL, then reduce by 20 units; ii) if the individual's median FG during the previous week is 80-120 mg / dL, then equal to the previous dose; iii) if the individual's median FG during the previous week is 121-140 mg / dL, then increase by 20 units; or iv) if the individual's median FG is >140 mg / dL, then increase by 40 units; b) If the prior dose is not a loading dose, the weekly maintenance dose is equal to: if the maintenance dose is the initial dose of the BIF, then equal to the expected weekly maintenance dose; or equal to the prior maintenance dose adjusted as necessary according to items (i)-(iv) above. Example 63. A BIF provided as in any of Examples 58 to 62, wherein the individual was being treated with >10 units / day of basal insulin prior to starting BIF treatment. Example 64.The BIF provided for use is as described in any of Examples 58 to 63, wherein the individual was being treated with >20 units / day of basal insulin prior to starting treatment with the BIF. Example 65. A BIF as described in any of Examples 58 to 62, wherein the individual has T2D and has a baseline FG ≤ 120 mg / dL and / or is on basal insulin therapy of <20 units / day prior to starting BIF treatment, and wherein the weekly maintenance dose is selected according to the following criteria: a) if the previous dose was a loading dose, the weekly maintenance dose is equal to the expected weekly maintenance dose adjusted as necessary according to the following items (i)-(iv): i) if the individual's median FG during the previous week was <80 mg / dL, then reduce by 20 units; ii) if the individual's median FG during the previous week was 80-120 mg / dL, then equal to the previous dose; iii) if the individual's median FG during the previous week was 121-140 mg / dL, then increase by 10 units; or iv) if the individual's median FG during the previous week was >140 mg / dL, then increase by 20 units; b) If the previous dose is not a loading dose, then the weekly maintenance dose is equal to the previous maintenance dose adjusted as necessary according to items (i)-(iv) above. Example 66. A BIF as described in any of Examples 58 to 62, wherein the individual has T2D and is on basal insulin therapy of <10 units / day prior to starting BIF therapy, and wherein the weekly maintenance dose is selected according to the following criteria: a) if the previous dose was a loading dose, the weekly maintenance dose is equal to the expected weekly maintenance dose adjusted as necessary according to the following items (i)-(iv): i) if the individual's median FG during the previous week was <80 mg / dL, then reduce by 20 units; ii) if the individual's median FG during the previous week was 80-120 mg / dL, then equal to the previous dose; iii) if the individual's median FG during the previous week was 121-140 mg / dL, then increase by 5 units; or iv) if the individual's median FG during the previous week was >140 mg / dL, then increase by 10 units; b) If the prior dose was not a loading dose, the weekly maintenance dose is equal to the prior dose adjusted as necessary according to items (i)-(iv) above. Example 67. A BIF provided as in any of Examples 63 to 66, wherein if the individual had a blood glucose episode of < 70 mg / dL in the previous week, the weekly maintenance dose is not increased. Example 68.If any of the BIFs in Examples 58 to 67 is used, the weekly maintenance dose is reduced by 40 units if the individual had any of the following in the previous week: a) ≥ 3 blood glucose episodes ≤ 70 mg / dL; b) ≥ 1 nocturnal blood glucose episode ≤ 70 mg / dL; c) ≥ 1 blood glucose episode ≤ 54 mg / dL; or d) any episode of severe hypoglycemia. Example 69. If any of the BIFs in Examples 62 to 68 is used, the individual has not been treated with MDI. Example 70. A BIF as described in any of Examples 58 to 61, wherein the individual has T2D and is being treated with MDI, wherein the weekly maintenance dose is selected according to the following criteria: a) If the weekly maintenance dose is the initial dose of the BIF, the weekly maintenance dose is approximately 7 times higher than the individual's daily basal insulin dose before starting BIF treatment; b) If the weekly maintenance dose is not the initial dose of the BIF and the individual had a baseline FG ≤ 120 mg / dL or a daily basal dose before starting < 20 units of BIF treatment, the weekly maintenance dose is equal to the previous maintenance dose adjusted as necessary according to the following criteria: i) If the individual's median FG during the previous week is < 80 mg / dL, the weekly maintenance dose is reduced by 10-20 units; ii) If the individual's median FG during the previous week is 80-120 mg / dL, the weekly maintenance dose remains unchanged; iii) If the individual's median FG during the previous week is 121-140 mg / dL... If the median FG in the previous week is >140 mg / dL, the weekly maintenance dose is increased by 10 units; iv) If the individual's median FG in the previous week is >140 mg / dL, the weekly maintenance dose is increased by 20 units; c) If the weekly maintenance dose is not the initial dose of the BIF and if the individual had a baseline FG >120 mg / dL and a basal dose ≥20 units / day before starting BIF treatment, the weekly maintenance dose is equal to the previous maintenance dose adjusted as necessary according to the following criteria: i) If the individual's median FG in the previous week is <80 mg / dL, the weekly maintenance dose is reduced by 20 units; ii) If the individual's median FG in the previous week is 80-120 mg / dL, the weekly maintenance dose remains unchanged; iii) If the individual's median FG in the previous week is 121-140 mg / dL, the weekly maintenance dose is increased by 20 units; iv) If the individual's median FG in the previous week is >140 mg / dL, the weekly maintenance dose is increased by 20 units; If the dose is 140 mg / dL, the weekly maintenance dose should be increased by 40 units. Example 71.The BIF provided in either Example 58 or 59 is used in an individual with T1D and the loading dose is determined according to the following criteria: a) If the individual's baseline FG ≤ 140 mg / dL, the loading dose = (the individual's daily basal insulin dose before starting BIF treatment) × 7 × 3; b) If the individual's baseline FG is 140-160 mg / dL, the loading dose = (the individual's daily basal insulin dose increased by approximately 10-20% before starting BIF treatment) × 7 × 3; c) If the individual's baseline FG > 160 mg / dL, the loading dose = (the individual's daily basal insulin dose increased by approximately 20-30% before starting BIF treatment) × 7 × 3. Example 72. A BIF used as described in any of Examples 58 to 59 or 71, wherein the individual has T1D and wherein the individual's first weekly maintenance dose is selected according to the following criteria: a) If the individual's baseline FG ≤ 140 mg / dL, the first weekly maintenance dose = (the individual's daily basal insulin dose before starting BIF treatment) × 7; b) If the individual's baseline FG is 140-160 mg / dL, the first weekly maintenance dose = (the individual's daily basal insulin dose increased by approximately 10-20% before starting BIF treatment) × 7; c) If the individual's baseline FG > 160 mg / dL, the first weekly maintenance dose = (the individual's daily basal insulin dose increased by approximately 20-30% before starting BIF treatment) × 7. Example 73.The BIF used in any of Examples 58-59 or 61-62, wherein the individual has T1D and wherein the individual's second and subsequent weekly maintenance dose is selected according to the following criteria: a) If the individual's median FG during the previous week is <80 mg / dL, the weekly maintenance dose is reduced to the previous lower dose; b) If the individual's median FG during the previous week is 80-120 mg / dL, the weekly maintenance dose remains unchanged; c) If the individual's median FG during the previous week is 121-150 mg / dL, the weekly maintenance dose is increased as follows: if the previous weekly maintenance dose is <100 U, increase by 5 units; or if the previous weekly maintenance dose is ≥100 U, increase by 10 units; d) If the individual's median FG during the previous week is 151-180 mg / dL, the weekly maintenance dose is increased as follows: if the previous weekly maintenance dose is <100 U, increase by 5 units; or if the previous weekly maintenance dose is ≥100 U, increase by 10 units; If the individual's median FG > 180 mg / dL during the previous week, the weekly maintenance dose is increased as follows: if the previous weekly maintenance dose < 100 U, the dose is increased by 20 units; or if the previous weekly maintenance dose ≥ 100 U, the dose is increased by 30 units. Example 74. The weekly maintenance dose is not increased if the individual has one or more incidents of hypoglycemia attributed to the BIF rather than the individual's prandial insulin. Example 75. The weekly maintenance dose is not increased if the individual has one or more incidents of nocturnal hypoglycemia attributed to the BIF rather than the individual's prandial insulin. Example 76. A BIF as described in any of Examples 70 to 75, wherein the weekly maintenance dose is not increased if the individual has one or more episodes of severe hypoglycemia. Example 77. A BIF as described in any of Examples 58 to 76, wherein the need for any adjustment to the weekly maintenance dose is determined at the following times: weekly during the first 12 weeks after initiation of BIF treatment; and every 4 weeks thereafter. Example 78. A BIF as described in any of Examples 58 to 77, wherein the treatment comprises improving glycemic control in the patient. Example 79. Use of a BIF as described in any of Examples 58 to 78 in the manufacture of a medicament for treating diabetes.

[0092] The present invention is further illustrated by the following examples, which should not be construed as limiting.

[0093] Example SAD and MAD Studies. The study was designed to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) effects of BIF in healthy volunteers and patients with type 2 diabetes mellitus (T2DM). The Single Elevation-Dose (SAD) study was a randomized, investigator- and individual-masked, placebo-controlled, single-dose, single-site dose escalation study conducted in healthy individuals and patients with T2D. The study explored six dose levels of BIF – 2, 10, 12, 17, 20, and 35 mg. BIF dose escalation was assessed in cohorts of 8 healthy individuals or 8 patients with T2D (6 patients per cohort based on BIF and 2 patients per cohort based on placebo). Staggered dosing was performed for each cohort, in which a new, higher dose of BIF was administered. Because the unit dose of BIF required to achieve glycemic control equivalent to one unit of basal insulin was unknown, BIF doses were expressed in milligrams. Blood samples were collected before administration, 8 hours after administration on day 1, and once daily on days 2–7, day 14, and during subsequent consultations (day 29).

[0094] BIF of plasma samples obtained during this study was analyzed using a validated enzyme-linked immunosorbent assay (ELISA). The lower limit of quantitation (LLOQ) was 300.00 pM, and the upper limit of quantitation was 10000.00 pM. Inter-analytical accuracy (relative error percentage [%)) during validation ranged from -1.0% to 5.4%. Inter-analytical precision (coefficient of variation [CV]%) during validation ranged from 4.8% to 9.6%.

[0095] Gluargine insulin in plasma samples was detected and analyzed using a validated high-performance liquid chromatography (HPLC) method and tandem mass spectrometry (MS / MS). The LLOQ of glargine insulin was 8.25 pM. The upper limit of quantitation for glargine insulin was 1649.4 pM. Interanalytical accuracy during the validation period for glargine insulin was as follows: Interanalytical precision (relative standard deviation %) during the validation period for glargine insulin ranged from 3.8% to 9.0%.

[0096] Based on the treatment received by the patient / individual, the complete analysis group for PK and PK / PD analysis consisted of all enrolled patients / individuals who received at least one dose of the study drug. BIF and PK parameter estimates for insulin glargine and its metabolites were calculated using standard non-compartmental analysis methods with Phoenix WinNonlin version 6.4 (Pharsight, USA). PD data were analyzed using S-Plus for Windows version 8.2.

[0097] The primary parameters used for analysis were the time to reach maximum BIF concentration (tmax), BIF half-life, and BIF peak-to-trough ratio. PD analysis was performed on patients with T2D based on FG (using fasting blood glucose from an 8-point glucose characteristic curve) version 7.3.

[0098] Fifty-seven patients with type 2 diabetes (T2D) and 16 healthy individuals participated in this study. All 16 healthy individuals completed the study. Of the 56 T2D patients who completed the study, 36 received insulin glargine (BIF) (6 received 2, 10, 12, 17, 20, and 35 mg respectively), 12 received placebo, and 8 received insulin glargine. Of the 16 healthy individuals, 12 received BIF (6 received 5 and 10 mg respectively) and 4 received placebo.

[0099] The pharmacokinetic results of the SAD study included all 36 patients with type 2 diabetes (T2D) and 10 healthy individuals who received bifidogenic infusion (BIF). Dose-response was linear in both healthy individuals and patients, with low diurnal and inter-individual variability in patients with T2D. On average, BIF reached its Cmax on day 4 following a single dose. The median (range) tmax for patients receiving 2 mg, 10 mg, 12 mg, 17 mg, 20 mg, and 35 mg 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. The median (range) tmax for healthy individuals receiving 5 mg or 10 mg were 3.0 (3.0–4.0) and 3.0 (1.0–6.0), respectively. In healthy individuals and patients with type 2 diabetes (T2D), the maximum concentration appears to increase proportionally with dose. In patients with T2D, BIF plasma concentrations are decreased, with a mean half-life of approximately 17 days. The calculated half-lives for different BIF doses in patients with T2D range from 14.8 to 18.5 days, and for two BIF doses in healthy individuals, they range from 11.8 to 15.5 days.

[0100] PD results from the SAD study indicate that a single dose of BIF causes a decrease in fasting glucose in patients with type 2 diabetes (T2D) that persists for at least 5 days after administration. BIF administration causes a decrease in glucose on the first day of administration. The decrease in fasting glucose (FG) is greater with increasing BIF concentration.

[0101] Data from the SAD study confirms clear evidence of glucose reduction in study participants with T2DM following a single dose of BIF in the range of 2 to 35 mg. BIF exhibits a prolonged time-of-action pattern of action following a single dose, supporting weekly dosing. In study participants with T2DM, BIF reached maximum concentrations approximately 4 days after administration, followed by a mean elimination half-life of approximately 17 days (range 11 to 22 days).

[0102] With a long elimination half-life, following a fixed weekly dosing regimen, steady-state PK is predicted to be reached in approximately 8 to 10 weeks at concentrations approximately 3 times higher than after a single dose due to accumulation. Therefore, based on the PK model, a loading dose strategy of 3 times the weekly dose will achieve steady-state exposure after one dose.

[0103] A 3x loading dose strategy was used in the Multiple Elevation (MAD) study. The MAD study was a three-site, randomized, open-label, active agent-controlled, multiple-dose, two-part, dose-escalation, and parallel-design study in patients with type 2 diabetes (T2D) to evaluate the safety and tolerability of insulin escalation (BIF). Dose escalation of BIF was evaluated in a cohort of up to eight patients with T2D (six receiving BIF and two receiving insulin glargine [Sanofi; Paris, France]). Patients receiving insulin glargine (U100) continued their usual dosing regimen until day 1, and patients not previously treated with insulin glargine were converted to an appropriate insulin glargine dose at the investigator's discretion. Patients assigned to the BIF group received a loading dose of 3x the weekly maintenance dose during the first week of dosing on day 1, and then received weekly maintenance doses (1, 2, 5, and 10 mg) once weekly for the next 5 weeks to achieve rapid steady-state concentrations. Patients were discharged from the CRU on day 8. Patients assigned to the insulin glargine control group received daily insulin glargine injections at the same dose and timing as their usual basal insulin. BIF and insulin glargine analysis were performed on plasma samples obtained during the study, and PK and PK / PD analyses were performed as described above for the SAD study.

[0104] Thirty-three patients with type 2 diabetes participated in the study, and 28 completed the study. The patients were between 40 and 69 years old, and 18 were male (Table 1). Twenty-five patients received a bifidogenic infusion (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 a BIF at week 6 (6 received 1 mg, 5 received 2 mg, 5 received 5 mg, and 6 received 10 mg).

[0105] Data indicate that the overall mean BIF tmax was 4.3 days across all study doses following the loading dose in week 1. The PK after a single loading dose was comparable to the concentration profile at week 6 (with one-third of a dose delivered weekly), indicating successful transition to a steady-state PK profile and supporting the loading dose strategy. In patients with T2D, the peak-to-trough ratio of dose-normalized BIF concentration over the 1-week period was approximately 1.14, which is considered steady-state.

[0106] The mean 7-point glucose characteristic curve was measured on day -1, day 4, and day 40. In all four BIF treatment groups, the glucose characteristic curve remained constant over time. Specifically, the glucose characteristic curves of patients receiving weekly BIF were consistent throughout the 6-week study. Furthermore, the 7-point glucose characteristic curve of BIF was similar to that of insulin glargine. Higher doses elicited a larger glucose response. There were no significant differences between individuals receiving BIF and those receiving insulin glargine.

[0107] Hypoglycemia was the most frequent treatment-related adverse reaction. Compared with insulin glargine (44.0% vs. 62.5%), fewer events were reported after BIF administration. Most events were managed with food or beverages.

[0108] Phase 2 study. This study was designed to evaluate the safety and efficacy of BIF versus insulin degludec in patients with type 2 diabetes mellitus (T2DM) previously treated with oral antidiabetic drugs and basal insulin over 32 weeks. The study design included a loading dose and two different algorithms for determining the weekly maintenance dose of BIF.

[0109] Determine the loading dose and expected weekly maintenance dose according to Table 19 below: Daily basal insulin dose before randomization Baseline HbA1c (%) Loading dose (mg) Expected weekly maintenance dose (mg) 10 IU - 19 IU <8.5 6 4 20 IU - 29 IU <8.5 10 6 30 IU - 39 IU <8.5 12 8 40 IU - 50 IU <8.5 18 10 >50 IU <8.5 twenty four 12 10 IU - 19 IU ≥8.5 12 4 20 IU - 29 IU ≥8.5 18 6 30 IU - 39 IU ≥8.5 twenty four 8 40 IU - 50 IU ≥8.5 30 10 >50 IU ≥8.5 36 12 Table 19. Abbreviations: IU = International Unit; HbA1c = Heme A1c

[0110] The two algorithms used in the study's BIF group employed different fasting glucose (FG) targets and adjustment intervals: for Algorithm 1, adjustments were made every 2 weeks, targeting FG ≤ 140 mg / dL; and for Algorithm 2, adjustments were made every 4 weeks, targeting FG ≤ 120 mg / dL. Dosage adjustments are described in Table 20 below: Criteria for determining dosage Algorithm 1 - Every 2 weeks Algorithm 2 - Every 4 weeks < 70 mg / dL - 1.5 mg - 1.5 mg 71 to 99 mg / dL - 1 mg - 1 mg 100 to 119 mg / dL 0 mg 0 mg 120 to 139 mg / dL 0 mg + 0.5 mg 140-180 mg / dL + 1 mg + 1 mg >180 mg / dL + 1.5 mg + 2 mg Number of hypoglycemic episodes triggered by dose reduction 1 1 dose reduction - 1 mg - 1 mg Dosage adjustment interval 14 days 30 days Table 20.

[0111] Degludec insulin was titrated to a free glucose target (FG) of ≤100 mg / dL using a modified Riddle target therapy algorithm. Study participants (N=399) were randomly assigned in a 1:1:1 ratio to one of three parallel treatment groups. The mean age of the participants was 60.2 years, the baseline HbA1c was 8.1%, and the duration of diabetes was 14.7 years. There were no statistically significant differences in demographics or baseline characteristics among the three treatment groups.

[0112] For the primary endpoint of HbA1c change from baseline to week 32, both BIF groups achieved non-inferiority (non-inferiority margin = 0.4%), 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. Consistent with different plasma glucose targets, insulin degludec achieved a greater reduction in glucose from baseline compared to the BIF groups. Similarly, when the assessed event was <70 mg / dL (3.9 mmol / L), both BIF groups showed significantly fewer hypoglycemic events (all documented events and nocturnal events) compared to insulin degludec. There was no significant difference in hypoglycemic events <54 mg / dL (3.0 mmol / L - all documented events and nocturnal events) among the three dosing groups. Both BIF groups had statistically significantly smaller weight gain compared to insulin degludec from baseline to week 32.

[0113] In summary, BIF was non-inferior to insulin degludec when administered weekly according to any dosing algorithm, as measured by changes in HbA1c after 32 weeks, with a lower recorded rate of return, nocturnal blood glucose <70 mg / dL, and less weight gain. Furthermore, no safety signals were detected.

[0114] The results validated the predictive ability of the PK / PD-IGI model and were used to update the model. The updated model was used to develop additional dose titration protocols for clinical trials, which are described in more detail below.

[0115] For patients previously treated with multiple daily injections. A multicenter, randomized, open-label, parallel, comparative-controlled study with three study periods was designed to evaluate the efficacy and safety of the BIF dosing algorithm compared to insulin degludec in patients with type 1 diabetes mellitus (T1DM) treated with MDI without interruption for at least 3 months. The study will last 26 weeks to ensure adequate exposure duration is necessary for assessing the efficacy and safety of insulin alpha. Insulin degludec is an active comparative agent in this study and will be used to compare the effects of BIF and daily basal insulin on glycemic control, hypoglycemia, and weight gain.

[0116] The efficacy and safety assessments included in this study are generally considered reliable and accurate relative to efficacy and safety assessments in individuals and populations with T1DM. The primary efficacy measure was the change in HbA1c from baseline to week 26. The secondary efficacy measures in this study were: the change in HbA1c from baseline to week 12; the change in FG from baseline to weeks 12 and 26; and the change in insulin dose with meals from baseline to weeks 12 and 26.

[0117] The following safety assessments will be assessed as secondary objectives: the incidence and rate of hypoglycemia; the incidence of treatment-induced SAE; and clinical laboratory assessments specifically focused on changes in hepatic transaminase levels.

[0118] Participants will be randomly assigned in a 1:1 ratio to receive BIF subcutaneously weekly, administered according to the methods and protocols described herein, or to receive degludec insulin subcutaneously daily, administered according to a modified Riddle algorithm.

[0119] Participants who complete treatment will provide at least 80% statistical power to demonstrate non-inferiority of HbA1c change from baseline to 26 weeks to insulin degludec based on the following assumptions: ● True mean difference = 0% ● 1.1% SD ● 0.4% NIM ● Using a two-sided alpha level of 0.1

[0120] Unless otherwise stated, all efficacy tests will be performed at a two-sided alpha level of 0.1, and all confidence intervals (CIs) will be given at a two-sided 90% level. The maximum total duration of study participation for each participant will be no more than 33 weeks across the following study periods: ● Study Period 1: Screening and introduction, approximately 2 weeks ● Study Period 2: Treatment, 26 weeks ● Study Period 3: Safety follow-up, 5 weeks

[0121] Procedures are implemented during the screening process to determine eligibility for inclusion in the study. The inclusion criteria are set out in Table 21 below. Study participant types and disease characteristics A diagnosis of T1DM lasting at least 1 year is required. The diagnosis of T1DM is based on a history of fasting C-peptide ≤0.30 nmol / L at the time of screening or before randomization. MDI has been used continuously for at least 3 months without interruption prior to screening. Characteristics of research participants Women of childbearing age who abstain from sexual relations with men or agree to use one highly effective method of contraception or a combination of two effective methods of contraception. Women who are infertile. All participants must meet the following criteria: ● Must be at least 18 years old when signing the informed consent form. ● When screened, the HbA1c value, measured by a central laboratory, is 5.6% to 9.5% (inclusive). ● Prior to screening, patients had been treated for 3 months with a stable regimen of insulin glargine (U-100 or U-300) once or twice daily, insulin detemir, or insulin degludec (U-100 or U-200). ● For at least 30 days prior to screening, the patient was currently treated in the MDI with the same SC rapid-acting analog insulin (lispro insulin U-100 or U-200, aspart insulin, FiAsp or glutalis insulin). ● With a body mass index (BMI) ≤35 kg / m² 2 No significant weight gain or loss (≥5%) in the past 3 months. ● In the researchers' view, having good motivation, ability and willingness: learning how to self-inject treatment; keeping a research diary as needed for this program; wearing the study-provided CGM (Dexcom G6) uninterrupted throughout the study duration and using the device to make treatment decisions; and having a normal wake-up / sleep pattern so that midnight to 6:00 AM will reliably reflect common sleep periods. ● In the researchers' view, proficiency lies in: counting carbohydrates; adjusting diet and dosage based on glucose readings to stabilize the insulin / carbohydrate ratio and correction factors; and adjusting insulin and dietary therapy during special circumstances (such as exercise, stress, intermittent illness). ● Willing and able to follow the consultation schedule throughout the full duration of the trial. ● Able to provide a signed informed consent form. Table 21.

[0122] The exclusion criteria are described in Table 22 below. Medical condition Within 6 months prior to screening, candidates must have had more than one emergency room visit or hospitalization due to poor glucose control (hyperglycemia or diabetic ketoacidosis [DKA]). Within 6 months prior to screening, candidates must have experienced any episode of severe hypoglycemia (defined as requiring assistance due to neurogenic hypoglycemia) and / or hypoglycemic unconsciousness. Significant lipotrophy, lipoatrophy, scarring, or h / o abscesses were observed in the injection area. Those with visual or hearing loss may have impaired ability to recognize CGM screens, warnings, and alarms. Cardiovascular (CV): Having any of the following CV conditions: acute myocardial infarction, New York Heart Association Class III or IV heart failure, or cerebrovascular accident (stroke). Gastrointestinal: Patients with gastroparesis or who have undergone gastric bypass (obesity treatment) or restrictive obesity treatment surgery (e.g., Lap-Band®) prior to screening. Liver: Significant clinical signs or symptoms of acute or chronic hepatitis, or any liver disease other than non-alcoholic fatty liver disease (NAFLD) (i.e., patients with NAFLD are eligible for inclusion), and / or elevated liver enzyme levels, as measured by a central laboratory at the time of screening and as indicated below: ● Total bilirubin (TBL) level > twice the upper limit of normal (ULN), or ● Alanine transaminase (ALT) / serum glutamate-pyruvate transaminase (SGPT) > 2.5 times ULN, or ● Aspartate transaminase (AST) / serum glutamate oxaloacetate transaminase (SGOT) > 2.5 times ULN kidney: ● Has a history of kidney transplantation ● Currently undergoing kidney dialysis ● At the time of screening, candidates must have serum creatinine > 2.0 mg / dL (177 µmol / L), or ● Estimated glomerular filtration rate (eGFR) <30 mL / min / 1.73 m 2 Those who have experienced significant weight loss or gain (>5%) within 3 months prior to screening. Having an active or untreated malignant tumor, or, in the investigator's view, a clinically significant malignant tumor (other than basal cell or squamous cell skin cancer) that has been in remission for less than 5 years or is at an increased risk of developing or recurring cancer. It is known that there is an allergic reaction or allergy to any of the investigational drug or its excipients. Patients with any other serious illness or condition (e.g., known drug or alcohol abuse / routine consumption or mental illness) that, in the investigator's view, would pose a significant risk to the patient, prevent the patient from adhering to and completing the protocol, or interfere with the interpretation of safety, efficacy, or PD data. Alcohol abuse / routine consumption was defined as the average daily intake of >3 units for men or >2 units for women in the 6 months prior to the study. One unit is equivalent to 8 g of alcohol: half a pint (about 240 mL) of beer, one glass (125 mL) of wine, or one (25 mL) of spirits. Those who have had blood transfusions or severe blood loss within 3 months prior to screening, or who have any blood disorders that may interfere with HbA1c measurement (e.g., heme disease, hemolytic anemia, sickle cell disease). It has fasting triglyceride levels >400 mg / dL or non-fasting triglyceride levels >600 mg / dL. Women of fertility i) Pregnant or intending to conceive ii) During lactation / breastfeeding (including using a breast pump) iii) Unwilling to maintain abstinence or use birth control as described in Appendix 4 iv) A positive pregnancy test at screening (first consultation). Note: A urine pregnancy test is performed at the third consultation. Previous / companion therapy Currently taking medications that can significantly affect blood sugar control (e.g., niacin [permitted if <1.0 g / day], bile acid sequestrants). Currently receiving chronic (lasting longer than 14 consecutive days) systemic glucocorticoid therapy (including intravenous, intramuscular, SC, and oral) or intra-articular (excluding local, intraocular, intranasal, and inhaled formulations) or having received such therapy within 4 weeks prior to screening, except for replacement therapy for adrenal insufficiency. Patients must be currently taking or have been taking prescription or over-the-counter medications to promote weight loss within the three months prior to screening. Participating patients must agree not to initiate any diet and / or exercise program intended for weight loss during the study period, except for lifestyle and dietary measures used to treat diabetes. At the time of screening, the patient was taking a total daily insulin dose >100 IU. Within 90 days prior to screening, the patient was receiving any oral or injectable medication intended to treat diabetes, except for rapid-acting and basal analog insulin in MDIs. The screening was conducted on blood pressure-lowering medications that were being used at doses that were not yet stable in the previous month. Previous / parallel clinical trial experience Currently involved in any other clinical research involving IP or any other type of medical research that is determined to be scientifically or medically incompatible with this study. Participants must have been enrolled within the last 30 days of a clinical trial involving the IP. If the previous IP had a long half-life, then 3 months or 5 half-lives (whichever is longer) should have elapsed. Any other research that has been completed or withdrawn from this study or investigation of BIF. Table 22.

[0123] Following the signing of the informed consent form (ICF), study participants will be trained on disease surveillance and management procedures, study diaries, and study procedures at the first consultation. Electronic participant diaries and paper participant signature slips will be provided at the second consultation and as specified in the activity schedule for future consultations. Baseline self-monitored blood glucose (SMBG) characteristic curves will be collected via continuous glucose monitoring (CGM) starting at the second consultation. Participants will continue their basal and short-acting insulin regimens during the introductory period until randomization.

[0124] For all study participants who meet the study entry criteria, the Dexcom G6® CGM device will be embedded and activated at the second visit. Participants will record two 6-point glucose characteristic curves (using the CGM device) on non-consecutive days between the second and third visits. These characteristic curves should include readings taken 2 hours before and after each major meal (breakfast, lunch, and dinner) during the day. The standard Dexcom G6 system will be used in a non-blinded mode according to the manufacturer's CGM instructions. Study participants will begin wearing the device at the second visit. Additionally, all study participants will be allowed to perform additional BG tests using their personal blood glucose (BG) meter, or SMBG measurements during outpatient visits. Treatment decisions will be based on CGM readings. The blood glucose meter does not need to be used to calibrate the CGM device. CGM calibration must be performed using the code provided for each sensor. Participants must use the study-specific CGM receiver and are not permitted to connect the CGM system's transmitter to their personal smartphone to ensure the availability of data downloaded from the receiver at the corresponding visit.

[0125] During the second consultation, research participants who meet the eligibility criteria will be trained on the use of the CGM device, CGM sensor replacement, explanations and alerts based on CGM-based BG values, and CGM requirements. For the first CGM session, research participants who meet all research entry criteria will have their CGM sensors embedded as part of the second consultation activity.

[0126] Participants who continue to meet the study criteria will be randomized to one of the two treatment groups. Following randomization at the third consultation, participants will participate in a 26-week treatment period. For patients randomized to the BIF group, the following IP administration guidelines apply: ● During weeks 0 to 8, field personnel will administer the IP at the patient's location. Participants will receive education and training on how to administer the IP themselves. ● During weeks 9 to 12, participants will administer the IP at the patient's location under the supervision of trained field personnel to ensure self-administration. ● During weeks 13 to 25, in addition to titration consultations, participants may administer the IP at home unless local regulations require it to be administered at the patient's location, or, as appropriate, weekly by field personnel. ● Self-injection information may be reviewed as needed throughout the study. Additional consultations may be conducted at any time during the study period if the investigator deems it necessary to ensure proper drug administration, titration, and study drug administration.

[0127] Following weekly subcutaneous (SC) administration of BIF, the estimated time to reach steady-state glucose levels, based on the long half-life of BIF, ranges from 4 to 16 weeks. Since achieving the therapeutic target for BIF within less than 12 weeks may be necessary in individuals with a low risk of hyperglycemia, a loading dose strategy is appropriate, provided an initial dose sufficient to achieve effective exposure is given, followed by individually optimized weekly dose adjustments to achieve the target response. Therefore, specifically, a dosing algorithm is developed for BIF to rapidly achieve the glycemic target. The dosing algorithm described below will be used by investigators to initiate and adjust BIF to achieve a target FG ≤100 mg / dL (<5.6 mmol / L).

[0128] Therefore, a single loading dose is recommended, followed by weekly dose adjustments. The loading dose is determined based on the patient's previously used basal insulin dose, baseline fasting glucose, and available BIF data to inform the 3x loading dose strategy. Dose adjustments are based on previous fasting glucose and hypoglycemic events. Changes to the dose recommended by these dose adjustment algorithms are also handled at the investigator's discretion and will take into account hypoglycemia and other safety concerns of study participants. In the event of deviations from the algorithm-recommended dose, the medical basis for such deviations must be documented by the principal investigator.

[0129] The initial BIF dose is determined based on the previous basal insulin dose and baseline fasting glucose. Participants may use insulin glargine, insulin detemir, or insulin degludec to enter the study. These insulins may be converted on a unit-to-unit basis, subject to product labeling, and are considered equivalent in this protocol. Due to the long half-life of BIF, changes in fasting glucose response can take several weeks to reach a steady-state response; therefore, to minimize the time required to achieve the desired target glycemic response, the loading dose strategy will be used only for the first dose.

[0130] The starting dose, i.e., the loading dose, will be determined according to the following instructions for converting the current basal insulin dose (in units, U) to the BIF dose (in mg). 1. Obtain the previous daily basal insulin dose of glargine, detemir, or degludec insulin assessed during the introduction period. Calculate the "basal insulin equivalent dose" (in mg) of BIF by dividing the total daily basal insulin dose (U) by a conversion factor of 7 U / mg. 2. Adjust the BIF dose 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. Median baseline FG (mg / dL) Median baseline FG a (mmol / L) BIF (basal insulin equivalent dose adjustment) (mg) b Previous basal insulin dose ≤ 15 U Previous basal insulin dose 16 - 30 U Previous basal insulin dose > 30 U < 80 < 4.4 - 0.25 - 1 - 1.5 80 - 100 4.4 - 5.5 No change No change No change 101 - 140 5.6 - 7.7 + 0.25 + 0.5 + 0.75 141 - 180 7.8 - 10.0 + 0.5 +1 +1.5 181 - 220 10.1 - 12.2 + 0.75 +1.5 +2 >220 >12.2 +1 +2 +3 Table 23. BIF Dose Adjustment (mg). a. Conversion from mg / dL to mmol / L is rounded to prevent overlap between threshold ranges and to resolve the issue of the glucose meter displaying one significant decimal place when reporting mmol / L readings. b. Add this dose adjustment to the basal insulin equivalent dose to obtain the total weekly BIF dose (in mg). 3. Multiply the expected starting weekly dose obtained in step 2 above by 3 to obtain the loading dose.

[0131] For example, if a participant uses 35 U of insulin degludec daily, that dose is converted to a 5 mg BIF according to step 1. If the participant has an FG value of 155 mg / dL, the dose adjustment for this participant according to step 2 and Table 15 will be +1.5 mg. Therefore, according to step 3, the expected starting weekly BIF for the participant will be 6.5 mg, and the participant's loading dose will be 19.5 mg.

[0132] At each subsequent field visit, the investigator will assess the study participants’ continued glycemic control from the previous week and, if necessary, inform the study participants of any required dose adjustments. Dose adjustments will be based on the median FG (determined from SMBG obtained from the CGM system) for at least 3 days (up to 7 days) up to one week prior to the visit.

[0133] To rapidly achieve the target FG of ≤100 mg / dL (<5.6 mmol / L) while minimizing the risk of hyperglycemia, a dose adjustment strategy was designed that provides a relatively large adjustment to the first weekly dose after the loading dose (i.e., the fourth weekly visit in this study) compared to the second weekly dose after the loading dose (i.e., the fifth weekly visit in this study), and a relatively large adjustment to the second weekly dose after the loading dose (i.e., the fifth weekly visit in this study) compared to all subsequent weekly doses. This dose adjustment strategy will be implemented according to the following instructions: 1. Obtain the initial total weekly dose as described above. (This is 1 / 3 of the loading dose). 2. Use Table 24 below to determine the required dose adjustment after carefully reviewing the participants' fasting glucose (3–7 days prior to the visit) and hypoglycemia recorded since the last BIF dose. Median fasting glucose (mg / dL) a Median fasting glucose (mmol / L) a,b Week 1 (4th consultation) (Second dose) c Week 2 (5th consultation) (Third dose) d Week 3 (6th consultation) and all subsequent weeks e <80 mg / dL or with any nocturnal hypoglycemia or multiple (≥3) episodes of hypoglycemia. f <4.4 mmol / L or having any nocturnal hypoglycemia or multiple (≥3) episodes of hypoglycemia. f D c - 1.5 mg D d - 1 mg D e - 0.5 mg 80 - 100 mg / dL 4.4 - 5.5 D c - 1 mg D d - 0.5 mg D e 101 - 140 mg / dL 5.6 - 7.7 D c D d D e + 0.25mg 141 - 180 mg / dL 7.8 - 10.0 D c + 1 mg D d + 0.5 mg D e + 0.25mg >180 mg / dL >10.0 D c + 2 mg D d + 1 mg D e + 0.5 mg Table 24. Weekly Dosage Adjustments. a. Based on the median FG from at least three fasting glucose readings from the previous week. b. Conversions from mg / dL to mmol / L are rounded to prevent overlap between threshold ranges and to resolve one significant decimal digit when reporting mmol / L readings. c. D for Week 1 (4th visit) is 1 / 3 of the dose administered at (Week 0, 3rd visit). d. D for Week 2 (5th visit) is the dose administered at Week 1 (4th visit). e. D for subsequent visits is the dose administered one week prior to the current visit. f. If any SMBG reading is recorded as <70 mg / dL (<3.9 mmol / L) at any time during the previous week, the BIF dose may not be increased. If multiple episodes of hypoglycemia with SMBG <70 mg / dL (<3.9 mmol / L) are recorded, follow the dose reduction guidelines based on the applicable visit number. If severe hypoglycemia (requiring assistance) occurs, or if any SMBG was recorded in the previous week at ≤54 mg / dL (≤3.0 mmol / L), the dose should be reduced by 1 mg.

[0134] For example, for a participant who has taken the 19.5 mg loading dose as described above, the initial weekly dose is 6.5 mg. If the participant has not reported hypoglycemia since self-administering the 19.5 mg loading dose and has a median FG of 150 mg / dL (using the Week 1 (4th Visit) column), the weekly dose should be increased by 1 mg. Therefore, the participant's first weekly dose after the loading dose (i.e., the 4th Visit) will be 7.5 mg. For the next weekly dose (i.e., the 5th Visit), if the participant has not reported hypoglycemia since the 7.5 mg dose and has a median FG of 153 mg / dL (using the Week 2 (5th Visit) column), the weekly dose should be increased by 0.5 mg. Therefore, the next weekly dose will be 8 mg. For the next weekly dose, using the "Week 3 (6th visit) and all subsequent weeks" column, if the participant had a median fasting glucose (FG) of 133 mg / dL but reported one episode of nocturnal hypoglycemia since the last dose, the dose should be reduced by 0.5 mg. Therefore, the next weekly dose will be 7.5 mg. Subsequent visits should be managed using the same method as for the 6th visit (Week 3), always confirming the BIF dose administered at the previous visit, the median fasting glucose in the week prior to the visit, and any hypoglycemic status since the last dose of the study drug.

[0135] From the third consultation (randomized group) until week 25, the dosing algorithm must be followed and will be monitored regularly by the research team. The safety of study participants will be closely monitored during the early stages of dose titration to determine if adjustments to the conversion and dose adjustment algorithms are necessary. If the safety of study participants is a concern, the investigator may adjust the doses recommended by the dose adjustment algorithms in Table 8.

[0136] Patients randomly assigned to the degludec insulin group will receive training under on-site supervision on Day 1, and will self-administer degludec insulin daily thereafter. The starting dose of degludec insulin will be the same as the basal insulin used by the study participant prior to the study. For subsequent dose adjustments, a dosing algorithm (adapted from Riddle et al., 2003) will be used by the investigator to initiate and adjust degludec insulin to target FG ≤100 mg / dL (<5.6 mmol / L) to achieve the patient's glycemic target.

[0137] When patient safety is a concern or when dose adjustment has not yet achieved the desired therapeutic effect, researchers may increase or decrease the dose of insulin degludec recommended by the dose adjustment algorithm, and must record the clinical rationale for the deviation and notify Lilly Medical via email.

[0138] During in-person or telephone consultations, investigators will assess the patient's continued glycemic control from the previous week and inform the patient of any necessary dose adjustments if necessary. Dosage will be based on the patient's glycemic levels. Adherence to the dosing algorithm provided for this study is mandatory from the 3rd consultation (randomization) to the 20th consultation (week 26) (inclusive). Dosage increases may be made at weekly intervals, but not earlier than 5 days after the previous increase. In some cases, patient consultations may occur earlier than 5 days due to an allowable consultation window; however, no dose increase should be considered if at least 5 days have passed since the previous increase. In contrast, the insulin degludec dose may be reduced at any time based on investigator judgment. Any deviations from this guidance must be supported by clinical evidence and reported to Eli Lilly and Company.

[0139] Insulin dosing algorithms have been reviewed by Strange (2007). The degludec insulin dosing escalation algorithm was adapted by Riddle et al. (2003) and is determined based on a definition known as the "algorithm FG". The algorithm FG is the median of the FGs (determined from the 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 is determined by the median of the FGs for the last 3 days. If the patient only measures their FG on 2 of the last 3 days, the smaller of the two FG values ​​is used as the algorithm FG. If only one FG measurement is available for the last 3 days, the researcher should use his / her judgment when determining whether a dose adjustment should be made based on that single FG value.

[0140] Because it is necessary to achieve glycemic targets for as many patients as possible, contingency measures are provided to accommodate planned consultations and to increase the dose of insulin degludec in a timely manner. Therefore, if the last dose increment is within the first 5 days, the dose increment is determined by the algorithmic FG, which is the smaller of the two FG values ​​on day 4 and day 5. If the dose increment is within the first 6 days, the algorithmic FG is the smaller of the two FG values ​​on day 5 and day 6. In both cases, if only one of the two FG values ​​is available, the researcher should use his / her judgment when determining whether a dose adjustment should be made based on that single FG value.

[0141] The dose escalation algorithm is defined as follows: ● If the algorithm FG is 101 to 120 mg / dL (5.6 to 6.7 mmol / L), the dose is increased by 2 U; ● If the algorithm FG is 121 to 140 mg / dL (6.8 to 7.8 mmol / L), the dose is increased by 4 U; ● If the algorithm FG is 141 to 180 mg / dL (7.9 to 10.0 mmol / L), the dose is increased by 6 U; and ● If the algorithm FG > 180 mg / dL (10.0 mmol / L), the dose is increased by 8 U.

[0142] Target treatment FG ≤100 mg / dL (<5.6 mmol / L). If any SMBG is recorded as <70 mg / dL (<3.9 mmol / L) at any time in the previous week, the insulin degludec dose will not be increased. If multiple episodes of hypoglycemia with SMBG <70 mg / dL (<3.9 mmol / L) are recorded, and severe hypoglycemia occurs (requiring support), or if any SMBG is recorded as ≤54 mg / dL (≤3.0 mmol / L) in the previous week, a dose reduction of 2 to 4 U may be permitted for each adjustment.

[0143] Participants in all groups will continue to use concomitant short-acting insulin throughout the treatment period. Interruptions or changes to the regimen are not permitted except in cases where dose adjustment is required for medical reasons or as permitted by the study protocol.

[0144] Participants will be instructed to record their fasting glucose (FG) daily in their electronic diary using the values ​​displayed on their CGM device after waking up. In addition, two 6-point SMBG characteristic curves (two hours before and after breakfast, lunch, and dinner) should be performed on non-consecutive days one week prior to the required consultation.

[0145] Based on the investigators' clinical judgment, participants who develop severe, persistent hyperglycemia will receive intermittent intensive insulin therapy. Participants requiring intermittent intensive insulin therapy will continue taking IP during the trial until they complete all study consultations.

[0146] All randomized participants should undergo a full efficacy and safety assessment approximately 1 week after the last BIF and 1 day after the last dose of insulin degludec, and a safety follow-up visit approximately 6 weeks after the last BIF and 5 weeks after the last dose of insulin degludec. During the safety follow-up study period, participants will continue CGM and will be switched back to their previously used basal insulin therapy as appropriate.

[0147] Participants who discontinued IP before completing their treatment period will be encouraged to continue their participation in the study and complete any scheduled study procedures prior to their 20th visit. The remaining participants in the study will receive an appropriate glucose-lowering regimen.

[0148] Participants who interrupt their IP for any reason and are unwilling to respond to security requests will be required to undergo an early termination (ET) consultation as their final research consultation.

[0149] For BIF versus insulin degludec, the results of model simulations based on the tested titration protocol support the non-inferiority of HbA1c variation from baseline.

[0150] Patients who have never received insulin therapy. A three-phase, multicenter, randomized, open-label, parallel, comparative-controlled study was designed to evaluate the efficacy and safety of BIF versus insulin degludec in patients with type 2 diabetes mellitus (T2DM) 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 was largely the same as the phase 2 study in T1D patients described above, but with a different target patient population and some other corresponding differences.

[0151] The cohort for this study included patients who: had 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; were 18 to 75 years old; had a baseline HbA1c value of 7.0% to 9.5% (inclusive) at screening; 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 3 months prior to screening and were willing to continue stable treatment throughout the study; and had a body mass index (BMI) between 20 and 45 kg / m2 (inclusive) without significant weight gain or loss (≥5%) in the past 3 months.

[0152] This cohort excludes participants who: have had more than one episode of ketoacidosis or hyperosmolar state / coma requiring hospitalization within the 6 months prior to screening; have had any episode of severe hypoglycemia and / or hypoglycemic unconsciousness within the 6 months prior to screening; have any of the following cardiovascular conditions: acute myocardial infarction, New York Heart Association Class III or IV heart failure, or cerebrovascular accident (stroke); have undergone gastric bypass surgery (for obesity treatment) or restrictive obesity treatment surgery (e.g., Lap-Band®) prior to screening; have obvious clinical signs or symptoms of acute or chronic hepatitis, or any other liver disease other than non-alcoholic fatty liver disease (NAFLD) (i.e., patients with NAFLD are eligible for participation), and / or have elevated liver enzyme measurements, such as: total bilirubin > 1.5 times the upper limit of normal (ULN) in the absence of Gilbert's syndrome, alanine transaminase (ALT). Serum glutamate-pyruvate transaminase (SGPT) > 2.0 times the ULN, or aspartate transaminase (AST) / serum glutamate-oxaloacetate transaminase (SGOT) > 2.0 times the ULN; with estimated glomerular filtration rate (eGFR) < 30 mL / min / 1.73 m2; with fasting triglycerides > 400 mg / dL or non-fasting triglycerides > 600 mg / dL. mg / dL; significant weight loss or gain (>5%) within 3 months prior to screening (first visit); active or untreated malignancy, or, in the investigator's view, a clinically significant malignancy (other than basal cell or squamous cell skin carcinoma) that has been in remission for less than 5 years or is at increased risk of developing or recurring cancer; known allergic reaction or hypersensitivity to any of the investigational drug or its excipients; any other serious illness or condition (e.g., known drug or alcohol abuse / routine wasting or mental illness) that, in the investigator's view, would pose a significant risk to the patient, prevent the patient from adhering to and completing the protocol, or interfere with the interpretation of safety, efficacy, or PD data; transfusion or severe blood loss within 3 months prior to screening, or any blood condition that may interfere with HbA1c measurement (e.g., heme disease, hemolytic anemia, sickle cell disease); currently taking medications that can significantly affect glycemic control (e.g., niacin [if <1.0 mg / dL]). [g / day, then allowed], bile acid sequestrants or pentoxyphylline; currently receiving chronic (>14 days) systemic glucocorticoid therapy (excluding topical, intraocular, intranasal and inhaled formulations) or having received such therapy for >14 days within one month prior to screening; currently taking or having taken prescription or over-the-counter (OTC) medications to promote weight loss within 3 months prior to screening.Participating patients must agree not to engage in the following behaviors: initiating a diet and / or exercise program aimed at weight loss during the study period, except for lifestyle and dietary measures used for diabetes treatment; being treated with sulfonylureas (SU), glitazone, alpha-glucosidase inhibitors, GLP-1 receptor agonists, or insulin within 3 months prior to screening, except for short-term insulin use for acute conditions (≤14 days within the last 6 months prior to screening); currently using or having used antihypertensive medications at doses that have not yet stabilized within 1 month prior to screening; and women of childbearing age who are pregnant or intend to conceive, are lactating / breastfeeding (including using a breast pump), or do not wish to maintain abstinence or use contraception.

[0153] Participants taking metformin (alone or in combination with a stable dose of a DPPIV inhibitor and / or an SGLT2 inhibitor) will continue to take the same dose to allow for reliable assessment of HbA1c at randomization. If a participant develops a contraindication to the use of metformin, a DPPIV inhibitor and / or an SGLT2 inhibitor (if used at screening) or to other prohibited medications between screening and randomization, they will be considered ineligible and will discontinue the trial prior to randomization.

[0154] For all participants who meet the study entry criteria, in addition to screening clinical laboratory assessment reports, a LibrePro sensor for flash glucose monitoring (FGM) will be implanted and activated at the first consultation for baseline FGM assessment. If a patient is ultimately deemed ineligible, the sensor may be removed and discarded, or the patient may continue to wear it for up to 14 days and return to the clinic for reading and diagnosis. All confirmed eligible participants should continue to wear the sensor for up to 14 days and wear it to the third consultation for removal, or if the third consultation occurs more than 14 days after implantation, the sensor should be brought to this consultation.

[0155] Participants will have three FGM sessions using the LibrePro system (Abbott) during the 14-day period prior to randomization, at the 15th visit, and at the 20th visit. Patients will remain unaware of these assessments until the study is completed.

[0156] (Week 0, 3rd visit) The BIF loading dose was based on baseline median fasting glucose and body weight at the 3rd visit. As described above in the study of T1D patients, a loading dose strategy was used to minimize the time required to achieve the desired target glycemic response and to reach steady-state concentrations within the first week. The loading dose consisted of a single dose that was approximately 3 times larger than the expected initial weekly maintenance dose based on the patient's median fasting glucose and body weight at the start of the study, and was determined using Table 25 below. Median baseline FG (mg / dL) Median baseline FG a (mmol / L) Weight (kg) at the third consultation ≤ 80 80.1 - 100 100.1 - 120 ≥ 120.1 ≤ 140 ≤ 7.7 3 mg 4.5 mg 6 mg 7.5 mg 141 - 180 7.8 - 10.0 6 mg 7.5 mg 10.5 mg 12 mg 181 - 220 10.1 - 12.2 9 mg 10.5 mg 12 mg 13.5 mg > 220 > 12.2 12 mg 13.5 mg 15 mg 16.5 mg Table 25. The loading dose of BIF was determined at the third consultation using the baseline median fasting glucose and body weight. Conversions from a mg / dL to mmol / L were rounded to prevent overlap between threshold ranges and to resolve the issue of the glucose meter displaying one significant decimal digit when reporting mmol / L readings.

[0157] For example, if a participant weighs 83 kg and has a median fasting glucose (FG) of 185 mg / dl, the initial dose of BIF would be 10.5 mg. This 10.5 mg dose represents a three-fold increase in the weekly maintenance dose expected based on the patient's median fasting glucose and weight at the start of the study; that is, based on the participant's weight and FG, the expected weekly maintenance dose would be 3.5 mg. However, in order to rapidly reach the target FG value, the weekly maintenance dose to be administered one week after the loading dose, and the actual weekly maintenance dose, will be adjusted based on the participant's FG value and any incidental hypoglycemic events during subsequent weeks, as described in more detail below.

[0158] Target treatment FG ≤100 mg / dL (<5.6 mmol / L). According to Table 26 below, subsequent weekly maintenance dose adjustments for BIF will be determined based on the median FG obtained for at least 3 days (up to 7 days) up to the week preceding the visit. All doses should be rounded to the nearest 0.25 mg. Median FG (mg / dL) a Median FG (mmol / L) a,e Week 1 (4th consultation) (Second dose) Week 2 (5th consultation) (Third dose) Subsequent Weeks c Dosage ≤5 mg Dosage > 5 mg <80 mg / dL or any nocturnal hypoglycemia or multiple episodes of hypoglycemia. d <4.4 mmol / L or with any nocturnal hypoglycemia or multiple episodes of hypoglycemia. d D b - 1.5 mg D b - 1.5 mg D c - 1.5 mg D c - 2 mg 80 - 100 mg / dL 4.4 - 5.5 D b - 1 mg D b - 0.5 mg No change No change 101 - 140 mg / dL 5.6 - 7.7 No change No change D c + 0.25 mg D c + 0.5 mg 141 - 180 mg / dL 7.8 - 10.0 Db + 3 mg D b + 1.5 mg D c + 0.5 mg D c + 1 mg >180 mg / dL > 10.0 D b + 5 mg D b + 3 mg D c + 0.75 mg D c + 1.5 mg Table 26. Weekly dose adjustments for BIF based on the previous week's dose (D), median fasting glucose, and episodes of hypoglycemia. a. Based on the median fasting glucose from at least three fasting glucose readings from the previous week. b. D for week 1 (4th visit) is 1 / 3 of the initial dose in Table 1. d. For week 2 (5th visit), the dose is the same as week 1 (4th visit). c. BIF dose adjustments starting in week 3 (6th visit) will be based on whether the previous (week 2) dose (D) is ≤5 mg or >5 mg and will be adjusted weekly until week 12 (15th visit), followed by dose adjustments at weeks 16 (17th visit), 20 (18th visit), and 24 (19th visit). D. If any SMBG reading is recorded as <70 mg / dL (<3.9 mmol / L) at any time during the previous week, the BIF dose may not be increased. If multiple episodes of hypoglycemia with SMBG <70 mg / dL (<3.9 mmol / L) are recorded, follow the dose reduction guidelines based on the applicable medical history number. When severe hypoglycemia (requiring support) occurs, or if any SMBG was recorded as ≤54 mg / dL (≤3.0 mmol / L) in the previous week, the dose should be reduced by 1 mg. Conversions from emg / dL to mmol / L are rounded to prevent overlap between threshold ranges and to resolve the issue of the glucometer displaying one significant decimal digit when reporting mmol / L readings.

[0159] For example, for the participant described above who received a loading dose of 10.5 mg, the expected starting weekly dose would be 3.5 mg. During subsequent weeks, the participant did not report hypoglycemia and the median FG was 175 mg / dL. Using the Week 1 (4th visit) column of Table 18, the participant's first weekly maintenance dose after the loading dose would be 6.5 mg. During the week following the first weekly maintenance dose, the participant did not report hypoglycemia and the median FG was 163. Using the Week 2 (5th visit) column, the weekly dose should be increased by 1.5 mg, so the second weekly maintenance dose would be 8.0 mg. During the week following the second weekly maintenance dose, the participant's median FG was 133 mg / dL. Using the "Subsequent Weeks" column, the weekly maintenance dose should be increased by 0.5 mg, so the third week 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.

[0160] An alternative therapeutic intervention should be considered in patients who develop severe, persistent hyperglycemia based on the following criteria (FDA 2008) after randomization: a) mean FG >270 mg / dL (>15.0 mmol / L) over any 2-week period or longer during the first 6 weeks after randomization; or b) mean FG >240 mg / dL (>13.3 mmol / L) over any 2-week period or longer from week 6 to week 12 after randomization; or c) mean FG >200 mg / dL (>11.1 mmol / L) over any 2-week period or longer after week 12.

[0161] Researchers should first confirm that the patient does not have an acute condition that would cause severe hyperglycemia and that the patient fully meets the prescribed treatment protocol after the first 12 weeks of the study. Researchers will decide, after considering relevant clinical guidelines, to consult with the patient regarding appropriate glucose-lowering interventions (emergency interventions). Permitted medications are listed in the table in section 6.5. Patients receiving a new intervention for hyperglycemia management should also continue to receive IP for the remaining duration of the trial.

[0162] Degludec insulin will be administered at an initial dose of 10 IU / day, as described on the approved product label. Subsequent dose adjustments will be determined and administered as described above in the Phase 2 study in patients with T1D.

[0163] For BIF versus insulin degludec, the results of model simulations based on the tested titration protocol support the non-inferiority of HbA1c variation from baseline.

[0164] Phase 3 study. Designed as a multicenter, randomized, parallel, comparative-controlled study with target therapy and three study periods, including screening / introduction, treatment, and safety follow-up. Planned treatment periods are 26, 52, and 78 weeks. The patient population includes: patients with T2DM previously treated with daily basal insulin (not MDI); patients with T2DM who have never received insulin therapy; patients with T2DM currently treated with MDI; and patients with T1DM.

[0165] This phase 3, multicenter, randomized, publicly labeled, comparative-controlled study evaluated the efficacy and safety of basal insulin in patients with type 2 diabetes mellitus (T2DM) treated with daily basal insulin (rather than MDI) in participants on basal insulin therapy. The study consisted of a 3-week screening / introduction period, a 78-week treatment period, and a 5-week safety follow-up period. The primary outcome was the change in HbA1c from baseline at week 26.

[0166] Participants are eligible to be included in the study only if they meet the pre-established inclusion criteria, which include the following: 1. Being at least 18 years old (or older according to local regulations) at screening; 2. Having a diagnosis of T2D currently treated with basal insulin according to WHO guidelines; 4. Having an HbA1c value of 6.5%–10% (inclusive) at screening; 5. Having been treated with a stable regimen of one of the following insulin regimens (up to 3 of the following, according to the local product label) for at least 90 days prior to screening, with or without non-insulin diabetes therapies (dipeptidyl peptidase-4) IV inhibitors; SGLT2 inhibitors; metformin; α-glucosidase inhibitors; GLP-1 receptor agonists): once daily U100 or U200 degludec insulin; once daily U100 or U300 glargine insulin; once or twice daily U100 detemir insulin; or once or twice daily human insulin NPH; 6. Having a HbA1c value of 45% or less at screening. Body mass index (kg / m2).

[0167] Participants will be excluded from the study if they meet any of the following criteria: 1. Significant weight gain or loss (e.g., ≥5%) in the investigator's view within the past 3 months; 2. Diagnosis of T1D, underlying autoimmune diabetes, or a specific type of diabetes other than T2D (e.g., monogenic diabetes, exocrine pancreatic disease, drug-induced or chemically induced diabetes); 3. Currently receiving or having received any of the following insulin therapies (except pregnancy) at any time within the past 6 months prior to screening, except for short-term treatment of acute conditions and a maximum of 4 consecutive weeks: mealtime insulin, insulin mixture, inhaled insulin, U-500 insulin, or continuous subcutaneous insulin infusion therapy; 4. Having received any of the following non-permitted diabetes medications within 90 days prior to screening: glinides, sulfonylureas, pramlintide, or thiazolinide; 5. Having had more than one episode of ketoacidosis or hyperosmolar state / coma within the past 6 months prior to screening. 5. History of hospitalization; 6. Currently receiving chronic (>14 days) systemic glucocorticoid therapy (excluding replacement therapy for adrenal insufficiency; local, intraocular, intranasal, inhaled formulations, or intra-articular injection) or having received such therapy for >14 days within one month prior to screening; 7. Cardiovascular: Having New York Heart Association Class IV heart failure or any of the following CV conditions within 3 months prior to screening: acute myocardial infarction, cerebrovascular accident (stroke), or coronary artery bypass surgery; 8. Gastrointestinal: Having undergone gastric bypass (obesity treatment), restrictive obesity treatment surgery (e.g., Lap-Band®), or sleeve gastrectomy within one year prior to screening; 9. Liver: Having obvious clinical signs or symptoms of acute or chronic hepatitis, cirrhosis, or any other liver disease other than NAFLD (i.e., study participants with NAFLD are eligible for participation), and / or having elevated liver enzyme levels, as measured by the central laboratory at screening and indicated as follows: total bilirubin > 9. Kidneys: History of kidney transplantation, currently undergoing dialysis, or having an eGFR <20 mL / min / 1.73 m2 as determined by the CKD-EPI equation, if measured by a central laboratory at the time of screening; 10. Active or untreated malignancy, or clinically significant malignancy (other than basal cell or squamous cell skin carcinoma) that has been in remission for less than 5 years or is at increased risk of developing or relapsing into cancer; 11. Known allergic reaction or hypersensitivity to any of the investigational drug or its excipients;10. Having any other serious illness or condition (e.g., known drug or alcohol abuse or mental illness) that, in the investigator's view, would pose a significant risk to the study participant and prevent the participant from adhering to and completing the protocol; 11. A current or recent (within a 6-month timeframe) history of any substance use disorder of any severity as defined in the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5), except for nicotine or caffeine use disorders; 12. Hematology: A history of blood transfusion or severe blood loss within 90 days prior to the first consultation (week -3), or a known heme disorder, hemolytic anemia, sickle cell anemia, or any other heme abnormality known to the investigator that interferes with HbA1c measurement.

[0168] Participants meeting the inclusion criteria will be randomly assigned in a 2:1 (BIF: insulin degludec) ratio to the following treatment groups: BIF: once weekly, and insulin degludec: once daily. The total duration of study participation for each participant, including screening and post-treatment follow-up, will be approximately 86 weeks over the following study periods: Study Period I: Screening and introduction, 3 weeks; Study Period II: Treatment, 78 weeks; and Study Period III: Safety follow-up, 5 weeks.

[0169] BIF will be administered once weekly using a pre-filled insulin pen (in 5-unit increments) at approximately the same time and on the same day each week. If a dose is missed, it should be administered as soon as possible if there are at least 3 days (72 hours) until the next scheduled dose. If the interval is less than 3 days before the next scheduled dose, the missed dose should be skipped and the next dose should be administered on the scheduled day. In all cases, the participant may subsequently resume their regular once-weekly dosing schedule. If necessary, the date of the weekly dose may be changed, provided that the last dose was administered at least 3 days prior.

[0170] Degludec insulin (U100) will be administered daily at approximately the same time each day using a commercially available pre-filled insulin pen (in 1-unit increments).

[0171] For BIF, the maximum number of units injected per dose in the form of a pre-filled BIF pen is 400 units. A dose greater than 400 units per week (approximately 57 units / day of basal insulin [57 x 7 days = 399]) would require more than one injection. The maximum single loading dose in this study was 1600 units, and the maximum weekly dose was 1400 units.

[0172] For insulin degludec, the maximum number of units of insulin degludec (U100) injected per dose is 80 units. Participants requiring more than 80 units per day will require more than one injection to deliver the full daily dose of insulin degludec.

[0173] For both treatments, participants will be instructed to rotate injection sites from one injection to the next, even when injecting into the same area.

[0174] The participant's initial and weekly BIF dose or daily dose of insulin degludec will be determined prior to randomization based on the participant's usual daily basal insulin dose. The starting dose takes into account the labeling of pre-study basal insulin regarding how units are converted between insulin types / regimens. For participants whose pre-study basal insulin regimens were typically adjusted to a more familiar once-daily (U-100) basal insulin regimen (e.g., twice-daily NPH or once-daily U-300 glargine insulin), the total daily dose is reduced by 20% and then multiplied by 7 to obtain the weekly dose equivalent.

[0175] The dosing and titration algorithm to be used will be based on the participant's allocation to either BIF or degludec insulin treatment, as described in more detail below. Participants will be instructed not to take their pre-study basal insulin on the day of randomization, as they will be administered the assigned study insulin on-site.

[0176] In both treatment groups, insulin adjustments will be made to achieve and maintain a FBG target of 80–120 mg / dL throughout the study. Active titration will occur between the 3rd and 15th visits (weeks 0 to 12) in both treatment groups and will be designated as the titration period, aiming to achieve stable insulin doses up to the 15th visit (week 12). During the maintenance period, monthly adjustments will be made from the 15th visit to the 38th visit (weeks 12 to 78).

[0177] Participants in both treatment groups will self-monitor their fasting blood glucose (FBG) daily. At least three FBG readings must be obtained for each individual day of the week to allow investigators to review the data for dose adjustment using titration algorithms for once-weekly or once-daily insulin. The median FBG used to determine dose adjustment is obtained from the three most recent FBGs from the previous week, starting at the sixth consultation (week 3). The median is the middle value when the three values ​​are arranged in ascending or descending order. For example, if a participant's FBGs over the past three consecutive days were 180, 202, and 190, the median is 190. If a participant has only two FBG readings for the week, the smaller of the readings is used to determine dose adjustment. If only one FBG measurement is available, the determination of dose change using only a single FBG value is at the investigator's discretion.

[0178] When considering any dose adjustment (in either treatment group), the investigator will review whether the participant has experienced any recorded episodes of hypoglycemia. If the participant has experienced any recorded BG ≤70 mg / dL (≤3.9 mmol / L) in the previous week, the dose should not be increased. In addition, if the criteria for dose reduction due to hypoglycemia are met, the basal dose in the previous week will be reduced, as described in more detail below.

[0179] In this section, dosing instructions for BIF are provided, which are used to start the dose at the 3rd consultation (week 0), administer the daily dose at the 4th consultation (week 1), and make subsequent dosing / dosage adjustments throughout the treatment period.

[0180] At the randomization consultation (week 0), the starting dose was determined based on FBG in the week prior to randomization. For participants with FBG > 120 mg / dL, the instructions in Table 27 should be followed, and for participants with FBG ≤ 120 mg / dL, the instructions in Table 20 should be followed. Note: If participants are taking NPH twice daily or U300 glargine insulin, the pre-study basal insulin dose should be reduced by 20% when the usual pre-study basal insulin dose is determined, and then the starting weekly dose should be calculated. step action Participant A (FBG > 120 mg / dL) 1. Determine common previous daily basal doses during the introduction period. 30 units / day 2. Calculate the starting weekly dose (multiply the common daily dose by 7 and round to the nearest 10). 210 units / week 3. Multiply the starting weekly dose by 3 to determine the loading dose. 630 unit loading dose Table 27. BIF Loading Dose Calculation - Participants with FBG > 120 mg / dL.

[0181] The loading dose should not exceed a dose of 1600 units. If the calculated loading dose is >1600 units, the maximum loading dose of 1600 units shall be given as a single dose at the third consultation (week 0). step action Instance participant B (FBG ≤120 mg / dL) 1. Since the introduction period, common previous daily basal doses have been reviewed. 30 units / day 2. Calculate the starting weekly dose (Multiply the usual daily dose by 7 and round to the nearest 10) 210 units / week Table 28. Calculation of Starting Weekly BIF - Participants with FBG ≤ 120 mg / dL. The maximum weekly dose should not exceed 1400 units. If the calculated weekly dose is greater than 1400 units, then only 1400 units are prescribed.

[0182] Fourth visit (Week 1): Start weekly dose. If the participant experienced hypoglycemia in the previous week and met any of the dose reduction criteria listed in Table 29, the starting weekly dose was reduced by 40 units to obtain the administered dose at the fourth visit (Week 1). Guidelines for reducing hypoglycemic doses based on BG values Unit dose reduction ≥3 episodes of ≤ 70 mg / dL (≤ 3.9 mmol / L) 40 units ≥1 nocturnal attack with ≤70 mg / dL (3.9 mmol / L) ≥1 seizure with <54 mg / dL (3.0 mmol / L) Any confirmed severe hypoglycemia Table 29. Reduced dose of BIF for hypoglycemia.

[0183] If the hypoglycemic dose reduction guidelines are not met, administer the starting weekly dose.

[0184] The following steps illustrate an example of calculating the weekly dose starting from the 4th consultation (week 1). step action Case patient B 1. The initial weekly dose was calculated and reviewed from the third consultation (week 0). 210 units / day 2. Determine whether any of the hypoglycemic dose reduction guidelines were met in the previous week (Table 21): If satisfied, reduce the starting weekly dose by 40 units. If the requirements are not met, administer the starting weekly dose. a. If the hypoglycemic dose reduction criteria are met, then ➢ Week 1 dose = 210 - 40 = 170 units / week b. If the hypoglycemia dose reduction guidelines are not met, then the dose for week 1 = 210 units / week. Table 30. Example calculation of starting weekly dose.

[0185] Fifth consultation (Week 2): Titrate to Week 77. 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 described in Table 29, reduce the previous weekly dose by 40 units.

[0186] If BG ≤70 mg / dL is not reported, the median FBG of the previous week and / or the pre-study basal insulin dose will be used, and dose adjustments will be made as needed according to the titration algorithm in Tables 31, 32 or 33. As indicated in Tables 31-33, if the median FBG is within the target range of 80 to 120 mg / dL (inclusive), the dose from the previous week will not be changed. Median FBG BIF dosage adjustment mg / dL Mmol / L unit <80 <4.4 (-) 20 units (decrease) 80-120 4.4-6.6 No change in dosage 121-140 6.7-7.7 (+) 20 units (increase) >140 >7.7 (+) 40 units (increase) Table 31. BIF dose adjustments for participants not described in Table 32 or Table 33 below.

[0187] For study participants who entered 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. Median FBG BIF dosage adjustment mg / dL Mmol / L unit <80 <4.4 (-) 20 units (decrease) 80-120 4.4-6.6 No change in dosage 121-140 6.7-7.7 (+) 10 units (increase) >140 >7.7 (+) 20 units (increase) Table 32. BIF dose adjustment for median FBG ≤120 mg / dL or pre-study basal insulin dose ≥10 units / day and <20 units / day.

[0188] For study participants who entered the study with a pre-study basal insulin dose of <10 units / day, the investigator may adjust the BIF dose according to Table 33. Median FBG BIF dosage adjustment mg / dL Mmol / L unit <80 <4.4 (-) 20 units (decrease) 80-120 4.4-6.6 No change in dosage 121-140 6.7-7.7 (+) 5 units (increase) >140 >7.7 (+) 10 units (increase) Table 33. BIF dose adjustment when the basal insulin dose was <10 units / day before the study.

[0189] In this section, instructions for administration of insulin degludec are provided, including the starting dose at the third visit (week 0), the daily dose at the fourth visit (week 1), and subsequent dosing / dose adjustments throughout the treatment period.

[0190] Third Consultation - (Week 0): Determine the degludec insulin dose for randomization based on the pre-study insulin dose equivalent. Follow the instructions in Table 34 to calculate the equivalent dose of degludec insulin to be administered once daily to the participant. Note: If the participant is taking NPH twice daily or U300 glargine insulin, the pre-study basal insulin dose should be reduced by 20% when determining the initial once-daily degludec insulin dose for the study. step action Instance participant C Pre-research insulin: Glargine insulin, 20 units (U100) once daily. Instance participant D Pre-research insulin: NPH, 10 units, twice daily 1. Determine common previous daily basal doses during the introduction period. 30 units / day 10 units × 2 = 20 units / day 2. Determine the daily dose of insulin degludec 210 units / week 20 units - [20 × 0.2] units = 20 units - 4 units = 16 units / day Table 34. Equivalent doses of insulin degludec.

[0191] From the 4th consultation (week 1) to the 38th consultation (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 that met the dose reduction guidelines in the previous week, the daily dose was reduced as described in Table 35. Guidelines for reducing hypoglycemic doses based on BG values Unit dose reduction ≥3 episodes of ≤ 70 mg / dL (≤ 3.9 mmol / L) 2-4 units ≥1 nocturnal attack with ≤70 mg / dL (3.9 mmol / L) ≥1 seizure with <54 mg / dL (3.0 mmol / L) Any confirmed severe hypoglycemia Table 35. Guidelines for reducing insulin degludec dose in cases of hypoglycemia.

[0192] If the hypoglycemic dose reduction criteria are not met, the dose adjustment shall be obtained using the median FBG of the previous week according to the titration algorithm in Table 36 or 37. For participants who entered the study with a pre-study basal insulin dose ≥10 units / day, the investigator may adjust the degludec insulin dose according to Table 36 below. Median FBG BIF dosage adjustment mg / dL Mmol / L unit <80 <4.4 (-) 2 units (decrease) 80-120 4.4-6.7 No dose change 121-140 6.7-7.8 (+) 4 units (increase) 141-180 7.8-10.0 (+) 6 units (increase) >180 >10 (+) 8 units (increase) Table 36. Adjustment of degludec insulin dose for participants with a pre-study basal insulin dose ≥10 units / day.

[0193] For participants who entered the study with a pre-study basal insulin dose of <10 units / day, the investigator may adjust the degludec insulin dose according to Table 37 below. Median FBG BIF dosage adjustment mg / dL Mmol / L unit <80 <4.4 (-) 2 units (decrease) 80-120 4.4-6.7 No dose change 121-140 6.7-7.8 (+) 1 unit (increase) 141-180 7.8-10.0 (+) 2 units (increase) >180 >10 (+) 3 units (increase) Table 37. Adjustment of degludec insulin dose for participants whose pre-study basal insulin dose was < 10 units / day.

[0194] The objectives and endpoints of the study are described in Table 38 below. Target end main To demonstrate the non-inferiority of insulin degludec in glycemic control Change in HbA1c from baseline at week 26 secondary To demonstrate the superiority of degludec insulin in the selected glycemic control parameters. ● Change in HbA1c from baseline at week 26 ● The rate of clinically significant nocturnal hypoglycemia (<54 mg / dL or severe) reported by participants during the treatment period up to week 78. ● The time period during which glucose levels measured via CGM collection before week 26 ranged between 70 and 180 mg / dL (inclusive). To investigate the efficacy of insulin degludec in terms of additional glycemic control parameters. ● Changes in HbA1c from baseline at weeks 52 and 78 ● Changes in fasting glucose from baseline as measured by SMBG at weeks 26, 52, and 78. ● Glucose changes measured during CGM sessions prior to weeks 26, 52, and 78. ● The time during which glucose levels measured during CGM sessions before week 52 and week 78 ranged between 70 and 180 mg / dL (inclusive). ● Insulin dosage at weeks 26, 52, and 78 To investigate its safety compared to insulin degludec. ● Incidence and rate of combined grade 2 and 3 hypoglycemic events during treatment ● Weight changes from baseline to weeks 26, 52, and 78 ● Hypoglycemic episodes with glucose <54 mg / dL during CGM sessions prior to weeks 26, 52, and 78. ● The time period defined as hyperglycemia with glucose >180 mg / dL during CGM sessions prior to weeks 26, 52, and 78. The therapeutic impact between BIF and insulin degludec was assessed based on a patient-reported outcomes questionnaire. ● Changes in TRIM-D from baseline at weeks 26, 52, and 78 ● Changes in DTSQ from baseline at weeks 26, 52, and 78 To investigate the therapeutic effects of BIF compared to insulin degludec on efficacy, safety, and other measures of patient-reported outcomes. effect ● Percentage of participants achieving HbA1c < 7% at weeks 26, 52, and 78 ● Percentage of participants who achieved HbA1c < 7% at week 26 without nocturnal blood glucose during the treatment period up to week 26. ● Percentage of participants who achieved HbA1c ≤ 6.5% at weeks 26, 52, and 78. ● Changes in fasting serum glucose from baseline at weeks 26, 52, and 78. Security ● Incidence and rate of grade 2 hypoglycemic events during treatment ● Incidence and rate of grade 3 hypoglycemic events during treatment ● Aggressive treatment of BIF - incidence of antibody appearance Patient Report Results ● Change in SIM-Q from baseline at week 26 ● Frequency of response to "Basal Insulin Experience: Likelihood of incorporating into routine" at weeks 26 and 78 ● Frequency of response to "basal insulin experience: preference" at weeks 26 and 78 Table 38. Objectives and Endpoints. Abbreviations: DTSQ = Diabetes Treatment Satisfaction Questionnaire - Revised Version; CGM = Continuous Glucose Monitoring; HbA1c = Heme A1c; SMBG = Self-Monitoring of Blood Glucose; SIM-Q = Simplified Questionnaire; T2D = Type 2 Diabetes; TRIM-D = Treatment-Related Impact Measurement - Diabetes.

[0195] A phase 3, parallel-design, open-label, randomized controlled trial was designed to evaluate the efficacy and safety of basal insulin (BIF) as weekly basal insulin compared with insulin degludec in insulin-naïve adults with T2D who had not previously received insulin therapy and whose T2D was not adequately controlled with oral antihyperglycemic agents (OAM) in the presence or absence of GLP-1RAs. Participants continued their previous stable therapy, with 0 to 3 non-insulin diabetes medications permitted during the study period.

[0196] Based on participant randomization, participants will be provided with pre-filled insulin pens delivering insulin doses in total weekly units for once-weekly subcutaneous BIF, or in daily units for once-daily degludec insulin. In both treatment groups, participants will be equipped with a glucometer for self-monitoring of blood glucose, and will be instructed on the identification and treatment of hypoglycemia and trained on protocol-related tasks. Researchers will determine participants' insulin doses according to the protocol and monitor dose adjustments to achieve glycemic targets while avoiding hypoglycemia. The primary endpoint of the study is at week 52. Treatment will last for 52 weeks, with emergency therapy starting 16 weeks later.

[0197] Regular periodic reviews of shielded safety data will be conducted by the research team (in accordance with the study’s trial-level safety review plan), and the external data monitoring committee will review unshielded safety data as it assesses safety in all BIF Phase 3 studies.

[0198] Key design features include those described in Table 39 below. Design and Features Basic principles Study duration 60 weeks This duration provides ample time for the initiation and optimization of insulin therapy after titration to stabilize glucose levels, and also allows for the assessment of the efficacy and safety of long-term use. Comparative agent Degludec insulin It is a fully characterized basal insulin administered via once-daily injection. It has the longest half-life among other commercially available basal insulins. Random grouping 1:1 (Weekly BIF: Daily insulin degludec) patient group ● PwT2D aged ≥18 years at the time of screening ● Patients may take a maximum of 3 doses of anti-hyperglycemic medication (OAM+ / -GLP-1 RA). ● Patients must have been on a stable dose for at least 3 months prior to screening and be willing to continue on a stable dose throughout the study. ●HbA1c 7.0%-10.5% (including endpoints) ● Body Mass Index (BMI) ≤45 kg / m² 2 No significant weight gain or loss (≥5%) in the past 3 months. ● A more detailed list of inclusion and exclusion criteria is provided below. The guidelines will allow for the assessment of BIF (compared to insulin degludec) in non-insulin-treated adults with PwT2D who have not previously received insulin therapy, with glycemic control at baseline ranging from fairly good to poor. Exposure N=888 LY=444, insulin degludec=444 Approximately 888 participants will be randomized 1:1 to either BIF or insulin degludec. Assuming a 15% dropout rate at week 52, approximately 377 participants will complete 52 weeks of treatment with LY and insulin degludec, respectively. The primary objective is to demonstrate a national nitric acid (NI) margin of 0.4%. However, this study provides an impetus for a 0.3% NI margin to meet global regulatory requirements. Using a two-sided 0.05 level and assuming a 1.1% SD, a 0.3% NI margin, and no difference in efficacy for changes in HbA1c from baseline, this sample size will provide at least 95% statistical power to demonstrate non-inferiority of BIF to insulin degludec. delivery method KwikPen Insulin Delivery Device The BIF KwikPen will be similar to the BASAGLAR KwikPen, which is adapted to deliver weekly doses of BIF in 5-unit increments. Dosing regimen Initiation and titration BIF are described below, based on findings from Phase 1 and Phase 2 studies and PK / PD modeling. Insulin dosage and recommended dose adjustments in the dosing algorithm will be integrated with a pen device marked in 5-unit increments. Instructions for initiating and titrating the comparative agent will follow the prescription information and standard care guidelines for once-daily degludec insulin. Appropriate starting doses and dose adjustment guidelines for targeted therapies using titratable insulin will be applied in clinical practice. New data from BIF and PK / PD modeling will guide dose titration. Table 39. Abbreviations: BG = Blood Glucose; CGM = Continuous Glucose Monitoring; FBG = Fasting Blood Glucose; FDA = U.S. Food and Drug Administration; FGM = Flash Glucose Monitoring; GLP-1 RA = Glucagon-like peptide-1 receptor agonist; HbA1c = Glycated heme A1c; LY = BIF; MIDD = Model-based drug development; NI = Non-inferiority; OAM = Oral antihyperglycemic agent; PD = Pharmacodynamics; PK = Pharmacokinetics; PwT2D = Humans with type 2 diabetes; SD = Standard Deviation.

[0199] The inclusion criteria for the study included the following: 1. Being at least 18 years old (or older according to local regulations) at the time of screening; 2. Having a diagnosis of type 2 diabetes (T2D) according to WHO guidelines; 3. Having a baseline glycated hemoglobin A1c (HbA1c) value of 7.0% to 10.5% (inclusive) at the time of screening; 4. Acceptable non-insulin diabetes therapies may include 0 to 3 of the following: sulfonylureas, thiazolidinediones (TZDs), dipeptidyl peptidase-4 (DPP-4) IV inhibitors, sodium-glucose cotransporter (SGLT)-2 inhibitors, biguanides (e.g., metformin), alpha-glucosidase inhibitors, or glucagon-like peptide-1 (GLP-1) receptor agonists; 5. Not having previously received insulin therapy. However, short-term insulin therapy lasting up to 14 days prior to the screening day is permitted, as is prior insulin therapy for gestational diabetes; 6. Having a BMI ≤45 kg / m2 at the time of screening and no significant weight gain or loss (≥5%) in the past 3 months; 7. In the investigator's view, having good motivation, ability, and willingness to learn how to self-inject the treatment, as required by this protocol.

[0200] An individual is excluded from the study if they meet any of the following criteria: 1. A diagnosis of type 1 diabetes, potential autoimmune diabetes, or a specific type of diabetes other than T2D (e.g., monogenic diabetes, exocrine pancreatic disease, drug-induced or chemically induced diabetes); 2. Receipt of any of the following non-permitted diabetes medications within the previous 30 days, including meglitinides, pramlintide, basal insulin, prandial insulin, insulin mixtures, inhaled insulin, or continuous subcutaneous insulin infusion therapy; 3. A history of more than one episode of ketoacidosis or hyperosmolar state / coma requiring hospitalization within the 6 months prior to screening; 4. Prior to screening 5. Any episode of severe hypoglycemia within the past 6 months; 6. Hypoglycemic unconsciousness as perceived by the investigator; 7. 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; 8. Gastrointestinal: Gastric bypass (obesity treatment) surgery, restrictive obesity treatment surgery (e.g., Lap-Band®), or sleeve gastrectomy within the past year prior to screening, or clinically significant gastroparesis as perceived by the investigator; 9. Liver: Acute or chronic hepatitis, cirrhosis, or non-alcoholic fatty liver disease (NAFLD). (i.e., study participants with NAFLD are eligible for participation) any obvious clinical signs or symptoms of liver disease other than those of NAFLD, and / or elevated liver enzyme measurements, such as those measured by a central laboratory at screening: total bilirubin > 2 times the upper limit of normal (ULN), alanine transaminase (ALT) / serum glutamate-pyruvate transaminase (SGPT) > 2.5 times the ULN, or aspartate transaminase (AST) / serum glutamate-oxaloacetate transaminase (SGOT) > 2.5 times the ULN, or alkaline phosphatase (ALP) > 2.5 times the ULN; 9. Kidneys: history of kidney transplantation, currently undergoing kidney dialysis, or with an estimated glomerular filtration rate (eGFR) < 20 mL / min / 1.73 calculated using the chronic kidney disease-epidemiological equation. m2, as determined by a central laboratory during screening; 10. Active or untreated malignancy, clinically significant malignancy (other than basal cell or squamous cell skin cancer) in the investigator's view, having been in remission for less than 5 years or being at increased risk of developing or recurring cancer; 11. Known allergic reaction or hypersensitivity to any of the investigational drug or its excipients; 12. Having any other serious illness or condition (e.g., known drug or alcohol abuse or mental illness) that, in the investigator's view, would pose a significant risk to the study participant and prevent the participant from adhering to and completing the protocol; 13. Current or recent (within a 6-month timeframe) evidence of a history of any substance use disorder as defined in DSM-5, of any severity in the investigator's view, except for nicotine or caffeine use disorders; 14.Hematology: A history of blood transfusion or severe blood loss within 90 days prior to the first consultation, or a known diagnosis of heme disorders, hemolytic anemia, sickle cell anemia, or any other heme abnormality known to the investigator as interfering with HbA1c measurement; 15. Currently receiving chronic (>14 days) systemic glucocorticoid therapy (excluding topical, intraocular, intranasal, and inhaled formulations) or having received such therapy for >14 days within one month prior to screening.

[0201] The timing and instructions for administering BIF and degludec insulin will be similar to those described above for the Phase 3 study of patients with T2DM treated with daily basal insulin, except that the participants in this study did not have a pre-study basal insulin dose, so a standardized expected weekly maintenance dose that is expected to be appropriate and tolerable for this patient population must be used.

[0202] For participants randomized to BIF, the expected weekly maintenance dose will be 100 U, and a 3x loading dose will be used; therefore, the initial dose at the fourth visit (week 1) will be 300 U. Any subsequent adjustments to the weekly maintenance dose will be determined based on the guidelines described above for the Phase 3 study of T2DM patients treated with daily basal insulin (affected by the hypoglycemia guidelines also described above).

[0203] For participants randomly assigned to receive insulin degludec, the initial dose on day 1 will be 10 U, and thereafter adjusted weekly according to the guidelines described above for the Phase 3 study of patients with T2DM treated with daily basal insulin.

[0204] Efficacy and safety objectives, assessments and endpoints are described in Table 40 below. Target main: To demonstrate the non-inferiority of HbA1c changes from baseline to week 52 relative to insulin degludec, with a non-inferiority margin of 0.4%. The primary efficacy measure is HbA1c, a widely used measure of glycemic control reflecting the cumulative glucose levels over the past 2 to 3 months. It has been found to be strongly associated with the risk of long-term diabetic complications. It is the recognized measure for evaluating the glucose-lowering efficacy of medications. Other secondary targets provide complementary information on glycemic control. Hypoglycemia, adverse events, and immunogenicity will be assessed to characterize safety. Key and secondary: 1. To demonstrate the non-inferiority (0.4% NI) of HbA1c change from baseline to week 52 in a subset of participants who were using oral antihyperglycemic agents in the absence of GLP-1 alone compared to insulin degludec. 2. To demonstrate the non-inferiority of HbA1c change from baseline to week 52 relative to insulin degludec in a subset of participants who were concurrently using oral antihyperglycemic agents and GLP-1 RA (0.4% NI). 3. Superiority of HbA1c change from baseline at week 52 4. Time interval (TIR) ​​between 70 and 180 mg / dL (inclusive) as measured by CGM at week 52. 5. The rate of clinically significant nocturnal hypoglycemia (<54 mg / dL or severe) events reported by participants from baseline to week 52. Key safety assessment ● Adverse events ● Hypoglycemia ● Allergic reaction / injection site reaction ● Immunogenicity Table 40. Efficacy and safety objectives, assessments, and endpoints

[0205] Treatment of Type 2 Diabetes Mellitus Patients with MDI

[0206] This phase 3, parallel-design, open-label, randomized controlled trial was designed to evaluate the efficacy and safety of BIF compared to insulin glargine in patients with type 2 diabetes who were taking basal insulin once or twice daily and at least two bolus insulin injections daily prior to study entry. Participants will continue their previous stable therapy with 0 to 3 permitted non-insulin diabetes medications during the study period.

[0207] Based on participant randomization, participants will be provided with pre-filled insulin pens delivering insulin doses in total weekly units for once-weekly subcutaneous BIF, or in daily units for once-daily glargine insulin. In both treatment groups, participants will be equipped with a glucometer for self-monitoring of blood glucose, and will be instructed on the identification and treatment of hypoglycemia and trained on protocol-related tasks. Researchers will determine participants' insulin doses and monitor dose adjustments as described below to achieve glycemic targets while avoiding hypoglycemia.

[0208] Key design features include those described in Table 41 below. Design and Features Basic principles Study duration 26 weeks This duration allows sufficient time for glucose levels to stabilize after switching from pre-study insulin therapy to study insulin. Comparative agent Glargine insulin It is a basal insulin that is fully characterized and administered via once-daily injection. Random grouping 1:1 (Weekly BIF: Daily glargine insulin) patient group ● PwT2D aged ≥18 years at the time of screening ● Patients may take a maximum of 3 doses of anti-hyperglycemic medication (OAM+ / -GLP-1 RA). ● Patients taking basal insulin and injecting mealtime insulin at least twice daily, with or without using OAM or GLP-1 RA. ● HbA1c 7.0%-10% (including endpoints) ● Basal insulin once or twice daily ● A more detailed list of inclusion and exclusion criteria is provided below. The guidelines will allow for the assessment of BIF (compared to insulin glargine) in adults taking basal and prandial insulin PwT2D, with glycemic control at baseline ranging from fairly good to poor. Exposure N=670 BIF=335, insulin glargine=335 Approximately 670 participants will be randomized 1:1 to either BIF or insulin glargine. Assuming a 15% dropout rate at week 26, approximately 285 participants will complete 26 weeks of treatment with either BIF or insulin glargine. The primary objective is to demonstrate national ineligibility (NI) based on a margin of 0.4% or 0.3%, depending on regulatory requirements. This study provides impetus for a 0.3% NI margin to meet global regulatory requirements. Using a two-sided 0.05 level and assuming a 1.1% SD, a 0.3% NI margin, and no difference in efficacy for changes in HbA1c from baseline, this sample size will provide at least 90% statistical power to demonstrate non-inferiority of BIF to insulin glargine. delivery method KwikPen Insulin Delivery Device The BIF KwikPen will be similar to the BASAGLAR KwikPen, which is adapted to deliver weekly doses of BIF in 5-unit increments. Dosing regimen The initiation and titration of BIF are described below, and are informed by findings from the Phase 1 and Phase 2 studies and PK / PD modeling. The following describes the starting dose, dose titration, titration frequency, and BG target for BIF treatment. The insulin dose and recommended dose adjustments in the dosing algorithm will be combined with a pen device marked in 10-unit increments. Instructions for initiating and titrating the comparative agent will follow the prescription information and standard care guidelines for once-daily glargine insulin. Appropriate starting doses and dose adjustment guidelines for targeted therapies using titratable insulin will be applied in clinical practice. New data from BIF and PK / PD modeling will guide dose titration. Table 41. Abbreviations: BG = Blood Glucose; CGM = Continuous Glucose Monitoring; FBG = Fasting Blood Glucose; FDA = U.S. Food and Drug Administration; FGM = Flash Glucose Monitoring; GLP-1 RA = Glucagon-like peptide-1 receptor agonist; HbA1c = Glycated heme A1c; MIDD = Model-based Drug Development; NI = Non-inferiority; OAM = Oral Antihyperglycemic Agent; PD = Pharmacodynamics; PK = Pharmacokinetics; PwT2D = Humans with Type 2 Diabetes; SD = Standard Deviation.

[0209] Inclusion criteria include the following: 1. At least 18 years of age (or older according to local regulations) at screening; 2. A diagnosis of type 2 diabetes (T2D) currently treated with basal insulin and at least twice daily bolus insulin injections according to WHO guidelines; 4. Total daily insulin intake less than or equal to 2 units / kg / day at screening; 5. Baseline HbA1c value of 7.0% to 10% (inclusive) at screening; 6. At least 90 days prior to screening, treated with a stable regimen of one of the following basal insulins according to the local product label, with or without non-insulin diabetes therapies: once daily U100 or U200 degludec insulin; once daily U100 or U300 glargine insulin; once or twice daily U100 detemir insulin; once or twice daily human insulin neutral protamine HAGDORN. 7. For at least 90 days prior to screening, participants must have been treated with a stable regimen of at least twice daily administration of one of the following insulins according to the local product label (with a mealtime insulin dose present before dinner): lispro insulin (U100 and U200); lispro insulin-aabc (U100 or U200); aspart insulin (U100; including Fiasp and Novolog); lisglutinin insulin (U100); regular insulin (U100); Acceptable non-insulin diabetes therapies may include 0 to up to 3 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 label at screening, and participants should be willing to continue stable administration according to the regimen throughout the study period. 8. A BMI ≤45 kg / m2 (inclusive) with no significant weight gain or loss (≥5%) in the past 3 months.

[0210] Exclusion criteria include the following: 1. Significant weight gain or loss (e.g., ≥5%) in the investigator's view within the past 3 months; 2. Diagnosis of type 1 diabetes or potential autoimmune diabetes or a specific type of diabetes other than T2D (e.g., monogenic diabetes, exocrine pancreatic disease, drug-induced or chemically induced diabetes); 3. Receiving any of the following insulin therapies at any time within the past 90 days (except for pregnancy), except for short-term treatment of acute conditions and a maximum of 4 consecutive weeks: insulin mixtures, Affreza (inhaled conventional human insulin), continuous subcutaneous insulin infusion therapy, conventional insulin U500; 4. Receiving any of the following non-permitted diabetes medications within the previous 90 days, including meglitinides, sulfonylureas, pramlintide, alpha-glucosidase inhibitors, or thiazolidinediones; 5. Prior to screening 6. History of more than one episode of ketoacidosis or hyperosmolar state / coma requiring hospitalization within the past 6 months; 7. Any episode of severe hypoglycemia within the past 6 months prior to screening; 8. Hypoglycemic unconsciousness as perceived by the investigator; 9. No intention to change CGM use during the study period (e.g., initiation, discontinuation, device change); 10. 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; 11. Gastrointestinal: Gastric bypass (obesity treatment) surgery, restrictive obesity treatment surgery (e.g., Lap-Band®), or sleeve gastrectomy within the past year prior to screening, or clinically significant gastroparesis as perceived by the investigator; 12. Liver: Acute or chronic hepatitis, or non-alcoholic fatty liver disease (NAFLD). (i.e., study participants with NAFLD are eligible for participation) any obvious clinical signs or symptoms of liver disease other than those of NAFLD, and / or elevated liver enzyme measurements, if measured by a central laboratory at screening and meeting the following criteria: total bilirubin > 2 times the upper limit of normal (ULN), except for a previous diagnosis of Gilber's disease; alanine transaminase / serum glutamate-pyruvate transaminase > 2.5 times the ULN; or aspartate transaminase / serum glutamate-oxaloacetate transaminase > 2.5 times the ULN; 12. Kidneys: history of kidney transplantation, currently undergoing kidney dialysis, or with an estimated glomerular filtration rate < 30 mL / min / 1.73 calculated using the chronic kidney disease-epidemiological equation. m2, as determined by a central laboratory during screening; 13. Active or untreated malignant tumors, or, in the investigator's view, clinically significant malignant tumors (other than basal cell or squamous cell skin cancer) that have been in remission for less than 5 years or are at increased risk of developing or recurring cancer; 13.Hematology: A history of blood transfusion or severe blood loss within 90 days prior to the first consultation, or a known diagnosis of heme disorders, hemolytic anemia, or sickle cell anemia, or any other heme abnormality known to the investigator as interfering with HbA1c measurement; 14. Currently receiving chronic (>14 days) systemic glucocorticoid therapy (excluding topical, intraocular, intranasal, and inhaled formulations) or having received such therapy for >14 days within one month prior to screening.

[0211] Instructions for initiating and titrating treatment with BIF are provided as described in Tables 42 and 43 below: Baseline median FPG Starting dose ≥120 mg / dL Previous daily basal dose (U) × 7 × 3 ≤120 mg / dL Previous daily basal dose (U) × 7 (dose doubling without loading) Table 42. Instructions for starting BIF treatment. Median FBG (mg / dL) BIF Adjustment (Unit) Baseline FG ≤ 120 mg / dL or daily basal dose < 20 units Baseline FG > 120 and daily basal dose ≥ 20 units <80 -10 to 20 a -20 80-120 No change No change 121-140 +10 +20 >140 +20 +40 Table 43. Instructions for determining the weekly maintenance dose of BIF. a. The dose may be reduced by 10-20 units, depending on the participant's FBG value and other individual clinical characteristics, at the investigator's discretion.

[0212] Efficacy and safety objectives, assessments and endpoints are described in Table 44 below. Design and Features Basic principles Target main: To demonstrate the non-inferiority of HbA1c changes from baseline to 26 weeks relative to insulin glargine. The primary efficacy measure is HbA1c, a widely used measure of glycemic control reflecting the cumulative glucose levels over the past 2 to 3 months. It has been found to be strongly associated with the risk of long-term diabetic complications. It is the recognized measure for evaluating the glucose-lowering efficacy of medications. Other secondary targets provide complementary information on glycemic control. Hypoglycemia, adverse events, and immunogenicity will be assessed to characterize safety. Key and secondary: • HbA1c variation from baseline • <7% in the absence of nocturnal hypoglycemia (<54 mg / dL or severe). • The rate of clinically significant nocturnal hypoglycemia (<54 mg / dL or severe) reported by participants during the treatment period up to week 26. Key safety assessment ● Adverse events ● Hypoglycemia ● Allergic reaction / injection site reaction ● Immunogenicity Table 44. Efficacy and safety objectives, assessments, and endpoints

[0213] A phase 3, parallel-design, open-label, randomized controlled trial for patients with type 1 diabetes (T1D) was designed to evaluate the efficacy and safety of insulin iodide (BIF) versus insulin degludec in participants with T1D treated with basal meal-based multivitamin diuretic (MDI) therapy prior to study entry. Further details of the study are provided in Table 45 below. The selection of the study population and insulin comparator was supported by available efficacy and safety data from a similar phase 2 study described above, comparing BIF and insulin degludec. Based on participant randomization, pre-filled insulin pens will be provided in total weekly units for once-weekly subcutaneous administration of BIF, or in daily units for once-daily administration of insulin degludec. In both treatment groups, participants will be equipped with non-blinded CGM and glucometers for diabetes management, and will be instructed on the identification and treatment of hypoglycemia and trained on protocol-related tasks. Investigators will determine participants' insulin doses according to the protocol and monitor dose adjustments to achieve glucose targets while avoiding hypoglycemia.

[0214] Key design features include those described in Table 45 below. Design and Features Basic principles Study duration 52 weeks This duration allows sufficient time for glucose levels to stabilize after switching from pre-study insulin therapy to study insulin. Comparative agent Degludec insulin It is a fully characterized basal insulin administered via once-daily injection. It has the longest half-life among other commercially available basal insulins. Random grouping 1:1 (Weekly BIF: Daily insulin degludec) patient group ● ≥18 years old ● T1D lasts for at least 1 year ● Treatment with basal mealtime insulin MDI therapy ● HbA1c 7.0%-10% (including endpoints) ● A more detailed list of inclusion and exclusion criteria is provided below. The guidelines will allow for the assessment of BIF (compared to insulin degludec) in adults with T1D on a baseline meal-based MDI therapy. patient group N=670 BIF=335, insulin degludec=335 Approximately 670 participants will be randomized 1:1 to receive either BIF or insulin degludec. Assuming a 15% dropout rate at week 26, approximately 285 participants will complete 26 weeks of treatment with BIF and insulin degludec, respectively. The primary objective is to demonstrate a national nitric acid (NI) margin of 0.4%. However, this study provides an impetus for a 0.3% NI margin to meet global regulatory requirements. Using a two-sided 0.05 level and assuming a 1.1% SD, a 0.3% NI margin, and no difference in efficacy for changes in HbA1c from baseline, this sample size will provide approximately 90% power to demonstrate non-inferiority of BIF over insulin degludec. delivery method KwikPen Insulin Delivery Device The BIF KwikPen will be similar to the BASAGLAR KwikPen, which is adapted to deliver weekly doses of BIF in 5-unit increments. Dosing regimen The initiation and titration of BIF (including the target therapy dosing algorithm) are described below and are based on findings from previous clinical studies and PK / PD modeling. Insulin dosage and recommended dose adjustments in the dosing algorithm will be combined with a pen device marked in 5-unit increments. Instructions for initiating and titrating the comparative agent will follow the prescription information and standard care guidelines for once-daily degludec insulin. The appropriate starting dose and dose adjustment guidelines for targeted therapies using titrable insulin will be applied in clinical practice. New data from this novel once-weekly insulin and PK / PD modeling will guide dose titration. Table 45. Abbreviations: CGM = Continuous Glucose Monitoring; FDA = U.S. Food and Drug Administration; HbA1c = Glycated Heme A1c; MIDD = Model-Based Drug Development; NI = Non-Inferiority; PD = Pharmacodynamics; PK = Pharmacokinetics; SD = Standard Deviation.

[0215] Inclusion criteria include the following: 1. At least 18 years of age at screening (or older according to local regulations); 2. A diagnosis of type 1 diabetes (T1D) according to WHO guidelines for at least 1 year prior to screening; 3. A heme A1c (HbA1c) value of 7.0% to 10% (inclusive) at screening; 4. Treatment with basal-meal insulin analog MDI therapy according to local product labels for at least 90 days prior to screening, including: a combination of basal insulin analogs (insulin glargine U-100, insulin glargine U-300, insulin degludec, insulin detemir) and meal-meal insulin analogs (insulin lispro, insulin aspart, insulin lisgludec, Fiasp, Lyumjev); and 5. A BMI ≤35.0 kg / m2.

[0216] Exclusion criteria include the following: 1. Diagnosis of type 2 diabetes or potential autoimmune diabetes; 2. History of more than one episode of diabetic ketoacidosis or hyperosmolar state / coma requiring hospitalization within 6 months prior to screening; 3. History of more than one episode of severe hypoglycemia (defined as hypoglycemia attributable to neurological dysfunction requiring assisted intervention) within 6 months prior to screening; 4. Hypoglycemic unconsciousness in the investigator's view; 5. Excessive insulin resistance, defined as receiving a total daily insulin dose >1.5 units / kg at the time of screening; 6. Cardiovascular (CV): Having New York Heart Association Class IV heart failure or any of the following CV conditions within 3 months prior to screening: acute myocardial infarction, cerebrovascular accident (stroke), or coronary artery bypass surgery; 7. Gastrointestinal: Having undergone gastric bypass (obesity treatment) surgery, restrictive obesity treatment surgery (e.g., Lap-Band®), or sleeve gastrectomy within 1 year prior to screening; having clinically significant gastroparesis in the investigator's view; 8. Liver: Having acute or chronic hepatitis, cirrhosis, or non-alcoholic fatty liver disease (NAFLD). (i.e., study participants with NAFLD are eligible for participation) any obvious clinical signs or symptoms of liver disease other than those of NAFLD, and / or elevated liver enzyme measurements, if measured by a central laboratory at screening and meeting the following criteria: total bilirubin > 2 times the upper limit of normal (ULN); alanine transaminase / serum glutamate-pyruvate transaminase > 2.5 times the ULN; or aspartate transaminase / serum glutamate-oxaloacetate transaminase > 2.5 times the ULN, alkaline phosphatase (ALP) > 2.5 times the ULN; 9. Kidneys: history of kidney transplantation, currently undergoing kidney dialysis, or with an estimated glomerular filtration rate < 30 mL / min / 1.73 calculated using the chronic kidney disease-epidemiological equation. m2, as determined by the central laboratory during screening; 10. Active or untreated malignant tumors, clinically significant malignant tumors (excluding basal cell or squamous cell skin cancer) in the investigator's view that have been in remission for less than 5 years or are at increased risk of developing or recurring cancer; 11. Hematology: transfusion or severe blood loss within 3 months prior to the first visit, or known heme disease, hemolytic anemia or sickle cell anemia, or any other heme abnormality known to the investigator that interferes with HbA1c measurement; 12. In screening (first visit) 13. Have been taking an insulin therapy regimen, including NPH insulin, U-500 insulin, regular human insulin, or any premixed insulin, within 90 days prior to the screening (first consultation); 14. Have been using human inhaled insulin powder (Afrezza) within 90 days prior to the screening (first consultation); 15. Have been using continuous subcutaneous insulin infusion (CSII) therapy within 90 days prior to the screening (first consultation); 16. Have received any oral or injectable medication other than insulin intended for the treatment of diabetes within 90 days prior to the screening (first consultation);Currently receiving chronic (>14 days) systemic glucocorticoid therapy (excluding replacement therapy for adrenal insufficiency; topical, intraocular, intranasal, or inhaled formulations) or having received such therapy for >14 days within one month prior to screening.

[0217] Instructions for initiating and titrating BIF (including the target therapy dosing algorithm) are described in Tables 46 and 47 below: Baseline FBG Loading dose First weekly maintenance dose ≤ 140 mg / dL Previous daily dose (U) × 7 × 3 Previous daily dose (U) × 7 141 - 160 mg / dL [Previous daily dose × 1.1 to 1.2 (i.e., increase dose by 10% to 20%)] × 7 × 3 [Previous daily dose × 1.1 to 1.2 (i.e., increase dose by 10% to 20%)] × 7 >160 mg / dL [Previous daily dose × 1.2 to 1.3 (i.e., increase dose by 20% to 30%)] × 7 × 3 [Previous daily dose × 1.2 to 1.3 (i.e., increase dose by 20% to 30%)] × 7 Table 46. Explanation for determining the loading dose and the first weekly maintenance dose. Median FPG (mg / dL) Adjustment Current dose < 100 U Current dose ≥100 U < 80 Previous lower dose Previous lower dose 80-120 No change No change 121-150 + 5 U +10 U 151-180 +10 U +20 U >180 +20 U +30 U Table 47. Dosage adjustments for subsequent weekly maintenance doses.

[0218] Additionally, guidelines are provided for reducing the dose to a previously lower dose in response to certain hypoglycemic events.

[0219] The modified Riddle target therapy algorithm was used to titrate degludec insulin to a FG target of 80-120 mg / dL.

[0220] Efficacy and safety objectives, assessments and endpoints are described in Table 48 below. Design and Features Basic principles Target main: To demonstrate the non-inferiority of HbA1c changes from baseline to insulin degludec. The primary efficacy measure is HbA1c, a widely used measure of glycemic control reflecting the cumulative glucose levels over the past 2 to 3 months. It has been found to be strongly associated with the risk of long-term diabetic complications. It is the recognized measure for evaluating the glucose-lowering efficacy of medications. Other secondary targets provide complementary information on glycemic control. Hypoglycemia, adverse events, and immunogenicity will be assessed to characterize safety. Key and secondary: ● HbA1c changes from baseline ● The rate of clinically significant nocturnal hypoglycemia (<54 mg / dL or severe) reported by participants during the treatment period up to week 52. ● The time during which CGM measurements collected during a CGM session fall within the normal blood glucose range of 70 to 180 mg / dL (inclusive). Key safety assessment ● Hypoglycemia ● Adverse events ● Allergy / Allergic reaction ● Immunogenicity ● Injection site reaction Table 48. Efficacy and safety objectives, assessments and endpoints.

[0221] Other studies on patients with type 2 diabetes mellitus (T2DM)

[0222] In other studies, key inclusion criteria included a prior diagnosis of diabetes based on stable background therapy, at least 18 years of age, approximately 7 to 10% of baseline HbA1c values, and a body mass index (BMI) between 20 and 45 kg / m2. Inclusion criteria and background therapy will vary depending on the study population.

[0223] The primary objective of these studies is to investigate the effect of BIF on glycemic control compared to commercially available basal insulins (such as insulin glargine or insulin degludec). The relevant primary endpoint is to demonstrate non-inferiority of BIF compared to one of these basal insulins in terms of changes in HbA1c from baseline. Secondary efficacy and safety endpoints may include the following: the percentage of participants who achieved their HbA1c target (with or without hypoglycemia); changes in fasting glucose; the rate of hypoglycemic events during treatment; changes in weight; the presence of anti-drug antibodies; and CGM-derived endpoints, such as the time to achieve, exceed, or fall below the target range.

[0224] Where applicable, study participants and their caregivers will be trained on the signs and symptoms of hyperglycemia and hypoglycemia, and on how to monitor glucose according to the protocol instructions. They may also have their glucose levels checked frequently as needed, and will be instructed to access the study site in cases of severe, persistent hyperglycemia or severe hypoglycemia during study interviews. Appropriate information on each episode of hypoglycemia will be collected in the study diary.

[0225] Self-monitoring of blood glucose or continuous glucose monitoring (using devices approved for this purpose) will be used to inform dose adjustments and monitor for hyperglycemia and hypoglycemia. Participants experiencing severe, persistent hyperglycemia based on specific predefined thresholds will receive additional glucose-lowering interventions (or emergency treatment). Additionally, in cases where patients meet the definition of increased hypoglycemia risk, instructions will be provided to first reduce the BIF dose according to individual dosing algorithms, and then, if necessary, discontinue the study drug. Detailed instructions on how to manage hyperglycemia and hypoglycemia will be provided to the study site and study participants. The safety of study participants will be closely monitored throughout the study period (including safety follow-up).

[0226] In a phase 3 study, the starting dose for participants who had not previously received insulin therapy was derived from FG and BW, similar to the approach described above in the phase 2 study for participants who had not previously received insulin therapy. Examples of such approaches are described in Table 49 below: Median FG value over 3 days (mg / DL) Weight(KG) ≤80 81-100 101-120 >120 100-140 120 IU 200 IU 240 IU 280 IU 141-180 250 IU 280 IU 420 IU 490 IU 181-220 370 IU 420 IU 560 IU 560 IU >220 490 IU 560 IU 630 IU 700 IU Table 49.

[0227] For participants who were previously treated with basal insulin, the starting dose will be determined based on the previous basal insulin dose and FG data.

[0228] Dosage adjustments will be determined based on the previous week's FG. A set of examples of guidelines for dosage adjustments are presented in Table 50 below: Median FPG value (mg / DL) over 3 days Dose adjustments (IU) based on previous insulin doses over the past few weeks. Week 2 Week 3 Week 4 and beyond ≤80 -70 -70 -14 81-100 -42 -28 No change 101-140 No change No change 14 141-180 120 70 28 >180 210 120 42 Table 50.

[0229] In addition to the FG-based guidelines for dose adjustment described above, dose reduction will be implemented based on any of the following hypoglycemic conditions: multiple episodes of recorded hypoglycemia with SMBG <70 mg / dL; severe hypoglycemia (requiring support); and / or hypoglycemia ≤54 mg / dL recorded in the previous week. Furthermore, if any SMBG reading was recorded as <70 mg / dL at any time in the previous week, the dose may not be increased.

[0230] Another study was designed to test a dosing regimen designed to provide simpler dosing guidelines while still achieving the desired blood glucose target, albeit more gradually, without increasing the risk of hypoglycemia.

[0231] The first dose administered in these studies differed from that given to participants who had never previously received insulin therapy, compared to participants previously treated with daily basal insulin. Participants previously treated with insulin started with approximately 70 IU. Participants previously treated with basal insulin received a loading dose calculated from their previous daily insulin dose based on a 1:1 conversion to a weekly dose multiplied by 3. For example, a participant taking 30 IU of daily glargine insulin would start with a BIF loading dose of 630 IU (30 IU × 7 days × 3). This loading dose strategy was designed to achieve effective exposure during this transition period to reduce transient hyperglycemia.

[0232] Subsequent weekly dose adjustments for all participants will be based on FG values, as shown in Table 51 below: FG value (mg / dL) Dosage adjustment (IU) <54 -28 55-70 -14 71-100 No change 101-125 14 >125 28 Table 51.

[0233] In addition, dose reduction will be implemented based on any of the following hypoglycemic conditions: multiple episodes of recorded hypoglycemia with SMBG <70 mg / dL; severe hypoglycemia (requiring support); and / or hypoglycemia ≤54 mg / dL recorded in the previous week. Furthermore, if any SMBG reading is recorded as <70 mg / dL at any time in the previous week, the dose may not be increased.

[0234] Sequence SEQ ID NO: 1 [Sequence List]

[0235] <![CDATA[ <110> Eli Lilly and Company, an American pharmaceutical company. <![CDATA[ <120> Methods for treating diabetes <![CDATA[ <130> X22854]]> <![CDATA[ <140> TW110146777]]> <![CDATA[ <141> 2021-12-14 <![CDATA[ <150> US 63 / 125,165 <![CDATA[ <151> 2020-12-14 <![CDATA[ <160> 1 ]]> <![CDATA[ <170> PatentIn version 3.5]]> <![CDATA[ <210> 1]]> <![CDATA[ <211> 299]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> Synthetic Constructs <![CDATA[ <400> 1]]> Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Glu 1 5 10 15 Leu Val Cys Gly Glu Arg Gly Phe His Tyr Gly Gly Gly Gly Gly Gly 20 25 30 Ser Gly Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys Thr Ser Thr Cys 35 40 45 Ser Leu Asp Gln Leu Glu Asn Tyr Cys Gly Gly Gly Gly Gly Gln Gly 50 55 60 Gly Gly Gly Gln Gly Gly Gly Gly Gly Gln Gly Gly Gly Gly Gly Glu Cys 65 70 75 80 Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe 85 90 95 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 100 105 110 Thr Cys Val Val Val Asp Val Ser His GluAsp Pro Glu Val Gln Phe 115 120 125 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 130 135 140 Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr 145 150 155 160 Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 165 170 175 Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr 180 185 190 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 195 200 205 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 210 215 220 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 225 230 235 240 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser 245 250 255 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 260 265 270 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 275 280 285 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 290 295

Claims

1. Use of insulin efsitora alfa for manufacturing a medicine to provide glycemic control for an individual in need of diabetes, wherein the individual has not previously received insulin therapy, and wherein the medicine is used in a manner comprising: a) administering an initial dose of insulin efsitora alfa to the individual weekly, the initial dose being a loading dose of 300 U, which is three times greater than the intended weekly maintenance dose; and b) administering a maintenance dose to the individual one week after the loading dose, wherein the maintenance dose is equal to the intended weekly maintenance dose adjusted as necessary according to (i)-(iv) the following: i) if the individual's median fasting glucose (FG) during the previous week is <80 mg / dL, then a reduction of 20 units; ii) if the individual's median FG during the previous week is 80-120 mg / dL, then no adjustment; iii) if the individual's median FG during the previous week is 121-140 mg / dL. If the median FG is >140 mg / dL, then increase by 20 units; or iv) if the median FG of the individual is >140 mg / dL, then increase by 40 units; and c) starting one week after the administration of the previous maintenance dose, administer one or more weekly maintenance doses to the individual once a week, wherein the weekly maintenance dose is equal to the previous maintenance dose adjusted as necessary according to items (i)-(iv) above.

2. As requested in item 1, wherein the individual has type 2 diabetes (T2D) and has a baseline FG ≤ 120 mg / dL before starting treatment with insulin α.

3. For the purposes of claim 1 or 2, the weekly maintenance dose shall be reduced by 40 units if the individual has any of the following in the preceding week: a) ≥ 3 episodes of blood glucose ≤ 70 mg / dL; b) ≥ 1 nocturnal blood glucose episode ≤ 70 mg / dL; c) ≥ 1 episode of blood glucose ≤ 54 mg / dL; or d) any episode of severe hypoglycemia.

4. As requested in paragraph 1 or 2, wherein the need for any weekly maintenance dose adjustment is determined at the following times: weekly during the first 12 weeks after initiation of insulin alpha treatment; and every 4 weeks thereafter.

5. As requested in item 1 or 2, wherein the drug is used to improve glycemic control in the individual.