Eli Lilly’s experimental obesity drug combination produced greater weight loss than its highest dose of tirzepatide alone in a 48-week mid-stage trial involving people with obesity and type 2 diabetes.
The regimen combines eloralintide, which targets the appetite-regulating hormone amylin, with a lower dose of tirzepatide, the active ingredient in Lilly’s weight-loss injection Zepbound and diabetes treatment Mounjaro.
Patients given the highest combination dose lost an average of up to 23.3% of their body weight, equivalent to around 54lb. The treatment consisted of 9mg of eloralintide and 15mg of tirzepatide.
By comparison, those taking 15mg of tirzepatide alone lost an average of 14.8%, or about 34.4lb. Eloralintide on its own produced weight loss of up to 12.3%, or 28.6lb.
The trial met its main objectives, Lilly said, raising the prospect of another treatment option for patients who have not achieved the results they wanted from existing GLP-1 medicines or who have struggled with their side effects.
Lilly plans to begin Phase 3 trials of the combination by the end of 2026. It also intends to test a co-formulated version, allowing both medicines to be delivered in a single injection.
Combination treatment also reduced blood sugar
Tirzepatide acts on the gut hormones GLP-1 and GIP, while eloralintide targets amylin, a pancreatic hormone involved in appetite and feelings of fullness. Lilly believes stimulating all three pathways may further suppress appetite and improve weight loss.
The combination reduced A1C, a measure of average blood sugar levels, by up to 2.9% on average. The highest dose of tirzepatide alone reduced A1C by up to 2.4%, while eloralintide alone lowered it by up to 1.4%.
However, the results also highlighted questions about how well patients tolerate the combination and whether they remain on treatment.
Between 10.8% and 27% of patients receiving the combination stopped treatment because of side effects, depending on the dose. That compared with 2.9% among those taking tirzepatide alone.
Up to 10.8% of patients taking eloralintide alone discontinued treatment because of side effects, compared with 16.7% of those given a placebo. Lilly said side effects were more common with the combination and were mainly gastrointestinal, generally mild or moderate, and most often occurred during dose increases.
Ken Custer, president of Lilly Cardiometabolic Health, cautioned against drawing firm conclusions from the discontinuation rates in the Phase 2 trial. He said the highest dose of tirzepatide had also recorded a rate of about 25% in a mid-stage trial in 2018.
“It’s probably not the best indicator of the tolerability of a medicine,” Mr Custer said. “We do things in Phase 1 and Phase 2 to test what the molecule can do from an efficacy perspective. We also learn from those studies about how we should administer them, and then we make changes. We do this every time.”
Lilly said it would adjust the dosing schedules for the combination in Phase 3, with Mr Custer saying the company expected to achieve “a very favorable balance of efficacy and tolerability”.
Lilly sees potential in three-hormone approach
The results were presented at the European Association for the Study of Diabetes meeting in Milan. The combination is being viewed as a potential rival to Novo’s CagriSema, which combines medicines targeting amylin and GLP-1.
Mr Custer said the approach could “turn out to be a really winning approach”, arguing that it engages three hormone systems involved in the body’s response to food rather than heavily targeting one.
The latest findings build on a Phase 1 trial in which adding 3mg of eloralintide to 5mg of tirzepatide resulted in 17% weight loss over 16 weeks among adults with obesity. The same dose of tirzepatide alone produced 10% weight loss, according to Lilly.
Eloralintide is also being developed as a standalone treatment. Lilly’s other next-generation obesity drug, retatrutide, targets GLP-1, GIP and glucagon.
