EA041605B1 - APPLICATIONS AND COMPOSITIONS CONTAINING DULAGLUTIDE - Google Patents

Description

This invention relates to the field of medicine. More specifically, the present invention relates to methods of administering new doses of dulaglutide and compositions containing such higher doses of dulaglutide.

Dilaglutide, the active ingredient in Trulicity®, is a glucagon-like peptide-1 receptor (GLP-1 RA) agonist that is approved for use as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (D2T). Two doses of dulaglutide per week, 0.75 and 1.5 mg, were studied in a Phase 3 development program and received regulatory approval in the United States of America, the European Union and other jurisdictions in 2014. Since their approval in 2014, these two doses of dulaglutide have been used to treat a variety of patients with D2T, resulting in a significant decrease in HbA1c levels with a low risk of hypoglycemia and weight loss.

While therapy with currently approved doses of dulaglutide has enabled the majority of patients enrolled in the Phase 3 program to achieve their glycemic goals (with or without other concomitant drugs for the treatment of D2T), a significant number of patients receiving approved therapy today, including dulaglutide do not achieve glycemic control goals (see, for example, 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 to provide improved efficacy of pharmaceutical agents while maintaining an overall acceptable benefit/risk profile.

Doses, methods and compositions of the present invention seek to meet this need. Advantages of the present invention include providing additional glycemic control as evidenced by, for example, further reduction in HbA1c levels and/or weight loss compared to currently approved doses of dulaglutide. In addition, the present invention provides such benefits while maintaining an acceptable safety risk profile and side effects.

Accordingly, the present invention provides a method for improving glycemic control in a subject having type 2 diabetes (T2D) as well as additional glycemic control, comprising:

a) identifying a subject who has D2T and needs additional glycemic control;

b) administering to said subject a first dose of dulaglutide once a week for at least four weeks;

c) increasing the dose to a second dose, with the first dose selected from the group consisting of 1.5 and 3.0 mg once a week, and the second dose selected from the group consisting of 3.0 and 4.5 mg once a week week.

In another aspect, the present invention provides a method for improving glycemic control in a subject having type 2 diabetes (T2D), as well as additional glycemic control, comprising:

a) identifying a subject who has D2T and needs additional glycemic control;

b) administering to said subject 0.75 mg of dulaglutide once a week for at least four weeks;

c) administering to said subject 1.5 mg of dulaglutide once a week for at least four weeks;

d) administering to said subject 3.0 mg once a week.

In some embodiments, the method further comprises increasing the dose from 3.0 mg to 4.5 mg once a week after the subject has been treated with a 3.0 mg dose for at least four weeks.

In another aspect, the present invention provides a method for improving glycemic control in a subject having type 2 diabetes (D2T) and receiving a 1.5 mg dose of dulaglutide once a week, but in need of additional glycemic control, comprising increasing the dose of dilaglutide administered to 3.0 mg once a week.

In another aspect, the present invention provides a method for improving glycemic control in a subject having type 2 diabetes (D2T) and receiving a 3.0 mg dose of dulaglutide once a week, but in need of additional glycemic control, comprising increasing the dose of dilaglutide administered to 4.5 mg once a week.

In another aspect, the present invention provides a method of administering dulaglutide to a subject having D2T and in need of additional glycemic control, wherein the improvement comprises administering 1.5 mg of dulaglutide once a week for at least four weeks, followed by an increase in dose to 3.0 mg once a day. once a week.

In another aspect, the present invention provides an improved method of administering dulaglutide to a subject having D2T and in need of additional glycemic control, wherein the improvement

- 1 041605 includes administration of 0.75 mg of dulaglutide once a week for at least four weeks, followed by an increase in dose to 1.5 mg of dulaglutide once a week for at least four weeks, followed by an increase in dose to 3.0 mg once a week.

In another aspect, the present invention provides an improved method of administering dulaglutide to a subject having D2T and in need of additional glycemic control, wherein the improvement comprises:

a) administration of 3.0 mg of dulaglutide once a week for at least four weeks;

b) increase the dose to 4.5 mg once a week.

In another aspect, the present invention provides a method for long-term weight control in a subject in need thereof, comprising:

a) administering to said subject 0.75 mg of dulaglutide once a week for at least four weeks;

b) administering to said subject 1.5 mg of dulaglutide once a week for at least four weeks;

c) increase the dose to 3.0 mg once a week.

In another aspect, the present invention provides a method for long-term weight control in a subject in need thereof, comprising:

a) identifying a subject previously treated with 1.5 mg of dulaglutide once a week for at least four weeks; And

b) increase the dose to 3.0 mg once a week.

In another aspect, the present invention provides a method for long-term weight control in a subject in need thereof, comprising:

a) identifying a subject previously treated with 3.0 mg dulaglutide once weekly for at least four weeks; And

b) increase the dose to 4.5 mg once a week.

In another aspect, the present invention provides 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;

d) polysorbate 80 at a concentration of 0.25 mg/ml.

In another aspect, the present invention provides dulaglutide for use in improving glycemic control in a subject having type 2 diabetes (D2T) and in need of additional glycemic control, comprising:

a) identifying a subject who has D2T and needs additional glycemic control;

b) administering to said subject a first dose of dulaglutide once a week for at least four weeks;

c) increasing the dose to a second dose, wherein the first dose is selected from the group consisting of 1.5 and 3.0 mg once a week, and the second dose is selected from the group consisting of 3.0 and 4.5 mg once a week in Week.

In another aspect, the present invention provides dulaglutide for use in improving glycemic control in a subject having type 2 diabetes (D2T) and in need of additional glycemic control, comprising:

a) identifying a subject who has D2T and needs additional glycemic control;

b) administering to said subject 0.75 mg of dulaglutide once a week for at least four weeks;

c) administering to said subject 1.5 mg of dulaglutide once a week for at least four weeks;

d) administering to said subject 3.0 mg once a week.

In another aspect, the present invention provides dulaglutide for use in improving glycemic control in a subject having type 2 diabetes (T2D) treated with dulaglutide 1.5 mg once weekly but in need of additional glycemic control, comprising: increasing the dose administered dulaglutide up to 3.0 mg once a week.

In another aspect, the present invention provides dulaglutide for use in improving glycemic control in a subject having type 2 diabetes (T2D) treated with dulaglutide 3.0 mg once weekly but in need of additional glycemic control, comprising: increasing the dose administered dulaglutide up to 4.5 mg once a week.

In another aspect, the present invention provides dulaglutide for use in providing long-term weight control in a subject in need thereof, comprising:

a) administering to said subject 0.75 mg of dulaglutide once a week for at least

- 2 041605 four weeks;

b) administering to said subject 1.5 mg of dulaglutide once a week for at least four weeks;

c) increase the dose to 3.0 mg once a week.

In another aspect, the present invention provides dulaglutide for use in long-term weight control in a subject in need thereof, comprising:

a) identifying a subject previously treated with 1.5 mg of dulaglutide once a week for at least four weeks; And

b) increase the dose to 3.0 mg once a week.

In another aspect, the present invention provides dulaglutide for use in long-term weight control in a subject in need thereof, comprising:

a) identifying a subject previously treated with 3.0 mg dulaglutide once weekly for at least four weeks; And

b) increase the dose to 4.5 mg once a week.

In another aspect, the present invention provides the use of dulaglutide for the manufacture of a medicament for improving glycemic control in a subject having type 2 diabetes (D2T) and in need of additional glycemic control, comprising:

a) identifying a subject who has D2T and needs additional glycemic control;

b) administering to said subject a first dose of dulaglutide once a week for at least four weeks;

c) increasing the dose to a second dose, with the first dose selected from the group consisting of 1.5 and 3.0 mg once a week, and the second dose selected from the group consisting of 3.0 and 4.5 mg once a week week.

In another aspect, the present invention provides the use of dulaglutide for the manufacture of a medicament for improving glycemic control in a subject having type 2 diabetes (D2T) and in need of additional glycemic control, comprising:

a) identifying a subject who has D2T and needs additional glycemic control;

b) administering to said subject 0.75 mg of dulaglutide once a week for at least four weeks;

c) administering to said subject 1.5 mg of dulaglutide once a week for at least four weeks;

d) administering to said subject 3.0 mg once a week.

In another aspect, the present invention provides the use of dulaglutide for the manufacture of a medicament for improving glycemic control in a subject having type 2 diabetes (T2D) receiving a 1.5 mg dose of dulaglutide once a week but in need of additional glycemic control, comprising increasing the dose of the administered dulaglutide up to 3.0 mg once a week.

In another aspect, the present invention provides the use of dulaglutide for the manufacture of a medicament for improving glycemic control in a subject having type 2 diabetes (T2D) receiving a 3.0 mg dose of dulaglutide once a week but in need of additional glycemic control, comprising increasing the dose of the administered dulaglutide up to 4.5 mg once a week.

In another aspect, the present invention provides the use of dulaglutide for the manufacture of a medicament for long-term weight control in a subject in need thereof, comprising:

a) administering to said subject 0.75 mg of dulaglutide once a week for at least four weeks;

b) administering to said subject 1.5 mg of dulaglutide once a week for at least four weeks;

c) increase the dose to 3.0 mg once a week.

In another aspect, the present invention provides the use of dulaglutide for the manufacture of a medicament for long-term weight control in a subject in need thereof, comprising:

a) identifying a subject previously treated with 1.5 mg of dulaglutide once a week for at least four weeks; And

b) increase the dose to 3.0 mg once a week.

In another aspect, the present invention provides the use of dulaglutide for the manufacture of a medicament for long-term weight control in a subject in need thereof, comprising:

a) identifying a subject previously treated with 3.0 mg dulaglutide once weekly for at least four weeks; And

b) increase the dose to 4.5 mg once a week.

Dulaglutide is a human GLP-1 RA that contains a GLP-1 analog dimer linked to

- 3 041605 at its C-terminus using a peptide linker with the N-terminus of the Fc analogue of the immunoglobulin part and identified by CAS registration number 923950-08-7. Each dulaglutide monomer has the amino acid sequence shown in SEQ ID NO: 1:

20 30 40 50 60

HGEGTFTSDVSSYLEEQAAKEFIAWLVKGGGGGGGSGGGGSGGGGSAESKYGPPCPPCPA 70 80 90 100 110120

PEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP 130 140 150 160 170180

REEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTL 190 200 210 220 230240

PPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLT 250 260270

VDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG

The two monomers are linked by disulfide bonds to form a dimer.

The structure, function, preparation and use of dulaglutide in the treatment of D2T are described in more detail in US 7452966 and US Patent Application Publication No. US20100196405.

As used herein, the term dulaglutide refers to any two-monomer GLP-1 RA protein dimer having the amino acid sequence of SEQ ID NO: 1, including any protein that is the subject of a registration dossier requiring registration of a GLP-1 RA product that is wholly or relies in part on data submitted to the regulatory body by Eli Lilly and Company regarding dulaglutide, whether or not the party requesting registration of said protein identifies the protein as dulaglutide or uses some other term.

Dulaglutide stimulates insulin synthesis and secretion and has been shown to provide improved glycemic control in patients with D2T compared with placebo, both when administered in combination with metformin. As noted above, the 0.75 and 1.5 mg doses of dulaglutide were selected for Phase 3 registration studies, submitted for regulatory approval, and were approved in 2014 and have since been used to provide glycemic control in thousands of patients with D2T. However, as also noted above, many D2T patients worldwide still cannot achieve their HbA1c goals and cannot control their weight, so new treatments are needed that can provide additional glycemic control and/or weight loss.

Although increasing the dose of a drug may in some cases lead to an increase in efficacy, increasing the dose of a drug also carries the risk of increased side effects. For example, administration of GLP-1 RA is known to result in a risk of nausea, diarrhea, and vomiting (see, for example, TRULICITY® Prescribing Information), and in 33 patients treated with 3.0 mg or higher doses of dulaglutide in Phase 1 dose studies and, in the Phase 2/3 dose determination part, the incidence of gastrointestinal (GI) side effects (AEs) commonly associated with GLP-1 RA treatment, such as nausea (17 patients, 52%) and vomiting (9 patients, 27%) was higher than the frequency reported with currently approved doses in Phase 3 registration 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 (A WARD-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). 5 out of 33 patients (15%) actually discontinued early treatment due to GI PE. In addition to gastrointestinal tolerance issues, earlier studies at higher doses also suggested that increasing the dose may also carry the risk of an unacceptable increase in heart rate (see e.g. Skrivanek, 2014). Indeed, following a series of open interim reviews of data in one of the studies mentioned above, which initially included seven doses ranging from 0.25 to 3.0 mg, the Data Monitoring Committee (DMC) recommended that patients be stopped randomizing patients to a dose of dulaglutide 3.0 mg due to a higher incidence of pancreatic enzymes above the upper limit of normal (ULN), an increase in heart rate (HR) and a higher incidence of side effects from the gastrointestinal tract (see, for example, Skrivanek, 2014). Thus, any increase in dose must strike a balance between sufficiently high efficacy without leading to unacceptable safety or tolerability problems.

Increased doses of 3.0 or 4.5 mg of dulaglutide once weekly have been found to be able to provide increased efficacy over currently available doses of 0.75 and 1.5 mg and can be administered with acceptable safety and tolerability profiles if prior to their appointment, an increasing dose selection scheme is used. Thus, the present invention provides for the administration of dulaglutide at doses of 3.0 and 4.5 mg once a week, as well as a dose selection regimen that results in acceptable safety and tolerability profiles when administered 3.0 and 4.5 mg doses. In subjects in whom dulaglutide treatment is first initiated, a dose titration regimen includes an initial treatment dose of 0.75 mg once weekly followed by an increase to 1.5 mg once weekly followed by an increase to 3.0 mg once a week. week, followed, if necessary, by increasing the dose to 4.5 mg once a week. However, in subjects already on dulaglutide who are in need of additional glycemic control, the dose adjustment regimen does not require a reduction in the subject's current dose. For example, in a subject who received 1.5 mg of dulaglutide once a week but needs additional glycemic control, the regimen does not require a dose reduction to 0.75 mg, but instead increases the dose to 3.0 mg, and then, if necessary, up to 4.5 mg. Similarly, in a subject who received 3.0 mg of dulaglutide once weekly but is in need of additional glycemic control, the regimen does not require dose reduction to 0.75 or 1.5 mg once weekly, but instead calls for a dose increase up to 4.5 mg. However, for any of the above embodiments of the dose selection scheme, the dose is preferably not increased to the next next dose in a progression until the current dose has been administered for at least four weeks.

However, it has also been found that increasing the concentration of dulaglutide also requires other modifications to existing commercial formulations, so the present invention also provides new formulations that ensure that formulations containing elevated doses of dulaglutide will remain chemically and physically stable and meet current product specifications for 2 years of storage in the refrigerator and 14 days of use.

Currently approved products containing dulaglutide are presented in the form of 0.5 ml aqueous solutions containing 0.75 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® Instructions for Use). PS80 is formulated to help provide protection from physical stress and to ensure that the dulaglutide protein remains physically stable through the product's shelf life, 2 years refrigerated storage, and a maximum of up to 14 days of use at room temperature. . Thus, the description of a product based on dulaglutide includes a lower PS80 concentration limit, above which the PS80 concentration must be maintained throughout the shelf life and period of use. In order to ensure that the PS80 concentration remains above this lower specification limit, to extend shelf life and period of use, currently approved dulaglutide products contain a PS80 concentration of 0.1 mg/0.5 ml (0.02% wt. /about.).

When the concentration of dulaglutide is increased to the higher doses contemplated in the methods of the present invention, the PS80 concentration decreases further than currently approved formulations due to increased hydrolysis, and formulation changes are necessary to ensure sufficient PS80 is present to meet the product description. and ensure physical stability. As described in more detail in the examples below, it has been determined that increasing the PS80 concentration to 0.025% will meet the PS80 specification limit throughout the shelf life and use at higher doses of dulaglutide contemplated in the methods of the present invention, but they should not be so high. to result in the formation of unacceptable visible particles as a result of the hydrolysis of PS80 or otherwise have any undesirable effect on the chemical or physical stability of the compositions. Thus, in certain embodiments, the methods of the present invention are carried out by administering elevated doses of dulaglutide to 0.5 ml aqueous solutions containing 3.0 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 some embodiments, the methods of the present invention are carried out by administering increased doses of dulaglutide to solutions of any volume containing 6.0 or 9.0 mg/ml dulaglutide, 0.14 mg/ml anhydrous citric acid, 46.4 mg/ml mannitol, 2 .74 mg/ml trisodium citrate dihydrate and 0.25 mg/ml polysorbate 80 (PS80).

Terms treatment, treat, treating, etc. include slowing or reversing the development of a disease or disorder. Said terms also include amelioration, improvement, reduction, elimination, or amelioration of one or more symptoms of a disorder or condition, even if said disorder or condition is not actually eliminated, and even if the progression of the disorder or condition is not itself retarded or reversed.

The subject refers to a mammal, preferably a human, with a disease, disorder or condition that would benefit from treatment with an increased dose of dulaglutide.

Glycemic control refers to the maintenance or reduction of HbA1c levels in a subject; improving glycemic control refers to lowering HbA1c; and in need of additional glycemic control refers to the need to lower HbA1c levels.

Long-term weight control refers to weight loss.

- 5 041605

HbAlc refers to the levels of glycated hemoglobin that develop when hemoglobin combines with glucose in the blood. HbA1c levels are a commonly used measure of glycemic control in diabetic patients, with a decrease in HbA1c usually indicating improved glycemic control. In the context of the methods of the present invention, the methods of the present invention lead to a decrease in HbA1c. In some embodiments, lowering HbA1c reduces relative HbA1c levels resulting from treatment with currently approved doses of 0.75 and 1.5 mg of dulaglutide.

In certain embodiments of the present invention, the doses and dosing regimens of dulaglutide described herein are for the treatment of obesity, long-term weight control, and/or non-therapeutic weight loss in subjects in need thereof. In certain embodiments, the subject has a body mass index (BMI) 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, subjects have a body mass index (BMI) greater than about 27 kg/m ² . In certain embodiments, the subject also has one or more weight-related comorbid conditions, such as D2T, hypertension, and/or dyslipidemia.

In certain embodiments, the dosages and dosage 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).

In some embodiments, the doses of dulaglutide and the administration regimens described herein are 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.

The treatments and uses described herein may be provided in simultaneous or sequential combination with other D2T treatments, including oral D2T treatments such as metformin, and/or other injectable medications, including fast-acting or basal insulins.

Additional embodiments of the present invention include the embodiments described below.

1. A method of improving glycemic control in a subject having type 2 diabetes (D2T), comprising administering to said subject an increased dose of dulaglutide once a week, the increased dose being selected from the group consisting of 3.0 and 4.5 mg of dulaglutide once a week. week.

2. A method for improving glycemic control in a subject having type 2 diabetes (D2T) and in need of additional glycemic control, comprising:

a) administering to said subject 1.5 mg of dulaglutide once a week;

b) administering to said subject an increased dose of dulaglutide once a week, the increased dose being selected from the group consisting of 3.0 and 4.5 mg of dulaglutide once a week.

3. A method for improving glycemic control in a subject having type 2 diabetes (D2T), comprising:

a) administering to said subject 0.75 mg of dulaglutide once a week; followed by

b) administering to said subject 1.5 mg of dulaglutide once a week; followed by

c) administering to said subject an increased dose of dulaglutide once a week.

4. A method for improving glycemic control in a subject having type 2 diabetes (D2T) and in need of additional glycemic control, comprising:

a) identifying a subject previously treated with 1.5 mg of dulaglutide once a week; followed by

b) administration of an increased dose of dulaglutide once a week.

5. The method of any one of embodiments 1-4, wherein 1.5 mg of dulaglutide is administered once a week for two or more weeks prior to administration of an increased dose of dulaglutide.

6. The method of any one of embodiments 1-5, wherein 1.5 mg of dulaglutide is administered once a week for at least four weeks prior to administration of an increased dose of dulaglutide.

7. An improved method of administering dulaglutide to a subject having (D2T) in need of additional glycemic control, wherein the improvement comprises administering an increased dose of dulaglutide selected from the group consisting of 3.0 and 4.5 mg once a week.

8. A method for improving glycemic control in a subject having type 2 diabetes (D2T) and in need of additional glycemic control, comprising:

a) administering to said subject 3.0 mg of dulaglutide once a week; followed by

b) administering to said subject 4.5 mg of dulaglutide once a week.

9. A method for improving glycemic control in a subject having type 2 diabetes (D2T), comprising:

a) administering to said subject 1.5 mg of dulaglutide once a week; followed by

b) administering to said subject 3.0 mg of dulaglutide once a week; followed by

c) administering to said subject 4.5 mg of dulaglutide once a week.

10. A method for improving glycemic control in a subject having type 2 diabetes (D2T) and in need of additional glycemic control, comprising:

- 6 041605

a) administering to said subject 0.75 mg of dulaglutide once a week; followed by

b) administering to said subject 1.5 mg of dulaglutide once a week; followed by

c) administering to said subject 3.0 mg of dulaglutide once a week; followed by

d) administering to said subject 4.5 mg of dulaglutide once a week.

11. A method for improving glycemic control in a subject having type 2 diabetes (D2T) and in need of additional glycemic control, comprising:

a) identifying a subject previously treated with 3.0 mg of dulaglutide once a week; followed by

b) administration of 4.5 mg of dulaglutide once a week.

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

13. The method of any of the above embodiments, wherein each identified dose of dulaglutide is administered for at least four weeks prior to administration of a subsequent increased dose of dulaglutide.

14. An improved method of administering dulaglutide to a subject having (D2T) who is receiving the first dose of dulaglutide but is in need of additional glycemic control, wherein the improvement comprises administering an increased dose of dulaglutide.

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.

16. An improved method according to any one of embodiments 14, 15, wherein the first dose of dulaglutide is administered two or more weeks prior to the second dose of dulaglutide.

17. An improved method according to any one of embodiments 14, 15, wherein the first dose of dulaglutide is administered for at least four weeks prior to the second dose of dulaglutide.

18. The method of any of the above embodiments, wherein the method results in a decrease in HbA1c.

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

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

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

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

23. A method for long-term weight control in a subject in need thereof, comprising administering to said subject dulaglutide in amounts according to any of the above embodiments.

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

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.

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.

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.

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.

29. A method of treating NASH in a subject in need thereof, comprising administering to said subject dulaglutide in amounts according to any of the above embodiments.

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

31. A method of treating CKD in a subject in need thereof, comprising administering to said subject dulaglutide in amounts according to any of the above embodiments.

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

- 7 041605

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

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

35. The method of any of the above embodiments, wherein administration of dulaglutide does not result in unacceptable GI tract tolerance.

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

37. The method according to any of the above embodiments, wherein the increased dose of dulaglutide is administered in 0.5 ml of an aqueous composition containing:

a) 0.07 mg of citric acid;

b) 23.2 mg mannitol;

c) 1.37 mg trisodium citrate;

d) about 0.125 to about 0.25 mg of polysorbate 80.

38. The method of Embodiment 37 wherein the amount of polysorbate 80 in the composition is about 0.125 mg.

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

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

41. A stable pharmaceutical composition containing:

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;

d) polysorbate 80 at a concentration of about 0.25 to 0.5 mg/ml.

42. A stable pharmaceutical composition according to embodiment 41, wherein the concentration of polysorbate 80 is about 0.25 mg/mL.

43. A stable pharmaceutical composition according to any one of embodiments 41 or 42, wherein the concentration of dulaglutide is 6.0 mg/mL.

44. A stable pharmaceutical composition according to any one of embodiments 41 or 42, wherein the concentration of dulaglutide is 9.0 mg/mL.

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

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

47. An auto-injector containing a stable pharmaceutical composition according to any one of embodiments 41-46.

48. A method for improving glycemic control in a subject having type 2 diabetes (D2T), comprising administering to said subject 0.5 ml of a stable pharmaceutical composition according to any one of embodiments 41-44.

49. Dulaglutide for use in improving glycemic control in a subject with type 2 diabetes (D2T) and in need of additional glycemic control, comprising:

a) identifying a subject who has D2T and needs additional glycemic control;

b) administering to said subject a first dose of dulaglutide once a week for at least four weeks;

c) increasing the dose to a second dose, where the first dose is selected from the group consisting of 1.5 and 3.0 mg once a week, and the second dose is selected from the group consisting of 3.0 and 4.5 mg once a week week.

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

51. Dulaglutide for use according to embodiment 49 wherein the subject was administered a 0.75 mg dose of dulaglutide for at least four weeks prior to the 1.5 mg dose.

52. Dulaglutide for use according to any one of embodiments 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 a dose of 3.0 mg for at least four weeks.

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

54. The use of dulaglutide for the manufacture of a medicament for improving glycemic control in a subject having type 2 diabetes (D2T) and in need of supplemental glycemic control.

- 8 041605 chesky control, including:

a) identifying a subject who has D2T and needs additional glycemic control;

b) administering to said subject a first dose of dulaglutide once a week for at least four weeks;

c) increasing the dose to a second dose, where the first dose is selected from the group consisting of 1.5 and 3.0 mg once a week, and the second dose is selected from the group consisting of 3.0 and 4.5 mg once a week week.

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

56. The use of embodiment 55 wherein the subject was treated with dulaglutide at a dose of 0.75 mg for at least four weeks prior to administration of the 1.5 mg dose.

57. Use according to any one of embodiments 54-56, further comprising increasing the dose from 3.0 mg to 4.5 mg once a week after the subject has been treated with a dose of 3.0 mg for at least four weeks.

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

59. Dulaglutide for use in improving glycemic control in a subject with type 2 diabetes (D2T) and in need of additional glycemic control, comprising:

a) identifying a subject who has D2T and needs additional glycemic control;

b) administering to said subject 0.75 mg of dulaglutide once a week for at least four weeks;

c) administering to said subject 1.5 mg of dulaglutide once a week for at least four weeks;

d) administering to said subject 3.0 mg once a week.

60. Dulaglutide for use according to embodiment 59, further comprising increasing the dose to 4.5 mg once weekly after the subject has been dosed at 3.0 mg once weekly for at least four weeks.

61. The use of dulaglutide for the manufacture of a medicament for improving glycemic control in a subject having type 2 diabetes (D2T) and in need of additional glycemic control, comprising:

a) identifying a subject who has D2T and needs additional glycemic control;

b) administering to said subject 0.75 mg of dulaglutide once a week for at least four weeks;

c) administering to said subject 1.5 mg of dulaglutide once a week for at least four weeks;

d) administering to said subject 3.0 mg once a week.

62. The use of Embodiment 61 further comprising increasing the dose to 4.5 mg once weekly after the subject has been dosed at 3.0 mg once weekly for at least four weeks.

63. Dulaglutide for use in improving glycemic control in a subject with type 2 diabetes (D2T) who is being treated with dulaglutide 1.5 mg once weekly but in need of additional glycemic control, comprising increasing the dose of dulaglutide administered to 3.0 mg once a week.

64. Dulaglutide for use according to embodiment 61, further comprising increasing the dose to 4.5 mg once weekly after the subject has been dosed at 3.0 mg once weekly for at least four weeks.

65. The use of dulaglutide for the manufacture of a medicament for improving glycemic control in a subject with type 2 diabetes (D2T) and receiving a 1.5 mg dose of dulaglutide once a week, but in need of additional glycemic control, including increasing the dose of dulaglutide administered to 3, 0 mg once a week.

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 of dulaglutide once weekly for a minimum of four weeks.

67. Dulaglutide for use to improve glycemic control in a subject with type 2 diabetes (D2T) who is being treated with dulaglutide 3.0 mg once weekly but in need of additional glycemic control, including increasing the dose of dulaglutide administered to 4.5 mg once a week.

68. Dulaglutide for use in providing long-term weight control in a subject in need of it, including:

- 9 041605

a) administering to said subject 0.75 mg of dulaglutide once a week for at least four weeks;

b) administering to said subject 1.5 mg of dulaglutide once a week for at least four weeks;

c) increase the dose to 3.0 mg once a week.

69. Dulaglutide for use according to embodiment 68, further comprising increasing the dose to 4.5 mg once weekly after the subject has been dosed at 3.0 mg once weekly for at least four weeks.

70. Dulaglutide for use in providing long-term weight control in a subject in need of it, including:

a) identifying a subject previously treated with 1.5 mg of dulaglutide once a week for at least four weeks; And

b) increase the dose to 3.0 mg once a week.

71. Dulaglutide for use according to embodiment 70, further comprising increasing the dose to 4.5 mg once weekly after the subject has been dosed at 3.0 mg once weekly for at least four weeks.

72. Dulaglutide for use in long-term weight control in a subject in need thereof, comprising:

a) identifying a subject previously treated with 3.0 mg dulaglutide once weekly for at least four weeks; And

b) increase the dose to 4.5 mg once a week.

73. The use of dulaglutide for the manufacture of a medicament for improving glycemic control in a subject with type 2 diabetes (D2T) and receiving a 3.0 mg dose of dulaglutide once a week, but in need of additional glycemic control, including increasing the dose of dulaglutide administered to 4, 5 mg once a week.

74. The use of dulaglutide for the manufacture of a medicament for long-term weight control in a subject in need thereof, including:

a) administering to said subject 0.75 mg of dulaglutide once a week for at least four weeks;

b) administering to said subject 1.5 mg of dulaglutide once a week for at least four weeks;

c) increase the dose to 3.0 mg once a week.

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 four weeks.

76. The use of dulaglutide for the manufacture of a medicament for long-term weight control in a subject in need thereof, comprising:

a) identifying a subject previously treated with 1.5 mg of dulaglutide once a week for at least four weeks; And

b) increase the dose to 3.0 mg once a week.

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 of dulaglutide once weekly for a minimum of four weeks.

78. The use of dulaglutide for the manufacture of a medicament for long-term weight control in a subject in need thereof, including:

a) identifying a subject previously treated with 3.0 mg dulaglutide once weekly for at least four weeks; And

b) increase the dose to 4.5 mg once a week.

79. Dulaglutide, for use according to any of the above embodiments, wherein a dose of 3.0 or 4.5 mg of dulaglutide is administered in 0.5 ml of an aqueous composition containing:

a) 0.07 mg of citric acid;

b) 23.2 mg mannitol;

c) 1.37 mg trisodium citrate;

d) polysorbate 80, in an amount from 0.125 to 0.25 mg.

80. Dulaglutide for use according to Embodiment 79 wherein the amount of polysorbate is 0.125 mg.

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

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

83. Dulaglutide for use in any of the above embodiments, wherein administration of an increased dose of dulaglutide does not result in unacceptable tolerability.

- 10 041605

84. Dulaglutide for use in any of the above embodiments, where the level

The subject's HbAlc is reduced.

85. Dulaglutide for use in any of the above embodiments wherein the subject's body weight is reduced.

The invention is further illustrated by the following examples, which should not be considered as limiting.

Examples

Phase 2 clinical trial.

The Phase 2 clinical trial is designed to evaluate the safety and efficacy of a single dose of dulaglutide 3.0 and 4.5 mg once a week, administered according to one of two dose selection algorithms, compared with placebo in patients with type 2 diabetes mellitus (D2T), treated with metformin monotherapy. The study is also intended to include diagnostic comparisons of 3.0 and 4.5 mg doses with dulaglutide 1.5 mg (the highest dose approved by regulatory authorities). The study is designed to predict whether higher doses will provide improved clinical benefits, including greater HbA1c reduction and greater weight loss, with an acceptable safety and tolerability profile.

The study was performed as a multicenter, randomized, double-blind, parallel-controlled, placebo-controlled study with three study periods (start-up, treatment, and safety follow-up) in D2T patients with inadequate glycemic control with metformin alone.

After screening and baseline, patients are randomized in a 1:1:1:1 ratio to weekly injections of dulaglutide 4.5, 3.0, or 1.5 mg or placebo in combination with stable doses of metformin. In each of the dulaglutide dose study groups (3.0 and 4.5 mg), patients are randomly assigned in a 1:1 ratio to one of two dulaglutide dose selection algorithms, and participants receive treatment for 18 weeks after double-blind randomization, including 6 weeks of the selection phase and 12 weeks of the maintenance phase using the final dose. During the 3.0 and 4.5 mg titration phase, the dose of dulaglutide is increased over 6 weeks according to one of two algorithms: (1) patients receive a dose of 1.5 mg dulaglutide once a week for the first 4 weeks (weeks 1-4) followed by a dose of dulaglutide 3.0 mg once a week for the next 2 weeks (weeks 5-6) (hereinafter 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 Algorithm 2 or A2). Two fitting algorithms are selected based on modeling and simulation, including data from several Phase 2 and Phase 3 studies, to evaluate the potential mitigating effect of doubling the adjusted doses (i.e., Algorithm 1) versus longer exposure at lower adjusted doses ( i.e. Algorithm 2).

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; dulaglutide 4.5 mg, 76. One patient randomized to placebo withdrew their consent to participate in the study at Visit 4 and did not receive any doses of study drug, so 317 patients received at least 1 dose of study drug and included targeted treatment ( ITT): placebo, 81; dulaglutide 1.5 mg, 81; dulaglutide 3.0 mg, 79; dulaglutide 4.5 mg, 76.

Summary of changes from baseline in HbA1c (%) and body weight (kg) at week 18 in the ITT population, excluding data collected after recovery (patients who had high blood glucose in need of rescue with another therapy), and discontinuation of the drug after the study are given in table. 1. HbA1c data also excludes results for patients showing large unexplained fluctuations in HbA1c levels that are considered physiologically implausible and are inconsistent with other available clinical information.

- 11 041605

Table 1

Change in HbAlc (%) and body weight (kg) at week 18 of the ITT population, excluding data on drug discontinuation or study drug discontinuation

Parameter Change in mean NC from baseline (SP) [and] Mean NC difference (95% CI) PBO Dula 1.5 Dula 3.0 Dula 4.5 Dula 1.5 PBO Dula 3.0 Dula 1.5 Dula 4.5 Dula 1.5 Change in HbAlc (%) -0.42 (0.097) [66] -1.24** (0.094) [72] 47** (0.097) [67] -1.50 (0.101)[58] -0.82** (-1.08, -0.56) -0.22 (-0.48, 0.03) -0.26 (-0.52, 0.00) Change in body weight (kg) -1.6 (0.41) [66] -2.9* (0.40) [71] 2**ΐ (0.41) [68] -4.4**1 (0.43) [59] -1.3* (-2.4, -0.2) -1.31 (-2.4, -0.2) -1.51 (-2.6, -0.3)

Abbreviations:

CI = confidence interval;

average NK = average value determined by the method of least squares;

PBO = placebo;

*P-value for comparing dulaglutide versus placebo <0.05;

**P-value for comparison of dulaglutide versus placebo <0.001;

fP value for comparison of dulaglutide versus dulaglutide 1.5 mg <0.05.

Notes: Dula XX is XX milligrams of dulaglutide given once a week.

At week 18, all three doses of dulaglutide significantly reduced HbA1c from baseline compared to placebo and significantly reduced body weight from baseline compared to placebo. HbA1c decreased by a mean of -1.24% in the 1.5 mg dulaglutide group compared to -1.47% in the 3.0 mg dulaglutide group (mean NC treatment difference -0.22%; 95% CI -0 .48%, 0.03%) and -1.50% in the dulaglutide 4.5 mg group (mean NC treatment difference -0.26%; 95% CI -0.52%, 0.00%). Body weight decreased by an average of -2.9 kg in the dulaglutide 1.5 mg group compared with -4.2 kg in the dulaglutide 3.0 mg group (mean NC treatment difference -1.3 kg; 95 % CI -2.4, 0.2), and -4.4 kg in the dulaglutide 4.5 mg group (mean NC treatment difference -1.5 kg; 95% CI -2.6, -0.3 ). The incremental efficacy of lowering HbA1c at both higher doses compared to 1.5 mg dulaglutide was greater in patient subgroups with higher baseline HbA1c levels.

In table. Table 2 shows the frequency of nausea, vomiting, and diarrhea by treatment, measured by prevalence (in any patient who had a new or ongoing complication during the interval), frequency (in any patient who had a complication onset during the interval), and first occurrence (any patient who had a first complication of this type during the interval) of complications within 3 time periods (weeks 0-6 [match period], weeks 6-10 [first 4 weeks after completion of match for patients in the 3 0 mg dulaglutide and 4.5 mg dulaglutide] and weeks 0-18 (treatment period)).

- 12 041605

table 2

Summary of prevalence, incidence, and first occurrence of nausea, vomiting, and diarrhea by treatment period and time period, and in patients with intent to treat

Complication / Parameter / Time period Placebo (#81) m/m (%) Dula 1.5 (#81) m/m (%) Dula 3.0 (#79) m/m (%) Dula 4.5 (#76) m/m (%) Nausea Prevalence Weeks 0-6 3/81 (3.7) 16/81 (19.8) 16/79 (20.3) 17/76 (22.4) Weeks 6-10 1/81 (1.2) 9/81 (11.1) 8/78 (10.3) 14/75 (18.7) Weeks 0-18 4/81 (4.9) 18/81 (22.2) 19/79(24.1) 23/76 (30.3) Incidence Weeks 0-6 3/81 (3.7) 16/81 (19.8) 16/79 (20.3) 17/76 (22.4) Weeks 6-10 1/81 (1.2) 6/81 (7.4) 5/78 (6.4) 10/75 (13.3) Weeks 0-18 4/81 (4.9) 18/81 (22.2) 19/79(24.1) 23/76 (30.3) Appearance Weeks 0-6 3/81 (3.7) 16/81 (19.8) 16/79 (20.3) 17/76 (22.4) Weeks 6-10 1/81 (1.2) 2/81 (2.5) 3/78 (3.8) 5/75 (6.7) Weeks 0-18 4/81 (4.9) 18/81 (22.2) 19/79(24.1) 23/76 (30.3) Vomit Prevalence Weeks 0-6 2/81 (2.5) 7/81 (8.6) 7/79 (8.9) 5/76 (6.6) Weeks 6-10 3/81 (3.7) 2/81 (2.5) 2/78 (2.6) 4/75 (5.3) Weeks 0-18 4/81 (4.9) 9/81 (11.1) 8/79(10.1) 10/76 (13.2) Incidence Weeks 0-6 2/81 (2.5) 7/81 (8.6) 7/79 (8.9) 5/76 (6.6) Weeks 6-10 2/81 (2.5) 2/81 (2.5) 2/78 (2.6) 3/75 (4.0) Weeks 0-18 4/81 (4.9) 9/81 (11.1) 8/79(10.1) 10/76 (13.2) Appearance Weeks 0-6 2/81 (2.5) 7/81 (8.6) 7/79 (8.9) 5/76 (6.6) Weeks 6-10 2/81 (2.5) 2/81 (2.5) 1/78 (1.3) 3/75 (4.0) Weeks 0-18 4/81 (4.9) 9/81 (11.1) 8/79(10.1) 10/76 (13.2) Diarrhea Prevalence Weeks 0-6 5/81 (6.2) 6/81 (7.4) 11/79 (13.9) 9/76 (11.8) Weeks 6-10 2/81 (2.5) 4/81 (4.9) 10/78 (12.8) 9/75 (12.0) Weeks 0-18 9/81 (11.1) 9/81 (11.1) 19/79(24.1) 15/76(19.7) Incidence Weeks 0-6 5/81 (6.2) 6/81 (7.4) 11/79(13.9) 9/76(11.8) Weeks 6-10 1/81 (1.2) 3/81 (3.7) 5/78 (6.4) 7/75 (9.3) Weeks 0-18 9/81 (11.1) 9/81 (11.1) 19/79(24.1) 15/76(19.7) Appearance Weeks 0-6 5/81 (6.2) 6/81 (7.4) 11/79(13.9) 9/76(11.8) Weeks 6-10 1/81 (1.2) 2/81 (2.5) 5/78 (6.4) 5/75 (6.7) Weeks 0-18 9/81(11.1) 9/81 (11.1) 19/79(24.1) 15/76(19.7)

Abbreviations:

m = number of patients with complications during the interval;

M = number of patients with data per interval;

N = number of randomized and treated patients;

Weeks = weeks.

The incidence of nausea and vomiting was higher in all three dulaglutide groups compared to placebo during all three time intervals. A dose-response was observed with respect to the incidence of nausea overall (weeks 0-18) in the dulaglutide groups, with the highest incidence in the 4.5 mg dulaglutide group (30.3%). In each dulaglutide treatment group, nausea was most common during the follow-up period (weeks 0-6) and decreased from weeks 6-10 onwards. The prevalence of vomiting varied from 6.6% to 8.9% in the dulaglutide groups during the fitting period and decreased during weeks 6-10. During all three time intervals, the frequency of diarrhea was basically the same in the placebo groups and dulaglutide 1.5 mg and above in the higher dose groups. More frequent reports of diarrhea in groups treated with dulaglutide 3.0 and 4.5 mg during the first 6 weeks continued for a period of 6-10 weeks and then decreased. The incidence of diarrhea was higher in the higher dose groups compared to the 1.5 mg group during the recruitment period before patients received the 3.0 or 4.5 mg doses; therefore, it appears that the differences were not entirely related to dose. In terms of frequency

- 13 041605 severe nausea, diarrhea and vomiting, some patients had any serious complications, and the frequency was generally similar in all four groups.

Although the incidence of nausea, vomiting, and diarrhea increased in patients treated with dulaglutide in a dose-dependent manner, and the proportion of patients who discontinued treatment due to adverse events was higher compared with the dulaglutide 1.5 mg group, the difference in complication rates between the high dose and 1.5 mg groups was small, and the rate of associated GI complications and treatment discontinuation was lower than that observed in those who completed the shorter duration dulaglutide study, which included patients receiving untitered doses >3, 0 mg, indicating that the A1 and A2 titration algorithms had a beneficial effect.

The number of patients randomized according to the selection algorithm in the groups with dulaglutide 3.0 and 4.5 mg 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. In the table. Table 3 shows incidence of nausea, vomiting, and diarrhea by dose and fitting algorithm for the two higher dose groups as measured by prevalence, frequency, and first occurrence over three key time periods (weeks 0-6 [fitting period]) , weeks 6-10 and weeks 0-18 [treatment period]).

Table 3

Pooled data on prevalence, incidence, and first onset of nausea, vomiting, and diarrhea using a dose and selection algorithm (Dulaglutide 3.0 mg and Dulaglutide 4.5 mg) and time period, enrolled patient population

Complication / Parameter / Time period G| euppy treatment/algorithm Algorithm groups 3.0 A1 (N=41) m/m (%) 3.0 A2 (N=38) m/M (%) 4.5 A1 (N=39) m/m (%) 4.5 A2 (N=37) m/m (%) A1 (N=80) m/m (%) A2 (N=75) m/m (%) Nausea Prevalence Weeks 0-6 1141 (20.8) 5/38 (13.2) 7/39(17.9) 10/37 (27.0) 18/80 (22.5) 15/75 (20.0) Weeks 6-10 5/40(12.5) 3/38 (7.9) 6/38 (15.8) 8/37(21.6) 11/78(14.1) 11/75 (14.7) Weeks 0-18 12/41 (29.3) 7/38 (18.4) 11/39(28.2) 12/37 (32.4) 23/80 (28.8) 19/75 (25.3) Incidence Weeks 0-6 11/41 (26.8) 5/38 (13.2) 7/39(17.9) 10/37 (27.0) 18/80 (22.5) 15/75 (20.0) Weeks 6-10 2/40 (5.0) 3/38 (7.9) 6/38 (15.8) 4/37(10.8) 8/78 (10.3) 7/75 (9.3) Weeks 0-18 12/41 (29.3) 7/38 (18.4) 11/39(28.2) 12/37 (32.4) 23/80 (28.8) 19/75 (25.3) Appearance Weeks 0-6 11/41 (26.8) 5/38 (13.2) 7/39(17.9) 10/37 (27.0) 18/80 (22.5) 15/75 (20.0) Weeks 6-10 1/40 (2.5) 2/38 (5.3) 3/38 (7.9) 2/37 (5.4) 4/78 (5.1) 4/75 (5.3) Weeks 0-18 12/41 (29.3) 7/38 (18.4) 11/39(28.2) 12/37 (32.4) 23/80 (28.8) 19/75 (25.3) Vomit Prevalence Weeks 0-6 o 41 (I4.O) 1/38 (2.6) 3/39 (7.7) 2/37 (5.4) 9/80(11.3) 3/75 (4.0) Weeks 6-10 1/40 (2.5) 1/38 (2.6) 0/38 4/37(10.8) 1/78 (1.3) 5/75 (6.7) Weeks 0-18 6/41 (14.6) 2/38 (5.3) 4/39(10.3) 6/37(16.2) 10/80 (12.5) 8/75 (10.7) Incidence Weeks 0-6 6/41 (14.6) 1/38 (2.6) 3/39 (7.7) 2/37 (5.4) 9/80(11.3) 3/75 (4.0) Weeks 6-10 1/40 (2.5) 1/38 (2.6) 0/38 3/37(8.1) 1/78 (1.3) 4/75 (5.3) Weeks 0-18 6/41 (14.6) 2/38 (5.3) 4/39(10.3) 6/37(16.2) 10/80 (12.5) 8/75 (10.7) Appearance Weeks 0-6 6/41 (14.6) 138(2.0) 3/39 (7.7) 2/37 (5.4) 9/80(11.3) 3/75 (4.0) Weeks 6-10 0/40 1/38 (2.6) 0/38 3/37(8.1) 0/78 4/75 (5.3) Weeks 0-18 6/41 (14.6) 2/38 (5.3) 4/39(10.3) 6/37(16.2) 10/80 (12.5) 8/75 (10.7) Diarrhea Prevalence Weeks 0-6 7/41 (17.1) 4 38(10.5) 6/39(15.4) 3/37(8.1) 13/80(16.3) 7/75 (9.3) Weeks 6-10 4/40(10.0) 6/38 (15.8) 5/38 (13.2) 4/37(10.8) 9/78(11.5) 10/75 (13.3) Weeks 0-18 8/41 (19.5) 11/38 (28.9) 9/39 (23.1) 6/37(16.2) 17/80(21.3) 17/75 (22.7) Incidence Weeks 0-6 7/41 (17.1) 4/38 (10.5) 6/39(15.4) 3/37(8.1) 13/80(16.3) 7/75 (9.3) Weeks 6-10 0/40 5/38 (13.2) 5/38 (13.2) 2/37 (5.4) 5/78 (6.4) 7/75 (9.3) Weeks 0-18 8/41 (19.5) 11/38 (28.9) 9/39 (23.1) 6/37(16.2) 17/80(21.3) 17/75 (22.7) Appearance Weeks 0-6 7/41 (17.1) 4/38 (10.5) 6/39(15.4) 3/37(8.1) 13/80(16.3) 7/75 (9.3) Weeks 6-10 0/40 5/38 (13.2) 3/38 (7.9) 2/37 (5.4) 3/78 (3.8) 7/75 (9.3) Weeks 0-18 8/41 (19.5) 11/38 (28.9) 9/39 (23.1) 6/37(16.2) 17/80(21.3) 17/75 (22.7)

Abbreviations:

A1 = Algorithm 1;

A2 = Algorithm 2;

m = number of patients with complications during the interval;

- 14 041605

M = number of patients with data per interval;

N = number of randomized and treated patients;

Weeks = weeks;

Prevalence = counts any patient who had a new or ongoing complication during the interval;

Incidence = counts any patient who had a complication that began during the interval;

Occurrence = Any patient who had the first occurrence of this type during the interval is counted.

The frequency of nausea is similar to A1 and A2 in general; there is a difference in the 3.0 mg group with a lower frequency in the A2 subgroup compared to the A1 subgroup, but this difference is considered unlikely to be related to the fitting algorithms, as suggested by similar frequencies in the 4.5 mg A1 and A2 subgroups. Most cases of nausea occur during the pick-up period, with few reports of new complications when the dose is increased to final doses (weeks 6-10).

The frequency of vomiting is similar to A1 and A2 in general; more patients in subgroup A1 than in subgroup A2 had events in the dulaglutide 3.0 mg group, and more patients in subgroup A2 than in subgroup A1 in the dulaglutide 4.5 mg group, but as and in the case of nausea, as described above, these differences are considered not related to the selection algorithms, since the differences between the A1 and A2 subgroups in the 3.0 and 4.5 mg groups were opposite. Most cases of emesis with A1 occur during the pick-up period and a few new cases have been reported after escalation to final doses (weeks 6-10). With A2, the frequency of vomiting was lower during the pick-up period, remained at the same level during the period of 6-10 weeks and began to decrease after 10 weeks and remained lower until 18 weeks.

The prevalence and incidence of diarrhea during the recruitment period (weeks 0-6) was 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, prevalence and incidence were lower in the dulaglutide 3.0 mg A1 and 4.5 mg dulaglutide A2 subgroups and higher in the dulaglutide 3.0 mg A2 and 4.5 mg dulaglutide A1 subgroups.

The observed pattern of occurrence of these events in A1 compared to A2 suggests that starting with a lower dose of dulaglutide (0.75 mg dulaglutide [used in A2] versus 1.5 mg dulaglutide [used in A1]), it is possible to reduce complication of portability of the GI tract during the selection period. The slower decline in the incidence of these events in group A2 compared to group A1 during the final phase of attitration (weeks 6-10) suggests that a longer follow-up period may be required to account for the development of tachyphylaxis in relation to gastrointestinal side effects from dulaglutide. .

As noted above, earlier studies at doses of 3.0 mg or more resulted in an increase in heart rate, which contributed in part to the discontinuation of 3.0 mg in the earlier study. Therefore, changes in heart rate were also measured in the present study and the collected data are presented in Table 1. 4.

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Table 4

Change in baseline heart rate in the treatment of the ITT population

Time (weeks) Changes in mean NC FR (bpm) (95% CI) [n] placebo Dula 1.5 Dula 3.0 Dula 4.5 2 0.22 (-1.50, 1.95) [80] 1.77 (0.03, 3.50) [80] 1.87 (0.12.3.62) [79] 1.91 (0.12, 3.70) [76] 4 -0.98 (-2.62, 0.66) [79] 1.09 (-0.57, 2.75) [78] 1.38 (-0.28, 3.05) [79] 1.97 (0.25, 3.69) [74] 6 -1.97 (-3.71, 0.23) [76] 0.52 (-1.22, 2.27) [77] 1.72 (-0.04, 3.47) [77] 2.07 (0.27, 3.87) [74] 7 -0.85 (-2.45, 0.75) [77] 2.13 (0.50.3.75) [76] 2.37 (0.75, 4.00) [77] 3.94 (2.27, 5.61) [74] 8 -0.06 (-1.90, 1.79) [76] 1.83 (-0.03, 3.68) [76] 1.86 (-0.00, 3.73) [76] 4.70 (2.78, 6.62) [72] 9 0.04 (-1.86, 1.77) [76] 0.79 (-1.04, 2.62) [75] 2.28 (0.44, 4.11) [76] 3.85 (1.96, 5.75) [71] 10 -1.80 (-3.53, 0.08) [77] 0.78 (-0.97, 2.52) [76] 2.18 (0.43, 3.93) [77] 2.65 (0.84, 4.46) [71] 14 0.28 (-1.44, 2.00) [76] -0.22 (-1.97, 1.53) [73] 0.58(-1.15.2.31) [78] 2.11 (0.29, 3.92) [69] 18 -1.40 (-3.20, 0.41) [75] -0.71 (-2.55, 1.12) [72] -0.04 (-1.86, 1.78) [75] 0.70 (-1.18, 2.58) [70]

Abbreviations:

LC = least squares;

HR = pulse rate;

Weeks = weeks;

CI = confidence interval;

n = sample size.

As indicated in Table. 4, mean changes in heart rate in the dulaglutide groups were similar throughout the treatment period and were similar at the end of the study.

In terms of determining the optimal dose titration strategy, patients initiated on dulaglutide 0.75 mg (for 2 weeks, A1) initially had fewer gastrointestinal problems than patients initiated on dulaglutide 1.5 mg (for 2 weeks). 4 weeks, A2), but these differences did not persist with further dose increases to 1.5 mg using A1. Differences were also noted between A1 and A2 in the dulaglutide 4.5 mg group after patients were upgraded to the final doses (in group A1 from 3.0 to 4.5 mg; in group A2 from 1.5 to 4.5 mg), with slightly lower tolerance in patients in group A2. These results suggest that further adjustments to the algorithms may be able to optimize dulaglutide titration at higher doses with respect to the duration of titration and dose levels needed to further minimize the risk of tolerability problems.

Phase 3 study.

A phase 3, multicenter, randomized, double-blind, parallel study designed with three study periods (lead-in, treatment, and safety surveillance) in D2T patients with inadequate glycemic control with metformin alone; the study is 52 weeks long, with the primary endpoint at 36 weeks. The study is designed to evaluate the efficacy and safety of single weekly administration of dulaglutide 3.0 and 4.5 mg compared with single administration of dulaglutide 1.5 mg.

The minimum sample size is approximately 1800 patients, assuming a registered (randomized) 15% dropout rate to obtain approximately 510 completions per group over 36 weeks. At the third visit, patients are randomized in a 1:1:1 ratio to weekly injections of dulaglutide 4.5, 3.0, or 1.5 mg in combination with stable doses of metformin.

Study doses of 4.5 and 3.0 mg were administered according to a fitting algorithm developed from PK/PD modeling of nausea and vomiting complications from the Phase 2 study described above to further alleviate unwanted gastrointestinal complications. tract. Modeling the impact of the PK/PD response of the Phase 2 study data also predicts that the daily incidence of nausea and vomiting at higher doses of dulaglutide will be lowest in the algorithms, starting at a dose of 0.75 mg with a slower increase in dose over an 8-week period, providing enough time to develop tolerance. Based on these results, pa

- The 16,041,605 patients in the present study are recruited through consecutive 4-week treatment segments starting at 0.75 mg once a week and then 1.5 mg once a week. At week 8, patients randomized to the 1.5 mg dulaglutide group continue to receive this dose until the end of the treatment period. Patients randomized to the 3.0 mg dulaglutide group will be increased to 3.0 mg once weekly at week 8 and will continue at this dose until the end of the treatment period. Patients assigned to the 4.5 mg dulaglutide group are increased to 3.0 mg once weekly at week 8 for 4 weeks followed by an increase to a final dose of 4.5 mg once weekly at week 12. Study participants are treated for 52 weeks, with major goals being assessed at 36 weeks. This step-by-step dose titration strategy is designed to further improve GI tolerance of the 3.0 and 4.5 mg doses relative to the dose observed in the Phase 2 study described above.

Composition stability studies.

A demonstration batch was prepared containing various concentrations of dulaglutide in the formulation used for the currently approved doses of dulaglutide, and the samples were placed in commercial dulaglutide primary packaging as indicated in Table 1. 5.

Table 5

Demo Series Composition

Dulaglutide concentration 3.0, 6.0, 9.0 and 12.0 mg/ml sodium citrate 2.74 mg/ml Citric acid anhydrous 0.13 mg/ml Mannitol 46.4 mg/ml Polysorbate-80 0.02% Primary packaging BD Gen 2 1ml long, uncoated plunger, West

Samples are placed on stability for up to 24 months. However, the study was terminated after 3 months due to an observed decrease in PS80 levels. Data obtained from PS80 concentrations are analyzed in JMP 12.1.0 software to predict PS80 levels under long-term storage conditions for 24 months. The activation energy (E _a ) of PS80 degradation is calculated and used to predict the PS80 content during long-term storage. Based on the second degree polynomial model, the point estimate for the activation energy E _a is 15.24 kcal/mol and the lower 95% confidence limit was 12.85 kcal/mol. Based on this analysis, with a baseline PS80 of 0.02% (w/v), the predicted 24 month PS80 prediction for the 12mg/ml dulaglutide formulation is expected to be below the specification limit for the current commercial dulaglutide. The 24-month PS80 prediction for the 9mg/ml dulaglutide formulation will also be close to the specification limit.

To assess the risk of non-compliance with the PS80 content specification (NSS) during 24 months of long-term storage, Monte Carlo simulations are performed in R 3.4.0 software using historical data for dulaglutide. The HCC risks associated with each high concentration level are summarized in Table 1. 6.

Table 6

Results of Monte Carlo simulation for 24 months of risk of NCC PS80

Dulaglutide concentration Probability of PS80% (w/v) HCC after 24 months storage at 2-8°C E _a = 15.24 E _a = 12.85 6 mg/ml 5x ^10'5 0.06692 9 mg/ml 0.10279 0.96191 12 mg/ml 0.89239 1

Monte Carlo simulation results showed excessive degradation using an asymptotic lower confidence limit for activation energy and thus high risk levels for shelf life. PS80 is present in the formulation of dulaglutide to provide protection against exercise stress, and the lower specification limit for PS80 has been set to ensure sufficient presence of PS80 over the maximum possible shelf life and periods of use to provide such physical protection.

Considering the preliminary analysis of the development stability study data indicating that the hydrolysis of polysorbate-80 was increased in formulations with a higher concentration of dulaglutide, it was decided to study formulation modifications. Increasing the level of polysorbate-80 in the formulation may result in adequate intact polysorbate-80 at the end of the expiration date, but hydrolysis of higher amounts of polysorbate-80 may result in visible particles. Thus, a surfactant range study was initiated to evaluate the effect of different levels of surfactants on stability.

Received samples containing dulaglutide at a concentration of 3, 6, 9 and 12 mg / ml, 10 mm citrate

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Claims (4)

buffer, 46.4 mg/ml mannitol and PS80 in the range from 0.002 to 0.05%, filled bottles and placed on stability at 30°C. Samples are taken at 0, 12, 25, 35, 46 and 74 days and tested for the presence of free oleic acid (FOC) - the hydrolysis product of PS80 - and particulate matter. The data show an increase in SOC with increasing concentration for compositions with a higher content of dulaglutide. At the same concentration of dulaglutide, elevated COC concentrations are the same for compositions having 0.02 and 0.05% of the original level of polysorbate-80. Particulate matter measured by microflow imaging (MFL) is equivalent for all compositions, regardless of the level of dulaglutide or polysorbate-80. The results confirm the usefulness of increasing the initial levels of polysorbate-80 to 0.05% without compromising the stability of dulaglutide. Based on the results of the development stability study and the surfactant study, a detailed statistical analysis of all available data is performed. The analysis leads to the conclusion that the level of the original polysorbate-80 in the composition for concentrations of 6.0 and 9.0 mg/ml should be increased from 0.02 to 0.025% (w/v). This elevated level is chosen to provide a high probability that even at the end of the expiration date there will be enough polysorbate-80 that meets the current approved specifications for a commercial product. Get a second demonstration series containing the same concentrations as in the first demonstration series described above, except for the increase in the concentration of PS80, as indicated in table. Table 7 Parameters of the second demonstration series Dulaglutide concentration 3.0, 6.0, 9.0 and 12.0 mg/ml Sodium citrate 2.74 mg/ml Citric acid anhydrous 0.13 mg/ml Mannitol 46.4 mg /ml Polysorbate-80 0.025% Primary Pack BD Gen 2 1 ml long syringe, uncoated plunger West Samples are placed for stability at 5, 25 and 30°C. The results of samples aged up to six months at 5 and 25°C and one month at 30°C show that the concentrated formulations are chemically and physically stable and that the PS80 concentration will remain above the lower specification limit throughout the shelf life. CLAIM 1. A method for improving glycemic control in a subject with type 2 diabetes (D2T) in need, comprising: a) administering to said subject an initial dose of 0.75 mg of dulaglutide once a week; b) increasing the dose to 1.5 mg of dulaglutide once a week; c) increasing the dose to 3.0 mg of dulaglutide once a week after four weeks on a dose of 1.5 mg; d) increasing the dose to 4.5 mg of dulaglutide once a week after four weeks on a dose of 3.0 mg. 2. The method of claim 1, wherein the dose increase in each of steps b) to d) is performed when there is a need to decrease the HbAlc level in the subject. 3. The method of claim 2, wherein administration of 4.5 mg of dulaglutide does not result in unacceptable gastrointestinal intolerance compared to administration of a dose of 1.5 mg of dulaglutide once a week. 4. The method of claim 3, wherein administration of 4.5 mg of dulaglutide once a week results in greater weight loss than administration of a dose of 1.5 mg of dulaglutide once a week. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2 -