UPDATE: Lilly's next obesity drug just cut an average of 58 pounds—prompting an all-out phase 3 blitz

Fifty-eight pounds. That’s how much weight patients lost on average at the end of 48 weeks when taking Eli Lilly’s next-generation obesity treatment. It equates to a mean 24% reduction in participants' body weight.

In a phase 2 study, Lilly found that retatrutide at the highest dose reduced weight by 16%, or 41 pounds, at 24 weeks, meeting the main goal. A secondary measure that extended the time period to 48 weeks is where the higher reductions were seen. The data were presented at the American Diabetes Association scientific sessions Monday and simultaneously published in The New England Journal of Medicine.

The results blow out of the water data from the currently approved medicines—Novo Nordisk’s Wegovy and Lilly’s own Mounjaro. Wegovy, which targets the glucagon-like peptide-1 (GLP-1) hormone, achieved a 12% reduction according to the data that underpinned its 2021 approval. Mounjaro is not yet approved for obesity but has been used off label for this purpose and has recently shown a 16% reduction. The med targets GLP-1 but also the glucose-dependent insulinotropic polypeptide (GIP) receptor.

Lilly Chief Scientific and Medical Officer Dan Skovronsky, M.D., Ph.D., who also serves as president of Lilly Research Laboratories, says that the secret sauce behind the new therapy is combining GLP-1 and GIP receptor agonists with a glucagon receptor agonist.

As for safety, the results were similar to other drugs in the class, including gastrointestinal side effects that were mild to moderate in severity. These events typically occurred during dose escalation. The trial included 338 patients who have obesity or are overweight and have weight-related conditions, except for Type 2 diabetes.

Lilly also looked at some exploratory endpoints, finding that retatrutide was associated with improvements in cardiometabolic measures such as systolic and diastolic blood pressure, triglycerides, LDL cholesterol, total cholesterol, HbA1c and fasting glucose and insulin during the study.

But the results seen in the phase 2 trial may not truly capture retatrutide’s full ability. Patients had yet to reach a weight plateau by the time the study ended, according to Ania Jastreboff, M.D., Ph.D., associate professor of medicine and pediatrics, endocrinology and metabolism at Yale School of Medicine. She also serves as director of the Yale Obesity Research Center and is co-director of the Yale Center for Weight Management.

“It appears that full weight reduction efficacy was not yet attained,” Jastreboff said in a Monday statement. That means Lilly will need to extend the study period in a planned phase 3 program to find out the full impact that retatrutide has on weight loss.

The phase 2 data have given Lilly what it needs to launch full throttle into a late-stage program that looks at obesity for chronic weight management and the many associated complications, Skovronsky said. The phase 3 TRIUMPH program will examine retatrutide in chronic weight management, obstructive sleep apnea and knee osteoarthritis in people with obesity and who are overweight.

Lilly has gone all-in on obesity, with a deep pipeline of assets that now includes retatrutide as its star. Also in the clinic is mazdutide, which recently showed a 15% weight reduction in a study conducted by Chinese partner Innovent. 

SVB Securities analysts called the results "highly compelling," noting the room for more weight reduction since the curve had not yet been met. The firm also pointed out that the results are "particularly impressive" because there was a larger proportion of men than women in the study. Women typically lose a higher proportion of weight than men do. 

Since the phase 2 trial had a more equal representation of men to women—with the latter representing 48% of the trial population, the results could mean retatrutide can achieve greater weight loss than other agents. Women had a 29% weight reduction, while men achieved 22%, according to SVB Securities. For comparison, Lilly's phase 3 SURMOUNT-1 trial of Mounjaro achieved a 22.5% weight reduction with 68% women. 

On safety, SVB Securities said a 16% discontinuation rate seems high, but Lilly is still tweaking the dose escalation procedure for retatrutide, so tolerability could be smoothed out in the coming phase 3 trials. There was a 7% rate of cutaneous hyperesthesia, a condition where the skin becomes over sensitive. An expert who spoke with SVB Securities suggested that this could be due to a vitamin deficiency experienced by patients as their appetite decreases. Lilly will need to assess this data and figure out how to manage it. 

Editor's Note: This story was updated at 9:01 a.m. ET on Monday, June 27, 2023, to include analyst commentary.