MET-097i (Berobenatide / PF-08653944)

Early human Weight Loss & Metabolism 3 sources

MET-097i is an investigational, ultra-long-acting, fully biased GLP-1 receptor agonist designed for once-monthly subcutaneous injection. It utilizes a proprietary HALO™ peptide lipidation technology to achieve a half-life of approximately 380 hours. Early clinical trials show it produces substantial weight loss comparable to weekly GLP-1 agonists, but with the convenience of monthly dosing and potentially without the need for dose titration.

01Dosing reference

Amount

Investigational doses range from 0.4 mg to 9.6 mg depending on the phase (titration vs maintenance)

Frequency

Once monthly (after potential weekly initiation phase)

Cycle

Continuous chronic use

Reference figures, not a recommendationThese values reflect amounts described in the literature and vendor documentation this database indexes. Use the reconstitution calculator to convert them into syringe units.

02Mechanism of action

Biased GLP-1 Receptor Activation

MET-097i binds to the GLP-1 receptor but acts as a 'fully biased' agonist, meaning it preferentially activates specific intracellular signaling pathways (like G-protein signaling) over others (like beta-arrestin recruitment).

Extended Albumin Binding

Using HALO™ technology, the peptide is lipidated to bind strongly to albumin in the blood, protecting it from rapid enzymatic degradation and extending its half-life to roughly 380 hours (about 16 days).

Appetite Suppression and Gastric Emptying

The sustained GLP-1 receptor activation continuously signals the brain to reduce appetite and slows gastric emptying, leading to prolonged satiety and significant weight loss with only once-monthly dosing.

03Human evidence

In the Phase 2b VESPER-1 trial, weekly dosing of MET-097i resulted in up to 14.1% placebo-adjusted weight loss after 28 weeks.

Randomized, double-blind, placebo-controlled trial in adults with obesity or overweight without type 2 diabetes.

In the Phase 2b VESPER-3 trial, switching from weekly titration to monthly maintenance dosing resulted in 10% to 12.3% placebo-adjusted weight loss at week 28, with no weight loss plateau observed.

Evaluated the efficacy and tolerability of transitioning to a four-fold equivalent monthly dose in patients without type 2 diabetes.

Phase 2a data showed an 11.3% mean body weight reduction at 12 weeks with weekly dosing, and demonstrated that pharmacological exposure accumulated approximately 4-fold over 12 weeks without titration.

120 patients separated into cohorts receiving various doses without titration, showing the potential for titration-free regimens.

04Preclinical evidence

MET-097i demonstrated a half-life of 24 hours in rats and 99 hours in pigs, significantly longer than semaglutide.

Pharmacokinetic studies measuring single and repeat subcutaneous administration in animal models.

At one-third the dose, MET-097i was equally effective as semaglutide and tirzepatide for body weight loss in diet-induced obese (DIO) mice.

22-day study comparing equimolar doses of MET-097i against other incretin therapies in DIO mice.

05What is known vs. unknown

Reasonably established

MET-097i has an exceptionally long half-life of approximately 380 hours, enabling once-monthly dosing.
It is a 'fully biased' GLP-1 receptor agonist, which may improve its therapeutic window and tolerability profile.
Clinical trials have shown it can achieve over 12% placebo-adjusted weight loss at 28 weeks with monthly maintenance dosing.
The drug's pharmacokinetic profile allows for a 4-fold accumulation over 12 weeks, potentially eliminating the need for the slow dose titration required by other GLP-1 agonists.
Metsera, the original developer of MET-097i, was acquired by Pfizer to advance the drug into Phase 3 clinical trials.

Unknowns & limits

Long-term safety and cardiovascular outcomes are not yet established, as the drug has only completed Phase 2 trials.
Because of its ultra-long half-life, if severe adverse effects occur, they may take significantly longer to resolve after discontinuing the medication compared to weekly GLP-1s.
It is not yet FDA-approved and remains an investigational drug.

06Safety & regulatory context

Regulatory statusMET-097i is currently an investigational drug in Phase 2/3 clinical trials and is not FDA-approved. In early trials, it has demonstrated a tolerability profile consistent with the GLP-1 receptor agonist class. The most common adverse events are gastrointestinal, such as nausea and vomiting, which were predominantly mild to moderate. Notably, the drug's ultra-long half-life means that while it offers the convenience of monthly dosing, any adverse effects that do occur could potentially persist longer than those from shorter-acting agents. There were minimal discontinuations due to adverse events in the Phase 2b trials.

07Compared with Semaglutide

MET-097i (Berobenatide / PF-08653944) vs. Semaglutide

Key difference

MET-097i has a half-life of ~380 hours allowing for once-monthly dosing and potentially titration-free initiation, whereas semaglutide has a ~7-day half-life requiring once-weekly injections and a strict 16-week dose escalation protocol.

When researchers discuss each

Researchers discuss semaglutide as the established gold standard with proven long-term cardiovascular benefits and extensive safety data, while MET-097i is discussed as a next-generation pipeline candidate that could revolutionize treatment adherence through its ultra-long-acting, once-monthly convenience.

08Glossary

Biased Agonism

A property of certain drugs where they bind to a receptor but preferentially activate one specific internal cellular pathway over others, potentially maximizing benefits while minimizing side effects.

Half-life

The time it takes for the concentration of a drug in the body to reduce by half. A longer half-life means the drug stays active in the body longer, requiring less frequent dosing.

Titration

The process of gradually increasing the dose of a medication over time to allow the body to adjust and minimize side effects.

09Knowledge check

Q1What is the primary advantage of MET-097i's ~380-hour half-life compared to current GLP-1 medications?

Q2What does it mean that MET-097i is a 'fully biased' GLP-1 receptor agonist?

Q3Which conclusion is best supported by the Phase 2 human trial data presented in the dossier?

Q4Which statement correctly summarizes the dossier's comparison between MET-097i and semaglutide?

Q5What safety or regulatory implication of MET-097i's ultra-long half-life is highlighted in the dossier?

10Sources

More in Weight Loss & Metabolism

See all

AOD-9604

Weight Loss & Metabolism

Human clinical

AOD-9604 is a modified fragment of human growth hormone (HGH) that includes amino acids 177-191. Research indicates it mimics the fat-burning effects of HGH by stimulating lipolysis and inhibiting lipogenesis, without the adverse effects on blood sugar or tissue growth typically associated with full-length HGH.

250-500 mcg/day

MOTS-c

Weight Loss & Metabolism

Early human

MOTS-c is a naturally occurring mitochondrial-derived peptide that plays a key role in regulating metabolic homeostasis and energy production. Research indicates it acts as an 'exercise mimetic' by activating AMPK, improving insulin sensitivity, and enhancing physical performance in animal models.

5-10 mg

GLP3-RT (Retatrutide)

Weight Loss & Metabolism

Human clinical

Retatrutide is an investigational triple hormone receptor agonist that targets GLP-1, GIP, and glucagon receptors. Clinical trials have shown unprecedented weight loss efficacy, surpassing dual agonists, by combining appetite suppression with increased energy expenditure.

N/A - Investigational Drug

Research and educational use onlyNothing on this site is medical advice, a prescription, or a recommendation for human use. Compounds documented here are research chemicals. Consult a qualified clinician before making any health decision.