The US Food and Drug Administration (FDA) has granted its Fast Track designation for the investigation of tirzepatide for the treatment of adults with obesity or who are overweight with weight-related comorbidities (including obstructive sleep apnea) to facilitate weight loss. Tirzepatide was FDA approved in May 2022 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus and is marketed under the brand name Mounjaro by Eli Lilly and Company.
Based on discussions with the FDA, Lilly plans to initiate a rolling submission of a new drug application (NDA) for tirzepatide in adults with obesity or overweight this year, which when complete, will be based primarily on results from two Phase 3 clinical trials: SURMOUNT-1, which is complete, and SURMOUNT-2, which is expected to complete by the end of April 2023. Lilly also has an ongoing phase 3 trial studying tirzepatide in people with obstructive sleep apnea (OSA) who are both unwilling or unable to use CPAP and those who are and plan to stay on CPAP. The rolling submission allows Lilly to submit completed sections of an application for review by FDA, rather than wait until all sections are completed.
Assuming positive SURMOUNT-2 results, Lilly aims to complete the submission shortly after SURMOUNT-2 data is available. The Fast Track designation, along with a rolling submission, accelerates tirzepatide’s path to FDA submission.
“We are pleased with the FDA’s decision to grant Fast Track designation for tirzepatide, and we look forward to completing our rolling submission next year,” says Mike Mason, president, Lilly Diabetes, in a release. “Obesity is a chronic disease that impacts the health of nearly 100 million Americans and is a significant driver of healthcare costs. While diet and exercise are important steps, most patients don’t achieve their desired treatment goals with only diet and exercise. We are dedicated to helping people living with obesity through our research and development of innovative treatments like tirzepatide, which produced significant weight reductions in patients taking tirzepatide for type 2 diabetes in SURPASS. Tirzepatide also helped nearly two-thirds of participants on the highest dose reduce their body weight by at least 20% in SURMOUNT-1.”
SURMOUNT-1 is a multi-center, randomized, double-blind, parallel, placebo-controlled trial, which compared the efficacy and safety of tirzepatide 5 mg, 10 mg, and 15 mg to placebo as an adjunct to a reduced-calorie diet and increased physical activity in adults without type 2 diabetes who have obesity, or overweight with at least one of the following comorbidities: hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease. The trial randomized 2,539 participants across the United States, Argentina, Brazil, China, India, Japan, Mexico, Russia, and Taiwan in a 1:1:1:1 ratio to receive either tirzepatide 5 mg, 10 mg, or 15 mg or placebo. The co-primary objectives of the study were to demonstrate that tirzepatide 10 mg and/or 15 mg was superior in percentage of body weight reductions from baseline and percentage of participants achieving ≥5% body weight reduction at 72 weeks compared to placebo. Participants who had pre-diabetes at study commencement will remain enrolled in SURMOUNT-1 for an additional 104 weeks of treatment following the initial 72-week completion date to evaluate the impact on body weight and potential differences in progression to type 2 diabetes at three years of treatment with tirzepatide compared to placebo.
All participants in the tirzepatide treatment arms started the study at a dose of tirzepatide 2.5 mg once-weekly and then increased the dose in a step-wise approach at four-week intervals to their final randomized maintenance dose of 5 mg (via a 2.5 mg step), 10 mg (via steps at 2.5 mg, 5 mg and 7.5 mg) or 15 mg (via steps at 2.5 mg, 5 mg, 7.5 mg, 10 mg, and 12.5 mg).
SURMOUNT-2 (NCT04657003) is a multi-center, randomized, double-blind, parallel, placebo-controlled trial comparing the efficacy and safety of tirzepatide 10 mg and 15 mg to placebo as an adjunct to a reduced-calorie diet and increased physical activity in adults with type 2 diabetes who have obesity or overweight. The trial randomized 938 participants across the U.S., Argentina, Brazil, India, Japan, Puerto Rico, Russia, and Taiwan in a 1:1:1 ratio to receive either tirzepatide 10 mg or 15 mg or placebo. The co-primary objectives of the study are to demonstrate that tirzepatide 10 mg and/or 15 mg is superior in percentage of body weight change from baseline and percentage of participants achieving ≥5% body weight reduction at 72 weeks compared to placebo.
The SURMOUNT Phase 3 global clinical development program for tirzepatide began in late 2019 and has enrolled more than 5,000 people with obesity or overweight across six clinical trials, four of which are global studies. Results from SURMOUNT-2, -3 and -4 are anticipated in 2023.
Tirzepatide is a once-weekly GIP (glucose-dependent insulinotropic polypeptide) receptor and GLP-1 (glucagon-like peptide-1) receptor agonist. Tirzepatide is a single novel molecule that activates the body’s receptors for GIP and GLP-1, which are natural incretin hormones. GIP is a hormone that may complement the effects of GLP-1 receptor agonism. GIP has been shown to decrease food intake while blunting the metabolic adaptive responses that usually occur with calorie restriction resulting in weight reductions, and when combined with GLP-1 receptor agonism, may result in greater effects on markers of metabolic dysregulation such as body weight, glucose and lipids. Tirzepatide is in phase 3 development for adults with obesity, or overweight with weight-related comorbidity. It is also being studied as a potential treatment for heart failure with preserved ejection fraction (HFpEF), obstructive sleep apnea (OSA), and non-alcoholic steatohepatitis (NASH). Studies of tirzepatide in chronic kidney disease and in morbidity/mortality in obesity are planned as well.