Follow the FOUNDAYO starting dosage and escalation described below to reduce the risk of gastrointestinal (GI) adverse reactions [see Warnings and Precautions (5.3), Adverse Reactions (6)].
- The starting dosage is 0.8 mg orally once daily. After at least 30 days on the 0.8 mg dosage, increase the dosage to 2.5 mg once daily.
- After at least 30 days on the 2.5 mg dosage, increase the dosage to 5.5 mg once daily.
- The dosage may be increased to the next dosage level (9 mg, 14.5 mg, or 17.2 mg once daily) after at least 30 days on the current dosage, based on treatment response and tolerability.
- The maximum dosage of FOUNDAYO is 17.2 mg once daily.
Adverse Reactions in Patients in Weight Management Clinical Trials
Pool of Two Placebo-Controlled Clinical Trials: FOUNDAYO was evaluated for safety in a pool of two randomized, double-blind, placebo-controlled trials that included 3155 adult patients with obesity or overweight treated with FOUNDAYO once daily for up to 72 weeks and a 2-week off-drug follow-up period (Trial 1 and Trial 2) [see Clinical Studies (14)]. The mean age of patients was 49 years and 41% were male. The population was 60% White, 25% Asian, 8% Black or African American, and 0.3% American Indian or Alaska Native; 35% identified as Hispanic or Latino ethnicity. At baseline, patients had an average BMI of 36.5 kg/m2, 51% with a BMI ≥35 kg/m2, 50% with hypertension, 49% with dyslipidemia, 31% with type 2 diabetes, 11% with obstructive sleep apnea, 3% with coronary artery disease, and 3% with cerebrovascular disease.
Across both trials, 8% of patients treated with FOUNDAYO (5.5 mg, 6%; 9 mg, 9%; and 17.2 mg, 10%) once daily permanently discontinued treatment as a result of adverse reactions compared to 3% of patients receiving placebo. The majority of patients (5%) who discontinued FOUNDAYO due to adverse reactions did so due to gastrointestinal adverse reactions.
Common Adverse Reactions
Table 1 shows common adverse reactions associated with the use of once daily FOUNDAYO in the pool of two placebo-controlled trials for weight management (Trials 1 and 2). These adverse reactions occurred more commonly with once daily FOUNDAYO than with placebo and occurred in at least 5% of patients treated with FOUNDAYO.
Table 1: Adverse Reactions Reported in ≥5% of FOUNDAYO-treated Adult Patients with Obesity or Overweight (With or Without Type 2 Diabetes) in Pool of Placebo-Controlled Trials (Trials 1 and 2)
|
| Adverse Reaction | Placebo
(N=1,576)
% | FOUNDAYO
5.5 mg once daily
(N=1,051)
% | FOUNDAYO
9 mg once daily
(N=1,055)
% | FOUNDAYO
17.2 mg once daily
(N=1,049)
% |
| Nausea
| 10
| 26
| 34
| 35
|
| Constipation
| 9
| 20
| 27
| 24
|
| Diarrhea
| 11
| 21
| 23
| 25
|
| Vomiting
| 4
| 13
| 21
| 24
|
| Dyspepsia
| 4
| 12
| 16
| 13
|
| Abdominal paina | 7
| 13
| 14
| 14
|
| Headache
| 7
| 8
| 9
| 9
|
| Abdominal distension
| 3
| 7
| 9
| 8
|
| Fatiguea | 4
| 6
| 7
| 9
|
| Eructation
| 1
| 6
| 8
| 8
|
| Gastroesophageal reflux disease
| 2
| 6
| 6
| 7
|
| Flatulence
| 2
| 5
| 6
| 6
|
| Hair lossa | 2
| 4
| 4
| 5
|
Gastrointestinal Adverse Reactions
In a pool of Trials 1 and 2, gastrointestinal adverse reactions occurred more frequently among patients treated with once daily FOUNDAYO 5.5 mg (60%), 9 mg (68%), and 17.2 mg (69%) than placebo (37%). More patients treated with once daily FOUNDAYO 5.5 mg (3%), 9 mg (6%), and 17.2 mg (6%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo (0.7%).
Of the FOUNDAYO-treated patients who reported GI adverse reactions, 60%, 36%, and 4% reported mild or moderate or severe adverse reactions, respectively. The incidence of nausea, vomiting, and diarrhea was higher during the FOUNDAYO dosage escalation period and decreased over time.
Hypoglycemia
In Trial 2, a trial of patients with type 2 diabetes and BMI ≥27 kg/m2, hypoglycemia (glucose <54 mg/dL) was reported in 2% of FOUNDAYO-treated patients versus 0.2% of placebo-treated patients. One patient treated with FOUNDAYO 5.5 mg once daily, and no patients receiving placebo reported severe hypoglycemia in Trial 2. In this trial, 7% of patients taking FOUNDAYO in combination with sulfonylurea reported hypoglycemia compared with 0.5% of patients not taking sulfonylurea.
In Trial 1, a trial of FOUNDAYO in adults with BMI ≥27 kg/m2 without type 2 diabetes, there was no systematic capturing of hypoglycemia, but glucose <54 mg/dL was reported in 0.6% of FOUNDAYO-treated patients and no placebo-treated patients. No patients in Trial 1 reported severe hypoglycemia.
Other Adverse Reactions
Acute Pancreatitis
In a pool of Trials 1 and 2, 6 events of acute pancreatitis were confirmed by adjudication in 6 FOUNDAYO-treated patients (0.14 patients per 100 years of exposure) versus 2 events in 1 placebo-treated patient (0.04 patients per 100 years of exposure).
Acute Kidney Injury
In a pool of Trials 1 and 2, acute kidney injury was reported in 0.2% of FOUNDAYO-treated patients compared to 0.05% of placebo-treated patients.
Hypotension
In a pool of Trials 1 and 2, hypotension occurred more frequently among patients taking FOUNDAYO (2%) than patients taking placebo (0.5%). Hypotension was more frequently seen in FOUNDAYO-treated patients on concomitant antihypertensive therapy (4%) compared to FOUNDAYO-treated patients not on antihypertensive therapy (1%).
Acute Gallbladder Disease
In a pool of Trials 1 and 2, cholelithiasis was reported in 1% of FOUNDAYO-treated patients and 0.7% of placebo-treated patients, and acute cholecystitis was reported in 0.4% of FOUNDAYO-treated patients and 0.3% of placebo-treated patients.
Tachycardia
In a pool of Trials 1 and 2, tachycardia (tachycardia, heart rate increased, and sinus tachycardia) was reported in 3% of patients treated with FOUNDAYO and 0.9% receiving placebo. Treatment with FOUNDAYO resulted in a mean increase in heart rate of 4 to 5 beats per minute from baseline compared to 0.5 beat per minute with placebo.
Hair Loss
Hair loss adverse reactions in FOUNDAYO-treated patients were associated with weight reduction. In a pool of Trials 1 and 2, hair loss was reported more frequently in female than male patients in the FOUNDAYO (7% female versus 0.9% male) and placebo (3% female versus 0.7% male) treatment groups.
Dizziness
In a pool of Trials 1 and 2, dizziness was reported in 4% of FOUNDAYO-treated patients and 3% of placebo-treated patients.
Dysgeusia
In a pool of Trials 1 and 2, dysgeusia was reported in 0.9% of FOUNDAYO-treated patients and 0.3% of placebo-treated patients.
Dysesthesia
In a pool of Trials 1 and 2, dysesthesia was reported in 0.3% and 1% of patients treated with FOUNDAYO 9 mg, and 17.2 mg, respectively, and 0.1% of patients receiving placebo. No patients taking FOUNDAYO 5.5 mg reported dysesthesia.
Hypersensitivity Reactions
In a pool of Trials 1 and 2, hypersensitivity reactions, including anaphylactic reaction, occurred in 0.5% of FOUNDAYO-treated patients compared to 0.3% of placebo-treated patients.
Laboratory Abnormalities
Amylase and Lipase Increase
In a pool of Trials 1 and 2, treatment with FOUNDAYO resulted in mean increases from baseline in serum pancreatic amylase concentrations of 16% to 20% and serum lipase concentrations of 26% to 31%, compared to mean increases from baseline in serum pancreatic amylase of 3% and serum lipase of 4% in placebo-treated patients. The clinical significance of elevations in amylase or lipase with FOUNDAYO is unknown in the absence of other signs and symptoms of pancreatitis.
Pregnancy Exposure Registry
There will be a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to FOUNDAYO (orforglipron) during pregnancy. Pregnant patients exposed to FOUNDAYO and healthcare providers are encouraged to contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979).
Risk Summary
Weight loss offers no benefit to a pregnant patient and may cause fetal harm. When a pregnancy is recognized, advise the pregnant patient of the risk to a fetus and discontinue FOUNDAYO.
There are no adequate and well-controlled studies of FOUNDAYO during pregnancy. Based on animal reproduction studies, there may be risks to the fetus from exposure to orforglipron during pregnancy.
Imbalances in malformations have been reported in rats and rabbits at low multiples of clinical exposure with GLP-1 receptor agonists active in those species. Orforglipron is not pharmacologically active in rats and rabbits.
In animal reproduction studies, oral administration of orforglipron to pregnant monkeys during organogenesis at doses lower than the maximum recommended human dose (MRHD) did not result in embryofetal effects. Higher dose levels and exposures could not be evaluated in monkeys due to dose limiting effects on body weight (see Data).
In a rabbit dose-range finding study, oral administration of orforglipron to pregnant rabbits during organogenesis at exposures 14 times the clinical exposure at the MRHD resulted in external malformations and decreases in fetal and placental weights in the absence of maternal toxicity (see Data). In the definitive rabbit study, oral administration of orforglipron to pregnant rabbits during organogenesis at exposures up to 6 times the clinical exposure at the MRHD did not result in embryofetal effects (see Data).
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The estimated background risk of major birth defects and miscarriage for the indicated population is increased when compared to the general population.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
Appropriate weight gain relative to pre-pregnancy weight is currently recommended for all pregnant patients, including those with obesity or overweight, due to the obligatory weight gain that occurs in maternal tissues during pregnancy.
Data
Animal Data
Embryofetal development was evaluated in pregnant monkeys administered orforglipron orally during organogenesis (gestation days 20 to 50) at doses of 0.15 and 0.7 mg/kg/day resulting in systemic exposures lower than the human exposure at the MRHD of 17.2 mg FOUNDAYO, based on AUC. No effects on pregnancy outcome, placental weight, fetal viability, fetal body weight, fetal measurements or external, visceral or skeletal evaluations were observed. Exposure in monkeys was lower than exposure at the MRHD. Higher dose levels and exposures cannot be achieved in pregnant monkeys due to on-target body weight effects.
Orforglipron is not pharmacologically active in rabbits. In a rabbit dose-range finding study, orforglipron was administered orally once daily during organogenesis (gestation days 7 to 19) at dose levels of 2, 20, and 200 mg/kg/day. These doses resulted in exposures that were approximately 0.03, 0.8 and 14 times, respectively, the clinical exposure at the MRHD, based on AUC. Statistically significant decreases in fetal and placental weights and external malformations in 2 fetuses from 2 dams were observed at 200 mg/kg/day. In the definitive rabbit study, orforglipron was given orally once daily during organogenesis (gestation days 7 to 19) at dose levels of 4, 40, and 200 mg/kg/day resulting in exposures approximately 0.06, 1.4, and 6.2 times the clinical exposure at the MRHD, respectively, based on AUC. No embryofetal effects were observed in the definitive rabbit study at any dose level.
Orforglipron is not pharmacologically active in rats. In a pre- and post-natal study in rats, orforglipron was administered orally once daily from implantation through lactation at doses of 5, 30, and 200 mg/kg/day, which resulted in exposures that were approximately 2.9, 4.5, and 13 times the clinical exposure at the MRHD, respectively, based on AUC. No effects were noted at any dose level in the F0 maternal rats or the F1 pups in the pre- and post-natal development study in rats.
In a tissue distribution study, [14C]orforglipron-derived radioactivity was not distributed to fetal tissues in pregnant rats.
Risk Summary
There are no data on the presence of orforglipron or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Orforglipron was present in the milk of lactating rats in in vivo testing (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. FOUNDAYO is not recommended for nursing women. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for FOUNDAYO and any potential adverse effects on the breastfed child from FOUNDAYO or from the underlying maternal condition.
Data
Animal Data: In a tissue distribution study, [14C]orforglipron-derived radioactivity was excreted into rat breast milk, with concentrations in milk 3-fold higher than in plasma.
Contraception
Based on animal reproduction studies, there may be risks to the fetus from exposure to orforglipron during pregnancy [see Pregnancy (8.1)]. Advise women of childbearing potential to use effective contraception during treatment with FOUNDAYO. The effect of FOUNDAYO on the absorption of oral contraceptives has not been evaluated in a clinical trial. Because delayed gastric emptying may affect the absorption of oral medications, advise patients using oral hormonal contraceptives to switch to a non-oral contraceptive method, or add a barrier method of contraception for 30 days after initiation with FOUNDAYO and for 30 days after each dose escalation [see Drug Interactions (7.3), Clinical Pharmacology (12.3)].
Cardiac Electrophysiology
At 1.4 times the mean of maximum concentrations provided by the maximum recommended FOUNDAYO dose (17.2 mg) once daily, clinically significant QTc interval prolongation was not observed.
Absorption
Maximum concentration of orforglipron is reached 4 to 8 hours post dose. Orforglipron tablet exposure increases in a dose-proportional manner. The geometric mean absolute bioavailability of orforglipron was 77% after a 0.8 mg dose.
Effect of food
No clinically relevant food effect on orforglipron exposure was observed. Following multiple doses of an investigational 37.5 mg orforglipron tablet, the AUC(0-24h) decreased by 19%, and Cmax decreased by 26% with food compared to fasted state. The tmax and t1/2 were unchanged.
Distribution
The mean steady-state volume of distribution of orforglipron is approximately 285 L, following intravenous dosing in healthy subjects. Orforglipron plasma protein binding is greater than 99%. FOUNDAYO is only for oral use.
Elimination
The mean systemic clearance of orforglipron is 7.15 L/hour. The elimination half-life is approximately 29 to 49 hours after an oral dose.
Metabolism
Orforglipron is metabolized primarily via hepatic CYP3A4 to several oxidative metabolites. These oxidative metabolites are excreted into the intestinal lumen.
Excretion
After administration of a single oral dose of 2.5 mg orforglipron, 87% of the dose was recovered in feces (all metabolites) and less than 1% of the dose was recovered in urine.
Special Populations
The intrinsic factors of age (18 to 92 years), sex, race (White, Asian, Black or African American, American Indian, Multiracial, or Hawaiian Pacific Islander), ethnicity (Hispanic, Non-Hispanic), body weight (56.4 to 227 kg), and renal impairment (eGFR 27.8 to 156 mL/min/1.73 m2) do not have a clinically relevant effect on the pharmacokinetics of orforglipron.
Patients with Hepatic Impairment
The pharmacokinetics of orforglipron after a single oral 0.8 mg dose was evaluated in patients with mild, moderate, and severe hepatic impairment (Child-Pugh Class A, B, and C, respectively) and in subjects with normal hepatic function. Orforglipron exposure was similar in patients with mild hepatic impairment and normal hepatic function. Orforglipron AUC(0-∞) increased by 1.7-fold and 4.6-fold in patients with moderate and severe hepatic impairment, respectively, compared to subjects with normal hepatic function. Cmax in patients with moderate and severe hepatic impairment was similar to Cmax in subjects with normal hepatic function [see Use in Specific Populations (8.6)].
Patients with Renal Impairment
Renal impairment does not impact the pharmacokinetics of orforglipron. The pharmacokinetics of orforglipron after a single oral 0.8 mg dose were evaluated in patients with severe renal impairment and ESRD compared with subjects who had normal renal function. Data from clinical trials have also shown that renal impairment in patients with overweight or obesity does not impact the pharmacokinetics of orforglipron [see Use in Specific Populations (8.7)].
Drug Interaction Studies
Clinical Studies and Model-Informed Approaches
Effects of Other Drugs on FOUNDAYO
Table 4 outlines the results of definitive clinical trials and physiologically based pharmacokinetic (PBPK) simulations assessing the effect of other drugs on orforglipron pharmacokinetics. Concomitant use of strong CYP3A4 inhibitors significantly increased exposure of orforglipron while concomitant use of moderate or strong CYP3A4 inducers led to reductions in orforglipron exposure [see Dose and Administration (2.2), Drug Interactions (7.1)].
Table 4: Potential for Other Drugs to Affect FOUNDAYO
|
| Concomitant Drug Category | Concomitant Drug (Dose) | Change in Orforglipron |
| AUC | Cmax |
| Strong CYP3A4 inhibitors
| Clarithromycin (500 mg twice daily)
| ↑3.5-fold
| ↑1.9-fold
|
| Moderate CYP3A4 inhibitors
| Verapamila (80 mg three times daily)
| ↑2-fold
| ↑1.6-fold
|
| Strong CYP3A4 inducers
| Carbamazepine (300 mg twice daily)
| ↓82%
| ↓55%
|
| Moderate CYP3A4 inducers
| Efavirenza (600 mg once daily)
| ↓61%
| ↓33%
|
| Weak CYP3A4 inducers
| Modafinila (200 mg once daily)
| ↓16%
| ↓7%
|
| OATP1B inhibitors
| Cyclosporine (200 mg twice daily)
| ↑2.6-fold
| ↑1.3-fold
|
| P-gp inhibitors
| Quinidine (200 mg twice daily)
| ↓12%
| ↓26%
|
| Acid reducing agents
| Esomeprazole (40 mg once daily)
| No effect
| No effect
|
Effects of FOUNDAYO on Other Drugs
Table 5 outlines the results of clinical assessments that evaluated the effect of orforglipron on other drugs. Concomitant use of orforglipron and simvastatin led to significant increases in the active metabolite simvastatin acid whether orforglipron was co-administered or dosing was staggered by 2 hours [see Drug Interactions (7.2)]. No clinically relevant changes were observed for orforglipron when used with rosuvastatin or atorvastatin.
Table 5: Potential for FOUNDAYO to Affect Other Drugs
| Concomitant Drug Category | Concomitant Drug
(Dose) | Orforglipron Dosage
| Change in Concomitant Drug |
| AUC | Cmax |
| Statin
| Simvastatin (prodrug) (20 mg)
| 17.2 mg once daily
| up to ↓16%
| up to ↓27%
|
| Simvastatin acid (active metabolite)
| 17.2 mg once daily
| ↑2- to 2.5-fold
| ↑2.3- to 2.5-fold
|
| Atorvastatin (40 mg)
| 14.5 mg once daily
| ↑1.5-fold
| ↑0.9-fold
|
| BCRP substrate
| Rosuvastatin (20 mg)
| 17.2 mg once daily
| ↑1.7-fold
| ↑1.3-fold
|
| CYP3A4 substrates
| Midazolam (200 mcg)
| 17.2 mg once daily
| ↑1.1-fold
| No effect
|
| P-gp substrates
| Digoxin (0.25 mg)
| 17.2 mg once daily
| ↑1.2-fold
| ↑1.2-fold
|
| OATP1B substrates
| Endogenous OATP1B biomarker coproporphyrin-1
| up to 14.5 mg once daily
| No effect
| No effect
|
Potential Drug Interactions due to Gastric Emptying Delay
Orforglipron delays gastric emptying and has the potential to affect the rate of absorption of other concomitantly administered oral drugs. The gastric emptying delay effect of orforglipron on acetaminophen Cmax was largest after the first dose of FOUNDAYO 0.8 mg with acetaminophen Cmax decreased by 28%. The effect diminished after repeated dosing of FOUNDAYO 17.2 mg.
In Vitro Assessments of Drug Interactions
CYP Enzymes: In in vitro studies, orforglipron did not inhibit or induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Orforglipron is a substrate of CYP3A4 and CYP2J2, and is not a substrate of CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, and CYP3A5.
Transporter Systems: Orforglipron did not inhibit OATP1B1, OATP1B3, OATP2B1, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2K. Orforglipron is a substrate of P-gp, OATP1B1 and OATP1B3, and is not a substrate of BCRP or OCT1.
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/m2), or with overweight (BMI 27 to <30 kg/m2) 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/m2. 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/m2 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/m2, 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.
Table 6: Changes from Baseline in Body Weight at Week 72 in Trials 1 and 2 in Patients with Obesity or Overweight with ≥1 Weight-related Comorbid Condition
Note: Baseline mean is calculated using all randomized patients. |
|
|
|
|
|
| Trial 1 (without diabetes) | Trial 2 (with type 2 diabetes) |
| Intent-to-Treat (ITT) Populationa | Placebo
once daily
N = 949 | FOUNDAYO
5.5 mg
once daily
N = 723 | FOUNDAYO
9 mg
once daily
N = 725 | FOUNDAYO
17.2 mg
once daily
N = 730 | Placebo
once daily
N = 630 | FOUNDAYO
5.5 mg
once daily
N = 329 | FOUNDAYO
9 mg
once daily
N = 332 | FOUNDAYO
17.2 mg
once daily
N = 322 |
| Body Weight | | | | | | | | |
| Baseline mean (kg)
| 103.9
| 103.2
| 102.2
| 103.1
| 101.2
| 102.3
| 102.7
| 99.8
|
| % Change from baselineb | -2.1
| -7.4
| -8.3
| -11.1
| -2.5
| -5.1
| -7
| -9.6
|
| % difference from placebo (95% CI)b | | -5.3
(-6.1, -4.4)c | -6.2
(-7.1, -5.3)c | -9
(-10, -8.1)c | | -2.6
(-3.5, -1.6)c | -4.5
(-5.4, -3.6)c | -7.1
(-8.1, -6.1)c |
| % of patients who lost ≥5% body weight | 26.8
| 59.6
| 63.1
| 71.5
| 26.8
| 47.4
| 54.7
| 67
|
| % difference from placebo (95% CI)d | | 32.7
(27.9, 37.6)c | 36.3
(31.5, 41.1)c | 44.7
(40, 49.3)c | | 20.6
(13.9, 27.3)c | 27.9
(21.3, 34.5)c | 40.2
(33.8, 46.6)c |
| % of patients who lost ≥10% body weight | 13
| 32.5
| 39.8
| 54.5
| 9.2
| 22.5
| 31.1
| 45.6
|
| % difference from placebo (95% CI)d | | 19.4
(15.1, 23.7)c | 26.8
(22.4, 31.1)c | 41.4
(37, 45.9)c | | 13.3
(8.1, 18.5)c | 21.9
(16.3, 27.5)c | 36.4
(30.5, 42.3)c |
| % of patients who lost ≥15% body weight | 6
| 14.3
| 20.1
| 35.9
| 3.1
| 6.7
| 14.4
| 25.9
|
| % difference from placebo (95% CI)d | | 8.3
(5.2, 11.4)c | 14.1
(10.7, 17.6)c | 29.8
(25.9, 33.7)c | | 3.6
(0.4, 6.8)e | 11.3
(7.3, 15.3)c | 22.8
(17.8, 27.8)c |
| % of patients who lost ≥20% body weight | 2.9
| 5.9
| 8.9
| 18.4
| 0.7
| 2.6
| 4.4
| 10.8
|
| % difference from placebo (95% CI)d | | 3
(0.9, 5.2)e | 6
(3.5, 8.4)c | 15.5
(12.4, 18.6)c | | 1.8
(-0.2, 3.8)e | 3.7
(1.4, 6)e | 10.1
(6.6, 13.5)e |
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)
Figure 1 (Fou Uspi F1 V1)
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
Figure 2 (Fou Uspi F2 V1)
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)
Figure 3 (Fou Uspi F3 V1)
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
Figure 4 (Fou Uspi F4 V1)
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.
Table 7: Changes from Baseline Anthropometry and Cardiometabolic Parameters at Week 72 in Trials 1 and 2 in Patients with Obesity or Overweight with ≥1 Weight-related Comorbid Condition
Note: Baseline mean is calculated using all randomized patients. For patients with missing baseline values, imputed values are used. |
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| Trial 1 (without diabetes) | Trial 2 (with type 2 diabetes) |
| Intent-to-Treat (ITT) Populationa | Placebo
once daily
N = 949 | FOUNDAYO
5.5 mg once daily
N = 723 | FOUNDAYO
9 mg once daily
N = 725 | FOUNDAYO
17.2 mg once daily
N = 730 | Placebo
once daily
N = 630 | FOUNDAYO
5.5 mg once daily
N = 329 | FOUNDAYO
9 mg once daily
N = 332 | FOUNDAYO
17.2 mg once daily
N = 322 |
| Waist Circumference (cm) |
| Baseline mean
| 112.8
| 112.2
| 112
| 112.4
| 115
| 116.8
| 116.2
| 114.7
|
| Change from baselineb | -3.1
| -7
| -8.2
| -10
| -2.8
| -5.4
| -6.3
| -8.3
|
| Difference from placebo (95% CI)b | | -3.9
(-4.7, -3.1)c | -5.1
(-5.9, -4.2)c | -6.9
(-7.8, -6)c | | -2.6
(-3.5, -1.6)d | -3.5
(-4.4, -2.6)d | -5.5
(-6.5, -4.6)c |
| Systolic Blood Pressure (mm Hg) |
| Baseline mean
| 125.8
| 125.4
| 125.1
| 125.8
| 130.6
| 131.3
| 132.1
| 132.5
|
| Change from baselineb | -1.4
| -5.7
| -5.1
| -6.4
| -1.5
| -4
| -4.2
| -4.6
|
| Difference from placebo (95% CI)b | | -4.2
(-5.4, -3)d | -3.7
(-4.8, -2.5)d | -4.9
(-6.1, -3.8)d | | -2.5
(-4.1, -0.8)d | -2.7
(-4.4, -1)d | -3
(-4.8, -1.2)d |
| Diastolic Blood Pressure (mm Hg) |
| Baseline mean
| 81.8
| 81
| 81.2
| 80.9
| 81
| 81.6
| 82.1
| 81.8
|
| Change from baselineb | -1.4
| -2.4
| -2.3
| -2.7
| -1.3
| -1.4
| -1.4
| -1.8
|
| Difference from placebo (95% CI)b | | -0.9
(-1.7, -0.1)d | -0.8
(-1.7, 0)d | -1.2
(-2, -0.4)d | | -0.1
(-1.2, 0.9)d | -0.1
(-1.2, 0.9)d | -0.6
(-1.6, 0.5)d |
| Pulse Rate (beats per minute) |
| Baseline mean
| 73.7
| 73
| 73
| 73.5
| 74.2
| 75.9
| 73.7
| 74.6
|
| Change from baselineb | 0.6
| 3.6
| 3.9
| 4.6
| 0.4
| 2.8
| 3.9
| 3.6
|
| Difference from placebo (95% CI)b | | 3.1
(2.2, 4)d | 3.4
(2.5, 4.2)d | 4.1
(3.1, 5)d | | 2.4
(1.3, 3.6)d | 3.5
(2.4, 4.6)d | 3.2
(2, 4.4)d |
| HbA1c (%) |
| Baseline mean
| 5.6
| 5.6
| 5.6
| 5.6
| 8
| 8
| 8.1
| 8.1
|
| Change from baselineb | -0.1
| -0.3
| -0.3
| -0.3
| -0.4
| -1.2
| -1.4
| -1.7
|
| Difference from placebo (95% CI)b | | -0.2
(-0.2, -0.2)d | -0.2
(-0.2, -0.2)d | -0.3
(-0.3, -0.2)d | | -0.8
(-1, -0.6)c | -1
(-1.2, -0.8)c | -1.2
(-1.4, -1.1)c |
| Total Cholesterol (mg/dL) |
| Baseline meane | 192.6
| 192.5
| 191.2
| 192.2
| 167.6
| 168
| 167.4
| 167.6
|
| Percent change from baselineb | -1.9
| -3.4
| -4.5
| -4.3
| -2.2
| -1.5
| -2
| -4.9
|
| Relative difference from placebo (95% CI)b | | -1.6
(-3.1, 0)d,f | -2.7
(-4.2, -1.1)d,f | -2.5
(-4, -0.9)d,f | | 0.7
(-2.2, 3.6)d,f | 0.1
(-2.6, 2.9)d,f | -2.7
(-5.3, -0.1)d,f |
| Non-HDL Cholesterol (mg/dL) |
| Baseline meane | 142.3
| 141.9
| 139.8
| 142.5
| 122.2
| 120.7
| 121.8
| 121
|
| Percent change from baselineb | -2
| -5.4
| -7
| -7.7
| -3
| -4.3
| -4.7
| -9.7
|
| Relative difference from placebo (95% CI)b | | -3.5
(-5.5, -1.4)d,f | -5.1
(-7, -3.1)d,f | -5.8
(-7.8, -3.8)d,f | | -1.3
(-5.1, 2.7)d,f | -1.7
(-5.4, 2.1)d,f | -6.9
(-10.2, -3.4)d,f |
| LDL Cholesterol (mg/dL) |
| Baseline meane | 114.4
| 115
| 113.3
| 114.6
| 84.7
| 84.3
| 84.1
| 85.3
|
| Percent change from baselineb | -1.6
| -3.8
| -5.5
| -4.9
| -3.1
| -0.2
| -0.7
| -5.5
|
| Relative difference from placebo (95% CI)b | | -2.2
(-4.5, 0.1)d,f | -4
(-6.2, -1.7)d,f | -3.3
(-5.5, -1)d,f | | 3.1
(-2.2, 8.6)d,f | 2.5
(-2.1, 7.4)d,f | -2.4
(-6.8, 2.2)d,f |
| HDL Cholesterol (mg/dL) |
| Baseline meane | 47.8
| 48.1
| 48.6
| 47
| 42
| 43.5
| 42.8
| 43.1
|
| Percent change from baselineb | -1
| 2.1
| 3.1
| 4.5
| 0.8
| 5.8
| 5.3
| 8
|
| Relative difference from placebo (95% CI)b | | 3.1
(1.4, 4.8)d,f | 4.1
(2.3, 5.8)d,f | 5.5
(3.8, 7.2)d,f | | 5
(2.5, 7.6)d,f | 4.4
(2.1, 6.8)d,f | 7.2
(4.7, 9.7)d,f |
| Triglycerides (mg/dL) |
| Baseline meane | 125.3
| 121.1
| 119.2
| 125.6
| 162.4
| 157.8
| 164.4
| 157.2
|
| Percent change from baselineb | -4
| -10.4
| -13.1
| -20
| -4.1
| -13.3
| -14.7
| -19.4
|
| Relative difference from placebo (95% CI)b | | -6.7
(-9.9, -3.3)d,f | -9.4
(-12.6,
-6.1)d,f | -16.6
(-19.5,
-13.6)d,f | | -9.6
(-14.5, -4.4)d,f | -11
(-15.6,
-6.2)d,f | -15.9
(-20.3,
-11.3)d,f |
Risk of Thyroid C-Cell Tumors
Inform patients that in studies with rodents, medicines that work like FOUNDAYO caused thyroid C-cell tumors and that the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, persistent hoarseness, dysphagia, or dyspnea) to their healthcare provider [see Boxed Warning, Warnings and Precautions (5.1)].
Acute Pancreatitis
Inform patients of the potential risk for acute pancreatitis and its symptoms: severe abdominal pain that may radiate to the back, and which may or may not be accompanied by nausea or vomiting. Instruct patients to discontinue FOUNDAYO promptly and contact their healthcare provider if pancreatitis is suspected [see Warnings and Precautions (5.2)].
Severe Gastrointestinal Adverse Reactions
Inform patients of the potential risk of severe gastrointestinal adverse reactions. Instruct patients to contact their healthcare provider if they have severe or persistent gastrointestinal symptoms [see Warnings and Precautions (5.3)].
Acute Kidney Injury Due to Volume Depletion
Inform patients of the potential risk of acute kidney injury due to dehydration and volume depletion associated with gastrointestinal adverse reactions. Advise patients to take precautions to avoid fluid depletion. Inform patients of the signs and symptoms of acute kidney injury and instruct them to promptly report any of these signs or symptoms or persistent (or extended) nausea, vomiting, and diarrhea to their healthcare provider [see Warnings and Precautions (5.4)].
Hypoglycemia
Inform patients of the risk of hypoglycemia and educate patients on the signs and symptoms of hypoglycemia. Advise patients taking insulin or insulin secretagogue therapy such as a sulfonylurea that they may have an increased risk of hypoglycemia when using FOUNDAYO and to report signs and/or symptoms of hypoglycemia to their healthcare provider [see Warnings and Precautions (5.5)].
Hypersensitivity Reactions
Inform patients that serious hypersensitivity reactions have been reported with use of FOUNDAYO. Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking FOUNDAYO and seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.6)].
Diabetic Retinopathy Complications in Patients with Type 2 Diabetes
Inform patients with type 2 diabetes to contact their healthcare provider if they experience changes in vision during treatment with FOUNDAYO [see Warnings and Precautions (5.7)].
Acute Gallbladder Disease
Inform patients of the risk of acute gallbladder disease. Instruct patients to contact their healthcare provider for appropriate clinical follow-up if gallbladder disease is suspected [see Warnings and Precautions (5.8)].
Pulmonary Aspiration During General Anesthesia or Deep Sedation
Inform patients that FOUNDAYO may cause their stomach to empty more slowly which may lead to complications with anesthesia or deep sedation during planned surgeries or procedures. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking FOUNDAYO [see Warnings and Precautions (5.9)].
Pregnancy
Advise a pregnant patient of the potential risk to a fetus. Advise patients to inform their healthcare provider if they are pregnant or intend to become pregnant during treatment with FOUNDAYO. Advise women of childbearing potential to use effective contraception during treatment with FOUNDAYO [see Use in Specific Populations (8.1, 8.3)]. Advise patients that there will be a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to FOUNDAYO during pregnancy [see Use in Specific Populations (8.1)].
Contraception
Use of FOUNDAYO may reduce the efficacy of oral hormonal contraceptives. Advise patients using oral hormonal contraceptives to switch to a non-oral contraceptive method or add a barrier method of contraception for 30 days after initiation with FOUNDAYO and for 30 days after each dose escalation [see Drug Interactions (7.3), Use in Specific Populations (8.3), Clinical Pharmacology (12.3)].
Administration
Inform patients to take one FOUNDAYO tablet orally once daily with or without food. Advise patients to swallow tablets whole and not to break, crush, or chew tablets [see Dosage and Administration (2.1)]. Advise patients to keep FOUNDAYO in the original bottle and carton to protect from light [see How Supplied/Storage and Handling (16.2)].
Missed Doses
Inform patients if a dose of FOUNDAYO is missed, it should be taken as soon as possible. Instruct patients not to double up the next dose. If 7 or more consecutive doses are missed, instruct patients to restart dosage escalation at a lower dosage [see Dosage and Administration (2.3)].
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Pat.: www.lilly.com/patents
OFG-0001-USPI-APRIL2026
