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Tirzepatide Demonstrated Significant and Superior Weight Loss Compared to Placebo in Two Pivotal Studies

Update: Zepbound (tirzepatide) Now FDA Approved for Obesity or Overweight with Weight-Related Comorbidities - November 8, 2023

INDIANAPOLIS, July 27, 2023. Eli Lilly announced results of Mounjaro (tirzepatide) phase 3 studies in adults with obesity or overweight with weight-related comorbidities, excluding type 2 diabetes. SURMOUNT-3 and SURMOUNT-4 met all primary and key secondary objectives for tirzepatide compared to placebo. Across SURMOUNT-3 and SURMOUNT-4, participants on tirzepatide following intensive lifestyle intervention or with continued tirzepatide treatment, achieved up to 26.6% mean weight loss, for the efficacy estimandi.

The overall safety profile of tirzepatide in both studies was similar to previously reported SURMOUNT and SURPASS trials and to that of incretin-based therapies approved for the treatment of obesity and overweight. The most commonly reported adverse events in both trials were gastrointestinal-related and generally mild to moderate in severity.

"The results of SURMOUNT-3 and -4 showed the highest level of weight loss observed in the SURMOUNT program to date," said Jeff Emmick, MD, Ph.D., senior vice president, product development, Lilly. "Whether taking tirzepatide for 88 weeks in SURMOUNT-4 or taking tirzepatide for 72 weeks following intensive caloric restriction in SURMOUNT-3, participants achieved similar mean weight reduction — about 26%. The findings from SURMOUNT-3 challenge the notion that patients living with obesity or overweight can achieve their weight loss goals with diet and exercise alone. Additionally, the findings from SURMOUNT-4 reinforce that obesity should be regarded like other chronic diseases where chronic therapy may be needed to maintain treatment benefits."

Results from SURMOUNT-3

SURMOUNT-3 evaluated the efficacy and safety of tirzepatide compared to placebo for 72 weeks after a 12-week intensive lifestyle intervention lead-in period that included a low-calorie diet, exercise and weekly counseling sessions. The trial randomized adults with obesity or overweight who had at least 5% body weight reduction by the end of the 12-week lead-in period to placebo or tirzepatide. At study entry, the mean body weight was 241.4 lb. (109.5 kg). At the end of the 12-week lead-in period, participants achieved 6.9% mean weight loss.

Tirzepatide met both co-primary endpoints demonstrating superiority to placebo during the 72-week double-blind treatment period. For the efficacy estimand, those taking tirzepatide, on average, lost an additional 21.1% of their body weight from randomization, a co-primary endpoint, compared to those taking placebo who experienced mean weight regain of 3.3% over 72 weeks, for a placebo-adjusted net weight change of -24.5%. In addition, 94.4% of those taking tirzepatide achieved an additional ≥5% body weight reduction from randomization, the other co-primary endpoint, compared to 10.7% in the placebo group over 72 weeks. In a secondary endpoint, participants receiving tirzepatide had a total mean weight reduction of 26.6% from study entry after 12 weeks of intensive lifestyle intervention followed by 72 weeks of tirzepatide treatment.

For the treatment-regimen estimandii, those taking tirzepatide, on average, lost an additional 18.4% of their body weight from randomization compared to those taking placebo who experienced mean weight regain of 2.5% over 72 weeks. In addition, 87.5% of those taking tirzepatide achieved an additional ≥5% body weight reduction from randomization compared with 16.5% in the placebo group over 72 weeks. Participants receiving tirzepatide had a total mean weight reduction of 24.3% from study entry after 12 weeks of intensive lifestyle intervention followed by 72 weeks of tirzepatide treatment.

The full results of the SURMOUNT-3 study will be presented at the ObesityWeek conference in October and submitted for publication in a peer-reviewed journal.

Results from SURMOUNT-4

SURMOUNT-4 evaluated the efficacy and safety of tirzepatide compared to placebo for 52 weeks after a 36-week open-label tirzepatide lead-in period. The trial had two periods: a 36-week open-label lead-in period during which all participants took tirzepatide, followed by a 52-week double-blind treatment period during which participants were randomized to either continue on tirzepatide or switch to placebo. For randomized participants, the mean body weight was 236.6 lb. (107.3 kg) at study entry. At the end of the 36-week tirzepatide lead-in period, they achieved 21.1% mean weight loss.

Tirzepatide met the primary endpoint of superior mean percent change in body weight compared to placebo from 36 weeks to 88 weeks, indicating sustained weight loss. For the efficacy estimand, those taking tirzepatide, on average, lost an additional 6.7% of their body weight from randomization, compared to those taking placebo who experienced mean weight regain of 14.8% from randomization at 88 weeks, for a placebo-adjusted net weight change of -21.4%. In a secondary endpoint, participants who remained on tirzepatide after randomization achieved a total of 26.0% mean body weight loss from study entry over the entire 88-week period.

For the treatment-regimen estimand, those taking tirzepatide, on average, lost an additional 5.5% of their body weight from randomization, compared to those taking placebo who experienced mean weight regain of 14.0% from randomization at 88 weeks. Participants who remained on tirzepatide after randomization achieved a total of 25.3% mean body weight loss from study entry over the entire 88-week period.

The full results of the SURMOUNT-4 study will be presented at the European Association for the Study of Diabetes Annual Meeting in October and submitted for publication in a peer-reviewed journal.

About SURMOUNT-3, SURMOUNT-4 and the SURMOUNT clinical trial program1

SURMOUNT-3 (NCT04657016) was a multi-center, randomized, double-blind, parallel, placebo-controlled trial comparing the efficacy and safety of tirzepatide to placebo for 72 weeks after a 12-week intensive lifestyle intervention lead-in period in adults with obesity or overweight with weight-related comorbidities, excluding type 2 diabetes. The trial enrolled 806 participants across the U.S., Argentina, Brazil and Puerto Rico to a lead-in period with intensive lifestyle intervention. After 12 weeks, 579 participants achieved at least 5% body weight reduction and were randomized in a 1:1 ratio to receive tirzepatide or placebo. The co-primary objectives of the study were to demonstrate that tirzepatide is superior in percentage change in body weight from randomization and percentage of participants achieving ≥5% body weight reduction from randomization at 72 weeks compared to placebo.


SURMOUNT-4 (NCT04660643) was a multi-center, randomized, double-blind, parallel, placebo-controlled trial comparing the efficacy and safety of tirzepatide to placebo in adults with obesity or overweight with weight-related comorbidities, excluding type 2 diabetes. The trial had two periods: a 36-week open-label lead-in period in which all participants took tirzepatide, and a subsequent 52-week double-blind treatment period in which participants were randomized to either continue on tirzepatide or switch to placebo. The trial enrolled 783 participants across the U.S., Argentina, Brazil, Puerto Rico and Taiwan into the open-label lead-in period and 670 participants were randomized in a 1:1 ratio in the 52-week double-blind treatment period to receive tirzepatide or placebo. The primary objective of the study was to demonstrate that tirzepatide is superior in percentage change in body weight from randomization at 88 weeks compared to placebo.

While SURMOUNT-1 and SURMOUNT-2 had fixed weekly tirzepatide doses, participants in SURMOUNT-3 and SURMOUNT-4 utilized a maximum tolerated dose of 10 mg or 15 mg once-weekly. The starting dose of 2.5 mg tirzepatide was increased by 2.5 mg every four weeks until maximum tolerated dose was achieved. Participants who tolerated 15 mg continued on 15 mg as their maximum tolerated dose. Participants who tolerated 10 mg but did not tolerate 15 mg continued on 10 mg as their maximum tolerated dose.

The SURMOUNT phase 3 global clinical development program for tirzepatide in chronic weight management began in late 2019 and has enrolled more than 5,000 people with obesity or overweight across six registration studies, four of which are global studies. The primary period of SURMOUNT-1 was completed in 2022 and SURMOUNT-2 was completed in the first half of 2023.

About tirzepatide
Tirzepatide is a once-weekly GIP (glucose-dependent insulinotropic polypeptide) receptor and GLP-1 (glucagon-like peptide-1) receptor agonist. Tirzepatide is a single molecule that activates the body's receptors for GIP and GLP-1, which are natural incretin hormones. Both GIP and GLP-1 receptors are found in areas of the human brain important for appetite regulation. Tirzepatide has been shown to decrease food intake and modulate fat utilization. Tirzepatide is in phase 3 development for adults with obesity or overweight with weight-related comorbidities. It is also being studied as a potential treatment for people with obesity and/or overweight with heart failure with preserved ejection fraction (HFpEF), obstructive sleep apnea (OSA) and non-alcoholic steatohepatitis (NASH). Studies of tirzepatide in chronic kidney disease (CKD) and in morbidity/mortality in obesity (MMO) are also ongoing.

Tirzepatide was approved as Mounjaro® (tirzepatide) by the FDA on May 13, 2022. Mounjaro is a glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

About Lilly

Lilly unites caring with discovery to create medicines that make life better for people around the world. We've been pioneering life-changing discoveries for nearly 150 years, and today our medicines help more than 51 million people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world's most significant health challenges, redefining diabetes care, treating obesity and curtailing its most devastating long-term effects, advancing the fight against Alzheimer's disease, providing solutions to some of the most debilitating immune system disorders, and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we're motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable.

References

  1. le Roux, C., Zhang, S., Aronne, L. et. al. Tirzepatide for the Treatment of Obesity: Rationale and Design of the SURMOUNT Clinical Development Program 2022 Obesity doi: 10.1002/oby.23612
SOURCE Eli Lilly and Company

Posted: July 2023

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