Metsera, Inc. (Nasdaq: MTSR) has unveiled encouraging topline data from its Phase 1 trial of MET-233i, a first-in-class, ultra-long-acting amylin analog intended for once-monthly subcutaneous injection. Designed using Metsera's proprietary HALO? peptide stabilization and lipidation platform, MET-233i is positioned to play a transformative role in obesity treatment, especially in combination with the company's GLP-1 receptor agonist, MET-097i.
According to the announcement released on June 9, 2025, MET-233i produced a placebo-subtracted mean weight loss of up to 8.4% at Day 36. The drug also demonstrated an observed half-life of 19 days, affirming its suitability for monthly dosing. “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 Dr. Steve Marso, Metsera's Chief Medical Officer.
The Phase 1 study was a randomized, double-blind, placebo-controlled trial that enrolled 80 overweight or obese participants without type 2 diabetes. MET-233i was tested both as a single ascending dose (0.15 mg to 2.4 mg) and in multiple ascending doses (0.15 mg to 1.2 mg) administered weekly over five weeks. The average participant had a baseline BMI of approximately 32.
Key pharmacokinetic findings included dose-linear behavior and a 19-day half-life—the most durable among known amylin analogs. This sustained exposure is consistent with Metsera's monthly GLP-1 candidate MET-097i, indicating strong potential for a monthly multi-NuSH (multi neuroendocrine hormone synergy) combination therapy.
Body weight reductions were dose-dependent, peaking at a placebo-subtracted mean of 8.4% following five weekly doses of 1.2 mg. Individual responses reached as high as 10.2%. The study also found that weight loss persisted for over four weeks after a single dose, attributed to the compound's extended half-life.
From a safety standpoint, MET-233i exhibited a favorable profile. "Gastrointestinal adverse events... were all mild, dose-dependent, and primarily confined to the first week of dosing," Metsera reported. No severe or serious adverse events were recorded, and starting doses of 0.15 mg and 0.3 mg mirrored placebo-like tolerability.
Metsera is moving swiftly to capitalize on these results. The company is currently conducting an extended monotherapy trial using 12 weekly doses of MET-233i followed by a matched monthly dose, with data expected in late 2025. Additionally, a co-administration trial with MET-097i has been extended to twelve weeks, and results are anticipated by year-end 2025 or early 2026.
The company also plans to release topline results from MET-034i, its ultra-long-acting GIP receptor agonist, in combination with MET-097i by the end of 2025. If successful, MET-034i would be the third compound developed via the HALO? platform to enter clinical trials.
Guggenheim Partners previously identified MET-233i's early data as one of Metsera's most “critical program milestones” for 2025, stating the readout could “substantially de-risk the program.” The firm projects the market for ultra-long-acting injectable incretin therapies could reach $19 billion by 2035.
As it stands, MET-233i is the only once-monthly amylin analog in clinical development, offering a distinct advantage over competitors. Novo Nordisk's combination of semaglutide and long-acting amylin analog cagrilintide, known as CagriSema, has failed to meet market expectations. In the REDEFINE 1 Phase III study, CagriSema delivered 22.7% weight loss at 68 weeks—short of the 25% anticipated—causing a $72 billion dip in Novo's market cap. Subsequent data releases also disappointed investors.
Guggenheim analysts believe Novo's flexible dosing protocol was an “unforced error” that left room for better-optimized competitors like MET-233i to gain traction. “In our view, Novo Nordisk not only unequivocally validated the amylin mechanism in obesity, but their unforced error opened up a lane for other amylin competitors—particularly those that are differentiated like Metsera's ultra-long acting MET-233i,” analysts wrote.
Additional players in the amylin space include Eli Lilly, which expects mid-2025 Phase II results for its candidate eloralintide, and AbbVie, which entered the field via a $2.2 billion agreement with Gubra.
