Eli Lilly and Company announced results from a late-stage clinical trial showing that its next-generation obesity treatment retatrutide delivered unprecedented weight-loss outcomes, outperforming its existing blockbuster drug Zepbound (tirzepatide).
In the Triumph-4 Phase III trial involving adults with obesity and knee osteoarthritis, participants receiving the highest dose of retatrutide lost an average of 28.7% of their body weight over 68 weeks, roughly 71.2 pounds, and experienced a 75.8% decrease in pain scores associated with osteoarthritis-related knee pain.
This beats out Zepbound’s 22.5% weight loss after 72 weeks. The more than 75% reduction in osteoarthritic knee pain scores was also superior to the 42% achieved with rival Novo Nordisk’s GLP-1 drug semaglutide.
The magnitude of weight reduction and symptom improvement led analysts to describe these results as among the strongest seen to date for any obesity therapy, positioning retatrutide as a potential new benchmark in the field.
Retatrutide, often dubbed a “triple-G” drug, works on three hormone receptors, GLP-1, GIP and glucagon, to suppress appetite, regulate glucose metabolism and increase calorie burning. This multi-target approach appears to deliver deeper and more sustained weight loss compared with earlier generations of incretin-based therapies, including single- and dual-agonist drugs.
In contrast, the company’s Zepbound, as well as diabetes equivalent Mounjaro, is a dual receptor agonist, targeting only GLP-1 and GIP.
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In addition to weight loss, more than two-thirds of treated patients in the trial reported substantial reductions in knee arthritis pain, and over one in eight reported being completely free of pain by the trial’s end, according to company-reported analyses.
After once-weekly injections for 68 weeks, patients on the higher 12-mg dose of retatrutide who lost an average of 28.7% of body weight (average weight loss of 71.2 pounds from a baseline of 248.5 pounds) were those who remained in the study and did not drop out. Patients treated with a lower 9-mg dose shed 26.4%, or 64.2 pounds, of their body weight.
When including patients who discontinued treatment, the average weight loss was lower at 23.7% of total body weight at Week 68.
The trial met both of its co-primary endpoints, which included weight loss and change in osteoarthritis pain. Patients who received retratride (both doses) experienced a 75% reduction in pain scores compared to a 40% decrease in the placebo group.
While the efficacy data impressed investors and clinicians alike, the safety and tolerability profile revealed some challenges. Side effects were consistent with those seen for obesity therapies, including gastrointestinal symptoms (nausea, diarrhea and constipation) and an elevated rate of dysesthesia (abnormal skin sensations), reported in about 20.9% of patients on the highest dose.
Overall discontinuation rates were higher in the active treatment group versus placebo, in part due to some participants withdrawing over perceived “excessive” weight loss.
In the trial, 18.2% of patients discontinued the high dose and 12.2% the lower dose due to adverse events, compared to the much lower 4% discontinuation rate in the placebo arm. Up to 16% of patients discontinued retatrutide because of adverse events in Phase II.
Lilly explained that the discontinuation rates were highly correlated with baseline body mass index (BMI). Excluding patients with a baseline BMI of 35 or higher (overweight and class 1 obesity), rates declined to 8.8% and 12.1% in the low- and high-dose groups, respectively, compared with 4.8% for placebo.
Despite these considerations, market response was positive, with Lilly shares rising a modest 1% after the news in early premarket trading.
“People with obesity and knee osteoarthritis often live with pain and restricted mobility, and may eventually require total joint replacement,” said Kenneth Custer, PhD, executive vice president and president, Lilly Cardiometabolic Health. “We are encouraged by the results of TRIUMPH-4, which highlight the powerful effect of retatrutide, a first-in-class triple agonist, on body weight, pain and physical function.”
Dr. Custer said Lilly has seven additional Phase III readouts expected in 2026, including results for a 4-mg maintenance dose.
“We believe retatrutide could become an important option for patients with significant weight loss needs and certain complications, including knee osteoarthritis,” he said.
The obesity treatment market, driven by unprecedented demand for effective weight-loss therapies, has been dominated in recent years by GLP-1 receptor agonists such as Zepbound and competitors like Novo Nordisk’s Wegovy. Retatrutide’s deeper average weight reductions and joint-pain improvements could elevate expectations from the blockbuster class of meds.
Competition is also intensifying on multiple fronts. GLP-1 rival Novo Nordisk is developing its own “triple-G” candidates and recently secured regulatory backing for a higher-dose formulation of Wegovy in the European Union.
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