Semeglutide for drug therapy

Abstract

The present invention relates to semeglutide for use in drug therapy in the form of weight management, including the treatment of obesity.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application date of October 10, 2018, application number 201880066425.9, and invention name “Semaglutide for drug treatment”.

[0002] The present invention relates to semaglutide for use in medical therapy as a form of weight management, including the treatment of obesity. background

[0004] Weight management, including the treatment of obesity, remains a challenge for many people. Recently approved drug treatments include It is the GLP-1 receptor agonist (GLP-1RA) liraglutide, approved for long-term weight management in people who are obese or overweight with at least one weight-related comorbid condition. The most common adverse events of GLP-1RA are gastrointestinal disturbances, especially nausea. There is still a need for improved drug treatments for weight management. Summary of the invention

[0005] In some embodiments, the present invention relates to a method for weight management of a subject in need thereof, wherein semaglutide is administered to the subject in an amount of 2.0-4.0 mg once a week. In some embodiments, the present invention relates to a method for weight management of a subject in need thereof, wherein semaglutide is administered to the subject in an amount of 2.2-2.7 mg per week.

[0006] Description of the invention

[0007] The inventors surprisingly found that semaglutide can be administered at high doses, such as 2.0-4.0 mg once a week, while achieving improved weight loss due to the unexpectedly beneficial ratio between the effect of semaglutide on weight loss and the safety profile observed at these high doses of semaglutide. The inventors were also surprised to find that the effect of semaglutide on weight loss continued to be improved by high doses of 0.3 mg or even 0.4 mg once a day. The inventors were also surprised to find that at these high doses, the increase in the safety profile, including gastrointestinal adverse events, was surprisingly lower than the improvement in weight loss. This was confirmed in the experimental part, where the change in the number of reported gastrointestinal adverse events was lower than the change in weight loss for high doses of 0.3 and 0.4 mg once a day. To our knowledge, there is no publication describing the relationship between weight loss and the safety profile of GLP-1 receptor agonists in a population of obese human subjects who do not suffer from type 2 diabetes, except for liraglutide, which is also discussed in this article.

[0008] The term "safety profile" as used herein refers to the adverse reactions of the administered drug or other substances, and includes gastrointestinal adverse events, such as nausea. In some embodiments, the term "increase in safety profile" as used herein refers to an increase in safety events, such as an increase in gastrointestinal adverse events. In some embodiments, the method of the present invention provides acceptable tolerability while improving treatment, such as improved weight management in the form of enhanced weight loss. In some embodiments, the term "safety profile" as used herein refers to tolerability. The term "gastrointestinal adverse events" as used herein refers to symptoms of gastrointestinal disorders of the system organ class defined by MedDRA classification (e.g., version 19.1). In some embodiments, "gastrointestinal adverse events" as used herein refers to symptoms selected from nausea, vomiting, diarrhea and constipation. In some embodiments, "gastrointestinal adverse events" as used herein refers to nausea.

[0009] In some embodiments, the present invention relates to a method for weight management of a subject in need thereof, wherein semaglutide is administered to the subject in an amount of 2.0-4.0 mg once a week. In some embodiments, the present invention relates to a method for weight management of a subject in need thereof, wherein semaglutide is administered to the subject in an amount of 2.2-2.7 mg per week.

[0010] In some embodiments, the methods of the invention provide improved weight loss, which is also relatively higher than the increase in gastrointestinal adverse events (such as nausea), especially at a dose of 0.3-0.4 mg of gosemaglutide per day (such as 2.2-2.7 mg per week or 2.0-4.0 mg once a week). In other words, in some embodiments, the methods of the invention provide an improved ratio between weight loss and gastrointestinal adverse events.

[0011] In some embodiments, the present invention relates to a method for treating type 2 diabetes in a subject in need thereof, wherein semaglutide is administered to the subject in an amount of 2.0-4.0 mg once a week. In some embodiments, the present invention relates to a method for treating type 2 diabetes in a subject in need thereof, wherein semaglutide is administered to the subject in an amount of 2.2-2.7 mg per week.

[0012] Semaglutide

[0013] The GLP-1RA semaglutide can be prepared as described in Example 4 of WO2006 / 097537. Semaglutide is also known as N 6.26-{18-[N-(17-carboxyheptadecanyl)-L-γ-glutamyl]-10-oxo-3,6,12,15-tetraoxa-9,18-diazaoctadecanoyl}-[8-(2-amino-2-propionic acid), 34-L-arginine] human glucagon-like peptide 1 (7-37), see WHO Drug Information Vol.24, No.1, 2010.

[0014] Application

[0015] In some embodiments, semaglutide is administered by injection. In some embodiments, semaglutide is administered subcutaneously, for example, by subcutaneous injection.

[0016] In some embodiments, the amount of semaglutide administered weekly is 2.2-2.7 mg. In some embodiments, the amount of semaglutide administered weekly is selected from 2.2-2.7 mg, 2.2-2.6 mg, and 2.3-2.5 mg. In some embodiments, the amount of semaglutide administered weekly is selected from 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, and 2.7 mg.

[0017] In some embodiments, semaglutide is administered once daily or once weekly.

[0018] In some embodiments, semaglutide is administered once a day in an amount selected from 0.32-0.37 mg, 0.32-0.36 mg, and 0.33-0.35 mg once a day. In some embodiments, semaglutide is administered once a day in an amount selected from 0.32 mg, 0.33 mg, 0.34 mg, 0.35 mg, 0.36 mg, 0.37 mg, and 0.37 mg once a day.

[0019] In some embodiments, semaglutide is administered once a week in an amount selected from 2.0-10.0 mg once a week. In some embodiments, semaglutide is administered once a week in an amount selected from 2.0-4.0 mg once a week. In some embodiments, semaglutide is administered once a week in an amount selected from 2.1-3.8 mg, 2.2-3.6 mg, and 2.3-3.4 mg. In some embodiments, semaglutide is administered once a week in an amount selected from 2.4-3.2 mg, 2.2-3.0 mg, and 2.0-2.8 mg. In some embodiments, semaglutide is administered once a week in an amount selected from 2.4-3.0 mg, 2.2-2.9 mg, and 2.0-2.8 mg. In some embodiments, semaglutide is administered once a week in an amount selected from 2.4-2.7 mg, 2.2-2.6 mg, and 2.0-2.5 mg. In some embodiments, semaglutide is administered once a week in an amount selected from about 2.2 mg, about 2.3 mg, or about 2.4 mg. In some embodiments, semaglutide is administered once a week in an amount selected from about 2.5 mg, about 2.6 mg, and about 2.7 mg.

[0020] In some embodiments, the drug substance administered according to the methods of the present invention consists of semaglutide.

[0021] Indications

[0022] In some embodiments, the present invention relates to a method of weight management. In some embodiments, the weight management is long-term weight management. In some embodiments, the weight management is selected from: weight loss, treatment and / or prevention of obesity, treatment and / or prevention of overweight and prevention of weight gain. In some embodiments, the present invention relates to a method of weight loss. In some embodiments, the present invention relates to a method of treating and / or preventing obesity. In some embodiments, the present invention relates to a method of treating and / or preventing overweight. In some embodiments, the present invention relates to a method of preventing weight gain. The term "overweight" as used herein refers to a condition in which the subject's BMI is at least 27, such as at least 27 to less than 30, including any number therebetween. The term "obesity" as used herein refers to a condition in which the subject's BMI is at least 30, such as at least 30 to less than 35, at least 35 to less than 40, or at least 40, including any number between 30 and 40. The term "BMI" as used herein refers to the subject's weight (in kilograms) divided by the square of the subject's height (in meters); the unit of BMI is kg / m 2 .

[0023] In some embodiments, the methods of the present invention provide improved weight loss due to the unexpectedly beneficial ratio between the effects of semaglutide on weight loss and gastrointestinal adverse events such as nausea. In some embodiments, the methods of the present invention reduce gastrointestinal adverse events in the subject. In some embodiments, the methods of the present invention reduce gastrointestinal adverse events in the form of nausea in the subject. In some embodiments, the term "reducing gastrointestinal adverse events" as used herein refers to fewer gastrointestinal adverse events occurring, for example compared to other doses of semaglutide.

[0024] In some embodiments, the subject of the method of the present invention is a human. In some embodiments, the subject of the method of the present invention is an adult. In some embodiments, the subject of the method of the present invention is a child (e.g., 2-11 years old). In some embodiments, the subject of the method of the present invention is a teenager (e.g., 12 years old to less than 18 years old, such as 12 to 16 years old or 12 years old to less than 16 years old). In some embodiments, the subject of the method of the present invention suffers from type 2 diabetes. In some embodiments, the subject treated according to the method of the present invention is obese (e.g., BMI ≥ 30, or as defined herein with respect to the term "obesity") or overweight (e.g., BMI ≥ 27 and BMI < 30, or as defined herein with respect to the term "overweight"). In some embodiments, the subject in the method of the present invention has at least one comorbid condition associated with weight (e.g., hypertension, type 2 diabetes, or dyslipidemia). In some embodiments, the subject of the method of the present invention has sleep apnea and / or urinary incontinence. In some embodiments, the subject in the method of the present invention has at least one comorbid condition associated with weight selected from hypertension, type 2 diabetes, dyslipidemia, sleep apnea, and urinary incontinence.

[0025] Pharmaceutical composition

[0026] In some embodiments, semaglutide is administered in the form of a pharmaceutical composition, which further comprises one or more pharmaceutically acceptable excipients, such as excipients selected from buffers, isotonic agents and preservatives. The terms "pharmaceutical composition" and "composition" are used interchangeably herein and refer to pharmaceutical compositions. In some embodiments, the composition is in the form of a solution or suspension such as an aqueous solution. In some embodiments, the pH of the composition is in the range of 6.0-10.0, such as 6.5-9.0 or 7.0-8.0. In some embodiments, the pH of the composition is in the range of 7.1-7.8, such as 7.2-7.6 or 7.3-7.5. In some embodiments, the pH of the composition is about 7.4. In some embodiments, the concentration of semaglutide in the composition is 0.01-50 mg / ml, such as 0.05-20 mg / ml or 0.1-10 mg / ml. In some embodiments, the concentration of semaglutide in the composition is 0.01-5 mg / ml, such as 0.05-2 mg / ml. In some embodiments, the composition comprises a buffer, such as a phosphate buffer. In some embodiments, the composition comprises an isotonic agent, such as propylene glycol. In some embodiments, the composition comprises a preservative, such as phenol. In some embodiments, the bulk drug in the composition is composed of semaglutide. In some embodiments, semaglutide is administered in the form of an aqueous composition (pH 7.4) comprising 4.1 mg / ml semaglutide, phosphate buffer, propylene glycol, and phenol as a preservative. In some embodiments, semaglutide is administered in the form of an aqueous composition (pH 7.4) comprising 4.1 mg / ml semaglutide, 1.42 mg / ml sodium hydrogen phosphate dihydrate, 14.0 mg / ml propylene glycol, and 5.50 mg / ml phenol. In some embodiments, hydrochloric acid and / or sodium hydroxide are used to adjust the pH of the composition.

[0027] In some embodiments, the term "a" means "one (kind) or more (kind)". In some embodiments, the specific value mentioned herein and given with respect to a number or interval can be understood as that specific value or about that specific value. In some embodiments, the term "about" refers to the value mentioned ± 10%. In some embodiments, the terms presented in the singular also include plural cases.

[0028] Embodiments of the present invention

[0029] Non-limiting embodiments of the present invention include:

[0030] 1. A method for weight management in a subject in need thereof, wherein semaglutide is administered to the subject in an amount of 2.0-4.0 mg once a week.

[0031] 2. A method for weight management in a subject in need thereof, wherein semaglutide is administered to the subject in an amount of 2.2-2.7 mg per week.

[0032] 3. The method according to any one of the preceding embodiments, wherein the method reduces gastrointestinal adverse events in the subject.

[0033] 4. The method according to the preceding embodiment, wherein said method reduces gastrointestinal adverse events in the form of nausea in said subject.

[0034] 5. The method according to any one of the preceding embodiments, wherein the weight management is long-term weight management.

[0035] 6. The method according to any one of the preceding embodiments, wherein the weight management is selected from:

[0036] a. Lose weight,

[0037] b. treatment and / or prevention of obesity,

[0038] c. Treating and / or preventing overweight, and

[0039] d. Prevent weight gain.

[0040] 7. The method according to any one of the preceding embodiments, wherein the amount of semaglutide administered per week is selected from 2.2-2.7 mg, 2.2-2.6 mg and 2.3-2.5 mg.

[0041] 8. The method according to any one of the preceding embodiments, wherein the amount of semaglutide administered weekly is selected from 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg and 2.7 mg.

[0042] 9. The method according to any one of the preceding embodiments, wherein the administration is once a day or once a week.

[0043] 10. The method according to any one of the preceding embodiments, wherein the semaglutide is administered once daily in an amount selected from 0.32-0.37 mg, 0.32-0.36 mg and 0.33-0.35 mg once daily.

[0044] 11. The method according to any one of the preceding embodiments, wherein the semaglutide is administered once daily in an amount selected from 0.32 mg, 0.33 mg, 0.34 mg, 0.35 mg, 0.36 mg, 0.37 mg and 0.37 mg once daily.

[0045] 12. The method according to any one of the preceding embodiments, wherein semaglutide is administered once a week in an amount selected from 2.1-3.8 mg, 2.2-3.6 mg and 2.3-3.4 mg.

[0046] 13. The method according to any one of the preceding embodiments, wherein semaglutide is administered once a week in an amount selected from 2.4-3.2 mg, 2.2-3.0 mg and 2.0-2.8 mg.

[0047] 14. The method according to any one of the preceding embodiments, wherein the semaglutide is administered once a week in an amount selected from 2.4-3.0 mg, 2.2-2.9 mg and 2.0-2.8 mg.

[0048] 15. The method according to any one of the preceding embodiments, wherein the semaglutide is administered once a week in an amount selected from 2.4-2.7 mg, 2.2-2.6 mg and 2.0-2.5 mg.

[0049] 16. The method according to any one of the preceding embodiments, wherein semaglutide is administered once a week in an amount selected from 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg and 2.7 mg.

[0050] 17. The method according to any one of the preceding embodiments, wherein the subject is obese (BMI ≥ 30) or overweight (BMI ≥ 27).

[0051] 18. The method according to the preceding embodiment, wherein the subject has at least one comorbid condition related to weight (such as hypertension, type 2 diabetes or dyslipidemia).

[0052] 19. The method according to any one of the preceding embodiments, wherein the semaglutide is administered subcutaneously, such as by subcutaneous injection.

[0053] 20. The method according to any one of the preceding embodiments, wherein semaglutide is administered in the form of a composition further comprising one or more pharmaceutically acceptable excipients.

[0054] 21. The method according to any one of the preceding embodiments, wherein the composition is in the form of a solution or a suspension, such as an aqueous solution.

[0055] 22. The method according to any one of the preceding embodiments, wherein the pH of the composition is in the range of 6.0-10.0, such as 6.5-9.0 or 7.0-8.0.

[0056] 23. The method according to any one of the preceding embodiments, wherein the pH of the composition is about 7.4.

[0057] 24. The method according to any one of the preceding embodiments, wherein the pharmaceutically acceptable excipients comprise one or more excipients selected from isotonicity agents, buffers and preservatives.

[0058] 25. The method according to any one of the preceding embodiments, wherein the concentration of semaglutide in the composition is 0.01-50 mg / ml, such as 0.05-20 mg / ml or 0.1-10 mg / ml.

[0059] 26. The method according to any one of the preceding embodiments, wherein the concentration of semaglutide in the composition is 0.01-5 mg / ml, such as 0.05-2 mg / ml.

[0060] 27. The method according to any one of the preceding embodiments, wherein the drug substance administered consists of semaglutide.

[0061] 28. The method according to any one of the preceding embodiments, wherein the subject is a human.

[0062] 29. A method according to any one of the preceding embodiments, wherein the subject is an adult, an adolescent or a child.

[0063] 30. The method according to any one of the preceding embodiments, wherein the subject suffers from type 2 diabetes. Example

[0064] Example 1: Semaglutide in obese subjects

[0065] A clinical trial was conducted to evaluate and compare the dose-response of once-daily semaglutide for five doses with once-daily liraglutide 3.0 mg and / or placebo in inducing and maintaining weight loss after 52 weeks in obese subjects without diabetes. The trial was designed as a 52-week randomized, double-blind, placebo-controlled, sixteen-group, parallel-group, multicenter, multinational trial that compared once-daily subcutaneous administration of semaglutide with placebo at five different doses (ranging from 0.05 mg / day to 0.4 mg / day) in obese subjects without diabetes. 3.0 mg / day of liraglutide was included as an active comparator. The trial was double-blind between active treatment and placebo treatment. In order to ensure that there were enough male samples, more than 70% of the trial population was not allowed to be female, and randomization was stratified according to gender. Subjects were randomized in a balanced manner (6:1 active treatment: placebo).

[0066] The primary endpoint was the relative change (%) in body weight from baseline at week 52. Key secondary endpoints included the proportion of subjects with a weight loss greater than or equal to 5% or 10% of baseline body weight at week 52 and the change in body weight from baseline to week 52. Supportive secondary safety endpoints also included gastrointestinal (GI) adverse events (i.e., nausea, vomiting, diarrhea, and constipation). During each site visit, individual subjects were asked via open-ended questions whether they had experienced any medical problems since the last visit. All medical problems observed by site staff or subjects were reported as adverse events, and the severity and causality of the adverse event were evaluated by the investigator. For this trial, subjects had site visits every 2 weeks for the first 20 weeks of the trial and then every 4 weeks.

[0067] The treatment groups were: (A) semaglutide, with a randomized target dose of 0.05, 0.1, 0.2, 0.3, or 0.4 mg (dose escalation every four weeks for dose levels above 0.05 mg); (B) semaglutide, with a randomized target dose of 0.3 or 0.4 mg (starting dose of 0.05 mg, with dose escalation every two weeks); (C) liraglutide 3.0 mg (starting dose of 0.6 mg, with dose escalation every week); and (D) placebo (matched to each active treatment group); all were administered by subcutaneous injection. Starting from the randomization visit, subjects in all treatment groups, including placebo, received monthly nutritional counseling and a reduced-calorie diet provided by a dietitian or equivalent qualified representative, and physical activity counseling provided by qualified personnel. A total of 957 subjects were randomized. A total of 777 subjects (81.2%) completed 52 weeks of treatment; 180 (18.8%) discontinued treatment early, with no clear dose-dependent trend. Key inclusion criteria for the trial were: male or female, aged ≥18 years at the time of informed consent; body mass index (BMI) ≥30.0 ​​kg / m at screening 2; and at least one unsuccessful attempt to lose weight, as determined by the investigator. Key exclusion criteria for the trial were: HbA1c ≥ 6.5% or diagnosed with type 1 or type 2 diabetes at screening; treatment with glucose-lowering medications within 90 days before screening; calcitonin ≥ 50 ng / L (pg / mL) at screening; personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2; history of pancreatitis (acute or chronic); obesity induced by endocrine disorders (e.g., Cushing's syndrome); treatment with any medication within 90 days before screening that, as determined by the investigator, could result in significant weight change; previous surgical treatment for obesity (liposuction and / or abdominoplasty performed more than 1 year before screening was permitted); history of major depressive disorder within 2 years before randomization; any history of suicide attempts in a lifetime; and women who were pregnant, breastfeeding, or attempting to become pregnant or of childbearing potential but not using adequate contraception (appropriate contraception as required by local regulations or practices).

[0068] Statistical analysis of efficacy endpoints: The primary analysis was based on the “jump-to-reference” multiple imputation method (J2R-MI). The week 52 data from subjects who discontinued the trial product but returned for a visit at week 52 were included in the analysis. First, the imputation model was estimated using only the week 52 weight (kg) measurements observed from the placebo group. Second, multiple copies (1000) of the full analysis set were generated by imputing missing values ​​in all treatment groups from the imputation model. The primary endpoint was calculated in each complete data set and analyzed using an analysis of covariance (ANCOVA) model. Third, the Rubin formula was used to summarize the 1000 analysis results. The analysis model provided pairwise treatment differences (95% confidence intervals [CI]) between semaglutide and placebo, between liraglutide 3.0 mg and placebo, between different semaglutide doses, and between semaglutide and liraglutide 3.0 mg at week 52. This multiple imputation approach allowed for the assumption that placebo-group subjects who were missing week 52 end-point data had responded similarly to placebo completers and that active-treatment subjects who were missing week 52 end-point data were in the placebo group throughout the trial, regardless of the time of discontinuation.

[0069] The baseline characteristics of the subjects, weight and body mass index (BMI), are shown in Table 1. The results are shown in Tables 2-6 herein.

[0070] Table 1: Baseline characteristics of subjects in each treatment group, expressed as mean (SD)

[0071] N Weight(kg) <![CDATA[BMI(kg / m 2 )]]> Sema 0.5mg 103 111(23.2) 39.1(6.5) Sema 0.1mg 102 111(21.5) 39.6(7.4) Sema 0.2mg 103 114(24.5) 40.1(7.0) Sema 0.3mg 103 112(23.0) 39.6(7.1) Sema 0.4mg 102 113(26.4) 39.9(8.8) Lira 3.0mg 103 109(21.9) 38.6(6.6) Placebo pool 136 114(25.4) 40.1(7.2)

[0072] N: number of subjects, Lira: liraglutide, Sema: semaglutide, SD: standard deviation.

[0073] Table 2: Weight Change (%) from Baseline to Week 52 by Treatment Group - Descriptive Statistics - Observed Data - Full Analysis Set

[0074]

[0075]

[0076] N: number of subjects, SD: standard deviation, on-treatment subjects: subjects who completed treatment until the end of the trial, in-trial subjects: subjects who completed treatment and subjects who discontinued treatment before the end of the trial but visited the clinic at week 52.

[0077] Table 3: Body weight change (%) from baseline to week 52 and treatment differences by treatment group - Primary statistical analysis - ANCOVA-J2R-MI - Full analysis set

[0078]

[0079] Sema: semaglutide, Lira: liraglutide, Placebo pool: Placebo subjects in all treatment groups, * : Data are presented as "estimate [95% CI]", N: number of subjects contributing to the analysis, CI: confidence interval. J2R-MI: Analysis of data from trials where missing observations were imputed from the pooled placebo group based on multiple (x1000) imputation with jump-to-reference. Response at week 52 was analysed using an analysis of covariance model with treatment, region and sex as factors and baseline weight as a covariate. Treatment comparisons were not adjusted for multiple testing.

[0080] Table 4: Body Weight Change (%) from Baseline at Week 52 - Results from Emax Dose-Response Simulations - ANCOVA-J2R-MI - Full Analysis Set

[0081]

[0082] Lira: liraglutide, Sema: semaglutide, * : The dose-response coefficient was estimated by the Emax three-parameter model,

[0083] ** :based on%.

[0084] Table 5: Summary of Gastrointestinal Adverse Events in Subjects Who Completed Treatment - Observed Data and Results from Emax Dose-Response Simulations - Full Analysis Set

[0085]

[0086] Lira: liraglutide, Sema: semaglutide, N: number of subjects, N e : number of subjects who experienced at least one event, %: percentage of subjects with at least one event, * : The dose-response coefficient was estimated by the Emax three-parameter model, ** :based on%.

[0087] Table 6: Summary of Gastrointestinal Adverse Events in the Form of Nausea in Subjects Who Completed Treatment - Observed Data - Full Analysis Set

[0088] N <![CDATA[N e ]]> ％ E Sema 0.05mg 103 32 31.1 41 Sema 0.1mg 102 42 41.2 80 Sema 0.2mg 103 45 43.7 74 Sema 0.3mg 103 43 41.7 69 Sema 0.4mg 102 49 48.0 94 Lira 3.0mg 103 46 44.7 89 Placebo Pool 136 24 17.6 30

[0089] Lira: liraglutide, Sema: semaglutide, N: number of subjects, N e : number of subjects who experienced at least one event, %: percentage of subjects who experienced at least one event, E: number of events

[0090] Surprisingly, the results in Tables 2-4 show that the effect of semaglutide on weight loss is also continuously improved by high doses of 0.3 mg or even 0.4 mg once a day. The results in Tables 5-6 show that at these high doses, the increase in gastrointestinal adverse events is relatively low, and compared with, for example, Table 4, these increases are surprisingly relatively lower than the improvement in weight loss. Specifically, the results in Tables 4-5 show that the dose of semaglutide that provides the same weight loss as 3.0 mg liraglutide is 0.08 mg semaglutide (95% CI is [-0.02; 0.57]), while the dose of semaglutide that provides the same level of gastrointestinal adverse events as 3.0 mg liraglutide is 0.28 mg semaglutide (95% CI is [-0.02; 0.57]); therefore, at the same level of gastrointestinal adverse events, semaglutide provides about 3 times the weight loss (about 3 times is calculated as (3.0 / 0.08) / (3.0 / 0.28)). In conclusion, these results suggest that semaglutide products for weight management may be administered at high doses, resulting in improved weight loss, given this unexpectedly favorable ratio between weight loss and gastrointestinal adverse events. Even more surprising, the ratio between weight loss and gastrointestinal adverse events was improved at the highest semaglutide dose of 0.3 mg and even 0.4 mg once daily compared with lower doses.

[0091] Example 2: Semaglutide in subjects with type 2 diabetes

[0092] For patients with T2D and HbA 1c7.0–10.0% (53–86 mmol / mol) and body mass index 24.0–40.0 kg / m 2 A 26-week, randomized, double-blind clinical trial was conducted in adult patients treated with diet and exercise ± metformin. Patients were randomized 2:2:1 to receive semaglutide, placebo, or liraglutide once daily by subcutaneous injection at one of four volume-matched doses (semaglutide: 0.05, 0.1, 0.2, 0.3 mg; liraglutide: 0.3, 0.6, 1.2, 1.8 mg). The primary endpoint was HbA from baseline to week 26. 1c The key exclusion criteria were a history of chronic or idiopathic acute pancreatitis and moderate to severe renal impairment (estimated glomerular filtration rate <60 mL / min / 1.73 m 2 ).

[0093] Trial Drug Administration: After a 2-week screening period, patients received trial drug for 26 weeks, followed by a 7-week follow-up period. Patients began treatment with 0.05 mg semaglutide, 0.3 mg liraglutide, or 50 μL placebo, all administered subcutaneously once daily, and were titrated every 4 weeks to their final randomized dose. This titration algorithm was used in all patients to ensure blinding to all products, so the escalation rate of liraglutide was slower than recommended in the label. Because treatments were volume-matched, the trial was double-blind within (but not between) each dose level of semaglutide, liraglutide, and placebo.

[0094] Table 7 shows the baseline characteristics of the subjects' weight and body mass index (BMI). The results of weight change and gastrointestinal adverse events are shown in Table 8.

[0095] Table 7: Baseline characteristics of subjects in each treatment group, expressed as mean (SD)

[0096]

[0097] n: number of subjects, Lira: liraglutide, Sema: semaglutide, SD: standard deviation

[0098] Table 8: Mean Weight Change from Baseline to Week 26 and Gastrointestinal Adverse Events, Including Nausea – Completion of Treatment – ​​Estimated Data

[0099]

[0100] Lira: liraglutide, Sema: semaglutide, N: number of subjects, N e: number of patients who experienced at least one event, %: percentage of patients who experienced at least one event, E: number of events. The "Completed Treatment" summary includes treatment-emergent adverse events with an onset on or after the first trial product dose date and before or on the last trial product dose date, plus 7 weeks plus a 7-day visit window for end-of-treatment follow-up (=56 days). The observation time is the duration of this period.

[0101] Surprisingly, the results in Table 8 show that the effect of semaglutide on weight loss is also consistently improved by the high dose of 0.3 mg once daily, and that at this high dose, the increase in gastrointestinal adverse events is relatively low and surprisingly relatively lower than the improvement in weight loss. In summary, these results therefore suggest that semaglutide products for weight management may be administered at high doses, resulting in improved weight loss, due to this unexpectedly good ratio between weight loss and gastrointestinal adverse events. Even more surprisingly, the ratio between weight loss and gastrointestinal adverse events was improved at the highest semaglutide dose of 0.3 mg once daily compared to lower doses.

[0102] Table 9: Changes in HbA1c (glycosylated hemoglobin)

[0103] N Mean change in HbA1c% (SD) Sema 0.05mg 64 -0.97(0.85) Sema 0.1mg 63 -1.30(1.03) Sema 0.2mg 65 -1.65(0.79) Sema 0.3mg 63 -1.96(0.95) Lira 0.3mg 64 -0.50(0.93) Lira 0.6mg 64 -0.88(0.90) Lira 1.2mg 64 -0.86(0.92) Lira 1.8mg 65 -1.32(0.78) Combined placebo group 129 -0.05(0.90)

[0104] Lira: liraglutide, Sema: semaglutide, N: number of subjects, SD: standard deviation

[0105] Although certain features of the present invention have been illustrated and described herein, many modifications, substitutions, changes and equivalents will now occur to those skilled in the art. Therefore, it should be understood that the appended claims are intended to cover all such modifications and changes that fall within the true scope of the invention.

Claims

1. A method for weight management in a subject in need thereof, wherein a. 2.0-10.0 mg once a week; or b. 2.2-2.7 mg per week Semaglutide is administered to the subject.

2. The method according to any one of the preceding claims, wherein the weight management is long-term weight management.

3. The method according to any one of the preceding claims, wherein the weight management is selected from the group consisting of: reducing weight, treating and / or preventing obesity, treating and / or preventing overweight and preventing weight gain.

4. The method according to any one of the preceding claims, wherein the amount of semaglutide administered weekly is selected from 2.2-2.7 mg, 2.2-2.6 mg and 2.3-2.5 mg.

5. The method according to any one of the preceding claims, wherein the administration is once a day or once a week.

6. The method according to any one of the preceding claims, wherein semaglutide is administered to the subject in an amount of 2.0-10.0 mg once a week.

7. The method according to any one of the preceding claims, wherein the semaglutide is administered subcutaneously, such as by subcutaneous injection.

8. The method according to any one of the preceding claims, wherein semaglutide is administered in the form of a composition further comprising one or more pharmaceutically acceptable excipients.

9. A method according to any one of the preceding claims, wherein the composition is in the form of a solution or suspension, such as an aqueous solution.

10. A method according to any preceding claim, wherein the pH of the composition is in the range of 6.0-10.0, such as 6.5-9.0 or 7.0-8.

0.

11. The method of any one of the preceding claims, wherein the pH of the composition is about 7.

4.

12. The method according to any one of the preceding claims, wherein the concentration of semaglutide in the composition is 0.01-50 mg / ml, such as 0.05-20 mg / ml or 0.1-10 mg / ml.

13. The method according to any one of the preceding claims, wherein the concentration of semaglutide in the composition is 0.01-5 mg / ml, such as 0.05-2 mg / ml.

14. The method according to any one of the preceding claims, wherein the subject has at least one weight-related comorbid condition selected from hypertension, type 2 diabetes, dyslipidemia, sleep apnea, and urinary incontinence.

15. The method of any one of the preceding claims, wherein the subject suffers from type 2 diabetes.

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