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The next generation of blockbuster obesity drugs is not trying to replace GLP-1 drugs.
Instead, drugmakers are developing treatments that can complement existing medications and further push weight loss, or offer new options to millions of people who might not benefit enough from GLP-1.
It’s the first potential for a new line of injections, pills and combination regimens targeting the amylin pathway, which involves a hormone released in the pancreas alongside insulin that helps regulate hunger and fullness. Amylin gives Elie Lilly And Novo another biological lever to exploit in the treatment of obesity and type 2 diabetes, either as an independent treatment or in addition to existing medications.
Lilly offered a promising glimpse of that strategy this week.
The company’s experimental amylin-targeting drug, eloralintide, contributed to significantly greater weight loss when combined with tirzepatide – the active ingredient in its blockbuster Zepbound and Mounjaro injections – in a phase 2 trial in patients with obesity and type 2 diabetes.
At 48 weeks, people receiving the highest dose lost an average of 23.3% of their body weight, compared to 14.8% in those taking only a high dose of tirzepatide. These numbers are based on an effectiveness analysis that assumes patients remained on treatment during the trial.
“These are encouraging results,” said Benjamin Bikman, a professor at Brigham Young University and a leading expert on metabolic health and insulin resistance. “Adults with type 2 diabetes generally lose less weight with these therapies than those without type 2 diabetes.”
Lilly is developing eloralintide both as a standalone treatment and as part of this combination therapy. The two components make up what some analysts see as a major future franchise for the company.
Leerink Partners analyst David Risinger forecasts annual sales of Lilly’s eloralintide products will be $23.2 billion by the end of 2035. He said he expects the standalone drug to launch first in 2029, followed by the combo in 2030.
“Millions of individuals, potentially more than 10 million people, have tried GLP-1s and failed for reasons of efficacy, tolerance or genetic issues where they just don’t respond,” Risinger told CNBC. “We believe that this new mechanism, this amylin analogue… will offer a major new therapeutic alternative to patients, both as monotherapy and as combination therapy.”
Risinger said he sees greater potential for standalone eloralintide given the “huge unrelated patient pool” that has not seen success with existing GLP-1s. Lilly still sees a clear opportunity to combine the 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 from a drug like eloralintide alone.”
Bikman also said he sees the combo as an opportunity for patients who started taking tirzepatide alone but saw their weight loss stabilize.
But Lilly still has a lot to prove. The data comes from a relatively small Phase 2 study that the company will need to confirm in Phase 3 trials, which begin later this year.
Lilly also aims to improve how patients tolerate the combination regimen in future studies. More patients taking both drugs — 10.8% to 27%, depending on dose — stopped treatment because of side effects, compared with 2.9% of people on tirzepatide alone in the trial.
“A therapy is only effective if patients can follow it, so tolerability in phase 3 will be as important as effectiveness,” Bikman said.
Dr. Caroline Apovian, co-director of the Center for Weight Management and Wellness at Brigham and Women’s Hospital, added that “27 percent is not a good number.”
Still, the findings add to a growing body of evidence that amylin could become an important tool against obesity and diabetes.
Lilly isn’t the only one betting that amylin can become a building block in the next generation of obesity drugs. Novo has spent years pursuing a similar strategy.
Novo’s investigational amylin drug, cagrilintide, showed significant weight loss as a stand-alone treatment in a late-stage trial. Its combination with semaglutide – together called CagriSema – resulted in even greater weight loss in clinical studies. CagriSema is expected to launch early next year, followed by standalone Cagrilintide and a higher-dose version of CagriSema in 2028.
Novo is also developing another treatment called amycretin, or zenagamtide, which is a unique molecule that reportedly targets both GLP-1 and amylin to treat obesity and type 2 diabetes. The Danish drugmaker is testing it as a once-weekly injection and daily oral tablet, and the drug showed promising phase 2 results earlier this year.
Amylin versus GLP-1
The first – and so far only – amylin treatment was approved in the United States more than two decades ago as a supplemental mealtime injection for people with diabetes who use insulin. But adoption was limited in part because it required multiple injections per day.
The new treatments in development are long-acting, meaning they are designed to mimic the hormone for a long time and can be taken once a week, Bikman said.
Amylin helps signal satiety, suppress appetite, and slow the movement of food through the stomach, similar to how GLP-1 does. But amylin achieves this by acting on a completely different biological pathway.
“It’s the same result, but a different approach,” Bikman told CNBC.
The idea is that targeting multiple pathways could produce more weight loss or other metabolic benefits than any single pathway can achieve on its own, and without relying entirely on higher doses of a single drug.
New data from Novo this week suggests the benefits could extend beyond physical changes.
CagriSema reduced “food noise” – persistent thoughts about food – and showed improvements in organ and bone health in a year-long functional magnetic resonance imaging study, which is a non-invasive method for measuring brain activity during specific tasks. Novo said CagriSema changed the way the brain responded to tempting, high-calorie foods in areas related to cravings, pleasure and self-control in obese or overweight people.
“The signal in the brain changes in a way that is actually associated with better quality of life,” Martin Holst Lange, Novo’s chief scientific officer, said in an interview.
The development of treatments targeting multiple hormonal pathways rather than just one is part of a broader shift in the race for obesity drugs, even beyond amylin.
Tirzepatide already combines GLP-1 with GIP, while Lilly’s experimental drug retatrutide also adds glucagon to the mix. Retatrutide has produced some of the most significant weight loss results reported to date in obesity drug trials, and Bikman said published data on the drug demonstrate substantial reductions in liver fat, triglycerides and fasting insulin.
It is too early to say for sure whether amylin combination drugs might be superior to tirzepatide or other new-generation treatments. They will first need to authorize more clinical trials and regulatory reviews.
But all of the drugs in development have a broader goal shared by several drugmakers: providing patients with a variety of obesity and diabetes treatment options to meet their individualized needs.
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