Metsera announced positive Phase 1 results for MET-233i, an ultra-long acting amylin analog that achieved up to 8.4% placebo-subtracted weight loss at Day 36, marking a significant advancement toward the first monthly amylin-GLP-1 combination therapy for obesity treatment.
The randomized, placebo-controlled, double-blind Phase 1 trial evaluated MET-233i in 80 participants with overweight or obesity without type 2 diabetes. The study tested single doses ranging from 0.15 mg to 2.4 mg, and multiple doses from 0.15 mg to 1.2 mg administered once weekly over five weeks without titration. The trial population had a mean baseline body mass index of approximately 32.
Exceptional Pharmacokinetic Profile
MET-233i demonstrated dose-linear pharmacokinetics with an observed half-life of 19 days from dose to 50% of Cmax, representing the most durable pharmacokinetic profile of any known amylin analog. This ultra-long half-life supports once-monthly dosing with simplified titration, a significant improvement over existing weekly amylin candidates.
"We are excited by these impressive results from MET-233i, which demonstrate exceptional efficacy with no safety signals, and enable the potential first monthly multi-NuSH combination," said Steve Marso, M.D., Chief Medical Officer of Metsera. "We observed five-week body weight loss comparable to that of leading GLP-1-based medicines, and we identified efficacious starting doses with placebo-like tolerability."
Robust Weight Loss Efficacy
The study showed dose-dependent weight loss, with the highest dose of 1.2 mg achieving a placebo-subtracted mean weight loss of 8.4% at Day 36. Individual responses reached as high as 10.2%. In the single ascending dose portion of the trial, substantial weight loss was maintained more than four weeks after dosing, supported by MET-233i's ultra-long pharmacokinetics.
MET-233i's exposure profile after multiple doses matched that of Metsera's GLP-1 receptor agonist candidate MET-097i, supporting combinability as a potential first-in-category once-monthly multi-NuSH combination. These results validate Metsera's proprietary HALO™ peptide stabilization and lipidation platform technology.
Favorable Safety and Tolerability Profile
The trial demonstrated favorable tolerability results with no safety signals. Gastrointestinal adverse events in the multiple ascending dose portion were all mild, dose-dependent, and primarily confined to the first week of dosing, indicating rapid onset of tolerance despite a three-fold accumulation of exposure over five weeks. Anticipated starting doses of 0.15 mg and 0.3 mg showed tolerability results comparable to placebo in both single and multiple dose portions.
No severe or serious adverse events were observed in either portion of the trial to date.
Clinical Significance and Market Position
"Amylin agonism has emerged as a central therapeutic mechanism for metabolic diseases, but candidates in development have been limited to weekly dosing," said Professor Carel le Roux, Director of the Metabolic Medicine Group and Chair in Experimental Pathology at University College Dublin. "The durability and efficacy of MET-233i in this trial, along with its combinability with Metsera's GLP-1 RA, make it the potential first monthly multi-NuSH combination candidate for patients seeking greater levels of well-tolerated weight loss with a more convenient dosing schedule."
Development Pipeline and Next Steps
Based on these positive results, Metsera is rapidly advancing MET-233i through multiple development pathways. An ongoing monotherapy trial evaluates 12 weekly doses of MET-233i with dose titration, followed by an exposure-matched monthly dose at week 13, with topline data expected in late 2025.
The company has extended an ongoing co-administration trial of MET-233i and MET-097i to twelve weeks, with topline data expected by year-end 2025 or early 2026. Additionally, Metsera expects to report topline clinical data from its ultra-long acting GIP receptor agonist, MET-034i, in combination with MET-097i, in late 2025.
MET-233i is being developed as both a monotherapy and in combination with MET-097i via the FDA biologic pathway, with the intent to pursue regulatory approval under a Biologics License Application (BLA) in the United States.
Platform Technology Validation
The results further substantiate Metsera's HALO™ platform technology, which enables peptides to bind simultaneously to albumin and drug targets. This design facilitates a half-life approaching that of albumin and exceeding other NuSH peptides, potentially enabling monthly dosing, improved tolerability, and improved scalability.
Metsera, founded in 2022 and based in New York City, is advancing a broad portfolio of oral and injectable incretin, non-incretin and combination therapies for obesity and metabolic diseases, positioning itself at the forefront of next-generation weight loss treatments.
