Tilzepide Composition and Use

Abstract

A composition comprising tilsipasib or a salt thereof at a concentration selected from the group consisting of 2.5 mg / mL, 40 mg / mL, and 50 mg / mL, NaCl, and dibasic sodium phosphate, and a method of administering such a tilsipasib composition are provided.

Description

Technical Field

[0001] The present invention relates to the field of medicine. More particularly, the present invention relates to methods of using novel dosages of tildepazide and to pharmaceutically sophisticated compositions comprising such dosages. The compositions provide commercially acceptable shelf-life stability, stability in use, and are associated with an acceptable patient experience.

Background Art

[0002] Diabetes is a chronic disease characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. In type 2 diabetes ("T2D"), the combined effects of insulin secretion deficiency and insulin resistance are associated with elevated blood glucose levels.

[0003] Tirzepatide is a glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide 1 (GLP1) receptor agonist (GIP / GLP1), which is the active ingredient in Mounjaro(trademark) and is approved for use as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (T2D). Tirzepatide is approved as a clear, colorless to pale yellow liquid for subcutaneous injection. The tirzepatide doses of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg once a week are administered once a week using a starting dose of 2.5 mg, increased to 5 mg once a week by subcutaneous injection after 4 weeks, and the dose is increased in 2.5 mg increments at least 4 weeks after the current dose. The maximum approved dose is 15 mg once a week subcutaneously. Tirzepatide was tested in a Phase 3 development program, and the once-weekly dose received regulatory approval in the United States (US), the European Union, and other jurisdictions in 2022 for use in the treatment of T2D. Since its approval in 2022, these doses of tirzepatide have been used to treat many patients with T2D. These doses have been tested in thousands of patients for use in chronic weight management. Treatment with currently approved tirzepatide allows substantially all patients included in the Phase 3 program (regardless of the use of other concomitant medications for T2D) to achieve glycemic goals, and patients with obesity or overweight in the Phase 3 trials achieved a 15.7% weight loss, but a significant number of patients receiving the approved treatment require additional chronic weight management to achieve weight management treatment goals. A significant number of patients receiving the approved treatment require additional weight management benefits. Such patients cannot achieve weight management goals using currently approved pharmaceutical treatments and / or dosages of agents that allow weight loss. It has been reported that higher doses of agents with GLP1 receptor agonist activity are limited by gastrointestinal adverse events. The US label for tirzepatide (May 2022) indicates that the use of tirzepatide can be associated with sometimes severe gastrointestinal adverse reactions. A dosing regimen is needed that allows administration of higher tirzepatide doses with an acceptable patient experience.There is a significant medical need for an agent that enables additional weight management while maintaining the overall acceptable risk / benefit profile and patient tolerance.

[0004] There is a need for a pharmaceutical composition having a higher dose of tizepatide that is stable for storage for at least 6 months.

[0005] Peptides have inherent physiochemical properties that often pose challenges in achieving stable and pharmaceutically elegant compositions. For example, peptide self-association, aggregation, adsorption to surfaces, solubility, and chemical stability present unique challenges to enabling the desired peptide composition. Bak, et.al., “Physicochemical and Formulation Developability Assessment for Therapeutic Peptide Delivery - A Primer - PMC(nih.gov)” AAPS J. 2015 Jan;17(1):144 - 155.

[0006] The compositions, dosages, and methods provide these benefits while maintaining an acceptable profile of safety risks and adverse events.

Summary of the Invention

Means for Solving the Problems

[0007] The present invention provides a pharmaceutically acceptable composition of tizepatide or a pharmaceutically acceptable salt thereof, the composition comprising more than 30 mg / mL of tizepatide or a pharmaceutically acceptable salt thereof, an isotonic agent, and sodium phosphate.

[0008] In one embodiment, the composition of tizepatide or a pharmaceutically acceptable salt thereof comprises more than 30 mg / mL of tizepatide or a pharmaceutically acceptable salt thereof, an isotonic agent, and dibasic sodium phosphate.

[0009] In one embodiment, a composition of tilzepati or a pharmaceutically acceptable salt thereof comprises tilzepati or a pharmaceutically acceptable salt thereof at a concentration of more than 30 mg / mL up to a maximum of 60 mg / mL, an isotonic agent, and dibasic sodium phosphate.

[0010] In one embodiment, the isotonic agent is NaCl. In one embodiment, the concentration of NaCl is from about 7 mg / mL to about 9 mg / mL. In one embodiment, the concentration of NaCl is from about 7.4 mg / mL to about 9.0 mg / mL. In one embodiment, the concentration of NaCl is about 8.2 mg / mL.

[0011] In one embodiment, the concentration of dibasic sodium phosphate is from about 0.7 mg / mL to about 1.5 mg / mL. In one embodiment, the concentration of dibasic sodium phosphate is about 1.34 mg / mL.

[0012] In one embodiment, the concentration of tilzepati or its salt is from about 40 mg / mL to about 50 mg / mL. In one embodiment, the concentration of tilzepati or a pharmaceutically acceptable salt thereof is about 40 mg / mL. In one embodiment, the concentration of tilzepati or its salt is about 50 mg / mL. In one embodiment, the concentration of tilzepati or its salt is about 2.5 mg / mL. In one embodiment, the concentration of tilzepati or a pharmaceutically acceptable salt thereof is from 40 mg / mL to 50 mg / mL. In one embodiment, the concentration of tilzepati or a pharmaceutically acceptable salt thereof is about 40 mg / mL. In one embodiment, the concentration of tilzepati or a pharmaceutically acceptable salt thereof is about 50 mg / mL. In one embodiment, the concentration of tilzepati or a pharmaceutically acceptable salt thereof is about 2.5 mg / mL.

[0013] In one embodiment, the concentration of tilsertide or a pharmaceutically acceptable salt thereof is from about 40 mg / mL to about 60 mg / mL. In one embodiment, the concentration of tilsertide or a pharmaceutically acceptable salt thereof is about 55 mg / mL. In one embodiment, the concentration of tilsertide or a pharmaceutically acceptable salt thereof is about 60 mg / mL. In one embodiment, the concentration of tilsertide or a pharmaceutically acceptable salt thereof is 60 mg / mL. In one embodiment, the concentration of tilsertide or a pharmaceutically acceptable salt thereof is 55 mg / mL. In one embodiment, or in a pharmaceutically acceptable salt thereof, the concentration is from 40 mg / mL to 60 mg / mL. In one embodiment, tilsertide or a pharmaceutically acceptable salt thereof is tilsertide as the free base.

[0014] In one embodiment, the concentration of tilzeyapatide or a salt thereof is from about 40 mg / mL to about 50 mg / mL, the concentration of NaCl is about 8.2 mg / mL, and the concentration of dibasic sodium phosphate is about 1.34 mg / mL. In one embodiment, the concentration of tilzeyapatide or a salt thereof is about 2.5 mg / mL, the concentration of NaCl is about 8.2 mg / mL, and the concentration of dibasic sodium phosphate is from about 1.2 mg / mL to about 1.34 mg / mL. In one embodiment, the concentration of tilzeyapatide or a pharmaceutically acceptable salt thereof is about 40 mg / mL, the concentration of NaCl is about 8.2 mg / mL, and the concentration of dibasic sodium phosphate is about 1.34 mg / mL. In one embodiment, the concentration of tilzeyapatide or a pharmaceutically acceptable salt thereof is about 50 mg / mL, the concentration of NaCl is about 8.2 mg / mL, and the concentration of dibasic sodium phosphate is about 1.34 mg / mL. In one embodiment, the concentration of tilzeyapatide or a pharmaceutically acceptable salt thereof is about 2.5 mg / mL, the concentration of NaCl is about 8.2 mg / mL, and the concentration of dibasic sodium phosphate is about 1.34 mg / mL to. In one embodiment, the concentration of tilzeyapatide is about 40 mg / mL, the concentration of NaCl is about 8.2 mg / mL, and the concentration of dibasic sodium phosphate is about 1.34 mg / mL, and the composition is provided in a single-use auto-injector device. In one embodiment, the concentration of tilzeyapatide is about 50 mg / mL, the concentration of NaCl is about 8.2 mg / mL, and the concentration of dibasic sodium phosphate is about 1.34 mg / mL, and the composition is provided in a single-use auto-injector device. In one embodiment, the concentration of tilzeyapatide is about 2.5 mg / mL, the concentration of NaCl is about 8.2 mg / mL, and the concentration of dibasic sodium phosphate is about 1.34 mg / mL to, and the composition is provided in a single-use auto-injector device.

[0015] In one embodiment, the concentration of tirlizepatide or a pharmaceutically acceptable salt thereof in the composition is selected from the group consisting of 2.5, 40, and 50 mg / mL. In one embodiment, tirlizepatide or a pharmaceutically acceptable salt thereof is administered as a 0.5 mL dose. In one embodiment, the composition comprises tirlizepatide or a pharmaceutically acceptable salt thereof formulated to deliver 1.25 mg / dose. In one embodiment, the concentration of tirlizepatide or a pharmaceutically acceptable salt thereof is selected from the group consisting of 1.25 mg / 0.5 mL, 20 mg / 0.5 mL, and 25 mg / 0.5 mL. In one embodiment, the concentration of tirlizepatide or a pharmaceutically acceptable salt thereof is 30 mg / 0.5 mL. In one embodiment, the concentration of tirlizepatide or a pharmaceutically acceptable salt thereof is the concentration of tirlizepatide as the free base.

[0016] In one embodiment, a method of treating chronic obesity in a subject in need thereof comprises administering 1.25 mg of tirlizepatide or a pharmaceutically acceptable salt thereof for at least 4 weeks.

[0017] In one embodiment, a method of treating chronic obesity in a pediatric subject in need thereof comprises administering 1.25 mg of tirlizepatide or a pharmaceutically acceptable salt thereof for at least 4 weeks.

[0018] In one embodiment, a method of treating type 2 diabetes in a subject in need thereof comprises administering 1.25 mg of tirlizepatide or a pharmaceutically acceptable salt thereof for at least 4 weeks.

[0019] In one embodiment, a method of treating type 2 diabetes in a pediatric subject in need thereof comprises administering 1.25 mg of tirlizepatide or a pharmaceutically acceptable salt thereof for at least 4 weeks.

[0020] In one embodiment, a method of chronic weight management in a pediatric subject comprises administering 1.25 mg of tirlizepatide or a pharmaceutically acceptable salt thereof to the subject in need thereof for at least 4 weeks.

[0021] In one embodiment, a method for chronic weight management in a subject in need of additional weight management, wherein the subject has obesity, identifying a subject having obesity and in need of additional weight management, administering to the subject at least 15 mg of once-weekly dose of tirzepatide or a pharmaceutically acceptable salt thereof for at least 4 weeks, after administering at least 15 mg of once-weekly dose of tirzepatide or a pharmaceutically acceptable salt thereof for at least 4 weeks, administering a once-weekly dose of tirzepatide or a pharmaceutically acceptable salt thereof that is 5 mg more than the last dose, wherein the maximum once-weekly dose of tirzepatide or a pharmaceutically acceptable salt thereof is 25 mg, the method.

[0022] The present invention is a method for chronic weight management in a subject in need of additional weight management, comprising identifying a subject who desires weight management and is in need of additional weight management, a) administering to the subject a dose of tirzepatide or a pharmaceutically acceptable salt thereof that is > 15 mg and < 20 mg once a week for at least 4 weeks, and increasing the dose to 20 mg once a week, provides a method.

[0023] Accordingly, the present invention is a method for chronic weight management in a subject in need of additional weight management, a) identifying a subject in need of additional weight management, b) administering to the subject a dose of 20 mg of tirzepatide or a pharmaceutically acceptable salt thereof once a week for at least about 4 weeks, c) increasing the dose by administering to the subject a dose of 25 mg of tirzepatide or a pharmaceutically acceptable salt thereof once a week, provides a method.

[0024] A method for chronic weight management in a subject in need of additional weight management, a) identifying a subject who desires weight management and is in need of additional weight management, b) administering to the subject a dose of 20 mg of tirzepatide or a pharmaceutically acceptable salt thereof once a week for at least about 4 weeks, c) increasing the dose by administering to the subject once a week a dose of 25 mg of tildesepatide or a pharmaceutically acceptable salt thereof, is provided.

[0025] In one aspect, a method for chronic weight management in a subject in need of additional weight management, comprising: a) identifying a subject having an initial BMI ≧ 30 kg / m 2 and in need of additional weight management; b) increasing the dose by administering to the subject once a week a dose of 20 mg of tildesepatide or a pharmaceutically acceptable salt thereof, is provided.

[0026] In another aspect, the present invention provides a method for providing chronic weight management to a subject in need of chronic weight management, comprising: a) identifying a subject who has been previously treated with at least 15 mg of tildesepatide or a pharmaceutically acceptable salt thereof once a week for at least 4 weeks; b) increasing the dose by administering once a week a dose of 20 mg of tildesepatide or a pharmaceutically acceptable salt thereof, is provided.

[0027] In another aspect, the present invention provides a method for providing chronic weight management to a subject in need of chronic weight management, comprising: a) identifying a subject who has been previously treated with at least 20 mg of tildesepatide or a pharmaceutically acceptable salt thereof once a week for at least 4 weeks; b) increasing the dose by administering once a week a dose of 25 mg of tildesepatide or a pharmaceutically acceptable salt thereof, is provided.

[0028] In another aspect, the present invention provides the use of tildesepatide for the manufacture of an agent for improving glycemic control in a subject having type 2 diabetes (T2D), being treated with a dose of 15 mg of tildesepatide once a week, but in need of further glycemic control, comprising increasing the dose of tildesepatide administered to 20 mg once a week.

[0029] In another aspect, the present invention provides the use of tirzepatide for the manufacture of an agent for improving glycemic control in a subject having type 2 diabetes (T2D) who has been treated with a once-weekly dose of 20 mg of tirzepatide for at least 4 weeks and who requires further glycemic control, the use of tirzepatide comprising increasing the dose of tirzepatide administered to 25 mg once a week.

[0030] In another aspect, the present invention provides the use of tirzepatide for the manufacture of an agent for providing chronic weight management to a subject in need thereof, a) administering 15 mg of tirzepatide once a week to the subject for at least about 4 weeks; b) increasing the dose by administering 20 mg of tirzepatide once a week to the subject for at least 4 weeks; c) increasing the dose by administering 25 mg of tirzepatide once a week, the use of tirzepatide being provided.

[0031] In another aspect, the present invention provides the use of tirzepatide for the manufacture of an agent for providing chronic weight management to a subject in need thereof, a) identifying a subject who has been previously treated with 15 mg of tirzepatide once a week for at least 4 weeks or a pharmaceutically acceptable salt thereof; b) increasing the dose by administering 20 mg of tirzepatide once a week or a pharmaceutically acceptable salt thereof, the use of tirzepatide being provided.

[0032] In another aspect, the present invention provides the use of tirzepatide for the manufacture of an agent for providing chronic weight management to a subject in need thereof, a) identifying a subject who has been previously treated with 20 mg of tirzepatide once a week for at least 4 weeks; b) increasing the dose by administering 25 mg of tildepepide or a pharmaceutically acceptable salt thereof once a week,

[0033] In one embodiment, the dose of the tildepepide composition is administered approximately once a week. In one embodiment, the dose of the tildepepide composition is administered once every 7 days.

[0034] In one embodiment, there is provided a method of treating diabetes, comprising administering to a human in need thereof an effective dose of one of the above compositions.

[0035] In one embodiment, there is provided a method of treating obesity, comprising administering to a human in need thereof an effective dose of one of the above compositions comprising 40 mg / mL of tildepepide or a pharmaceutically acceptable salt thereof. In one embodiment, there is provided a method of treating obesity, comprising administering to a human in need thereof an effective dose of one of the above compositions comprising 50 mg / mL of tildepepide or a pharmaceutically acceptable salt thereof. In one embodiment, there is provided a method of providing therapeutic weight loss, comprising administering to a human in need thereof an effective dose of one of the above compositions. In one embodiment, there is provided a method of providing therapeutic weight loss, comprising administering to a human in need thereof an effective dose of a composition comprising 40 mg / mL of tildepepide or a pharmaceutically acceptable salt thereof. In one embodiment, tildepepide is the free base.

[0036] In one embodiment, a method of additional weight management in a subject in need of additional weight management, wherein the subject has a BMI ≧ 27 kg / m 2 and at least one weight-related co-morbidity, administering to the subject at least 4 weeks of a once-weekly dose of 2.5 mg of tildepepide or a pharmaceutically acceptable salt thereof, after 4 weeks, increasing the once-weekly dose of tildepepide or a pharmaceutically acceptable salt thereof by administering a 5 mg dose, Increase the dose by 2.5 mg increments at least 4 weeks after the current dose, if additional weight management is required at least 4 weeks after once weekly 15 mg of tirzepatide or a pharmaceutically acceptable salt thereof, including increasing the dose by 5.0 mg increments at least 4 weeks after the current dose, wherein the maximum dose is 25 mg of tirzepatide or a pharmaceutically acceptable salt thereof subcutaneously once weekly, is a method.

[0037] In one embodiment, a method of additional weight management in a subject in need of additional weight management, wherein the subject has a BMI ≥ 27 kg / m 2 and at least one weight-related co-morbidity, administering to the subject at least 4 weeks once weekly 2.5 mg dose of tirzepatide or a pharmaceutically acceptable salt thereof, after 4 weeks, increasing the once weekly dose of tirzepatide or a pharmaceutically acceptable salt thereof by administering a 5 mg dose, increasing the dose by 2.5 mg increments at least 4 weeks after the current dose, if additional weight management is required at least 4 weeks after once weekly 15 mg of tirzepatide or a pharmaceutically acceptable salt thereof, including increasing the dose by 2.5 mg increments at least 4 weeks after the current dose by administering at least 4 weeks once weekly 17.5 mg tirzepatide dose, and if additional weight management is required, increasing the dose by 2.5 mg increments at least 4 weeks after the current dose, wherein the maximum dose is 25 mg of tirzepatide or a pharmaceutically acceptable salt thereof subcutaneously once weekly, is a method.

[0038] In one embodiment, a method of additional weight management in a subject in need of additional weight management, wherein the subject has a BMI ≥ 30 kg / m 2 having, administering to the subject at least 4 weeks once weekly 2.5 mg dose of tirzepatide or a pharmaceutically acceptable salt thereof, After 4 weeks, increase the once-weekly dose of tildesideptide or a pharmaceutically acceptable salt thereof by administering a 5 mg dose, increase the dose by 2.5 mg increments at least 4 weeks after the current dose, if additional weight management is required at least 4 weeks after once-weekly administration of 15 mg of tildesideptide or a pharmaceutically acceptable salt thereof, including increasing the dose by 2.5 mg increments at least 4 weeks after the current dose by administering a once-weekly dose of 17.5 mg of tildesideptide for at least 4 weeks, and increasing the dose by 2.5 mg increments at least 4 weeks after the current dose if additional weight management is required, wherein the maximum dose is 25 mg of tildesideptide or a pharmaceutically acceptable salt thereof subcutaneously once a week, is a method.

[0039] In one embodiment, a method for additional weight management in a subject having obesity and in need of additional weight management, administering to the subject a once-weekly dose of 2.5 mg of tildesideptide, after 4 weeks, increasing the dose by administering 5 mg of tildesideptide once a week, increasing the dose by 2.5 mg increments at least 4 weeks after the current dose, after at least 4 weeks at a once-weekly dose of 15 mg of tildesideptide, including increasing the dose by 5.0 mg increments at least 4 weeks after the current dose, wherein the maximum dose is 25 mg of tildesideptide subcutaneously once a week, is a method.

[0040] In one embodiment, BMI ≧ 27 kg / m 2 and a method for additional weight management in a subject having at least one weight-related co-morbidity and in need of additional weight management, administering to the subject a once-weekly dose of 2.5 mg of tildesideptide or a pharmaceutically acceptable salt thereof, after 4 weeks, increasing the once-weekly dose of tildesideptide or a pharmaceutically acceptable salt thereof to 5 mg, Increase the dose by an increment of 2.5 mg at least 4 weeks after the current dose, at least 4 weeks after a dose of 15 mg of tildepepide or a pharmaceutically acceptable salt thereof once weekly, including increasing the dose by an increment of 5.0 mg at least 4 weeks after the current dose, wherein the maximum dose is 25 mg of tildepepide or a pharmaceutically acceptable salt thereof subcutaneously once weekly, a method.

[0041] In one embodiment, a method of providing a therapeutic taper, comprising administering to a human in need thereof an effective amount of a composition comprising 40 mg / mL of tildepepide or a pharmaceutically acceptable salt thereof, a method is provided. In one embodiment, a method of providing a therapeutic taper, comprising administering to a human in need thereof an effective amount of a composition comprising 50 mg / mL of tildepepide or a pharmaceutically acceptable salt thereof, a method is provided. In one embodiment, a method of providing a therapeutic taper, comprising administering to a human in need thereof an effective amount of a composition comprising 60 mg / mL of tildepepide or a pharmaceutically acceptable salt thereof, a method is provided. In one embodiment, tildepepide or a pharmaceutically acceptable salt thereof is the tildepepide free base.

[0042] In one embodiment, a method of treating obesity in a subject having an initial body mass index (BMI) ≧ 30 kg / m 2 comprising administering 40 mg / mL of tildepepide or a pharmaceutically acceptable salt thereof, a method. In one embodiment, a method of treating obesity in a subject having an initial body mass index (BMI) ≧ 30 kg / m 2 comprising administering 50 mg / mL of tildepepide or a pharmaceutically acceptable salt thereof, a method. In one embodiment, a method of treating an overweight subject having an initial BMI ≧ 27 kg / m 2 comprising administering 60 mg / mL of tildepepide or a pharmaceutically acceptable salt thereof to a subject having a BMI ≧ 27 kg / m 2A method for an overweight subject having at least one weight-related complication. In one embodiment, the weight-related complication is at least one condition selected from the group consisting of hypertension, type 2 diabetes, and dyslipidemia. In one embodiment, the initial body mass index (BMI) ≥ 30 kg / m 2 A method for treating obesity in a subject having. In one embodiment, the initial body mass index (BMI) ≥ 27 kg / m 2 A method for treating obesity in a subject having.

[0043] In one embodiment, a method for treating a pediatric patient having an initial body mass index at the 95th percentile or above, standardized for age and gender, comprising administering an effective amount of tirzepatide or a pharmaceutically acceptable salt thereof once a week. In one embodiment, a method for treating a pediatric patient 12 years of age or older having an initial body mass index at the 95th percentile or above, standardized for age and gender, comprising administering an effective amount of tirzepatide or a pharmaceutically acceptable salt thereof once a week. In one embodiment, a method for treating a pediatric subject having an initial body mass index at the 95th percentile or above, standardized for age and gender, comprising administering 2.5 mg / mL of tirzepatide or a pharmaceutically acceptable salt thereof for at least 4 weeks. In one embodiment, a method for treating a pediatric subject having an initial body mass index at the 95th percentile or above, standardized for age and gender, comprising administering 1.25 mg of tirzepatide or a pharmaceutically acceptable salt thereof. In one embodiment, a method for chronic weight management for a pediatric subject, wherein the subject has an initial BMI at the 85th percentile or above, standardized for age and gender, and has at least one weight-related co-morbidity. In one embodiment, a method for treating a pediatric patient, wherein tirzepatide is in free base form.

[0044] In one embodiment, the initial BMI ≥ 30 kg / m 2Subjects having [it] achieve at least a 15% weight loss. In one embodiment, the initial BMI ≥ 30 kg / m 2 Subjects having [it] achieve at least a 17% weight loss. In one embodiment, the initial BMI ≥ 30 kg / m 2 Subjects having [it] achieve at least a 20% weight loss.

[0045] In one embodiment, subjects with type 2 diabetes and an initial BMI ≥ 27 kg / m 2 Subjects having [it] achieve at least a 15% weight loss. In one embodiment, subjects with type 2 diabetes and an initial BMI ≥ 27 kg / m 2 Subjects having [it] achieve at least a 17% weight loss. In one embodiment, subjects with type 2 diabetes and an initial BMI ≥ 27 kg / m 2 Subjects having [it] achieve at least a 20% weight loss.

[0046] In one embodiment, subjects with weight-related comorbidities and an initial BMI ≥ 27 kg / m 2 Subjects having [it] achieve at least a 15% weight loss. In one embodiment, subjects with weight-related comorbidities and an initial BMI ≥ 27 kg / m 2 Subjects having [it] achieve at least a 17% weight loss. In one embodiment, subjects with weight-related comorbidities and an initial BMI ≥ 27 kg / m 2 Subjects having [it] achieve at least a 20% weight loss.

[0047] In one embodiment, a method for treating obesity in a subject having an initial body mass index (BMI) ≥ 30 kg / m 2 comprising administering 40 mg / mL of tirlpazide or a pharmaceutically acceptable salt thereof, wherein the subject achieves at least a 15% weight loss. In one embodiment, the initial body mass index (BMI) ≥ 30 kg / m 2 A method for treating obesity in a subject having [it] comprising administering 50 mg / mL of tirlpazide or a pharmaceutically acceptable salt thereof, wherein the subject achieves at least a 15% weight loss. In one embodiment, the initial body mass index (BMI) ≥ 30 kg / m 2A method of treating obesity in a subject having, comprising administering 40 mg / mL of tirlpazotide or a pharmaceutically acceptable salt thereof, wherein the subject achieves at least a 20% weight loss. In one embodiment, the initial body mass index (BMI) ≧ 30 kg / m 2 A method of treating obesity in a subject having, comprising administering 50 mg / mL of tirlpazotide or a pharmaceutically acceptable salt thereof, wherein the subject achieves at least a 20% weight loss. In one embodiment, type 2 diabetes and an initial BMI ≧ 27 kg / m 2 A method of treating an overweight subject having, comprising administering 40 mg / mL of tirlpazotide or a pharmaceutically acceptable salt thereof, with an initial BMI ≧ 27 kg / m 2 and ≦ 30 kg / m 2 such that the overweight subject having achieves at least a 15% weight loss. In one embodiment, type 2 diabetes and an initial BMI ≧ 27 kg / m 2 A method of treating an overweight subject having, comprising administering 50 mg / mL of tirlpazotide or a pharmaceutically acceptable salt thereof, with an initial BMI ≧ 27 kg / m 2 and ≦ 30 kg / m 2 such that the overweight subject having achieves at least a 15% weight loss. In one embodiment, type 2 diabetes and an initial BMI ≧ 27 kg / m 2 A method of treating an overweight subject having, comprising administering 40 mg / mL of tirlpazotide or a pharmaceutically acceptable salt thereof, with an initial BMI ≧ 27 kg / m 2 and ≦ 30 kg / m 2 such that the overweight subject having achieves at least a 20% weight loss. In one embodiment, type 2 diabetes and an initial BMI ≧ 27 kg / m 2 A method of treating an overweight subject having, comprising administering 50 mg / mL of tirlpazotide or a pharmaceutically acceptable salt thereof, with an initial BMI ≧ 27 kg / m 2 and ≦ 30 kg / m 2A method for an overweight subject having [conditions] to achieve at least a 20% weight loss. In one embodiment, it is a method for treating an overweight subject wherein tirzepatide is in free base form. In one embodiment, it is a method for treating obesity wherein tirzepatide is in free base form. In one embodiment, tirzepatide or a pharmaceutically acceptable salt thereof is administered in a 0.5 mL composition.

[0048] In one embodiment, a method for treating an overweight subject having weight-related comorbidities and an initial BMI ≥ 27 kg / m 2 comprising administering 40 mg / mL of tirzepatide or a pharmaceutically acceptable salt thereof, wherein the initial BMI ≥ 27 kg / m 2 and ≤ 30 kg / m 2 for an overweight subject having [conditions] to achieve at least a 15% weight loss. In one embodiment, a method for treating an overweight subject having weight-related comorbidities and an initial BMI ≥ 27 kg / m 2 comprising administering 50 mg / mL of tirzepatide or a pharmaceutically acceptable salt thereof, wherein the initial BMI ≥ 27 kg / m 2 and ≤ 30 kg / m 2 for an overweight subject having [conditions] to achieve at least a 15% weight loss. In one embodiment, a method for treating an overweight subject having weight-related comorbidities and an initial BMI ≥ 27 kg / m 2 comprising administering 40 mg / mL of tirzepatide or a pharmaceutically acceptable salt thereof, wherein the initial BMI ≥ 27 kg / m 2 and ≤ 30 kg / m 2 for an overweight subject having [conditions] to achieve at least a 20% weight loss. In one embodiment, a method for treating an overweight subject having weight-related comorbidities and an initial BMI ≥ 27 kg / m 2 comprising administering 50 mg / mL of tirzepatide or a pharmaceutically acceptable salt thereof, wherein the initial BMI ≥ 27 kg / m 2 and ≤ 30 kg / m 2 for an overweight subject having [conditions] to achieve at least a 20% weight loss.

[0049] In certain embodiments, the weight-related co-morbid condition is at least one selected from the group consisting of hypertension, dyslipidemia, prediabetes, type 2 diabetes, obstructive sleep apnea, and cardiovascular disease.

[0050] In certain embodiments, the weight-related co-morbid condition is at least one condition selected from the group consisting of hypertension, type 2 diabetes, and dyslipidemia.

[0051] In one embodiment, one of the above compositions for use as a medicament is provided.

[0052] In one embodiment, one of the above compositions for use in the treatment of diabetes is provided. In one embodiment, one of the above compositions for use in the treatment of obesity is provided.

[0053] In one embodiment, one of the above compositions for use in providing therapeutic weight loss is provided. In one embodiment, one of the above compositions for use in providing non-therapeutic weight loss is provided.

[0054] According to another aspect of the invention, an article of manufacture comprising one of the above compositions is provided. In certain embodiments, the article of manufacture is a multi-use vial. In certain embodiments, the article of manufacture is a prefilled syringe. In certain embodiments, the article of manufacture is an auto-injector device (“auto-injector”). Examples of auto-injectors contemplated herein are presented in U.S. Patent No. 8,734,394.

[0055] As used herein, “obesity” means a body mass index (BMI) of 30 kg / m 2 or greater. As used herein, “weight management” means the behaviors, techniques, and physiological processes that contribute to a person's ability to achieve and maintain a healthy weight. The healthy weight for a particular patient can be determined in consultation with a medical professional, but the World Health Organization generally defines “overweight” as a BMI of 25 kg / m 2An individual having a BMI exceeding 2 may refer to a subject having an initial BMI of 27 kg / m or more. In certain embodiments, the subject in need of chronic weight management is 27 kg / m 2Refers to a subject having the above initial BMI and having at least one weight-related co-morbidity. Chronic weight management treatment promotes the ability of patients to achieve healthy weight goals. In one embodiment, "chronic weight management" means, for example, that the subject achieves a healthy weight goal and maintains a weight within the range of the healthy weight goal for a certain period of time. In one embodiment, "chronic weight management" means that the subject achieves a healthy weight goal and maintains a weight within the range of the healthy weight goal for at least 3 months. In one embodiment, the subject achieves a healthy weight goal and maintains the weight within the range of the healthy weight goal for at least 6 months. In one embodiment, "chronic weight management" means that the subject achieves a healthy weight goal and maintains the weight within the range of the healthy weight goal for at least 1 year. In one embodiment, "chronic weight management" means that the patient achieves a healthy weight goal and generally maintains the weight within the range of the healthy weight goal. As used herein, "generally maintaining the weight" means that for most of the period, the subject's weight is within the range of the healthy weight goal. In one embodiment, "generally maintaining the weight" means that the subject's weight does not increase by more than 15% of the healthy target weight during the specified period. In one embodiment, "chronic weight management" means that the patient achieves a healthy weight goal and improves the measure of at least one weight-related co-morbidity. In one embodiment, "chronic weight management" means that the patient achieves a healthy weight goal or the patient reduces weight to achieve the treatment goal of at least one weight-related co-morbidity. As used herein, a subject "in need of additional chronic weight management" cannot achieve the desired weight loss goal. In certain embodiments, "in need of additional weight management" means that the subject cannot achieve a healthy weight goal using at least once-weekly 15 mg treatment of tirzepatide. In certain embodiments, "in need of additional weight management" means that the subject cannot achieve a healthy weight goal using at least once-weekly 15 mg treatment of tirzepatide and cannot achieve the treatment goal for at least one weight-related co-morbidity. In certain embodiments, a "pediatric patient in need of chronic weight management" is a pediatric subject having an initial body mass index at or above the 95th percentile standardized for age and gender.

[0056] In certain embodiments, a "pediatric patient in need of chronic weight management" is a pediatric subject having an initial body mass index of 85th percentile or greater, standardized for age and gender, and having at least one weight-related co-morbidity. As used herein, "pediatric" may preferably refer to subjects less than 20 years of age. In certain embodiments, "pediatric" refers to subjects over 12 years of age. In certain embodiments, "pediatric" refers to subjects less than 18 years of age. In certain embodiments, a "pediatric patient in need of chronic weight management" is a pediatric subject having an initial body mass index of 90th percentile or greater, standardized for age and gender.

[0057] As used herein, "tirzepatide" means a GIP / GLP1 co-agonist peptide as described in US9,474,780 and identified by CAS Registry Number: 2023788-19-2. Tirzepatide is described in Example 1 of U.S. Patent No. 9,474,780 and has the following sequence, YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS wherein X1 is Aib, X2 is Aib, the K at position 20 is chemically modified by the attachment of (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γGlu)1-CO-(CH2) 18 -CO2H to the epsilon-amino group of the K side chain, and the C-terminal amino acid is amidated as a C-terminal primary amide (SEQ ID NO: 1).

[0058] In certain embodiments of the invention, "tirzepatide" means a compound of the following formula (SEQ ID NO: 1).

[0059]

Chemical formula

[0060] In certain embodiments of the invention, SEQ ID NO: 2 means a GIP / GLP1 co-agonist compound, YX1EGTFTSDYSIX2LDKIAQKAX3VQWLIAGGPSSGAPPPS In the formula, X1 is Aib, X2 is Aib, the Lys at position 20 is chemically modified by the attachment of a C16 - C20 fatty acid or a derivative thereof to the epsilon - amino group of the Lys side chain, X3 is Phe, the C - terminal amino acid is optionally amidated as a C - terminal primary amide or is a pharmaceutically acceptable salt thereof.

[0061] In certain embodiments, as used herein, SEQ ID NO: 3 means a GIP / GLP1 core agonist compound: YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS (SEQ ID NO: 3) In the formula, X1 is Aib, X2 is Aib, and the Lys at position 20 is chemically modified by the attachment of a fatty acid selected from the group consisting of the following to the epsilon - amino group of the Lys side chain,

[0062]

Chemical formula

[0063] As used herein, the term "C16 - C20 fatty acid" means a dibasic acid having 16 - 20 carbon atoms. In one embodiment, the C16 - C20 fatty acid suitable for use herein can be a saturated dibasic acid. In one embodiment, the fatty acid is C20. In one embodiment, the fatty acid is ([2-(2 - amino - ethoxy)-ethoxy]-acetyl)2-(γGlu) a -CO-(CH2) b -CO2H, where a is 1 - 2 and b is 10 - 18.

[0064] In certain embodiments, the C16-C20 fatty acids are as follows

[0065]

Chem.

[0066] In certain embodiments, the C16-C20 fatty acids are as follows:

[0067]

Chem.

[0068] In certain embodiments, the C16-C20 fatty acids are as follows:

[0069]

Chem.

[0070] As used herein, "derivative" means that one atom or atomic group is replaced by another atom or atomic group. As used herein, "derivative" can be a structural analog of a C16-C20 fatty acid.

[0071] In certain embodiments, tilsepamide (SEQ ID NO: 1) is preferred.

[0072] As used herein, "pharmaceutically acceptable salt" is well known to those skilled in the art. In one embodiment, it is a pharmaceutically acceptable salt that is the tilsepamide trifluoroacetate salt.

[0073] As used herein, the term "surfactant-free" means that the composition does not contain an added surfactant or contains only a very small amount of added surfactant.

[0074] The composition of the present invention has a concentration of 32 mg / mL to 55 mg / mL of tildepazide or a pharmaceutically acceptable salt thereof. The composition of the present invention has a concentration of 36 mg / mL to 55 mg / mL of tildepazide or a pharmaceutically acceptable salt thereof. In one embodiment, the concentration of tildepazide or a pharmaceutically acceptable salt thereof is from about 40 mg / mL to about 60 mg / mL. In one embodiment, the concentration of tildepazide is selected from the group consisting of 40 mg / mL and 60 mg / mL. In one embodiment, the concentration of tildepazide or a pharmaceutically acceptable salt thereof is from about 40 mg / mL to about 60 mg / mL. In one embodiment, the concentration of tildepazide is selected from the group consisting of 40 mg / mL and 50 mg / mL. Such a composition can be provided in a prefilled syringe or an auto-injector device. Such a prefilled syringe can be useful for administering 0.5 milliliters of such a composition per dose per patient.

[0075] The composition of the present invention has a concentration of 32 mg / mL to 55 mg / mL of SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof. The composition of the present invention has a concentration of 36 mg / mL to 55 mg / mL of SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof. In one embodiment, the concentration of SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof is from about 40 mg / mL to about 60 mg / mL. In one embodiment, the concentration of SEQ ID NO: 2 is selected from the group consisting of 40 mg / mL and 60 mg / mL. In one embodiment, the concentration of SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof is from about 40 mg / mL to about 60 mg / mL. In one embodiment, the concentration of SEQ ID NO: 2 is selected from the group consisting of 40 mg / mL and 50 mg / mL.

[0076] The composition of the present invention has a concentration of 32 mg / mL to 55 mg / mL of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof. The composition of the present invention has a concentration of 36 mg / mL to 55 mg / mL of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof. In one embodiment, the concentration of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof is from about 40 mg / mL to about 60 mg / mL. In one embodiment, the concentration of SEQ ID NO: 3 is selected from the group consisting of 40 mg / mL and 60 mg / mL. In one embodiment, the concentration of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof is from about 40 mg / mL to about 60 mg / mL. In one embodiment, the concentration of SEQ ID NO: 3 is selected from the group consisting of 40 mg / mL and 50 mg / mL. Such a composition can be provided in a prefilled syringe or an auto-injector device. Such a prefilled syringe can be useful for administering 0.5 milliliters of such a composition per dose per patient.

[0077] The composition of the present invention has a concentration of 32 mg / mL to 55 mg / mL of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof. The composition of the present invention has a concentration of 36 mg / mL to 55 mg / mL of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof. In one embodiment, the concentration of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof is from about 40 mg / mL to about 60 mg / mL. In one embodiment, the concentration of SEQ ID NO: 4 is selected from the group consisting of 40 mg / mL and 60 mg / mL. In one embodiment, the concentration of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof is from about 40 mg / mL to about 60 mg / mL. In one embodiment, the concentration of SEQ ID NO: 4 is selected from the group consisting of 40 mg / mL and 50 mg / mL. Such a composition can be provided in a prefilled syringe or an auto-injector device. Such a prefilled syringe can be useful for administering 0.5 milliliters of such a composition per dose per patient.

[0078] The composition is sterile when first manufactured. When provided in a multi-use vial or cartridge, an antibacterial preservative compound or mixture of compounds that is compatible with the other components of the composition may be added at a strength sufficient to meet applicable regulatory antibacterial preservative requirements. Pharmaceutically acceptable preservatives are well known in the art. (See, e.g., Remington: The Science and Practice of Pharmacy (D.B. Troy, Editor, 21st Edition, Lippincott, Williams & Wilkins, 2006). In one embodiment, the preservative is metacresol. In one embodiment, the preservative is phenol. In the composition of the present invention for single-use prefilled syringes, the composition does not require a preservative. In one embodiment, the composition does not contain a surfactant.

[0079] The pH of the tils peptides composition of the present invention is typically 6.5 to 7.5 and, if required to achieve the desired pH, is adjusted using physiologically appropriate acids and bases. In one embodiment, the pH target for the composition of tils peptides or a pharmaceutically acceptable salt thereof is 6.7 to 7.3. The experience of the injection site in the patient is a consideration for compositions administered subcutaneously. It is desirable to select a composition associated with an acceptable patient injection site experience. For example, NaCl and citrate are associated with a stinging sensation accompanied by pain at the injection site. (Laursen, T.; Hansen, B.; Fisker, S. Pain perception after subcutaneous injections of media containing different buffers. Basic & Clinical Pharmacology & Toxicology 2006, 98, (2), 218 - 221.), (Fransson, J.; Espander - Jansson, Local tolerance of subcutaneous injections. Journal of Pharmacy and Pharmacology 1996, 48, (10), 1012 - 1015.) Since solutions that are not approximately isotonic with body fluids can cause a stinging sensation accompanied by pain when administered, it is further desirable to match as closely as possible the tonicity (i.e., osmotic pressure) of the body fluid at the injection site when administering the composition. The composition is desirably approximately isotonic with body fluid at the injection site. The present composition containing tils peptides or a pharmaceutically acceptable salt thereof, NaCl, and disodium phosphate is associated with an acceptable patient injection site experience.

[0080] The pH of the composition of SEQ ID NO: 2 of the present invention is typically 6.5 to 7.5 and, if required to achieve the desired pH, is adjusted using physiologically appropriate acids and bases. In one embodiment, the pH target for the composition of SEQ ID NO: 2 is 6.7 to 7.3.

[0081] The pH of the composition of SEQ ID NO: 3 of the present invention is typically from 6.5 to 7.5 and is adjusted using physiologically appropriate acids and bases if needed to achieve the desired pH. In one embodiment, the pH target of the composition of SEQ ID NO: 3 is from 6.7 to 7.3.

[0082] The pH of the composition of SEQ ID NO: 4 of the present invention is typically from 6.5 to 7.5 and is adjusted using physiologically appropriate acids and bases if needed to achieve the desired pH. In one embodiment, the pH target of the composition of SEQ ID NO: 4 is from 6.7 to 7.3.

[0083] In one embodiment, the pH is adjusted using a base to facilitate dissolution in a buffer solution. Addition of an acid to the composition may be required to adjust the pH to the desired pH range. In one embodiment, NaOH is used to facilitate dissolution of tildepazide or a pharmaceutically acceptable salt thereof in the buffer. In one embodiment, HCl is added to adjust the pH of a composition containing dissolved tildepazide or a pharmaceutically acceptable salt thereof to the desired pH range.

[0084] The composition of the present invention is typically administered subcutaneously. The composition is typically administered using a prefilled disposable pen, a reusable pen, or an auto - pen injector. The composition may be administered using a multi - use vial, a single - use vial, or a pump device. In one embodiment, the device is an auto - injection device as described by U.S. Patent No. 8,734,394.

[0085] Compositions containing 40 mg / mL or 50 mg / mL of tildepazide, NaCl, and dibasic sodium phosphate provide desirable shelf-life stability and provide an acceptable injection site experience to patients. Similarly, compositions containing 2.5 mg / mL of tildepazide, NaCl, and dibasic sodium phosphate provide desirable shelf-life stability and provide an acceptable injection site experience to patients. As used herein, "shelf-life stability" is measured under controlled conditions at about 5 degrees Celsius. Compositions containing 40 mg / mL of tildepazide, NaCl, and dibasic sodium phosphate provide acceptable in-use stability. Similarly, compositions containing 50 mg / mL of tildepazide, NaCl, and dibasic sodium phosphate provide acceptable in-use stability. As used herein, the term "in-use stability" refers to the stability of a composition measured under controlled conditions at about 25 degrees Celsius or about 30 degrees Celsius. As used herein, "shelf-life stability" means that when measured using at least one method described herein, the degradation of tildepazide at about 5 degrees Celsius is within an acceptable range for degradation products approved by a regulatory agency. As used herein, "in-use stability" means that when measured using at least one method described herein, the degradation of tildepazide at about 25 degrees Celsius is within an acceptable range for degradation products approved by a regulatory agency. In certain embodiments, the regulatory agency is the U.S. Food and Drug Administration.

[0086] Increasing the dose of a drug can, in some cases, achieve an increase in efficacy, but increasing the dose of a drug also carries a greater risk of side effects. For example, administration of a GIP / GLP-1 receptor agonist is known to have a risk of nausea and / or diarrhea. Thus, any increase in dose must balance sufficient increased efficacy with no unacceptable safety or tolerability issues.

[0087] It has been discovered that increased doses of 20 mg or 25 mg of tirzepatide once weekly can result in increased efficacy compared to doses up to 15 mg. In certain embodiments, the subject achieves at least a 17% weight loss. In certain embodiments, the subject achieves at least a 20% weight loss. In certain embodiments, the subject achieves at least a 22% weight loss. Doses of 20 mg or 25 mg of tirzepatide once weekly can be administered with an acceptable safety and tolerability profile when used to administer the dosing regimens provided herein. Accordingly, the present invention provides for administering a dose of at least 15 mg of tirzepatide once weekly for at least 4 weeks prior to administering 20 mg for at least 4 weeks, resulting in an acceptable safety and tolerability profile when administering the 20 mg and 25 mg doses. In subjects starting tirzepatide treatment for the first time, the dosing regimen starts at a dose of 2.5 mg once weekly for at least 4 weeks, then increases the dose to 5 mg once weekly for 4 weeks, then increases the dose to 7.5 mg once weekly for at least 4 weeks, then increases the dose to 10 mg once weekly for at least 4 weeks, then increases the dose to 12.5 mg for at least 4 weeks, then increases the dose to 15 mg for at least 4 weeks, then increases the dose to 20 mg for at least 4 weeks, and then optionally increases the dose to 25 mg once weekly. However, in subjects who have already been administered tirzepatide but require additional weight management, the dosing regimen does not call for reducing the subject's current dose. For example, in a subject who has been administered 15 mg of tirzepatide once weekly but requires additional weight management, the regimen does not call for reducing the dose to 2.5 mg, but instead specifies increasing the dose to 20 mg once weekly for at least 4 weeks and then optionally increasing to 25 mg. Similarly, in a subject who has been administered 20 mg of tirzepatide once weekly but requires additional weight management, the regimen does not call for reducing the dose to 2.5 mg or 15 mg once weekly, but instead specifies increasing the dose to 25 mg.However, for any of the above embodiments of the dosing regimen, the dose is preferably not increased to a series of subsequent doses until the current dose has been administered for at least 4 weeks. In certain embodiments, the dose is increased to 20 mg of tildepazide once weekly without administering a 17.5 mg dose of tildepazide once weekly. In certain embodiments, the dose is increased to 20 mg of tildepazide once weekly without administering a 17.5 mg dose of tildepazide once weekly for 4 weeks prior to the initial 20 mg dose of tildepazide once weekly. In certain embodiments, the dose is increased to 25 mg of tildepazide once weekly without administering a 22.5 mg dose of tildepazide once weekly. In certain embodiments, the dose is increased to 25 mg of tildepazide once weekly without administering a 22.5 mg dose of tildepazide once weekly for 4 weeks prior to the initial 25 mg dose of tildepazide once weekly. In certain embodiments, the 25 mg dose of tildepazide once weekly is administered without administering 17.5 mg and 22.5 mg doses. In certain embodiments, the 25 mg dose of tildepazide once weekly is administered in less than 4 weeks after the initial 20 mg dose of tildepazide once weekly.

[0088] Furthermore, increasing the concentration of tilzeyapatide may require other modifications to the composition, so the present invention also provides a composition containing an increased dose of tilzeyapatide that maintains chemical and physical stability over a two-year refrigerated shelf life and maximum use period and meets current product specifications. In one embodiment, the composition is stable for at least three months. In one embodiment, the composition is stable for at least six months. In one embodiment, the composition is stable for at least three months at 5 degrees Celsius. In one embodiment, the composition is stable for at least six months at 30 degrees Celsius. In one embodiment, the composition is stable for approximately two years at 5 degrees Celsius. In one embodiment, the composition is stable for approximately two years at 30 degrees Celsius. In one embodiment, the composition is an active pharmaceutical ingredient with a purity of at least 90% at the end of the shelf life. In one embodiment, the composition is an active pharmaceutical ingredient with a purity of at least 95% at the end of the shelf life. In one embodiment, the composition is tilzeyapatide with a purity of at least 90% after approximately two years at 5 degrees Celsius. In one embodiment, the composition is tilzeyapatide with a purity of at least 90% after approximately two years at 30 degrees Celsius. In one embodiment, the composition is tilzeyapatide with a purity of at least 95% after at least six months at 5 degrees Celsius. In one embodiment, the composition is tilzeyapatide with a purity of at least 95% after at least six months at 30 degrees Celsius.

[0089] Similarly, decreasing the concentration of tilzeyapatide may require other modifications to the composition, so the present invention also provides a composition containing 2.5 mg / mL of tilzeyapatide that maintains chemical and physical stability over a two-year refrigerated shelf life and maximum use period and meets current product specifications.

[0090] The tilsepatide compositions tested in the Phase 3 clinical trials are provided as 0.5 mL aqueous solutions containing a dose selected from the group consisting of 2.5, 5, 7.5, 10, 12.5, and 15 mg of tilsepatide. In one embodiment, it is a lower dose composition containing 1.25 mg of tilsepatide. Such lower dose compositions may be beneficial for pediatric patients or patients who require such doses. In one embodiment, it is a higher dose composition containing a dose selected from the group consisting of 20 and 25 mg of tilsepatide. The compositions at 1.25, 20, and 25 mg doses provide protection against physical stress and it is necessary to ensure that tilsepatide maintains physical stability over the product shelf life period and maximum use period of 2 years under refrigerated conditions.

[0091] As used herein, "shelf life" means the time during which a substance can be stored and remain suitable for use. As used herein, "suitable for use" means that the percent purity of tilsepatide, as measured by reverse phase HPLC, is within the regulatory approval specifications for degradation products. As used herein, "purity" means the percentage of the active pharmaceutical ingredient remaining in the composition after a certain period. In certain embodiments, the shelf life is 2 years at 30 degrees Celsius. In certain embodiments, the shelf life is 2 years at 5 degrees Celsius. In certain embodiments, the shelf life is at least 6 months at 5 degrees Celsius. In certain embodiments, the shelf life is at least 6 months at 30 degrees Celsius. In certain embodiments, tilsepatide with a purity of 92% as measured by reverse phase HPLC is suitable for use. In certain embodiments, tilsepatide with a purity of about 95% as measured by reverse phase HPLC is suitable for use. In certain embodiments, tilsepatide with a purity of about 90% as measured by reverse phase HPLC is suitable for use. In certain embodiments, tilsepatide with a purity of about 85% as measured by reverse phase HPLC is suitable for use. In certain embodiments, tilsepatide with a purity of about 80% as measured by reverse phase HPLC is suitable for use.

[0092] As used herein, the term "about" refers to an amount within 10 percent (10%) of the recited numerical value, and the intended amount can be within 10% below the recited amount or within 10% above the recited amount.

[0093] As used herein, terms such as "treat," "treating," "treatment," and the like mean including delaying or attenuating the progression of a disease, disorder, or condition. 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 delayed or reversed.

[0094] "Subject" refers to a mammal, preferably a human, having a disease, disorder, or condition who would benefit from treatment with increased doses of tildepazide.

[0095] "Glycemic control" refers to maintaining or reducing the HbA1c level of a subject. "Improvement" in glycemic control refers to a reduction in HbA1c, and "further need" for glycemic control refers to the need for a reduction in HbA1c.

[0096] "Chronic weight management" refers to a desired reduction in weight. "Chronic weight management" may refer to a treatment for reducing the subject's BMI to approach or achieve the subject's healthy weight goal. "HbA1c" refers to the level of glycated hemoglobin that occurs when hemoglobin binds to glucose in the blood. HbA1c levels are a commonly used measure of glycemic control in patients with diabetes, and a decrease in HbA1c levels generally indicates an improvement in glycemic control. In the context of the methods of the present invention, the methods of the present invention result in a reduction in HbA1c.

[0097] In certain embodiments of the present invention, the tildepazide dosages and dosing regimens described herein are provided for the treatment of obesity, chronic weight management, and / or non-therapeutic weight loss in a subject in need thereof. In certain embodiments, the subject has a body mass index of about 25 kg / m 2has a body mass index (BMI) greater than. In certain embodiments, the subject has a BMI of about 26 kg / m 2 has a body mass index (BMI) greater than. In certain embodiments, the subject has a BMI of about 27 kg / m 2 has a body mass index (BMI) greater than. In certain embodiments, the subject also has one or more weight-related comorbidities such as T2D, hypertension, and / or dyslipidemia.

[0098] 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), non-alcoholic steatohepatitis (NASH), or chronic kidney disease (CKD).

[0099] In certain embodiments, the tilsepatide dosages and dosing regimens described herein are provided for the prevention and / or treatment of cognitive impairment and / or neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and / or multiple sclerosis.

[0100] The treatment methods and uses described herein can be provided in combination with other T2D treatments, simultaneously or sequentially, including oral T2D medications such as metformin, and / or other injectable medications including rapid-acting or basal insulin.

[0101] Example #1 - Composition Containing NaCl The composition is prepared substantially as described herein. Compositions containing 2.5, 40, or 50 mg / mL of tilsepatide each contain the components listed in Table 1. Compositions suitable for clinical use are shown in Table 2. An acid or base is optionally added to achieve the desired pH range. Water is added in a sufficient quantity (q.s.) to a total final volume of 1 milliliter.

[0102]

Table 1

[0103]

Table 2

[0104]

Table 3

[0105] Stability test during size exclusion chromatography (SEC) This procedure is a gradient-free size exclusion HPLC method with UV detection at 214 nm and is designed to determine the relative amounts of the tiludronate monomer and total aggregates. The monomer and aggregates are reported as peak area percent relative to the total area. The procedure demonstrates the stability measured by its ability to degrade known impurities from tiludronate. This test compares an alternative composition with the composition of the present invention prepared as shown in Table 1.

[0106] Stability test of shelf life RP-HPLC: This procedure is a gradient reverse-phase HPLC method with UV detection at 214 nm and is designed to determine the amount, identity, and purity of tildepazilide in drug products. High-performance liquid chromatography (HPLC) equipped with a UV detector, a cooled autosampler, a gradient analytical pump, a column heater, and an appropriate data collection system is used with a peptide (core shell) 2.6 μm, 4.6 × 250 mm column. Mobile phase A is 0.1% (v / v) trifluoroacetic acid (TFA) in water. Mobile phase B is 0.1% TFA in acetonitrile (ACN). The diluent is 5 mM sodium phosphate, 140 mM NaCl at pH 7. A flow rate of 1.2 mL / min is used with a gradient. The autosampler is at 5°C ± 3°C. The column temperature is 60°C ± 2°C, a 10 μL injection volume (about 10 μg) is used, and the runtime is about 60 minutes. Identity is determined by matching the retention time of the main peak with that of the main peak of an external reference standard. The amount is determined by comparison of the main peak area with the corresponding peak in the external reference standard. Impurities and related substances are reported as percent peak area relative to the total area. This procedure measures stability by degrading known impurities from tildepazilide. A composition containing 50 mg / mL of tildepazilide with NaCl as an isotonic agent provides acceptable stability during at least 6 months of use as shown by a tildepazilide purity of greater than 89% at 30°C for 6 months.

[0107] Compositions containing 50 mg / mL or 60 mg / mL of tildepazilide with NaCl as an isotonic agent provide an acceptable shelf life of at least 6 months at both 5°C and 25°C as shown by the following results. These tests demonstrate an acceptable shelf life of at least 6 months at pH 6.5 to pH 7.5 as shown by the tests reported below using 30 mg / 0.5 with NaCl as an isotonic agent.

[0108] Comparison of purity by RP-HPLC at high concentration (25 mg / 0.5 mL) with 2.5 mg / 0.5 mL and 15 mg / 0.5 mL (30°C)

[0109]

Table 4

[0110] Comparison of purity by RP-HPLC at high concentrations (25 mg / 0.5 mL and 30 mg / 0.5 mL) and 2.5 mg / 0.5 mL and 15 mg / 0.5 mL (25 °C)

[0111]

Table 5

[0112] Stability test of storage life of size exclusion chromatography (SEC) Using the size exclusion stability test method and RP-HPLC described above in this specification, a composition containing 2.5 mg / mL of tildepazilide, an isotonic agent, and NaCl as a stabilizer was evaluated to ensure the stability during use of the low-concentration composition. The size exclusion stability test method was applied to high doses to evaluate the stability during use. Size exclusion chromatography can measure tildepazilide aggregates and determine the percentage of tildepazilide monomers. This method uses size exclusion HPLC with UV detection and is an indicator of stability. High-performance liquid chromatography is equipped with a UV detector, a cooled autosampler, a temperature-controlled column compartment with a BEH 125 Å (3.5 μm, 7.8 mm × 300 mm) size exclusion chromatography column, and a data collection system. Size exclusion chromatography is completed using a reference standard of 10 mM sodium citrate at pH 6.5. The mobile phase is 0.05% trifluoroacetic acid (TFA) in 50% acetonitrile (ACN). The column temperature is maintained at 25 °C, and the autosampler temperature is 2 - 8 °C. The flow rate is 0.5 mL / min. The detection wavelength is 214 nm. The runtime after equilibration is approximately 30 minutes. Verification is completed, and system suitability is inspected throughout the entire analysis using an injection of the test standard following the blank, and subsequent injections, as well as at the end of the run. The monomer % is determined using the formula = (monomer peak area / total protein peak area) * × 100. The total high molecular weight species % can be determined using the formula: (Σ high molecular weight peak areas (peaks after the monomer) * × 100) / total protein peak area. The following results support a shelf life of at least 6 months at 5 °C, as the tildepazilide aggregates are less than 1% for all concentrations tested at 5 °C. The results support a shelf life of at least 6 months at 30 °C, as the tildepazilide aggregates are 1 percent or less for all concentrations tested.

[0113] Comparison of high concentration (25 mg / 0.5 mL) with 2.5 mg / 0.5 mL and 15 mg / 0.5 mL by SEC HMWS (30 °C)

[0114]

Table 6

[0115] Comparison of high concentrations (25 mg / 0.5 mL and 30 mg / 0.5 mL) with 2.5 mg / 0.5 mL and 15 mg / 0.5 mL by SEC HMWS (25 °C)

[0116]

Table 7

[0117] Example 3 Clinical Study Using a randomized double-blind placebo-controlled trial, the efficacy and safety of 20 mg and 25 mg of tilzepatide once a week are evaluated. In this trial, participants have type 2 diabetes and obesity (class II obesity). This trial includes, as described, 1) a screening period, 2) a dose escalation period, 3) a high-dose treatment period, 4) an extension period, and 5) a post-treatment follow-up period. All doses are administered using subcutaneous injection. All participants in this trial must be treated with metformin at a minimum dose of 1500 mg / day for at least 3 months prior to screening. The pre-screening metformin dose and formulation (short-acting or long-acting) should be maintained during screening and through randomization. During the trial, participants receive an interview regarding gastrointestinal symptoms.

[0118] Period I - Screening All screening activities must be conducted within a 35-day period. The purpose of the screening procedure is to establish eligibility and obtain blood samples for clinical laboratory evaluations necessary to confirm eligibility. Once eligibility is confirmed, an extended eye examination is performed by an ophthalmologist or optometrist. Participants are provided with a paper diary and begin recording blood glucose measurements and any hypoglycemic events. Two 7-point blood glucose measurements are collected on 2 non-consecutive days within 2 weeks of each visit. The 7-point blood glucose measurements consist of measurements before and 2 hours after each of the 3 main meals of the day and at bedtime.

[0119] Period II - Dose Escalation Following randomization, participants receive training on self-injection of the investigational drug. The date, time, and location of the first administration of the study intervention are recorded. At this visit, participants receive counseling on diabetes and weight management. Starting from randomization, all participants receive the study intervention according to the randomized group during a 24-week escalation period. The escalation for those receiving tildesatide includes a dosing schedule that starts at a dose of 2.5 mg per week for 4 weeks and increases in 2.5 mg increments, and thus, subjects receive once-weekly doses of 2.5 mg (4 weeks), 5 mg (4 weeks), 7.5 mg (4 weeks), 10 mg (4 weeks), 12.5 mg (4 weeks), 15 mg (4 weeks). Subjects randomized to placebo receive placebo treatment throughout the dose escalation period.

[0120] Discontinuation or reduction of metformin during the study should be appropriately documented and recorded. A participant is considered protocol non-compliant if they change the dose or discontinue metformin for reasons other than severe persistent hypoglycemia, contraindications according to the label for each country, or if a short-term discontinuation is in accordance with the label for metformin in each country.

[0121] Period III - High Dose Treatment Participants who were randomly assigned to tildesepotide at the third visit and did not discontinue the study intervention will be randomly assigned to a maintenance dose of tildesepotide (15 mg, 20 mg, or 25 mg) at the ninth visit. High doses of tildesepotide (above 15 mg / week) will be further titrated in 5 mg increments every 4 weeks until reaching the randomized dose of 20 mg or 25 mg. To achieve the assigned dose, all participants are required to receive two injections once a week starting at week 24 (i.e., the 20 mg dose is injected using two 10 mg fixed-dose pens once a week, while the 25 mg dose is then injected using one 10 mg fixed-dose pen and one 15 mg fixed-dose pen once a week to provide a total weekly dose of 25 mg as desired).

[0122] These participants will receive the study intervention according to the randomized group during the 20-week high-dose period. Participants randomized to placebo at the third visit will undergo sham re-randomization at the ninth visit and continue to receive placebo during the treatment period. Participants who permanently discontinued the study intervention before the ninth visit will not be re-randomized and will continue the study until the 14th visit.

[0123] Period IV - Primary endpoint (14th visit) Participants randomized to placebo at the third visit will complete the treatment period at the 14th visit without the assigned intervention. These participants will complete all 14th visit procedures and proceed to the 48-week safety follow-up visit. Participants who discontinued the study intervention (according to randomization) before the ninth visit will complete the treatment period at this visit. These participants will complete all 14th visit procedures and proceed to the 48-week safety follow-up visit. All other participants randomized to tildesepotide will complete the 14th visit procedures and continue the study for a 36-week extension period.

[0124] Period V - Extension period All participants randomly assigned to the maintenance dose of tildesatide at the 9th visit (2nd randomization) complete all visits during the extension period and complete the safety follow-up visit at week 84. The extension up to 80 weeks allows for 52 weeks of treatment at the highest dose achieved during dose escalation.

[0125] Post-treatment follow-up visit All post-treatment safety follow-up visits are conducted approximately 4 weeks following the last treatment period visit or the final assessment visit. All participants are required to complete the safety follow-up visit.

[0126] Combination therapy. Metformin was selected as the required concomitant antihyperglycemic agent. The minimum dose is at least 1500 mg / day to ensure the maximum effectiveness of metformin before adding additional therapy. Participants are instructed to maintain metformin throughout the treatment period until the last administration of the randomized treatment, except in special circumstances.

[0127] In certain embodiments, the embodiments are as follows. 1. (Embodiment 1) A pharmaceutical composition comprising SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof, wherein the concentration of the compound of SEQ ID NO: 2 is selected from the group consisting of about 2.5 mg / mL, about 40 mg / mL, about 50 mg / mL, and about 60 mg / mL, SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof, NaCl, and dibasic sodium phosphate. 2. A pharmaceutical composition comprising SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof, wherein the concentration of the compound of SEQ ID NO: 2 is selected from the group consisting of about 2.5 mg / mL, about 40 mg / mL, and about 50 mg / mL, SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof, NaCl, and dibasic sodium phosphate. 3. The pharmaceutical composition embodied by Embodiment 1, wherein the concentration of the compound of SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof is about 40 mg / mL or about 50 mg / mL. 4. The pharmaceutical composition embodied by Embodiment 1, wherein the concentration of the compound of SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof is about 2.5 mg / mL. 5. A pharmaceutical composition embodied by any one of Embodiments 3 to 4, wherein the concentration of disodium phosphate is from about 0.7 mg / mL to about 1.5 mg / mL. 6. A pharmaceutical composition embodied by Embodiment 5, wherein the concentration of disodium phosphate is about 1.34 mg / mL. 7. A pharmaceutical composition embodied by Embodiment 6, wherein the concentration of the compound of SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 2.5 mg / mL, about 40 mg / mL, and about 50 mg / mL. 8. A pharmaceutical composition embodied by Embodiment 7, wherein the concentration of the compound of SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof is selected from the group consisting of 40 and 50 mg / mL. 9. A pharmaceutical composition embodied by Embodiment 7, wherein the concentration of NaCl is from about 7 mg / mL to about 9 mg / mL. 10. A pharmaceutical composition embodied by Embodiment 9, wherein the concentration of NaCl is from about 7.4 mL to about 9.0 mg / mL. 11. A pharmaceutical composition embodied by Embodiment 10, wherein the concentration of NaCl is about 8.2 mg / mL. 12. A pharmaceutical composition embodied by Embodiment 1, wherein the concentration of the compound of SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof is selected from the group consisting of 2.5, 40, and 50 mg / mL, the concentration of disodium phosphate is from about 0.7 mg / mL to about 1.5 mg / mL, and the concentration of NaCl is from about 7 mg / mL to about 9 mg / mL. 13. A pharmaceutical composition embodied by Embodiment 12, wherein the concentration of the compound of SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof is selected from the group consisting of 2.5, 40, and 50 mg / mL, the concentration of disodium phosphate is about 1.34 mg / mL, and the concentration of NaCl is about 8.2 mg / mL. 14. A pharmaceutical composition embodied by Embodiment 13, wherein the composition is provided in an auto-injector device. 15. A pharmaceutical composition embodied by Embodiment 13, wherein the pH of the composition is from about 6.5 to about 7.5. 16. A pharmaceutical composition embodied by Embodiment 15, wherein the pH is from about 6.7 to about 7.3. 17. A pharmaceutical composition embodied by Embodiment 16, further comprising one or more preservatives. 18. A pharmaceutical composition embodied by Embodiment 17. 19. The composition further comprises a preservative selected from the group consisting of metacresol and phenol. 20. A pharmaceutical composition embodied by Embodiment 1, wherein the concentration of the compound of SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof is selected from about 2.5 mg / mL, 40 mg / mL, and 50 mg / mL, dibasic sodium phosphate is from about 0.7 to about 1.5 mg / mL, and NaCl is from about 7 mg / mL to about 9 mg / mL. 21. A pharmaceutical composition embodied by Embodiment 20, wherein the dosage of the composition is about 0.5 mL. 22. A pharmaceutical composition embodied by Embodiment 20, wherein the composition is administered using an auto-injector device. 23. A pharmaceutical composition embodied by any one of Embodiments 1 to 22, wherein the compound is SEQ ID NO: 2. 24. A method of treating diabetes, comprising administering to a human in need thereof an effective dose of the pharmaceutical composition embodied by Embodiment 20. 25. A method of treating diabetes embodied by Embodiment 24, wherein the dosage is administered once a week. 26. A method of treating obesity, comprising administering to a human in need thereof an effective dose of the pharmaceutical composition embodied by Embodiment 20. 27. A method of treating obesity embodied by Embodiment 26, wherein the dosage is administered using an auto-injector device. 28. A method of treating obesity embodied by Embodiment 26, wherein the dosage is administered once a week. 29. A pharmaceutical composition embodied by Embodiment 20 for use in the treatment of T2D. 30. A pharmaceutical composition embodied by Embodiment 20 for use in the treatment of obesity. 31. A method for chronic weight management in a subject having obesity and in need of additional weight management, comprising: identifying a subject having obesity and in need of additional weight management; administering to the subject a compound of SEQ ID NO: 2 at a dose of once a week for at least 4 weeks at a minimum of 15 mg; after administering a dose of 15 mg of SEQ ID NO: 2 once a week for at least 4 weeks, administering a dose of SEQ ID NO: 2 selected from the group consisting of 20 mg and 25 mg once a week. 32. The method for chronic weight management embodied by Embodiment 31, wherein the once-a-week dose of SEQ ID NO: 2 is 20 mg. 33. administering to the subject a compound of SEQ ID NO: 2 at a dose of 20 mg once a week for at least 4 weeks; after administering a dose of 20 mg of SEQ ID NO: 2 once a week for at least 4 weeks, administering a dose of SEQ ID NO: 2 at 25 mg once a week, the method for chronic weight management embodied by Embodiment 31. 34. A method for chronic weight management in a subject in need of additional weight management, comprising: identifying a subject in need of additional weight management; administering to the subject a dose of 15 mg of a compound of SEQ ID NO: 2 once a week; after at least 1 week, administering to the subject a dose of 20 mg of SEQ ID NO: 2 once a week for at least 2 weeks; after at least 2 weeks, administering to the subject a dose of 25 mg of SEQ ID NO: 2 once a week. 35. A pharmaceutical composition comprising SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof, wherein the concentration of the compound of SEQ ID NO: 3 is selected from the group consisting of about 2.5 mg / mL, about 40 mg / mL, about 50 mg / mL, and about 60 mg / mL, SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof, NaCl, and dibasic sodium phosphate. 36. A pharmaceutical composition comprising SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof, wherein the concentration of the compound of SEQ ID NO: 3 is selected from the group consisting of about 2.5 mg / mL, about 40 mg / mL, and about 50 mg / mL, and further comprising NaCl and dibasic sodium phosphate. 37. The pharmaceutical composition according to embodiment 35, wherein the concentration of the compound of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof is about 40 mg / mL or about 50 mg / mL. 38. The pharmaceutical composition according to embodiment 35, wherein the concentration of the compound of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof is about 2.5 mg / mL. 39. 39. The pharmaceutical composition according to any one of embodiments 35 to 38, wherein the concentration of dibasic sodium phosphate is about 0.7 mg / mL to about 1.5 mg / mL. 40. The pharmaceutical composition according to embodiment 39, wherein the concentration of dibasic sodium phosphate is about 1.34 mg / mL. 41. The pharmaceutical composition according to embodiment 40, wherein the concentration of the compound of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 2.5 mg / mL, about 40 mg / mL, and about 50 mg / mL. 42. The pharmaceutical composition according to embodiment 41, wherein the concentration of the compound of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof is selected from the group consisting of 40 and 50 mg / mL. 43. The pharmaceutical composition according to embodiment 41, wherein the concentration of NaCl is about 7 mg / mL to about 9 mg / mL. 44. 44. The pharmaceutical composition according to embodiment 43, wherein the concentration of NaCl is about 7.4 mL to about 9.0 mg / mL. 45. The pharmaceutical composition according to embodiment 44, wherein the concentration of NaCl is about 8.2 mg / mL. 46. A pharmaceutical composition embodied by Embodiment 34, wherein the concentration of the compound of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof is selected from the group consisting of 2.5, 40, and 50 mg / mL, the concentration of dibasic sodium phosphate is from about 0.7 mg / mL to about 1.5 mg / mL, and the concentration of NaCl is from about 7 mg / mL to about 9 mg / mL. 47. A pharmaceutical composition embodied by Embodiment 46, wherein the concentration of the compound of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof is selected from the group consisting of 2.5, 40, and 50 mg / mL, the concentration of dibasic sodium phosphate is about 1.34 mg / mL, and the concentration of NaCl is about 8.2 mg / mL. 48. A pharmaceutical composition embodied by Embodiment 47, wherein the composition is provided in an auto-injector device. 49. A pharmaceutical composition embodied by Embodiment 47, wherein the pH of the composition is from about 6.5 to about 7.5. 50. A pharmaceutical composition embodied by Embodiment 49, wherein the pH is from about 6.7 to about 7.3. 51. A pharmaceutical composition embodied by Embodiment 50, further comprising one or more preservatives. 52. 53. A pharmaceutical composition embodied by Embodiment 51, wherein the composition further comprises a preservative selected from the group consisting of metacresol and phenol. 54. A pharmaceutical composition embodied by Embodiment 35, wherein the concentration of the compound of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof is selected from about 2.5 mg / mL, 40 mg / mL, and 50 mg / mL, dibasic sodium phosphate is from about 0.7 to about 1.5 mg / mL, and NaCl is from about 7 mg / mL to about 9 mg / mL. 55. A pharmaceutical composition embodied by Embodiment 53, wherein the dose of the composition is about 0.5 mL. 56. A pharmaceutical composition embodied by Embodiment 53, wherein the composition is administered using an auto-injector device. 57. A pharmaceutical composition embodied by any one of Embodiments 35 to 55, wherein the compound is SEQ ID NO: 3. 57. A method for treating diabetes, comprising administering to a human in need of treatment an effective dose of the pharmaceutical composition embodied by Embodiment 35. 58. The method for treating diabetes according to Embodiment 57, wherein the dose is administered once a week. 59. A method for treating obesity, comprising administering to a human in need of treatment an effective dose of the pharmaceutical composition embodied by Embodiment 50. 60. The method for treating obesity according to Embodiment 59, wherein the dose is administered using an auto-injection device. 61. The method for treating obesity according to Embodiment 59, wherein the dose is administered once a week. 62. The pharmaceutical composition embodied by Embodiment 53 for use in the treatment of T2D. 63. The pharmaceutical composition embodied by Embodiment 53 for use in the treatment of obesity. 64. A method for chronic weight management in a subject having obesity and in need of additional weight management, identifying a subject having obesity and in need of additional weight management, administering to the subject a once-weekly dose of the compound of SEQ ID NO: 3 that is at least 15 mg for at least 4 weeks, after administering the once-weekly 15 mg dose of SEQ ID NO: 3 for at least 4 weeks, administering a once-weekly dose of SEQ ID NO: 3 selected from the group consisting of 20 mg and 25 mg. 65. The method for chronic weight management according to Embodiment 64, wherein the once-weekly dose of SEQ ID NO: 3 is 20 mg. 66. administering to the subject a once-weekly 20 mg dose of the compound of SEQ ID NO: 3 for at least 4 weeks, The method for chronic weight management embodied by Embodiment 64, comprising administering a once-weekly 25 mg dose of SEQ ID NO: 3 after administering the once-weekly 20 mg dose of SEQ ID NO: 3 for at least 4 weeks. 67. A method for chronic weight management in a subject in need of additional weight management, Identifying a subject in need of additional weight management, and administering to the subject a dose of the compound of SEQ ID NO: 3 at 15 mg once a week, and after at least one week, administering to the subject a dose of 20 mg of SEQ ID NO: 3 once a week for at least two weeks, and after at least two weeks, administering to the subject a dose of 25 mg of SEQ ID NO: 3 once a week, a method comprising. 68. A pharmaceutical composition embodied by Embodiment 35, wherein the concentration of the compound of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof is selected from the group consisting of 2.5, 40, and 50 mg / mL, the concentration of dibasic sodium phosphate is from about 0.7 mg / mL to about 1.5 mg / mL, and the concentration of NaCl is from about 7 mg / mL to about 9 mg / mL. 69. A pharmaceutical composition embodied by Embodiment 46, wherein the concentration of the compound of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof is selected from the group consisting of 2.5, 40, and 50 mg / mL, the concentration of dibasic sodium phosphate is about 1.34 mg / mL, and the concentration of NaCl is about 8.2 mg / mL. 70. A pharmaceutical composition embodied by Embodiment 69, wherein the composition is provided in an auto-injector device. 71. A pharmaceutical composition embodied by Embodiment 35, wherein the pH of the composition is from about 6.5 to about 7.5. 72. A pharmaceutical composition embodied by Embodiment 71, wherein the pH is from about 6.7 to about 7.3. 73. A pharmaceutical composition comprising SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof, wherein the concentration of the compound of SEQ ID NO: 4 is selected from the group consisting of about 2.5 mg / mL, about 40 mg / mL, about 50 mg / mL, and about 60 mg / mL, NaCl, and dibasic sodium phosphate. 74. A pharmaceutical composition comprising SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof, wherein the concentration of the compound of SEQ ID NO: 4 is selected from the group consisting of about 2.5 mg / mL, about 40 mg / mL, and about 50 mg / mL, NaCl, and dibasic sodium phosphate. A pharmaceutical composition embodied by Embodiment 73, wherein the concentration of the compound of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof is about 40 mg / mL or about 50 mg / mL. A pharmaceutical composition embodied by Embodiment 73, wherein the concentration of the compound of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof is about 2.5 mg / mL. 77. A pharmaceutical composition embodied by any one of Embodiments 73 to 76, wherein the concentration of dibasic sodium phosphate is about 0.7 mg / mL to about 1.5 mg / mL. A pharmaceutical composition embodied by Embodiment 77, wherein the concentration of dibasic sodium phosphate is about 1.34 mg / mL. A pharmaceutical composition embodied by Embodiment 78, wherein the concentration of the compound of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 2.5 mg / mL, about 40 mg / mL, and about 50 mg / mL. A pharmaceutical composition embodied by Embodiment 79, wherein the concentration of the compound of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof is selected from the group consisting of 40 and 50 mg / mL. A pharmaceutical composition embodied by Embodiment 79, wherein the concentration of NaCl is about 7 mg / mL to about 9 mg / mL. 82. A pharmaceutical composition embodied by Embodiment 81, wherein the concentration of NaCl is about 7.4 mL to about 9.0 mg / mL. A pharmaceutical composition embodied by Embodiment 82, wherein the concentration of NaCl is about 8.2 mg / mL. A pharmaceutical composition embodied by Embodiment 73, wherein the concentration of the compound of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof is selected from the group consisting of 2.5, 40, and 50 mg / mL, the concentration of dibasic sodium phosphate is about 0.7 mg / mL to about 1.5 mg / mL, and the concentration of NaCl is about 7 mg / mL to about 9 mg / mL. A pharmaceutical composition embodied by Embodiment 84, wherein the concentration of the compound of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof is selected from the group consisting of 2.5, 40, and 50 mg / mL, the concentration of dibasic sodium phosphate is about 1.34 mg / mL, and the concentration of NaCl is about 8.2 mg / mL. 86. A pharmaceutical composition embodied by Embodiment 85, wherein the composition is provided in an auto-injector device. 87. A pharmaceutical composition embodied by Embodiment 84, wherein the pH of the composition is about 6.5 to about 7.5. 88. A pharmaceutical composition embodied by Embodiment 87, wherein the pH is about 6.7 to about 7.3. 89. A pharmaceutical composition embodied by Embodiment 85, further comprising one or more preservatives. 90. A pharmaceutical composition embodied by Embodiment 89, wherein the composition further comprises a preservative selected from the group consisting of metacresol and phenol. 91. A pharmaceutical composition embodied by Embodiment 73, wherein the concentration of the compound of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof is selected from about 2.5 mg / mL, 40 mg / mL, and 50 mg / mL, dibasic sodium phosphate is about 0.7 to about 1.5 mg / mL, and NaCl is about 7 mg / mL to about 9 mg / mL. 92. A pharmaceutical composition embodied by Embodiment 91, wherein the dose of the composition is about 0.5 mL. 93. A pharmaceutical composition embodied by Embodiment 92, wherein the composition is administered using an auto-injector device. 94. A pharmaceutical composition embodied by any one of Embodiments 73 to 93, wherein the compound is SEQ ID NO: 4. 95. A method for treating diabetes, comprising administering an effective dose of the pharmaceutical composition embodied by Embodiment 73 to a human in need of treatment. 96. A method for treating diabetes embodied by Embodiment 95, wherein the dose is administered once a week. 97. A method of treating obesity, comprising administering to a human in need of treatment an effective dose of the pharmaceutical composition embodied by Embodiment 73. 98. A method of treating obesity according to Embodiment 97, wherein the dose is administered using an autoinjector device. 99. A method of treating obesity according to Embodiment 97, wherein the dose is administered once a week. 100. A pharmaceutical composition according to Embodiment 73 for use in the treatment of T2D. 101. A pharmaceutical composition according to Embodiment 73 for use in the treatment of obesity. 102. A method of chronic weight management in a subject having obesity and in need of additional weight management, comprising: identifying a subject having obesity and in need of additional weight management; administering to the subject a once-weekly dose of the compound of SEQ ID NO: 4 that is at least 15 mg for at least 4 weeks; after administering the once-weekly 15 mg dose of SEQ ID NO: 4 for at least 4 weeks, administering a once-weekly dose of SEQ ID NO: 4 selected from the group consisting of 20 mg and 25 mg. 103. A method of chronic weight management according to Embodiment 102, wherein the once-weekly dose of SEQ ID NO: 4 is 20 mg. 104. administering to the subject a once-weekly 20 mg dose of the compound of SEQ ID NO: 4 for at least 4 weeks; after administering the once-weekly 20 mg dose of SEQ ID NO: 4 for at least 4 weeks, administering a once-weekly 25 mg dose of SEQ ID NO: 4. A method of chronic weight management according to Embodiment 102. 105. A method of chronic weight management in a subject in need of additional weight management, comprising: identifying a subject in need of additional weight management; administering to the subject a once-weekly 15 mg dose of the compound of SEQ ID NO: 4; after at least 1 week, administering to the subject a once-weekly 20 mg dose of SEQ ID NO: 4 for at least 2 weeks; A method comprising administering to the subject a once-weekly dose of 25 mg of SEQ ID NO: 4 after at least 2 weeks. 106. A pharmaceutical composition embodied by Embodiment 73, wherein the concentration of the compound of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof is selected from the group consisting of 2.5, 40, and 50 mg / mL, the concentration of dibasic sodium phosphate is from about 0.7 mg / mL to about 1.5 mg / mL, and the concentration of NaCl is from about 7 mg / mL to about 9 mg / mL. 107. A pharmaceutical composition embodied by Embodiment 106, wherein the concentration of the compound of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof is selected from the group consisting of 2.5, 40, and 50 mg / mL, the concentration of dibasic sodium phosphate is about 1.34 mg / mL, and the concentration of NaCl is about 8.2 mg / mL. 108. A pharmaceutical composition embodied by Embodiment 107, wherein the composition is provided in an autoinjector device. 109. A pharmaceutical composition embodied by Embodiment 73, wherein the pH of the composition is from about 6.5 to about 7.5. 110. A pharmaceutical composition embodied by Embodiment 109, wherein the pH is from about 6.7 to about 7.3.

[0128] Sequence SEQ ID NO: 1 Tilzepatipeptide YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS Wherein X1 is Aib, X2 is Aib, the K at position 20 is to the epsilon-amino group of the K side chain (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)1-CO-(CH2) 18 is chemically modified by the bond of -CO2H, The C-terminal amino acid is amidated as a C-terminal primary amide.

[0129] SEQ ID NO: 2 YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS In the formula, X1 is Aib, X2 is Aib, the K at position 20 is chemically modified by the binding of a C16 - C20 fatty acid or its derivative to the epsilon - amino group of the K side chain, and the C - terminal amino acid is optionally amidated as a C - terminal primary amide.

[0130] SEQ ID NO: 3 YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS (SEQ ID NO: 3) In the formula, X1 is Aib, X2 is Aib, the K at position 20 is chemically modified by the binding of a fatty acid selected from the group consisting of the following to the epsilon - amino group of the K side chain,

[0131]

Chemical formula

[0132] SEQ ID NO: 4

[0133]

Chemical formula

Claims

1. A pharmaceutical composition comprising tildepazotide or a pharmaceutically acceptable salt thereof, NaCl, and sodium phosphate, wherein the concentration of the tildepazotide or pharmaceutically acceptable salt is from about 40 mg / mL to about 60 mg / mL.

2. The pharmaceutical composition according to claim 1, wherein the sodium phosphate is dibasic sodium phosphate.

3. The pharmaceutical composition according to any one of claims 1 to 2, wherein the pH of the composition is from about 6.5 to about 7.

5.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pH of the composition is from about 6.7 to about 7.

3.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the concentration of the tildepazotide or pharmaceutically acceptable salt is from about 40 mg / mL to about 50 mg / mL.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the tildepazotide is the free base.

7. The pharmaceutical composition according to any one of claims 2 to 6, wherein the concentration of the dibasic sodium phosphate is from about 0.7 mg / mL to about 1.5 mg / mL.

8. The pharmaceutical composition according to any one of claims 2 to 7, wherein the concentration of the dibasic sodium phosphate is about 1.34 mg / mL.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the concentration of the NaCl is from about 7 mg / mL to about 9 mg / mL.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the concentration of the NaCl is from about 7.4 mg / mL to about 9.0 mg / mL.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the concentration of the NaCl is about 8.2 mg / mL.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the composition has a stability of at least about 6 months shelf life.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the composition has a stability of at least about 2 years shelf life.

14. The pharmaceutical composition according to any one of claims 1 to 11, wherein the composition has a stability of at least about 3 months during use.

15. The pharmaceutical composition according to any one of claims 1 to 11, wherein the composition has a stability of at least about 6 months during use.

16. A pharmaceutical composition comprising tildepepide or a pharmaceutically acceptable salt thereof, NaCl, and dibasic sodium phosphate, wherein the concentration of the tildepepide is selected from the group consisting of about 2.5 mg / mL, about 40 mg / mL, about 50 mg / mL, and about 60 mg / mL.

17. The pharmaceutical composition according to claim 16, wherein the composition has a stability of at least about 3 months of shelf life.

18. The pharmaceutical composition according to any one of claims 16 and 17, wherein the composition has a stability of at least about 6 months of shelf life.

19. The pharmaceutical composition according to any one of claims 16 to 18, wherein the composition has a stability of at least about 2 years of shelf life.

20. The pharmaceutical composition according to any one of claims 16 to 19, wherein the concentration of tildepepide or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 2.5 mg / mL, about 40 mg / mL, and about 50 mg / mL.

21. The pharmaceutical composition according to any one of claims 16 to 20, wherein the concentration of the tildepepide or a pharmaceutically acceptable salt thereof is about 40 mg / mL or about 50 mg / mL.

22. The pharmaceutical composition according to any one of claims 16 to 20, wherein the concentration of the tildepepide or a pharmaceutically acceptable salt thereof is about 2.5 mg / mL.

23. The pharmaceutical composition according to any one of claims 16 to 22, wherein the concentration of dibasic sodium phosphate is about 0.7 mg / mL to about 1.5 mg / mL.

24. The pharmaceutical composition according to any one of claims 16 to 23, wherein the concentration of dibasic sodium phosphate is about 1.34 mg / mL.

25. The pharmaceutical composition according to any one of claims 16 to 24, wherein the concentration of the NaCl is about 7 mg / mL to about 9 mg / mL.

26. The pharmaceutical composition according to any one of claims 16 to 25, wherein the concentration of the NaCl is about 7.4 mg / mL to about 9.0 mg / mL.

27. The pharmaceutical composition according to any one of claims 16 to 26, wherein the concentration of the NaCl is about 8.2 mg / mL.

28. The concentration of tiludronate or a pharmaceutically acceptable salt thereof is selected from the group consisting of 2.5, 40, and 50 mg / mL, the concentration of dibasic sodium phosphate is from about 0.7 mg / mL to about 1.5 mg / mL, and the concentration of NaCl is from about 7 mg / mL to about 9 mg / mL, the pharmaceutical composition according to any one of claims 16 to 22.

29. The concentration of tiludronate or a pharmaceutically acceptable salt thereof is selected from the group consisting of 2.5 mg / mL, 40 mg / mL, and 50 mg / mL, the concentration of dibasic sodium phosphate is about 1.34 mg / mL, and the concentration of NaCl is about 8.2 mg / mL, the pharmaceutical composition according to any one of claims 16 to 22 or claim 28.

30. The pharmaceutical composition according to any one of claims 16 to 29, wherein the composition is provided in an auto-injector device.

31. The pharmaceutical composition according to any one of claims 16 to 30, wherein the pH of the composition is from about 6.5 to about 7.

5.

32. The pharmaceutical composition according to any one of claims 16 to 31, wherein the pH is from about 6.7 to about 7.

3.

33. The pharmaceutical composition according to any one of claims 16 to 32, further comprising one or more preservatives.

34. The pharmaceutical composition according to any one of claims 16 to 33, wherein the composition further comprises a preservative selected from the group consisting of metacresol and phenol.

35. The concentration of tiludronate or a pharmaceutically acceptable salt thereof is selected from 2.5 mg / mL, 40 mg / mL, and 50 mg / mL, dibasic sodium phosphate is from 0.7 mg / mL to about 1.5 mg / mL, and the concentration of NaCl is from 7 mg / mL to 9 mg / mL, the pharmaceutical composition according to any one of claims 16 to 22.

36. The pharmaceutical composition according to any one of claims 19 to 35, wherein tiludronate is the free base.

37. The pharmaceutical composition according to any one of claims 19 to 36, wherein the dose of the composition is about 0.5 mL.

38. The pharmaceutical composition according to any one of claims 19 to 37, wherein the composition is administered using an auto-injector device.

39. A pharmaceutical composition comprising tilsertide or a pharmaceutically acceptable salt thereof, wherein the concentration of the tilsertide is from about 40 mg / mL to about 60 mg / mL and the pH of the composition is from about 6.7 to about 7.

3.

40. The pharmaceutical composition according to claim 39, wherein the tilsertide is a free base.

41. The pharmaceutical composition according to any one of claims 39 to 40, wherein the concentration of the tilsertide is from about 40 mg / mL to about 50 mg / mL.

42. The pharmaceutical composition according to any one of claims 39 to 41, wherein the concentration of the tilsertide is selected from the group consisting of about 40 mg / mL and about 50 mg / mL.

43. The pharmaceutical composition according to any one of claims 39 to 42, wherein the concentration of the tilsertide is selected from the group consisting of 40 mg / mL and 50 mg / mL.

44. A pharmaceutical composition comprising tilsertide or a pharmaceutically acceptable salt thereof, wherein the concentration of the tilsertide is selected from the group consisting of about 2.5 mg / mL, about 40 mg / mL, and about 50 mg / mL, and the pH of the composition is from about 6.7 to about 7.

3.

45. The pharmaceutical composition according to any one of claims 1 to 44, wherein the tilsertide consists of SEQ ID NO:

1.

46. The pharmaceutical composition according to any one of claims 1 to 45 for use in the treatment of T2D.

47. The pharmaceutical composition according to any one of claims 1 to 45 for use in the treatment of obesity.

48. A method of treating diabetes, comprising administering to a human in need thereof an effective amount of the pharmaceutical composition according to any one of claims 1 to 45.

49. The method of treating diabetes according to claim 48, wherein the effective amount is administered as a once-weekly dose.

50. A method of treating obesity, comprising administering to a human in need thereof an effective amount of the pharmaceutical composition according to any one of claims 1 to 45.

51. The method of treating obesity according to claim 50, wherein the effective amount is administered using an auto-injector device.

52. The method of treating obesity according to claim 50 or 51, wherein the effective amount is administered as a once-weekly dose.

53. The pharmaceutical composition according to any one of claims 1 to 45 for use in the treatment of T2D.

54. The pharmaceutical composition according to any one of claims 1 to 45 for use in the treatment of obesity.

55. A method for chronic weight management in a subject in need of additional weight management, wherein the subject has obesity, identifying a subject having obesity and in need of additional weight management, administering to the subject at least 15 mg of tirlpazide or a pharmaceutically acceptable salt thereof once a week for at least 4 weeks, after administering at least 15 mg of tirlpazide or a pharmaceutically acceptable salt thereof once a week for at least 4 weeks, administering once a week a dose of tirlpazide or a pharmaceutically acceptable salt thereof that is 5 mg more than the last dose, comprising a method wherein the maximum once-a-week dose of tirlpazide or a pharmaceutically acceptable salt thereof is 25 mg.

56. The method for chronic weight management according to claim 55, wherein at least one of the once-a-week doses of tirlpazide or a pharmaceutically acceptable salt thereof is 20 mg.

57. administering to the subject 20 mg of tirlpazide or a pharmaceutically acceptable salt thereof once a week for at least 4 weeks, after administering 20 mg of tirlpazide or a pharmaceutically acceptable salt thereof once a week for at least 4 weeks, administering 25 mg of tirlpazide or a pharmaceutically acceptable salt thereof once a week, comprising the method for chronic weight management according to any one of claims 55 or 56.

58. The method according to any one of claims 55 to 57, wherein tirlpazide is the free base.

59. A method for chronic weight management in a subject in need of additional weight management, identifying a subject in need of additional weight management, administering to the subject 15 mg of tirlpazide or a pharmaceutically acceptable salt thereof once a week, after at least 1 week, administering to the subject 20 mg of tirlpazide or a pharmaceutically acceptable salt thereof once a week for at least 2 weeks, after administering 20 mg of tirlpazide or a pharmaceutically acceptable salt thereof once a week for at least 2 weeks, administering 25 mg of tirlpazide or a pharmaceutically acceptable salt thereof once a week, comprising a method.

60. The method according to claim 59, wherein 20 mg of tirlpazide or a pharmaceutically acceptable salt thereof is administered once a week for at least 4 weeks.

61. The method according to any one of claims 59 or 60, wherein 15 mg of tirlpazide is administered once a week for at least 4 weeks.

62. The method according to any one of claims 59 to 61, wherein the tirzepatide is a free base.

63. A method for chronic weight management in a subject in need of additional weight management, comprising: identifying a subject in need of additional weight management; administering to the subject at least 20 mg of tirzepatide or a pharmaceutically acceptable salt thereof once a week for at least 2 weeks; after administering at least 20 mg of tirzepatide or a pharmaceutically acceptable salt thereof once a week for at least 2 weeks, administering to the subject 25 mg of tirzepatide or a pharmaceutically acceptable salt thereof once a week.

64. The method according to claim 63, wherein 20 mg of tirzepatide or a pharmaceutically acceptable salt thereof is administered once a week without prior administration of a 17.5 mg tirzepatide dose once a week.

65. The method according to any one of claims 63 or 64, wherein 25 mg of tirzepatide or a pharmaceutically acceptable salt thereof is administered once a week without prior administration of a 22.5 mg tirzepatide dose once a week.

66. The method according to any one of claims 63 to 65, wherein 20 mg of tirzepatide or a pharmaceutically acceptable salt thereof is administered at least 4 weeks once a week.

67. A method for chronic weight management in a subject in need of chronic weight management, comprising administering a tirzepatide or a pharmaceutically acceptable salt thereof selected from the group consisting of 20 mg and 25 mg of tirzepatide or a pharmaceutically acceptable salt thereof as a subcutaneous dose once a week.

68. A method for chronic weight management in a pediatric patient in need of chronic weight management, comprising administering at least 4 weeks 1.25 mg of tirzepatide or a pharmaceutically acceptable salt thereof once a week.

69. A method for chronic weight management in a subject with an initial body mass index (BMI) of 27 kg / m ２ or less, wherein the subject has at least one weight-related co-morbidity, the method comprising administering once a week a tirzepatide selected from the group consisting of 20 mg of tirzepatide or a pharmaceutically acceptable salt thereof and 25 mg of tirzepatide or a pharmaceutically acceptable salt thereof.

70. The method according to claim 69, wherein 20 mg of tirzepatide or a pharmaceutically acceptable salt thereof is administered once a week.

71. The method according to claim 69 or 70, wherein 25 mg of tirzepatide or a pharmaceutically acceptable salt thereof is administered once a week.

72. The method according to any one of claims 69 to 71, wherein the tirzepatide or a pharmaceutically acceptable salt thereof is administered subcutaneously.

73. The method according to any one of claims 69 to 72, wherein the tirzepatide is a free base.

74. A method in a subject in need of treatment for obesity, wherein the subject in need of treatment is a pediatric subject, and the method comprises administering to the subject 1.25 mg of tildesepatide or a pharmaceutically acceptable salt thereof once a week for at least 4 weeks.

75. A method in a subject in need of treatment for type 2 diabetes, wherein the subject in need of treatment is a pediatric subject, and the method comprises administering to the subject 1.25 mg of tildesepatide or a pharmaceutically acceptable salt thereof once a week for at least 4 weeks.

76. A method for a subject in need of additional weight management, wherein the subject has a BMI ≥ 27 kg / ２ and has at least one weight-related co-morbidity, Administering to the subject 2.5 mg of tildesepatide or a pharmaceutically acceptable salt thereof once a week for at least 4 weeks; After 4 weeks, increasing the once-weekly dose of the tildesepatide or a pharmaceutically acceptable salt thereof to 5 mg; After at least 4 weeks at the current dose, increasing the dose by 2.5 mg increments; In the case where additional weight management is required after at least 4 weeks with 15 mg of tildesepatide or a pharmaceutically acceptable salt thereof once a week, After at least 4 weeks at the current dose, increasing the dose by 5.0 mg increments; and The maximum dose is 25 mg of tildesepatide or a pharmaceutically acceptable salt thereof subcutaneously once a week.

77. The method according to claim 76, wherein the maximum dose required for weight management is 20 mg of tildesepatide or a pharmaceutically acceptable salt thereof once a week.

78. The method according to any one of claims 76 and 77, wherein administration of 20 mg of tildesepatide or a pharmaceutically acceptable salt thereof once a week results in a greater weight loss than administration of 15 mg of tildesepatide or a pharmaceutically acceptable salt thereof once a week.

79. The method according to any one of claims 76 to 78, wherein the maximum dose required for weight management is 25 mg of tildesepatide or a pharmaceutically acceptable salt thereof once a week.

80. The method according to any one of claims 76 to 79, wherein administration of 25 mg of tildesepatide or a pharmaceutically acceptable salt thereof once a week results in a greater weight loss than administration of 15 mg of tildesepatide or a pharmaceutically acceptable salt thereof once a week.

81. The method according to any one of claims 76 to 80, wherein when further weight loss is required, the administration is repeated by increasing the current dose of tildesepatide or a pharmaceutically acceptable salt thereof by 5.0 mg increments after 4 weeks.

82. The method according to any one of claims 76 to 81, wherein when further blood glucose control is required in the subject, the current dose of tildepazide or a pharmaceutically acceptable salt thereof is increased by 5.0 mg after 4 weeks and the administration is repeated.

83. The method according to any one of claims 76 to 82, wherein tildepazide is the free base.

84. The method in a subject in need of additional weight management, wherein the subject is obese, administering to the subject at least 4 weeks a dose of 2.5 mg of tildepazide or a pharmaceutically acceptable salt thereof once a week; after 4 weeks, increasing the once-a-week dose of the tildepazide or a pharmaceutically acceptable salt thereof to 5 mg; increasing the dose by 2.5 mg increments after at least 4 weeks at the current dose; if additional weight management is required after at least 4 weeks with 15 mg of tildepazide or a pharmaceutically acceptable salt thereof once a week, increasing the dose by 5.0 mg increments after at least 4 weeks at the current dose, comprising: The method, wherein the maximum dose is 25 mg of tildepazide or a pharmaceutically acceptable salt thereof subcutaneously once a week.

85. The method according to claim 84, wherein the maximum dose required for weight management is 20 mg of tildepazide or a pharmaceutically acceptable salt thereof once a week.

86. The method according to any one of claims 84 or 85, wherein administration of 20 mg of tildepazide or a pharmaceutically acceptable salt thereof once a week results in a greater weight loss than administration of 15 mg of tildepazide or a pharmaceutically acceptable salt thereof once a week.

87. The method according to any one of claims 84 to 86, wherein the maximum dose required for chronic weight management is 25 mg of tildepazide or a pharmaceutically acceptable salt thereof once a week.

88. The method according to any one of claims 84 to 87, wherein administration of 25 mg of tildepazide or a pharmaceutically acceptable salt thereof once a week results in a greater weight loss than administration of 15 mg of tildepazide or a pharmaceutically acceptable salt thereof once a week.

89. The method according to any one of claims 84 to 88, wherein when additional weight loss is required, the current dose of tildepazide or a pharmaceutically acceptable salt thereof is increased by 5.0 mg increments after 4 weeks and the administration is repeated.

90. The method according to any one of claims 84 to 89, wherein when further glycemic control is required in the subject, the administration is repeated by increasing the current dose of tildepazide or a pharmaceutically acceptable salt thereof by 5.0 mg after 4 weeks.

91. The method according to any one of claims 84 to 90, wherein tildepazide is the free base.

92. The method for a subject in need of further glycemic control, wherein the subject has type 2 diabetes, administering to the subject at least 4 weeks a dose of 2.5 mg of tildepazide or a pharmaceutically acceptable salt thereof once a week; after 4 weeks, increasing the once-a-week dose of the tildepazide or a pharmaceutically acceptable salt thereof to 5 mg; increasing the dose by 2.5 mg increments after at least 4 weeks at the current dose; if further glycemic control is required after at least 4 weeks with a dose of 15 mg of tildepazide or a pharmaceutically acceptable salt thereof once a week, increasing the dose by 5.0 mg increments after at least 4 weeks at the current dose, comprising: The method, wherein the maximum dose is 25 mg of tildepazide or a pharmaceutically acceptable salt thereof subcutaneously once a week.

93. The method according to claim 92, wherein the maximum dose required for further glycemic control is 20 mg of tildepazide or a pharmaceutically acceptable salt thereof once a week.

94. The method according to any one of claims 92 or 93, wherein administration of 20 mg of tildepazide or a pharmaceutically acceptable salt thereof once a week provides better glycemic control than administration of 15 mg of tildepazide or a pharmaceutically acceptable salt thereof once a week.

95. The method according to any one of claims 92 to 94, wherein the maximum dose required for glycemic control is 25 mg of tildepazide or a pharmaceutically acceptable salt thereof once a week.

96. The method according to any one of claims 92 to 95, wherein when additional weight loss is required in the subject, the administration is repeated by increasing the current dose of tildepazide or a pharmaceutically acceptable salt thereof by 5.0 mg after 4 weeks.

97. The method according to any one of claims 92 to 96, wherein when further glycemic control is required in the subject, the administration is repeated by increasing the current dose of tildepazide or a pharmaceutically acceptable salt thereof by 5.0 mg after 4 weeks.

98. The method according to any one of claims 92 to 97, wherein the chilzepide is a free base.

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