In the WEGOVY clinical trials for weight reduction and long-term maintenance, 233 (9%) WEGOVY-treated patients were aged 65 to 75 years and 23 (1%) WEGOVY-treated patients were aged 75 years and older

[see Clinical Studies (

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

Overview of Clinical Studies in Adults

The safety and efficacy of WEGOVY 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; and one 68-week, randomized, double-blind trial that investigated 2 different doses of WEGOVY 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 weekly during a 16-week period followed by 52 weeks on maintenance dose. In Study 5 (NCT#03548987), WEGOVY was escalated during a 20-week run-in period, and patients who reached a WEGOVY 2.4 mg subcutaneous weekly dosage after the run-in period were randomized to either continued treatment with WEGOVY or placebo for 48 weeks. In Study 6 (NCT#03811574), WEGOVY 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 Studies 2, 3, and 5, 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 (1,200-1,800 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/m²) or with overweight (BMI 27 to 29.9 kg/m²) 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 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/m².

Study 3 was a 68-week trial that enrolled 807 patients with type 2 diabetes and BMI greater than or equal to 27 kg/m². Patients included in the trial had HbA_1c7-10% 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 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/m².

Study 4 was a 68-week trial that enrolled 611 patients with obesity (BMI greater than or equal to 30 kg/m²) or with overweight (BMI 27 to 29.9 kg/m²) 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 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/m².

Study 5 was a 68-week trial that enrolled 902 patients with obesity (BMI greater than or equal to 30 kg/m²) or with overweight (BMI 27 to 29.9 kg/m²) 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 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 and were then randomized in a 2:1 ratio to either continue on WEGOVY 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/m².

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/m²and at least one weight-related comorbid condition or with BMI 27 to 34.9 kg/m²and at least two weight-related comorbid conditions. The patients were randomized 2:1:1 to receive 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/m². At baseline, 24.7% of patients had type 2 diabetes mellitus.

Results

The proportions of patients who discontinued study drug in Studies 2, 3, and 4 was 16% for the WEGOVY-treated group and 19.1% for the placebo-treated group, and 6.8% of patients treated with WEGOVY and 3.2% of patients treated with placebo discontinued 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 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, WEGOVY 2.4 mg, and placebo, respectively.

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

Table 6

Table 6. Changes in Body Weight at Week 68 in Studies 2, 3, and 4

Baseline mean (kg)% change from baseline (LSMean)% difference from placebo (LSMean) (95% CI)% difference from placebo (LSMean) (95% CI)% difference from placebo (LSMean) (95% CI)% difference from placebo (LSMean) (95% CI)


	Study 2 (Obesity or overweight with comorbidity)		Study 3 (Type 2 diabetes with obesity or overweight)		Study 4 (Obesity or overweight with comorbidity undergoing intensive lifestyle therapy)
Intention-to-Treat¹	PLACEBO N=655	WEGOVY N=1306	PLACEBO N=403	WEGOVY N=404	PLACEBO N=204	WEGOVY N=407
Body Weight

105.2	105.4	100.5	99.9	103.7	106.9

-2.4	-14.9	-3.4	-9.6	-5.7	-16

	-12.4 (‑13.3; ‑11.6)^*		-6.2 (-7.3; -5.2)^*		-10.3 (-11.8; -8.7)^*
% of Patients losing greater than or equal to 5% body weight	31.1	83.5	30.2	67.4	47.8	84.8

	52.4 (48.1; 56.7)^*		37.2 (30.7; 43.8)^*		37 (28.9; 45.2)^*
% of Patients losing greater than or equal to 10% body weight	12	66.1	10.2	44.5	27.1	73

	54.1 (50.4; 57.9)^*		34.3 (28.4; 40.2)^*		45.9 (38; 53.7)^*
% of Patients losing greater than or equal to 15% body weight	4.8	47.9	4.3	25.1	13.2	53.4

	43.1 (39.8; 46.3)^*		20.7 (15.7; 25.8)^*		40.2 (33.1; 47.3)^*

LSMean = least squares mean; CI = confidence interval

¹The 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 and placebo, respectively. In Study 3, at week 68, the body weight was missing for 4% and 6.7% of patients randomized to WEGOVY 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 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 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 resulted in a statistically significant reduction in body weight compared with placebo (

Table 7

). Because patients who discontinued WEGOVY 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.

Table 7. Changes in Body Weight at Week 68 in Study 5 (Obesity or Overweight with Comorbidity after 20-week Run-in)

Mean at week 0 (kg)Mean at week 20 (SD) (kg)% change from week 20 at week 68 (LSMean)% difference from placebo (LSMean) (95% CI)


		WEGOVY N=803¹
Body Weight (only randomized patients)

107.2
		PLACEBO N=268	WEGOVY N=535
Body Weight

95.4 (22.7)	96.5 (22.5)

6.9	-7.9

	-14.8 (-16; -13.5)^*

LSMean = least squares mean; CI = confidence interval

¹902 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 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 resulted in a statistically significant reduction in body weight compared with placebo. Greater proportions of patients treated with WEGOVY 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 Study 6 in East-Asian Patients (WEGOVY 1.7 mg)

Baseline mean (kg)% change from baseline (LSMean)% difference from placebo

(LSMean) (95% CI)% difference from placebo (LSMean) (95% CI)% difference from placebo (LSMean) (95% CI)% difference from placebo (LSMean) (95% CI)


	Study 6 (BMI ≥35 kg/m²with at least one comorbidity or BMI 27-34.9 kg/m²with at least two comorbidities)
Intention-to-treat¹	PLACEBO N=101	WEGOVY 1.7 mg N=101	WEGOVY 2.4 mg N=199
Body Weight

90.2	86.1	86.9

-2.1	-9.6	-13.2

	-7.5 (-9.6; -5.4)*	-11.1 (-12.9; -9.2)*
% of Patients losing greater than or equal to 5% body weight	19.4	72.8	84

	53.3 (41; 65.6)*	64.5 (54.8; 74.3)*
% of Patients losing greater than or equal to 10% body weight	4.5	39.1	59.9

	34.5 (23.9; 45.1)*	55.4 (47.3; 63.6)*
% of Patients losing greater than or equal to 15% body weight	2.6	20.8	38.2

	18.2 (9.8; 26.7)*	35.6 (27.9; 43.3)*

LSMean = least squares mean; CI = confidence interval

¹The 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, WEGOVY 2.4 mg, 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.

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 5

and

Figure 6

for Studies 2 and 3. 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 and placebo curves at approximately 66%, and 12%, respectively, which correspond to the values shown in

Table 6

Figure 5.
Change in body weight (%) from baseline to week 68 (Study 2)

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

Figure 6. Change in body weight (%) from baseline to week 68 (Study 3)

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

The time courses of weight loss with WEGOVY and placebo from baseline through week 68 are depicted in

Figure 7

Figure 8

and

Figure 9

Figure 7.
Change from baseline (%) in body weight (Study 2 on left and Study 3 on right)

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 5^aon right)

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

^aChange 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)

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.

Effect of WEGOVY on Anthropometry and Cardiometabolic Parameters in Adults

Changes in waist circumference and cardiometabolic parameters with WEGOVY are shown in

Table 9

for Studies 2, 3, and 4; in

Table 10

for Study 5; and in

Table 11

for Study 6.

Table 9. Changes in Anthropometry and Cardiometabolic Parameters at Week 68 in Studies 2, 3, and 4

Baseline

Changes from baseline (LSMean¹)

Coverage for Wegovy