Foundayo results

Overview of Trials 1 and 2

The effectiveness of FOUNDAYO has been established in combination with a reduced-calorie diet and increased physical activity to reduce excess body weight and maintain weight reduction long term in adults with obesity or adults with overweight in the presence of at least one weight-related comorbid condition based on adequate and well-controlled trials of an investigational orforglipron formulation (Trials 1 and 2), referred to in this section as FOUNDAYO. This section of labeling presents efficacy data from administration of the investigational orforglipron formulation shown as equivalent dosages of once daily FOUNDAYO [see Dosage and Administration (2.1)] .

FOUNDAYO was studied in two randomized, double-blind, placebo-controlled trials (Trials 1 and 2) in adults aged 18 years and older. In these trials, all patients received standard lifestyle intervention which included instruction on reduced-calorie diet and physical activity counseling (recommended minimum of 150 minutes/week) that began with the first dose of trial medication or placebo and continued throughout the trials.

In Trial 1 patients were randomized in a 3:3:3:4 ratio to FOUNDAYO 5.5 mg once daily, 9 mg once daily, 17.2 mg once daily, or placebo once daily. In Trial 2 patients were randomized in a 1:1:1:2 ratio to FOUNDAYO 5.5 mg once daily, 9 mg once daily, 17.2 mg once daily, or placebo once daily. In Trials 1 and 2, dosages were titrated according to the dosage escalation described in Section 2.1 . In these trials, the primary efficacy parameter was mean percent change in body weight after 72 weeks of treatment.

Trial 1 (NCT05869903) was a 72-week trial that enrolled 3,127 adult patients with obesity (BMI ≥30 kg/m 2 ), or with overweight (BMI 27 to <30 kg/m 2 ) and at least one weight-related comorbid condition, such as dyslipidemia, hypertension, obstructive sleep apnea, or cardiovascular disease; patients with type 2 diabetes were excluded. At baseline, mean age was 45 years (range 18 to 88 years), 64% were female, 56% were White, 28% were Asian, 9% were Black or African American, and 0.4% were American Indian/Alaska Native. A total of 38% were Hispanic or Latino ethnicity. Mean baseline body weight was 103.2 kg and mean BMI was 37 kg/m 2 . At baseline, 40% of patients had hypertension, 39% had dyslipidemia, 11% had obstructive sleep apnea, 1.4% had coronary artery disease, and 1.5% had cerebrovascular disease.

Trial 2 (NCT05872620) was a 72-week trial that enrolled 1,613 adult patients with BMI ≥27 kg/m 2 and type 2 diabetes. Patients included in the trial had baseline HbA1c 7% to 10% and were treated with either diet and exercise alone, or any oral anti-hyperglycemic agent except dipeptidyl peptidase-4 (DPP-4) inhibitors or GLP-1 receptor agonists. Patients who were taking injectable glucose-lowering agents, including insulin, GLP-1 receptor agonists, or pramlintide were also excluded. At baseline, mean age was 57 years (range 20 to 92 years), 47% were female, 71% were White, 17% were Asian, 7% were Black or African American, and 0.3% were American Indian/Alaska Native. A total of 30% were Hispanic or Latino ethnicity. Mean baseline body weight was 101.4 kg, mean BMI was 35.6 kg/m 2 , and mean HbA1c was 8%. At baseline, 74% of patients had hypertension, 71% had dyslipidemia, 13% had obstructive sleep apnea, 7% had coronary artery disease, 5% had cerebrovascular disease, and 11% had diabetic retinopathy.

Results for Trials 1 and 2

The proportions of patients who discontinued trial drug in Trial 1 were 22%, 22%, and 24% for the 5.5 mg, 9 mg, and 17.2 mg once daily FOUNDAYO-treated groups, respectively, and 30% for the placebo-treated group. The proportion of patients who discontinued trial drug in Trial 2 were 19%, 22%, and 20% for the 5.5 mg, 9 mg, and 17.2 mg once daily FOUNDAYO-treated groups, respectively, and 20% for the placebo-treated group.

For Trials 1 and 2, the primary efficacy parameter was mean percent change in body weight from baseline to Week 72. After 72 weeks of treatment in Trials 1 and 2, there was a statistically significant reduction in body weight in the FOUNDAYO-treated groups compared with the placebo groups (see Table 6 ). A reduction in body weight was observed with FOUNDAYO regardless of age, sex, race, ethnicity, baseline BMI, and glycemic status.

The time courses of weight reduction from baseline with FOUNDAYO and placebo through Week 72 are depicted in Figure 1 for Trial 1 and Figure 2 for Trial 2.

Figure 1: Change Over Time in Body Weight in Trial 1 in Patients with Obesity or Overweight with ≥1 Weight-related Comorbid Condition (without Type 2 Diabetes)

Abbreviation: W72 TRE = treatment effect under treatment regimen estimand at Week 72.

Displayed results are from randomized patients and treatment regimen estimand data points set. (1) Observed mean value from Week 0 to Week 72, and (2) model-based estimate ± standard error at Week 72 using primary modified multiple imputation.

Figure 2: Change Over Time in Body Weight in Trial 2 in Patients with Obesity or Overweight and Type 2 Diabetes

Abbreviation: W72 TRE = treatment effect under treatment regimen estimand at Week 72.

Displayed results are from randomized participants and treatment regimen estimand data points set. (1) Observed mean value from Week 0 to Week 72, and (2) model-based estimate ± standard error at Week 72 using primary modified multiple imputation.

The cumulative frequency distributions of percentage change in body weight are shown in Figure 3 for Trial 1 and Figure 4 for Trial 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 reduction. For example, the vertical line arising from -10% in Figure 3 intersects the FOUNDAYO 17.2 mg once daily and placebo curves at approximately 55% and 13%, respectively, which correspond to the values shown in Table 6 .

Figure 3: Changes in Body Weight (%) from Baseline to Week 72 in Trial 1 in Patients with Obesity or Overweight with ≥1 Weight-related Comorbid Condition (without Type 2 Diabetes)

Note: Based on average percent weight change of each randomized patient within each specific treatment group from 100 imputed datasets including observed data and imputed data using the primary modified multiple imputation method for missing values.

Figure 4: Changes in Body Weight (%) from Baseline to Week 72 in Trial 2 in Patients with Obesity or Overweight and Type 2 Diabetes

Based on average percent weight change of each randomized patient within each specific treatment group from 100 imputed datasets including observed data and imputed data using the primary modified multiple imputation method for missing values.

Effect of FOUNDAYO on Anthropometry and Cardiometabolic Parameters in Trials 1 and 2

Changes in waist circumference and cardiometabolic parameters with FOUNDAYO are shown in Table 7 for Trial 1 and Trial 2.