Methods of using doraglutide and compositions containing doraglutide

Abstract

The present invention relates to methods of using doraglutide and compositions containing doraglutide. The present invention relates to methods of using new doses of doraglutide and compositions containing such higher doses of doraglutide.

Description

This application is a divisional application of the invention patent application with the application date of November 13, 2018, application number 201880075369.5, and invention name “Methods for using dulaglutide and compositions containing dulaglutide”. Technical Field

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

[0002] Dulaglutide, The active ingredient in , a glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA), is approved 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 III development program and received regulatory approval in the United States (US), the European Union, and other jurisdictions in 2014. Since their approval in 2014, these two doses of dulaglutide have been used to treat many patients with T2D, resulting in significant reductions in HbA1c and weight loss with a low risk of hypoglycemia.

[0003] Although treatment with currently approved doses of dulaglutide enables the majority of patients enrolled in Phase III programs to achieve their glycemic goals (with or without other T2D concomitant medications), a significant number of patients receiving currently approved therapies (including dulaglutide) do not achieve 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). Therefore, there remains an important medical need for agents that provide enhanced efficacy while maintaining an overall acceptable benefit / risk profile. Summary of the Invention

[0004] The doses, methods, and compositions of the present invention attempt to address this need. Benefits of the present invention include providing additional glycemic control and / or weight loss, as demonstrated, for example, by further reductions in HbA1c, compared to currently approved doses of dulaglutide. Furthermore, the present invention provides these benefits while maintaining an acceptable safety risk and adverse event profile.

[0005] Accordingly, 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) Identify subjects with T2D who require further glycemic control; b) administering to the subject a first dose of dulaglutide once weekly for a minimum of four weeks; and c) increasing the dose to a second dose, wherein the first dose is selected from 1.5 and 3.0 mg once weekly, and the second dose is selected from 3.0 and 4.5 mg once weekly.

[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 improved glycemic control, comprising: a) Identify subjects with T2D who require further glycemic control; b) administering 0.75 mg of dulaglutide to the subject once weekly for a minimum of four weeks; c) administering 1.5 mg of dulaglutide to the subject once weekly for a minimum of four weeks; and d) administering 3.0 mg once weekly 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 four weeks.

[0008] In another aspect, the present invention provides a method of improving glycemic control in a subject having type 2 diabetes (T2D) and being treated with a once-weekly 1.5 mg dose of dulaglutide who needs further glycemic control, comprising: increasing the administered dose of dulaglutide to 3.0 mg once weekly.

[0009] In another aspect, the present invention provides a method of improving glycemic control in a subject having type 2 diabetes (T2D) and being treated with a once-weekly 3.0 mg dose of dulaglutide who needs further glycemic control, comprising: increasing the administered dose of dulaglutide to 4.5 mg once-weekly.

[0010] In another aspect, the present invention provides an improved method of administering dulaglutide to a subject with T2D who requires improved glycemic control, wherein the improvement comprises administering 1.5 mg of dulaglutide once weekly for a minimum of four 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 who is in need of further glycemic control, wherein the improvement comprises administering 0.75 mg of dulaglutide once weekly for a minimum of four weeks, then increasing the dose to 1.5 mg of dulaglutide once weekly for a minimum of four 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 with T2D who is in need of improved glycemic control, wherein the improvement comprises: a) administration of 3.0 mg of dulaglutide once weekly for a minimum of four weeks; and b) Increase the dose to 4.5 mg once a week.

[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 subject for a minimum of four weeks; b) administering 1.5 mg of dulaglutide to the subject once weekly for a minimum of four weeks; and c) Increase the dose to 3.0 mg once a week.

[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 had previously been treated with dulaglutide 1.5 mg once weekly for a minimum of four weeks; and b) Increase the dose to 3.0 mg once a week.

[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 had previously been treated with dulaglutide 3.0 mg once weekly for a minimum of four weeks; and b) Increase the dose to 4.5 mg once a week.

[0016] In another aspect, the present invention provides a stable pharmaceutical formulation comprising: a) dulaglutide at a concentration selected from 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) in need of additional glycemic control, comprising: a) Identify subjects with T2D who require further glycemic control; b) administering to the subject a first dose of dulaglutide once weekly for a minimum of four weeks; and c) increasing the dose to a second dose, wherein the first dose is selected from 1.5 and 3.0 mg once weekly, and the second dose is selected from 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) Identify subjects with T2D who require further glycemic control; b) administering 0.75 mg of dulaglutide to the subject once weekly for a minimum of four weeks; c) administering 1.5 mg of dulaglutide to the subject once weekly for a minimum of four weeks; and d) administering 3.0 mg once weekly to the subject.

[0019] In another aspect, the present invention provides dulaglutide for improving glycemic control in a subject having type 2 diabetes (T2D) and being treated with a once-weekly dose of 1.5 mg dulaglutide but requiring further glycemic control, comprising: increasing the administered dose of dulaglutide to 3.0 mg once weekly.

[0020] In another aspect, the present invention provides dulaglutide for improving glycemic control in a subject having type 2 diabetes (T2D) and being treated with a once-weekly 3.0 mg dose of dulaglutide but requiring further glycemic control, comprising: increasing the administered dose of dulaglutide to 4.5 mg once weekly.

[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 subject for a minimum of four weeks; b) administering 1.5 mg of dulaglutide to the subject once weekly for a minimum of four weeks; and c) Increase the dose to 3.0 mg once a week.

[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 who had previously been treated with dulaglutide 1.5 mg once weekly for a minimum of four weeks; and b) Increase the dose to 3.0 mg once a week.

[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 had previously been treated with dulaglutide 3.0 mg once weekly for a minimum of four weeks; and b) Increase the dose to 4.5 mg once a week.

[0024] In another aspect, the present invention provides the use of dulaglutide for the preparation of a medicament for improving glycemic control in a subject with type 2 diabetes (T2D) who needs additional glycemic control, comprising: a) Identify subjects with T2D who require further glycemic control; b) administering to the subject a first dose of dulaglutide once weekly for a minimum of four weeks; and c) increasing the dose to a second dose, wherein the first dose is selected from 1.5 and 3.0 mg once weekly, and the second dose is selected from 3.0 and 4.5 mg once weekly.

[0025] In another aspect, the present invention provides a use of dulaglutide for the preparation of a medicament for improving glycemic control in a subject with type 2 diabetes (T2D) who needs further glycemic control, comprising: a) Identify subjects with T2D who require further glycemic control; b) administering 0.75 mg of dulaglutide to the subject once weekly for a minimum of four weeks; c) administering 1.5 mg of dulaglutide to the subject once weekly for a minimum of four weeks; and d) administering 3.0 mg once weekly to the subject.

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

[0027] In another aspect, the present invention provides a use of dulaglutide for the preparation of a medicament for improving glycemic control in a subject having type 2 diabetes (T2D) and being treated with a once-weekly dose of 3.0 mg dulaglutide 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 preparing a medicament for providing chronic weight management to a subject in need thereof, comprising: a) administering 0.75 mg of dulaglutide once weekly to the subject for a minimum of four weeks; b) administering 1.5 mg of dulaglutide to the subject once weekly for a minimum of four weeks; and c) Increase the dose to 3.0 mg once a week.

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

[0030] In another aspect, the present invention provides a use of dulaglutide for preparing a medicament for providing chronic weight management to a subject in need thereof, comprising: a) identifying subjects who had previously been treated with dulaglutide 3.0 mg once weekly for a minimum of four weeks; and b) Increase the dose to 4.5 mg once a week. DETAILED DESCRIPTION

[0031] Dulaglutide is a human GLP-1RA comprising a dimer of a GLP-1 analog fused at its C-terminus via a linker peptide 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 monomer of dulaglutide has the amino acid sequence set forth in SEQ ID NO: 1:

[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 Pat. No. 7,452,966 and U.S. Patent Application Publication No. US20100196405. As used herein, the term "dulaglutide" refers to any GLP-1RA 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 submission for a GLP-1RA product seeking approval that relies, in whole or in part, on data regarding dulaglutide submitted to regulatory agencies by Eli Lilly and Company, regardless of whether the group seeking approval of the protein actually identifies the protein as dulaglutide or uses another term.

[0033] Dulaglutide stimulates insulin synthesis and secretion and has been shown to provide improved glycemic control in patients with T2D compared to placebo (both administered in combination with metformin). As noted above, the 0.75 mg and 1.5 mg doses of dulaglutide were selected for Phase III registrational studies, submitted for regulatory approval, received approval in 2014, and have since been used to provide glycemic control for tens of thousands of patients with T2D. However, as also noted above, many patients with T2D worldwide still fail to achieve their HbA1c goals and struggle with weight management, necessitating new therapies that can provide additional glycemic control and / or weight loss.

[0034] Although increasing the dose of a drug can achieve improved efficacy in some cases, increasing the dose of a drug also carries a higher risk of side effects. For example, administration of GLP-1RAs is known to carry the risk of nausea, diarrhea, and vomiting (see, e.g., Prescribing Information), and in 33 patients treated with dulaglutide at doses of 3.0 mg or higher in a Phase 1 dosing study and in the dose-finding portion of a Phase 2 / 3 study, the incidence of gastrointestinal (GI) adverse events (AEs) commonly associated with treatment with GLP-1RAs—e.g., nausea (17 patients, 52%) and vomiting (9 patients, 27%)—was higher than the rates reported in Phase 3 registrational trials with currently approved doses (see, e.g., Barrington et al., A 5-week study of the pharmacokinetics and pharmacokinetics 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 early due to GI AEs. In addition to GI tolerability issues, early studies of higher doses have also shown that increasing the dose may also carry the risk of unacceptable increases in heart rate (see, for example, Skrivanek 2014).Indeed, after a review of numerous unblinded interim data from one of the aforementioned studies, which initially included seven doses ranging from 0.25 mg to 3.0 mg, the Data Monitoring Committee (DMC) recommended stopping randomization of patients to the 3.0 mg dose of dulaglutide due to a higher incidence of pancreatic enzyme values 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 dose increase must strike a balance between sufficiently enhancing efficacy and not leading to unacceptable safety or tolerability issues.

[0035] It has been found that increasing 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 if an upward dose titration regimen is used before their administration. Therefore, the present invention provides for the administration of 3.0 mg and 4.5 mg doses of dulaglutide once weekly, as well as dose titration regimens that result in an acceptable safety and tolerability profile when the 3.0 mg and 4.5 mg doses are administered. In subjects who are first starting dulaglutide treatment, the dose titration regimen includes starting treatment with a dose of 0.75 mg 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. However, in subjects already taking dulaglutide but requiring further glycemic control, the dose titration regimen does not require a reduction in the subject's current dose. For example, in a subject who has been receiving 1.5 mg dulaglutide once weekly but needs further glycemic control, the regimen does not require a dose reduction to 0.75 mg, but rather a continued increase in dose to 3.0 mg and then, optionally, to 4.5 mg. Similarly, in a subject who has been receiving 3.0 mg dulaglutide once weekly but needs further glycemic control, the regimen does not require a dose reduction to 0.75 mg or 1.5 mg once weekly, but rather a continued increase in dose to 4.5 mg. However, for any of the above embodiments of the dose titration regimen, it is preferred that the dose not be increased to the next dose in the progression until the current dose has been administered for at least four weeks.

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

[0037] Currently approved products containing dulaglutide are supplied as 0.5 mL of aqueous solution containing 0.75 mg or 1.5 mg of dulaglutide and the following excipients: anhydrous citric acid (0.07 mg), mannitol (23.2 mg), polysorbate 80 (PS80) (0.10 mg), and trisodium citrate dihydrate (1.37 mg) ( Highlighted section of the prescribing information). PS80 is provided in this formulation to help provide protection against physical stress and ensure that the dulaglutide protein remains physically stable throughout the product's shelf life (2 years under refrigerated conditions) and maximum use period (up to 14 days at room temperature). The dulaglutide product specifications therefore include a lower limit for PS80 concentration, above which the PS80 concentration must be maintained throughout the shelf life and use period. To ensure that the PS80 concentration remains above the lower specification limit throughout the shelf life and use period, currently approved dulaglutide products are prepared with a PS80 concentration of 0.1 mg / 0.5 mL (0.02% w / v).

[0038] As the concentration of dulaglutide is increased to the higher doses provided in the methods of the present invention, the concentration of PS80 further decreases compared to currently approved formulations due to increased hydrolysis, and changes to the formulation are required to ensure that sufficient PS80 is present to meet product specifications and provide physical stability. As described in more detail in the following examples, it was determined that increasing the PS80 concentration to 0.025% would ensure that the PS80 specification limits would be met throughout the shelf life and use period at the higher doses of dulaglutide provided in the methods of the present invention, but would not be so high as to generate unacceptable visible particulates resulting from the hydrolysis of PS80 or otherwise have any undesirable effects on the chemical or physical stability of the formulation. Therefore, in certain embodiments, the methods of the present invention are performed by administering increasing doses of dulaglutide in the form of 0.5 mL of an aqueous solution containing 3.0 mg or 4.5 mg of dulaglutide, anhydrous citric acid (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 performed by administering increasing doses of dulaglutide in the form of a solution containing, in any volume, 6.0 mg or 9.0 mg / mL of dulaglutide, 0.14 mg / mL of anhydrous citric acid, 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 "treating," "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 itself is not slowed or reversed.

[0040] A "subject" is a mammal, preferably a human, having a disease, disorder or condition that would benefit from treatment with increasing doses of dulaglutide.

[0041] "Glycemic control" refers to maintaining or reducing a subject's HbA1c level; "improving" glycemic control refers to reducing HbA1c; and "needing further" glycemic control refers to needing to reduce HbA1c.

[0042] “Chronic weight management” refers to weight loss.

[0043] "HbA1c" refers to the level of glycated hemoglobin that develops when hemoglobin binds to glucose in the blood. HbA1c levels are a commonly used measure of glycemic control in diabetic patients, 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 relative to the reduction in HbA1c levels resulting from treatment with the currently approved 0.75 mg and 1.5 mg doses of dulaglutide.

[0044] In certain embodiments of the present invention, the dulaglutide dosages and dosing regimens described herein are provided for obesity treatment, chronic weight management, and / or non-therapeutic weight loss in a subject in need thereof. In certain embodiments, the subject has a weight of greater than about 25 kg / m 2 In certain embodiments, the subject has a body mass index (BMI) greater than about 26 kg / m 2 In certain embodiments, the subject has a body mass index (BMI) greater than about 27 kg / m 2 In certain embodiments, the subject also has one or more weight-related comorbidities, such as T2D, hypertension, and / or dyslipidemia.

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

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

[0047] The treatment methods and uses described herein can be provided in combination, simultaneously or sequentially, with other T2D treatments, including oral T2D agents such as metformin, and / or other injectable agents including rapid-acting or basal insulin.

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

[0049] 2. A method of improving glycemic control in a subject having type 2 diabetes (T2D) and in need of improved glycemic control, comprising: a) administering 1.5 mg of dulaglutide once weekly to the subject; and b) administering to the subject increasing doses of dulaglutide once weekly, wherein the increasing doses are selected from 3.0 mg and 4.5 mg dulaglutide once weekly.

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

[0051] 4. A method of improving glycemic control in a subject having type 2 diabetes (T2D) and in need of improved glycemic control, comprising: a) Identify subjects who have been previously treated with 1.5 mg dulaglutide once weekly; then b) Administer increasing doses of dulaglutide once weekly.

[0052] 5. The method of any one of embodiments 1-4, wherein 1.5 mg of dulaglutide is administered once weekly for two or more weeks prior to administration of the increasing dose of dulaglutide.

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

[0054] 7. An improved method of administering dulaglutide to a subject with (T2D) in need of improved glycemic control, wherein the improvement comprises administering increasing doses of dulaglutide selected from 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 improved glycemic control, comprising: a) administering 3.0 mg of dulaglutide once weekly to the subject; followed by b) administering 4.5 mg of dulaglutide once weekly to the subject.

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

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

[0058] 11. A method of improving glycemic control in a subject having type 2 diabetes (T2D) and in need of improved glycemic control, comprising: a) Identify subjects who have been previously treated with dulaglutide 3.0 mg once weekly; then b) Administer 4.5 mg of dulaglutide once weekly.

[0059] 12. The method of any preceding embodiment, wherein each dose of dulaglutide is administered once weekly for two or more weeks prior to administration of the increasing dose of dulaglutide.

[0060] 13. The method of any preceding embodiment, wherein each identified dose of dulaglutide is administered for a minimum of four weeks prior to administration of the next increased dose of dulaglutide.

[0061] 14. A method of improving the administration of dulaglutide to a subject with (T2D) who is receiving a first dose of dulaglutide and who requires 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 one of embodiments 14-15, wherein the first dose of dulaglutide has been administered two or more weeks prior to the administration of the second dose of dulaglutide.

[0064] 17. The improved method of any one of embodiments 14-15, wherein the first dose of dulaglutide has been administered for a minimum of four weeks prior to administration of the second dose of dulaglutide.

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

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

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

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

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

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

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

[0072] 25. The method of any preceding embodiment, wherein the method results in a reduction in body weight of at least about 1 kg compared to treatment with 1.5 mg dulaglutide once weekly.

[0073] 26. The method of any preceding embodiment, wherein the method results in a reduction in body weight of at least about 1.3 kg compared to treatment with 1.5 mg dulaglutide once weekly.

[0074] 27. The method of any preceding embodiment, wherein the method results in a reduction in body weight of at least about 1.5 kg compared to treatment with 1.5 mg dulaglutide once weekly.

[0075] 28. The method of any preceding embodiment, wherein the method results in a reduction in body weight of at least about 2 kg compared to treatment with 1.5 mg dulaglutide once weekly.

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

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

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

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

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

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

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

[0083] 36. The method of any preceding embodiment, wherein administration of dulaglutide does not result in an unacceptable increase in pulse rate.

[0084] 37. The method of any preceding embodiment, wherein the increasing dose of dulaglutide is administered in the form of 0.5 mL of an aqueous composition comprising: a) 0.07 mg citric acid; b) 23.2 mg 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 according to any one of embodiments 37-38, wherein the composition remains chemically and physically stable for 2 years at 2-8°C.

[0087] 40. The method according to any one 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 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 approximately 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 according to any one of embodiments 41 or 42, wherein the concentration of dulaglutide is 6.0 mg / mL.

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

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

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

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

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

[0096] 49. Dulaglutide for use in improving glycemic control in a subject with type 2 diabetes (T2D) who requires additional glycemic control comprising: a) Identify subjects with T2D who require further glycemic control; b) administering to the subject a first dose of dulaglutide once weekly for a minimum of four weeks; and c) increasing the dose to a second dose, wherein the first dose is selected from 1.5 and 3.0 mg once weekly, and the second dose is selected from 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 has been treated with a 0.75 mg dose of dulaglutide for a minimum of four weeks prior to administration of the 1.5 mg dose.

[0099] 52. Dulaglutide for use according to any one of embodiments 50 or 51, 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 four 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 preparation of a medicament for improving glycemic control in a subject with type 2 diabetes (T2D) who requires additional glycemic control, comprising: a) Identify subjects with T2D who require further glycemic control; b) administering to the subject a first dose of dulaglutide once weekly for a minimum of four weeks; and c) increasing the dose to a second dose, wherein the first dose is selected from 1.5 and 3.0 mg once weekly, and the second dose is selected from 3.0 and 4.5 mg once weekly.

[0102] 55. The use according to 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 has been treated with a 0.75 mg dose of dulaglutide for a minimum of four weeks prior to administration of the 1.5 mg dose.

[0104] 57. The use of any one 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 four weeks.

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

[0106] 59. Dulaglutide for improving glycemic control in a subject with type 2 diabetes (T2D) who requires further glycemic control, comprising: a) Identify subjects with T2D who require further glycemic control; b) administering 0.75 mg of dulaglutide to the subject once weekly for a minimum of four weeks; c) administering 1.5 mg of dulaglutide to the subject once weekly for a minimum of four weeks; and d) administering 3.0 mg once weekly to the 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 3.0 mg dose once weekly for a minimum of four weeks.

[0108] 61. Use of dulaglutide for the preparation of a medicament for improving glycemic control in a subject with type 2 diabetes (T2D) who needs further glycemic control, comprising: a) Identify subjects with T2D who require further glycemic control; b) administering 0.75 mg of dulaglutide to the subject once weekly for a minimum of four weeks; c) administering 1.5 mg of dulaglutide to the subject once weekly for a minimum of four weeks; and d) administering 3.0 mg once weekly to the 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 3.0 mg dose once weekly for a minimum of four weeks.

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

[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 3.0 mg dose once weekly for a minimum of four weeks.

[0112] 65. Use of dulaglutide for the preparation of a medicament for improving glycemic control in a subject having type 2 diabetes (T2D) and being treated with a once-weekly dose of 1.5 mg dulaglutide but requiring further glycemic control, comprising: increasing the administered dose of dulaglutide to 3.0 mg once weekly.

[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 once weekly of dulaglutide for a minimum of four weeks.

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

[0115] 68. 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 subject for a minimum of four weeks; b) administering 1.5 mg of dulaglutide to the subject once weekly for a minimum of four weeks; and c) Increase the dose to 3.0 mg once a week.

[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 3.0 mg dose once weekly for a minimum of four weeks.

[0117] 70. Dulaglutide for use in providing chronic weight management in a subject in need thereof, comprising: a) identifying subjects who had previously been treated with dulaglutide 1.5 mg once weekly for a minimum of four weeks; and b) Increase the dose to 3.0 mg once a week.

[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 3.0 mg dose once weekly for a minimum of four weeks.

[0119] 72. Dulaglutide for use in providing chronic weight management in a subject in need thereof, comprising: a) identifying subjects who had previously been treated with dulaglutide 3.0 mg once weekly for a minimum of four weeks; and b) Increase the dose to 4.5 mg once a week.

[0120] 73. Use of dulaglutide for the preparation of a medicament for improving glycemic control in a subject having type 2 diabetes (T2D) and being treated with a once-weekly dose of 3.0 mg dulaglutide but requiring further glycemic control, comprising: increasing the administered dose of dulaglutide to 4.5 mg once-weekly.

[0121] 74. Use of dulaglutide for the preparation of a medicament for providing chronic weight management to a subject in need thereof, comprising: a) administering 0.75 mg of dulaglutide once weekly to the subject for a minimum of four weeks; b) administering 1.5 mg of dulaglutide to the subject once weekly for a minimum of four weeks; and c) Increase the dose to 3.0 mg once a week.

[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 once weekly of dulaglutide for a minimum of four weeks.

[0123] 76. Use of dulaglutide for the preparation of a medicament for providing chronic weight management to a subject in need thereof, comprising: a) identifying subjects who had previously been treated with dulaglutide 1.5 mg once weekly for a minimum of four weeks; and b) Increase the dose to 3.0 mg once a week.

[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 once weekly of dulaglutide for a minimum of four weeks.

[0125] 78. Use of dulaglutide for the preparation of a medicament for providing chronic weight management to a subject in need thereof, comprising: a) identifying subjects who had previously been treated with dulaglutide 3.0 mg once weekly for a minimum of four weeks; and b) Increase the dose to 4.5 mg once a week.

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

[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 one 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 one 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 preceding embodiment, wherein administration of increasing doses of dulaglutide does not result in unacceptable tolerability.

[0131] 84. Dulaglutide for use according to any preceding embodiment, wherein the subject has reduced HbA1c.

[0132] 85. Dulaglutide for use according to any preceding embodiment, wherein the subject experiences a decrease in body weight.

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

[0134] Phase 2 clinical study. The Phase 2 clinical trial was 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 was also designed to include an exploratory comparison of the 3.0 and 4.5 mg doses with dulaglutide 1.5 mg (the highest dose approved by regulatory authorities). The trial was designed to predict whether the increased dose would provide improved clinical benefit, including greater HbA1c reduction and greater weight loss, with an acceptable safety and tolerability profile.

[0135] The study was 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 who had inadequate glycemic control on metformin only.

[0136] After screening and run-in periods, patients were randomized in a 1:1:1:1 ratio to weekly injections of dulaglutide 4.5 mg, 3.0 mg, or 1.5 mg, or placebo, in combination with a stable dose of metformin. Within each study's dulaglutide dose group (3.0 mg and 4.5 mg), patients were randomly assigned in a 1:1 ratio to one of two dulaglutide dose titration algorithms, and participants were treated in a double-blind manner for 18 weeks after randomization, including a 6-week titration phase and a 12-week maintenance treatment phase at the final dose. During the titration period in the 3.0 and 4.5 mg groups, the dose of dulaglutide was gradually increased over 6 weeks according to one of two algorithms: (1) patients received dulaglutide 1.5 mg once weekly for the first 4 weeks (weeks 1-4) and then dulaglutide 3.0 mg once weekly for the next 2 weeks (weeks 5-6) (hereinafter referred to as "algorithm 1" or "A1"); or (2) patients received dulaglutide 0.75 mg once weekly for the first 2 weeks (weeks 1-2) and then dulaglutide 1.5 mg once weekly for the next 4 weeks (weeks 3-6) (hereinafter referred to as "algorithm 2" or "A2"). These two titration algorithms were selected based on modeling and simulations that included data from several phase 2 and phase 3 trials to evaluate the potential mitigating effects of titrating the dose in multiples (i.e., algorithm 1) versus longer exposure to a lower titrated dose (i.e., algorithm 2).

[0137] A total of 505 patients were screened and 318 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 at Visit 4 and did not receive any dose of study drug, resulting in 317 patients who received at least one dose of study drug and comprised 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] 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, excluding data collected post-rescue (patients with hyperglycemia requiring rescue with another therapy) and after study drug discontinuation. The HbA1c data also exclude results for patients who exhibited large, unexplained HbA1c fluctuations that were considered physiologically implausible and inconsistent with other available clinical information.

[0139] Table 1. Change in HbA1c (%) and weight (kg) at Week 18, ITT population, excluding post-rescue or study drug discontinuation data. Abbreviations: CI = confidence interval; LS mean = least squares mean; PBO = placebo. * The P-value for the comparison of dulaglutide vs. placebo was <0.05. ** The P-value for the comparison of dulaglutide vs. placebo was <0.001. P-value < 0.05 for the comparison of dulaglutide vs. dulaglutide 1.5 mg. Note: Dula XX represents XX mg of dulaglutide administered once weekly.

[0140] At week 18, all three doses of dulaglutide significantly reduced HbA1c from baseline 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 a decrease of -1.47% in the dulaglutide 3.0 mg group (LS mean treatment difference, -0.22%; 95% CI -0.48%, 0.03%) and a decrease of -1.50% in the dulaglutide 4.5 mg group (LS mean treatment difference, -0.26%; 95% CI -0.52%, 0.00%). Weight decreased by a mean of -2.9 kg in the dulaglutide 1.5 mg group, compared with a decrease of -4.2 kg in the dulaglutide 3.0 mg group (LS mean treatment difference, -1.3 kg; 95% CI -2.4, 0.2) and a decrease of -4.4 kg in the dulaglutide 4.5 mg group (LS mean treatment difference, -1.5 kg; 95% CI -2.6, -0.3). In the subgroup of patients with higher baseline HbA1c levels, both higher doses had a greater incremental efficacy in lowering HbA1c relative to dulaglutide 1.5 mg.

[0141] Table 2 summarizes the frequency of treatment-emergent nausea, vomiting, and diarrhea as measured by the prevalence (any patient with a new or ongoing event during this interval), incidence (any patient whose event began during this interval), and first onset (any patient whose first event of this type occurred during this interval) of these events over three time 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]).

[0142] Table 2. Summary of the prevalence, incidence, and first episode of nausea, vomiting, and diarrhea by treatment and period, 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.

[0143] The frequency of nausea and vomiting was higher in all three dulaglutide groups compared to placebo during all three time intervals. There was a dose-response in the frequency of nausea across the dulaglutide groups overall (weeks 0-18), with the highest frequency in the dulaglutide 4.5 mg group (30.3%). Within each dulaglutide treatment group, nausea was most frequent during the titration period (weeks 0-6) and decreased from weeks 6-10 onward. The prevalence of vomiting ranged from 6.6% to 8.9% across the dulaglutide groups during the titration period and decreased during weeks 6-10. The frequency of diarrhea was generally similar in the placebo and dulaglutide 1.5 mg groups across all three time intervals and was higher in the higher dose groups. Diarrhea, which was reported more frequently in the dulaglutide 3.0 mg and 4.5 mg groups during the initial 6 weeks, continued during weeks 6-10 and then decreased thereafter. During the titration period before patients received the 3.0 mg or 4.5 mg dose, the incidence of diarrhea was higher in the higher dose group compared to the 1.5 mg group; therefore, the difference did not appear to be entirely dose-related. With respect to the incidence of severe nausea, diarrhea, and vomiting, few patients had any serious events, and the prevalence was generally similar across all four treatment groups.

[0144] Although the incidence of nausea, vomiting, and diarrhea increased in a dose-dependent manner among patients treated with dulaglutide, and a higher proportion of patients discontinued study treatment due to adverse events than in the dulaglutide 1.5 mg group, the difference in incidence between the high-dose group and the 1.5 mg group was modest, and the frequency of related GI events and treatment discontinuations was lower than those observed in completed dulaglutide trials of shorter duration that included patients who received nontitrated doses of 3.0 mg or more, suggesting a beneficial effect of titration algorithms A1 and A2.

[0145] The number of patients randomized by the titration algorithm in the dulaglutide 3.0 mg and 4.5 mg groups was 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 for the two higher dose groups, depending on the dose and titration algorithm, as measured by the prevalence, incidence, and first onset of these events during the three key periods (0-6 weeks [titration period], 6-10 weeks, and 0-18 weeks [treatment period]).

[0146] Table 3. Summary of the prevalence, incidence, and first episode of nausea, vomiting, and diarrhea by dose and titration algorithm (dulaglutide 3.0 mg and dulaglutide 4.5 mg) and period, 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 is calculated for any patient with a new or ongoing event during the interval. Incidence is calculated for any patient whose event began during the interval. Onset is calculated for any patient whose first event of that type occurred during the interval.

[0147] The frequency of nausea was generally similar in A1 and A2; there was some variation within the 3.0 mg group, with a lower frequency in the A2 subgroup compared to the A1 subgroup, but this difference is unlikely to be considered related to the titration algorithm, as shown by the similar frequencies in the A1 and A2 subgroups in the 4.5 mg group. Most nausea events occurred during the titration period, with few new events reported after uptitration to the final dose (6-10 weeks).

[0148] The frequency of vomiting was generally similar in A1 and A2; more patients had events in the A1 subgroup than in the A2 subgroup within the dulaglutide 3.0 mg group, and more patients had events in the A2 subgroup than in the A1 subgroup within the dulaglutide 4.5 mg group, but similar to nausea as described above, these differences are not considered to be related to the titration algorithm, as the differences between the A1 and A2 subgroups within the 3.0 mg and 4.5 mg groups were in opposite directions. Most vomiting events in A1 occurred during the titration period, and few new events were reported after titration to the final dose (6-10 weeks). For A2, the frequency of vomiting was lower during the titration period, remained at similar levels during weeks 6-10, and began to decrease after week 10 and remained lower until week 18.

[0149] 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.

[0150] The pattern of incidence of these events observed in A1 versus A2 suggests that starting with a lower dulaglutide dose (dulaglutide 0.75 mg [used in A2] vs. dulaglutide 1.5 mg [used in A1]) reduces GI intolerance events during the titration period. The slower reduction in the frequency of these events in the A2 group compared with the A1 group during the final up-titration period (6-10 weeks) suggests that a longer titration period is required to develop tachyphylaxis to the GI side effects of dulaglutide.

[0151] As mentioned above, earlier studies with doses of 3.0 mg and higher resulted in an increase in pulse rate, which in part led to the discontinuation of the 3.0 mg group in the earlier studies. Therefore, changes in pulse rate were also measured in this study, and the collected data are provided below. In Table 4: Table 4. Change from baseline in heart rate with treatment in the ITT population. Abbreviations: LS = least squares; PR = pulse rate; wks = weeks; CI = confidence interval; n = sample size.

[0152] As shown in Table 4 above, mean changes in pulse rate were similar between the dulaglutide groups throughout the treatment period and at the end of the study.

[0153] Based on the determination of the optimal dose titration strategy, patients who started treatment with dulaglutide 0.75 mg (2 weeks, A1) initially had fewer GI issues than patients who started with dulaglutide 1.5 mg (4 weeks, A2), but these differences were not maintained after further up-titration of A1 to 1.5 mg. Differences were also noted between A1 and A2 in the dulaglutide 4.5 mg group as patients titrated up to their final dose (from 3.0 mg to 4.5 mg in the A1 group; from 1.5 mg to 4.5 mg in the A2 group), with patients in the A2 group being slightly less well tolerated. These results suggest that further adjustments to the algorithm may be able to optimize dulaglutide titration at higher doses in terms of the titration duration and dose level required to further minimize the risk of tolerability issues.

[0154] Phase 3 study This phase 3, multicenter, randomized, double-blind, parallel-arm study was designed with three study periods (lead-in, treatment, and safety follow-up) in patients with T2D who had inadequate glycemic control on metformin only; the study had a treatment duration of 52 weeks, with 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.

[0155] A minimum sample size of approximately 1800 patients was enrolled (randomized), assuming a 15% dropout rate, to achieve approximately 510 completers per group at week 36. At visit 3, patients were 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.

[0156] With the goal of further mitigating gastrointestinal adverse events, study doses of 4.5 and 3.0 mg were administered according to a titration algorithm designed based on PK / PD modeling of nausea and vomiting events from the aforementioned Phase 2 study. PK / PD exposure-response modeling of the Phase 2 study data also predicted that the daily incidence of nausea and vomiting at higher dulaglutide doses would be lowest with an algorithm that started with 0.75 mg and escalated more slowly over 8 weeks to allow adequate time for tolerability to develop. Based on these findings, patients in this study were 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 continued on this dose for the remainder of the treatment period. Patients randomized to the 3.0 mg dulaglutide group were increased to 3.0 mg once weekly at Week 8 and continued on this dose for the remainder of the treatment period. Patients assigned to the 4.5 mg dulaglutide group were escalated to 3.0 mg once weekly for 4 weeks at week 8, followed by a final dose of 4.5 mg once weekly at week 12. Study participants were treated for 52 weeks, with the primary endpoint assessed at week 36. This gradual, stepwise dose-titration strategy was designed to further improve GI tolerability at the 3.0 mg and 4.5 mg doses compared to that observed in the aforementioned Phase 2 study.

[0157] Preparation stability study Validation batches containing various concentrations of dulaglutide in formulations for currently approved dulaglutide doses were prepared and samples were filled into commercial primary packaging of dulaglutide as shown in Table 5 below: Dulaglutide concentration 3.0, 6.0, 9.0, and 12.0 mg / mL Sodium citrate 2.74 mg / mL Anhydrous citric acid 0.13 mg / mL Mannitol 46.4 mg / mL Polysorbate 80 0.02％ Primary packaging BDGen21mLLong,WestUncoatedPlunger Table 5. Validation batch composition.

[0158] The samples were placed for a maximum of 24 months to determine stability. However, after 3 months, the study was stopped due to the observed decrease in PS80 content. The data obtained for PS80 concentration were analyzed in JMP 12.1.0 software to predict the PS80 content under 24 months of long-term storage conditions. The activation energy (E) for PS80 degradation was calculated. a ) and used to predict the PS80 content during long-term storage. Based on the quadratic polynomial model, the activation energy E aThe point estimate is 15.24 kcal / mol and the 95% lower confidence limit is 12.85 kcal / mol. Based on this analysis, starting with a PS80 content of 0.02% (w / v), the 24-month predicted value for PS80 of the 12 mg / mL dulaglutide formulation is predicted to be below the specification limit for the current commercial dulaglutide. The 24-month predicted value for PS80 of the 9 mg / mL dulaglutide formulation is also close to the specification limit.

[0159] To assess the risk of PS80 content being out of specification (OOS) during long-term storage for 24 months, Monte Carlo simulations were performed in R3.4.0 software, leveraging historical dulaglutide data. The OOS risk associated with each high concentration level is summarized in Table 6 below: Table 6. Monte Carlo simulation results of PS80 OOS risk over 24 months Results from Monte Carlo simulations indicate a high risk of excessive degradation and, therefore, shelf-life OOS using the asymptotic lower confidence limit for the activation energy. PS80 is present in the dulaglutide formulation to provide protection against physical stress, and the PS80 lower specification limit was set to ensure that sufficient PS80 is present throughout the maximum possible shelf life and use period to provide this physical protection.

[0160] Given that preliminary data analysis from a development stability study indicated increased polysorbate 80 hydrolysis in higher concentration dulaglutide formulations, it was decided to explore formulation modifications. Increasing the polysorbate 80 content in the formulation might result in sufficient intact polysorbate 80 at the end of shelf life, but hydrolysis of higher amounts of polysorbate 80 could lead to the appearance of visible particles. Therefore, a surfactant range study was initiated to evaluate the effects of varying surfactant levels on stability.

[0161] Samples containing 3, 6, 9, and 12 mg / mL dulaglutide concentrations, 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 stored at 30°C for stability testing. Samples were taken at 0, 12, 25, 35, 46, and 74 days and tested for free oleic acid (FOA)—a hydrolysis product of PS80—and particulate matter. The data showed that the rate of increase in FOA increased with formulations with higher dulaglutide concentrations. At the same dulaglutide concentration, the rate of increase in FOA was the same for formulations with a starting polysorbate 80 content of 0.02% and 0.05%. Particulate matter, as measured by microfluidics imaging (MFI), was equivalent for all formulations, regardless of the dulaglutide or polysorbate 80 content. The results support the ability to increase the starting polysorbate 80 content up to 0.05% without compromising dulaglutide stability.

[0162] Based on the results of the developmental stability studies and surfactant studies, a detailed statistical analysis of all available data was performed. This analysis concluded that the starting polysorbate 80 content in the formulation should be increased from 0.02% to 0.025% (w / v) at concentrations of 6.0 and 9.0 mg / mL. This increased content was selected so that there was a high probability that there would be enough polysorbate 80 to meet the currently approved commercial specifications even at the end of the shelf life.

[0163] A second validation batch was prepared containing the same concentrations as used in the first validation batch above, except that the PS80 concentration was increased, as shown in Table 7 below: Dulaglutide concentration 3.0, 6.0, 9.0, and 12.0 mg / mL Sodium citrate 2.74 mg / mL Anhydrous citric acid 0.13 mg / mL Mannitol 46.4 mg / mL Polysorbate 80 0.025％ Primary packaging BDGen21mLLongSyringe, WestUncoatedPlunger Table 7. Second validation batch parameters.

[0164] Stability was determined by placing samples 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 indicated that the concentrated formulation was chemically and physically stable, and the PS80 concentration remained above the lower specification limit throughout the shelf life.

Claims

1. A stable pharmaceutical preparation comprising: a) dulaglutide at a concentration selected from 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.

2. The stable pharmaceutical formulation of claim 1, wherein the concentration of polysorbate 80 is 0.25 mg / mL.

3. The stable pharmaceutical formulation according to any one of claims 1-2, wherein the concentration of dulaglutide is 6.0 mg / mL.

4. The stable pharmaceutical formulation of any one of claims 1-2, wherein the concentration of dulaglutide is 9.0 mg / mL.

5. The stable pharmaceutical formulation according to any one of claims 1 to 4, wherein the formulation remains chemically and physically stable at 2-8°C for 24 months.

6. The stable pharmaceutical formulation of any one of claims 1 to 5, wherein the formulation remains chemically and physically stable at 30°C for 14 days.

7. Use of dulaglutide in the preparation of a medicament for use in a method for improving glycemic control in a subject with type 2 diabetes (T2D), the method comprising administering to the subject 0.5 mL of the stable pharmaceutical formulation of any one of claims 27 to 32.

8. The use of claim 7, wherein the formulation is provided as a 0.5 mL aqueous solution.

9. An autoinjector comprising the stable pharmaceutical formulation according to any one of claims 1 to 5.

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