The next generation of blockbuster obesity drugs are not trying to replace GLP-1 drugs.
Instead, drug companies are developing treatments that can complement existing drugs to further promote weight loss or provide new options for the millions of people who may not get the full benefit from GLP-1.
This is an early possibility for new injections, pills, and combination treatments that target the amylin pathway, a hormone released in the pancreas along with insulin that helps regulate hunger and satiety. amylin gives Eli Lilly, Novo Several other companies are introducing other biological tools to treat obesity and type 2 diabetes, either as stand-alone treatments or on top of existing drugs.
Lilly offered a promising glimpse into that strategy this week.
The company’s experimental amylin-targeted drug, elolarintide, was able to produce significant weight loss in Phase 2 trials in patients with obesity and type 2 diabetes when combined with tirzepatide, the active ingredient in blockbuster products Zepbound and Mounjaro injections.
At 48 weeks, those who received the highest dose of the combination lost an average of 23.3% of their body weight, compared with 14.8% for those who took the high dose of tirzepatide alone. These numbers are based on an efficacy analysis that assumes patients continued treatment in the trial.
“These are encouraging results,” said Benjamin Bickman, a professor at Brigham Young University and a leading expert on metabolic health and insulin resistance. “Adults with type 2 diabetes typically lose less weight with these treatments than adults without diabetes.”
Lilly is developing eloralintide as a stand-alone treatment and as part of combination therapy. These two elements make up what some analysts see as the company’s future major franchises.
Leerink Partners analyst David Reisinger expects annual sales of Lilly’s eloralintide products to reach $23.2 billion by the end of 2035. He said he expects single drugs to be launched first in 2029, followed by combination drugs in 2030.
“There are millions of people, probably more than 10 million, who have tried GLP-1 and have not responded to it for efficacy reasons, tolerability issues, genetic issues, etc.,” Reisinger told CNBC. “We believe that this new mechanism, this amylin analog, offers a major new treatment for patients, both as monotherapy and as combination therapy.”
Reisinger said he sees great potential for eloralintide alone, given the “huge, independent patient pool” where existing GLP-1s have not seen success. Lilly believes there is still a clear opportunity to combine drugs.
“Patients may not get what they need from a drug like tirzepatide,” Ken Custer, president of Lilly Cardiometabolic Health, said in an interview. “They may not get what they need with drugs like eloralintide alone.”
Bickman also said he sees the combination as an opportunity for patients who started on tirzepatide alone but whose weight loss plateaued.
But Lily still has a lot to prove. The data comes from a relatively small Phase 2 trial, which the company needs to confirm in a Phase 3 trial starting later this year.
Lilly also aims to improve how well patients tolerate the combination therapy in future studies. In this trial, more patients taking both drugs discontinued treatment due to side effects (10.8% to 27%, depending on dose) compared to 2.9% of patients taking tirzepatide alone.
“Therapies are only effective if patients are able to continue treatment, so tolerability in phase 3 becomes as important as efficacy,” Bikman said.
“27% is not a good number,” added Dr. Caroline Apovian, co-director of the Weight Management and Wellness Center at Brigham and Women’s Hospital.
Still, the results add to the growing body of evidence that amylin could be an important tool against obesity and diabetes.
Lilly isn’t alone in betting on amylin’s potential as a building block for the next generation of obesity drugs. Novo has been pursuing a similar strategy for years.
Cagrilintide, Novo’s experimental amylin-based drug, showed significant weight loss as a monotherapy in late-stage trials. In clinical studies, even greater weight loss was obtained when combined with semaglutide, called “kaglisema.” Kagrisema is expected to be launched early next year, followed by stand-alone Kagrilintide and higher-dose versions of Kagrisema in 2028.
Novo is also developing another treatment called amicletin (xenagamtide). This is a single molecule that targets both GLP-1 and amylin to treat obesity and type 2 diabetes. The Danish drugmaker is testing the drug as a once-weekly injection and daily oral tablet, and the drug showed promising Phase 2 results earlier this year.
including some companies pfizer, AstraZeneca and Viking Therapeuticshas also developed its own amylin products.
The first, and currently only, amylin therapy was approved in the United States more than 20 years ago as a mealtime booster injection for diabetics using insulin. However, its adoption was limited, in part because it required multiple injections per day.
The new treatments being developed are long-acting, designed to mimic hormones on a sustained basis, and can be taken once a week, Bickman said.
Amylin, like GLP-1, signals satiety, suppresses appetite, and helps slow the movement of food through the stomach. However, amylin accomplishes this by acting on an entirely different biological pathway.
“The outcome is the same, but the approach is different,” Bickman told CNBC.
The idea is that by targeting multiple pathways, we can produce more weight loss and other metabolic benefits than can be achieved with a single pathway alone, without relying entirely on high doses of a single drug.
New data released by Novo this week suggests the benefits may go beyond physical changes.
CagriSema reduced “food noise” (persistent thoughts about food) and showed improved organ and bone health in a year-long functional magnetic resonance imaging study, a non-invasive method of measuring brain activity during specific tasks. Novo said Caglisema altered the brain’s response to appealing high-calorie foods in areas related to craving, pleasure and self-control in obese and overweight people.
“The signals in the brain actually change in ways that are associated with improved quality of life,” Martin Horst Lange, Novo’s chief scientific officer, said in an interview.
Beyond amylin, the development of treatments that target multiple hormonal pathways rather than just one is part of a broader shift in the obesity drug race.
Tirzepatide already combines GLP-1 and GIP, but Lilly’s experimental drug letartortide also has glucagon added to it. Retatortide has produced some of the largest weight loss results ever reported in trials of an obesity drug, and Bickman said published data on the drug shows significant reductions in liver fat, triglycerides, and fasting insulin.
It is too early to say whether the amylin combination is better than tirzepatide or other next-generation treatments. They first need to clear more clinical trials and regulatory reviews.
However, all drugs in development work toward a broader goal shared by multiple drug companies. It’s about providing patients with a variety of obesity and diabetes treatment options to meet their individual needs.
