ATLANTA — The investigational ultra long-acting injectable GLP-1 receptor agonist (RA) MET-097 produced up to 14% weight loss, with the potential for improved tolerability compared with other GLP-1 RAs and once-monthly dosing, new phase 2 data suggested.

Findings from Metsera’s phase 2b VESPER-1 trial along with early VESPER-3 trial data were presented on November 6, 2025, at Obesity Week 2025 by John B. Buse, MD, PhD, professor of medicine at The University of North Carolina at Chapel Hill. On November 7, the company announced its acquisition by Pfizer, following a bidding war with Novo Nordisk.

In September 2025, Metsera released top-line data from VESPER-1 and interim VESPER-3 trials, with the former designed to establish dosing regimens for planned phase 3 trials.

“The phase 2b results suggest that MET-097 may be the best-tolerated GLP-1 receptor agonist with efficacy on par with dual agonists. The long half-life creates opportunities for easier initiation and titration as well as once-monthly dosing providing for less burden to patients and providers at lower cost and with better adherence and persistence,” Buse told Medscape Medical News.

Asked to comment, session moderator Barbara A. Gower, PhD, chair and professor in the Department of Nutrition Sciences at The University of Alabama at Birmingham, told Medscape Medical News, “The once-monthly dosing is attractive. The lack of having to ramp it up is attractive. And [Buse] said that he’s getting effectiveness that’s about equivalent to the dual agonist. I would say it seems promising, and it has some advantages compared to some of the other drugs in the lack of requirement for the dose escalation and the once-monthly treatment.”

However, regarding the once-monthly dosing, Gower commented, “I don’t know how much of an advantage that is from a patient perspective, if it really is that big of a deal.”

Designed to Overcome Dosing, Tolerability Issues of Other GLP-1 RAs

In VESPER-1, 239 adults with obesity or overweight with comorbidities were randomized to one of five groups: Subcutaneously injected placebo, or weekly MET-097 doses of 0.4 mg, 0.6 mg, 0.9 mg, or 1.2 mg, without titration, for 28 weeks.

Those completing the 28 weeks were eligible for an extension study using higher MET-097 doses in the two lower-dose groups and low doses in the placebo group. Weekly dosing was continued for 8 weeks into the extension, then dropped to less frequent dosing thereafter.

Overall, just seven participants (2.9%) discontinued due to adverse events, including one (2.1%) in the 0.9 mg group, three (6.3%) in the 1.2 mg group, and two (4.2%) in the placebo group.

Weight loss from baseline at 28 weeks was dose-dependent, ranging from 6.4% with the 0.4 mg dose to 12.5% with the 1.2 mg dose. There was a gain of 1.7% in the placebo group. Placebo-subtracted weight loss ranged from 8.1% with 1.4 mg to 13.1% with 1.2 mg.

“Even at lower doses, weight loss was clinically meaningful, confirming a clear dose dependent relationship in weight loss,” Buse commented.

Weight loss continued through the extension phase with no plateaus seen by week 36. “The body weight loss is consistent with that that has been observed with dual agonists, highlighting the advantage of full receptor bias,” Buse said.

There were just three serious adverse events, two in the 0.4 mg group and one in the 0.6 mg group, but none with the two higher doses. Rates of nausea (ranging from 27.1% with placebo to 50.0% with 1.2 mg), vomiting (12.5% to 27.7%), and diarrhea (10.4% to 22.9%) were comparable to those of GLP-1 RAs, despite the lack of titration. Most were mild-to-moderate in severity. There were no unexpected safety signals.

“Tolerance builds rapidly and most of the adverse events are confined to the first few weeks. They’re closer to the background rate observed in placebo after that. We can also see that in the 0.4 mg group, which is the proposed starting dose for titration, the tolerability in each week is very comparable to placebo,” Buse said.

As an explanation for why the gastrointestinal (GI) side effects in the placebo group were fairly high, Buse pointed out that the public has become very aware of this phenomenon with GLP-1 RAs, and that the informed consent process for the clinical trials reiterates it. Thus, “it is becoming more common for the placebo group to have GI adverse events at a higher rate than might be expected. Perhaps this can be explained by the so-called nocebo effect, where participants expect to be nauseous or to have vomiting.”

But, he said, that the risk differences compared with placebo for nausea, vomiting, and diarrhea across the dose groups show “a consistent signal of excellent tolerability, better than one would expect in the absence of titration, highlighting the advantage of durability and small, smooth pharmacokinetics.”

VESPER 3: Interim Findings for the Effect of Titration

VESPER 3 is an ongoing phase 2b randomized, double-blind, placebo-controlled trial with a planned enrollment of 250 adults with obesity or overweight with comorbidities. The primary objective is to evaluate efficacy and tolerability of multiple monthly doses, but it includes an initial weekly titration period examining tolerability with 2- or 3-step titration regimens.

In a pre-specified analysis of that weekly phase, tolerability of the 1.2 mg dose improved with two titration steps, from 0.4 mg to 0.8 mg to 1.2 mg. Compared with the rates seen in VESPER-1, the titration reduced nausea by 44% (22.9% to 12.8%), vomiting by 11% (12.5% to 11.1%), and diarrhea by 101% (12.5% to -0.1%). “This further supports the hypothesis that the smooth pharmacokinetics associated with long half-life can improve tolerability,” Buse said.

Based on the phase 2b data, Metsera — now Pfizer — anticipates initiating a phase 3 program for MET-097 in late 2025. Other phase 2b trials are examining a range of less-frequent doses for induction and maintenance of weight loss, and drug use in patients with type 2 diabetes with top-line results expected in early 2026. Top-line final results for monthly dosing at 28 weeks in VESPER-3 are expected in late 2025 or early 2026.

The company is also further studying MET-97 as the backbone for four other clinical programs:

• MET-233/097, a first-in-category monthly combination with MET-233i, an ultra-long-acting amylin agonist, is in ongoing 12-week Phase 1/2a trials with topline data expected at the end of 2025 or early 2026.
• MET-034/097, a combination with MET-034, an ultra long-acting GLP-1 RA, is initiating Phase 1 clinical studies.
• MET-097_o, an oral form of MET-097, is currently being evaluated in Phase 1 trials.
• MET-815, a prodrug of MET-097i designed for quarterly maintenance dosing, is in Investigational New Drug-enabling studies.

Buse reported receiving research support from Corcept, Dexcom, and Novo Nordisk; consulting fees from Altimmune, Antag, Amgen, ApStem, Aqua Medical, AstraZeneca, Boehringer-Ingelheim, CeQur, Corcept Therapeutics, Dexcom, Eli Lilly, Embecta, GentiBio, Glyscend, Insulet, Medtronic MiniMed, Mellitus Health, Metsera, Novo Nordisk, Pendulum Therapeutics, Praetego, Stability Health, Tandem, Terns, Vertex, and Zealand Pharma; and stock options from Glyscend, Mellitus Health, Metsera, Pendulum Therapeutics, Praetego, and Stability Health. Gower had no disclosures.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X @MiriamETucker and BlueSky @miriametucker.bsky.social.