Zepbound

Disease-Associated Maternal and/or Embryo/Fetal Risk

Appropriate weight gain based on 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.

Animal Data

In pregnant rats given twice weekly subcutaneous doses of 0.02, 0.1, and 0.5 mg/kg tirzepatide [0.03-, 0.07-, and 0.5-fold the maximum recommended human dose (MRHD) of 15 mg once weekly based on AUC] during organogenesis, increased incidences of external, visceral, and skeletal malformations, increased incidences of visceral and skeletal developmental variations, and decreased fetal weights coincided with pharmacologically-mediated reductions in maternal body weights and food consumption at 0.5 mg/kg. In pregnant rabbits given once weekly subcutaneous doses of 0.01, 0.03, or 0.1 mg/kg tirzepatide (0.01-, 0.06-, and 0.2-fold the MRHD) during organogenesis, pharmacologically mediated effects on the gastrointestinal system resulting in maternal mortality or abortion in a few rabbits occurred at all dose levels. Reduced fetal weights associated with decreased maternal food consumption and body weights were observed at 0.1 mg/kg. In a pre- and post-natal study in rats administered subcutaneous doses of 0.02, 0.10, or 0.25 mg/kg tirzepatide twice weekly from implantation through lactation, F1 pups from F0 maternal rats given 0.25 mg/kg tirzepatide had statistically significant lower mean body weight when compared to controls from post-natal day 7 through post-natal day 126 for males and post-natal day 56 for females.

Gastrointestinal Adverse Reactions

In a pool of Study 1 and 2, gastrointestinal adverse reactions occurred more frequently among patients receiving ZEPBOUND (5 mg 56%, 10 mg 56%, 15 mg 56%) than placebo (30%). More patients receiving ZEPBOUND 5 mg (1.9%), ZEPBOUND 10 mg (3.3%), and ZEPBOUND 15 mg (4.3%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo (0.5%). The majority of nausea, vomiting, and/or diarrhea events occurred during dose escalation and decreased over time.

Hypotension

In a pool of Study 1 and 2, hypotension occurred more frequently among patients taking ZEPBOUND (1.6%) than patients taking placebo (0.1%). Hypotension was more frequently seen in ZEPBOUND-treated patients on concomitant antihypertensive therapy (2.2%) compared to ZEPBOUND-treated patients not on antihypertensive therapy (1.2%). Hypotension also occurred in association with gastrointestinal adverse events and dehydration.

Hypersensitivity Reactions

In a pool of Study 1 and 2, immediate hypersensitivity reactions (within one day after drug administration) occurred in 2.1% of ZEPBOUND-treated patients compared to 0.4% of placebo-treated patients, while non-immediate hypersensitivity reactions occurred in 3.5% of ZEPBOUND-treated patients compared to 2.7% of placebo-treated patients. Among ZEPBOUND-treated patients, hypersensitivity reactions were more frequent in those with anti-tirzepatide antibodies (6.2%) compared to those who did not develop anti-tirzepatide antibodies (3%) [see Clinical Pharmacology ]. The majority of the hypersensitivity reactions in trials were skin reactions (e.g., rash, itching).

Injection Site Reactions

In ZEPBOUND-treated patients in a pool of Study 1 and 2, injection site reactions were more frequent in those with anti-tirzepatide antibodies (11.3%) compared to those who did not develop anti-tirzepatide antibodies (1%) [see Clinical Pharmacology ].

Hair Loss

Hair loss adverse reactions in ZEPBOUND-treated patients were associated with weight reduction. In a pool of Study 1 and 2, hair loss was reported more frequently in female than male patients in the ZEPBOUND (7.1% female versus 0.5% male) and placebo (1.3% female versus 0% male) treatment groups. No ZEPBOUND-treated patients and one placebo-treated patient discontinued study treatment due to hair loss.

Acute Kidney Injury

In a pool of Study 1 and 2, acute kidney injury was reported in 0.5% of ZEPBOUND-treated patients compared to 0.2% of placebo-treated patients.

Acute Gallbladder Disease

In a pool of Study 1 and 2, cholelithiasis was reported in 1.1% of ZEPBOUND-treated patients and 1% of placebo-treated patients, cholecystitis was reported in 0.7% of ZEPBOUND-treated patients and 0.2% of placebo-treated patients, and cholecystectomy was reported in 0.2% of ZEPBOUND-treated patients and no placebo-treated patients.

Hypoglycemia

In Study 2, a trial of patients with type 2 diabetes mellitus and BMI ≥27 kg/m2, hypoglycemia (plasma glucose <54 mg/dL) was reported in 4.2% of ZEPBOUND-treated patients versus 1.3% of placebo-treated patients.

In Study 1, a trial of ZEPBOUND in adults with obesity/overweight without type 2 diabetes mellitus, there was no systematic capturing of hypoglycemia, but plasma glucose <54 mg/dL was reported in 0.3% of ZEPBOUND-treated patients versus no placebo-treated patients.

Heart Rate Increase

In a pool of Study 1 and 2, treatment with ZEPBOUND resulted in a mean increase in heart rate of 1 to 3 beats per minute compared to no increase in placebo-treated patients.

Dysesthesia

In a pool of Study 1 and 2, dysesthesia occurred more frequently among patients receiving ZEPBOUND (5 mg 0.2%, 10 mg 0.2%, 15 mg 0.4%) than placebo (0.1%).

Dysgeusia

In a pool of Study 1 and 2, dysgeusia was reported by 0.4% of ZEPBOUND-treated patients and no placebo-treated patients.

Dry Mouth

In a pool of Study 1 and 2, dry mouth or dry throat was reported by 1% of ZEPBOUND-treated patients and 0.1% of placebo-treated patients.

Amylase and Lipase Increase

In a pool of Study 1 and 2, treatment with ZEPBOUND resulted in mean increases from baseline in serum pancreatic amylase concentrations of 20% to 25% and serum lipase concentrations of 28% to 35%, compared to mean increases from baseline in pancreatic amylase of 2.1% and serum lipase of 5.8% in placebo-treated patients. The clinical significance of elevations in amylase or lipase with ZEPBOUND is unknown in the absence of other signs and symptoms of pancreatitis.

Metabolism

Tirzepatide is metabolized by proteolytic cleavage of the peptide backbone, beta-oxidation of the C20 fatty diacid, and amide hydrolysis.

Excretion

The primary excretion routes of tirzepatide metabolites are via urine and feces. Intact tirzepatide is not observed in urine or feces.

Patients with Renal Impairment

Renal impairment does not impact the pharmacokinetics of tirzepatide. The pharmacokinetics of tirzepatide after a single 5 mg dose were evaluated in patients with different degrees of renal impairment (mild, moderate, severe, ESRD) compared with subjects with normal renal function. Data from clinical studies have also shown that renal impairment in patients with overweight or obesity does not impact the pharmacokinetics of tirzepatide [see Use in Specific Populations ].

Patients with Hepatic Impairment

Hepatic impairment does not impact the pharmacokinetics of tirzepatide. The pharmacokinetics of tirzepatide after a single 5 mg dose were evaluated in patients with different degrees of hepatic impairment (mild, moderate, severe) compared with subjects with normal hepatic function [see Use in Specific Populations ].

Potential for Tirzepatide to Influence the Pharmacokinetics of Other Drugs

In vitro studies have shown low potential for tirzepatide to inhibit or induce CYP enzymes, and to inhibit drug transporters.

ZEPBOUND delays gastric emptying and thereby has the potential to impact the absorption of concomitantly administered oral medications [see Drug Interactions ].

The impact of tirzepatide on gastric emptying was greatest after a single dose of 5 mg and diminished after subsequent doses.

Following a first dose of tirzepatide 5 mg, acetaminophen maximum concentration (Cmax) was reduced by 55%, and the median peak plasma concentration (tmax) occurred 1 hour later. After coadministration at Week 6 with tirzepatide 15 mg, there was no meaningful impact on acetaminophen Cmax and tmax. Overall acetaminophen exposure (AUC0-24hr) was not influenced.

Following administration of a combined oral contraceptive (0.035 mg ethinyl estradiol and 0.25 mg norgestimate) in the presence of a single dose of tirzepatide 5 mg, mean Cmax of ethinyl estradiol, norgestimate, and norelgestromin was reduced by 59%, 66%, and 55%, while mean AUC was reduced by 20%, 21%, and 23%, respectively. A delay in tmax of 2.5 to 4.5 hours was observed.

Overview of Study 1 and Study 2

The efficacy of ZEPBOUND for weight reduction in conjunction with a reduced-calorie diet and increased physical activity was studied in two randomized, double-blind, placebo-controlled fixed-dosage trials (Study 1 and Study 2) in adults aged 18 years and older. In Studies 1 and 2, all patients received a standard lifestyle intervention which included instruction on a reduced-calorie diet (approximately 500 kcal/day deficit) and increased physical activity counseling (recommended minimum of 150 min/week) that began with the first dose of study medication or placebo and continued throughout the trial. Patients also received counseling on behavior modification strategies to adhere to diet and exercise recommendations. In both trials, weight reduction was assessed after 72 weeks of treatment (at least 52 weeks at maintenance dose).

Study 1 (NCT04184622) was a 72-week trial that enrolled 2,539 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 mellitus were excluded. Patients were randomized in a 1:1:1:1 ratio to once weekly fixed dosage of ZEPBOUND 5 mg, ZEPBOUND 10 mg, ZEPBOUND 15 mg, or placebo, with an escalation period of up to 20 weeks followed by the maintenance period. At baseline, mean age was 45 years (range 18-84 years), 68% were female, 71% were White, 11% were Asian, 9% were American Indian/Alaska Native, and 8% were Black or African American. A total of 48% were Hispanic or Latino ethnicity. Mean baseline body weight was 104.8 kg and mean BMI was 38 kg/m2. Baseline characteristics included 32% with hypertension, 30% with dyslipidemia, 8% with obstructive sleep apnea, and 3% with cardiovascular disease.

Study 2 (NCT04657003) was a 72-week trial that enrolled 938 adult patients with BMI ≥27 kg/m2 and type 2 diabetes mellitus. Patients included in the trial had HbA1c 7-10% 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 insulin or injectable GLP-1 receptor agonists for type 2 diabetes mellitus were excluded. Patients were randomized in a 1:1:1 ratio to once weekly fixed dosage of ZEPBOUND 10 mg, ZEPBOUND 15 mg, or placebo with an escalation period of up to 20 weeks followed by the maintenance period. At baseline, mean age was 54 years (range 18-85 years), 51% were female, 76% were White, 13% were Asian, and 8% were Black or African American. A total of 60% were Hispanic or Latino ethnicity. Mean baseline body weight was 100.7 kg and mean BMI was 36.1 kg/m2. Baseline characteristics included 66% with hypertension, 61% with dyslipidemia, 8% with obstructive sleep apnea, and 10% with cardiovascular disease.

Results for Study 1 and Study 2

The proportions of patients who discontinued study drug in Study 1 were 14.3%, 16.4%, and 15.1% for the 5 mg, 10 mg, and 15 mg ZEPBOUND-treated groups, respectively, and 26.4% for the placebo-treated group. The proportions of patients who discontinued study drug in Study 2 were 9.3% and 13.8% for the 10 mg and 15 mg ZEPBOUND-treated groups, respectively, and 14.9% for the placebo-treated group.

For Studies 1 and 2, weight reduction was assessed after 72 weeks of treatment (at least 52 weeks at maintenance dose). In both studies, the primary efficacy parameters were mean percent change in body weight and the percentage of patients achieving ≥5% weight reduction from baseline to Week 72 (see Table 2).

After 72 weeks of treatment, ZEPBOUND resulted in a statistically significant reduction in body weight compared with placebo, and greater proportions of patients treated with ZEPBOUND 5 mg, 10 mg, and 15 mg achieved at least 5% weight reduction compared to placebo. Among patients treated with ZEPBOUND 10 mg and 15 mg, greater proportions of patients achieved at least 10%, 15%, and 20% weight reduction compared to placebo (see Table 2). A reduction in body weight was observed with ZEPBOUND irrespective of age, sex, race, ethnicity, baseline BMI, and glycemic status.

The cumulative frequency distributions of change in body weight are shown in Figure 1 for Study 1 and Figure 2 for Study 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, note that the vertical line arising from -10% in Figure 1 intersects the ZEPBOUND 15 mg and placebo curves at approximately 83.5%, and 18.8%, respectively, which correspond to the values shown in Table 2.

Figure 1: Changes in Body Weight (%) from Baseline to Week 72 in Study 1 in Patients with Obesity or Overweight (without Type 2 Diabetes)

Note: Based on average percent weight change of each randomized patient within each specific treatment arm from 100 imputed datasets including observed data and imputed data using hybrid approach for missing values.

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

Note: Based on average percent weight change of each randomized patient within each specific treatment arm from 100 imputed datasets including observed data and imputed data using hybrid approach for missing values.

The time courses of weight reduction with ZEPBOUND and placebo from baseline through Week 72 are depicted in Figure 3 for Study 1 and Figure 4 for Study 2.

Figure 3: Change from Baseline (%) in Body Weight in Study 1 in Patients with Obesity or Overweight (without Type 2 Diabetes)

Note: Displayed results are from the Intent-to-Treat Population. (1) Observed mean value from Week 0 to Week 72, and (2) least-squares mean ± standard error at Week 72 hybrid imputation (HI).

Figure 4: Change from Baseline (%) in Body Weight in Study 2 in Patients with Obesity or Overweight and Type 2 Diabetes

Note: Displayed results are from the Intent-to-Treat Population. (1) Observed mean value from Week 0 to Week 72, and (2) least squares mean ± standard error at Week 72 hybrid imputation (HI).

Changes in waist circumference and cardiometabolic parameters with ZEPBOUND are shown in Table 3 for Study 1 and Study 2.

Overview of Study 3

Study 3 (NCT04657016) was an 84-week trial with a 12-week intensive lifestyle intervention lead-in period (Week -12 to Week 0), followed by a 72-week randomized treatment period of ZEPBOUND versus placebo (Week 0 to Week 72) with a standard lifestyle intervention. Only patients who lost ≥5% body weight during the 12-week intensive lifestyle lead-in period entered the 72-week randomized treatment period. The trial initially enrolled 806 adult patients (aged 18 years and older) 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 mellitus were excluded. During the intensive lifestyle intervention lead-in period, lifestyle instruction was delivered 8 times over 12 weeks by a dietician or dietician-equivalent, with all patients receiving instruction to exercise for at least 150 minutes per week and to reduce their caloric intake to approximately 1,200 kcal/day (females) or 1,500 kcal/day (males). Patients also received counseling on behavior modification strategies to adhere to diet and exercise recommendations. At the end of the 12-week intensive lifestyle intervention lead-in period, 579 patients who achieved ≥5% weight reduction were randomized in a 1:1 ratio to ZEPBOUND or placebo for 72 weeks. ZEPBOUND dosages were escalated over a period of up to 20 weeks to a maximum tolerated dosage (MTD) of 10 mg or 15 mg subcutaneous once weekly. During the randomized treatment period, patients received a standard lifestyle instruction every 12 weeks on reduced-calorie diet (approximately 500 kcal/day deficit) and increased physical activity (recommended minimum of 150 min/week) that began with the first dose of ZEPBOUND or placebo and continued throughout the 72-week treatment period; behavior modification strategies were recommended as needed. Weight reduction was assessed after 72 weeks of treatment (at least 52 weeks at maintenance dose).

For the 579 patients who were randomized, mean body weight at enrollment prior to entering the 12-week lifestyle lead-in period (Week -12) was 109.5 kg and mean BMI was 38.6 kg/m2. At randomization (Week 0), after the 12-week intensive lifestyle lead-in period, mean body weight was 101.9 kg and mean BMI was 35.9 kg/m2. The mean age of patients randomized to treatment was 46 years (range 18-77 years), 63% were female, 86% were White, 11% were Black or African American, and 1% were Asian. A total of 54% were Hispanic or Latino ethnicity. Baseline characteristics for the 579 randomized patients included 34% with hypertension, 26% with dyslipidemia, 10% with obstructive sleep apnea, and 2% with cardiovascular disease.

Results for Study 3

At the end of the 12-week intensive lifestyle intervention lead-in, for patients who subsequently entered the randomized treatment period (n=579), the average body weight loss due to lifestyle was 6.9% (Week -12 to Week 0). Eighty-six percent (86%) of ZEPBOUND-treated patients had a maximum tolerated dosage of 15 mg weekly based on their final dose during the double-blind treatment period. The time course of weight reduction during the lead-in and from Week 0 to Week 72 with ZEPBOUND and placebo are depicted in Figure 5.

Figure 5: Change in Body Weight (%) After 12-Week Intensive Lifestyle Intervention Lead-In Followed by Randomized Treatment and a Standard Lifestyle Intervention (Study 3) in Patients with Obesity or Overweight

Note: Displayed results are from the randomized Population. (1) Observed mean value from Week -12 to Week 72, and (2) least squares mean ± standard error at Week 72 hybrid imputation (HI). Change from Week -12 is not a primary endpoint in Study 3.

The proportions of patients who discontinued study drug after randomization were 21.3% for the ZEPBOUND-treated group and 30.5% for the placebo-treated group.

For Study 3, the primary efficacy parameters were mean percent change in body weight from randomization (Week 0) to Week 72 and the percentage of patients achieving ≥5% weight reduction from randomization (Week 0) to Week 72. Amongst randomized patients who already lost ≥5% body weight during the 12-week intensive lifestyle lead-in period, subsequent treatment with ZEPBOUND resulted in a statistically significant reduction in body weight compared to placebo from randomization (Week 0) to Week 72. A greater proportion of patients treated with ZEPBOUND achieved at least 5%, 10%, 15%, and 20% weight reduction from Week 0 to Week 72 compared to placebo (see Table 4).

Changes in waist circumference and cardiometabolic parameters are shown in Table 5.

Overview of Study 4

Study 4 (NCT04660643) was an 88-week randomized withdrawal trial in which all patients received open-label ZEPBOUND during a 36-week lead-in period, followed by randomization to either continue ZEPBOUND or switch to placebo for 52 weeks. The trial enrolled 783 adult patients (aged 18 years and older) 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 mellitus were excluded. All patients received a standard lifestyle intervention which included instruction on a reduced-calorie diet (approximately 500 kcal/day deficit) and increased physical activity counseling (recommended minimum of 150 min/week) that began with the first dose of ZEPBOUND, during the lead-in period, and continued throughout the trial. During the 36-week open-label ZEPBOUND lead-in period, ZEPBOUND dosages were escalated over a period of up to 20 weeks to an MTD of 10 mg or 15 mg subcutaneous once weekly. After the lead-in period, patients were randomized at Week 36 to continue ZEPBOUND or switch to placebo for 52 weeks.

Of the 783 patients who started ZEPBOUND at Week 0, 14.4% discontinued treatment before randomization at Week 36, and adverse events were the most common reason for discontinuation (6.8%). At Week 36, a total of 670 patients were randomized in a 1:1 ratio to ZEPBOUND MTD or placebo for 52 weeks. For the 670 randomized patients, at study entry (Week 0) mean body weight was 107.3 kg and mean BMI was 38.4 kg/m2, and at randomization (Week 36, after the open-label ZEPBOUND lead-in period) mean body weight was 85.2 kg and mean BMI was 30.5 kg/m2. Among the randomized patients, the mean age was 49 years (range 19-81 years), 71% were female, 80% were White, 11% were Black or African American, and 7% were Asian. A total of 44% were Hispanic or Latino ethnicity. Baseline characteristics for the 670 randomized patients included 35% with hypertension, 32% with dyslipidemia, 12% with obstructive sleep apnea, and 6% with cardiovascular disease.

Results for Study 4

At the end of the 36-week open-label ZEPBOUND lead-in period, of the 670 randomized patients, 93% were on ZEPBOUND MTD of 15 mg weekly and 7% were on MTD of 10 mg weekly. After open-label ZEPBOUND treatment, randomized patients (n=670) had an average body weight loss of 20.9% (Week 0 to Week 36). The time course of weight reduction from Week 0 through Week 88 is depicted in Figure 6.

Figure 6: Change in Body Weight (%) After 36-Week Open-Label Treatment Followed by Randomized Withdrawal (Study 4) in Patients with Obesity or Overweight

Note: Displayed results are from the randomized population. (1) Displayed results are observed mean value from Week 0 to Week 88 and (2) least squares mean ± standard error at Week 88 hybrid imputation (HI). Change from Week 0 was not a primary endpoint in Study 4.

The proportions of patients who discontinued study drug after randomization at Week 36 were 10.4% for the ZEPBOUND-treated group and 17.9% for the placebo-treated group.

For Study 4, the primary efficacy parameter was mean percent change in body weight from randomization (Week 36) to Week 88. After weight loss with ZEPBOUND treatment during the open-label lead-in period (Week 0 to Week 36), continued treatment with ZEPBOUND from randomization (Week 36) to Week 88 resulted in a statistically significant reduction in body weight compared with placebo (see Table 6).

Changes in waist circumference and cardiometabolic parameters in Study 4 are shown in Table 7.