Methods of Using Dulaglutide and Compositions Containing Dulaglutide

Abstract

The present invention relates to methods for improving glycemic control in subjects with type 2 diabetes (T2D) and in need of additional glycemic control, particularly to compositions containing new and high doses of dulaglutide. The present invention provides a method for treating dulaglutide in a subject, comprising administering a first dose of dulaglutide once weekly for at least four weeks and then escalating the dose to a second dose administered once weekly, wherein the first dose is selected from the group consisting of 1.5 and 3.0 mg, and the second dose is selected from the group consisting of 3.0 and 4.5 mg. The present invention also provides a stable aqueous pharmaceutical formulation comprising: a) dulaglutide at a concentration selected from the group consisting of 6.0 or 9.0 mg / mL, b) mannitol at a concentration of 46.4 mg / mL, c) trisodium citrate at a concentration of 2.74 mg / mL, and d) polysorbate 80 at a concentration of 0.25 to 0.5 mg / mL.

Description

[Technical Field]

[0001] The present invention relates to the field of medicine. More particularly, the present invention relates to methods of using new doses of dulaglutide and compositions containing such higher doses of dulaglutide. [Background technology]

[0002] Dulaglutide, the active ingredient in Trulicity®, is a glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1 RA) approved for use as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (T2D). Two once-weekly doses of dulaglutide, 0.75 mg and 1.5 mg, were studied in a Phase 3 development program and were granted regulatory approval in the United States (US), European Union, and other jurisdictions in 2014. Since approval in 2014, these two doses of dulaglutide have been used to treat many patients with T2D, resulting in significant reductions in HbA1c with a low risk of hypoglycemia and weight loss.

[0003] Although therapy with dulaglutide at currently approved doses has enabled the majority of patients enrolled in Phase 3 programs to achieve glycemic goals (with or without the use of other concomitant medications for T2D), a significant number of patients given currently approved therapies that include dulaglutide do not reach their glycemic control goals (see, e.g., Stark Casagrande et al. The prevalence of meeting A1c, blood pressure, and LDL goals among people with diabetes, 1988-2010. Diabetes Care. 2013;36(8):2271-2279). Thus, there remains a significant medical need to provide enhanced efficacy of pharmaceutical agents while also maintaining an overall acceptable benefit / risk profile. Summary of the Invention

[0004] The doses, methods, and compositions of the present invention are intended to meet that need. Benefits of the present invention include providing additional glycemic control, as evidenced, for example, by further reductions in HbA1c, and / or weight loss compared to currently approved doses of dulaglutide. Furthermore, the present invention provides such benefits while maintaining an acceptable profile of safety risks and adverse events.

[0005] Accordingly, the present invention provides a method for improving glycemic control in a subject having type 2 diabetes (T2D) and in need of additional glycemic control, comprising: a) identifying subjects with T2D and in need of further glycemic control; b) administering to said subject a first dose of dulaglutide once weekly for a minimum of 4 weeks; and c) escalating the dose to a second dose; the first dose is selected from the group consisting of 1.5 and 3.0 mg once weekly, and the second dose is selected from the group consisting of 3.0 and 4.5 mg once weekly; A method is provided.

[0006] In another aspect, the present invention provides a method of improving glycemic control in a subject having type 2 diabetes (T2D) and in need of additional glycemic control, comprising: a) identifying subjects with T2D and in need of further glycemic control; b) administering 0.75 mg of dulaglutide once weekly to the aforementioned subjects for a minimum of 4 weeks; c) administering 1.5 mg of dulaglutide once weekly to said subjects for a minimum of 4 weeks; and d) administering 3.0 mg once a week to the subject.

[0007] In certain embodiments, the method further comprises increasing the 3.0 mg dose to 4.5 mg once weekly after the subject has been treated with the 3.0 mg dose for a minimum of 4 weeks.

[0008] In another aspect, the present invention provides a method for improving glycemic control in a subject who has type 2 diabetes (T2D) and is being treated with a 1.5 mg dose of dulaglutide once a week but requires further glycemic control, comprising increasing the administered dose of dulaglutide to 3.0 mg once a week.

[0009] In another aspect, the present invention provides a method for improving glycemic control in a subject who has type 2 diabetes (T2D) and is being treated with a 3.0 mg dose of dulaglutide once a week but requires further glycemic control, comprising increasing the administered dose of dulaglutide to 4.5 mg once a week.

[0010] In another aspect, the present invention provides an improved method of administering dulaglutide to a subject with T2D and in need of further glycemic control, wherein the improvement comprises administering 1.5 mg of dulaglutide once weekly for at least 4 weeks, and then increasing the dose to 3.0 mg once weekly.

[0011] In another aspect, the present invention provides an improved method of administering dulaglutide to a subject with T2D and in need of further glycemic control, wherein the improvement comprises administering 0.75 mg of dulaglutide once weekly for at least 4 weeks, then increasing the dose to 1.5 mg of dulaglutide once weekly for at least 4 weeks, and then increasing the dose to 3.0 mg once weekly.

[0012] In another aspect, the present invention provides an improved method of administering dulaglutide to a subject having T2D and in need of additional glycemic control, wherein the improvement comprises: a) 3.0 mg of dulaglutide administered once weekly for a minimum of 4 weeks, and b) Increase the dose to 4.5 mg once weekly. The present invention provides a method comprising:

[0013] In another aspect, the present invention provides a method of providing chronic weight management to a subject in need thereof, comprising: a) administering 0.75 mg of dulaglutide once weekly to the aforementioned subjects for a minimum of 4 weeks; b) administering 1.5 mg of dulaglutide once weekly to said subjects for a minimum of 4 weeks; and c) increasing the dose to 3.0 mg once weekly.

[0014] In another aspect, the present invention provides a method of providing chronic weight management to a subject in need thereof, comprising: a) Identifying subjects who have previously been treated with 1.5 mg of dulaglutide once weekly for a minimum of 4 weeks; and b) Increase the dose to 3.0 mg once weekly. The present invention provides a method comprising:

[0015] In another aspect, the present invention provides a method of providing chronic weight management to a subject in need thereof, comprising: a) Identifying subjects who have previously been treated with 3.0 mg of dulaglutide once weekly for a minimum of 4 weeks; and b) Increase the dose to 4.5 mg once weekly. The present invention provides a method comprising:

[0016] In another aspect, the present invention provides a stable pharmaceutical formulation comprising: a) dulaglutide at a concentration selected from the group consisting of 6.0 or 9.0 mg / mL; b) mannitol at a concentration of 46.4 mg / mL; c) trisodium citrate at a concentration of 2.74 mg / mL, and d) Polysorbate 80 at a concentration of 0.25 mg / mL.

[0017] In another aspect, the present invention provides dulaglutide for use in improving glycemic control in a subject having type 2 diabetes (T2D) and in need of additional glycemic control, comprising: a) identifying subjects with T2D and in need of further glycemic control; b) administering to said subject a first dose of dulaglutide once weekly for a minimum of 4 weeks; and c) escalating the dose to a second dose; Provided is dulaglutide for use, wherein the first dose is selected from the group consisting of 1.5 and 3.0 mg once weekly, and the second dose is selected from the group consisting of 3.0 and 4.5 mg once weekly.

[0018] In another aspect, the present invention provides dulaglutide for use in improving glycemic control in a subject having type 2 diabetes (T2D) and in need of further glycemic control, comprising: a) identifying subjects with T2D and in need of further glycemic control; b) administering 0.75 mg of dulaglutide once weekly to the aforementioned subjects for a minimum of 4 weeks; c) administering 1.5 mg of dulaglutide once weekly to said subjects for a minimum of 4 weeks; and d) administering 3.0 mg once a week to the subject.

[0019] In another aspect, the present invention provides dulaglutide for use in improving glycemic control in a subject who has type 2 diabetes (T2D) and is being treated with a dose of 1.5 mg dulaglutide once a week but requires further glycemic control, comprising increasing the administered dose of dulaglutide to 3.0 mg once a week.

[0020] In another aspect, the present invention provides dulaglutide for use in improving glycemic control in a subject who has type 2 diabetes (T2D) and is being treated with a dose of dulaglutide of 3.0 mg once a week but requires further glycemic control, comprising increasing the administered dose of dulaglutide to 4.5 mg once a week.

[0021] In another aspect, the present invention provides dulaglutide for use in providing chronic weight management in a subject in need thereof, comprising: a) administering 0.75 mg of dulaglutide once weekly to the aforementioned subjects for a minimum of 4 weeks; b) administering 1.5 mg of dulaglutide once weekly to said subjects for a minimum of 4 weeks; and c) increasing the dose to 3.0 mg once weekly.

[0022] In another aspect, the present invention provides dulaglutide for use in providing chronic weight management in a subject in need thereof, comprising: a) Identifying subjects previously treated with 1.5 mg dulaglutide once weekly for at least 4 weeks; b) increasing the dose to 3.0 mg once weekly.

[0023] In another aspect, the present invention provides dulaglutide for use in providing chronic weight management in a subject in need thereof, comprising: a) Identifying subjects who have previously been treated with 3.0 mg of dulaglutide once weekly for a minimum of 4 weeks; and b) increasing the dose to 4.5 mg once weekly.

[0024] In another aspect, the present invention provides a use of dulaglutide for the manufacture of a medicament for improving glycemic control in a subject having type 2 diabetes (T2D) and in need of additional glycemic control, comprising: a) identifying subjects with T2D and in need of further glycemic control; b) administering to said subject a first dose of dulaglutide once weekly for a minimum of 4 weeks; and c) escalating the dose to a second dose; The use is provided wherein the first dose is selected from the group consisting of 1.5 and 3.0 mg once weekly, and the second dose is selected from the group consisting of 3.0 and 4.5 mg once weekly.

[0025] In another aspect, the present invention provides a use of dulaglutide for the manufacture of a medicament for improving glycemic control in a subject having type 2 diabetes (T2D) and in need of further glycemic control, comprising: a) identifying subjects with T2D and in need of further glycemic control; b) administering 0.75 mg of dulaglutide once weekly to the aforementioned subjects for a minimum of 4 weeks; c) administering 1.5 mg of dulaglutide once weekly to said subjects for a minimum of 4 weeks; and d) administering 3.0 mg once a week to the subject.

[0026] In another aspect, the present invention provides a use of dulaglutide for the manufacture of a medicament for improving glycemic control in a subject having type 2 diabetes (T2D) and being treated with a dose of 1.5 mg dulaglutide once a week but requiring further glycemic control, comprising increasing the administered dose of dulaglutide to 3.0 mg once a week.

[0027] In another aspect, the present invention provides a use of dulaglutide for the manufacture of a medicament for improving glycemic control in a subject having type 2 diabetes (T2D) and being treated with a 3.0 mg dose of dulaglutide once weekly but requiring further glycemic control, comprising increasing the administered dose of dulaglutide to 4.5 mg once weekly.

[0028] In another aspect, the present invention provides a use of dulaglutide for the manufacture of a medicament for providing chronic weight management in a subject in need thereof, comprising: a) administering 0.75 mg of dulaglutide once weekly to the aforementioned subjects for a minimum of 4 weeks; b) administering 1.5 mg of dulaglutide once weekly to said subjects for a minimum of 4 weeks; and c) increasing the dose to 3.0 mg once weekly.

[0029] In another aspect, the present invention provides a use of dulaglutide for the manufacture of a medicament for providing chronic weight management in a subject in need thereof, comprising: a) Identifying subjects who have previously been treated with 1.5 mg of dulaglutide once weekly for a minimum of 4 weeks; and b) Increase the dose to 3.0 mg once weekly. Provide for use, including

[0030] In another aspect, the present invention provides a use of dulaglutide for the manufacture of a medicament for providing chronic weight management in a subject in need thereof, comprising: a) Identifying subjects who have previously been treated with 3.0 mg of dulaglutide once weekly for a minimum of 4 weeks; and b) increasing the dose to 4.5 mg once weekly.

[0031] Dulaglutide is a human GLP-1 RA, comprising a dimer of a GLP-1 analog fused at its C-terminus via a peptide linker to the N-terminus of an analog of the Fc portion of an immunoglobulin, and is identified by CAS Registry Number 923950-08-7. Each dulaglutide monomer is represented by SEQ ID NO:1: 10 20 30 40 50 60 HGEGTFTSDVSSYLEEQAAKEFIAWLVKGGGGGGGSGGGGGSGGGGSAESKYGPPCPPCPA 70 80 90 100 110 120 PEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP 130 140 150 160 170 180 REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTL 190 200 210 220 230 240 PPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLT 250 260 270 VDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 1) It has the amino acid sequence shown in

[0032] The two monomers are linked by a disulfide bond to form a dimer. The structure, function, production, and use of dulaglutide in the treatment of T2D are described in more detail in US 7,452,966 and US Patent Application Publication No. US 20100196405. As used herein, the term "dulaglutide" refers to any GLP-1 RA protein dimer of two monomers having the amino acid sequence of SEQ ID NO: 1, including any protein that is the subject of a regulatory agency application seeking approval of a GLP-1 RA product that relies in whole or in part on data submitted to a regulatory agency by Eli Lilly and Company regarding dulaglutide, regardless of whether the person seeking approval of such protein actually identifies the protein as dulaglutide or uses some other term.

[0033] Dulaglutide stimulates insulin synthesis and secretion and has been shown to provide improved glycemic control in patients with type 2 disease (T2D) compared with placebo, both when administered in combination with metformin. As noted above, dulaglutide doses of 0.75 mg and 1.5 mg were selected for a phase 3 registration study, submitted for regulatory approval, and approved in 2014. Since then, they have been used to provide glycemic control in thousands of patients with type 2 disease (T2D). However, as noted above, many patients with type 2 disease worldwide continue to struggle with weight management without reaching HbA1c goals, and new therapies that can provide additional glycemic control and / or weight loss are needed.

[0034] Although increasing the dose of a drug can achieve increased efficacy in some cases, increasing the dose of a drug also carries a greater risk of side effects.For example, administration of GLP-1 RAs is known to carry risks of nausea, diarrhea, and vomiting (see, e.g., Trulicity® prescribing information), and in 33 patients treated with 3.0 mg or higher doses of dulaglutide in a Phase 1 dosing study and the dose-finding portion of a Phase 2 / 3 study, the incidence of gastrointestinal (GI) adverse events (AEs) commonly associated with treatment with GLP-1 RAs, such as nausea (17 patients, 52%) and vomiting (9 patients, 27%), was higher than the incidence reported using currently approved doses in Phase 3 clinical trials (see, e.g., Barrington et al. A 5-week study of the pharmacokinetics and pharmacodynamics of LY2189265, a novel, long-acting glucagon-like peptide-1 analogue, in patients with type 2 diabetes. Diabetes Obes Metab. 2011;13(5):426-433; Skrivanek et al. Dose-finding results in an adaptive, seamless, randomized trial of once-weekly dulaglutide combined with metformin in type 2 diabetes patients (AWARD-5). Diabetes Obes. Metab. 2014;16(8):748-756; Jendle et al. Efficacy and safety of dulaglutide in the treatment of type 2 diabetes: a comprehensive review of the dulaglutide clinical data focusing on the AWARD phase 3 clinical trial program. Diabetes Metab Res Rev. 2016;32(8):776-790). Five of 33 patients (15%) actually discontinued treatment prematurely due to GI AEs.In addition to GI tolerability issues, early studies at higher doses also suggested that increasing the dose may also carry the risk of causing an unacceptable increase in heart rate (see, e.g., Skrivanek 2014). Indeed, after extensive open-label interim data review in one of the above-referenced studies, which initially included seven doses ranging from 0.25 mg to 3.0 mg, the Data Monitoring Committee (DMC) recommended halting randomization of patients to the 3.0 mg dose of dulaglutide because of a higher incidence of pancreatic enzyme levels above the upper limit of normal (ULN), increased heart rate (HR), and a higher incidence of GI adverse events (see, e.g., Skrivanek 2014). Therefore, any increase in dose must provide a balance between sufficiently enhanced efficacy without introducing unacceptable safety or tolerability issues.

[0035] It has been discovered that increased doses of 3.0 mg or 4.5 mg of dulaglutide once weekly can provide enhanced efficacy compared to the currently available 0.75 mg and 1.5 mg doses and can be administered with an acceptable safety and tolerability profile when an upward dose titration regimen is used prior to administration. Thus, the present invention provides for the administration of 3.0 mg and 4.5 mg of dulaglutide once weekly, along with a dose titration regimen that results in an acceptable safety and tolerability profile when administering the 3.0 mg and 4.5 mg doses. In subjects who are starting dulaglutide treatment for the first time, the dose titration regimen includes starting treatment with a 0.75 mg dose once weekly, then increasing the dose to 1.5 mg once weekly, then increasing the dose to 3.0 mg once weekly, and then, optionally, increasing the dose to 4.5 mg once weekly. In subjects who are already receiving dulaglutide but need further glycemic control, however, the dose titration regimen does not require a reduction in the subject's current dose. For example, in a subject who is receiving 1.5 mg of dulaglutide once a week but needs further glycemic control, the regimen does not require a reduction in the dose to 0.75 mg, but instead increases the dose to 3.0 mg and then optionally to 4.5 mg. Similarly, in a subject who is receiving 3.0 mg of dulaglutide once a week but needs further glycemic control, the regimen does not require a reduction in the dose to 0.75 mg or 1.5 mg once a week, but instead increases the dose to 4.5 mg. For any of the above embodiments of the dose titration regimen, however, the dose is preferably not increased to the next dose until the current dose has been administered for at least four weeks.

[0036] However, it was discovered that increasing dulaglutide concentration also required other modifications to current commercial formulations, and therefore the present invention also provides new formulations that ensure that compositions containing increased doses of dulaglutide remain chemically and physically stable throughout a 2-year refrigerated shelf life and 14-day use period and meet current product specifications.

[0037] Currently approved products containing dulaglutide are provided in a 0.5 mL aqueous solution containing either 0.75 mg or 1.5 mg of dulaglutide, as well as the following excipients: citric acid anhydrous (0.07 mg), mannitol (23.2 mg), polysorbate 80 (PS80) (0.10 mg), and trisodium citrate dihydrate (1.37 mg) (Trulicity® prescribing information highlights). PS80 is provided in the formulation to help provide protection from physical stress and ensure that the dulaglutide protein remains physically stable for the duration of the product shelf life (2 years under refrigerated conditions) and maximum use period (up to 14 days at room temperature). Dulaglutide product specifications therefore include a lower PS80 concentration limit above which the concentration must remain throughout the shelf life and use period. To ensure that the concentration of PS80 remains above its specified lower limit throughout the duration of its shelf life and use, currently approved dulaglutide products contain a PS80 concentration of 0.1 mg / 0.5 mL (0.02% w / v) at the time of manufacture.

[0038] When the concentration of dulaglutide is increased to the higher doses provided in the methods of the invention, the concentration of PS80 decreases more than in the currently approved formulation due to increased hydrolysis, and modifications to the formulation were required to ensure sufficient PS80 is present to meet product specifications and provide physical stability. As described in more detail in the Examples below, it was determined that increasing the concentration of PS80 to 0.025% ensures that the PS80 specification limits can be met throughout shelf-life and use with the higher dulaglutide doses provided in the methods of the invention, but is not so high as to produce unacceptable visible particulate matter resulting from PS80 hydrolysis or otherwise have any undesirable effect on the chemical or physical stability of the formulation. Thus, in certain embodiments, the methods of the invention are carried out by administering increased doses of dulaglutide in 0.5 mL of aqueous solution containing 3.0 mg or 4.5 mg of dulaglutide, citric acid anhydrous (0.07 mg), mannitol (23.2 mg), trisodium citrate dihydrate (1.37 mg), and polysorbate 80 (PS80) (0.125 mg). In certain embodiments, the methods of the invention are carried out by administering increased doses of dulaglutide in any volume of solution containing 6.0 mg or 9.0 mg / mL of dulaglutide, 0.14 mg / mL of citric acid anhydrous, 46.4 mg / mL of mannitol, 2.74 mg / mL of trisodium citrate dehydrate, and 0.25 mg / mL of polysorbate 80 (PS80).

[0039] As used herein, the terms "treatment," "treat," "treating," and the like are intended to include slowing or attenuating the progression of a disease or disorder. These terms also include alleviating, ameliorating, attenuating, eliminating, or reducing one or more symptoms of a disorder or condition, even if the disorder or condition is not actually eliminated and even if the progression of the disorder or condition is not itself slowed or reversed.

[0040] "Subject" refers to a mammal, preferably a human, having a disease, disorder, or condition that would benefit from treatment with increased doses of dulaglutide.

[0041] "Glycemic control" refers to maintaining or reducing a subject's HbA1c levels, "improving" glycemic control refers to reducing HbA1c, and "requiring" "further" glycemic control refers to the need for a reduction in HbA1c.

[0042] "Chronic weight management" refers to weight loss.

[0043] "HbA1c" refers to the level of glycated hemoglobin, which occurs when hemoglobin combines with glucose in the blood. HbA1c levels are a commonly used indicator of glycemic control in patients with diabetes, and reduced HbA1c levels generally indicate improved glycemic control. In the context of the methods of the present invention, the methods of the present invention result in a reduction in HbA1c. In certain embodiments, the reduction in HbA1c is compared to the HbA1c levels resulting from treatment with currently approved doses of 0.75 mg and 1.5 mg dulaglutide.

[0044] In certain embodiments of the present invention, the doses and administration regimens of dulaglutide described herein are provided for the treatment of obesity, chronic weight management and / or non-therapeutic weight loss in a subject in need thereof. 2 In certain embodiments, the subject has a higher body mass index (BMI). 2 In certain embodiments, the subject has a higher body mass index (BMI). 2 have a higher body mass index (BMI). In certain embodiments, the subject also has one or more weight-related comorbid conditions, such as T2D, hypertension, and / or dyslipidemia.

[0045] In certain embodiments, the doses and administration regimens described herein are provided for the treatment of other diseases or conditions, such as fatty liver disease (FLD), non-alcoholic steatohepatitis (NASH) or chronic kidney disease (CKD).

[0046] In certain embodiments, the doses and administration regimens of dulaglutide described herein are provided for the prevention and / or treatment of cognitive impairment and / or neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and / or multiple sclerosis.

[0047] The therapeutic methods and uses described herein may be provided in simultaneous or sequential combination with other T2D treatments, including oral T2D medications such as metformin, and / or other injectable medications, including rapid-acting or basal insulin.

[0048] Additional embodiments of the present invention are described below: 1. A method for improving glycemic control in a subject with type 2 diabetes (T2D), comprising administering to said subject an increased dose of dulaglutide once weekly, wherein the increased dose is selected from the group consisting of 3.0 mg and 4.5 mg of dulaglutide once weekly.

[0049] 2. A method of improving glycemic control in a subject having type 2 diabetes (T2D) and in need of further glycemic control, comprising: a) administering 1.5 mg of dulaglutide once weekly to said subject; and b) administering to the subject an increased dose of dulaglutide once a week, wherein the increased dose is selected from the group consisting of 3.0 mg and 4.5 mg of dulaglutide once a week.

[0050] 3. A method of improving glycemic control in a subject with type 2 diabetes (T2D), comprising: a) administering to said subject 0.75 mg of dulaglutide once weekly, followed by: b) administering 1.5 mg of dulaglutide once weekly to said subject, followed by: c) administering to the subject an increased dose of dulaglutide once a week.

[0051] 4. A method of improving glycemic control in a subject having type 2 diabetes (T2D) and in need of further glycemic control, comprising: a) Identifying subjects previously treated with 1.5 mg of dulaglutide once weekly, followed by: b) administering an increased dose of dulaglutide once weekly.

[0052] 5. The method of any of embodiments 1-4, wherein 1.5 mg of dulaglutide is administered once a week for two or more weeks prior to administering the increased dose of dulaglutide.

[0053] 6. The method of any of embodiments 1-5, wherein 1.5 mg of dulaglutide is administered once weekly for a minimum of 4 weeks prior to administering the increased dose of dulaglutide.

[0054] 7. An improved method of administering dulaglutide to a subject with type 2 diabetes (T2D) in need of further glycemic control, wherein the improvement comprises administering an increased dose of dulaglutide selected from the group consisting of 3.0 mg and 4.5 mg once weekly.

[0055] 8. A method of improving glycemic control in a subject having type 2 diabetes (T2D) and in need of further glycemic control, comprising: a) administering 3.0 mg of dulaglutide once weekly to the aforementioned subject, followed by b) administering 4.5 mg of dulaglutide to the subject once a week.

[0056] 9. A method of improving glycemic control in a subject with type 2 diabetes (T2D), comprising: a) administering 1.5 mg of dulaglutide once weekly to the aforementioned subjects, followed by: b) administering 3.0 mg of dulaglutide once weekly to said subject, followed by: c) administering 4.5 mg of dulaglutide to the subject once a week.

[0057] 10. A method of improving glycemic control in a subject having type 2 diabetes (T2D) and in need of further glycemic control, comprising: a) administering to said subject 0.75 mg of dulaglutide once weekly, followed by: b) administering 1.5 mg of dulaglutide once weekly to said subject, followed by: c) administering 3.0 mg of dulaglutide once weekly to said subject, followed by: d) administering 4.5 mg of dulaglutide to the subject once a week.

[0058] 11. A method of improving glycemic control in a subject having type 2 diabetes (T2D) and in need of further glycemic control, comprising: a) Identifying subjects previously treated with 3.0 mg dulaglutide once weekly, followed by: b) administering 4.5 mg of dulaglutide once weekly.

[0059] 12. The method of any of the above embodiments, wherein each dose of dulaglutide is administered once weekly for two or more weeks prior to administering the increased dose of dulaglutide.

[0060] 13. The method of any of the above embodiments, wherein each identified dose of dulaglutide is administered for a minimum of 4 weeks before administering a subsequent escalated dose of dulaglutide.

[0061] 14. An improved method of administering dulaglutide to a subject with type 2 diabetes (T2D) who is receiving a first dose of dulaglutide but needs further glycemic control, wherein the improvement comprises administering an increased dose of dulaglutide.

[0062] 15. The improved method of embodiment 14, wherein the first dose of dulaglutide is 1.5 mg and the second dose of dulaglutide is 3.0 mg.

[0063] 16. The improved method of any of embodiments 14-15, wherein the first dose of dulaglutide is administered for two or more weeks before administering the second dose of dulaglutide.

[0064] 17. The improved method of any of embodiments 14-15, wherein the first dose of dulaglutide is administered for a minimum of 4 weeks before administering the second dose of dulaglutide.

[0065] 18. The method of any of the above embodiments, wherein the method results in a reduction in HbA1c.

[0066] 19. The method of any of the above embodiments, wherein the method results in a reduction in HbA1c of greater than about 0.1% compared to treatment with 1.5 mg of dulaglutide once weekly.

[0067] 20. The method of any of the above embodiments, wherein the method results in a reduction in HbA1c of greater than about 0.2% compared to treatment with 1.5 mg of dulaglutide once weekly.

[0068] 21. The method of any of the above embodiments, wherein the method results in a reduction in HbA1c of greater than about 0.3% compared to treatment with 1.5 mg of dulaglutide once weekly.

[0069] 22. The method of any of the above embodiments, wherein the method results in a reduction in HbA1c of greater than about 0.5% compared to treatment with 1.5 mg of dulaglutide once weekly.

[0070] 23. A method of providing chronic weight management to a subject in need thereof, comprising administering to said subject an amount of dulaglutide according to any of the above embodiments.

[0071] 24. The method of any of the above embodiments, wherein the method results in weight loss.

[0072] 25. The method of any of the above embodiments, wherein the method results in a weight loss of at least about 1 kg compared to treatment with 1.5 mg of dulaglutide once a week.

[0073] 26. The method of any of the above embodiments, wherein the method results in a weight loss of at least about 1.3 kg compared to treatment with 1.5 mg of dulaglutide once a week.

[0074] 27. The method of any of the above embodiments, wherein the method results in a weight loss of at least about 1.5 kg compared to treatment with 1.5 mg of dulaglutide once a week.

[0075] 28. The method of any of the above embodiments, wherein the method results in a weight loss of at least about 2 kg compared to treatment with 1.5 mg of dulaglutide once a week.

[0076] 29. A method for treating NASH in a subject in need thereof, comprising administering to said subject an amount of dulaglutide according to any of the above embodiments.

[0077] 30. A method of treating a metabolic disease in a subject in need thereof, comprising administering to said subject an amount of dulaglutide according to any of the above embodiments.

[0078] 31. A method of treating CKD in a subject in need thereof, comprising administering to said subject an amount of dulaglutide according to any of the above embodiments.

[0079] 32. A method of treating Alzheimer's disease in a subject in need thereof, comprising administering to said subject an amount of dulaglutide according to any of the above embodiments.

[0080] 33. A method of treating Parkinson's disease in a subject in need thereof, comprising administering to said subject an amount of dulaglutide according to any of the above embodiments.

[0081] 34. A method of treating multiple sclerosis in a subject in need thereof, comprising administering to said subject an amount of dulaglutide according to any of the above embodiments.

[0082] 35. The method of any of the above embodiments, wherein administration of dulaglutide does not result in unacceptable GI tolerability.

[0083] 36. The method of any of the above embodiments, wherein administration of dulaglutide does not result in an unacceptable increase in heart rate.

[0084] 37. Increasing doses of dulaglutide are administered in a 0.5 mL aqueous composition, wherein the aqueous composition is a) 0.07 mg citric acid, b) 23.2 mg of mannitol; c) 1.37 mg trisodium citrate, and d) about 0.125 to about 0.25 mg polysorbate 80.

[0085] 38. The method of embodiment 37, wherein the amount of polysorbate 80 in the composition is about 0.125 mg.

[0086] 39. The method of any of embodiments 37-38, wherein the composition remains chemically and physically stable at 2-8°C for 2 years.

[0087] 40. The method of any of embodiments 37-39, wherein the composition remains chemically and physically stable at 30° C. for 14 days.

[0088] 41. A stable pharmaceutical composition comprising: a) dulaglutide at a concentration selected from the group consisting of 6.0 or 9.0 mg / mL; b) mannitol at a concentration of 46.4 mg / mL; c) trisodium citrate at a concentration of 2.74 mg / mL, and d) A stable pharmaceutical composition comprising polysorbate 80 at a concentration of about 0.25 to 0.5 mg / mL.

[0089] 42. The stable pharmaceutical composition of embodiment 41, wherein the concentration of polysorbate 80 is about 0.25 mg / mL.

[0090] 43. The stable pharmaceutical composition of either embodiment 41 or 42, wherein the concentration of dulaglutide is 6.0 mg / mL.

[0091] 44. The stable pharmaceutical composition of either embodiment 41 or 42, wherein the concentration of dulaglutide is 9.0 mg / mL.

[0092] 45. The stable pharmaceutical composition of either embodiment 41 or 42, wherein the composition remains chemically and physically stable at 2-8° C. for 2 years.

[0093] 46. ​​The stable pharmaceutical composition of any of embodiments 41, 42, or 45, wherein the composition remains chemically and physically stable at 30° C. for 14 days.

[0094] 47. An autoinjector comprising the stable pharmaceutical composition of any of embodiments 41-46.

[0095] 48. A method of improving glycemic control in a subject with type 2 diabetes (T2D), comprising administering to said subject 0.5 mL of the stable pharmaceutical composition of any of embodiments 41-44.

[0096] 49. Dulaglutide for use in improving glycemic control in a subject with type 2 diabetes (T2D) and in need of additional glycemic control, a) identifying subjects with T2D and in need of further glycemic control; b) administering to said subject a first dose of dulaglutide once weekly for a minimum of 4 weeks; and c) escalating the dose to a second dose; Dulaglutide for use, wherein the first dose is selected from the group consisting of 1.5 and 3.0 mg once weekly, and the second dose is selected from the group consisting of 3.0 and 4.5 mg once weekly.

[0097] 50. Dulaglutide for use according to embodiment 49, wherein the first dose is 1.5 mg and the second dose is 3.0 mg.

[0098] 51. Dulaglutide for use according to embodiment 49, wherein the subject is treated with a 0.75 mg dose of dulaglutide for a minimum of 4 weeks prior to administering the 1.5 mg dose.

[0099] 52. Dulaglutide for use according to either embodiment 50 or 51, further comprising increasing the dose of 3.0 mg to 4.5 mg once a week after the subject has been treated with the 3.0 mg dose for a minimum of 4 weeks.

[0100] 53. Dulaglutide for use according to embodiment 49, wherein the first dose is 3.0 mg and the second dose is 4.5 mg.

[0101] 54. Use of dulaglutide for the manufacture of a medicament for improving glycemic control in a subject having type 2 diabetes (T2D) and in need of additional glycemic control, comprising: a) identifying subjects with T2D and in need of further glycemic control; b) administering to said subject a first dose of dulaglutide once weekly for a minimum of 4 weeks; and c) escalating the dose to a second dose; The use wherein the first dose is selected from the group consisting of 1.5 and 3.0 mg once weekly and the second dose is selected from the group consisting of 3.0 and 4.5 mg once weekly.

[0102] 55. The use of embodiment 54, wherein the first dose is 1.5 mg and the second dose is 3.0 mg.

[0103] 56. The use of embodiment 55, wherein the subject is treated with a 0.75 mg dose of dulaglutide for a minimum of 4 weeks prior to administering the 1.5 mg dose.

[0104] 57. The use of any of embodiments 54-56, further comprising increasing the 3.0 mg dose to 4.5 mg once weekly after the subject has been treated with the 3.0 mg dose for a minimum of 4 weeks.

[0105] 58. The use of embodiment 54, wherein the first dose is 3.0 mg and the second dose is 4.5 mg.

[0106] 59. Dulaglutide for use in improving glycemic control in a subject having type 2 diabetes (T2D) and in need of further glycemic control, a) identifying subjects with T2D and in need of further glycemic control; b) administering 0.75 mg of dulaglutide once weekly to the aforementioned subjects for a minimum of 4 weeks; c) administering 1.5 mg of dulaglutide once weekly to said subjects for a minimum of 4 weeks; and d) administering 3.0 mg once weekly to the aforementioned subject.

[0107] 60. Dulaglutide for use according to embodiment 59, further comprising increasing the dose to 4.5 mg once weekly after the subject has been administered a dose of 3.0 mg once weekly for a minimum of 4 weeks.

[0108] 61. Use of dulaglutide for the manufacture of a medicament for improving glycemic control in a subject having type 2 diabetes (T2D) and in need of further glycemic control, comprising: a) identifying subjects with T2D and in need of further glycemic control; b) administering 0.75 mg of dulaglutide once weekly to the aforementioned subjects for a minimum of 4 weeks; c) administering 1.5 mg of dulaglutide once weekly to said subjects for a minimum of 4 weeks; and d) administering 3.0 mg once weekly to said subject.

[0109] 62. The use of embodiment 61, further comprising increasing the dose to 4.5 mg once weekly after the subject has been administered a dose of 3.0 mg once weekly for a minimum of 4 weeks.

[0110] 63. Dulaglutide for use in improving glycemic control in a subject with type 2 diabetes (T2D) and who is being treated with a dose of 1.5 mg dulaglutide once a week but who requires further glycemic control, comprising increasing the administered dose of dulaglutide to 3.0 mg once a week.

[0111] 64. Dulaglutide for use according to embodiment 61, further comprising increasing the dose to 4.5 mg once weekly after the subject has been administered a dose of 3.0 mg once weekly for a minimum of 4 weeks.

[0112] 65. Use of dulaglutide for the manufacture of a medicament for improving glycemic control in a subject with type 2 diabetes (T2D) and who is being treated with a dose of 1.5 mg dulaglutide once a week but who needs further glycemic control, comprising increasing the administered dose of dulaglutide to 3.0 mg once a week.

[0113] 66. The use of embodiment 65, further comprising increasing the dose to 4.5 mg once weekly after the subject has been treated with 3.0 mg dulaglutide once weekly for a minimum of 4 weeks.

[0114] 67. Dulaglutide for use in improving glycemic control in a subject with type 2 diabetes (T2D) and who is being treated with a dose of dulaglutide of 3.0 mg once a week but who requires further glycemic control, comprising increasing the administered dose of dulaglutide to 4.5 mg once a week.

[0115] 68. Dulaglutide for use in providing chronic weight management in a subject in need thereof, a) administering 0.75 mg of dulaglutide once weekly to the aforementioned subjects for a minimum of 4 weeks; b) administering 1.5 mg of dulaglutide once weekly to said subjects for a minimum of 4 weeks; and c) Dulaglutide for use, including increasing the dose to 3.0 mg once weekly.

[0116] 69. Dulaglutide for use according to embodiment 68, further comprising increasing the dose to 4.5 mg once weekly after the subject has been administered a dose of 3.0 mg once weekly for a minimum of 4 weeks.

[0117] 70. Dulaglutide for use in providing chronic weight management in a subject in need thereof, a) Identifying subjects who have previously been treated with 1.5 mg of dulaglutide once weekly for a minimum of 4 weeks; and b) Dulaglutide for use, including increasing the dose to 3.0 mg once weekly.

[0118] 71. Dulaglutide for use according to embodiment 70, further comprising increasing the dose to 4.5 mg once weekly after the subject has been administered a dose of 3.0 mg once weekly for a minimum of 4 weeks.

[0119] 72. Dulaglutide for use in providing chronic weight management in a subject in need thereof, a) Identifying subjects who have previously been treated with 3.0 mg of dulaglutide once weekly for a minimum of 4 weeks; and b) Dulaglutide for use, including increasing the dose to 4.5 mg once weekly.

[0120] 73. Use of dulaglutide for the manufacture of a medicament for improving glycemic control in a subject with type 2 diabetes (T2D) and who is being treated with a dose of dulaglutide of 3.0 mg once a week but who requires further glycemic control, comprising increasing the administered dose of dulaglutide to 4.5 mg once a week.

[0121] 74. Use of dulaglutide for the manufacture of a medicament for providing chronic weight management in a subject in need thereof, comprising: a) administering 0.75 mg of dulaglutide once weekly to the aforementioned subjects for a minimum of 4 weeks; b) administering 1.5 mg of dulaglutide once weekly to said subjects for a minimum of 4 weeks; and c) increasing the dose to 3.0 mg once weekly.

[0122] 75. The use of embodiment 74, further comprising increasing the dose to 4.5 mg once weekly after the subject has been treated with 3.0 mg of dulaglutide once weekly for a minimum of 4 weeks.

[0123] 76. Use of dulaglutide for the manufacture of a medicament for providing chronic weight management in a subject in need thereof, comprising: a) Identifying subjects who have previously been treated with 1.5 mg of dulaglutide once weekly for a minimum of 4 weeks; and b) increasing the dose to 3.0 mg once weekly.

[0124] 77. The use of embodiment 76, further comprising increasing the dose to 4.5 mg once weekly after the subject has been treated with 3.0 mg dulaglutide once weekly for a minimum of 4 weeks.

[0125] 78. Use of dulaglutide for the manufacture of a medicament for providing chronic weight management in a subject in need thereof, comprising: a) Identifying subjects who have previously been treated with 3.0 mg of dulaglutide once weekly for a minimum of 4 weeks; and b) increasing the dose to 4.5 mg once weekly.

[0126] 79. A dose of 3.0 mg or 4.5 mg of dulaglutide is administered in a 0.5 mL aqueous composition, the aqueous composition being a) 0.07 mg citric acid, b) 23.2 mg of mannitol; c) 1.37 mg trisodium citrate, and d) Polysorbate 80 in an amount of 0.125 to 0.25 mg; Dulaglutide for use according to any of the above embodiments.

[0127] 80. Dulaglutide for use according to embodiment 79, wherein the amount of polysorbate is 0.125 mg.

[0128] 81. Dulaglutide for use according to any of embodiments 79-80, wherein the composition remains chemically and physically stable at 2-8°C for 24 months.

[0129] 82. Dulaglutide for use according to any of embodiments 79-81, wherein the composition remains chemically and physically stable at 30°C for 14 days.

[0130] 83. Dulaglutide for use according to any of the above embodiments, wherein administration of increased doses of dulaglutide does not result in unacceptable tolerability.

[0131] 84. Dulaglutide for use in any of the above embodiments, wherein the subject's HbA1c is lowered.

[0132] 85. Dulaglutide for use in any of the above embodiments, wherein the subject loses weight.

[0133] This invention is further illustrated by the following examples which should not be construed as limiting. [Example]

[0134] Phase 2 clinical study A Phase 2 clinical trial is being designed to evaluate the safety and efficacy of once-weekly dulaglutide 3.0 mg and 4.5 mg administered according to one of two dose-titration algorithms compared with placebo in patients with type 2 diabetes (T2D) treated with metformin monotherapy. The trial is also designed to include a pilot comparison of the 3.0 and 4.5 mg doses of dulaglutide to 1.5 mg (the highest dose approved by regulatory agencies). The trial aims to predict whether increasing doses provide improved clinical benefit, including greater reductions in HbA1c and weight loss, with an acceptable safety and tolerability profile.

[0135] The study is designed as a multicenter, randomized, double-blind, parallel-arm, placebo-controlled trial with three study periods (lead-in, treatment, and safety follow-up) in patients with T2D with inadequate glycemic control on metformin alone.

[0136] After screening and lead-in periods, patients will be randomized in a 1:1:1:1 ratio to weekly injections of dulaglutide 4.5 mg, 3.0 mg, or 1.5 mg in combination with a stable dose of metformin, or placebo. Within each investigational dulaglutide dose arm (3.0 mg and 4.5 mg), patients will be randomly assigned in a 1:1 ratio to one of two dulaglutide dose titration algorithms, and participants will be treated for 18 weeks after double-blind randomization, including a 6-week titration period and a 12-week maintenance treatment period at the final dose. During the titration period in the 3.0 and 4.5 mg arms, the dulaglutide dose was titrated over 6 weeks according to one of two algorithms: (1) patients received 1.5 mg of dulaglutide once weekly for the first 4 weeks (Weeks 1-4), followed by 3.0 mg of dulaglutide once weekly for the next 2 weeks (Weeks 5-6) (hereafter, "Algorithm 1" or "A1"), or (2) patients received 0.75 mg of dulaglutide once weekly for the first 2 weeks (Weeks 1-2), followed by 1.5 mg of dulaglutide once weekly for the next 4 weeks (Weeks 3-6) (hereafter, "Algorithm 2" or "A2"). The two titration algorithms were selected based on modeling and simulations including data from several phase 2 and 3 trials to evaluate the potential mitigating effect of doubling the titration dose (i.e., Algorithm 1) versus longer exposure at a lower titration dose (i.e., Algorithm 2).

[0137] A total of 505 patients were screened, and 318 patients were randomized to treatment: placebo, 82; dulaglutide 1.5 mg, 81; dulaglutide 3.0 mg, 79; and dulaglutide 4.5 mg, 76. One patient randomized to placebo withdrew consent to participate in the study at visit 4 and did not receive any dose of study drug, leaving 317 patients receiving at least one dose of study drug and including the intention-to-treat (ITT) population: placebo, 81; dulaglutide 1.5 mg, 81; dulaglutide 3.0 mg, 79; and dulaglutide 4.5 mg, 76.

[0138] Excluding data collected after rescue (patients with high blood glucose requiring rescue with another therapy) and after study drug discontinuation, a summary of the change from baseline in HbA1c (%) and body weight (kg) at Week 18 in the ITT population is provided below in Table 1. The HbA1c data also exclude results for patients who demonstrated large unexplained oscillations in HbA1c that were considered physiologically unacceptable and inconsistent with other available clinical information.

[0139] [Table 1]

[0140] Table 1. Change in HbA1c (%) and body weight (kg) at week 18 in the ITT population excluding data after rescue or study drug discontinuation. Abbreviations: CI = confidence interval, LSmean = least squares mean, PBO = placebo. * P value <0.05 for comparison of dulaglutide to placebo. ** P value <0.001 for comparison of dulaglutide to placebo. † P value <0.05 for comparison of dulaglutide to dulaglutide 1.5 mg. Note: DuraXX represents XX milligrams of dulaglutide administered once weekly.

[0141] At week 18, all three doses of dulaglutide significantly reduced HbA1c from baseline compared with placebo and significantly reduced body weight from baseline compared with placebo.HbA1c decreased by a mean of -1.24% in the dulaglutide 1.5 mg group compared with -1.47% in the dulaglutide 3.0 mg group (LS mean treatment difference, -0.22%; 95% CI, -0.48%, 0.03%) and -1.50% in the dulaglutide 4.5 mg group (LS mean treatment difference, -0.26%; 95% CI, -0.52%, 0.00%). Body weight decreased by a mean of -2.9 kg in the dulaglutide 1.5 mg group compared with 4.2 kg in the dulaglutide 3.0 mg group (LS mean treatment difference, -1.3 kg; 95% CI -2.4, 0.2) and -4.4 kg in the dulaglutide 4.5 mg group (LS mean treatment difference, -1.5 kg; 95% CI -2.6, -0.3). The incremental effectiveness of both higher doses compared with dulaglutide 1.5 mg in reducing HbA1c was greater in the subgroup of patients with higher baseline HbA1c levels.

[0142] Table 2 summarizes the frequency of treatment-emergent nausea, vomiting, and diarrhea as measured by event prevalence (any patient who had a new or ongoing event during the interval), incidence (any patient who had an event that began during the interval), and onset (any patient who had the first event of that type during the interval) over three periods (Weeks 0-6 [titration period], Weeks 6-10 [the first 4 weeks after completion of titration for patients in the dulaglutide 3.0 mg and dulaglutide 4.5 mg groups], and Weeks 0-18 [treatment period]).

[0143] [Table 2]

[0144] Table 2. Summary of prevalence, incidence, and first occurrence of nausea, vomiting, and diarrhea by treatment and duration, and intention-to-treat population. Abbreviations: m = number of patients with an event during the interval; M = number of patients with data during the interval; N = number of patients randomized and treated; Wks = weeks.

[0145] The incidence of nausea and vomiting was higher in all three dulaglutide groups compared with placebo during all three time intervals. There was a dose response in the incidence of nausea overall (weeks 0-18) across the dulaglutide groups, with the highest incidence occurring in the dulaglutide 4.5 mg group (30.3%). In each dulaglutide treatment group, nausea was most frequent during the titration period (weeks 0-6) and decreased during weeks 6-10 and thereafter. The incidence of vomiting ranged from 6.6% to 8.9% across the dulaglutide groups during the titration period and decreased during the week 6-10 period. During all three time intervals, the incidence of diarrhea was generally similar in the placebo and dulaglutide 1.5 mg groups and was higher in the high-dose group. More frequent reports of diarrhea in the dulaglutide 3.0 mg and 4.5 mg groups during the first 6 weeks continued during weeks 6–10 and then decreased. The incidence of diarrhea was higher in the high-dose group compared with the 1.5 mg group during the titration period before patients received the 3.0 mg or 4.5 mg doses, so the difference was likely not entirely dose-related. In terms of the incidence of severe nausea, diarrhea, and vomiting, few patients had any serious events, and the incidence rates were generally similar in all four treatment groups.

[0146] The incidence of nausea, vomiting, and diarrhea increased in a dose-dependent manner in patients treated with dulaglutide, and the proportion of patients who discontinued study treatment due to adverse events was higher in the dulaglutide 1.5 mg group compared with the dulaglutide 1.5 mg group; however, the difference in incidence between the high-dose and 1.5 mg groups was small, and the frequency of related GI events and treatment discontinuations was lower than that observed in completed dulaglutide studies of shorter duration that included patients receiving non-titrated doses of ≥ 3.0 mg, indicating that titration algorithms A1 and A2 had a beneficial effect.

[0147] The numbers of patients randomized by the titration algorithm in the dulaglutide 3.0 mg and 4.5 mg groups were as follows: dulaglutide 3.0 mg A1, 41; dulaglutide 3.0 mg A2, 38; dulaglutide 4.5 mg A1, 39; dulaglutide 4.5 mg A2, 37. Table 3 summarizes the frequency of nausea, vomiting, and diarrhea by dose and titration algorithm for the two higher-dose groups, as measured by the prevalence, incidence, and first occurrence of events over three key periods (weeks 0–6 [titration period], weeks 6–10, and weeks 0–18 [treatment period]).

[0148] [Table 3]

[0149] Table 3. Summary of prevalence, incidence, and first occurrence of nausea, vomiting, and diarrhea by dose and titration algorithm (dulaglutide 3.0 mg and dulaglutide 4.5 mg) and duration, intention-to-treat population. Abbreviations: A1 = Algorithm 1; A2 = Algorithm 2; m = number of patients with an event during the interval; M = number of patients with data during the interval; N = number of patients randomized and treated; Wks = weeks. Prevalence counts any patient who had a new or ongoing event during the interval. Incidence counts any patient who had an event that began during the interval. Onset counts any patient who had the first event of that type during the interval.

[0150] The frequency of nausea was similar overall with A1 and A2, with differences within the 3.0 mg group, with a lower frequency in the A2 subgroup compared to the A1 subgroup, but this difference does not appear to be related to the titration algorithm, as suggested by the similar frequency within the A1 and A2 subgroups in the 4.5 mg group. Most nausea events occurred during the titration period, with few new events reported upon upward titration to the final dose (weeks 6-10).

[0151] The frequency of vomiting was similar overall with A1 and A2; more patients in the A1 subgroup had events in the dulaglutide 3.0 mg group than in the A2 subgroup, and more patients in the A2 subgroup had events in the dulaglutide 4.5 mg group than in the A1 subgroup. However, the differences between the A1 and A2 subgroups in the 3.0 mg and 4.5 mg groups were in opposite directions, suggesting that, similar to nausea, these differences are not related to the titration algorithm. Most emetic events with A1 occurred during the titration period, with few new events reported upon upward titration to the final dose (weeks 6–10). With A2, the frequency of vomiting was lower during the titration period, remained at similar levels between weeks 6 and 10, began to decrease after week 10, and remained lower through week 18.

[0152] During the titration period (weeks 0-6), the prevalence and incidence of diarrhea were higher in the dulaglutide 3.0 mg A1 and dulaglutide 4.5 mg A1 subgroups and lower in the dulaglutide 3.0 mg A2 and 4.5 mg A2 subgroups. During weeks 6-10, the prevalence and incidence were lower in the dulaglutide 3.0 mg A1 and dulaglutide 4.5 mg A2 subgroups and higher in the dulaglutide 3.0 mg A2 and dulaglutide 4.5 mg A1 subgroups.

[0153] The observed pattern of incidence of these events in A1 vs. A2 suggests that starting with a lower dulaglutide dose (0.75 mg dulaglutide [used in A2] vs. 1.5 mg dulaglutide [used in A1]) may reduce GI tolerability events during the titration period. The slower decrease in the frequency of these events in groups A2 vs. A1 during the final up-titration period (weeks 6-10) suggests that a longer titration period may be required to allow for the development of tachyphylaxis to the GI side effects of dulaglutide.

[0154] As noted above, the initial studies of the 3.0 mg and higher doses resulted in an increase in heart rate, which was partially attributed to discontinuation of the 3.0 mg arm in the initial studies. Therefore, changes in heart rate were also measured in this study, and the collected data are provided in Table 4 below.

[0155] [Table 4]

[0156] Table 4. Change from baseline in heart rate with treatment in the ITT population. Abbreviations: LS = least squares; PR = heart rate; wks = weeks; CI = confidence interval; n = sample size.

[0157] As indicated in Table 4 above, the mean change in heart rate across the dulaglutide groups was similar throughout the treatment period and at the end of the study.

[0158] In determining the optimal dose titration strategy, patients who initiated treatment with dulaglutide 0.75 mg (2 weeks, A1) initially experienced fewer GI problems than patients who initiated dulaglutide 1.5 mg (4 weeks, A2), but these differences were not maintained upon further upward titration to 1.5 mg with A1. Differences were also observed between A1 and A2 in the dulaglutide 4.5 mg group when patients were upwardly titrated to their final dose (3.0 mg to 4.5 mg in the A1 arm; 1.5 mg to 4.5 mg in the A2 arm), with tolerability being slightly lower in patients in the A2 arm. These results suggest that further adjustments to the algorithm may optimize dulaglutide titration using higher doses in terms of the duration of titration and the required dose level, further minimizing the risk of tolerability problems.

[0159] Phase 3 study A phase 3, multicenter, randomized, double-blind, parallel-arm study with three study periods (lead-in, treatment, and safety follow-up) was designed in patients with T2D with inadequate glycemic control on metformin alone, with a treatment duration of 52 weeks and a primary endpoint at week 36. The study was designed to evaluate the efficacy and safety of once-weekly dulaglutide 3.0 mg and 4.5 mg compared with once-weekly dulaglutide 1.5 mg.

[0160] A minimum sample size of approximately 1800 patients will be enrolled (randomized), assuming a 15% dropout rate, to yield approximately 510 completers per arm at week 36. At visit 3, patients will be randomized in a 1:1:1 ratio to weekly injections of dulaglutide 4.5 mg, 3.0 mg, or 1.5 mg in combination with a stable dose of metformin.

[0161] To further mitigate gastrointestinal adverse events, the 4.5 and 3.0 mg investigational doses will be administered according to a titration algorithm designed based on PK / PD modeling of nausea and vomiting events from the Phase 2 study described above. PK / PD exposure-response modeling of the Phase 2 study data also predicts that the daily incidence of nausea and vomiting at higher dulaglutide doses will be lowest in an algorithm starting at a 0.75 mg dose with a slower dose escalation over an 8-week period, allowing sufficient time for tolerance to develop. Based on these findings, patients in this study will be titrated through sequential 4-week treatment segments, starting with 0.75 mg once weekly followed by 1.5 mg once weekly. At Week 8, patients randomized to the 1.5 mg dulaglutide group will continue on this dose for the remainder of the treatment period. Patients randomized to the 3.0 mg dulaglutide group will be titrated to 3.0 mg once weekly at Week 8 and continue on this dose for the remainder of the treatment period. Patients assigned to the 4.5 mg dulaglutide group will be titrated to 3.0 mg once weekly for 4 weeks at week 8, and then to a final dose of 4.5 mg once weekly at week 12. Study participants will be treated for 52 weeks, with the primary objective assessed at week 36. This gradual, stepwise dose titration strategy aims to further improve GI tolerability at the 3.0 mg and 4.5 mg doses compared to that observed in the Phase 2 study described above.

[0162] Formulation stability studies Demonstration batches containing various concentrations of dulaglutide in the formulation used for the currently approved dulaglutide doses will be prepared and samples will be filled into commercial primary packaging for dulaglutide as shown in Table 5 below.

[0163] [Table 5]

[0164] The samples were allowed to remain stable for up to 24 months. However, after 3 months, the study was stopped due to the observed decrease in the level of PS80. The data obtained regarding PS80 concentration was analyzed in JMP 12.1.0 software to predict the PS80 content at 24-month long-term storage conditions. The activation energy (E) for PS80 decomposition was calculated. a ) is calculated and used to predict PS80 content over long-term storage. Based on a second-order polynomial model, the activation energy E a The point estimate for PS80 was 15.24 kcal / mol, with a lower 95% confidence limit of 12.85 kcal / mol. Based on this analysis, starting with a PS80 level of 0.02% (w / v), the 24-month prediction of PS80 for the 12 mg / mL dulaglutide formulation is predicted to be lower than the specification limit for the current commercial dulaglutide. The 24-month prediction of PS80 for the 9 mg / mL dulaglutide formulation is also close to the specification limit.

[0165] To assess the risk of PS80 content out of specification (OOS) during 24 months of long-term storage, a Monte Carlo simulation utilizing historical dulaglutide data is performed in R 3.4.0 software. The OOS risk associated with each high concentration level is summarized in Table 6 below.

[0166] [Table 6]

[0167] Results from the Monte Carlo simulation indicated excessive degradation using the asymptotic lower confidence limit for the activation energy, thus indicating a high risk level for shelf-life OOS. PS80 is present in dulaglutide formulations to provide protection from physical stress, and the lower specification limit for PS80 was set to ensure sufficient PS80 was present throughout the maximum possible shelf-life and use period to provide that physical protection.

[0168] Given preliminary data analysis from development stability studies indicating that polysorbate-80 hydrolysis increased in higher-strength dulaglutide formulations, it was decided to investigate modifications to the formulation. While increasing the level of polysorbate-80 in the formulation may result in sufficient intact polysorbate-80 at the end of shelf life, hydrolysis of greater amounts of polysorbate-80 may result in the appearance of visible particles. Therefore, a surfactant ranging study was initiated to evaluate the impact of varying levels of surfactant on stability.

[0169] Samples containing dulaglutide concentrations of 3, 6, 9, and 12 mg / mL, 10 mM citrate buffer, 46.4 mg / mL mannitol, and PS80 concentrations ranging from 0.002% to 0.05% were prepared, filled into vials, and stabilized at 30°C. Samples were collected on days 0, 12, 25, 35, 46, and 74 and tested for free oleic acid (FOA), a hydrolysis product of PS80, and particulate matter. The data show an increase in FOA with increasing ratios for formulations with higher dulaglutide strengths. At the same dulaglutide concentration, the increase in FOA ratio is the same for formulations with starting levels of 0.02% and 0.05% polysorbate-80. Particulate matter, measured by microflow imaging (MFI), is comparable for all formulations, regardless of dulaglutide or polysorbate-80 levels. The results support that the starting level of polysorbate-80 can be increased to as much as 0.05% without degrading dulaglutide stability.

[0170] Based on the results of the development stability and surfactant studies, a detailed statistical analysis of all available data is performed. The analysis concludes that the starting polysorbate-80 level in the formulation should be increased to 0.02%-0.025% (w / v) for the 6.0 and 9.0 mg / mL strengths. Selecting this increased level provides a high probability that sufficient polysorbate-80 will be present at the end of the shelf life to meet currently approved specifications for commercial products.

[0171] A second demonstration batch is prepared containing the same concentrations used in the first demonstration batch above, except for an increased concentration of PS80, as shown in Table 7 below.

[0172] [Table 7]

[0173] Samples are placed at stability conditions at 5° C., 25° C., and 30° C. Results from samples held at 5° C. and 25° C. for up to 6 months and at 30° C. for 1 month indicate that the concentrated formulation is chemically and physically stable, and that PS80 concentrations remain above the lower specification limit throughout the shelf life.

Claims

1. A pharmaceutical composition for improving glycemic control in a subject with type 2 diabetes (T2D) insufficiently controlled with metformin and in need of further glycemic control, comprising dulaglutide as an active ingredient, a) the subject is administered 0.75 mg of dulaglutide once weekly for at least 4 weeks; b) the subject is then administered 1.5 mg of dulaglutide once weekly for a minimum of 4 weeks; c) The pharmaceutical composition is then used to administer a 3.0 mg dose of dulaglutide to the subject once a week for a minimum of 4 weeks.

2. a) 3.0 mg dulaglutide; b) 0.07 mg citric acid; c) 23.2 mg mannitol; d) 1.37 mg trisodium citrate, and e) Polysorbate 80 in an amount of 0.125 mg to 0.25 mg; 10. The pharmaceutical composition of claim 1, wherein the composition is a 0.5 mL aqueous composition.

3. 3. The pharmaceutical composition of claim 2, wherein the amount of polysorbate is 0.125 mg.

4. 4. The pharmaceutical composition of claim 2, wherein the composition remains chemically and physically stable at 2-8° C. for 24 months.

5. 5. The pharmaceutical composition according to any one of claims 2 to 4, wherein the composition remains chemically and physically stable at 30°C for 14 days.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the increased dose of dulaglutide does not result in unacceptable tolerability.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the HbA1c of the subject is reduced.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the subject loses weight.

9. The pharmaceutical composition according to any one of claims 1 to 8, which is for injection.

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