WEGOVY (Page 6 of 11)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year carcinogenicity study in CD-1 mice, subcutaneous doses of 0.3, 1 and 3 mg/kg/day (2-, 8-, and 22-fold the maximum recommended human dose [MRHD] of 2.4 mg/week, based on AUC) were administered to the males, and 0.1, 0.3 and 1 mg/kg/day (0.6-, 2-, and 5-fold MRHD) were administered to the females. A statistically significant increase in thyroid C-cell adenomas and a numerical increase in C-cell carcinomas were observed in males and females at all dose levels (greater than or equal to 0.6 times human exposure).

In a 2-year carcinogenicity study in Sprague Dawley rats, subcutaneous doses of 0.0025, 0.01, 0.025 and 0.1 mg/kg/day were administered (below quantification, 0.2-, 0.4-, and 2-fold the exposure at the MRHD). A statistically significant increase in thyroid C-cell adenomas was observed in males and females at all dose levels, and a statistically significant increase in thyroid C-cell carcinomas was observed in males at greater than or equal to 0.01 mg/kg/day, at clinically relevant exposures.

Human relevance of thyroid C-cell tumors in rats is unknown and could not be determined by clinical studies or nonclinical studies [see Boxed Warning and Warnings and Precautions (5.1)]. Semaglutide was not mutagenic or clastogenic in a standard battery of genotoxicity tests (bacterial mutagenicity [Ames] human lymphocyte chromosome aberration, rat bone marrow micronucleus).

In a combined fertility and embryo-fetal development study in rats, subcutaneous doses of 0.01, 0.03 and 0.09 mg/kg/day (0.04-, 0.1-, and 0.4-fold the MRHD) were administered to male and female rats. Males were dosed for 4 weeks prior to mating, and females were dosed for 2 weeks prior to mating and throughout organogenesis until Gestation Day 17. No effects were observed on male fertility. In females, an increase in estrus cycle length was observed at all dose levels, together with a small reduction in numbers of corpora lutea at greater than or equal to 0.03 mg/kg/day. These effects were likely an adaptive response secondary to the pharmacological effect of semaglutide on food consumption and body weight.

14 CLINICAL STUDIES

Overview of Clinical Studies

The safety and efficacy of WEGOVY for chronic weight management (weight loss and maintenance) in conjunction with a reduced calorie diet and increased physical activity were studied in three 68-week, randomized, double-blind, placebo-controlled trials and one 68-week, randomized, double-blind, placebo withdrawal trial. In Studies 1, 2, and 3, 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 4, WEGOVY was escalated during a 20-week run-in period, and patients who reached WEGOVY 2.4 mg after the run-in period were randomized to either continued treatment with WEGOVY or placebo for 48 weeks.

In Studies 1, 2 and 4, all patients received instruction for a reduced calorie meal 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 3, patients received an initial 8-week low-calorie diet (total energy intake 1000 to 1200 kcal/day) followed by 60 weeks of a reduced calorie diet (1200-1800 kcal/day) and increased physical activity (100 mins/week with gradual increase to 200 mins/week).

Study 1 was a 68-week trial that enrolled 1961 patients with obesity (BMI greater than or equal to 30 kg/m2) or with overweight (BMI 27-29.9 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 18-86), 74.1% were women, 75.1% were White, 13.3% were Asian and 5.7% were Black or African American. A total of 12.0% were Hispanic or Latino. Mean baseline body weight was 105.3 kg and mean BMI was 37.9 kg/m2.

Study 2 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 HbA1c 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 or placebo. At baseline, the mean age was 55 years (range 19-84), 50.9% were women, 62.1% were White, 26.2% were Asian and 8.3% were Black or African American. A total of 12.8% were Hispanic or Latino. Mean baseline body weight was 99.8 kg and mean BMI was 35.7 kg/m2.

Study 3 was a 68-week trial that enrolled 611 patients with obesity (BMI greater than or equal to 30 kg/m2) or with overweight (BMI 27-29.9 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, 81.0% were women, 76.1% were White, 19.0% were Black or African American and 1.8% were Asian. A total of 19.8% were Hispanic or Latino. Mean baseline body weight was 105.8 kg and mean BMI was 38.0 kg/m2.

Study 4 was a 68-week trial that enrolled 902 patients with obesity (BMI greater than or equal to 30 kg/m2) or with overweight (BMI 27-29.9 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 women, 83.7% were White, 13% were Black or African American, and 2.4% Asian. A total of 7.8% were Hispanic or Latino. Mean body weight at randomization (week 20) was 96.1 kg and mean BMI at randomization (week 20) was 34.4 kg/m2.

The proportions of patients who discontinued study drug in Studies 1, 2, and 3 was 16.0% 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 4, the proportions of patients who discontinued study drug were 5.8% and 11.6% for WEGOVY and placebo, respectively.

14.1 Weight Management Studies in Adults with Overweight or Obesity

For Studies 1, 2 and 3, 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 4.

Table 4. Changes in Body Weight at Week 68 in Studies 1, 2 and 3

Study 1 (Obesity or overweight with comorbidity) Study 2 (Type 2 diabetes with obesity or overweight) Study 3 (Obesity or overweight with comorbidity undergoing intensive lifestyle therapy)
Intention-to-Treata PLACEBO N = 655 WEGOVY N = 1306 PLACEBO N = 403 WEGOVY N = 404 PLACEBO N = 204 WEGOVY N = 407

Body Weight

Baseline mean (kg)

105.2

105.4

100.5

99.9

103.7

106.9

% change from baseline (LSMean)

-2.4

-14.9

-3.4

-9.6

-5.7

-16.0

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

-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

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

52.4

(48.1; 56.7)*

37.2 (30.7; 43.8)*

37.0 (28.9; 45.2)*

% of Patients losing greater than or equal to 10% body weight

12.0

66.1

10.2

44.5

27.1

73.0

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

54.1

(50.4; 57.9)*

34.3 (28.4; 40.2)*

45.9 (38.0; 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

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

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

a The intent-to-treat population includes all randomized patients. In Study 1, at week 68, the body weight was missing for 7.2% and 11.9% of patients randomized to WEGOVY and placebo, respectively. In Study 2, at week 68, the body weight was missing for 4.0% and 6.7% of patients randomized to WEGOVY and placebo, respectively. In Study 3, 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 4, 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 5). 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 5. Changes in Body Weight at Week 68 — Study 4 (Obesity or overweight with comorbidity after 20 week run-in)

WEGOVY

N = 803a

Body Weight (only randomized patients)

Mean at week 0 (kg)

107.2

PLACEBO

N = 268

WEGOVY

N = 535

Body Weight

Mean at week 20 (SD) (kg)

95.4 (22.7)

96.5 (22.5)

% change from week 20 at week 68 (LSMean)

6.9

-7.9

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

-14.8 (-16.0; -13.5)*

LSMean = least squares mean; CI = confidence interval

a 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 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.

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 4 and Figure 5 for Studies 1 and 2. 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 1 intersects the WEGOVY and placebo curves at approximately 66%, and 12%, respectively, which correspond to the values shown in Table 4.

Figure 4. Change in body weight (%) from baseline to week 68 (Study 1)

fig 4
(click image for full-size original)

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

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

fig 5
(click image for full-size original)

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 Figures 6 and Figure 7.

Figure 6. Change from baseline (%) in body weight (Study 1 on left and Study 2 on right)

fig 6
(click image for full-size original)

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

Figure 7. Change from baseline (%) in body weight (Study 3 on left and Study 4a on right)

fig 7
(click image for full-size original)

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 4. Dotted line indicates time of randomization. Randomized patients (shown) do not include 99 patients that discontinued during the 20 week run-in period.

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