The next card after GLP-1: Why are Eli Lilly and Novo Nordisk both betting on amylin?

Eli Lilly's Phase II clinical data released this week adds a key piece to its obesity drug roadmap after GLP-1: its experimental amylin drug eloralintide, in combination with telpotetide, resulted in an average weight loss of 23.3% over 48 weeks in the highest dose group, far exceeding the 14.8% in the high-dose telpotetide monotherapy group.

The goal of next-generation obesity drugs is not to replace GLP-1, but to combine new weight loss mechanisms.

Eli Lilly and Novo Nordisk are developing a range of injectable, oral, and combination regimens around amylin—a hormone released in the pancreas along with insulin to help regulate hunger and satiety—to set a higher ceiling for weight loss while providing alternatives for patients who do not respond well to GLP-1.

Eli Lilly Phase II data: 23.3% weight loss, but tolerability remains to be seen.

Eli Lilly is pursuing eloralintide in two lines—both as a standalone therapy and in combination with its blockbuster drug telpotide. The Phase 2 clinical trial announced this week, targeting obese patients with type 2 diabetes, showed an average weight loss of 23.3% over 48 weeks in the highest-dose combination group and 14.8% in the high-dose telpotide monotherapy group. These data are based on efficacy analysis, assuming all enrolled patients completed the full course of treatment.

"These results are encouraging," commented Benjamin Bikman, a metabolic health expert at Brigham Young University. "People with type 2 diabetes typically experience less weight loss with this type of therapy than those without diabetes."

Leerink Partners analyst David Risinger predicts that Eli Lilly's eloralintide product line will reach annual sales of $23.2 billion by the end of 2035, with monotherapy expected to launch in 2029 and combination therapy following in 2030. He believes the potential of standalone eloralintide may be even greater because "there may be more than 10 million people who have tried GLP-1 but failed due to insufficient efficacy, tolerability issues, or genetic factors."

In an interview, Ken Custer, president of Eli Lilly's Cardiometabolic Health, stated, "Patients may not get the full benefits they need from telpotide, or they may not get them from eloralintide monotherapy." Bikman also believes that combination therapy offers new possibilities for patients who have reached a plateau in weight loss with telpotide monotherapy.

But Eli Lilly still has much to prove. The data comes from a smaller Phase II trial, with Phase III trials scheduled to begin later this year. Tolerability is a key challenge: the rate of discontinuation due to side effects ranged from 10.8% to 27% in the combination therapy groups at different doses, compared to only 2.9% in the telposide monotherapy group. Dr. Caroline Apovian, co-director of the Weight Management Center at Brigham and Women's Hospital, stated bluntly, "27% is not a good number." Bikman also emphasized, "A therapy is only effective if patients can continue to use it, therefore tolerability in the Phase III trial will be just as important as efficacy."

Novo Nordisk's amylin strategy: CagriSema to launch next year

Novo Nordisk has been investing in the amylinin field for many years. Its amylinin drug cagrillintide has shown significant weight loss as a standalone therapy in a late-stage clinical trial. CagriSema, a combination of cagrillintide and semaglutide, has demonstrated even greater weight loss in clinical studies and is expected to launch early next year. Standalone cagrillintide and high-dose CagriSema are expected to launch in 2028.

New data released this week by Novo Nordisk shows that CagriSema's effects extend beyond weight loss. In a year-long fMRI study of the brain, the drug reduced "food noise"—persistent thoughts about food—and improved organ and bone health. The study showed that CagriSema altered the responses of areas in the brains of obese or overweight individuals associated with cravings, pleasure, and self-control to high-calorie foods. "The signaling in the brain changed in a way that is associated with improved quality of life," said Martin Holst Lange, Novo Nordisk's chief scientific officer, in an interview.

Novo Nordisk is also developing amycretin (also known as zenagamtide), a drug that uses a single molecule to mimic the effects of two hormones, GLP-1 and amylin, and is being tested in both weekly injection and daily oral tablet forms. Positive Phase II clinical results were announced earlier this year.

The era of multi-target therapy: from dual-target to triple-target therapy

Amylin is not a new drug. The United States approved the first amylin therapy more than 20 years ago, but the drug required multiple daily injections, limiting its availability. Currently, the next-generation amylin drugs under development are all long-acting formulations that can be injected once a week.

Amylin helps create a feeling of fullness, suppresses appetite, and slows gastric emptying—effects similar to GLP-1—but the two work through completely different mechanisms. "The results are the same, but the pathways are different," Bikman told CNBC. The logic of combining the two mechanisms is intuitive: simultaneously mobilizing multiple hormonal signals may lead to greater weight loss while avoiding pushing the dosage of a single drug to its limit.

This line of thinking has extended beyond amylin. Telpotetide itself is already a drug that targets both GLP-1 and GIP, while Eli Lilly's experimental drug retatrutide goes a step further, targeting three hormones simultaneously: GLP-1, GIP, and glucagon. Clinical trials have reported the largest weight loss data to date, and published data show that this drug is particularly effective in reducing liver fat, triglycerides, and fasting insulin. Pfizer, AstraZeneca, and Viking Therapeutics are also developing their own amylin products.

It is too early to determine whether amylin combination therapies are superior to telposide or other next-generation therapies, as more clinical trials and regulatory approvals are still pending. However, the competitive landscape of obesity drugs is rapidly evolving, moving from dual-target to triple-target therapies, and from injection to oral administration.

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