Should amylin have been obesity therapeutics’ primary target from the start?

 

While GLP-1 medicines have become synonymous with weight loss, at least one expert thinks amylin would have been the go-to target if biopharma had been focused on the blockbuster indication 10 years ago. A new wave of therapies is now exploring this potentially gentler mechanism.

As Novo’s amylin/GLP-1 combo CagriSema nears possible FDA approval and amylin-targeting assets from Eli Lilly and Zealand Pharma yield late-stage data, experts are touting the potential of the amylin approach to be a more tolerable option for weight management than the ubiquitously popular GLP-1s.

“It’s a great mechanism that everyone should be paying attention to,” Hyung Heon Kim, president and CEO of MetaVia, said during a BioSpace webinar last month.

BMO Capital Markets Head of Healthcare Research Evan Seigerman agreed, calling amylin “the next hot target” in the obesity space. The weight loss benefits of GLP-1s—initially indicated for diabetes—were a serendipitous discovery, Seigerman noted. But the analyst said he was struck by a comment from a key opinion leader who told him that if the biopharma industry had been focused on weight loss 10 years ago, amylin would have been the target of choice.

Why amylin?

Eli Lilly’s Zepbound and Novo’s Wegovy, and the other GLP-1 drugs in their portfolios or under development by biopharma writ large, work by activating the GLP-1 receptors to trigger the secretion of insulin and inhibition of glucagon release. In so doing, the medicines help to balance appetite and food cravings.

But they don’t work for everyone, and amylin-targeting molecules could bust through weight loss plateaus in order to treat patients who may not respond well to GLP-1 drugs like Lilly’s Zepbound or Novo’s Wegovy, Seigerman said. “[Key opinion leaders] need something else like this in their armamentarium because not all patients respond to either one of them,” he added.

GLP-1-based medicines also come with myriad side effects, most commonly gastrointestinal. There is a belief among experts that amylin-based weight loss drugs might offer a gentler option, with fewer adverse effects.

Roche CEO Thomas Schinecker talked up the tolerability of his company’s Zealand Pharma–partnered amylin analog petrelintide. “If you don’t want side effects, you can take a highly tolerable amylin” drug, Schinecker told reporters in April during Roche’s first-quarter 2026 earnings call.

Amylin/GLP-1 agonist combo therapies could achieve the same level of weight loss but with better tolerability by including lower doses of GLP-1 than do current monotherapies, Seigerman said. Indeed, Novo in June touted “low” dropout rates in the REDEFINE-1 and REDEFINE-2 trials of CagriSema, which combines semaglutide and the long-acting amylin analog cagrilintide. Patients in REDEFINE-1 lost 22.7% of their body weight at 68 weeks—below Novo’s own projections of around 25% but on par with current GLP-1 drugs.

“Taking the best GLP-1 out there at this point in time, adding essentially an amylin . . . you’re able to get efficacy beyond where people may plateau on [semaglutide] for sure, and maybe even Zepbound,” Seigerman said of CagriSema.

As to the demand for these therapies, Seigerman pointed to the bidding war between Novo and Pfizer last year over fledgling obesity biotech Metsera—a prize Pfizer ultimately won for nearly $10 billion.

“When you talk to Pfizer and Novo about the Metsera bidding war . . . they were both going at this company because they wanted their amylin,” he said. Just months before the bidding war began, an ultra-long-acting amylin injection the biotech was developing elicited 8.4% placebo-adjusted weight loss at 36 days in a Phase 1 trial.

The state of play

Novo is nearing the regulatory finish line with CagriSema. The Danish pharma filed for FDA approval of its amylin combo last December, and analysts are anticipating a decision this quarter.

If approved, CagriSema would be the first amylin drug to hit the market for weight loss, but it has many potential competitors in the pipeline.

Novo’s chief rival Eli Lilly stole headlines at the European Association for the Study of Diabetes (EASD) annual meeting a few weeks ago, revealing robust weight loss generated by a combination of its amylin agonist eloralintide and powerhouse dual GIP/GLP-1 agonist Zepbound. In the Phase 2b trial, patients with obesity or overweight and type 2 diabetes who took the combo, called EloraTZP, lost an average of 23.3% of their weight at the 48-week mark, compared to 14.8% for those given Zepbound alone and 3% for placebo comparators.

The trial did record muddled safety data, with adverse event–tied discontinuations across the dosing groups of EloraTZP ranging from 10.8% and 27%, compared with 0% to 10.8% for eloralintide alone, 2.9% for tirzepatide only and 16.7% for placebo.

EloraTZP’s Phase 2 results were “met with mixed reaction owing to the tolerability trade-off,” BNP Paribas wrote in an Oct. 5 note, which noted tolerability as a key theme at EASD.

Nevertheless, the data package as a whole was enough for Lilly to take EloraTZP to Phase 3. Meanwhile, the pharma is expecting results from a Phase 3 study of eloralintide as a monotherapy in 2028. Analysts are expecting big things from the drug.

“We expect eloralintide to be a mega-blockbuster given its differentiated benefit-tolerability profile and potential role for patients who failed GLP-1 therapy due to efficacy or tolerability challenges,” Leerink Partners wrote in a note to investors on Sept. 15.

As for Zealand’s Roche-partnered petrelintide, the companies reported Phase 2 data last week that William Blair found both “intriguing” and “underwhelming.” The long-acting human amylin analog elicited up to 9.2% mean weight loss at week 28 depending on the dose—which William Blair said was comparable to eloralintide and Zepbound and superior to Wegovy at the same time point. But the analysts were less impressed by petrelintide’s ability to lower blood sugar.

This isn’t the first time petrelintide has failed to impress analysts and investors. In March, the investigational drug lowered body weight by more than 10% after 42 weeks in a mid-stage study. While the result fell well short of analyst expectations, minimal side effects were reported in the trial.

“We believe Zealand achieved the goal of demonstrating highly encouraging tolerability for petrelintide, though the magnitude of weight loss disappointed,” William Blair wrote at the time.

As clinical data begin to differentiate the field, Novo is looking ahead to a potential launch of CagriSema. The asset has had a rocky developmental journey, missing Novo’s own projections for the therapy in a December 2024 readout from the Phase 3 REDEFINE 1 trial and falling to Zepbound in the head-to-head Phase 3 REDEFINE 4 trial in February. Last month, however, CagriSema did best Lilly’s GIP/GLP-1 agonist in another Phase 3 test, REIMAGINE 5.

Seigerman described CagriSema as “a bit of a sleeper asset.”

Whichever next-gen weight loss assets eventually steal market share, amylin will almost undoubtedly be among them. Seigerman cited his conversation about how it may have been the top choice over GLP-1s if the field could start over.

“That says to me,” he said, “that amylin is going to be very important.”

https://www.biospace.com/drug-development/should-amylin-have-been-obesity-therapeutics-primary-target-from-the-start