Eli Lilly and Company reported positive topline results from TRIUMPH-1, a Phase 3 trial evaluating the investigational triple hormone receptor agonist retatrutide in adults with obesity or overweight and at least one weight-related comorbidity, without diabetes. Retatrutide, which targets GIP, GLP-1 and glucagon receptors, met the primary and key secondary endpoints at all tested doses (4 mg, 9 mg and 12 mg) over 80 weeks, with each dose producing clinically meaningful weight loss.
In the primary analysis, participants receiving retatrutide 9 mg and 12 mg lost an average of 64.4 lbs (25.9%) and 70.3 lbs (28.3%), respectively, while those on the 4 mg dose lost 47.2 lbs (19.0%). Among participants on the 12 mg dose, 65.3% reached a body mass index (BMI) below 30 at week 80, including 37.5% of those who entered the study with class 3 obesity (BMI ≥40). In a prespecified blinded extension in participants with BMI ≥35 who continued 12 mg to 104 weeks, average weight loss reached 85.0 lbs (30.3%).
Using the treatment-regimen estimand, retatrutide also showed consistent benefit across doses. At week 80, percent weight changes were -17.6% (-19.8 kg; -43.7 lbs) for 4 mg, -23.7% (-26.7 kg; -58.9 lbs) for 9 mg and -25.0% (-28.2 kg; -62.1 lbs) for 12 mg, compared with -3.9% (-4.4 kg; -9.7 lbs) for placebo. At week 104 (to maximum tolerated dose), percent changes were -25.7% (-30.6 kg; -67.5 lbs) for 4 mg, -28.7% (-35.6 kg; -78.4 lbs) for 9 mg and -29.9% (-38.1 kg; -83.9 lbs) for 12 mg, versus -18.9% (-22.3 kg; -49.1 lbs) for placebo. Retatrutide also improved several cardiometabolic risk measures, including waist circumference, non-HDL cholesterol, triglycerides, systolic blood pressure and high-sensitivity C-reactive protein.
Ania Jastreboff, M.D., Ph.D., lead investigator and professor at Yale School of Medicine, said all doses produced meaningful weight reduction for nearly all participants and that those with severe obesity on the highest dose lost on average 30% of body weight over two years. She added that retatrutide led to clear improvements in cardiometabolic health measures and may become an important future option in clinical practice.
Lilly highlighted that retatrutide may support a range of treatment needs from the 4 mg dose, which achieved close to 20% weight loss with one dose escalation, to the 12 mg dose, which produced weight loss at a level historically associated with bariatric surgery. Kenneth Custer, Ph.D., executive vice president and president of Lilly Cardiometabolic Health, said the data suggest a patient-centric approach to obesity treatment, positioning retatrutide alongside the company’s existing medicines Zepbound (tirzepatide) and Foundayo (orforglipron).
The safety profile of retatrutide in TRIUMPH-1 was generally consistent with other incretin-based therapies. The most common adverse events with retatrutide 4 mg, 9 mg and 12 mg versus placebo were nausea (28.6%, 38.4%, 42.4% vs. 14.8%), diarrhea (25.2%, 34.1%, 32.0% vs. 13.5%), constipation (23.8%, 25.9%, 26.1% vs. 10.9%), vomiting (10.6%, 22.8%, 25.3% vs. 4.8%) and upper respiratory tract infection (14.2%, 12.2%, 13.1% vs. 11.6%). Dysesthesia occurred in 5.1%, 12.3% and 12.5% of retatrutide patients at 4 mg, 9 mg and 12 mg, respectively, versus 0.9% with placebo; urinary tract infections occurred in 7.5%, 8.8% and 8.4% of retatrutide-treated patients compared with 5.3% with placebo. These events were generally mild to moderate, most resolved during treatment, and most affected participants remained on therapy. Discontinuation due to adverse events was 4.1%, 6.9% and 11.3% for the 4 mg, 9 mg and 12 mg retatrutide arms, respectively, versus 4.9% with placebo.
Lilly plans to present additional TRIUMPH-1 findings at the 86th American Diabetes Association Scientific Sessions, along with further data from its cardiometabolic pipeline. More detailed results will appear at upcoming medical meetings and in peer-reviewed publications. The company also expects to share results later this year from other Phase 3 trials in the TRIUMPH program, including TRIUMPH-2 in adults with obesity or overweight and type 2 diabetes, and TRIUMPH-3 in adults with obesity or overweight and established cardiovascular disease.
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