Eli Lilly has tied its amylin-Zepbound combination treatment eloraTZP to 23.3% average weight loss in patients struggling with both obesity or overweight and type 2 diabetes, topping its own triple-G drug candidate retatrutide in that traditionally tricky-to-treat population.

At the highest dose, the cocktail of amylin receptor agonist eloralintide and Lilly's approved GIP/GLP-1 med Zepbound (tirzepatide) yielded average weight loss of 54.1-pounds at 48 weeks, with A1C-lowering benefits shown, too, in patients with the comorbid metabolic conditions.

Lilly based that interpretation on the efficacy estimand, which represents the efficacy had all randomized participants taken their study treatment as directed for 48 weeks. Based on the readout, Lilly plans to initiate phase 3 trials with eloraTZP in 2026's fourth quarter.

The Big Pharma has been busy with obesity as it reported topline data from a phase 3 retatrutide trial in July, with the full results 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 retatrutide 12 mg lost at least 25% of their body weight.

This most recent study, also presented at EASD, pitted eloraTZP at different doses, plus each drug on its own, against placebo in 367 adults with obesity or overweight and type 2 diabetes.

The 23.3% average weight loss figure is both "comparable to tirzepatide in patients without T2D" and it is "notable given the efficacy attenuation typically seen with diabetes," analysts at Citi wrote in a Wednesday note to clients. Moreover, those results from the highest dose of the combination drug came in "comfortably above our 17% [weight loss] bar," they said.

EloraTZP was developed by Lilly to activate three nutrient-stimulated hormones, GIP, GLP-1, and amylin. These hormones are key metabolic and hormone 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 been gaining attention recently as an obesity drug target. It works to slow digestion, block excess sugar production and acts on the brain to signal to the body that you are full after eating.

The greatest weight loss from Lilly's trial readout was seen in patients treated with eloralintide 9 mg and Zepbound 15 mg, with an average loss of 54.1 pounds compared to baseline at 48 weeks. Eloralintide alone at the 6 mg dose induced weight loss of an average of up to 28.6 pounds, while those taking Zepbound 15 mg alone lost an average of 34.4 pounds.

The higher, 9-mg dose of eloralintide, when used solo in patients, charted 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 are seeing the potential benefit of targeting multiple hormonal pathways to address both," Liana K. Billings, M.D., director of clinical and genetics research in diabetes and cardiometabolic disease at Endeavor Health, Evanston, Illinois, and lead study author, said in the release. "We need to continue building on these findings so that, in the future, we can offer patients more treatment options that address both weight and glucose and better reflect the complexity of living with type 2 diabetes and obesity."

Tolerability and safety may prove an issue for Lilly's experimental cocktail, however.

Adverse events were seen more frequently in the combination arm compared to eloralintide or tirzepatide alone and were mainly gastrointestinal in nature. Treatment discontinuations were seen in up to 27% of patients treated with eloraTZP.

The Citi analysts believe that the high discontinuations due to adverse events could be due to the simultaneous initiation of both components of the combo, likely amplifying tolerability challenges. The Citi team also noted that "optimized phase 3 titration could preserve efficacy while improving adherence."

Lilly's results come amid a larger deluge of metabolic readouts this week.

Today, Zealand Pharma shared primary endpoint data on its Roche-partnered amylin analog petrelintide, showing 9.8% average weight loss at week 28. Cross-trial comparisons suggest petrelintide’s efficacy is unlikely to lead the amylin field, though putting different studies side by side is an imperfect tool. Eli Lilly saw up to 11.3% weight loss at Week 12 of a phase 1 trial of eloralintide, rising to up to 20.1% at Week 48 of a phase 2 study.

Novo is also attempting the amylin angle by combining its amylin analog, cagrilintide, with the company’s well-known GLP-1 semaglutide to make CagriSema. This combination has endured some setbacks as it missed one of the endpoints of a phase 3 study in patients with Type 2 diabetes back in early August.