An Eli Lilly drug candidate designed to hit three metabolic targets led patients to lose an average of 28.7% of their body weight in a late-stage clinical trial, setting a new high mark in the competitive chase to develop next-generation obesity medications.
But the preliminary Phase 3 results also show high rates of patients discontinuing treatment, which will be something to watch in the coming year for this weekly injectable medication, retatrutide. The data reported Thursday are the first from a broad clinical trial program expected to yield seven additional Phase 3 trial readouts in 2026.
Lilly became a dominant player in obesity drugs with Zepbound, a weekly injectable medication whose main component is a peptide engineered to bind to and activate two gut receptors, GLP-1 and GIP. Retatrutide hits both of those targets and adds a third one, the glucagon receptor.
The results reported Thursday come from a 68-week Phase 3 test of two dose levels of retatrutide in adults with obesity or overweight. The 445 study participants did not have diabetes but they did have knee osteoarthritis; along with measuring the drug’s effect on weight loss, assessing pain and joint movement is a co-primary endpoint of the study. All participants started at a 2 mg weekly dose that was increased every four weeks until reaching the target dose.
The 28.7% average weight loss (32.3 kg or 71.2 pounds) was for the 12 mg dose, the higher of the two doses evaluated in the study. Weight loss in the placebo arm was 2.1% (2.1 kg or 4.6 pounds). According to a scale used to assess pain, in which a higher score indicates greater pain and disability, the study drug led to an average 4.4 point reduction in score (74.3%) while the score in the placebo arm fell an average of 2.4 points (40.3%).
The most common adverse events reported from the study were nausea, diarrhea, constipation, and decreased appetite — all consistent with the side effects of currently available obesity drugs. The discontinuation rate for the high dose was 18.2% compared to 4% for the placebo. Lilly said discontinuations were highly correlated with participants’ baseline body mass index “and included discontinuations for perceived excessive weight loss.” The company plans to present more detailed clinical trial results at a future medical meeting and in a peer-reviewed journal.
Leerink Partners analyst David Risinger said in a research note that the retatrutide results are in line with the firm’s expectations of weight loss in the mid-to-high 20% range. By comparison, the Phase 3 test of Zepbound showed 22% absolute weight loss for the 15 mg dose measured at 68 weeks. Risinger said the gastrointestinal adverse events in the retatrutide study were in line with Zepbound, but he also noted the higher rate of discontinuations: 18.2% for retatrutide versus 6.2% for 15 mg Zepbound.
“To conclude, we view retatrutide as offering additional benefits for patients and raising the bar for future tirzepatide competitors,” he said.
Retatrutide’s broad Phase 3 program has enrolled more than 5,800 study participants. These clinical trials are assessing the drug’s effect on obesity along with 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 metabolic dysfunction-associated steatotic liver disease.
Photo: Peter Dazeley, Getty Images
