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 a Chinese patent application with an application date of October 10, 2018, an application number of 201880066425.9, and an invention title of "Semaglutide for Pharmaceutical Treatment".

[0002] The present invention relates to semaglutide for pharmaceutical treatment, which is in the 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 pharmaceutical treatments include the GLP-1 receptor agonist (GLP-1RA) liraglutide, which is approved for long-term weight management in people with obesity or overweight with at least one weight-related comorbid condition. The most common adverse event of GLP-1RA is gastrointestinal disorders, especially nausea. There is still a need for improved pharmaceutical treatments for weight management. Summary of the Invention

[0005] In some embodiments, the present invention relates to 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. In some embodiments, the present invention relates to 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.

[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 unexpected beneficial ratio between the effect of semaglutide on weight loss and the safety profile observed with these high doses of semaglutide. The inventors also surprisingly found that the effect of semaglutide on weight loss continues to improve with high doses of 0.3 mg or even 0.4 mg once a day. The inventors also surprisingly found that at these high doses, the increase in the safety profile, including gastrointestinal adverse events, is surprisingly lower than the improvement in weight loss. This was confirmed in the experimental section, where for the high doses of 0.3 and 0.4 mg once a day, the change in the number of reported gastrointestinal adverse events was lower than the change in weight loss. To our knowledge, no publication has described the relationship between weight loss and the safety profile of GLP-1 receptor agonists in an obese human subject population without type 2 diabetes, other than liraglutide, which is also discussed herein.

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

[0009] In some embodiments, the present invention relates to 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. In some embodiments, the present invention relates to 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.

[0010] In some embodiments, the methods of the present invention provide improved weight loss, which is also relatively higher than the increase in gastrointestinal adverse events such as nausea, particularly at high semaglutide doses of 0.3 - 0.4 mg 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 present 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-Carboxyheptadecanoyl)-L-γ-glutamyl]-10-oxo-3,6,12,15-tetraoxa-9,18-diazaoctadecanoyl}-[8-(2-Amino-2-propanoic acid),34-L-arginine] Glucagon-like peptide 1(7-37) human, see WHO Drug Information Vol.24, No.1, 2010.

[0014] Administer

[0015] In some embodiments, semaglutide is administered by injection. In some embodiments, semaglutide is administered subcutaneously, such as 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 daily, and the dosage is selected from 0.32 - 0.37 mg once daily, 0.32 - 0.36 mg once daily, and 0.33 - 0.35 mg once daily. In some embodiments, semaglutide is administered once daily, and the dosage is 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.

[0019] In some embodiments, semaglutide is administered once a week, and the dosage is selected from 2.0 - 10.0 mg once a week. In some embodiments, semaglutide is administered once a week, and the dosage is selected from 2.0 - 4.0 mg once a week. In some embodiments, semaglutide is administered once a week, and the dosage is 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, and the dosage is 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, and the dosage is 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, and the dosage is 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, and the dosage is selected from approximately 2.2 mg, approximately 2.3 mg, or approximately 2.4 mg. In some embodiments, semaglutide is administered once a week, and the dosage is selected from approximately 2.5 mg, approximately 2.6 mg, and approximately 2.7 mg.

[0020] In some embodiments, the active pharmaceutical ingredient administered according to the method of the present invention consists of semaglutide.

[0021] Indications

[0022] In some embodiments, the present invention relates to a method for 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 for weight loss. In some embodiments, the present invention relates to a method for treatment and / or prevention of obesity. In some embodiments, the present invention relates to a method for treatment and / or prevention of overweight. In some embodiments, the present invention relates to a method for prevention of weight gain. As used herein, the term "overweight" refers to a condition in which the subject has a BMI of at least 27, such as at least 27 to less than 30, including any number therebetween. As used herein, the term "obesity" refers to a condition in which the subject has a BMI of 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. As used herein, the term "BMI" refers to the weight of the subject (in kilograms) divided by the square of the height of the subject (in meters); the unit of BMI is kg / m 2 2.

[0023] In some embodiments, due to the unexpected beneficial ratio between the weight loss effect of semaglutide and gastrointestinal adverse events such as nausea, the methods of the present invention provide improved weight loss. In some embodiments, the methods of the present invention reduce the gastrointestinal adverse events in the subject. In some embodiments, the methods of the present invention reduce the gastrointestinal adverse events in the form of nausea in the subject. In some embodiments, the term "reduce 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 an adolescent (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 has 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 for the term "obesity") or overweight (e.g., BMI ≥ 27 and BMI < 30, or as defined herein for the term "overweight"). In some embodiments, the subject in the method of the present invention has at least one weight-related comorbid condition (such as 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 weight-related comorbid condition selected from hypertension, type 2 diabetes, dyslipidemia, sleep apnea, and urinary incontinence.

[0025] Drug 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 a pharmaceutical composition. 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 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 active pharmaceutical ingredient in the composition consists 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 disodium hydrogen phosphate dihydrate, 14.0 mg / ml propylene glycol, and 5.50 mg / ml phenol. In some embodiments, the pH of the composition is adjusted using hydrochloric acid and / or sodium hydroxide.

[0027] In some embodiments, the term "a" means "one or more". In some embodiments, specific values mentioned herein and given with respect to numbers or intervals can be understood as that specific value or approximately that specific value. In some embodiments, the term "about" means the recited value ± 10%. In some embodiments, terms presented in the singular form also include the 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 the method reduces gastrointestinal adverse events in the form of nausea in the 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. Weight loss,

[0037] b. Treating and / or preventing obesity,

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

[0039] d. Preventing 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 per week 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 semaglutide is administered once a day, and the dosage is selected from 0.32 - 0.37 mg once a day, 0.32 - 0.36 mg once a day, and 0.33 - 0.35 mg once a day.

[0044] 11. The method according to any one of the preceding embodiments, wherein semaglutide is administered once a day, and the dosage is 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.

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

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

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

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

[0049] 16. A method according to any one of the foregoing embodiments, wherein the semaglutide is administered once a week, and the dosage is selected from 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, and 2.7 mg.

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

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

[0052] 19. A method according to any one of the foregoing embodiments, wherein the semaglutide is administered subcutaneously, for example, by subcutaneous injection.

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

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

[0055] 22. A method according to any one of the foregoing 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. A method according to any one of the foregoing embodiments, wherein the pH of the composition is about 7.4.

[0057] 24. A method according to any one of the foregoing embodiments, wherein the pharmaceutically acceptable excipients include one or more excipients selected from the group consisting of isotonic agents, buffers, and preservatives.

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

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

[0060] 27. A method according to any one of the foregoing embodiments, wherein the active pharmaceutical ingredient administered consists of semaglutide.

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

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

[0063] 30. A method according to any one of the foregoing embodiments, wherein the subject has type 2 diabetes. Examples

[0064] Example 1: Semaglutide in Obese Subjects

[0065] A clinical trial was conducted to evaluate and compare the dose - response of once - daily semaglutide at 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 - arm, parallel - group, multi - center, multinational trial that compared once - daily subcutaneous administration of semaglutide at five different doses (ranging from 0.05 mg / day to 0.4 mg / day) with placebo in obese subjects without diabetes. Liraglutide at 3.0 mg / day was included as an active comparator. The trial was double - blind between active treatment and placebo treatment. To ensure a sufficient number of male samples, no more than 70% of the trial population was allowed to be female, and randomization was stratified by gender. Subjects were randomized in a balanced manner (6:1 active treatment: placebo).

[0066] The primary endpoint was the relative change (%) in body weight at 52 weeks relative to baseline. Key secondary endpoints included the proportion of subjects with a weight loss of greater than or equal to 5% or 10% of baseline body weight at 52 weeks, and the change in body weight from baseline to 52 weeks. Supportive secondary safety endpoints also included gastrointestinal (GI) adverse events (i.e., nausea, vomiting, diarrhea, and constipation). During each in-person 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 the in-person staff or the subjects were reported as adverse events, and the severity and causality of the adverse event were evaluated by the investigators. For this trial, subjects had in-person visits every 2 weeks during the first 20 weeks of the trial and then every 4 weeks.

[0067] The treatment groups were: (A) semaglutide, with randomized target doses of 0.05, 0.1, 0.2, 0.3, or 0.4 mg (for dose levels above 0.05 mg, dose escalation was performed every four weeks); (B) semaglutide, with randomized target doses of 0.3 or 0.4 mg (starting dose of 0.05 mg, dose escalation was performed every two weeks); (C) liraglutide 3.0 mg (starting dose of 0.6 mg, dose escalation was performed once a 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 calorie-reduced diet provided by a dietitian or an equivalent qualified representative, as well as physical activity counseling provided by a qualified person. The trial population, consisting of a total of 957 subjects, was randomly assigned. A total of 777 subjects (81.2%) completed 52 weeks of treatment; 180 (18.8%) terminated treatment early, with no apparent dose-dependent trend. The key inclusion criteria for this trial were: male or female, age ≥ 18 years at the time of signing the informed consent form; body mass index (BMI) ≥ 30.0 kg / m 2; and at least one unsuccessful weight loss attempt, as judged by the investigator. Key exclusion criteria for the trial were: HbA1c ≥ 6.5% at screening or diagnosis of type 1 or type 2 diabetes; treatment with hypoglycemic agents within 90 days before screening; calcitonin ≥ 50 ng / L (pg / mL) at screening; personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 syndrome; history of (acute or chronic) pancreatitis; obesity induced by endocrine disorders (e.g., Cushing's syndrome); treatment with any drug that, in the judgment of the investigator, might cause significant weight change within 90 days before screening; previous surgical treatment for obesity (liposuction and / or abdominoplasty performed more than 1 year before screening was permitted); history of severe depressive disorder within 2 years before randomization; any history of suicide attempt in a lifetime; and women who were pregnant, lactating, planning to become pregnant, or fertile but not using appropriate contraception (appropriate contraceptive measures as required by local regulations or practice).

[0068] Statistical analysis of efficacy endpoints: The primary analysis was based on the "jump-to-reference" multiple imputation method (J2R-MI). The 52-week data from subjects who discontinued the trial product but returned for a visit at week 52 were included in this analysis. First, the imputation model was estimated using only the 52-week weight (kg) measurements observed in the placebo group. Second, multiple copies (1000) of the full analysis set were generated by imputing the missing values in all treatment groups from this imputation model. The primary endpoint was calculated in each complete dataset and analyzed using an analysis of covariance (ANCOVA) model. Third, the 1000 analysis results were summarized using Rubin's formula. 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 were provided by this analysis model. Using this multiple imputation method, it was assumed that the response of placebo group subjects missing the week 52 endpoint data was similar to that of completers in the placebo group, and that throughout the trial, active treatment group subjects missing the week 52 endpoint data were in the placebo group regardless of the discontinuation time.

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

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

[0071] N Body 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: Change in body weight (%) 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, Subjects on-treatment: Subjects who completed treatment until the end of the trial, Subjects in-trial: Subjects who completed treatment and subjects who discontinued treatment before the end of the trial but were seen at week 52.

[0077] Table 3: Change in body weight (%) 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 shown as "Estimate [95% CI]", N: Number of subjects contributing to the analysis, CI: Confidence Interval. J2R - MI: Analysis of data from the trial in which missing observations were imputed from the pooled placebo group using jump - to - reference multiple (x1000) imputation method. Using an analysis of covariance model with treatment, region, and sex as factors and baseline body weight as a covariate, the response at week 52 was analyzed. Treatment comparisons were not adjusted for multiple testing.

[0080] Table 4: Change in body weight (%) relative to baseline at week 52 - Results from Emax dose - response simulation - ANCOVA - J2R - MI - Full analysis set

[0081]

[0082] Lira: Liraglutide, Sema: Semaglutide, * : Dose - response coefficients were 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 simulation - 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, * : Estimated dose-response coefficient by the Emax three-parameter model, ** : Based on %.

[0087] Table 6: Summary of gastrointestinal adverse events in the form of nausea among 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 even at high doses of 0.3 mg or even 0.4 mg once daily, the effect of semaglutide on weight loss continues to improve. The results in Tables 5 - 6 show that at these high doses, the increase in gastrointestinal adverse events is relatively low, and compared to, 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 semaglutide dose that provides the same weight loss as 3.0 mg liraglutide is 0.08 mg semaglutide (95% CI [-0.02; 0.57]), while the semaglutide dose that provides the same level of gastrointestinal adverse events as 3.0 mg liraglutide is 0.28 mg semaglutide (95% CI [-0.02; 0.57]); thus, at the same level of gastrointestinal adverse events, semaglutide provides approximately 3 times more weight loss (approximately 3 times is calculated as (3.0 / 0.08) / (3.0 / 0.28)). In summary, these results suggest that due to this unexpectedly favorable ratio between weight loss and gastrointestinal adverse events, semaglutide products for weight management may be administered at high doses, resulting in improved weight loss. Even more surprisingly, compared to lower doses, the ratio between weight loss and gastrointestinal adverse events is improved at the highest semaglutide doses of 0.3 mg or even 0.4 mg once daily.

[0091] Example 2: Semaglutide in Subjects with Type 2 Diabetes

[0092] For subjects with T2D, HbA 1cFor adult patients with HbA1c of 7.0–10.0% (53–86 mmol / mol) and body mass index of 24.0–40.0 kg / m 2 , a 26-week randomized, double-blind clinical trial was conducted with treatment by diet and exercise ± metformin. Patients were randomized 2:2:1 to receive once-daily semaglutide, placebo, or liraglutide 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 the change in HbA 1c from baseline to week 26. Key exclusion criteria were chronic or idiopathic acute pancreatitis and a history of 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 the trial drug for 26 weeks, followed by a 7-week follow-up period. Patients initiated treatment with 0.05 mg semaglutide, 0.3 mg liraglutide, or 50 μL placebo, all administered subcutaneously once daily and titrated every 4 weeks until their final randomized dose. This titration algorithm was used in all patients to ensure blindness to all products, so the titration rate of liraglutide was slower than that recommended in the label. Since the treatments were volume-matched, the trial was double-blind within each dose level (rather than between) 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, presented as mean (SD)

[0096]

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

[0098] Table 8: Mean weight change and gastrointestinal adverse events from baseline to week 26, including nausea – treatment completed – 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 that occurred on or after the date of the first dose of the investigational product and before or at the date of the last dose of the investigational product, plus 7 weeks plus a 7-day visit window for end-of-treatment follow-up (= 56 days). The observation period is the duration of this period.

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

[0102] Table 9: Changes in HbA1c (glycated 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) Pooled 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 invention have been set forth and described herein, many modifications, substitutions, variations, and equivalents will now occur to those of ordinary skill in the art. Accordingly, it is to be understood that it is intended to cover all such modifications and variations that fall within the true scope of the present invention by the appended claims.

Claims

1. A method for weight management in a subject in need thereof, wherein a. in an amount of 2.0 - 10.0 mg once a week; or b. in an amount of 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: weight loss, treatment and / or prevention of obesity, treatment and / or prevention of overweight, and prevention of weight gain.

4. The method according to any one of the preceding claims, 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.

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, for example, 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. The 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. The method according to any one of the preceding claims, 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 according to 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 according to any one of the preceding claims, wherein the subject has type 2 diabetes.

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