Leaflet WEGOVY 25mg tablets

Pharmacotherapeutic group: Drugs used in diabetes, glucagon-like peptide-1 (GLP-1) analogues, ATCcode: A10BJ06.

Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1. Semaglutide acts asa GLP-1 receptor agonist that selectively binds to and activates the GLP-1 receptor, the target fornative GLP-1.

GLP-1 is a physiological regulator of appetite and calorie intake, and the GLP-1 receptor is present inseveral areas of the brain involved in appetite regulation.

Animal studies show that semaglutide works in the brain through the GLP-1 receptor. Semaglutide hasdirect effects on areas in the brain involved in homeostatic regulation of food intake in thehypothalamus and the brainstem. Semaglutide may affect the hedonic reward system through directand indirect effects in brain areas including the septum, thalamus and amygdala.

Clinical studies show that semaglutide reduces energy intake, increases feelings of satiety, fullness andcontrol of eating, reduces feelings of hunger, and frequency and intensity of cravings. In addition,semaglutide reduces the preference for high fat foods.

Semaglutide orchestrates the homeostatic and hedonic contributions with executive function toregulate caloric intake, appetite, reward and food choice.

In addition, in clinical studies semaglutide has shown to reduce blood glucose in a glucose dependentmanner by stimulating insulin secretion and lowering glucagon secretion when blood glucose is high.

The mechanism of blood glucose lowering also involves a minor delay in gastric emptying in the earlypostprandial phase. During hypoglycaemia, semaglutide diminishes insulin secretion and does notimpair glucagon secretion.

GLP-1 receptors are also expressed in the heart, vasculature, immune system and kidneys.

Semaglutide has a beneficial effect on plasma lipids, lowered systolic blood pressure and reducedinflammation in clinical studies. Furthermore, animal studies have shown that semaglutide attenuatedthe development of atherosclerosis and had an anti-inflammatory action in the cardiovascular system.

The mechanism of action of semaglutide for cardiovascular risk reduction is likely multifactorial, inpart driven by weight loss effects and effects on known cardiovascular risk factors (reduction in bloodpressure, improvements in lipid profile and glucose metabolism, and anti-inflammatory effects asdemonstrated by reductions in high-sensitivity C-reactive protein (hsCRP)). The exact mechanism ofcardiovascular risk reduction has not been established.

Semaglutide reduces appetite by increasing feelings of fullness and satiety, while lowering hunger andprospective food consumption.

In patients with type 2 diabetes, oral semaglutide equivalent to a dose of 9 mg compared to placebolowered fasting triglyceride and very-low-density lipoproteins (VLDL) cholesterol concentrations by19% [8; 28] and 20% [5; 33], respectively. The postprandial triglyceride and VLDL cholesterolresponse to a high fat meal was reduced by 24% [9; 36] and 21% [7; 32], respectively. ApoB48 wasreduced both in fasting and postprandial state by 25% [2; 42] and 30% [15; 43], respectively.

The efficacy and safety of 25 mg orally administered semaglutide (tablet) once daily for weightmanagement in combination with a reduced calorie intake and increased physical activity have beenevaluated in a 64-week double-blinded randomised placebo-controlled phase 3b trial (OASIS 4)including 307 patients (205 randomised to treatment with orally administered semaglutide).

Treatment with oral semaglutide demonstrated superior, clinically meaningful, and sustained weightloss compared with placebo in patients with obesity (BMI ≥ 30 kg/m2), or overweight (BMI≥ 27 kg/m2 to < 30 kg/m2) and at least one weight-related comorbidity. Furthermore, across the trials,a higher proportion of patients achieved ≥ 5%, ≥ 10%, ≥ 15% and ≥ 20% weight loss with semaglutidecompared with placebo. The reduction in body weight occurred irrespective of the presence ofgastrointestinal symptoms such as nausea, vomiting or diarrhoea.

Treatment with oral semaglutide also showed statistically significant improvements in waistcircumference, and physical functioning compared to placebo.

Efficacy was demonstrated with oral semaglutide regardless of age, gender, race, ethnicity, baselinebody weight, BMI, presence of type 2 diabetes and level of renal function. Variations in efficacyexisted within all subgroups. Relatively greater weight loss was observed in women and in patientswithout type 2 diabetes as well as in patients with a lower versus higher baseline body weight.

In addition, the efficacy and safety of subcutaneous semaglutide for weight management incombination with a reduced calorie intake and increased physical activity were evaluated in four68 weeks double-blinded randomised placebo-controlled phase 3a trials (STEP 1-4). A total of 4 684patients (2 652 randomised to treatment with subcutaneously administered semaglutide) were includedin these trials. The efficacy and safety were similar between OASIS 4 and STEP 1 regardless of theroute of administration.

OASIS 4: Weight management - once daily Wegovy 25 mg tablet (semaglutide 25 mg)

In a 64-week phase 3b trial, 307 adult patients with obesity (BMI ≥ 30 kg/m2) or with overweight(BMI ≥ 27 kg/m2 to < 30 kg/m2) and at least one weight-related comorbidity, were randomised to oncedaily orally administered semaglutide or placebo. All patients were on a reduced-calorie diet andincreased physical activity throughout the trial.

Weight loss occurred early and continued throughout the trial. At end of treatment (week 64), theweight loss was superior and clinically meaningful compared with placebo (see Table 2 and Figure 1).

Furthermore, a higher proportion of patients achieved ≥ 5%, ≥ 10%, ≥ 15% and ≥ 20% weight losswith orally administered semaglutide compared with placebo (see Table 2). Among patients withprediabetes at baseline, a higher proportion of patients had a normo-glycaemic status at end oftreatment with orally administered semaglutide compared to placebo (71.1% vs. 33.3%).

Table 2 OASIS 4: Results at week 64

Semaglutide 25 mg Placebotablet

Full analysis set (N) 205 102

Baseline (kg) 106.4 104.8

Change (%) from baseline1,2 -13.6 -2.2

Difference (%) from placebo1 [95% CI] -11.4 [-13.9; -9]*

Change (kg) from baseline1 -14.2 -2.2

Difference (kg) from placebo1 [95% CI] -12.0 [-14.6; -9.5]*

Patients (%) achieving weight loss ≥ 5%3 76.3* 30.5

Patients (%) achieving weight loss ≥ 10%3 59.8* 14.1

Patients (%) achieving weight loss ≥ 15%3 47.0* 5.4

Patients (%) achieving weight loss ≥ 20%3 27.5* 3

Waist circumference (cm)

Baseline 114 113.6

Change from baseline1 -12.2 -2.8

Difference from placebo1 [95% CI] -9.5 [-12.4; -6.6]*

Systolic blood pressure (mmHg)

Baseline 131 131

Change from baseline1 -6.8 -5.4

Difference from placebo1 [95% CI] -1.4 [-4.6; 1.8]

* p< 0.0001 (unadjusted 2-sided) for superiority.1 Estimated using an ANCOVA model using multiple imputation based on all data irrespective of prematurediscontinuation of randomised treatment or initiation of other anti-obesity medication or bariatric surgery.2 During the trial, randomised treatment was permanently discontinued by 18% and 25.5% of patientsrandomised to oral semaglutide 25 mg and placebo, respectively. Assuming that all randomised patients stayedon treatment and did not receive additional anti-obesity therapies, the estimated changes from randomisation toweek 64 for body weight based on a Mixed Model for Repeated Measures including all observations until firstdiscontinuation were -16.6% and -2.8% for oral semaglutide 25 mg and placebo respectively.3 Estimated from binary regression model based on same imputation procedure as in primary analysis.

Weeks

Oral sema 25 mg Placebo Multiple imputation (MI)

Observed values for patients completing each scheduled visit and estimates with multiple imputations (MI) fromretrieved dropouts.

Figure 1 OASIS 4: Mean change in body weight (%) from baseline to week 64

While some patients have not achieved the same exposure with oral semaglutide 25 mg andsubcutaneous semaglutide 2.4 mg, data from the following trials with the subcutaneous formulationare considered informative for the oral formulation.

In a 68-week double-blind trial, 1 961 patients with obesity (BMI ≥ 30 kg/m2), or with overweight(BMI ≥ 27 kg/m2 to < 30 kg/m2) and at least one weight-related comorbidity were randomised tosubcutaneous semaglutide or placebo. All patients were on a reduced-calorie diet and increasedphysical activity throughout the trial.

Weight loss occurred early and continued throughout the trial. At end of treatment (week 68), theweight loss was superior and clinically meaningful compared with placebo. Furthermore, a higherproportion of patients achieved ≥ 5%, ≥ 10%, ≥ 15% and ≥ 20% weight loss with semaglutidecompared with placebo.

In a 68-week, double-blind trial, 1 210 patients with overweight or obesity (BMI ≥ 27 kg/m2) andtype 2 diabetes were randomised to either semaglutide 2.4 mg, semaglutide 1 mg once-weekly orplacebo. Patients included in the trial had insufficiently controlled diabetes (HbA1c 7-10%) and weretreated with either: diet and exercise alone or 1-3 oral antidiabetic drugs. All patients were on areduced-calorie diet and increased physical activity throughout the trial.

Treatment with semaglutide for 68 weeks resulted in superior and clinically meaningful reduction inbody weight and in HbA1c compared to placebo.

Change in body weight (%)

In a 68-week double-blind trial, 611 patients with obesity (BMI ≥ 30 kg/m2), or with overweight (BMI≥ 27 kg/m2 to <30 kg/m2) and at least one weight-related comorbidity were randomised tosubcutaneous semaglutide or placebo. During the trial, all patients received intensive behaviouraltherapy (IBT) consisting of a very restrictive diet, increased physical activity and behaviouralcounselling.

Treatment with semaglutide and IBT for 68 weeks resulted in superior and clinically meaningfulreduction in body weight compared to placebo.

In a 68-week double-blind trial, 902 patients with obesity (BMI ≥ 30 kg/m2), or with overweight (BMI≥ 27 kg/m2 to < 30 kg/m2) and at least one weight-related comorbidity were included in the trial. Allpatients were on a reduced-calorie diet and increased physical activity throughout the trial. Fromweek 0 to week 20 (run-in), all patients received subcutaneous semaglutide. At week 20 (baseline),patients who had reached the maintenance dose of subcutaneous semaglutide 2.4 mg were randomisedto continue treatment or switch to placebo.

Patients who had reached the maintenance dose of 2.4 mg at week 20 (baseline) and continuedtreatment with semaglutide for 48 weeks (week 20-68) continued losing weight and had a superiorand clinically meaningful reduction in body weight compared to those switched to placebo.

Oral semaglutide showed statistically significant improvement in physical functioning scores andmore patients with oral semaglutide achieved a clinically meaningful improvement compared toplacebo. Physical functioning was assessed using the obesity-specific questionnaire Impact of Weighton Quality of Life Lite Clinical Trials Version (IWQOL-Lite-CT).

SELECT: Cardiovascular outcomes trial in patients with overweight or obesity

No cardiovascular outcomes clinical studies have been performed with oral semaglutide 25 mg inindividuals with established cardiovascular disease and BMI ≥ 27 kg/m2.

SELECT was a randomised, double-blind, placebo-controlled, event driven trial which included17 604 patients with established cardiovascular disease and BMI≥ 27 kg/m2. Patients were randomisedto either subcutaneous semaglutide 2.4 mg (n=8 803) or placebo (n=8 801) in addition to standard-of-care. The median time in trial was 41.8 months.

The study population consisted of female and male patients, with a mean age of 61.6 years. The mean

BMI was 33.3 kg/m2 and mean body weight was 96.7 kg. Patients with history of type 1 and type 2diabetes were excluded.

The primary endpoint was the time from randomisation to first occurrence of major adversecardiovascular events (MACE), defined as a composite endpoint consisting of cardiovascular death(including undetermined cause of death), non-fatal myocardial infarction, or non-fatal stroke.

Superiority of subcutaneous semaglutide 2.4 mg versus placebo for MACE was confirmed with ahazard ratio of 0.80 [0.72; 0.90][95% CI], corresponding to a relative risk reduction in MACE of 20%. The reduction of MACE with subcutaneous semaglutide 2.4 mg was not impacted by age, gender,race, ethnicity, BMI at baseline, or level of renal function impairment.