Eli Lilly's drug targeting 3 obesity targets sets new high standard for weight loss in clinical trial
An Eli Lilly and Company drug candidate designed to hit three metabolic targets led to an average weight loss of 28.7% in patients in a late-stage clinical trial, setting a new high in the race to develop the next generation of obesity drugs.
But preliminary phase 3 results also showed a high rate of patients discontinuing treatment, which will be something to watch in the coming year for the weekly injectable drug retarglutide. The data reported Thursday is the first from a broad clinical trial program expected to yield seven additional Phase 3 trial readouts in 2026.
Eli Lilly has become the dominant player in obesity drugs with Zepbound, a once-weekly injection based on a modified peptide that binds to and activates two intestinal receptors: GLP-1 and GIP. Retalglutide hits both of these targets and adds a third target, the glucagon receptor.
The results released Thursday were from a 68-week Phase 3 trial of two dose levels of retarglutide in adults who were obese or overweight. 445 study participants did not have diabetes but had knee osteoarthritis; in addition to measuring the drug's effect on weight loss, pain and joint motion were assessed as co-primary endpoints of the study. All participants started with a dose of 2 mg per week and increased every four weeks until they reached their target dose.
The average weight loss was 28.7% (32.3 kg or 71.2 pounds) at the 12 mg dose, which was the higher of the two doses evaluated in the study. The placebo group lost 2.1% (2.1 kilograms or 4.6 pounds) of body weight. On a scale used to assess pain, in which higher scores indicate greater pain and disability, the study drug caused an average decrease in scores of 4.4 points (74.3%), compared with an average decrease of 2.4 points (40.3%) in the placebo group.
The most common adverse events reported in the study were nausea, diarrhea, constipation, and decreased appetite—all of which are consistent with side effects of currently available weight loss drugs. The discontinuation rate was 18.2% in the high-dose group and 4% in the placebo group. Eli Lilly said discontinuation was highly correlated with participants' baseline body mass index, “including discontinuation due to perceived excessive weight loss.” The company plans to publish more detailed clinical trial results at future medical meetings and peer-reviewed journals.
Leerink Partners analyst David Risinger said in a research note that retarglutide's results were in line with the company's expectations for a weight loss in the mid-to-high range of 20%. By comparison, Zepbound's Phase 3 testing showed an absolute weight loss of 22% with the 15 mg dose measured at 68 weeks. Risinger said gastrointestinal adverse events in the retarglutide study were consistent with Zepbound, but he also noted higher discontinuation rates: 18.2% for retarglutide versus 6.2% for Zepbound 15 mg.
“Overall, we believe retarglutide provides additional benefits to patients and raises the bar for future tezepatide competitors,” he said.
Retatrutide's extensive Phase 3 program has enrolled more than 5,800 study participants. These clinical trials are evaluating the drug's effects on obesity and at least one weight-related medical problem: type 2 diabetes, knee osteoarthritis, moderate to severe obstructive sleep apnea, chronic low back pain, cardiovascular and renal outcomes, and fatty liver disease associated with metabolic dysfunction.
Photo: Peter Dazeley, Getty Images
