Metsera’s long-acting obesity drug sheds 8.4% weight in phase 1, fueling once-monthly GLP-1 combo plan

D&D Pharmatech's U.S. partner Metsera’s amylin analog MET-233i cut up to 8.4 percent of body weight in just five weeks in a phase 1 trial, according to topline results shared on Monday. These results back the biotech’s push to launch the first once-monthly fixed-dose obesity combo with a GLP-1 agonist.

The subcutaneous analog, designed for potency, durability and seamless pairing with Metsera’s GLP-1 receptor agonist MET-097i, delivered dose-linear pharmacokinetics with a 19-day observed half-life.

In the phase 1 trial of 80 adults with overweight or obesity, MET-233i showed a tolerability profile that closely matched placebo at low doses and reported no serious or severe adverse events.

MET-233i is a first-in-class monthly amylin with “the longest observed half life of any amylin we're aware of in development,” Metsera's Chief Financial Officer Christopher Visioli said during Monday’s readout. 

He added that the analog “has the potential for best in class characteristics including weight loss at the high end of the competitive landscape inclusive of GLP1 based medicines and excellent starting tolerability.”

The top weekly dose of 1.2 mg led to a mean placebo-subtracted weight loss of 8.4 percent, with individual drops reaching 10.2 percent. In the single-dose group, 2.4 mg triggered as much as 5.3 percent placebo-adjusted weight loss by Day 8.

Metsera's Chief Medical Officer Steve Marso said the level of weight loss seen over five weeks rivals what’s typically achieved with GLP-1s over longer treatment periods. He emphasized the molecule’s “very strong monotherapy profile” and ability to deliver results without titration.

That profile stems from HALO, Metsera’s internal peptide lipidation and stabilization platform. The technology enables peptides to bind albumin and their target receptor simultaneously, which prolongs half-life and allows for matched pharmacokinetics between co-formulated drugs. 

MET-233i’s exposure curve closely mirrors that of MET-097i, paving the way for what the company calls a multi-NuSH regimen that combines amylin and GLP-1 targeting agents in a fixed, once-monthly dose.

Beyond MET-233i and MET-097i, Metsera said it is preparing to bring a third HALO-built candidate into the clinic. The company’s ultra-long-acting GIP receptor agonist MET-034i is expected to enter a combination trial later this year.

For now, MET-233i is leading the way. Marso said gastrointestinal side effects, primarily nausea, were “largely confined to the first week,” with later events described as “sporadic” and “mild.”

Two low-dose cohorts, 0.15 and 0.3 mg, showed “similar tolerability with placebo,” he added, making them strong candidates for onboarding without titration ramps.

Metsera is already expanding its clinical program. A 12-week monotherapy trial testing a shift from weekly to monthly dosing is underway, with readouts expected in late 2025. A co-administration trial of MET-233i and MET-097i has been extended and will deliver topline data by the end of this year or early 2026.

Outside experts agree the results are worth watching. Professor Carel le Roux, director of the Metabolic Medicine Group at University College Dublin, said the findings suggest MET-233i could become “the potential first monthly multi-NuSH combination candidate” for patients looking for potent, well-tolerated weight loss therapies that are easier to maintain.