MET-097i: A Fully Biased Ultra-long Acting GLP-1 Receptor Agonist

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MET-097i: A Fully Biased Ultra-long Acting GLP-1 Receptor Agonist

Jul 09, 2025

  • MET-097i is the lead investigational therapy from Metsera, designed as a fully biased GLP-1 receptor agonist with ultra-long-acting properties. Administered via SC injection, it leverages Metsera’s proprietary HALO platform and has shown a preliminary half-life of 15–16 days, indicating the potential for once-monthly dosing with flexible titration options. 
  • Metsera shared clinical findings from the Phase I/II trial of MET-097i through two presentations, highlighting changes in body weight and tolerability outcomes following twelve weekly doses as well as a single monthly dose. The presentations are titled
    • A 12-week Trial of MET-097—A Potent and Ultra-Long-Acting GLP-1 Receptor Agonist
    • Safety, Tolerability, PK, and Efficacy of MET-097—A Next-Generation Nutrient-Stimulated Hormone Peptide Analog for Chronic Weight Management.

Presentation 1: A 12-week Trial of MET-097i—A Potent and Ultra-long Acting GLP-1 Receptor Agonist

Trial Design

Metsera conducted a randomized, double-blind, placebo-controlled Phase I/II study to evaluate the efficacy, safety, tolerability, and pharmacokinetics of MET-097i—a fully biased, ultra-long-acting GLP-1 receptor agonist. The trial enrolled 120 adult participants with obesity or overweight (BMI 27–38 kg/m²) but without diabetes or significant comorbidities. The study included five cohorts, each receiving 12 once-weekly (QW) SC doses of MET-097i across various dose levels (0.4 mg to 1.2 mg), followed by a single higher-dose administration intended to simulate monthly dosing (2× or 4× the weekly dose).

Participants were evenly distributed among treatment and placebo arms (20 MET-097i vs. 4 placebo per cohort), and primary efficacy was measured by percent change from baseline (%CFB) in body weight at Day 85. Additional assessments included metabolic parameters, Adverse Events (AEs), and tolerability, with follow-up through Day 115.

Results

Efficacy Outcomes

Weekly administration of MET-097i resulted in substantial, dose-dependent weight loss, with placebo-subtracted percentage change from baseline at Day 85 reaching –11.3% in the 1.2 mg group, –10.3% in the 1.0 mg group, and –9.3% in the 0.8 mg group.

Notably, weight loss did not plateau, indicating a sustained therapeutic effect. After a single high-dose monthly injection on Day 85, weight reduction continued through Day 115, with the 4× monthly dose arm (1.2/4.8 mg) showing placebo-corrected mean weight loss of –15.0%.

Safety and Tolerability

The safety profile of MET-097i was in line with the GLP-1 class, with no unexpected AEs. Gastrointestinal side effects, primarily mild nausea and vomiting, were dose-dependent (up to 65% and 60% in the 1.2 mg group vs. 15% and 5% in placebo, respectively). One serious AE (calculous cholecystitis) was deemed treatment-related, but no discontinuations were attributed to adverse events.

Metabolic Effects

Notable improvements in cardiometabolic markers were observed, including a reduction in LDL cholesterol by up to –23.0 mg/dL, a decrease in total cholesterol by –32.5 mg/dL, and a systolic blood pressure drop of up to –11.6 mmHg in the 1.2 mg group, indicating broader metabolic benefits beyond weight loss.

Conclusion
The Phase I/II trial establishes MET-097i as a promising ultra-long-acting GLP-1 receptor agonist with the potential for monthly dosing and minimal titration. The agent induced robust, dose-dependent weight loss with sustained effects post-treatment, a favorable safety profile, and added metabolic benefits. These findings provide strong rationale for the ongoing Phase IIb trials investigating simplified weekly and monthly dosing regimens.

Presentation 2: Safety, Tolerability, PK, and Efficacy of MET-097—A Next-generation Nutrient-stimulated Hormone Peptide Analog for Chronic Weight Management

Trial Design

The study was a randomized, double-blind, placebo-controlled Phase I trial conducted at a single site (NCT06857617). Participants were adults with a BMI between 27 kg/m2 and 38 kg/m² and normal kidney function (eGFR ≥90 mL/min), without diabetes or elevated cardiovascular risk factors. The trial featured two parts: Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) cohorts. In the SAD arm, participants were randomized 6:2 to MET-097 or placebo across seven escalating dose levels. In the MAD arm, six dose cohorts received weekly injections of MET-097 or placebo, with one group receiving four weeks of 0.8 mg followed by a 5th week of 1.6 mg to test the tolerability of accelerated titration.

Efficacy Outcomes

MET-097 demonstrated a clear dose-dependent reduction in body weight, with the 1.2 mg dose group achieving a 7.5% mean weight loss from baseline by Day 36. Impressively, this effect was sustained even after the end of the dosing period, with a mean weight loss of 8.1% at Day 57 and 7.5% at Day 85. These findings suggest that MET-097 not only induces significant short-term weight loss but also has the potential for durable efficacy with relatively few doses. The ability to escalate doses with minimal tolerability issues further enhances its clinical appeal.

Safety and Tolerability

Safety data were encouraging, with no serious TEAEs reported across all cohorts. Most adverse events were mild gastrointestinal symptoms, such as nausea and vomiting, consistent with the known class effects of GLP-1 receptor agonists. Notably, vomiting was largely confined to the first week of dosing, indicating a rapid onset of tolerance. Even in the cohort that underwent a twofold dose escalation in the final week, only a single case of moderate vomiting was observed, highlighting the favorable tolerability profile of MET-097.

Pharmacokinetics

Pharmacokinetic analysis revealed that MET-097 has a mean time to peak concentration of approximately 18 days, with predictable, dose-proportional plasma levels and minimal variability. The accumulation ratio after five weekly doses was approximately three, and a two-fold dose increase resulted in a predictable rise in drug exposure. These features are attributed to the drug’s ultra-long half-life, which supports the potential for monthly dosing—a major advantage over current weekly GLP-1-based therapies and a key differentiator in terms of patient adherence and convenience.

KOL Views

The first wave of obesity drugs was based mainly on the gut hormone GLP-1, but drugmakers are looking for medicines that target other hormones or help preserve muscle while losing fat for their next generation of drugs.– Expert Opinion

The data strengthen the view of MET-097i as the potential first ultra-long acting GLP-1 receptor agonist. The powerful reductions in weight affirm earlier studies. We are also excited by the emerging tolerability and dosing profile of MET-097i, which may offer versatility and meaningful advantages for patients.– Expert Opinion

Conclusion

The ADA 2025 data on MET-097 mark an important step forward in the evolution of GLP-1 therapies. With compelling early efficacy, simplified dosing, and a well-tolerated safety profile, MET-097 is well-positioned to meet the needs of patients who struggle with adherence to existing therapies. It is a promising addition to the growing obesity and cardiometabolic market, particularly as it targets the need for durable, high-compliance solutions.

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