Wegovy results

Cardiovascular Outcomes Trial in Adult Patients with Cardiovascular Disease and Either Obesity or Overweight

Overview of Clinical Trial

Study 1 (NCT03574597) was a multi-national, multi-center, placebo-controlled, double-blind trial to determine the effect of WEGOVY injection relative to placebo on major adverse CV events (MACE) when added to current standard of care, which included management of CV risk factors and individualized healthy lifestyle counseling (including diet and physical activity) in adults with established CV disease and either obesity or overweight. The primary endpoint, MACE, was the time to first occurrence of a three-part composite outcome which included CV death, non-fatal myocardial infarction, and non-fatal stroke. During the 16-week dose escalation period, patients were titrated to WEGOVY 2.4 mg injected subcutaneously once weekly or placebo. Patients who could not tolerate the recommended escalation dosage could stay at a lower dose level.

All patients were 45 years or older, with an initial BMI of 27 kg/m 2 or greater and established CV disease (prior myocardial infarction, prior stroke, or peripheral arterial disease). Patients with a history of type 1 or type 2 diabetes were excluded. Concomitant CV therapies could be adjusted, at the discretion of the investigator, to ensure participants were treated according to the current standard of care for patients with established CV disease.

In this trial, 17,604 patients were randomized to WEGOVY injection or placebo. At baseline, the mean age was 62 years (range 45 to 93), 72% were male, 84% were White, 4% were Black or African American, and 8% were Asian, and 10% were Hispanic or Latino. Mean baseline body weight was 97 kg and mean BMI was 33 kg/m 2 . At baseline, prior myocardial infarction was reported in 76% of randomized individuals, prior stroke in 23%, and peripheral arterial disease in 9%. Heart failure was reported in 24% of patients. At baseline, CV disease and risk factors were managed with lipid-lowering therapy (90%), platelet aggregation inhibitors (86%), angiotensin converting enzyme inhibitors or angiotensin II receptor blockers (74%), and beta blockers (70%). A total of 10% had moderate renal impairment (eGFR 30 to <60 mL/min/1.73m 2 ) and 0.4% had severe renal impairment eGFR <30 mL/min/1.73m 2 .

Results

In total, 96.9% of patients completed the trial, and vital status was available for 99.4% of patients. The median follow-up duration was 41.8 months. A total of 31% of WEGOVY injection-treated patients and 27% of placebo-treated patients permanently discontinued study drug. Of those patients on treatment at 1 year, 76% were on the 2.4 mg dose, 8% were on the 1.7 mg dose, and 16% were on lower doses. Of those patients on treatment at 2 years, 77% were on the 2.4 mg dose, 7% were on the 1.7 mg dose, and 17% were on lower doses.

For the primary analysis, a Cox proportional hazards model was used to test for superiority. Type 1 error was controlled across multiple tests.

WEGOVY injection significantly reduced the risk for first occurrence of MACE. The estimated hazard ratio (95% CI) was 0.80 (0.72, 0.90) (see Figure 2 and Table 6 ).

Figure 2. Cumulative Incidence Function: Time to First Occurrence of MACE in Study 1 with WEGOVY Injection

Data from the in-trial period. Cumulative incidence estimates are based on time from randomization to first EAC-confirmed cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke with non-CV death modeled as competing risk using the Aalen-Johansen estimator. Patients without events of interest were censored at the end of their in-trial observation period. Time from randomization to first cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke was analyzed using a Cox proportional hazards model with treatment as categorical fixed factor. The hazard ratio and confidence interval are adjusted for the group sequential design using the likelihood ratio ordering.

HR: Hazard ratio; CI: confidence interval; CV: cardiovascular

The treatment effect for the primary composite endpoint, its components, and other relevant endpoints in Study 1 are shown in Table 6 .

Table 6. Treatment Effect for MACE and Other Events in Study 1 with WEGOVY Injection

* p-value <0.001, one-sided p-value

1 Primary endpoint

2 Adjusted for group sequential design using the likelihood ratio ordering.

3 CV death was the first confirmatory secondary endpoint in the testing hierarchy and superiority was not confirmed.

4 Confirmatory secondary endpoint. Not statistically significant based on the prespecified testing hierarchy.

5 Not included in the prespecified testing hierarchy for controlling type-I error.

6 Effect on heart failure has not been established.

NOTE: Time to first event was analyzed in a Cox proportional hazards model with treatment as factor. For patients with multiple events, only the first event contributed to the composite endpoint.

Table 7. Mean Changes in Anthropometry and Cardiometabolic Parameters at Week 104 in Study 11,2

1 Parameters listed in the table were not included in the pre-specified hierarchical testing.

2 Responses were analyzed using an ANCOVA with treatment as fixed factor and baseline value as covariate. Before analysis, missing data were multiple imputed. The imputation model (linear regression) was done separately for each treatment arm and included baseline value as a covariate and was fitted to all subjects with a measurement regardless of treatment status at Week 104.

3 For body weight the ‘change from baseline’ and ‘difference to placebo’ the unit is percentage change from baseline.

4 Baseline value is the geometric mean.

The reduction of MACE with WEGOVY injection was not impacted by age, sex, race, ethnicity, BMI at baseline, or level of renal function impairment.

Weight Reduction and Long-term Maintenance Studies in Adults with Obesity or Overweight

Overview of Clinical Trials in Adults

The efficacy of WEGOVY once weekly subcutaneous injection for weight reduction and long-term maintenance of body weight in conjunction with a reduced-calorie diet and increased physical activity were studied in three 68-week, randomized, double-blind, placebo-controlled trials; one 68-week, randomized, double-blind, placebo withdrawal trial; one 68-week, randomized, double-blind trial that investigated two different doses of WEGOVY injection versus placebo and two 72-week randomized, double-blind trials that investigated two different doses of WEGOVY injection versus placebo. In Studies 2 (NCT#03548935), 3 (NCT#03552757), and 4 (NCT#03611582), WEGOVY or matching placebo was escalated to 2.4 mg subcutaneous injection weekly during a 16-week period followed by 52 weeks on maintenance dose. In Study 5 (NCT#03548987), WEGOVY injection was escalated during a 20-week run-in period, and patients who reached a WEGOVY 2.4 mg subcutaneous injection weekly dosage after the run-in period were randomized to either continued treatment with WEGOVY injection or placebo for 48 weeks. In Study 6 (NCT#03811574), WEGOVY injection was escalated to 1.7 mg or 2.4 mg subcutaneous weekly dosages or placebo over 12 to 16 weeks followed by 52 weeks on either maintenance dose. In Study 8 (NCT#05646706) and Study 9 (NCT#05649137) WEGOVY injection was escalated to 2.4 mg or 7.2 mg subcutaneous weekly dosages or placebo over 20 weeks followed by 52 weeks on maintenance dose.

The efficacy of WEGOVY 25 mg oral once daily tablet for weight reduction and long-term maintenance of body weight in conjunction with a reduced-calorie diet and increased physical activity was evaluated in a 64-week randomized, double-blind, placebo-controlled trial [Study 7 (NCT#05564117)]. WEGOVY tablet or matching placebo was escalated to a 25 mg tablet once daily during a 12-week period followed by 52-week maintenance period.

In Studies 2, 3, 5, 7, 8 and 9, all patients received instruction for a reduced-calorie diet (approximately 500 kcal/day deficit) and increased physical activity counseling (recommended to a minimum of 150 min/week) that began with the first dose of study medication or placebo and continued throughout the trial. In Study 4, patients received an initial 8-week low-calorie diet (total energy intake 1,000 to 1,200 kcal/day) followed by 60 weeks of a reduced-calorie diet (1200 to 1800 kcal/day) and increased physical activity (100 mins/week with gradual increase to 200 mins/week).

Study 2 was a 68-week trial that enrolled 1,961 patients with obesity (BMI greater than or equal to 30 kg/m 2 ) or with overweight (BMI 27 to 29.9 kg/m 2 ) and at least one weight-related comorbid condition, such as treated or untreated dyslipidemia or hypertension; patients with type 2 diabetes mellitus were excluded. Patients were randomized in a 2:1 ratio to either WEGOVY injection or placebo. At baseline, mean age was 46 years (range 18 to 86), 74% were female, 75% were White, 13% were Asian and 6% were Black or African American. A total of 12% were Hispanic or Latino ethnicity. Mean baseline body weight was 105.3 kg and mean BMI was 37.9 kg/m 2 .

Study 3 was a 68-week trial that enrolled 807 patients with type 2 diabetes and BMI greater than or equal to 27 kg/m 2 . Patients included in the trial had HbA 1c 7-10% and were treated with either: diet and exercise alone or 1 to 3 oral anti‑diabetic drugs (metformin, sulfonylurea, glitazone or sodium-glucose co-transporter 2 inhibitor). Patients were randomized in a 1:1 ratio to receive either WEGOVY injection or placebo. At baseline, the mean age was 55 years (range 19 to 84), 51% were female, 62% were White, 26% were Asian and 8% were Black or African American. A total of 13% were Hispanic or Latino ethnicity. Mean baseline body weight was 99.8 kg and mean BMI was 35.7 kg/m 2 .

Study 4 was a 68-week trial that enrolled 611 patients with obesity (BMI greater than or equal to 30 kg/m 2 ) or with overweight (BMI 27 to 29.9 kg/m 2 ) and at least one weight-related comorbid condition such as treated or untreated dyslipidemia or hypertension; patients with type 2 diabetes mellitus were excluded. The patients were randomized in a 2:1 ratio to receive either WEGOVY injection or placebo. At baseline, the mean age was 46 years, 81% were female, 76% were White, 19% were Black or African American and 2% were Asian. A total of 20% were Hispanic or Latino ethnicity. Mean baseline body weight was 105.8 kg and mean BMI was 38 kg/m 2 .

Study 5 was a 68-week trial that enrolled 902 patients with obesity (BMI greater than or equal to 30 kg/m 2 ) or with overweight (BMI 27 to 29.9 kg/m 2 ) and at least one weight-related comorbid condition such as treated or untreated dyslipidemia or hypertension; patients with type 2 diabetes mellitus were excluded. Mean body weight at baseline for the 902 patients was 106.8 kg and mean BMI was 38.3 kg/m². All patients received WEGOVY injection during the run-in period of 20 weeks that included 16 weeks of dose escalation. Trial product was permanently discontinued before randomization in 99 of 902 patients (11%); the most common reason was adverse reactions (n=48, 5.3%); 803 patients reached WEGOVY 2.4 mg injection and were then randomized in a 2:1 ratio to either continue on WEGOVY injection or receive placebo. Among the 803 randomized patients, the mean age was 46 years, 79% were female, 84% were White, 13% were Black or African American, and 2% Asian. A total of 8% were Hispanic or Latino ethnicity. Mean body weight at randomization (Week 20) was 96.1 kg and mean BMI at randomization (Week 20) was 34.4 kg/m 2 .

Study 6 was a 68-week trial that enrolled 401 East-Asian patients (Japan and South Korea) with BMI greater than or equal to 35 kg/m 2 and at least one weight-related comorbid condition or with BMI 27 to 34.9 kg/m 2 and at least two weight-related comorbid conditions. The patients were randomized 2:1:1 to receive subcutaneous injection of WEGOVY 2.4 mg, WEGOVY 1.7 mg, or placebo. At baseline, the mean age was 51 years, 63% were male, and all patients were Asian. Mean baseline body weight was 87.5 kg and mean BMI was 31.9 kg/m 2 . At baseline, 24.7% of patients had type 2 diabetes mellitus.

Study 7 was a 64-week trial that enrolled 307 patients with obesity (BMI greater than or equal to 30 kg/m 2 ) or with overweight (BMI 27-29.9 kg/m 2 ) and at least one weight-related comorbid condition, such as treated or untreated dyslipidemia or hypertension; patients with type 2 diabetes mellitus were excluded. Patients were randomized in a 2:1 ratio to either WEGOVY 25 mg tablet or placebo. At baseline, mean age was 48 years, 79% were women, 92% were White, 1% were Asian and 7% were Black or African American. A total of 7.8% were Hispanic or Latino ethnicity. Mean baseline body weight was 106 kg and mean BMI was 38 kg/m 2 .

Study 8 was a 72-week trial that enrolled 1,407 patients with obesity (BMI greater than or equal to 30 kg/m 2 ), patients with type 2 diabetes mellitus were excluded. Patients were randomized in a 5:1:1 ratio to either WEGOVY 7.2 mg, WEGOVY 2.4 mg or placebo once weekly. At baseline, mean age was 47 years (range 18 to 80), 74% were female, 86% were White, 4% were Asian and 9% were Black or African American. A total of 5% were Hispanic or Latino ethnicity. Mean baseline body weight was 113 kg and mean BMI was 39.9 kg/m 2 .

Study 9 was a 72-week trial that enrolled 512 patients with obesity and type 2 diabetes. Patients included in the trial had HbA 1c 7 to 10% and were treated with either: diet and exercise alone or 1 to 3 oral antidiabetic drugs (metformin, sulfonylurea, glitazone or sodium-glucose co-transporter 2 inhibitor). Patients were randomized in a 3:1:1 ratio to receive either WEGOVY 7.2 mg, WEGOVY 2.4 mg or placebo once weekly. At baseline, the mean age was 56 years (range 19 to 79), 52% were female, 84% were White, 6% were Asian and 9% were Black or African American. A total of 6% were Hispanic or Latino ethnicity. Mean baseline body weight was 110.1 kg and mean BMI was 38.6 kg/m 2 .

Results

In Studies 2, 3, and 4, 16% of WEGOVY injection-treated patients and 19% of the placebo-treated patients discontinued therapy. In these studies, 6.8% of WEGOVY injection-treated patients and 3.2% of placebo-treated patients discontinued their treatment due to an adverse reaction [see Adverse Reactions (6.1)] . In Study 5, the proportions of patients who discontinued study drug were 5.8% and 11.6% for WEGOVY injection and placebo, respectively. In Study 6, the proportions of patients who discontinued study drug were 7.9%, 6.5%, and 3% for WEGOVY 1.7 mg injection, WEGOVY 2.4 mg injection, and placebo, respectively. In Study 7, the proportions of patients who discontinued study drug were 18% and 25.5% for WEGOVY 25 mg tablet and placebo, respectively. Adverse reactions led to treatment discontinuation in 6.8% of patients treated with WEGOVY 25 mg tablet and 5.9% patients receiving placebo. In Study 8, 5.4% of patients treated with WEGOVY 7.2 mg and 1% patients treated with placebo permanently discontinued treatment as a result of adverse reactions. In Study 9, 5.5% of patients treated with WEGOVY 7.2 mg and 2% patients treated with placebo permanently discontinued treatment as a result of adverse reactions.

For Studies 2, 3 and 4, the primary efficacy parameters were mean percent change in body weight and the percentages of patients achieving greater than or equal to 5% weight loss from baseline to Week 68.

After 68 weeks, treatment with WEGOVY injection resulted in a statistically significant reduction in body weight compared with placebo. Greater proportions of patients treated with WEGOVY injection achieved 5%, 10% and 15% weight loss than those treated with placebo as shown in Table 8 .

• Table 8. Changes in Body Weight at Week 68 in Studies 2, 3, and 4 with WEGOVY 2.4 mg Injection

LSMean = least squares mean; CI = confidence interval

1 The intent-to-treat population includes all randomized patients. In Study 2, at Week 68, the body weight was missing for 7.2% and 11.9% of patients randomized to WEGOVY injection and placebo, respectively. In Study 3, at Week 68, the body weight was missing for 4% and 6.7% of patients randomized to WEGOVY injection and placebo, respectively. In Study 4, at Week 68, the body weight was missing for 8.4% and 7.4% of patients randomized to WEGOVY injection and placebo, respectively. Missing data were imputed from retrieved subjects of the same randomized treatment arm (RD-MI).

2 Not included in the pre-specified hierarchical testing.

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

For Study 5, the primary efficacy parameter was mean percent change in body weight from randomization (Week 20) to Week 68.

From randomization (week 20) to Week 68, treatment with WEGOVY injection resulted in a statistically significant reduction in body weight compared with placebo ( Table 9 ). Because patients who discontinued WEGOVY injection during titration and those who did not reach the 2.4 mg weekly dose were not eligible for the randomized-treatment period, the results may not reflect the experience of patients in the general population who are first starting WEGOVY injection.

Table 9. Changes in Body Weight at Week 68 in Study 5 (Obesity or Overweight with Comorbidity After 20-week Run-in) with WEGOVY 2.4 mg Injection

LSMean = least squares mean; CI = confidence interval

1 902 patients were enrolled at Week 0 with a mean baseline body weight of 106.8 kg. The intent-to-treat population includes all randomized patients. At Week 68, the body weight was missing for 2.8% and 6.7% of patients randomized to WEGOVY injection and placebo, respectively. Missing data were imputed from retrieved subjects of the same randomized treatment arm (RD-MI).

* p<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity.

For Study 6, the primary efficacy parameters were mean percent change in body weight and the percentage of patients achieving greater than or equal to 5% weight loss from baseline to Week 68.

After 68 weeks, treatment with WEGOVY 1.7 mg and 2.4 mg injection resulted in a statistically significant reduction in body weight compared with placebo. Greater proportions of patients treated with WEGOVY injection achieved 5%, 10%, and 15% weight loss than those treated with placebo as shown in Table 10 .

Table 10. Changes in Body Weight at Week 68 in Study 6 in East-Asian Patients with WEGOVY 1.7 and 2.4 mg Injection

LSMean = least squares mean; CI = confidence interval

1 The intent-to-treat population includes all randomized patients. At baseline, 24.7% of patients had type 2 diabetes mellitus. At Week 68, the body weight was missing for 3%, 3%, and 1% of patients randomized to WEGOVY 1.7 mg injection, WEGOVY 2.4 mg injection, and placebo, respectively. Missing data were imputed from retrieved subjects of the same randomized treatment arm (RD-MI).

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

For Study 7, the primary efficacy parameters were mean percent change in body weight and the percentages of patients achieving greater than or equal to 5% weight loss from baseline to Week 64.

After 64 weeks, treatment with WEGOVY 25 mg tablets resulted in a statistically significant reduction in body weight compared with placebo. Greater proportions of patients treated with WEGOVY 25 mg tablets achieved 5%, 10%, 15% and 20% weight loss than those treated with placebo as shown in Table 11 .

Table 11. Changes in Body Weight at Week 64 in Study 7 with WEGOVY 25 mg Tablets

LSMean = least squares mean; CI = confidence interval

1 The intent-to-treat population includes all randomized patients. In Study 7, at Week 64, the body weight was missing for 6.3% and 11.8% of patients randomized to WEGOVY tablets and placebo, respectively.

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

3 Model based estimates are based on an analysis of covariance (or logistic regression for the 5%, 10%, 15% or 20% achievement endpoints) including treatment as a factor and baseline value as a covariate. Missing data were multiple imputed from retrieved subjects of the same randomized treatment arm (RD-MI). The imputation model was a linear regression of the endpoint with gender as factor and baseline value of the endpoint, timing and the value of last available observation – on study (LAO-OS) of the endpoint as covariates, imputed by treatment status. For the 5%, 10%, 15% or 20% achievement endpoints, the missing body weight measurements were imputed before performing the logistic regression analyses.

RD-MI: Retrieved Drop-outs Multiple Imputation

For Studies 8 and 9, the primary efficacy parameters were mean percent change in body weight and the percentages of patients achieving greater than or equal to 5% weight loss from baseline to Week 72.

After 72 weeks of treatment, WEGOVY 7.2 mg injection resulted in a statistically significant reduction in body weight compared with placebo in Studies 8 and 9 (see Table 12 and Figures 6 and 10 ).

Table 12. Changes in Body Weight at Week 72 in Studies 8 and 9 with WEGOVY 7.2 mg Injection

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

** This endpoint was not included in the hierarchy testing and is only for informative purposes.

1 The intent-to-treat population includes all randomized patients. In Study 8, at Week 72, the body weight was missing for 5.5%, 6.0% and 15.0% of patients randomized to WEGOVY 7.2 mg, WEGOVY 2.4 mg and placebo, respectively. In Study 9, at week 72, the body weight was missing for 5.2% and 6.9% of patients randomized to WEGOVY 7.2 mg and placebo, respectively.

a Model based estimates are based on an analysis of covariance (or logistic regression for the 5%, 10%, 15% or 20% achievement endpoints) including treatment as a factor and baseline value as a covariate. Missing data were multiple imputed from retrieved subjects of the same randomized treatment arm (RD-MI) in Study 8 or all retrieved subjects regardless of treatment arm assignment in Study 9. The imputation model was a linear regression of the endpoint with gender as factor and baseline value of the endpoint, timing and the value of last available observation – on study (LAO-OS) of the endpoint as covariates, imputed by treatment status. For the 5%, 10%, 15% or 20% achievement endpoints, the missing body weight measurements were imputed before performing the logistic regression analyses.

RD-MI: Retrieved Drop-outs Multiple Imputation

A reduction in body weight was observed with WEGOVY irrespective of age, sex, race, ethnicity, BMI at baseline, body weight (kg) at baseline, and level of renal function impairment.

The cumulative frequency distributions of change in body weight are shown in Figure 3 , Figure 4 , Figure 5 and Figure 6 for Studies 2, 3, 7 and 8. One way to interpret this figure is to select a change in body weight of interest on the horizontal axis and note the corresponding proportions of patients (vertical axis) in each treatment group who achieved at least that degree of weight loss. For example, note that the vertical line arising from ‑10% in Study 2 intersects the WEGOVY injection and placebo curves at approximately 66%, and 12%, respectively, which correspond to the values shown in Table 8 .

Figure 3. Change in Body Weight (%) from Baseline to Week 68 (Study 2) with WEGOVY Injection

Observed data from in-trial period including imputed data for missing observations (RD-MI).

Figure 4. Change in Body Weight (%) from Baseline to Week 68 (Study 3) with WEGOVY Injection

Observed data from in-trial period including imputed data for missing observations (RD-MI).

Figure 5. Change in Body Weight (%) from Baseline to Week 64 (Study 7) with WEGOVY 25 mg Tablets

Observed data from in-trial period including imputed data for missing observations (RD-MI). The missing observation was the patient-level average from the 1,000 imputed datasets.

Figure 6. Change in Body Weight (%) from Baseline to Week 72 (Study 8) with WEGOVY 7.2 mg Injection

Observed data from in-trial period including imputed data for missing observations (RD-MI). Missing observations were multiply (x1000) imputed from retrieved participants of the same randomized treatment arm and missing value was replaced by the average across imputations.

The time courses of weight loss with WEGOVY injection and placebo from baseline through Week 68 are depicted in Figures 7 , 8 , and 9 , and through Week 72 in Figure 10 .

Figure 7. Change from Baseline (%) in Body Weight (Study 2 on Left and Study 3 on Right) with WEGOVY Injection

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

Figure 8. Change from Baseline (%) in Body Weight (Study 4 on Left and Study 5a on Right) with WEGOVY Injection

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

a Change from Week 0 was not a primary endpoint in Study 5. Dotted line indicates time of randomization. Randomized patients (shown) do not include 99 patients that discontinued during the 20-week run-in period.

Figure 9. Change in Body Weight (%) from Baseline to Week 68 (Study 6 in East-Asian Patients) with WEGOVY Injection

Observed values for patients completing each scheduled visit and estimates with multiple imputations from retrieved dropouts (RD-MI). At baseline, 24.7% of patients had type 2 diabetes mellitus.

Figure 10. Mean Change in Body Weight (%) from Baseline to Week 72 (WEGOVY 7.2 mg Injection– Study 8)

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

Effect of WEGOVY Injection on Anthropometry and Cardiometabolic Parameters in Adults

Changes in waist circumference and cardiometabolic parameters with WEGOVY injection are shown in Table 13 for Studies 2, 3, and 4; in Table 14 for Study 5; in Table 15 for Study 6; Table 16 for Study 7, and in Table 17 for Studies 8 and 9.

Table 13. Changes in Anthropometry and Cardiometabolic Parameters at Week 68 in Studies 2, 3 and 4 with WEGOVY Injection

Missing data were imputed from retrieved subjects of the same randomized treatment arm (RD-MI).

1 Model based estimates based on an analysis of covariance model including treatment (and stratification factors for Study 3 only) as a factor and baseline value as a covariate.

2 Not included in the pre-specified hierarchical testing (except HbA 1c for Study 3).

3 Model based estimates based on a mixed model for repeated measures including treatment (and stratification factors for Study 3 only) as a factor and baseline values as a covariate.

4 Baseline value is the geometric mean.

Table 14. Mean Changes in Anthropometry and Cardiometabolic Parameters in Study 5 (Obesity or Overweight with Comorbidity After 20-week Run-in)1 with WEGOVY Injection

Missing data were imputed from retrieved subjects of the same randomized treatment arm (RD-MI).

1 Model based estimates based on an analysis of covariance model including treatment as a factor and baseline value as a covariate.

2 Not included in the pre-specified hierarchical testing.

3 Model based estimates based on a mixed model for repeated measures including treatment as a factor and baseline values as a covariate.

4 Baseline value is the geometric mean.

Table 15. Mean Changes in Anthropometry and Cardiometabolic Parameters at Week 68 in Study 6 in East-Asian Patients with WEGOVY Injection

Missing data were imputed from retrieved subjects of the same randomized treatment arm (RD-MI). At baseline, 24.7% of patients had type 2 diabetes mellitus.

1 Model based estimates based on an analysis of covariance model including treatment and type 2 diabetes status as factors and baseline value as a covariate.

2 Not included in the pre-specified hierarchical testing.

3 Model based estimates based on a mixed model for repeated measures including treatment and type 2 diabetes status as factors and baseline values as a covariate.

4 Baseline value is the geometric mean.

Table 16. Mean Changes in Anthropometry and Cardiometabolic Parameters in Study 7 with WEGOVY 25 mg Tablets (Obesity or Overweight with Comorbidity)

1 Model based estimates are based on an analysis of covariance including treatment as a factor and baseline value as a covariate. Missing data were multiple imputed from retrieved subjects of the same randomized treatment arm (RD-MI). The imputation model was a linear regression of the endpoint with gender as factor and baseline value of the endpoint, timing and the value of last available observation – on study (LAO-OS) of the endpoint as covariates, imputed by treatment status.

RD-MI: Retrieved Drop-outs Multiple Imputation

2 Not included in the pre-specified hierarchical testing.

3 Baseline value is the geometric mean.

Table 17. Changes in Anthropometry and Cardiometabolic Parameters at Week 72 in Studies 8 and 9 (WEGOVY 7.2 mg Injection)

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

The difference or relative difference from placebo was comparison between Wegovy 7.2 mg and the placebo arms.

1 Model based estimates based on an analysis of covariance model including randomized treatment as factor and baseline value as a covariate Missing data were multiple imputed from retrieved subjects of the same randomized treatment arm (RD-MI) in Study 8 or all retrieved subjects regardless of treatment arm assignment in Study 9. The imputation model was a linear regression of the endpoint with gender as factor and baseline value of the endpoint, timing and the value of last available observation – on study (LAO-OS) of the endpoint as covariates, imputed by treatment status.

RD-MI: Retrieved Drop-outs Multiple Imputation

• 2 Not included in the pre-specified hierarchical testing (except the comparison between placebo and Wegovy 7.2 mg in Study 8 and Study 9 for waist circumference and HbA 1c for Study 9).

3 Baseline value is the geometric mean.

Weight Reduction and Long-term Maintenance Study of WEGOVY Injection in Pediatric Patients Aged 12 Years and Older with Obesity

Overview of Clinical Trial in Pediatric Patients

WEGOVY injection was evaluated to reduce excess body weight in pediatric patients aged 12 years of age and older with obesity in a 68-week, double-blind, randomized, parallel group, placebo-controlled, multi-center trial in 201 pubertal pediatric patients aged 12 years and older with BMI corresponding to ≥95th percentile standardized for age and sex (Study 10) (NCT#04102189). After a 12-week lifestyle run-in period (including dietary recommendations and physical activity counseling), patients were randomized 2:1 to WEGOVY injection once weekly or placebo once weekly. WEGOVY injection or matching placebo was escalated to 2.4 mg or maximally tolerated dose during a 16-week period followed by 52 weeks on maintenance dose. Of WEGOVY injection-treated patients who completed the trial, 86.7% were on the 2.4 mg dosage at the end of the trial; for 5% of patients, 1.7 mg was the maximum tolerated dosage.

The mean age was 15 years; 38% of patients were male; 79% were White, 8% were Black or African American, 2% were Asian, and 11% were of other or unknown race; and 11% were of Hispanic or Latino ethnicity. The mean baseline body weight was 108 kg, and mean BMI was 37 kg/m 2 .

Results

The proportions of patients who discontinued study drug were 10% for the WEGOVY injection-treated group and 10% for the placebo-treated group.

The primary endpoint was percent change in BMI from baseline to Week 68. After 68 weeks, treatment with WEGOVY injection resulted in a statistically significant reduction in percent BMI compared with placebo. Greater proportions of patients treated with WEGOVY injection achieved ≥5% reduction in baseline BMI than those treated with placebo as shown in Table 18 .

Table 18. Changes in Weight and BMI at Week 68 in Pediatric Patients with Obesity Aged 12 Years and Older in Study 10 with WEGOVY 2.4 mg Injection in Study 10

LSMean = least squares mean; CI = confidence interval

a The intention-to-treat population includes all randomized patients. Missing data were imputed using available data according to value and timing of last available observation on treatment and endpoint’s baseline value from retrieved subjects (RD-MI). At Week 68, the BMI was missing for 2.2% and 7.5% of patients randomized to WEGOVY injection and placebo, respectively.

b Parameters not included in the pre-specified hierarchical testing.

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

The time course of change in BMI with WEGOVY injection and placebo from baseline through Week 68 is depicted in Figure 11 . The cumulative frequency distribution of change in BMI is shown in Figure 12 .

Figure 11. Change from Baseline (%) in BMI in Pediatric Patients with Obesity Aged 12 Years and Older in Study 10 with WEGOVY Injection

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

Figure 12. Change in BMI (%) from Baseline to Week 68 in Pediatric Patients with Obesity Aged 12 Years and Older in Study 10 with WEGOVY Injection

Observed data from in-trial period including imputed data for missing observations (RD-MI).

Effect of WEGOVY Injection on Anthropometry and Cardiometabolic Parameters in Pediatric Patients with Obesity Aged 12 Years and Older

Changes in waist circumference and cardiometabolic parameters with WEGOVY injection are shown in Table 19 for the study in pediatric patients aged 12 years and older.

Table 19. Mean Changes in Anthropometry and Cardiometabolic Parameters in Pediatric Patients with Obesity Aged 12 Years and Older in Study 10 with WEGOVY Injection

1 Parameters listed in the table were not included in the pre-specified hierarchical testing.

2 Missing data were imputed using available data according to value and timing of last available observation on treatment and endpoint’s baseline value from retrieved subjects (RD-MI). Model based estimates based on an analysis of covariance model including treatment and stratification groups (gender, Tanner stage group) and the interaction between stratification groups as factors and baseline value as a covariate.

3 Model based estimates based on a mixed model for repeated measures including treatment as a factor and baseline value as a covariate all nested within visit.

4 For patients without type 2 diabetes at randomization (N=129 for WEGOVY injection-treated patients and N=64 for placebo-treated patients).

5 Baseline value is the geometric mean.

Noncirrhotic Metabolic Dysfunction-associated Steatohepatitis with Moderate to Advanced Liver Fibrosis in Adults Treated with WEGOVY Injection

Overview of Clinical Trial

The efficacy of WEGOVY injection was evaluated based on an efficacy analysis at Week 72 in Study 11 (NCT#04822181), a 240-week, randomized, double-blind, placebo-controlled trial. Enrolled patients had a baseline or recent liver biopsy showing clinically significant MASLD (metabolic dysfunction-associated steatotic liver disease), defined as MASH with fibrosis stage 2 or 3 and a non-alcoholic fatty liver disease (NAFLD) Activity Score (NAS) ≥4 with a score of 1 or more in steatosis, lobular inflammation, and hepatocyte ballooning. Efficacy determination was based on the effect of WEGOVY injection on resolution of steatohepatitis without worsening of liver fibrosis and on at least one stage improvement in liver fibrosis without worsening of steatohepatitis, on post-baseline liver biopsies collected at 72 weeks.

The Week 72 analysis included 800 F2 and F3 (at eligibility) patients randomized 1:2 to receive placebo (n=266) or WEGOVY once weekly (n=534), in addition to standard of care for cardiometabolic comorbidities and healthy lifestyle counseling. WEGOVY injection or matching placebo was escalated to 2.4 mg once weekly during the initial 16 weeks of the treatment period. Dose escalation could be prolonged or patients could remain at a lower dose if 2.4 mg once weekly was not tolerable.

Demographic and baseline characteristics were balanced between treatment and placebo groups. Overall, the median (Q1 to Q3) age of patients at baseline was 57 (49 to 65) years, 57% were female, 18% were Hispanic, 68% were White, 27% were Asian, and 0.6% were Black or African American. Median (Q1 to Q3) body mass index (BMI) was 34 (30 to 38) kg/m 2 and median (Q1 to Q3) body weight was 93 (79 to 110) kg. Baseline characteristics are presented in Table 20 .

Table 20. Baseline Characteristics in Adults Patients with Noncirrhotic MASH with Stage 2 to Stage 3 Fibrosis in Study 11

a Less than 5% missingness in the variable is omitted.

b Lean MASH defined as BMI <25 kg/m 2 for non-Asian patients and BMI <23 kg/m 2 for Asian patients.

Among the 79% of the patients with vibration-controlled transient elastography (VCTE) at baseline, median (Q1 to Q3) VCTE was 10.9 (8.6 to 15.5) kPa, which may not be representative of the entire study population. The 21% of patients with missing VCTE at baseline had higher percentages of being female and having baseline diabetes, hypertension, and dyslipidemia.

Results

Table 21 presents the Week 72 histopathology primary endpoint results comparing WEGOVY injection with placebo on:

1) the estimated percentage of patients with resolution of steatohepatitis and no worsening of liver fibrosis and 2) the estimated percentage of patients with at least one stage improvement in liver fibrosis and no worsening of steatohepatitis. The secondary endpoint results of the estimated percentage of patients with resolution of steatohepatitis and improvement in liver fibrosis at Week 72 are also presented. Two pathologists independently read the liver biopsies for each patient; a third pathologist performed adjudication if consensus could not be reached between the two pathologists. WEGOVY injection demonstrated improvement on these histopathology endpoints at Week 72 compared to placebo.

Table 21. Efficacy Results at Week 72 in Adult Patients with Noncirrhotic MASH with Stage 2 or

Stage 3 Fibrosis in Study 11 of WEGOVY Injection

* Results were statistically significant.

Endpoints were evaluated according to the MASH Clinical Research Network (CRN). Resolution of steatohepatitis is defined as a score of 0 to 1 for lobular inflammation, 0 for ballooning, and any value for steatosis. No worsening of steatohepatitis is defined as no increase from baseline in score for ballooning, lobular inflammation, or steatosis.

Estimated using pooled Mantel-Haenszel (MH) estimates stratified by baseline type 2 diabetes status (presence or absence) and baseline fibrosis stage (F2 or F3) with missing data handled by reference-based multiple imputation and 95% confidence intervals (CIs) calculated using Rubin’s rule to pool Sato’s estimate of standard errors across the imputed datasets.

Another secondary endpoint was the percent change in body weight from baseline to Week 72. Patients treated with WEGOVY injection (mean baseline body weight 95.4 kg) achieved an average of 10.5% weight loss from baseline at Week 72, and patients treated with placebo (mean baseline weight 97.6 kg) achieved an average of 2% weight loss from baseline at Week 72; treatment with WEGOVY injection resulted in an average of 8.5% greater weight loss from baseline compared to placebo (95% CI: 7.4% to 9.5%).

Starting at Week 12 and through Week 72, there was a trend of greater reductions from baseline in average ALT and AST in the WEGOVY injection group as compared to the placebo group.