Methods and systems for managing diabetes

Abstract

This disclosure relates generally to systems, methods and devices used in connection with the management of diseases such as diabetes.

Description

METHODS AND SYSTEMS FOR MANAGING DIABETES FIELD

[0001] This disclosure relates generally to systems, methods and devices used in connection with the management of diseases such as diabetes. Embodiments include systems, methods and devices for use in connection with long-acting medications for managing glucose levels in a subject. BACKGROUND

[0002] Diabetes is a chronic disorder characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Type 1 diabetes (T1D) is characterized by little or no insulin secretory capacity, and patients with T1D require insulin for survival. Type 2 diabetes (T2D) is characterized by elevated blood glucose levels resulting from impaired insulin secretion, insulin resistance, excessive hepatic glucose output, and / or contributions from all of the above. In many patients with T2D, the disease progresses to a requirement for insulin therapy. Treatment of persons with T2D typically begins with prescribed weight loss, exercise, and a diabetic diet, but when these measures fail to control elevated blood sugars, then oral medications and incretin-based therapy may be necessary. When these medications are still insufficient, treatment with insulin is considered. T2D patients whose disease has progressed to the point that insulin therapy is required are generally started on a single daily injection of a long-acting, basal insulin.

[0003] Treatment regimens involving daily injections of existing insulin therapies can be burdensome to administer and can result in undesired side effects, such as hypoglycemia (low blood glucose levels) and weight gain. Therefore, some persons with diabetes are unwilling or unable to comply, or are incapable of complying, with the insulin therapy necessary to maintain close control of blood glucose levels.

[0004] Insulin products with longer duration of action are under development. Insulin products of these types may require fewer injections than currently available insulin products, including, for example, once-weekly. Such products have the potential to improve acceptance and compliance.

[0005] There remains a need for insulin therapies requiring fewer injections than currently available insulin products. The capability of efficaciously providing such insulin therapies, for example either without increasing or by reducing risk of undesired side effects such ashypoglycemia, compared to currently available insulin products would be desirable. Such insulin therapies that can be administered in a manner that allows patients to relatively quickly reach steady-state serum levels would be particularly desirable. Tools or devices capable of effectively and efficiently providing these needs would be advantageous. SUMMARY

[0006] This disclosure relates generally to systems, methods and devices used in connection with the management of diseases such as diabetes.

[0007] According to an embodiment of the present disclosure, a system includes a computing device programmed to calculate a weekly recommended insulin dose for a subject using an operation comprising: determining a base dose amount of a weekly insulin, determining a dose adjustment amount, and calculating the weekly recommended insulin dose based on the base dose amount and the dose adjustment amount. The base dose amount is based, at least in part, on a prior administered dose amount of the weekly insulin. The dose adjustment amount is based, at least in part, on one or more blood glucose measurements.

[0008] According to another embodiment of the present disclosure, method of providing glycemic control in a subject in need thereof having diabetes is provided. The method includes administering to the subject a weekly dose of insulin efsitora alfa, wherein the weekly dose is determined by: determining a base dose amount, determining a dose adjustment amount, and calculating a recommended dose amount based on the base dose amount and the dose adjustment amount. The base dose amount is based, at least in part, on a prior administered dose amount of insulin efsitora alfa. The dose adjustment amount is based, at least in part, on one or more blood glucose measurements.

[0009] According to yet another embodiment of the present disclosure, a system includes a computing device programmed to determine whether to suspend insulin dose calculations using an operation comprising: repeatedly calculating a dose amount of weekly insulin based on a prior administered dose amount and a prior blood glucose level, determining that no subsequent blood glucose levels have been logged or detected within a set period of time, and suspending the repeatedly calculating the dose amount in response to the determining that no subsequent blood glucose levels have been logged or detected within the set period of time.BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The above-mentioned and other features and advantages of this disclosure, and the manner of attaining them, will become more apparent and will be better understood by reference to the following description of embodiments of the invention taken in conjunction with the accompanying drawings, wherein:

[0011] FIG.1 is a diagrammatic illustration of a system for managing diabetes, according to some embodiments;

[0012] FIG.2 depicts a flowchart of a method to calculate subsequent doses after a first weekly dose, according to some embodiments; and

[0013] FIG. 3 depicts a flowchart of a method to suspend further insulin dose recommendations, according to some embodiments.

[0014] Corresponding reference characters indicate corresponding parts throughout the several views. The exemplifications set out herein illustrate exemplary embodiments of the invention and such exemplifications are not to be construed as limiting the scope of the invention in any manner. DETAILED DESCRIPTION

[0015] Certain embodiments of the present disclosure are directed to approaches for determining dosing regimens, uses, and methods of treatment for long-acting insulin receptor agonists suitable for once-weekly dosing in persons with T2D. Further, certain embodiments are directed to approaches for determining when to suspend weekly doses.

[0016] The following description outlines various approaches for calculating doses for subjects transitioning to or already prescribed long-acting insulin. Calculating doses can be carried out by devices such as smart phones, tablets, or other computers. For example, upon being prescribed a weekly insulin by a health care provider (HCP), a person with T2D can download and access an application to a smart phone, and the application can be programmed to calculate and recommend doses, generate alerts, recommend dose suspensions, and perform other functions as described herein. The application can receive input data (e.g., administered dose amounts, blood glucose levels such as fasting blood glucose levels, data from a HCP), generate metadata (e.g., timestamps), generate alerts and suspensions, and calculate doses for the patient to administer via injection.Long-Acting Insulin

[0017] When used herein, the terms “insulin” or “insulin receptor agonist” refer to a protein that binds to and activates the insulin receptor, resulting in a lowering of blood glucose levels and / or suppression of hepatic glucose output, characteristics which can be tested and measured using known techniques. The term “long-acting insulin receptor agonist” refers to an insulin receptor agonist having a prolonged pharmacokinetic and / or pharmacodynamic profile to control blood glucose levels between meals when administered no more frequently than once or twice daily. When used herein in connection with an insulin receptor agonist, the terms “once-weekly” and “suitable for once-weekly dosing” refers to a long-acting insulin receptor agonist with a pharmacokinetic and / or pharmacodynamic profile that is sufficiently prolonged to control blood glucose levels between meals when administered no more frequently than once weekly. Examples of such molecules include fusion proteins and are described in U.S. Patent Application Publication 2016 / 0324932, including insulin efsitora alfa (also referred to herein as Basal Insulin-Fc (BIF)).

[0018] Insulin efsitora alfa or BIF is a long-acting basal insulin with a typical half-life of approximately seventeen days, with the associated interindividual variability. Compared with daily basal insulin products, the prolonged half-life enables BIF as a weekly basal injection product that may bring significant convenience and flexibility to persons or other users with diabetes.

[0019] BIF comprises a dimer of an insulin receptor agonist fused to a human IgG Fc region, wherein the insulin receptor agonist comprises an insulin B-chain analog fused to an insulin A-chain analog through the use of a first peptide linker and wherein the C- terminal residue of the insulin A-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 is identified by CAS registry number 2131038-11-2, which provides the following chemical names: (1) Insulin [16-glutamic acid, 25-histidine, 27-glycine, 28-glycine, 29-glycine, 30-glycine] (human B-chain) fusion protein with peptide (synthetic 7-amino acid linker) fusion protein with insulin [47-threonine, 51-aspartic acid, 58-glycine] (human A-chain) fusion protein with peptide (synthetic 20-amino acid linker) fusion protein with immunoglobulin G2 (human Fc fragment), dimer; and (2) Homo sapiens Insulin B-chain [Y16>Y(16),F25>H(25), TPKT27-30>GGGG(27-30)] (1-30) fusion protein with diglycylseryltetraglycyl (31-37) Insulin A-chain [I10>T(47), Y14>D(51), N21>G(58)] (38-58) fusion protein with tris(tetraglycylglutaminyl)pentaglycyl (59-78) Homo sapiens Immunoglobulin heavy constant gamma 2 {del-CH1, hinge-(7-12), CH2, CH3[K107>del(300)]} (79-299), dimer 15 (80-80':83-83')-bisdisulfide, expressed in CHO cells, alfa glycosylated.

[0020] Each monomer of BIF has the amino acid sequence set forth in SEQ ID NO:1: FVNQHLCGSHLVEALELVCGERGFHYGGGGGGSGGGGGIVEQCCTSTCSL DQLENYCGGGGGQGGGGQGGGGQGGGGGECPPCPAPPVAGPSVFLFPPKP KDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFN STFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPM LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:1). Each monomer includes intrachain disulfide bonds between cysteine residues at positions 7 and 44, 19 and 57, 43 and 48, 114 and 174 and 220 and 278. The two monomers are attached by disulfide bonds between the cysteine residues at positions 80 and 83 to form the dimer. BIF’s structure, function and production are described in more detail in U.S. Patent Application Publication No.2016 / 0324932.

[0021] When used herein, the term “insulin efsitora alfa” or “BIF” refers to any insulin receptor agonist comprised of two monomers having the amino acid sequence of SEQ ID NO:1, including any protein that is the subject of a regulatory submission seeking approval of an insulin receptor agonist product that relies in whole or part upon data submitted to a regulatory agency by Eli Lilly and Company relating to BIF, regardless of whether the party seeking approval of said product actually identifies the insulin receptor agonist as BIF or uses some other term.

[0022] Embodiments of criteria and guidelines for determining loading doses and weekly maintenance doses are described in more detail below. Further, certain embodiments are directed to approaches for determining when to suspend weekly doses. System

[0023] FIG.1 illustrates a system 100 operative to assist in the management of diabetes, as described herein. System 100 includes one or more computing devices 110, a glucosesensing device 120, and a drug delivery device 140 communicatively coupled over a network 150. System 100 allows persons with diabetes to receive recommended insulin doses and allows a health care provider to monitor and control (e.g., suspend, edit, restart, or cancel) aspects of the subjects’ insulin dosing regimen.

[0024] In the illustrated embodiment, the one or more computing devices 110 includes a mobile device such as a smartphone, a laptop, desktop, tablet, and / or server computer, for example. Computing device 110 includes a processor 112, a memory 116, a display / user- interface (UI) 118, and a communication device 119 for communicating with other devices over the network 150. The processor 112, which may include one or more processing circuits, is configured to execute software and / or firmware stored in memory 116 and containing instructions that, when executed by processor 112, causes computing device 110 to perform the functions described herein. Illustratively, processor 112 includes dosing logic 114 (also referred to as application or “app” 114) that is operative to calculate and display dose recommendations, suspensions, and alerts, as described herein. The term "logic" or “app” as used herein may include software and / or firmware executing on one or more programmable processors, application-specific integrated circuits (ASICs), field- programmable gate arrays (FPGAs), digital signal processors (DSPs), hardwired logic, or combinations thereof. In some embodiments, multiple computing devices 110 each include versions or portions of dosing logic 114 that cooperate to implement the operations described herein. For example, the HCP may also have access to a version of dosing logic 114 via a computing device 110 (e.g., tablet or laptop) to provide input and to monitor and control aspects of the subject’s dosing regimen.

[0025] The display / user interface 118 may be used by users such as the patient or health care provider in accordance with any or all of the methods described herein. Display / user interface 118 is operative to provide user input data to the system 100 and to display data, information, and prompts generated by the system 100. Insulin doses calculated by dosing logic 114 are displayed by the display. Display / UI 118 includes at least one input device for receiving user input and providing the user input to the system 100. In some embodiments, display / UI 118 includes a graphical user interface (GUI) including a touchscreen display operative to display data and receive user inputs. The touchscreen display allows the user to interact with presented information, menus, buttons, and other data to receive information from the system 100 and to provide user input into the system.Alternatively and additionally, a keyboard, keypad, microphone, mouse pointer, or other suitable user input device may be provided.

[0026] Network 150 includes one or more wired and / or wireless networks to facilitate communication between the various devices of system 100 (i.e., via communication devices 119 such as antennas, signal processing circuits, ports, etc.). In some embodiments, for example, the network 150 includes one or more local area networks (LAN), the internet, and / or one or more wide area networks (WAN). LANs may include WiFi and near field or short-range communication networks such as Bluetooth®, for example. WANs may include cellular networks, for example. Components of system 100 may be communicatively coupled to one another by different components of network 150. For example, the patient’s device 110 may communicate directly with the glucose sensing device 120 and / or drug delivery device 140 via WiFi and / or Bluetooth while communicating over a cellular or internet network with the HCP’s computing device 110 or a server.

[0027] Memory 116 of computing device 110 and memory of any other device of system 100 may be any suitable computer readable medium that is accessible by a processor. The memory may be a single storage device or multiple storage devices, may be located internally or externally to the processor, and may include both volatile and non-volatile media. Exemplary memory includes random-access memory (RAM), read- only memory (ROM), electrically erasable programmable ROM (EEPROM), flash memory, a magnetic storage device, optical disk storage, or other suitable non-transitory or other medium which is configured to store data and which is accessible by the processor. The memory may include cloud storage.

[0028] Glucose sensing device 120 includes any sensor adapted to measure a glucose level of a person with diabetes, such as a blood glucose monitor (BGM), a continuous glucose monitor (CGM), and / or a flash glucose monitor (FGM). Glucose sensing device 120 includes a processor 122 in communication with a display / UI 124 and is capable of extracting and / or analyzing analyte (e.g., blood or interstitial fluid) from the body of the person with diabetes to measure and record the person’s glucose levels. Display / UI 124 displays the measured glucose levels. An optional communication device 126 allows glucose sensing device 120 to communicate measured glucose levels directly to other devices or components over network 150.

[0029] Drug delivery device 140 may include any conventional or otherwise known device configured to deliver doses of insulin to a person with diabetes. An exemplary device 140 is a mechanically actuated device, such as an injector pen, syringe, or autoinjector, configured to enable a user (e.g., patient, caregiver, HCP) to select and otherwise control the amount of insulin that is delivered. For example, a dose determined in accordance with devices and methods described herein may be communicated to the user via the display / UI 118 of the computing device 110, and the user may operate the delivery device 140 to deliver the recommended dose.

[0030] Drug delivery device 140 may be configured as a re-usable device that may be re-filled with insulin once its store of insulin is exhausted or may be configured as a disposable device that is designed to be discarded and replaced once its store of insulin is exhausted. Some embodiments of drug delivery device 140 include optional integrated or attachable electronics (e.g., processor 142, dose detection sensor 144, communication device 146) configured to measure and record the timestamp and amount of dose delivered and to communicate this information to computing device(s) 110 over network 150. In some embodiments, a device 140 such as an on-body injector or a pump is operative to receive the recommended dose directly from computing device 110 and to automatically deliver the corresponding dose upon initiation or activation by the user.

[0031] The insulin dose administered to the subject may be logged (i.e., recorded) in the dosing app 114 by the subject, caregiver, or HCP via a user input device at the computing device 110, such as a touchscreen or keyboard for example. In some embodiments, dosing app 114 is configured to prompt the patient to log the administered dose in the app 114 after recommending the dose and once the patient has administered the recommended dose via the delivery device 140. In some embodiments, the administered dose amount may be logged in the system automatically when the insulin delivery device 140 is equipped with electronics to detect and communicate the delivered dose information to the dosing app 114 via network 150.

[0032] The following describes approaches for calculating initial one-time starting doses, first weekly doses, subsequent maintenance doses, dose suspensions, and alerts. These approaches are carried out by one or more devices of the system 100.Median Fasting Blood Glucose

[0033] The median fasting blood glucose of the subject is used for various dose calculation, suspension, and alert scenarios described herein. The median fasting blood glucose may be determined by dosing logic 114 in different ways depending on the availability of recent fasting blood glucose measurements input by the subject or HCP and / or received from the glucose sensing device 120. In certain embodiments, if multiple fasting blood glucose readings have been recorded in the app in one day, only the lowest fasting blood glucose reading from that day is used in determining the median fasting blood glucose. In certain embodiments, if three or more fasting blood glucose readings have been recorded in the app since the last logged dose (within the past seven days), a median of the latest three readings is used to calculate the median fasting blood glucose level used for the calculations described herein. As another example, if only two fasting blood glucose measurements have been logged or detected since the last dose was logged, the lesser of the two measurements is used by dosing logic 114 as the median fasting blood glucose level. As another example, if there is only one fasting blood glucose measurement logged or detected since the last dose was logged, that measurement is used by dosing logic 114 as the median fasting blood glucose level. As yet another example, if no fasting blood glucose readings have been logged or detected since the last logged dose, dosing logic 114 assumes that the median fasting blood glucose is in a normal range (e.g., 80 mg / dL – 120 mg / dL) for purposes of making the calculations described herein. One-Time Starting Dose

[0034] Starting administration of once-weekly insulin receptor agonists using a standard weekly dosing regimen could result in pharmacokinetic steady-state not being reached for multiple weeks. In addition, the long elimination half-life of such products when administered once-weekly for multiple weeks may result in peak concentration levels significantly greater than the peak serum concentration level that would be observed after administration of a single dose. Accordingly, in certain embodiments, the methods, uses, and dosing regimens described herein include determination and administration of an initial “one-time starting dose”, also referred to as a “loading dose”, to reduce the time to reach pharmacokinetic steady state. Thus, when used herein, the term “one-time starting dose” or “loading dose” refers to a first dose of long-acting insulin receptor agonistsuitable for once-weekly dosing administered to a given subject that is larger than the dose that would be expected to be used for long-term of maintenance treatment. The one- time starting doses described herein generally comprise a single dose that is greater than the expected weekly maintenance dose that allows a near steady-state concentration to be reached within the first week after administering the single dose.

[0035] When used herein, the term “expected weekly maintenance dose,” refers to the dose of insulin receptor agonist suitable for once-weekly dosing that would be expected to be needed to provide glycemic control in a given subject. The expected weekly maintenance dose is determined prior to initiation of treatment with the insulin receptor agonist suitable for once-weekly dosing, whereas weekly maintenance doses administered during the course of treatment are determined based on various criteria described in more detail below. In certain embodiments for subjects who are insulin-naïve, 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 subjects already being treated with a daily basal insulin, the initial weekly maintenance dose or “expected weekly maintenance dose” may be based on factors such as the subject’s current daily basal insulin dose and / or the subject’s fasting glucose (FG), and optionally other factors such as frequency and severity of hypoglycemia and body weight (BW).

[0036] In some embodiments, the dosing logic 114 determines the one-time starting dose based on inputs received from the HCP through the HCP’s computing device 110 (e.g., tablet, laptop) of system 100 of FIG.1. Exemplary HCP inputs used for determining the one-time starting dose includes the subject’s history with insulin (e.g., insulin naive, or switching from a daily basal insulin, or switching from another weekly insulin) and fasting blood glucose level as determined or confirmed by the HCP. Alternatively, the HCP may directly recommend a one-time starting dose through system 100. In either case, dosing app 114 of the patient’s computing device 110 (e.g., smartphone) receives and displays the recommended one-time starting dose on display 118.

[0037] In certain embodiments, the one-time starting dose ranges from about 1.5 to about 5 times greater than the expected weekly maintenance dose. In certain embodiments, the one-time starting dose ranges from about 1.5 to about 3 times greaterthan the expected weekly maintenance dose. In certain embodiments, the loading dose is about 1.5, 1.6, 1.8, 2 or 3 times greater than the expected weekly maintenance dose.

[0038] For BIF, steady-state serum concentration levels following initiation of once- weekly dosing is predicted to be reached after approximately 8 to 10 or 12 weeks of once- weekly administration without a loading dose. A near steady-state concentration can be reached within the first week of dosing when using a loading dose approximately 3-fold higher than the initial weekly maintenance dose or expected weekly maintenance dose. In certain preferred embodiments, the insulin receptor agonist suitable for once weekly dosing is BIF, and the loading dose is about 3 times greater than the initial weekly maintenance dose or expected weekly maintenance dose.

[0039] Where the subject is already being treated with an existing basal insulin, such as insulin degludec or insulin glargine, and is being switched to an insulin receptor agonist suitable for once-weekly dosing, the expected weekly maintenance dose of insulin receptor agonist suitable for once-weekly dosing is typically based at least in part on the subject’s current basal insulin dose. Because such a subject’s daily basal insulin doses are being replaced by a single dose each week, the daily dose in units must be translated into a weekly dose, referred to herein as the “daily basal dose weekly equivalent,” that would be expected to provide the same level of insulin activity each day upon reaching steady-state through once-weekly dosing. The daily basal dose weekly equivalent could be expressed in insulin units or mg. If expressed in insulin units, the daily dose of units of once-daily basal insulin prior to initiation of treatment with a once-weekly insulin receptor agonist would be multiplied by 7 in order to obtain the daily basal dose weekly equivalent of once-weekly insulin receptor agonist. For example the daily basal dose weekly equivalent for a subject who had been receiving 42 units / day of insulin degludec prior to initiation of treatment with a once-weekly insulin receptor agonist would by 294 units.

[0040] In certain embodiments, the once-weekly insulin receptor agonist is provided in a delivery device (e.g., injector pen) that allows for adjustment in 5- or 10-unit increments, so when determining doses of once-weekly insulin to be administered, the daily basal dose weekly equivalent calculated as described above may be rounded to the nearest 5 or 10 units. Thus, in certain embodiments when the once weekly insulin is provided in a delivery device allowing for dose adjustments in 10-unit increments, a dailybasal dose weekly equivalent of 294 units, calculated as described above, could be rounded to 300 units or 290 units.

[0041] Returning to calculation of a one-time starting dose, patients who are not currently being treated with a basal insulin and who are starting on a once-weekly insulin receptor agonist — sometimes referred to as “insulin-naive” patients — do not have an existing daily basal insulin dose. Thus, for such patients, in certain embodiments, the one- time starting dose is set at a fixed level regardless of the other characteristics of the patient. In such embodiments, the starting dose of BIF can be 300 units (U), however, alternatives can include one-time starting doses less than 300 units (U) as determined by the HCP.

[0042] A different one-time starting dose approach can be used for persons with T2D already being treated with an existing daily basal insulin regime and switching to once- weekly BIF – also referred to as “basal switch” patients. For example, if the patient is currently taking a daily basal insulin and has a fasting blood glucose (e.g., a median fasting blood glucose level) less than a threshold (e.g., 120 mg / dL), the one-time starting dose can be the patient’s usual daily basal dose multiplied by a factor (e.g., seven), where the usual basal dose is the current dose of the daily basal insulin. However, if the median fasting blood glucose of the patient on a daily basal insulin regime is greater than the threshold, the one-time starting dose can be the usual daily basal dose multiplied by a larger factor (e.g., 21), where the usual basal dose is the current dose of the daily basal insulin. In either scenario, for patients currently on neutral protamine hagedorn (NPH) twice daily or insulin glargine U300, the usual daily basal dose used in the calculation is a reduced factor (e.g., 80%) of the patient’s current dose of the daily basal insulin. In certain embodiments, the fasting blood glucose is entered into the computing system 100 by the patient’s health care provider (HCP) who will provide guidance for the one-time starting dose, or the HCP can determine which one-time starting dose the PwD shall receive even if the fasting blood glucose is not provided.

[0043] A different one-time starting dose approach for BIF can be used for persons with T2D already being treated with a weekly insulin regime. If the patient is currently on weekly insulin, the one-time starting dose for BIF can be skipped or can be limited to a maximum amount (e.g., not be greater than a current weekly insulin dose times a multiple such as three).

[0044] Regardless of the one-time starting dose approach, a maximum one-time starting dose in all cases can be set at 2100 U — which is 100 units / day x 7 x 3 = 2100 units. First Weekly Dose

[0045] A first weekly dose is either the first dose after the starting dose or the very first dose if no starting dose was prescribed. The amount of the first weekly dose can vary depending on certain circumstances. The dosing app 114 determines the first weekly dose based on inputs received from the HCP or the patient through system 100. Exemplary inputs used for determining the first weekly dose includes the patient’s insulin history (e.g., insulin naive, or switching from a daily basal insulin, or switching from another weekly insulin) and recent fasting blood glucose levels. The dosing app 114 may receive the fasting blood glucose levels from the glucose sensing device 120, or the HCP or patient may directly enter the fasting blood glucose levels into the system. The dosing app 114 receives and displays the first weekly dose on display 118.

[0046] If the patient is insulin naïve and no hypo fasting blood glucose readings (e.g., readings below a threshold such as 70 mg / dL) have been logged in the app 114 or otherwise detected within a set time period (e.g., since the last prescribed dose logged in the app 114), the first weekly dose may be a set amount (e.g., 100 units). However, if the patient is insulin naïve and at least one hypo fasting blood glucose reading has been logged or detected since the last logged dose, the first weekly dose may be a lower amount (e.g., 60 units).

[0047] If the patient is switching from a daily basal regimen and is on a regular or reduced adjustment schedule, and no hypo fasting blood glucose readings have been logged or detected in the app 114, the first weekly dose can be the patient’s usual daily basal dose times a factor (e.g., seven). However, if the patient is switching from a daily basal regimen and is on a regular or reduced adjustment schedule, and at least one hypo fasting blood glucose reading has been logged or detected since the last logged dose, the app 114 may recommend the first weekly dose to be the patient’s daily basal dose times a factor (e.g., seven) minus a set correction amount (e.g., 40 units).

[0048] For patients that were previously on weekly insulin and no hypo fasting blood glucose readings have been logged or detected, the first weekly dose may be the patient’s usual weekly insulin dose from the previous weekly regimen. For patients that werepreviously on a weekly insulin but have had a hypo reading logged or detected, the first weekly dose may be their usual weekly insulin dose minus a correction amount (e.g., 40 units). Subsequent Doses

[0049] After the one-time starting dose and the first weekly dose, dosing app 114 determines subsequent doses or weekly maintenance doses using the following approach.

[0050] In certain embodiments, new subsequent doses are intended to be calculated immediately before taking the dose. As such, if a calculated dose has not been recorded (e.g., logged in the app 114, via patient input or data from the delivery device, as having been administered to the patient) within twenty-four hours of requesting the dose in the app 114, the dosing app 114 allows a new dose to be calculated in place of the prior calculated dose if requested in the app 114 after the twenty-four hour period.

[0051] Additional global rules or boundaries are applied by dosing app 114 when calculating subsequent doses. As one example, dosing app 114 rounds the doses to the nearest ten units, or to the nearest five units. The rounding may be based on the minimum incremental adjustment allowed by the delivery device 140 (e.g., injector pen). As another example, dosing app 114 allows a maximum recommended dose amount of 1,400 units and a minimum recommended dose amount of 60 units. As another example, a new dose cannot be requested in the app 114 less than a certain time period (e.g., three days or 72 hours) after the previous logged dose — even if a patient requests a dose recommendation in the app within the time period. In such a case, the app 114 generates a notification to the patient to wait until the next dose is due. If a dose is requested outside the minimum time range but within a second time range (e.g., seven days), the patient is alerted or notified that the weekly dose is not yet due, but dosing app 114 still calculates and displays the dose recommendation to the patient.

[0052] In the illustrated embodiment, the dosing app 114 determines the subsequent doses after the first weekly dose based on various inputs including the median fasting blood glucose level, any hypoglycemia events since the last logged dose, a base dose, and a dose adjustment, as described below. The dosing app 114 calculates a subsequent dose based on the inputs and displays the recommended subsequent dose on display 118 for the subject.

[0053] FIG.2 illustrates an exemplary flowchart of a method 200 carried out by dosing logic 114 to calculate subsequent doses after the first weekly dose, according to some embodiments. The various numerical ranges and values provided in the exemplary method 200 may be modified and customized for different patients. At block 202, dosing logic 114 determines a base dose based on a prior administered dose. In particular, the base dose is calculated based on the previous (most recent) dose recommended by dosing logic 114 and the previous administered (logged) dose. If the patient administered the previous recommended dose (i.e., the recommended dose and logged dose are the same amount), the base dose is set to the value of the previous recommended dose amount. If the patient administered more than the previous recommended dose (i.e., the logged dose exceeds the recommended dose amount), the base dose is set to the value of the previous recommended dose amount. If the patient administered a dose less than the previous recommended dose (e.g., the logged dose is in a range of 70% – 99% of the previous recommended dose), and the dose adjustment (determined at block 204) is equal to or less than 0, then the base dose is set as the dose amount that was actually administered. However, if the patient administered a dose that was significantly less than the previous recommended dose (e.g., the logged dose is less than 70% of the previous recommended dose), and the dose adjustment (determined at block 204) is equal to or less than 0, then the base dose will be set at a minimum dose level (e.g., 70% of the previous recommended dose). If the patient administered a dose that was any amount less than the previous recommended dose and the current dose adjustment (determined at block 204) is greater than zero, the base dose is set at the previous recommended dose and the current dose adjustment is set to zero. Finally, if the patient did not record (i.e., log in app 114) a previous dose following a previous dose recommendation, the base dose is set as the previous dose recommendation.

[0054] At block 204, dosing logic 114 determines a dose adjustment amount based on one or more blood glucose measurements of the patient since the last dose recommendation. The dose adjustment is set to zero (i.e., no adjustment) if the median fasting blood glucose level is within a desired or target glucose range (e.g., 80 mg / dL – 120 mg / dL). The dose adjustment is also set to zero if there have been fewer than a threshold amount (e.g., three) of blood glucose readings within a low glucose range (e.g.,54 mg / dL – 70 mg / dL). In these scenarios, the base dose amount calculated at block 202 is used as the final recommended dose amount.

[0055] The amount of the dose adjustment calculated at block 204 may be based on the occurrence of one or more blood glucose readings being below a predetermined threshold or threshold range that indicates hypoglycemia. The blood glucose readings may be obtained since the last administered dose, or alternatively over a predetermined prior period (e.g., over the last seven days). A larger dose adjustment (e.g., a reduction of 40 units) is set by dosing logic 114 in the event that: (1) three or more blood glucose readings are logged or detected within a first hypo range (e.g., 54 mg / dL – 70 mg / dL); (2) one or more blood glucose readings are logged or detected below a first minimum threshold (e.g., 54 mg / dL); or (3) one or more nocturnal (e.g., overnight) hypoglycemic episodes are logged or confirmed in the app by the patient. A smaller dose adjustment (e.g., a reduction of 20 units) is set by dosing logic 114 if the calculated median fasting blood glucose level is less than a second minimum threshold (e.g., 80 mg / dL).

[0056] The amount of the dose adjustment calculated at block 204 may be based on the occurrence of one or more fasting blood glucose readings being above a predetermined threshold or threshold range that indicates hyperglycemia. In this hyperglycemia scenario, the dose adjustment is further based on a predetermined adjustment schedule that is assigned to the patient in dosing logic 114 by the HCP via the HCP’s interface. The HCP assigns the patient a regular adjustment schedule (with dose adjustment amount being relatively more units) or a reduced adjustment schedule (with the dose adjustment amount being relatively fewer units). For example, if the calculated median fasting blood glucose level is within a predetermined range indicating hyperglycemia (e.g., 120 mg / dL – 140 mg / dL), dosing logic 114 sets a larger dose adjustment if the patient is on the regular adjustment schedule (e.g., an increase of 20 units) than if the patient is on the reduced adjustment schedule (e.g., an increase of 10 units). If the calculated median fasting blood glucose level is higher than an upper threshold of the hyper range (e.g., greater than 140 mg / dL), the dose adjustment for each schedule is even larger (e.g., an increase of 40 units if on the regular adjustment schedule, and an increase of 20 units if on the reduced adjustment schedule).

[0057] At block 206 of FIG.2, dosing logic 114 calculates the recommended dose amount based on the base dose amount and the dose adjustment amount. For example, ifthe dose adjustment is a reduction (i.e., for hypoglycemic adjustments described above), the recommended dose amount is the difference between the base amount determined at block 202 and the dose adjustment amount determined at block 204. If the dose adjustment is an increase (i.e., for hyperglycemic adjustments described above), the recommended dose amount is the sum of the base amount and the dose adjustment amount. The dosing logic 114 displays the recommended dose to the patient via the display / UI 118 (FIG.1).

[0058] In an exemplary embodiment of the present disclosure, a method of providing glycemic control in a subject in need thereof having diabetes includes administering to the subject a weekly dose of insulin efsitora alfa. In this method, the weekly dose is determined by determining a base dose amount, determining a dose adjustment amount, and calculating a recommended dose amount based on the base dose amount and the dose adjustment amount. The base dose amount is based, at least in part, on a prior administered dose amount of insulin efsitora alfa. The dose adjustment amount is based, at least in part, on one or more blood glucose measurements.

[0059] In one example, the base dose amount is based on a recommended dose amount of the previous weekly dose and an administered dose amount of the previous weekly dose. In one example, if the administered dose amount matches or exceeds the recommended dose amount of the previous weekly dose, the base dose amount is the recommended dose amount of the previous weekly dose. If the administered dose amount is less than the recommended dose amount of the previous weekly dose, and the dose adjustment amount is equal to zero, the base dose amount is the administered dose amount of the previous weekly dose. If the administered dose amount is less than the recommended dose amount of the previous weekly dose, and the dose adjustment amount is greater than zero, the base dose amount is the recommended dose amount of the previous weekly dose and the dose adjustment amount is set to zero.

[0060] In another example, the method further includes determining a median fasting blood glucose level based on the one or more blood glucose measurements, as described herein. In this example, the dose adjustment amount is zero if the median fasting blood glucose level (e.g., since the last administered dose) is between 80 mg / dL and 120 mg / dL or if less than three of the blood glucose measurements (e.g., since the last administered dose) are between 54 mg / dL and 70 mg / dL. The dose adjustment amount is a dosereduction of 40 units from the base dose amount if at least three of the blood glucose measurements are less than 70 mg / dL or if at least one of the blood glucose measurements is less than 54 mg / dL. The dose adjustment amount is a dose reduction of 20 units from the base dose amount if the median fasting blood glucose level is less than 80 mg / dL. The median fasting blood glucose level and blood glucose measurements used in these calculations may be since the last administered dose of weekly insulin, or alternatively over a predetermined period (e.g., over the last seven days).

[0061] In another example, prior to determining the weekly dose of insulin, the method includes administering to the subject an initial dose of insulin efsitora alfa that is a one- time starting dose. The one-time starting dose may be three times larger than an expected weekly maintenance dose, for example. Additionally, the expected weekly maintenance dose may be approximately seven times larger than the subject’s daily dose of basal insulin prior to initiation of treatment with insulin efsitora alfa. Additional exemplary parameters and determinations of the one-time starting dose, the expected weekly maintenance dose, and a first weekly dose prior to the determination and administration of the weekly maintenance doses are described herein. Alerts and Suspension

[0062] As a safety guardrail, in certain instances, a dose is not calculated by dosing logic 114, resulting in dose recommendations being suspended. Additionally or alternatively, one or more alerts may be generated and communicated to the device of the patient and / or their health care provider. Determining whether to suspend dosing calculations and / or generate an alert is based, at least in part, on blood glucose measurements of the patient. In the illustrative embodiment, the alerts described below are generated by dosing logic 114 and sent to the device interface of the HCP and / or patient, as applicable.

[0063] As one example, if a threshold number (e.g., two) of glucose measurements indicating hypoglycemia (e.g., less than 54 mg / dL) have been logged or detected in a certain time period (e.g., past seven days), an alert is sent to the patient’s healthcare provider. In this example, dosing logic 114 continues to recommend doses to the patient according to the titration plan despite the alert unless the HCP suspends the plan via their interface.

[0064] As another example, if a threshold number (e.g., six) of glucose measurements indicating hypoglycemia (e.g., less than 54 mg / dL) have been logged or detected in a certain time period (e.g., past 14 days), dosing logic 114 automatically suspends further dose calculations and alerts the HCP that the titration plan has been suspended for that patient.

[0065] As another example, if an average fasting blood glucose of the patient after a certain time period (e.g., 12 weeks) is above a threshold (e.g., 240 mg / dL), dosing logic 114 sends an alert to the patient’s healthcare provider.

[0066] As another example, if no fasting blood glucose measurements have been logged or detected in a certain time period (e.g., seven or more consecutive days), dosing logic 114 sends an alert to the patient.

[0067] As another example, if no fasting blood glucose measurements have been logged or detected in a certain time period (e.g., 14 or more consecutive days) and no hypo events have been logged or detected, dosing logic 114 prompts the patient in the app to enter or provide fasting blood glucose readings. If the patient adds the readings, dosing logic 114 may calculate the next dose.

[0068] As another example, if (1) no fasting blood glucose measurements have been logged or detected within a certain time range (e.g., more than 21 days but less than 28 days) but (2) there have been one or more recorded or logged glucose measurements that indicate hypoglycemia (e.g., measurements less than 70 mg / dL) but that do not trigger a suspension, dosing logic 114 may prompt the patient to log fasting blood glucose readings (and to administer a calculated dose), and the healthcare provider may be alerted.

[0069] As another example, if no fasting blood glucose measurements have been logged or detected for more than a certain time period (e.g., more than 28 days), dosing logic 114 may suspend further dosing calculations (in some embodiments, even if a hypo measurement has been logged or detected), and the healthcare provider may be alerted.

[0070] As another example, further dosing calculations may be suspended if a dose calculation has not been requested (e.g., by the patient or healthcare provided) with a certain time period (e.g., 21 or more days), and the healthcare provider may be alerted.

[0071] As another example, if use of a different insulin is logged or detected, dosing calculations may be suspended, and the healthcare provider may be alerted.

[0072] As another example, if a certain time period has passed (e.g., more than seven days) since an administered dose was logged or detected, the patient may be alerted. Another alert may be communicated to the patient if a second time period has passed (e.g., more than 14 days).

[0073] As another example, if a certain time period has passed (e.g., more than 21 days) since an administered dose was logged or detected and no hypo events have been detected, dosing calculations may be suspended, and the healthcare provider may be alerted.

[0074] As another example, if an administered dose was greater than a certain amount of the calculated dose (e.g., greater than 200% of the calculated dose), dosing calculations may be suspended. Similarly, if multiple doses were administered within a certain time period (e.g., four days) and the doses total more than a certain amount of the calculated dose (e.g., greater than 200% of the calculated dose), dosing calculations may be suspended.

[0075] As another example, if multiple administered doses (e.g., three administered doses) have been logged or detected over multiple weeks (e.g., approximately three weeks) and each of the administered doses is greater than a threshold (e.g., greater than 150% from the calculated dose), dosing calculations may be suspended. In this example, the multiple administered doses could include a cumulative amount of doses recorded over a certain time period (e.g., four days).

[0076] As another example, if administered doses have been logged or detected over multiple weeks (e.g., approximately three weeks) and each of the administered doses is less than a threshold (e.g., less than 25% from the calculated dose), dosing calculations may be suspended.

[0077] In certain embodiments, when dosing calculations are suspended, the user interface 118 displays the last dose logged as having been administered, information about why dosing calculations were suspended, and guidance (e.g., next steps) to work with a healthcare provider to resume dosing calculations. In the event that dosing calculations were suspended, a healthcare provider may remotely withdraw the suspension to allow dose calculations to resume.

[0078] FIG.3 illustrates an exemplary flowchart of a method 300 carried out by dosing logic 114 to suspend further insulin dose recommendations, according to someembodiments. At block 302, dosing logic 114 repeatedly calculates a recommended dose amount of weekly insulin based on a prior administered dose amount and a prior blood glucose level, as described herein. For example, dosing logic 114 may calculate a new dose amount of weekly insulin every seven days. Each new recommended dose amount is displayed on a user interface. At block 304, dosing logic 114 determines that no subsequent blood glucose levels have been logged or detected within a set period of time, such as 21 days or 28 days for example. At block 306, dosing logic 114 suspends the repeatedly calculating the dose amount in response to the determining that no subsequent blood glucose levels have been logged or detected within the set period of time.

[0079] In some situations, smaller “split” doses administered (and logged) at different times may be considered part of the same logged dose for purposes of calculating subsequent doses. A split dose can occur, for example, when a recommended dose is greater than the number of units of insulin remaining in the reservoir (e.g., cartridge) of the delivery device. Once the remaining insulin is administered from the cartridge, a new full cartridge can be used to supply the rest of the recommended dose.

[0080] In certain embodiments, dosing logic 114 sets the sum of all split doses as the full administered dose for purposes of subsequent calculations when: any later split dose taken within a first time period (e.g., 48 hours) after an initial split dose and within a second time period (e.g., 72 hours) of the initial dose recommendation. As such, when a split dose is detected, the subsequent dose can be calculated based on the sum of the components of the split dose as well as the timestamp of the last dose recorded.

[0081] The present disclosure is intended to embrace alternatives, modifications and variances. Additionally, while several embodiments of the present disclosure have been illustrated and / or discussed herein, it is not intended that the disclosure be limited thereto, as it is intended that the disclosure be as broad in scope as the art will allow and that the specification be read likewise. Therefore, the above description should not be construed as limiting, but merely as exemplifications of particular embodiments.

Claims

WHAT IS CLAIMED IS:

1. A system comprising: a computing device programmed to calculate a weekly recommended insulin dose for a subject using an operation comprising: determining a base dose amount of a weekly insulin, determining a dose adjustment amount, calculating the weekly recommended insulin dose based on the base dose amount and the dose adjustment amount, wherein base dose amount is based, at least in part, on a prior administered dose amount of the weekly insulin, wherein the dose adjustment amount is based, at least in part, on one or more blood glucose measurements.

2. The system of claim 1, the operation further comprising receiving a logged dose amount corresponding to the previous weekly recommended insulin dose, wherein the base dose amount is based on the previous weekly recommended insulin dose and the logged dose amount.

3. The system of claim 2, wherein if the logged dose amount matches or exceeds the previous weekly recommended insulin dose, the base dose amount is set as the previous weekly recommended insulin dose.

4. The system of claim 2, wherein if the logged dose amount is less than the previous weekly recommended insulin dose, and the dose adjustment amount is equal to zero, the base dose amount is set as the logged dose amount.

5. The system of claim 4, wherein if the logged dose amount is less than 70% of the previous weekly recommended insulin dose, and the dose adjustment amount is equal to zero, the base dose amount is set as 70% of the previous weekly recommended insulin dose.

6. The system of claim 2, wherein if the logged dose amount is less than the previous weekly recommended insulin dose, and the dose adjustment amount is greater than zero, the base dose amount is set as the previous weekly recommended insulin dose and the dose adjustment amount is set to zero.

7. The system of claim 1, wherein if a logged dose amount corresponding to the previous weekly recommended insulin dose is not received by the computing device, the base dose amount is set as previous weekly recommended insulin dose.

8. The system of claim 1, the operation further comprising determining a median fasting blood glucose level based on the one or more blood glucose measurements.

9. The system of claim 8, wherein the dose adjustment amount is set to zero if the median fasting blood glucose level is within a first target range, or less than three of the blood glucose measurements are within a second target range that is lower than the first target range.

10. The system of claim 9, wherein the first target range is between 80 mg / dL and 120 mg / dL, and the second target range is between 54 mg / dL and 70 mg / dL.

11. The system of claim 8, wherein the dose adjustment amount is a dose reduction of 40 units from the base dose amount if at least three of the blood glucose measurements are less than 70 mg / dL, or at least one of the blood glucose measurements is less than 54 mg / dL.

12. The system of claim 8, wherein dose adjustment amount is a dose reduction of 20 units from the base dose amount if the median fasting blood glucose level is less than 80 mg / dL.

13. The system of claim 8, the operation further comprising receiving a dose adjustment schedule at the computing device, wherein if the median fasting blood glucose level is greater than 120 mg / dL but less than 140 mg / dL, the dose adjustment amount is a dose increase of 20 units from the base dose amount, and if the median fasting blood glucose level is greater than 140 mg / dL, the dose adjustment amount is a dose increase of 40 units from the base dose amount.

14. The system of claim 8, the operation further comprising receiving a dose adjustment schedule at the computing device, wherein if the median fasting blood glucose level is greater than 120 mg / dL but less than 140 mg / dL, the dose adjustment amount is a dose increase of 10 units from the base dose amount, and if the median fasting blood glucose level is greater than 140 mg / dL, the dose adjustment amount is a dose increase of 20 units from the base dose amount.

15. The system of claim 1, further comprising a graphical user interface operative to display the weekly recommended insulin dose; a glucose sensing device operative to provide the one or more blood glucose measurements; and an insulin delivery device operative to deliver the weekly recommended insulin dose of the weekly insulin to the subject.

16. A method of providing glycemic control in a subject in need thereof having diabetes, the method comprising: administering to said subject a weekly dose of insulin efsitora alfa, wherein the weekly dose is determined by: determining a base dose amount, determining a dose adjustment amount, calculating a recommended dose amount based on the base dose amount and the dose adjustment amount, wherein the base dose amount is based, at least in part, on a prior administered dose amount of insulin efsitora alfa, wherein the dose adjustment amount is based, at least in part, on one or more blood glucose measurements.

17. The method of claim 16, wherein the base dose amount is based on a recommended dose amount of the previous weekly dose and an administered dose amount of the previous weekly dose.

18. The method of claim 17, wherein if the administered dose amount matches or exceeds the recommended dose amount of the previous weekly dose, the base dose amount is equal to the recommended dose amount of the previous weekly dose, if the administered dose amount is less than the recommended dose amount of the previous weekly dose, and the dose adjustment amount is equal to zero, the base dose amount is equal to the administered dose amount of the previous weekly dose, andif the administered dose amount is less than the recommended dose amount of the previous weekly dose, and the dose adjustment amount is greater than zero, the base dose amount is equal to the recommended dose amount of the previous weekly dose and the dose adjustment amount is set to zero.

19. The method of claim 16, further comprising determining a median fasting blood glucose level based on the one or more blood glucose measurements, wherein the dose adjustment amount is zero if the median fasting blood glucose level is between 80 mg / dL and 120 mg / dL, or less than three of the blood glucose measurements are between 54 mg / dL and 70 mg / dL.

20. The method of claim 16, further comprising determining a median fasting blood glucose level based on the one or more blood glucose measurements, wherein the dose adjustment amount is a dose reduction of 40 units from the base dose amount if at least three of the blood glucose measurements are less than 70 mg / dL, or at least one of the blood glucose measurements is less than 54 mg / dL; and the dose adjustment amount is a dose reduction of 20 units from the base dose amount if the median fasting blood glucose level is less than 80 mg / dL.

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