What Is MET-233i (PF-08653945)? The Monthly Amylin Peptide Being Developed Alone and With GLP-1

The next wave of amylin drugs is not only about finding new ways to control appetite.

Researchers are also trying to make these peptides last much longer.

One of the clearest examples is MET-233i, now also known as PF-08653945 or PF’3945.

Originally developed by Metsera and now part of Pfizer’s obesity pipeline, MET-233i is an investigational ultra-long-acting amylin analogue with additional calcitonin-receptor activity.

Its standout feature is duration.

Early human research reported an observed half-life of approximately 19 days, creating the possibility of once-monthly dosing rather than weekly administration.

And Pfizer is not only studying MET-233i by itself.

It is also being combined with the ultra-long-acting GLP-1 agonist berobenatide, formerly MET-097i, in a large Phase 2 programme. (Pfizer⁠)

What Is MET-233i?

MET-233i is an engineered peptide designed to activate the amylin receptor system.

Pfizer currently describes PF-08653945 as an amylin analogue with dual amylin and calcitonin receptor activity. (Pfizer⁠)

That means it differs slightly from compounds designed to activate a single amylin receptor subtype.

Its development strategy is based around two ideas:

• powerful amylin-related appetite signalling
• extremely long duration of action

Why Does Amylin Matter?

Amylin is a naturally occurring peptide hormone released from pancreatic beta cells alongside insulin after a meal.

It contributes to:

• satiety
• smaller meal size
• meal termination
• delayed gastric emptying
• regulation of post-meal glucagon

Researchers increasingly see amylin as one of the most promising metabolic pathways beyond GLP-1.

What Makes MET-233i Different?

There are now several experimental amylin drugs.

But MET-233i was specifically engineered for:

ultra-long duration

and

combination compatibility.

Metsera designed the molecule using lipidation technology intended to extend its time in circulation while also improving its solubility.

The goal was to create an amylin compound that could potentially be administered monthly and could be co-formulated with another long-acting peptide.

Why Is Solubility Important?

This sounds like a minor technical detail, but it matters enormously for peptide development.

Natural amylin has a tendency to form aggregates or fibrils.

That can complicate:

• formulation
• storage
• injection
• potency
• manufacturing

MET-233i was specifically engineered to reduce this fibril-forming tendency and improve formulation behaviour.

That makes it easier to develop concentrated, long-acting injections and potentially combine it with other peptides. (SEC⁠)

How Long Does MET-233i Last?

Early Phase 1 results reported an observed half-life of approximately:

19 days.

That is exceptionally long for an appetite-regulating peptide. (Metsera Investors⁠)

A half-life of this duration provides a pharmacological basis for investigating monthly administration.

What Did the Early Human Trial Show?

In early Phase 1 research, MET-233i produced notable reductions in body weight.

Metsera reported placebo-adjusted average weight reduction of up to approximately:

8.4% by Day 36

after five doses in one early study programme. (Metsera Investors⁠)

That was an early-stage trial rather than a definitive obesity study, so the number should not be compared directly with results from year-long Phase 3 trials.

But it provided enough evidence to support continued development.

Why Is 8.4% in an Early Trial Interesting?

Because early Phase 1 studies are generally designed primarily to evaluate:

• safety
• pharmacokinetics
• tolerability
• dose exposure

rather than long-term effectiveness.

Seeing a substantial weight signal at that stage makes the compound scientifically interesting.

The larger question is whether the effect continues over six months, one year or longer.

Has MET-233i Moved Beyond Phase 1?

Yes.

Pfizer now lists MET-233i as a Phase 2 chronic weight-management programme. (Pfizer⁠)

The company is studying it:

• as monotherapy
• and together with berobenatide

This is a significant step beyond the initial Metsera programme.

What Is SOLIS-1?

SOLIS-1 is a large Phase 2b study evaluating:

• MET-233i alone
• berobenatide alone
• the two compounds together
• placebo

in adults with overweight or obesity.

The trial plans to include approximately 940 participants.

It began in May 2026 and is expected to continue into 2027. (Clinical Trials Finder⁠)

What Is Berobenatide?

Berobenatide was previously known as:

MET-097i

and is now also identified as:

PF-08653944 / PF’3944.

It is an ultra-long-acting GLP-1 receptor agonist.

Pfizer is developing it for both:

• weekly use
• monthly use

and it has already progressed into Phase 3 development. (Pfizer⁠)

Why Combine MET-233i With Berobenatide?

The combination brings together:

GLP-1

and

amylin/calcitonin receptor signalling.

That is conceptually similar to CagriSema, which combines semaglutide with cagrilintide.

But Pfizer’s programme has an additional objective:

match the duration of both compounds so they can potentially be administered monthly together.

That is a major technical challenge.

Why Do Matching Half-Lives Matter?

Imagine combining two drugs where:

one lasts seven days

and the other lasts three weeks.

Their biological effects would rise and fall at different rates.

This can make:

• dosing
• titration
• efficacy
• adverse effects

harder to control.

MET-233i and berobenatide were deliberately developed with broadly compatible long-duration pharmacokinetic profiles.

Pfizer specifically highlights this as part of the rationale for the combination. (Q4 Capital⁠)

Could This Become a Monthly GLP-1 + Amylin Combination?

That is the goal being investigated.

Pfizer describes berobenatide plus MET-233i as a combination programme for chronic weight management.

The company’s 2026 catalyst list specifically identifies:

Berobenatide + PF’3945 / MET-233i

as an active clinical combination programme. (Pfizer⁠)

If successful, it could provide an alternative to weekly GLP-1/amylin combinations.

Why Is Monthly Dosing Such a Big Deal?

Many metabolic peptide treatments require injections every week.

That is already manageable for many patients.

But obesity is a chronic condition, potentially requiring treatment over many years.

A monthly injection would mean roughly:

12 injections per year

rather than:

52 injections per year.

That could potentially reduce treatment burden considerably.

Would Monthly Automatically Be Better?

No.

Convenience only matters if the treatment also provides:

• strong efficacy
• acceptable tolerability
• predictable exposure
• long-term safety

A drug administered less frequently but producing greater side effects or less reliable appetite control would not necessarily be preferable.

That is exactly what Phase 2 and later Phase 3 trials need to establish.

How Is MET-233i Different From Cagrilintide?

Both influence amylin-related pathways.

Cagrilintide is best known for its combination with semaglutide in CagriSema.

MET-233i is being developed around an ultra-long-acting monthly platform.

The two compounds also have different receptor profiles and molecular designs.

Clinical results from one should therefore not be assumed to apply to the other.

How Is MET-233i Different From Petrelintide?

Petrelintide is a long-acting human amylin analogue being developed primarily as a once-weekly treatment.

MET-233i is being engineered around the possibility of much less frequent administration.

Petrelintide is currently further ahead in late-stage monotherapy research.

MET-233i’s major differentiator is its monthly-duration strategy.

How Is MET-233i Different From ABBV-295?

ABBV-295 is another long-duration amylin analogue where monthly dosing is being explored.

Both therefore represent the same broader shift:

from weekly amylin toward extended-duration amylin therapy.

But their molecular designs, receptor profiles and clinical programmes are different.

MET-233i also has a clearly developed matched-duration GLP-1 combination strategy.

How Is MET-233i Different From Eloralintide?

Eloralintide is designed to preferentially activate the:

AMY1 receptor.

MET-233i is described by Pfizer as having:

dual amylin and calcitonin receptor activity. (Pfizer⁠)

This illustrates one of the biggest unanswered questions in amylin research:

Should researchers target amylin receptors very selectively?

Or could broader amylin/calcitonin receptor activity provide useful additional effects?

Could MET-233i Be Combined With Other Peptides?

In principle, its long duration and formulation properties were deliberately designed to support combination development.

Pfizer’s broader metabolic pipeline includes additional peptide programmes targeting:

• GLP-1
• GIP
• amylin

and combination strategies between them. (Pfizer⁠)

But every specific combination requires independent clinical testing.

Could It Be Combined With Retatrutide?

This is a biologically interesting idea because retatrutide activates:

• GIP
• GLP-1
• glucagon

while MET-233i adds amylin-related activity.

That resembles the broad biological concept behind the new cagrilintide + retatrutide research.

However, there is currently no basis for assuming that MET-233i + retatrutide would behave like cagrilintide + retatrutide.

Different amylin analogues have different receptor profiles and pharmacokinetics.

It would require its own research programme.

What Is Particularly Interesting About SOLIS-1?

Its size.

SOLIS-1 is expected to include around 940 people, making it much more informative than the small first-in-human studies that generated the initial excitement. (PfizerClinicalTrials.com⁠)

It should help establish:

• optimal MET-233i dose
• monotherapy effectiveness
• combination effectiveness
• tolerability
• whether the GLP-1/amylin effects are additive
• suitable dosing schedules

What Does “Additive Weight Loss” Mean?

When two treatments are combined, there are several possibilities.

The combination could produce:

less effect than expected

roughly the sum of each component

or

a greater-than-expected synergistic effect.

Early Metsera data suggested additional weight reduction when MET-233i and MET-097i were combined, but the larger SOLIS programme is needed to establish the magnitude reliably.

Does Adding Amylin Always Improve GLP-1 Therapy?

We do not yet know.

Several companies are now testing