Eli Lilly linked its amylin-Zepbound combination treatment eloraTZP to an average weight loss of 23.3% in patients with both obesity or overweight and type 2 diabetes, surpassing its own triple G drug candidate, retatrutide, in this traditionally difficult-to-treat population.
At the highest dose, the Lilly’s-approved cocktail of amylin receptor agonist eloralintide and GIP/GLP-1 med Zepbound (tirzepatide) resulted in an average weight loss of 54.1 pounds at 48 weeks, with benefits in HbA1C reduction as well. in patients with comorbid metabolic conditions.
Lilly based this interpretation on the efficacy estimate, which represents the effectiveness if all randomized participants had taken their study treatment as directed for 48 weeks. Based on these results, Lilly plans to initiate phase 3 trials with eloraTZP in the fourth quarter of 2026.
Big pharma has been busy with obesity since it released topline data from a Phase 3 trial of retatrutide in July, and the full results were presented this week at the 62nd annual meeting of the European Association for the Study of Diabetes (EASD) in Milan, Italy. Lilly’s triple G update showed that 34.9% of patients given 12 mg of retatrutide lost at least 25% of their body weight.
This most recent study, also presented at EASD, pitted eloraTZP at different doses, plus each drug separately, against placebo in 367 adults with obesity or overweight and type 2 diabetes.
The average weight loss figure of 23.3% is both “comparable to tirzepatide in patients without T2D” and is “remarkable given the attenuation of effectiveness typically seen with diabetes,” Citi analysts wrote in a note to clients Wednesday. Additionally, results from the highest dose of the combination drug were “comfortably above our 17% (weight loss) mark,” they said.
EloraTZP was developed by Lilly to activate three nutrient-stimulated hormones, GIP, GLP-1 and amylin. These hormones are key metabolic and hormonal regulators that are produced in the gut and pancreas to control blood sugar, digestion and appetite.
Amylin, which is co-secreted with insulin by pancreatic beta cells, has recently attracted attention as a drug target for obesity. It works by slowing digestion, blocking excess sugar production, and acting on the brain to signal the body that you are full after eating.
The greatest weight loss from Lilly’s trial results was seen in patients treated with eloralintide 9 mg and Zepbound 15 mg, with an average loss of 54.1 pounds from baseline at 48 weeks. Elorallintide alone at the 6 mg dose induced an average weight loss of up to 28.6 pounds, while those taking Zepbound 15 mg alone lost an average of 34.4 pounds.
The highest dose of 9 mg of eloralintide, when used alone in patients, resulted in an average weight loss of 25.8 pounds, below the threshold reported by its lower dose counterpart.
“Obesity and type 2 diabetes are interconnected, and we see the potential benefit of targeting multiple hormonal pathways to treat both,” Liana K. Billings, MD, director of diabetes and cardiometabolic disease clinical and genetic research at Endeavor Health, Evanston, Illinois, and lead study author, said in the statement. “We must continue to build on these findings so that in the future we can offer patients more treatment options that take both weight and blood sugar into account and better reflect the complexity of life with type 2 diabetes and obesity.”
Tolerance and safety, however, may prove problematic for Lilly’s experimental cocktail.
Adverse events were observed more frequently in the combination arm than in the eloralintide or tirzepatide alone arm and were primarily gastrointestinal in nature. Treatment discontinuations were observed in up to 27% of patients treated with eloraTZP.
Citi analysts believe that the many discontinuations due to adverse events could be due to the simultaneous launch of both components of the combo, likely amplifying tolerability issues. The Citi team also noted that “optimized phase 3 titration could preserve efficacy while improving compliance.”
Lilly’s results come amid a larger deluge of metabolic results this week.
Today, Zealand Pharma shared primary endpoint data for its amylin analogue petrelintide in partnership with Roche, showing an average of 9.8%. weight loss at week 28. Cross-trial comparisons suggest that petrelintide is unlikely to lead in amylin effectiveness, although putting different studies side by side is an imperfect tool. Eli Lilly saw weight loss of up to 11.3% at week 12 of a phase 1 trial of eloralintide, and up to 20.1% at week 48 of a phase 2 study.
Novo is also trying to tackle the amylin angle by combining its amylin analogue, cagrilintide, with the company’s well-known GLP-1 semaglutide to make CagriSema. This combination suffered some setbacks because it failed to meet one of the endpoints in a phase 3 study conducted in early August in patients with type 2 diabetes.
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