Metsera Announces Positive Phase 1 Data of First-in-Class Once-Monthly Amylin Candidate MET-233i

Metsera, Inc. recently announced positive topline data from the Phase 1 clinical trial of MET-233i, an ultra-long acting amylin analog engineered for class-leading durability, potency, and combinability with Metsera’s fully-biased monthly GLP-1 receptor agonist candidate, MET-097i. In the study, MET-233i demonstrated up to 8.4% mean placebo-subtracted weight loss at Day 36, a 19-day observed half-life supporting once-monthly dosing, and a favorable tolerability profile with no safety signals.

“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, MD, 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. These data position MET-233i as a potential best-in-class amylin and support a category-leading profile in combination with MET-097i.”

The randomized, placebo-controlled, double-blind Phase 1 trial was designed to evaluate the pharmacokinetics, efficacy, and safety of subcutaneous MET-233i in 80 participants with overweight or obesity without type 2 diabetes. MET-233i was evaluated at single doses from 0.15 mg to 2.4 mg, and multiple doses from 0.15 mg to 1.2 mg given once weekly over five weeks without titration. The trial population was broadly balanced in gender between MET-233i and placebo and had a mean baseline body mass index of approximately 32.

Topline results from the Phase 1 trial include:

• Dose-linear pharmacokinetics with an observed half-life of 19 days from dose to 50% of Cmax. This represents the most durable pharmacokinetic profile of any known amylin analog and supports the potential for once-monthly dosing with simplified titration. MET-233i’s exposure profile after multiple doses matched that of MET-097i, supporting combinability as a potential first-in-category once-monthly multi-NuSH combination. These data further substantiate HALO™, Metsera’s proprietary, novel peptide stabilization and lipidation platform technology.
• Body weight loss up to 8.4%. Body weight loss was dose-dependent, ranging up to a placebo-subtracted mean of 8.4% at Day 36 after five weekly doses of 1.2 mg, with individual responses as high as 10.2%. In the single ascending dose (SAD) portion of the trial, substantial weight loss was maintained more than four weeks after dosing, supported by the ultra-long pharmacokinetics observed for MET-233i.
• Favorable tolerability results. Gastrointestinal adverse events in the multiple ascending dose (MAD) portion of the trial were all mild, dose-dependent, and primarily confined to the first week of dosing, implying 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 demonstrated tolerability results comparable to placebo in both the SAD and the MAD portions of the trial.
• No safety signals. There were no severe or serious adverse events observed in the SAD or MAD portion of the trial to date.

“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.”

Based on these positive topline data, Metsera is rapidly advancing MET-233i as a monotherapy and in combination with MET-097i:

• An ongoing monotherapy trial evaluates 12 weekly doses of MET-233i with dose titration, followed by an exposure-matched monthly dose at week 13. Topline data from this trial are expected in late 2025.
• Metsera 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.

The company also expects to report topline clinical data from its ultra-long acting GIP receptor agonist, MET-034i, in combination with MET-097i, in late 2025. We anticipate that MET-034i will be the third peptide engineered with Metsera’s HALO™ platform to enter clinical testing.

MET-233i is an ultra-long acting, subcutaneously injectable monthly amylin analog engineered for class-leading durability, potency, and combinability in solution with Metsera’s fully-biased, ultra-long acting GLP-1 RA candidate MET-097i, with matched solubility parameters and observed half-lives. MET-233i is being explored in clinical studies as a monotherapy and in combination with MET-097i. Metsera is developing the combination of MET-233i and MET-097i via the FDA biologic pathway with the intent to pursue the combination’s regulatory approval in the United States under a BLA.

HALO is Metsera’s novel peptide stabilization and lipidation platform technology that enables peptides to bind simultaneously to albumin and to a drug target, designed to facilitate a half-life approaching that of albumin and exceeding that of other NuSH peptides. This ultra-long half-life may enable monthly dosing, improved tolerability, and improved scalability.

Metsera is a clinical-stage biopharmaceutical company accelerating the next generation of medicines for obesity and metabolic diseases. Metsera is advancing a broad portfolio of oral and injectable incretin, non-incretin and combination therapies with potential best-in-class profiles to address multiple therapeutic targets and meet the future needs of a rapidly evolving weight loss treatment landscape. Metsera was founded in 2022 and is based in New York City. For more information, please visit us at www.metsera.com and follow us on LinkedIn and X.

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