Metsera's MET-233i Achieves 8.4% Weight Loss in Phase 1 Trial

Highlights

• MET-233i achieved up to 8.4% placebo-subtracted weight loss at Day 36.
• Observed 19-day half-life supports once-monthly dosing without titration.
• No severe or serious adverse events observed; mild GI side effects limited to initial week.
• Current trials include MET-233i monotherapy and combination therapy with GLP-1 candidate MET-097i; results expected late 2025.
• MET-233i is the only known monthly amylin therapy in clinical development.
• Metsera's HALO? platform underpins its entire multi-NuSH therapeutic strategy.
• Analysts see strong market potential as competitors like Novo Nordisk falter.

Promising Results from Once-Monthly Amylin Analog

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.

Trial Design and Pharmacokinetics

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.

Clinical Efficacy and Safety Profile

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.

Strategic Pipeline and Industry Context

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.

Market Outlook and Competitive Landscape

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.