Why Lilly and Novo are betting on amylin to power a new wave of obesity drugs after GLP-1s

The next generation of blockbuster obesity drugs isn't trying to replace GLP-1 medicines.

Instead, drugmakers are developing treatments that can complement existing drugs and push weight loss further, or offer new options for potentially millions of people who may not get enough benefit from GLP-1s.

That's the early potential of a new slate 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 Eli Lilly and Novo another biological lever to pull in treating obesity and Type 2 diabetes, either as an independent treatment or layered on top of existing drugs.

Lilly offered a promising glimpse of that strategy this week.

The company's experimental amylin-targeting drug, eloralintide, helped produce substantially more weight loss when combined with tirzepatide – the active ingredient in its blockbuster Zepbound and Mounjaro shots – in a Phase 2 trial on patients with obesity and Type 2 diabetes.

At 48 weeks, people receiving the highest-dose combination lost an average of 23.3% of their body weight, compared with 14.8% among those only taking a high dose of tirzepatide. Those figures are based on efficacy analysis that assumes patients remained on treatment in the trial.

"These are encouraging results," said Benjamin Bikman, a professor at Brigham Young University and leading expert on metabolic health and insulin resistance. "Adults with type 2 diabetes typically lose less weight on these therapies than those without diabetes."

Lilly is developing eloralintide both as a standalone treatment and as part of that combo therapy. The two components make up what some analysts view as a major future franchise for the company.

Leerink Partners analyst David Risinger forecasts $23.2 billion in annual sales for Lilly's eloralintide products by the end of 2035. He said he expects the standalone drug to launch first in 2029, followed by the combo in 2030.

"There are millions of individuals, potentially over 10 million people, who have tried GLP-1s and failed due to efficacy reasons, tolerability issues, or genetic issues where they simply do not respond to one," Risinger told CNBC. "We think this novel mechanism, this amylin analog … will offer a major new treatment alternative for patients, both as a monotherapy and as a combination therapy. "

Risinger said he sees greater potential for standalone eloralintide given the "huge independent patient pool" that hasn't seen success on existing GLP-1s. Lilly still sees a clear opportunity for pairing the medications.

"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 a eloralintide on its own."

Bikman also said he sees the combo as an opportunity for patients who started on tirzepatide alone but saw their weight loss plateau.

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 will begin later this year.

Lilly also aims to improve how well patients tolerate the combo regimen in later studies. More patients taking both drugs — 10.8% to 27%, depending on the dose — discontinued treatment due to side effects, compared with the 2.9% of people on tirzepatide alone in the trial.

"A therapy is only effective if patients can remain on it, so tolerability in Phase 3 will be as important as efficacy," Bikman said.

Dr. Caroline Apovian, co-director of the Center for Weight Management and Wellness at Brigham and Women's Hospital, added that "27% is not a good number."

Still, the results add to a growing body of evidence that amylin could become an important tool against obesity and diabetes.

Lilly isn't alone in betting that amylin can become a building block for the next generation of obesity drugs. Novo has spent years pursuing a similar strategy.

Novo's experimental amylin-based drug, cagrilintide, has shown meaningful weight loss as a standalone treatment in a late-stage trial. Combining it with semaglutide – together dubbed CagriSema – has produced 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 single molecule that would target both GLP-1 and amylin to treat obesity and Type 2 diabetes. The Danish drugmaker is testing it as a once-weekly injection and a daily oral tablet, and the drug showed promising Phase 2 results earlier this year.

## Amylin vs. GLP-1

The first – and so far only – amylin therapy was approved in the U.S. more than two decades ago as an add-on mealtime injection for people with diabetes who use insulin. But adoption was limited in part because it required multiple injections a day.

New therapies in development are long-acting, meaning they are designed to mimic the hormone in a sustained way and can be taken once a week, Bikman said.

Amylin helps signal fullness, suppress appetite and slow the movement of food through the stomach, similar to what GLP-1 does. But amylin achieves that by acting on an entirely different biological pathway.

"It's the same outcome, 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 that the benefits could go beyond physical changes.

CagriSema reduced "food noise" — persistent thoughts about food — and showed improvements to organ and bone health in a yearlong functional magnetic resonance imaging study, which is a noninvasive method to measure brain activity during specific tasks. Novo said CagriSema changed how the brain reacted to tempting, high-calorie foods in areas linked to cravings, pleasure and self-control in people with obesity or who were overweight.

"The signal in the brain changes in a way that actually is associated with improved quality of life," Martin Holst Lange, Novo's chief scientific officer, said in an interview.

Developing treatments that target several hormone pathways rather than one is part of a broader shift in the obesity drug race, even beyond amylin.

Tirzepatide already pairs GLP-1 with GIP, while Lilly's experimental drug retatrutide also adds glucagon to the mix. Retatrutide has produced some of the largest weight loss results reported in obesity drug trials to date, and Bikman said published data on the drug demonstrate substantial reductions in liver fat, triglycerides and fasting insulin.

It's too early to definitively say whether combination amylin drugs could be superior to tirzepatide or other next-generation treatments. They'll have to clear more clinical trials and regulatory reviews first.

But all the medicines in development are working toward a broader goal shared by several drugmakers: giving patients a variety of obesity and diabetes treatment options to meet their individualized needs.