WEGOVY 0.5mg FLEXTOUCH injection for pre-filled pen medication leaflet

Wegovy 0.25 mg solution for injection in pre-filled pen

Wegovy 0.5 mg solution for injection in pre-filled pen

Wegovy 1 mg solution for injection in pre-filled pen

Wegovy 1.7 mg solution for injection in pre-filled pen

Wegovy 2.4 mg solution for injection in pre-filled pen

Wegovy 0.25 mg FlexTouch solution for injection in pre-filled pen

Wegovy 0.5 mg FlexTouch solution for injection in pre-filled pen

Wegovy 1 mg FlexTouch solution for injection in pre-filled pen

Wegovy 1.7 mg FlexTouch solution for injection in pre-filled pen

Wegovy 2.4 mg FlexTouch solution for injection in pre-filled pen

Each single-dose pre-filled pen contains 0.25 mg semaglutide* in 0.5 mL solution. One mL of solutioncontains 0.5 mg of semaglutide*.

Each single-dose pre-filled pen contains 0.5 mg semaglutide* in 0.5 mL solution. One mL of solutioncontains 1 mg of semaglutide*.

Each single-dose pre-filled pen contains 1 mg semaglutide* in 0.5 mL solution. One mL of solutioncontains 2 mg of semaglutide*.

Each single-dose pre-filled pen contains 1.7 mg semaglutide* in 0.75 mL solution. One mL of solutioncontains 2.27 mg of semaglutide*.

Each single-dose pre-filled pen contains 2.4 mg semaglutide* in 0.75 mL solution. One mL of solutioncontains 3.2 mg of semaglutide*.

Wegovy 0.25 mg FlexTouch solution for injection pre-filled pen

Each pre-filled pen contains 1 mg semaglutide* in 1.5 mL solution. One mL of solution contains0.68 mg semaglutide*. One pre-filled pen contains 4 doses of 0.25 mg.

Wegovy 0.5 mg FlexTouch solution for injection pre-filled pen1.5 mL: Each pre-filled pen contains 2 mg semaglutide* in 1.5 mL solution. One mL of solutioncontains 1.34 mg semaglutide*. One pre-filled pen contains 4 doses of 0.5 mg.

3 mL: Each pre-filled pen contains 2 mg semaglutide* in 3 mL solution. One mL of solution contains0.68 mg semaglutide*. One pre-filled pen contains 4 doses of 0.5 mg.

Wegovy 1 mg FlexTouch solution for injection pre-filled pen

Each pre-filled pen contains 4 mg semaglutide* in 3 mL solution. One mL of solution contains1.34 mg semaglutide*. One pre-filled pen contains 4 doses of 1 mg.

Wegovy 1.7 mg FlexTouch solution for injection pre-filled pen

Each pre-filled pen contains 6.8 mg semaglutide* in 3 mL solution. One mL of solution contains2.27 mg semaglutide*. One pre-filled pen contains 4 doses of 1.7 mg.

Wegovy 2.4 mg FlexTouch solution for injection pre-filled pen

Each pre-filled pen contains 9.6 mg semaglutide* in 3 mL solution. One mL of solution contains3.2 mg semaglutide*. One pre-filled pen contains 4 doses of 2.4 mg.

*human glucagon-like peptide-1 (GLP-1) analogue produced in Saccharomyces cerevisiae cells byrecombinant DNA technology.

For the full list of excipients, see section 6.1.

Solution for injection (injection)

Clear and colourless isotonic solution; pH=7.4.

Wegovy is indicated as an adjunct to a reduced-calorie diet and increased physical activity for weightmanagement, including weight loss and weight maintenance, in adults with an initial Body Mass Index(BMI) of

* ≥30 kg/m2 (obesity), or

* ≥27 kg/m2 to <30 kg/m2 (overweight) in the presence of at least one weight-related comorbiditye.g. dysglycaemia (prediabetes or type 2 diabetes mellitus), hypertension, dyslipidaemia,obstructive sleep apnoea or cardiovascular disease.

For trial results with respect to cardiovascular risk reduction, obesity-related heart failure, andpopulations studied, see section 5.1.

Wegovy is indicated as an adjunct to a reduced-calorie diet and increased physical activity for weightmanagement in adolescents ages 12 years and above with

* obesity* and

* body weight above 60 kg.

Treatment with Wegovy should be discontinued and re-evaluated if adolescent patients have notreduced their BMI by at least 5% after 12 weeks on the 2.4 mg or maximum tolerated dose.

*Obesity (BMI ≥95th percentile) as defined on sex- and age-specific BMI growth charts (CDC.gov) (see Table 1).

Table 1 BMI cut-off points for obesity (≥95th percentile) by sex and age for paediatric patientsaged 12 and older (CDC criteria)

Age (years) BMI (kg/m2) at 95th Percentile

Males Females12 24.2 25.212.5 24.7 25.713 25.1 26.313.5 25.6 26.814 26.0 27.214.5 26.4 27.715 26.8 28.115.5 27.2 28.516 27.5 28.916.5 27.9 29.317 28.2 29.617.5 28.6 30.0

The maintenance dose of semaglutide 2.4 mg once-weekly is reached by starting with a dose of0.25 mg. To reduce the likelihood of gastrointestinal symptoms, the dose should be escalated over a16-week period to a maintenance dose of 2.4 mg once weekly (see Table 2). In case of significantgastrointestinal symptoms, consider delaying dose escalation or lowering to the previous dose untilsymptoms have improved. Weekly doses higher than 2.4 mg are not recommended.

Table 2 Dose escalation schedule

Dose escalation Weekly dose

Week 1-4 0.25 mg

Week 5-8 0.5 mg

Week 9-12 1 mg

Week 13-16 1.7 mg

Maintenance dose 2.4 mg

For adolescents ages 12 years and above, the same dose escalation schedule as for adults should beapplied (see Table 2). The dose should be increased until 2.4 mg (maintenance dose) or maximumtolerated dose has been reached. Weekly doses higher than 2.4 mg are not recommended.

When initiating semaglutide in patients with type 2 diabetes, consider reducing the dose ofconcomitantly administered insulin or insulin secretagogues (such as sulfonylureas) to reduce the riskof hypoglycaemia, see section 4.4.

If a dose is missed, it should be administered as soon as possible and within 5 days after the misseddose. If more than 5 days have passed, the missed dose should be skipped, and the next dose should beadministered on the regularly scheduled day. In each case, patients can then resume their regular onceweekly dosing schedule. If more doses are missed, reducing the starting dose for re-initiation shouldbe considered.

No dose adjustment is required based on age. Therapeutic experience in patients ≥85 years of age islimited.

No dose adjustment is required for patients with mild or moderate renal impairment. Experience withthe use of semaglutide in patients with severe renal impairment is limited. Semaglutide is notrecommended for use in patients with severe renal impairment (eGFR <30 mL/min/1.73m2) includingpatients with end-stage renal disease (see sections 4.4, pct. 4.8 and 5.2).

No dose adjustment is required for patients with mild or moderate hepatic impairment. Experiencewith the use of semaglutide in patients with severe hepatic impairment is limited. Semaglutide is notrecommended for use in patients with severe hepatic impairment and should be used cautiously inpatients with mild or moderate hepatic impairment (see sections 4.4 and 5.2).

No dose adjustment is required for adolescents ages 12 years and above.

The safety and efficacy of semaglutide in children below 12 years of age have not been established.

Subcutaneous use.

Wegovy is administered once weekly at any time of the day, with or without meals.

It is to be injected subcutaneously in the abdomen, in the thigh or in the upper arm. The injection sitecan be changed. It should not be administered intravenously or intramuscularly.

The day of weekly administration can be changed if necessary, as long as the time between two dosesis at least 3 days (>72 hours). After selecting a new dosing day, once-weekly dosing should becontinued.

When administering Wegovy pre-filled pen for single use, the pen should be pressed firmly against theskin until the yellow bar has stopped moving. The injection takes about 5-10 seconds.

Patients should be advised to read the instruction for use included in the package leaflet carefullybefore administering the medicinal product.

For further information before administration see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Aspiration in association with general anaesthesia or deep sedation

Cases of pulmonary aspiration have been reported in patients receiving GLP-1 receptor agonistsundergoing general anaesthesia or deep sedation. Therefore, the increased risk of residual gastriccontent due to delayed gastric emptying (see section 4.8) should be considered prior to performingprocedures with general anaesthesia or deep sedation.

Use of GLP-1 receptor agonists may be associated with gastrointestinal adverse reactions that cancause dehydration, which in rare cases can lead to a deterioration of renal function.

Patients should be advised of the potential risk of dehydration in relation to gastrointestinal side effectsand take precautions to avoid fluid depletion.

Acute pancreatitis has been observed with the use of GLP-1 receptor agonists (see section 4.8).

Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis issuspected, semaglutide should be discontinued; if confirmed, semaglutide should not be restarted.

Caution should be exercised in patients with a history of pancreatitis.

In the absence of other signs and symptoms of acute pancreatitis, elevations in pancreatic enzymesalone are not predictive of acute pancreatitis.

Semaglutide should not be used as a substitute for insulin in patients with type 2 diabetes.

Semaglutide should not be used in combination with other GLP-1 receptor agonist products. It has notbeen evaluated and an increased risk of adverse reactions related to overdose is considered likely.

Insulin and sulfonylurea are known to cause hypoglycaemia. Patients treated with semaglutide incombination with a sulfonylurea or insulin may have an increased risk of hypoglycaemia. The risk ofhypoglycaemia can be lowered by reducing the dose of sulfonylurea or insulin when initiatingtreatment with a GLP-1 receptor agonist.

In patients with diabetic retinopathy treated with semaglutide, an increased risk of developing diabeticretinopathy complications has been observed (see section 4.8). Rapid improvement in glucose controlhas been associated with a temporary worsening of diabetic retinopathy, but other mechanisms cannotbe excluded. Patients with diabetic retinopathy using semaglutide should be monitored closely andtreated according to clinical guidelines. There is no experience with Wegovy in patients with type 2diabetes with uncontrolled or potentially unstable diabetic retinopathy. In these patients, treatmentwith Wegovy is not recommended.

The safety and efficacy of Wegovy have not been investigated in patients:- treated with other products for weight management,- with type 1 diabetes,- with severe renal impairment (see section 4.2),- with severe hepatic impairment (see section 4.2),- with congestive heart failure New York Heart Association (NYHA) class IV.

Use in these patients is not recommended.

There is limited experience with Wegovy in patients:- aged 85 years or more (see section 4.2),- with mild or moderate hepatic impairment (see section 4.2),- with inflammatory bowel disease,- with diabetic gastroparesis.

Use with caution in these patients.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free’.

Semaglutide delays gastric emptying and could potentially influence the absorption of concomitantlyadministered oral medicinal products. No clinically relevant effect on the rate of gastric emptying wasobserved with semaglutide 2.4 mg, probably due to a tolerance effect. Semaglutide should be usedwith caution in patients receiving oral medicinal products that require rapid gastrointestinalabsorption.

Semaglutide delays the rate of gastric emptying as assessed by paracetamol pharmacokinetics during astandardised meal test. Paracetamol AUC0-60min and Cmax were decreased by 27% and 23%,respectively, following concomitant use of semaglutide 1 mg. The total paracetamol exposure(AUC0-5h) was not affected. No clinically relevant effect on paracetamol was observed withsemaglutide. No dose adjustment of paracetamol is necessary when administered with semaglutide.

Semaglutide is not anticipated to decrease the effectiveness of oral contraceptives. It did not changethe overall exposure of ethinylestradiol and levonorgestrel to a clinically relevant degree, when an oralcontraceptive combination medicinal product (0.03 mg ethinylestradiol/0.15 mg levonorgestrel) wasco-administered with semaglutide. Exposure of ethinylestradiol was not affected; an increase of 20%was observed for levonorgestrel exposure at steady state. Cmax was not affected for any of thecompounds.

Semaglutide did not change the overall exposure of atorvastatin following a single dose administrationof atorvastatin (40 mg). Atorvastatin Cmax was decreased by 38%. This was assessed not to beclinically relevant.

Semaglutide did not change the overall exposure or Cmax of digoxin following a single dose of digoxin(0.5 mg).

Semaglutide did not change the overall exposure or Cmax of metformin following dosing of 500 mgtwice daily over 3.5 days.

Semaglutide did not change overall exposure or Cmax of R- and S-warfarin following a single dose ofwarfarin (25 mg), and the pharmacodynamic effects of warfarin as measured by the internationalnormalised ratio (INR) were not affected in a clinically relevant manner. However, cases of decreased

INR have been reported during concomitant use of acenocoumarol and semaglutide. Upon initiation ofsemaglutide treatment in patients on warfarin or other coumarin derivatives, frequent monitoring of

INR is recommended.

Interaction studies have only been performed in adults.

Women of childbearing potential are recommended to use contraception when treated withsemaglutide (see section 4.5).

Studies in animals have shown reproductive toxicity (see section 5.3). There are limited data from theuse of semaglutide in pregnant women. Therefore, semaglutide should not be used during pregnancy.

If a patient wishes to become pregnant, or pregnancy occurs, semaglutide should be discontinued.

Semaglutide should be discontinued at least 2 months before a planned pregnancy due to the long half-life (see section 5.2).

In lactating rats, semaglutide was excreted in milk. A risk to a breast-fed child cannot be excluded.

Semaglutide should not be used during breast-feeding.

The effect of semaglutide on fertility in humans is unknown. Semaglutide did not affect male fertilityin rats. In female rats, an increase in oestrous length and a small reduction in number of ovulationswere observed at doses associated with maternal body weight loss.

Semaglutide has no or negligible influence on the ability to drive or use machines. However, dizzinesscan be experienced mainly during the dose escalation period. Driving or use of machines should bedone cautiously if dizziness occurs.

If semaglutide is used in combination with a sulfonylurea or insulin, patients should be advised to takeprecautions to avoid hypoglycaemia while driving and using machines (see section 4.4).

In four phase 3a trials, 2 650 adult patients were exposed to Wegovy. The duration of the trials were68 weeks. The most frequently reported adverse reactions were gastrointestinal disorders includingnausea, diarrhoea, constipation and vomiting.

Table 3 lists adverse reactions identified in clinical trials in adults and post-marketing reports. Thefrequencies are based on a pool of the phase 3a trials.

Adverse reactions associated with Wegovy are listed by system organ class and frequency. Frequencycategories are defined as: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to<1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000) and not known (cannot be estimated fromthe available data).

Table 3 Frequency of adverse reactions of semaglutide

MedDRAsystem organ Verycommon Common Uncommon Rare Not knownclass

Immune system Anaphylacticdisorders reaction

Metabolism and Hypoglycaemnutrition ia in patientsdisorders with type 2diabetesa

Nervous system Headacheb Dizzinessbdisorders Dysgeusiab,c

Dysaesthesiaa

Eye disorders Diabeticretinopathy inpatients withtype 2diabetesa

Cardiac Hypotensiondisorders Orthostatichypotension

Increasedheart ratea,c

Gastrointestinal Vomitinga,b Gastritisb,c Acute Intestinaldisorders Diarrhoeaa,b Gastrooesoph pancreatitisa obstruction

Constipationa, ageal reflux Delayedb diseaseb gastric

Nauseaa,b Dyspepsiab emptying

Abdominal Eructationbpainb,c Flatulenceb

Abdominaldistensionb

Hepatobiliary Cholelithiasisdisorders a

Skin and Hair lossa Angioedemasubcutaneoustissue disorders

General Fatigueb,c Injection sitedisorders and reactionscadministrationsite conditions

Investigations Increasedamylasec

Increasedlipaseca) see description of selected adverse reactions belowb) mainly seen in the dose-escalation periodc) Grouped preferred terms

The below information on specific adverse reactions, unless otherwise specified, pertains to the phase3a trials.

Over the 68 weeks trial period, nausea occurred in 43.9% of patients when treated with semaglutide(16.1% for placebo), diarrhoea in 29.7% (15.9% for placebo) and vomiting in 24.5% (6.3% forplacebo). Most events were mild to moderate in severity and of short duration. Constipation occurredin 24.2% of patients treated with semaglutide (11.1% for placebo) and was mild to moderate inseverity and of longer duration. In patients treated with semaglutide, median duration of nausea was8 days, vomiting 2 days, diarrhoea 3 days, and constipation 47 days.

Patients with moderate renal impairment (eGFR ≥30 to <60 mL/min/1.73m2) may experience moregastrointestinal effects when treated with semaglutide.

The gastrointestinal events led to permanent treatment discontinuation in 4.3% of patients.

The frequency of adjudication-confirmed acute pancreatitis reported in phase 3a clinical trials was0.2% for semaglutide and <0.1% for placebo, respectively. In SELECT, the cardiovascular outcomestrial, the frequency of acute pancreatitis confirmed by adjudication was 0.2% for semaglutide and0.3% for placebo.

Cholelithiasis was reported in 1.6% and led to cholecystitis in 0.6% of patients treated withsemaglutide. Cholelithiasis and cholecystitis was reported in 1.1% and 0.3%, respectively, of patientstreated with placebo.

Hair loss was reported in 2.5% of patients treated with semaglutide and in 1.0% of patients treatedwith placebo. The events were mainly of mild severity and most patients recovered while on continuedtreatment. Hair loss was reported more frequently in patients with a greater weight loss (≥20%).

In the phase 3a trials, a mean increase of 3 beats per minute (bpm) from a baseline mean of 72 bpmwas observed in patients treated with semaglutide. The proportions of subjects with an increase inpulse from baseline ≥10 bpm at any timepoint during the on-treatment period were 67.0% in thesemaglutide group vs. 50.1% in the placebo group.

Consistent with the potentially immunogenic properties of medicinal products containing proteins orpeptides, patients may develop antibodies following treatment with semaglutide. The proportion ofpatients testing positive for anti-semaglutide antibodies at any time post-baseline was low (2.9%) andno patients had anti-semaglutide neutralising antibodies or anti-semaglutide antibodies withendogenous GLP-1 neutralising effect at end-of-trial. During treatment, high semaglutideconcentrations might have lowered the sensitivity of the assays, hence the risk of false negativescannot be excluded. However, in subjects testing positive for antibodies during and after treatment, thepresence of antibodies was transient and with no apparent impact on efficacy and safety.

In STEP 2, clinically significant hypoglycaemia was observed in 6.2% (0.1 events/patient year) ofsubjects treated with semaglutide compared with 2.5% (0.03 events/patient year) of subjects treatedwith placebo. Hypoglycaemia with semaglutide was seen both with and without concomitant use ofsulfonylurea. One episode (0.2% of subjects, 0.002 events/patient year) was reported as severe in asubject not concomitantly treated with a sulfonylurea. The risk of hypoglycaemia was increased whensemaglutide was used with a sulfonylurea.

In STEP-HFpEF-DM, clinically significant hypoglycaemia was observed in 4.2% of subjects in boththe semaglutide and placebo groups when used in combination with sulfonylurea and/or insulin(0.065 events/patient year with semaglutide and 0.098 events/patient year with placebo).

A 2-year clinical trial investigated semaglutide 0.5 mg and 1 mg vs. placebo in 3 297 patients withtype 2 diabetes, with high cardiovascular risk, long duration of diabetes and poorly controlled bloodglucose. In this trial, adjudicated events of diabetic retinopathy complications occurred in morepatients treated with semaglutide (3.0%) compared to placebo (1.8%). This was observed in insulin-treated patients with known diabetic retinopathy. The treatment difference appeared early andpersisted throughout the trial. In STEP 2, retinal disorders were reported by 6.9% of patients treatedwith Wegovy, 6.2% of patients treated with semaglutide 1 mg, and 4.2% of patients treated withplacebo. The majority of events were reported as diabetic retinopathy (4.0%, 2.7%, and 2.7%,respectively) and non-proliferative retinopathy (0.7%, 0%, and 0%, respectively).

Dysaesthesia

Events related to a clinical picture of altered skin sensation such as paraesthesia, pain of skin, sensitiveskin, dysaesthesia and burning skin sensation were reported in 2.1% of patients treated withsemaglutide 2.4 mg and 1.2% of patients treated with placebo. The events were mild to moderate inseverity and most patients recovered while on continued treatment.

In a clinical trial conducted in adolescents of 12 years to below 18 years with obesity or overweightwith at least one weight-related comorbidity, 133 patients were exposed to Wegovy. The trial durationwas 68 weeks.

Overall, the frequency, type and severity of adverse reactions in the adolescents were comparable tothat observed in the adult population. Cholelithiasis was reported in 3.8% of patients treated with

Wegovy and 0% of patients treated with placebo.

No effects on growth or pubertal development were found after 68 weeks of treatment.

In the SELECT and SUSTAIN 6 trials, in adults with established cardiovascular disease, the adversereaction profile was similar to that seen in the weight management phase 3a trials.

In the HFpEF trials, in adults with obesity related heart failure with preserved ejection fraction (HFpEF),the adverse reaction profile was similar to that seen in the weight management phase 3a trials.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Overdose with semaglutide may be associated with gastrointestinal disorders which could lead todehydration. In the event of overdose the patient should be observed for clinical signs and appropriatesupportive treatment initiated.

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 have 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 a phase 1 trial, energy intake during an ad libitum meal was 35%lower with semaglutide compared to placebo after 20 weeks of dosing. This was supported byimproved control of eating, less food cravings and a relative lower preference for high fat food. Foodcravings were further assessed in STEP 5 by a Control of Eating Questionnaire (CoEQ). At week 104,the estimated treatment difference both for control of cravings and craving of savoury foodsignificantly favoured semaglutide, whereas no clear effect was seen for craving of sweet food.

Semaglutide 1 mg compared to placebo lowered fasting triglyceride and very low density lipoproteins(VLDL) concentrations by 12% and 21%, respectively. The postprandial triglyceride and VLDLresponse to a high fat meal was reduced with >40%.

The efficacy and safety of semaglutide for weight management in combination with a reduced calorieintake and increased physical activity were evaluated in four 68 weeks double-blinded randomisedplacebo-controlled phase 3a trials (STEP 1-4). A total of 4 684 adult patients (2 652 randomised totreatment with semaglutide) were included in these trials. Furthermore, the two-year efficacy andsafety of semaglutide compared to placebo were evaluated in a double-blinded randomised placebo-controlled phase 3b trial (STEP 5) including 304 patients (152 in treatment with semaglutide).

Treatment with semaglutide demonstrated superior, clinically meaningful, and sustained weight losscompared 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 higherproportion of patients achieved ≥5%, ≥10%, ≥15% and ≥20% weight loss with semaglutide comparedwith placebo. The reduction in body weight occurred irrespective of the presence of gastrointestinalsymptoms such as nausea, vomiting or diarrhoea.

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

Efficacy was demonstrated regardless of age, sex, race, ethnicity, baseline body weight, BMI,presence of type 2 diabetes and level of renal function. Variations in efficacy existed within allsubgroups. Relatively greater weight loss was observed in women and in patients without type 2diabetes as well as in patients with a lower versus higher baseline body weight.

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 tosemaglutide or placebo. All patients were on a reduced-calorie diet and increased physical activitythroughout 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 (see Table 4 and Figure 1).

Furthermore, a higher proportion of patients achieved ≥5%, ≥10%, ≥15% and ≥20% weight loss withsemaglutide compared with placebo (see Table 4). Among patients with prediabetes at baseline, ahigher proportion of patients had a normo-glycaemic status at end of treatment with semaglutidecompared to placebo (84.1% vs. 47.8%).

Table 4 STEP 1: Results at week 68

Semaglutide 2.4 mg Placebo

Full analysis set (N) 1 306 655

Baseline (kg) 105.4 105.2

Change (%) from baseline1,2 -14.9 -2.4

Difference (%) from placebo1 [95% CI] -12.4 [-13.4; -11.5]* -

Change (kg) from baseline -15.3 -2.6

Difference (kg) from placebo1 [95% CI] -12.7 [-13.7; -11.7] -

Patients (%) achieving weight loss ≥5%3 83.5* 31.1

Patients (%) achieving weight loss ≥10%3 66.1* 12.0

Patients (%) achieving weight loss ≥15%3 47.9* 4.8

Waist circumference (cm)

Baseline 114.6 114.8

Change from baseline1 -13.5 -4.1

Difference from placebo1 [95% CI] -9.4 [-10.3; -8.5]* -

Systolic blood pressure (mmHg)

Baseline 126 127

Change from baseline1 -6.2 -1.1

Difference from placebo1 [95% CI] -5.1 [-6.3; -3.9]* -

* p<0.0001 (unadjusted 2-sided) for superiority.1 Estimated using an ANCOVA model using multiple imputation based on all data irrespective of discontinuation of randomised treatment orinitiation of other anti-obesity medication or bariatric surgery.2 During the trial, randomised treatment was permanently discontinued by 17.1% and 22.4% of patients randomised to semaglutide 2.4 mgand placebo, respectively. Assuming that all randomised patients stayed on treatment and did not receive additional anti-obesity therapies,the estimated changes from randomisation to week 68 for body weight based on a Mixed Model for Repeated Measures including allobservations until first discontinuation were -16.9% and -2.4% for semaglutide 2.4 mg and placebo respectively.3 Estimated from binary regression model based on same imputation procedure as in primary analysis.

- 2.8 -2.4

- 14.9

- 15.6(MI)

Weeks

Wegovy Placebo Multiple imputation (MI)

Observed values for patients completing each scheduled visit, and estimates with multiple imputations (MI) from retrieved dropouts

Figure 1 STEP 1: Mean change in body weight (%) from baseline to week 68

Following the 68-week trial, a 52-week off-treatment extension was conducted including 327 patientswho had completed the main trial period on the maintenance dose of semaglutide or placebo. In theoff-treatment period from week 68 to week 120, mean body weight increased in both treatmentgroups. However, for patients that had been treated with semaglutide for the main trial period theweight remained 5.6% below baseline compared to 0.1% for the placebo group.

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 (see Table 5 and Figure 2).

Table 5 STEP 2: Results at week 68

Semaglutide 2.4 mg Placebo

Full analysis set (N) 404 403

Baseline (kg) 99.9 100.5

Change (%) from baseline1,2 -9.6 -3.4

Difference (%) from placebo1 [95% CI] -6.2 [-7.3;-5.2]* -

Change (kg) from baseline -9.7 -3.5

Difference (kg) from placebo1 [95% CI] -6.1 [-7.2;-5.0] -

Patients (%) achieving weight loss ≥5%3 67.4* 30.2

Patients (%) achieving weight loss ≥10%3 44.5* 10.2

Patients (%) achieving weight loss ≥15%3 25.0* 4.3

Waist circumference (cm)

Baseline 114.5 115.5

Change from baseline1 -9.4 -4.5

Difference from placebo1 [95% CI] -4.9 [-6.0; -3.8]* -

Systolic blood pressure (mmHg)

Baseline 130 130

Change from baseline1 -3.9 -0.5

Difference from placebo1 [95% CI] -3.4 [-5.6; -1.3]** -

HbA1c (mmol/mol (%))

Baseline 65.3 (8.1) 65.3 (8.1)

Change from baseline1 -17.5 (-1.6) -4.1 (-0.4)

Difference from placebo1 [95% CI] -13.5 [-15.5; -11.4] -(-1.2 [-1.4; -1.1])* -

* p<0.0001 (unadjusted 2-sided) for superiority; **p<0.05 (unadjusted 2-sided) for superiority.1 Estimated using an ANCOVA model using multiple imputation based on all data irrespective of discontinuation of randomised treatment orinitiation of other anti-obesity medication or bariatric surgery.2 During the trial, randomised treatment was permanently discontinued by 11.6% and 13.9% of patients randomised to semaglutide 2.4 mgand placebo, respectively. Assuming that all randomised patients stayed on treatment and did not receive additional anti-obesity therapies,the estimated changes from randomisation to week 68 for body weight based on a Mixed Model for Repeated Measures including allobservations until first discontinuation were -10.6% and -3.1% for semaglutide 2.4 mg and placebo respectively3 Estimated from binary regression model based on same imputation procedure as in primary analysis.

- 3.3 -3.4

- 9.9 -9.6(MI)

Weeks

Wegovy Placebo Multiple imputation (MI)

Observed values for patients completing each scheduled visit, and estimates with multiple imputations (MI) from retrieved dropouts

Figure 2 STEP 2: Mean change in body weight (%) from baseline to week 68

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 to semaglutideor placebo. During the trial, all patients received intensive behavioural therapy (IBT) consisting of avery restrictive diet, increased physical activity and behavioural counselling.

Treatment with semaglutide and IBT for 68 weeks resulted in superior and clinically meaningfulreduction in body weight compared to placebo (see Table 6).

Table 6 STEP 3: Results at week 68

Semaglutide 2.4 mg Placebo

Full analysis set (N) 407 204

Baseline (kg) 106.9 103.7

Change (%) from baseline1,2 -16.0 -5.7

Difference (%) from placebo1 [95% CI] -10.3 [-12.0;-8.6]* -

Change (kg) from baseline -16.8 -6.2

Difference (kg) from placebo1 [95% CI] -10.6 [-12.5;-8.8] -

Patients (%) achieving weight loss ≥5%3 84.8* 47.8

Patients (%) achieving weight loss ≥10%3 73.0* 27.1

Patients (%) achieving weight loss ≥15%3 53.5* 13.2

Waist circumference (cm)

Baseline 113.6 111.8

Change from baseline1 -14.6 -6.3

Difference from placebo1 [95% CI] -8.3 [-10.1; -6.6]* -

Systolic blood pressure (mmHg)

Baseline 124 124

Change from baseline1 -5.6 -1.6

Difference from placebo1 [95% CI] -3.9 [-6.4; -1.5]* -

* p<0.005 (unadjusted 2-sided) for superiority.1 Estimated using an ANCOVA model using multiple imputation based on all data irrespective of discontinuation of randomised treatment orinitiation of other anti-obesity medication or bariatric surgery.2 During the trial, randomised treatment was permanently discontinued by 16.7% and 18.6% of patients randomised to semaglutide 2.4 mgand placebo, respectively. Assuming that all randomised patients stayed on treatment and did not receive additional anti-obesity therapies,the estimated changes from randomisation to week 68 for body weight based on a Mixed Model for Repeated Measures including allobservations until first discontinuation were -17.6% and -5.0% for semaglutide 2.4 mg and placebo respectively3 Estimated from binary regression model based on same imputation procedure as in primary analysis.

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 semaglutide. At week 20 (baseline), patients who hadreached the maintenance dose of 2.4 mg were randomised to continue treatment or switch to placebo.

At week 0 (start of run-in period) patients had a mean body weight of 107.2 kg and a mean BMI of38.4 kg/m2.

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 (see

Table 7 and Figure 3). The body weight increased steadily from week 20 to week 68 in patientsswitching to placebo at week 20 (baseline). Nevertheless, the observed mean body weight was lowerat week 68 than at start of the run-in period (week 0) (see Figure 3). Patients treated with semaglutidefrom week 0 (run-in) to week 68 (end of treatment) achieved a mean change in body weight of -17.4%, with weight loss ≥5% achieved by 87.8%, ≥10% achieved by 78.0%, ≥15% achieved by 62.2%and ≥20% achieved by 38.6% of these patients.

Table 7 STEP 4: Results from week 20 to week 68

Semaglutide 2.4 mg Placebo

Full analysis set (N) 535 268

Baseline1 (kg) 96.5 95.4

Change (%) from baseline1,2,3 -7.9 6.9

Difference (%) from placebo2 [95% CI] -14.8 [-16.0; -13.5]* -

Change (kg) from baseline -7.1 6.1

Difference (kg) from placebo2 [95% CI] -13.2 [-14.3; -12.0] -

Waist circumference (cm)

Baseline 105.5 104.7

Change from baseline1 -6.4 3.3

Difference from placebo2 [95% CI] -9.7 [-10.9; -8.5]* -

Systolic blood pressure (mmHg)

Baseline1 121 121

Change from baseline1,2 0.5 4.4

Difference from placebo2 [95% CI] -3.9 [-5.8; -2.0]* -

* p<0.0001 (unadjusted 2-sided) for superiority.1 Baseline = week 202 Estimated using an ANCOVA model using multiple imputation based on all data irrespective of discontinuation of randomised treatment orinitiation of other anti-obesity medication or bariatric surgery.3 During the trial, randomised treatment was permanently discontinued by 5.8% and 11.6% of patients randomized to semaglutide 2.4 mg andplacebo, respectively. Assuming that all randomised patients stayed on treatment and did not receive additional anti-obesity therapies, theestimated changes from randomisation to week 68 for body weight based on a Mixed Model for Repeated Measures including allobservations until first discontinuation were -8.8% and 6.5% for semaglutide 2.4 mg and placebo respectively.

- 5.4 -5.0

- 17.7 -17.4(MI)

Weeks

Wegovy Placebo Multiple imputation (MI)

Observed values for patients completing each scheduled visit, and estimates with multiple imputations (MI) from retrieved dropouts

Figure 3 STEP 4: Mean change in body weight (%) from week 0 to week 68

In a 104-week double-blind trial, 304 patients with obesity (BMI ≥30 kg/m2), or with overweight(BMI ≥27 to <30 kg/m2) and at least one weight-related comorbidity, were randomised to semaglutideor placebo. All patients were on a reduced-calorie diet and increased physical activity throughout thetrial. At baseline, patients had a mean BMI of 38.5 kg/m2, a mean body weight of 106.0 kg.

Treatment with semaglutide for 104 weeks resulted in a superior and clinically meaningful reductionin body weight compared to placebo. Mean body weight decreased from baseline through to week 68with semaglutide after which a plateau was reached. With placebo, mean body weight decreased less,and a plateau was reached after approximately 20 weeks of treatment (see Table 8 and Figure 4).

Patients treated with semaglutide achieved a mean change in body weight of -15.2%, with weight loss≥5% achieved by 74.7%, ≥10% achieved by 59.2% and ≥15% achieved by 49.7% of these patients.

Among patients with prediabetes at baseline, 80% and 37% achieved a normo-glycaemic status at endof treatment with semaglutide and placebo, respectively.

Table 8 STEP 5: Results at week 104

Semaglutide 2.4 mg Placebo

Full analysis set (N) 152 152

Baseline (kg) 105.6 106.5

Change (%) from baseline1, 2 -15.2 -2.6

Difference (%) from placebo1 [95% CI] -12.6 [-15.3; -9.8]* -

Change (kg) from baseline -16.1 -3.2

Difference (kg) from placebo1 [95% CI] -12.9 [-16.1; -9.8] -

Patients (%) achieving weight loss ≥5%3 74.7* 37.3

Patients (%) achieving weight loss ≥10%3 59.2* 16.8

Patients (%) achieving weight loss ≥15%3 49.7* 9.2

Waist circumference (cm)

Baseline 115.8 115.7

Change from baseline1 -14.4 -5.2

Difference from placebo1 [95% CI] -9.2 [-12.2; -6.2]* -

Systolic blood pressure (mmHg)

Baseline 126 125

Change from baseline1 -5.7 -1.6

Difference from placebo1 [95% CI] -4.2 [-7.3; -1.0]* -

* p<0.0001 (unadjusted 2-sided) for superiority.

1 Estimated using an ANCOVA model using multiple imputation based on all data irrespective of discontinuation of randomised treatment orinitiation of other anti-obesity medication or bariatric surgery.2 During the trial, randomised treatment was permanently discontinued by 13.2% and 27.0% of patients randomised to semaglutide 2.4 mgand placebo, respectively. Assuming that all randomised patients stayed on treatment and did not receive additional anti-obesity therapies,the estimated changes from randomisation to week 104 for body weight based on a Mixed Model for Repeated Measures including allobservations until first discontinuation were -16.7% and -0.6% for semaglutide and placebo respectively.3 Estimated from binary regression model based on same imputation procedure as in primary analysis.

- 1.9 -2.6

- 15.2

- 15.9

Weeks

Wegovy Placebo Multiple imputation (MI)

Observed values for patients completing each scheduled visit, and estimates with multiple imputations (MI) from retrieved dropouts

Figure 4 STEP 5: Mean change in body weight (%) from week 0 to week 104

In a 68-week, randomised, open-label, pairwise placebo-controlled trial, 338 patients with obesity(BMI ≥30 kg/m2), or with overweight (BMI ≥27 to <30 kg/m2) and at least one weight-relatedcomorbidity, were randomised to semaglutide once weekly, liraglutide 3 mg once daily or placebo.

Semaglutide once weekly and liraglutide 3 mg were open-label, but each active treatment group wasdouble-blinded against placebo administered at the same dosing frequency. All patients were on areduced-calorie diet and increased physical activity throughout the trial. At baseline, patients had amean BMI of 37.5 kg/m2, a mean body weight of 104.5 kg.

Treatment with semaglutide once weekly for 68 weeks resulted in superior and clinically meaningfulreduction in body weight compared to liraglutide. Mean body weight decreased from baseline throughto week 68 with semaglutide. With liraglutide, mean body weight decreased less (see Table 9). 37.4%of the patients treated with semaglutide lost ≥20%, compared to 7.0% treated with liraglutide. Table 9shows the results of the confirmatory endpoints ≥10%, ≥15% and ≥20% weight loss.

Table 9 STEP 8: Results of a 68-week trial comparing semaglutide with liraglutide

Semaglutide 2.4 mg Liraglutide 3 mg

Full analysis set (N) 126 127

Baseline (kg) 102.5 103.7

Change (%) from baseline1, 2 -15.8 -6.4

Difference (%) from liraglutide1 [95% CI] -9.4 [-12.0;-6.8]* -

Change (kg) from baseline -15.3 -6.8

Difference (kg) from liraglutide1 [95% CI] -8.5 [-11.2;-5.7] -

Patients (%) achieving weight loss ≥10%3 69.4* 27.2

Patients (%) achieving weight loss ≥15%3 54.0* 13.4

Patients (%) achieving weight loss ≥20%3 37.4* 7.0

* p<0.005 (unadjusted 2-sided) for superiority.1 Estimated using an ANCOVA model using multiple imputation based on all data irrespective of discontinuation of randomised treatment orinitiation of other anti-obesity medication or bariatric surgery.2 During the trial, randomised treatment was permanently discontinued by 13.5% and 27.6% of patients randomised to semaglutide 2.4 mgand liraglutide 3 mg, respectively. Assuming that all randomised patients stayed on treatment and did not receive additional anti-obesitytherapies, the estimated changes from randomisation to week 68 for body weight based on a Mixed Model for Repeated Measures includingall observations until first discontinuation were -16.7% and -6.7% for semaglutide 2.4 mg and liraglutide 3 mg respectively.3 Estimated from binary regression model based on same imputation procedure as in primary analysis.

STEP 9: Weight management in patients with knee osteoarthritis

In a 68-week double-blind trial, 407 patients with obesity and moderate knee osteoarthritis (OA) ofone or both knees were randomised to either semaglutide or placebo, as an adjunct to counselling on areduced-calorie diet and increased physical activity. The treatment effect on knee OA-related pain wasassessed by the Western Ontario and McMaster Universities Osteoarthritis 3.1 Index (WOMAC). Thisindex is designed to evaluate changes in symptoms and lower extremity functioning associated withtreatment in patients suffering from OA of the hip and/or knee. At baseline, patients had a mean BMIof 40.3 kg/m2 and a mean body weight of 108.6 kg. All patients had a clinical diagnosis of knee OAwith a mean baseline WOMAC pain score of 70.9 (on a scale of 0-100).

Treatment with semaglutide for 68 weeks resulted in superior and clinically significant reduction inbody weight compared to placebo (see Table 10).

Treatment with semaglutide demonstrated a clinically meaningful improvement in knee OA-relatedpain compared to the placebo (see Table 10). The improvements in knee OA-related pain withsemaglutide were achieved without an increase in the use of pain medication.

Table 10 STEP 9: Results at week 68

Semaglutide 2.4 mg Placebo

Full analysis set (N) 271 136

Baseline (kg) 108.7 108.5

Change (%) from baseline1,2 -13.7 -3.2

Difference (%) from placebo1 [95% CI] -10.5 [-12.3; -8.6]* -

Patients (%) achieving weight loss ≥5%3 85.2* 33.6

WOMAC pain score4

Baseline 72.8 67.2

Change from baseline1,2 -41.7 -27.5

Difference from placebo1 [95% CI] -14.1 [-20.0, -8.3]* -

Patients (%) achieving clinically meaningful 59.0 35.0improvement 3, 5

* p< 0.0001 (unadjusted 2-sided) for superiority.1 Estimated using an ANCOVA model using multiple imputation based on all data irrespective of discontinuation of randomised treatment orinitiation of other anti-obesity therapies or other knee OA interventions and regardless of compliance with wash out period for painmedication (the latter only relevant for WOMAC related endpoint). During the trial, randomised treatment was permanently discontinued by12.5% and 21.3% of patients randomised to semaglutide 2.4 mg and placebo, respectively.2 Based on a Mixed Model for Repeated Measures assuming that all randomised patients stayed on treatment and did not receive additionalanti-obesity therapies or additional knee OA interventions and complied with washout period for pain medication (the latter only relevant forknee OA related pain), including all observations until first discontinuation the estimated changes from baseline to week 68 for body weightwere -14.5% and -2.3% (semaglutide 2.4 mg and placebo, respectively) and for WOMAC pain score: -43.0 and -28.3 (semaglutide 2.4 mgand placebo, respectively).3 Estimated from logistic regression model based on same imputation procedure as for the primary analysis.4 WOMAC scores are presented on a scale from 0-100, with lower scores representing less disability.5 The change in WOMAC pain score of ≤ -37.3 was used as a threshold for meaningful improvement. The threshold was derived from trialdata using anchor-based methods.

In a sub-study in STEP 1 (N = 140), body composition was measured using dual energy X-rayabsorptiometry (DEXA). The results of the DEXA assessment showed that treatment with semaglutidewas accompanied by greater reduction in fat mass than in lean body mass leading to an improvementin body composition compared to placebo after 68 weeks. Furthermore, this reduction in total fat masswas accompanied by a reduction in visceral fat. These results suggest that most of the total weight losswas attributable to a reduction in fat tissue, including visceral fat.

Semaglutide showed small improvements in physical functioning scores. Physical functioning wasassessed using both the generic health-related quality of life questionnaire Short Form-36v2 Health

Survey, Acute Version (SF-36) and the obesity-specific questionnaire Impact of Weight on Quality of

Life Lite Clinical Trials Version (IWQOL-Lite-CT).

SELECT: Cardiovascular outcomes trial in patients with overweight or obesity

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 semaglutide 2.4 mg (n=8 803) or placebo (n=8 801) in addition to standard-of-care. Themedian time in trial was 41.8 months. Vital status was available for 99.4% of subjects in the trial.

The study population consisted of 27.7% female and 72.3% male patients, with a mean age of61.6 years, including 38.2% patients ≥ 65 years (n=6 728) and 7.8% patients ≥ 75 years (n=1 366).

The mean BMI was 33.3 kg/m2 and mean body weight was 96.7 kg. Patients with history of type 1 andtype 2 diabetes 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. Theprimary endpoint, time to first MACE, occurred in 1 270 of the 17 604 patients included in the

SELECT trial. Specifically, 569 first MACE (6.5%) were recorded among the 8 803 patients treatedwith semaglutide, compared to 701 first MACE (8.0%) among the 8 801 patients treated with placebo.

A total of 63 (11.1%) of the first MACE with semaglutide and 80 (11.4%) with placebo wereundetermined cause of death.

Superiority of semaglutide 2.4 mg versus placebo for MACE was confirmed with a hazard ratio of0.80 [0.72; 0.90][95% CI], corresponding to a relative risk reduction in MACE of 20 % (see Figure 5).

The effect on each component to the reduction of MACE is shown in Figure 6. The reduction of

MACE with semaglutide 2.4 mg was not impacted by age, sex, race, ethnicity, BMI at baseline, orlevel of renal function impairment.

Analysis of the cardiovascular death (the first confirmatory secondary endpoint) resulted in a hazardratio of 0.85 [0.71; 1.01][95% CI].

Placebo

Sema 2.4 mg4 HR: 0.8095% CI[0.72 - 0.90]0 6 12 18 24 30 36 42 48

Patients at risk Time from randomisation (months)

Sema 2.4 mg 8 803 8 695 8 561 8 427 8 254 7 229 5 777 4 126 1 734

Placebo 8 801 8 652 8 487 8 326 8 164 7 101 5 660 4 015 1 672

Data from the in-trial period. Cumulative incidence estimates are based on time from randomisation to first EAC-confirmed MACE withnon-CV death modelled as competing risk using the Aalen-Johansen estimator. Subjects without events of interest were censored at the end

Patients with Event (%)of their in-trial observation period. Time from randomisation to first MACE was analysed using a Cox proportional hazards model withtreatment as categorical fixed factor. The hazard ratio and confidence interval are adjusted for the group sequential design using thelikelihood ratio ordering. The x-axis is truncated at 50 months where approximately 10% of the population was still in the trial.

HR: hazard ratio, CI: Confidence interval, Sema 2.4 mg: semaglutide 2.4 mg.

CV: cardiovascular, EAC: event adjudication committee, MACE: major adverse cardiovascular event.

Figure 5: Time from randomisation to first MACE Cumulative incidence function plot

Number of events/analysed subjects(Sema 2.4 mg;

HR [95% CI] Placebo)

Primary endpoints and components

Primary endpoint 0.80 [0.72; 0.90] 569/8 803; 701/8 801

CV death 0.85 [0.71; 1.01] 223/8 803; 262/8 801

Non-fatal MI 0.72 [0.61; 0.85] 234/8 803; 322/8 801

Non-fatal stroke 0.93 [0.74; 1.15] 154/8 803; 165/8 801

Secondary confirmatory endpoints

Heart failure composite 0.82 [0.71; 0.96] 300/8 803; 361/8 801

Favours Favours

All-cause death Sema 2.4 mg Placebo 0.81 [0.71; 0.93] 375/8 803; 458/8 8010.4 0.6 1 1.4 2

Data from the in-trial period. Time from randomisation to each endpoint was analysed using a Cox proportional hazards model withtreatment as categorical fixed factor. Subjects without events of interest were censored at the end of their in-trial period. For the primaryendpoint the HR and CI were adjusted for the group sequential design using likelihood ratio ordering. Secondary endpoints are not undermultiplicity control. CV death includes both cardiovascular death and undetermined cause of death.

HR: hazard ratio, CI: Confidence interval, Sema 2.4 mg: semaglutide 2.4 mg.

CV: cardiovascular, MI: myocardial infarction, Heart failure (HF) composite consisting of HF hospitalisation, urgent HF visit or CV death.

Figure 6: Forest plot of time from randomisation to first MACE, MACE components andsecondary confirmatory endpoints

SUSTAIN 6: Cardiovascular outcomes trial in patients with type 2 diabetes

In the SUSTAIN 6 trial, 3 297 patients with insufficiently controlled type 2 diabetes and at high risk ofcardiovascular events were randomised to semaglutide s.c. 0.5 mg or 1 mg once-weekly or placebo inaddition to standard-of-care. The treatment duration was 104 weeks. The mean age was 65 years andthe mean BMI was 33 kg/m2.

The primary endpoint was the time from randomisation to first occurrence of a major adversecardiovascular event (MACE): cardiovascular death, non-fatal myocardial infarction or non-fatalstroke. The total number of the MACE was 254, including 108 (6.6%) with semaglutide and146 (8.9%) with placebo.

The cardiovascular safety of treatment with semaglutide 0.5 or 1 mg was confirmed as the hazard ratio(HR) for semaglutide vs. placebo was 0.74, [0.58, 0.95] [95% CI], driven by a decrease in the rate ofnon-fatal stroke and non-fatal myocardial infarction with no difference in cardiovascular death (see

Figure 7).

HR: 0.7495% CI 0.58: 0.95

Number of subjects at risk

Semaglutide

Placebo

Time from randomization (week)

Semaglutide Placebo

Figure 7: Kaplan-Meier plot of time to first occurrence of the composite outcome:

Cardiovascular death, non-fatal myocardial infarction or non-fatal stroke (SUSTAIN 6)

STEP-HFpEF and STEP-HFpEF-DM: Functional outcome trials in patients with heart failure withpreserved ejection fraction without and with type 2 diabetes

In two 52-week double-blinded clinical trials, 529 patients with obesity-related heart failure withpreserved ejection fraction (STEP-HFpEF), and 616 patients with obesity-related HFpEF and type 2diabetes (STEP-HFpEF-DM) were randomised to be treated with either semaglutide 2.4 mg or placeboonce weekly in addition to standard of care treatment.

At baseline, 66.2% and 70.6% of the patients were classified as New York Heart Association (NYHA)class II, 33.6% and 29.2% were NYHA class III and 0.2% and 0.2% were NYHA class IV, in STEP-

HFpEF and STEP HFpEF-DM respectively. Mean age was 68 years in both trials, median leftventricular ejection fraction (LVEF) was 57.0% and 56.0%, and mean BMI was 38.5 kg/m2 and37.9 kg/m2. The STEP-HFpEF trial included 56.1% females, whereas 44.3% were female in STEP-

HFpEF-DM. A high proportion of patients were on cardiovascular medications including ~ 81% ondiuretics, ~ 81% on beta blockers, ~ 34% on angiotensin converting enzyme (ACE) inhibitors and ~45% on angiotensin receptor blockers (ARBs).

In STEP-HFpEF-DM patients were also receiving standard of care glucose lowering medications ofwhich 32.8% were treated with sodium/glucose cotransporter-2 inhibitor (SGLT-2i) and 20.8% weretreated with insulin.

The treatment effect of semaglutide 2.4 mg on heart failure symptoms was assessed using the Clinical

Summary Score of the Kansas City Cardiomyopathy Questionnaire (KCCQ-CSS) which includes thedomains of symptom (frequency and burden) and physical limitation. The score ranges from 0 to 100,with higher scores representing better health status. The treatment effect of semaglutide 2.4 mg on 6-

Minute Walk Distance (6MWD) was assessed by the 6-Minute Walk Test (6MWT). Baseline valuesof KCCQ-CSS and 6MWD reflect a highly symptomatic population.

In both trials treatment with semaglutide 2.4 mg resulted in a superior effect on both KCCQ-CSS and6MWD (Table 11). Benefits were seen both in heart failure symptoms and physical function.

Patients with event (%)

Table 11 Results of 6MWD, KCCQ-CSS and body weight from the two 52-weekrandomised trials (STEP-HFpEF and STEP-HFpEF-DM)

STEP-HFpEF STEP-HFpEF-DM

Semaglutide Placebo Semaglutide Placebo2.4 mg 2.4 mg

Full analysis set (N) 263 266 310 306

KCCQ-CSS (score)

Baseline (mean)1 57.9 55.5 58.8 56.4

Change from baseline2 16.6 8.7 13.7 6.4

Difference from placebo2 7.8 [4.8; 10.9] 7.3 [4.1; 10.4][95% CI]

Patients (%) experiencing 43.2 32.5 42.7 30.5meaningful change36MWD (metres)

Baseline (mean)1 319.6 314.6 279.7 276.7

Change from baseline2 21.5 1.2 12.7 -1.6

Difference from placebo2 20.3 [8.6; 32.1] 14.3 [3.7; 24.9][95% CI]

Patients (%) with meaningful 47.9 34.7 43.8 30.6change4

Baseline (kg)1 108.3 108.4 106.4 105.2

Change (%) from baseline2 -13.3 -2.6 -9.8 -3.4

Difference (%) from placebo2 -10.7 [-11.9; -9.4] -6.4 [-7.6; -5.2][95% CI]1 Observed mean.2 Estimated using an ANCOVA model using multiple imputation and for KCCQ and 6MWD, also a composite imputation based on all datairrespective of discontinuation of randomised treatment or initiation of other anti-obesity medication or bariatric surgery.3 Meaningful within patient change threshold of 17.2 points for STEP-HFpEF trial and 16.3 points for STEP-HFpEF-DM trial (derived usingan anchor-based method based on a 1-category improvement in Patient Global Impression of Status (PGI-S)). Percentages are based onsubjects with an observation at the visit.4 Meaningful within patient change threshold of 22.1 metres for STEP-HFpEF trial and 25.6 metres for STEP-HFpEF-DM trial (derivedusing an anchor-based method using “moderately better” in Patient Global Impression of Change (PGI-C)). Percentages are based onsubjects with an observation at the visit.

The treatment benefit of semaglutide over placebo was consistent across all subpopulations defined byage, sex, BMI, race, ethnicity, region, systolic blood pressure (SBP), LVEF and concomitant heartfailure therapy.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Wegovy in one or more subsets of the paediatric population in the treatment of weight management(see section 4.2 for information on paediatric use).

STEP TEENS: Weight management in adolescent patients

In a 68-week double-blind trial 201 pubertal adolescents, ages 12 to <18 years, with obesity oroverweight and at least one weight-related comorbidity were randomised 2:1 to semaglutide orplacebo. All patients were on a reduced-calorie diet and increased physical activity throughout thetrial.

At end of treatment (week 68), the improvement in BMI with semaglutide was superior and clinicallymeaningful compared with placebo (see Table 12 and Figure 8). Furthermore, a higher proportion ofpatients achieved ≥5%, 10% and ≥15% weight loss with semaglutide compared with placebo (see

Table 12).

Table 12 STEP TEENS: Results at week 68

Semaglutide 2.4 mg Placebo

Full analysis set (N) 134 67

BMI

Baseline (BMI) 37.7 35.7

Change (%) from baseline1,2 -16.1 0.6

Difference (%) from placebo1 [95% CI] -16.7 [-20.3; -13.2]* -

Baseline (BMI SDS) 3.4 3.1

Change from baseline in BMI SDS1 -1.1 -0.1

Difference from placebo1 [95% CI] -1.0 [-1.3; -0.8] -

Body Weight

Baseline (kg) 109.9 102.6

Change (%) from baseline1 -14.7 2.8

Difference (%) from placebo1 [95% CI] -17.4 [-21.1; -13.8] -

Change (kg) from baseline1 -15.3 2.4

Difference (kg) from placebo1 [95% CI] -17.7 [-21.8; -13.7] -

Patients (%) achieving weight loss ≥5%3 72.5* 17.7

Patients (%) achieving weight loss ≥10%3 61.8 8.1

Patients (%) achieving weight loss ≥15%3 53.4 4.8

Waist circumference (cm)

Baseline 111.9 107.3

Change from baseline1 -12.7 -0.6

Difference from placebo1 [95% CI] -12.1 [-15.6; -8.7] -

Systolic blood pressure (mmHg)

Baseline 120 120

Change from baseline1 -2.7 -0.8

Difference from placebo1 [95% CI] -1.9 [-5.0; 1.1] -

* p<0.0001 (unadjusted 2-sided) for superiority.1 Estimated using an ANCOVA model using multiple imputation based on all data irrespective of discontinuation of randomised treatment orinitiation of other anti-obesity medication or bariatric surgery.2 During the trial, randomised treatment was permanently discontinued by 10.4% and 10.4% of patients randomised to semaglutide 2.4 mgand placebo, respectively. Assuming that all randomised patients stayed on treatment and did not receive additional anti-obesity therapies,the estimated changes from randomisation to week 68 for BMI based on a Mixed Model for Repeated Measures including all observationsuntil first discontinuation were -17.9% and 0.6% for semaglutide 2.4 mg and placebo respectively3 Estimated from logistic regression model based on same imputation procedure as in primary analysis.

0.6

- 0.1

- 16.2 -16.1(MI)

Weeks

Wegovy Placebo Multiple imputation (MI)

Observed values for patients completing each scheduled visit, and estimates with multiple imputations (MI) from retrieved dropouts

Figure 8 STEP TEENS: Mean change in BMI (%) from baseline to week 68

Compared to native GLP-1, semaglutide has a prolonged half-life of around 1 week making it suitablefor once weekly subcutaneous administration. The principal mechanism of protraction is albuminbinding, which results in decreased renal clearance and protection from metabolic degradation.

Furthermore, semaglutide is stabilised against degradation by the DPP-4 enzyme.

The average semaglutide steady state concentration following s.c. administration of the semaglutidemaintenance dose was approximately 75 nmol/L in patients with overweight (BMI ≥27 kg/m2 to<30 kg/m2) or obesity (BMI ≥30 kg/m2) based on data from phase 3a trials, where 90% of patients hadaverage concentrations between 51 nmol/L and 110 nmol/L. The steady state exposure of semaglutideincreased proportionally with doses from 0.25 mg up to 2.4 mg once weekly. Steady state exposurewas stable with time as assessed up to week 68. Similar exposure was achieved with s.c.administration of semaglutide in the abdomen, thigh, or upper arm. The absolute bioavailability ofsemaglutide was 89%.

The mean volume of distribution of semaglutide following s.c. administration in patients withoverweight or obesity was approximately 12.4 L. Semaglutide is extensively bound to plasma albumin(>99%).

Prior to excretion, semaglutide is extensively metabolised through proteolytic cleavage of the peptidebackbone and sequential beta-oxidation of the fatty acid side chain. The enzyme neutral endopeptidase(NEP) was identified as one of the active metabolic enzymes.

The primary excretion routes of semaglutide-related material are via the urine and faeces.

Approximately 3% of the absorbed dose was excreted in the urine as intact semaglutide.

The clearance of semaglutide in patients with overweight (BMI ≥27 kg/m2 to <30 kg/m2) or obesity(BMI ≥30 kg/m2) was approximately 0.05 L/h. With an elimination half-life of approximately 1 week,semaglutide will be present in the circulation for approximately 7 weeks after the last dose of 2.4 mg.

Age had no effect on the pharmacokinetics of semaglutide based on data from phase 3 trials includingpatients 18-86 years of age.

Gender, race (White, Black or African American, Asian) and ethnicity (Hispanic or Latino, non-

Hispanic or -Latino) had no effect on the pharmacokinetics of semaglutide based on data from phase3a trials.

Body weight had an effect on the exposure of semaglutide. Higher body weight was associated withlower exposure; a 20% difference in body weight between individuals will result in an approximate18% difference in exposure. The 2.4 mg weekly dose of semaglutide provided adequate systemicexposures over the body weight range of 54.4−245.6 kg evaluated for exposure response in the clinicaltrials.

Renal impairment did not impact the pharmacokinetics of semaglutide in a clinically relevant manner.

This was shown with a single dose of 0.5 mg semaglutide for patients with different degrees of renalimpairment (mild, moderate, severe or patients in dialysis) compared with patients with normal renalfunction. This was also shown for patients with overweight (BMI ≥27 kg/m2 to <30 kg/m2) or obesity(BMI ≥30 kg/m2) and mild to moderate renal impairment based on data from phase 3a trials.

Hepatic impairment did not have any impact on the exposure of semaglutide. The pharmacokinetics ofsemaglutide were evaluated in patients with different degrees of hepatic impairment (mild, moderate,severe) and compared with patients with normal hepatic function in a study with a single dose of0.5 mg semaglutide.

Prediabetes and diabetes did not have any clinically relevant effect on the exposure of semaglutidebased on data from phase 3 trials.

Development of anti-semaglutide antibodies when treated with semaglutide occurred infrequently (seesection 4.8) and the response did not appear to influence semaglutide pharmacokinetics.

Paediatrics

Pharmacokinetic properties for semaglutide were assessed in a clinical trial for adolescent patientswith obesity or overweight and at least one weight-related comorbidity ages 12 to <18 years(124 patients, body weight 61.6-211.9 kg). The semaglutide exposure in adolescents was similar tothat in adults with obesity or overweight.

Safety and efficacy of semaglutide in children below 12 years of age have not been studied.

Preclinical data reveal no special hazards for humans based on conventional studies of safetypharmacology, repeat-dose toxicity or genotoxicity.

Non-lethal thyroid C-cell tumours observed in rodents are a class effect for GLP-1 receptor agonists.

In 2-year carcinogenicity studies in rats and mice, semaglutide caused thyroid C-cell tumours atclinically relevant exposures. No other treatment-related tumours were observed. The rodent C-celltumours are caused by a non-genotoxic, specific GLP-1 receptor mediated mechanism to whichrodents are particularly sensitive. The relevance for humans is considered to be low, but cannot becompletely excluded.

In fertility studies in rats, semaglutide did not affect mating performance or male fertility. In femalerats, an increase in oestrous cycle length and a small reduction in corpora lutea (ovulations) wereobserved at doses associated with maternal body weight loss.

In embryo-foetal development studies in rats, semaglutide caused embryotoxicity below clinicallyrelevant exposures. Semaglutide caused marked reductions in maternal body weight and reductions inembryonic survival and growth. In foetuses, major skeletal and visceral malformations were observed,including effects on long bones, ribs, vertebrae, tail, blood vessels and brain ventricles. Mechanisticevaluations indicated that the embryotoxicity involved a GLP-1 receptor mediated impairment of thenutrient supply to the embryo across the rat yolk sac. Due to species differences in yolk sac anatomyand function, and due to lack of GLP-1 receptor expression in the yolk sac of non-human primates,this mechanism is considered unlikely to be of relevance to humans. However, a direct effect ofsemaglutide on the foetus cannot be excluded.

In developmental toxicity studies in rabbits and cynomolgus monkeys, increased pregnancy loss andslightly increased incidence of foetal abnormalities were observed at clinically relevant exposures. Thefindings coincided with marked maternal body weight loss of up to 16%. Whether these effects arerelated to the decreased maternal food consumption as a direct GLP-1 effect is unknown.

Postnatal growth and development were evaluated in cynomolgus monkeys. Infants were slightlysmaller at delivery but recovered during the lactation period.

In juvenile rats, semaglutide caused delayed sexual maturation in both males and females. Thesedelays had no impact upon fertility and reproductive capacity of either sex, or on the ability of thefemales to maintain pregnancy.

Disodium phosphate, dihydrate

Sodium chloride

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

Disodium phosphate, dihydrate

Phenol

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injection

In the absence of compatibility studies this medicinal product must not be mixed with other medicinalproducts.

Pre-filled pen, single-dose1 year.

Wegovy may be stored unrefrigerated for up to 28 days at a temperature not above 30°C. Discard thepen if it has been out of the refrigerator for more than 28 days.

Wegovy 0.25 mg FlexTouch solution for injection in pre-filled pen

Before use: 2 years.

After first use: 6 weeks. Store below 30°C or in a refrigerator (2°C to 8°C).

Wegovy 0.5 mg FlexTouch solution for injection in pre-filled pen

Wegovy 1 mg FlexTouch solution for injection in pre-filled pen

Wegovy 1.7 mg FlexTouch solution for injection in pre-filled pen

Wegovy 2.4 mg FlexTouch solution for injection in pre-filled pen

Before use: 3 years.

After first use: 6 weeks. Store below 30°C or in a refrigerator (2°C to 8°C).

Store in a refrigerator (2°C to 8°C). Keep away from the cooling element.

Do not freeze.

Store the pen in the original carton in order to protect from light.

Keep the pen cap on when the pen is not in use in order to protect it from light.

Pre-filled pen, single-dose1 mL glass syringe (type I glass) with attached stainless steel needle, rigid needle shield (type

II/polyisoprene) and a rubber plunger (type I/chlorobutyl).

Pre-filled pen, FlexTouch (0.25, 0.5 mg) 1.5 mL pre-filled pen1.5 mL glass cartridge (type I glass) closed at the one end with a rubber plunger (chlorobutyl) and atthe other end with an aluminium cap with a laminated rubber sheet (bromobutyl/polyisoprene)inserted. The cartridge is assembled into a disposable pre-filled pen made of polypropylene,polyoxymethylene, polycarbonate and acrylonitrile butadiene styrene.

Pre-filled pen, FlexTouch (0.5 1, 1.7 and 2.4 mg) 3 mL pre-filled pen3 mL glass cartridge (type I glass) closed at the one end with a rubber plunger (chlorobutyl) and at theother end with an aluminium cap with a laminated rubber sheet (bromobutyl/polyisoprene) inserted.

The cartridge is assembled into a disposable pre-filled pen made of polypropylene, polyoxymethylene,polycarbonate and acrylonitrile butadiene styrene.

Pre-filled pen, single-dose (0.25, 0.5, 1, 1.7 and 2.4 mg)

Pack size of 4 pre-filled pens.

Pack size of 1 pre-filled pen and 4 disposable NovoFine Plus needles.

Pack sizes:1 pre-filled pen and 4 disposable NovoFine Plus needles.3 pre-filled pens and 12 disposable NovoFine Plus needles.

Not all pack sizes may be marketed.

Wegovy should not be used if it does not appear clear and colourless.

The pen should not be used if it has been frozen.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

The pen is for single-dose only.

This pen is for multi-use. It contains 4 doses.

The patient should be advised to discard the injection needle in accordance with local requirementsafter each injection and store the Wegovy pen without an injection needle attached. This may preventblocked needles, contamination, infection, leakage of solution and inaccurate dosing.

The pen is for use by one person only.

Wegovy can be administered with 30G, 31G, and 32G disposable needles up to a length of 8 mm.

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

EU/1/21/1608/001

EU/1/21/1608/002

EU/1/21/1608/003

EU/1/21/1608/004

EU/1/21/1608/005

EU/1/21/1608/006

EU/1/21/1608/007

EU/1/21/1608/008

EU/1/21/1608/009

EU/1/21/1608/010

EU/1/21/1608/011

EU/1/21/1608/012

Date of first authorisation: 06 January 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.