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GLP-1 has transformed metabolic research.
But one of the most interesting developments in 2026 is how quickly researchers are beginning to look outside the incretin system altogether.
Instead of targeting GLP-1, GIP, glucagon or amylin, scientists are investigating pathways involving muscle, mitochondria, liver metabolism, melanocortin signalling and even the body’s endocannabinoid system.
One particularly interesting compound is CRB-913.
CRB-913 is an investigational once-daily oral compound being developed by Corbus Pharmaceuticals.
Rather than activating GLP-1 receptors, CRB-913 targets the cannabinoid-1 receptor — CB1.
More specifically, it has been designed to act primarily outside the brain.
That’s important because researchers have tried targeting CB1 for obesity before — with significant problems.
CRB-913 represents an attempt to revisit the biology while avoiding some of the issues that prevented earlier CB1 drugs from succeeding.
What is CRB-913?
CRB-913 is an investigational peripherally restricted CB1 inverse agonist.
It’s being developed as a once-daily oral treatment for obesity and related metabolic conditions.
That description sounds complicated, but there are two particularly important parts:
CB1 refers to the cannabinoid type-1 receptor.
Peripherally restricted means the compound has been designed to have limited penetration into the brain.
The latter characteristic could be crucial.
Earlier attempts to block CB1 demonstrated potentially useful metabolic effects but encountered serious problems because they also affected CB1 receptors within the central nervous system. Modern researchers are therefore investigating whether CB1 activity can instead be modified predominantly in peripheral tissues.
What is the CB1 receptor?
CB1 is part of the body’s endocannabinoid system.
Despite the name, this system isn’t simply about cannabis.
Humans naturally produce signalling molecules called endocannabinoids, which interact with cannabinoid receptors throughout the body.
CB1 receptors are found within the brain but also occur in peripheral tissues involved in metabolism.
Research has connected CB1 signalling with processes involving:
- appetite and energy balance;
- adipose tissue;
- insulin sensitivity;
- lipid metabolism;
- liver metabolism;
- and metabolic efficiency.
That made CB1 an attractive obesity target long before the current GLP-1 era.
Haven’t scientists tried CB1 drugs before?
Yes — and this history is extremely important.
One of the best-known examples was rimonabant.
Rimonabant blocked CB1 receptors and was introduced in Europe as an obesity treatment in the 2000s.
However, it crossed into the brain and was associated with significant psychiatric adverse effects, including depression and anxiety.
Its European marketing authorisation was ultimately suspended.
That largely halted enthusiasm for first-generation CB1 antagonists.
But researchers didn’t necessarily conclude that the underlying metabolic biology was wrong.
Instead, another question emerged:
What if you could block peripheral CB1 receptors without substantially blocking CB1 receptors in the brain?
That is the idea behind the newer generation of compounds.
How is CRB-913 different from rimonabant?
The major intended difference is brain exposure.
Rimonabant affected central CB1 receptors.
CRB-913 has been designed to be highly peripherally restricted, meaning researchers are attempting to minimise penetration across the blood-brain barrier.
Corbus describes CRB-913 as having approximately 100-fold lower brain exposure than plasma exposure in preclinical research.
That doesn’t automatically prove that psychiatric risks have been eliminated.
Larger and longer clinical trials will be needed to establish safety.
But scientifically, it represents an attempt to separate the potentially useful peripheral metabolic effects of CB1 inhibition from unwanted central nervous system effects.
Is CRB-913 a GLP-1?
No.
And that’s exactly why this compound is interesting for our series.
CRB-913 doesn’t target:
GLP-1
GIP
glucagon
or amylin.
It targets the CB1 receptor.
So this isn’t another variation on semaglutide, tirzepatide or retatrutide.
It’s an attempt to influence metabolism through a fundamentally different biological system.
Is CRB-913 a peptide?
No.
CRB-913 is an oral small molecule.
This distinguishes it from peptide-based metabolic compounds such as semaglutide and tirzepatide.
It’s also different from oral small molecules such as orforglipron and aleniglipron, because those compounds still target the GLP-1 receptor.
CRB-913 combines two increasingly important trends:
oral small-molecule drug development
and
non-incretin metabolic targets.
What did the CANYON-1 trial find?
This is the particularly current part.
Corbus announced topline results from its Phase 1b CANYON-1 study in September 2026.
The trial involved adults with obesity who received once-daily CRB-913 or placebo for 28 days.
Corbus reported dose-dependent reductions in body weight, with the highest investigated dose producing a placebo-adjusted reduction of approximately 4.1% after four weeks.
The company also reported that weight reduction had not plateaued by the end of the treatment period.
These findings are interesting — but this was an early-stage, short-duration study.
Four-week Phase 1b results shouldn’t be compared directly with 48-, 68- or 72-week trials of established metabolic medicines.
The next stages of development will tell us much more.
Is CRB-913 going into Phase 2?
Yes, that’s the plan.
Following the CANYON-1 results, Corbus said it intends to discuss the clinical-development programme with the FDA and expects to begin a Phase 2 monotherapy study during the first half of 2027.
The company is also investigating another particularly interesting possibility:
combining CRB-913 with GLP-1 therapy.
That could create an entirely different research strategy.
Why combine CB1 inhibition with GLP-1?
Because the mechanisms are different.
GLP-1 receptor agonists primarily influence incretin-related signalling.
Peripheral CB1 inhibition potentially affects different metabolic pathways.
Researchers can therefore ask whether two complementary mechanisms could produce effects that neither achieves independently.
This reflects a much larger change happening throughout metabolic research.
Instead of continually attempting to make one molecule activate more receptors, researchers are also exploring combinations of mechanistically different therapies.
Could CRB-913 reduce appetite?
Potentially, but the biology is more complicated than simply describing it as an appetite suppressant.
The endocannabinoid system participates in food intake and energy regulation, while peripheral CB1 signalling may influence metabolism through tissues including adipose tissue and the liver.
Recent experimental research suggests peripheral CB1 inhibition can influence food intake and metabolic efficiency even without relying entirely on conventional gut-brain vagal signalling.
The clinical importance of these mechanisms still needs to be established.
Does CRB-913 affect cannabis receptors?
It affects one of the same receptor systems involved in cannabinoid biology — CB1.
But that doesn’t mean CRB-913 produces cannabis-like effects.
Quite the opposite pharmacologically.
Cannabinoid compounds such as THC can activate CB1 receptors.
CRB-913 is designed as a CB1 inverse agonist, reducing signalling associated with that receptor.
So although the same receptor family is involved, the pharmacological direction is fundamentally different.
What is an inverse agonist?
This is another question likely to appear in searches.
An antagonist blocks another substance from activating a receptor.
An inverse agonist goes somewhat further by reducing the receptor’s baseline activity.
CB1 receptors can display activity even when another molecule isn’t actively stimulating them.
An inverse agonist can shift that activity in the opposite direction.
This is why scientific descriptions generally refer to CRB-913 specifically as a CB1 inverse agonist rather than simply a blocker.
CRB-913 vs GLP-1 drugs: what’s the difference?
The mechanisms are fundamentally different.
Semaglutide: GLP-1 receptor agonist.
Tirzepatide: GIP + GLP-1 receptor agonist.
Retatrutide: GIP + GLP-1 + glucagon receptor agonist.
CRB-913: peripheral CB1 inverse agonist.
This makes direct percentage comparisons particularly unhelpful.
CRB-913 is also at a much earlier stage of development than established incretin medicines.
The scientifically interesting question isn’t currently whether CRB-913 “beats” a GLP-1.
It’s whether peripheral CB1 inhibition works sufficiently well and safely in humans to become another useful metabolic mechanism.
What is monlunabant?
CRB-913 isn’t the only modern compound investigating peripheral CB1 biology.
Monlunabant, formerly known as INV-202, is another oral peripheral CB1 inverse agonist under clinical development.
Novo Nordisk acquired its original developer, Inversago Pharma, in 2023.
The existence of several programmes is significant because it suggests renewed pharmaceutical interest in the CB1 pathway rather than CRB-913 being an isolated experiment.
A 2026 review of emerging obesity pharmacology specifically identified peripherally restricted CB1 antagonism as one of the important non-incretin mechanisms currently being explored.
Why did researchers return to CB1?
Because an unsuccessful first generation of medicines doesn’t necessarily invalidate a biological target.
Sometimes the problem is where a drug acts, rather than the target itself.
The original CB1 experience demonstrated both sides of the equation:
CB1 blockade produced metabolic effects.
But central CB1 blockade created unacceptable problems.
Modern medicinal chemistry potentially allows researchers to design molecules with much tighter control over where they travel within the body.
CRB-913 is therefore an example of scientists revisiting an older biological hypothesis using newer drug-design technology.
Is CRB-913 approved?
No.
CRB-913 remains an early-stage investigational compound.
It isn’t an approved obesity medicine in the UK, United States or elsewhere.
Phase 1 results establish only an early part of the evidence needed for drug development.
Much larger Phase 2 and eventually Phase 3 trials would be required before regulatory approval could even be considered.
Can you buy CRB-913?
There is no authorised CRB-913 medicine available for routine clinical use.
Any products appearing online under the names of experimental compounds shouldn’t be assumed to contain the pharmaceutical material investigated in regulated clinical trials.
When will CRB-913 be available?
There is no established release date.
The proposed Phase 2 programme isn’t expected to begin until 2027.
That places CRB-913 considerably earlier in development than compounds such as orforglipron, zenagamtide and several other metabolic candidates we’ve recently covered.
But that is also what makes it useful from an emerging-research perspective.
We’re following the pathway before it becomes widely known.
What happens next?
There are two immediate things worth watching.
First is ObesityWeek 2026, scheduled for November, where Corbus says detailed CANYON-1 findings will be presented.
The second is the proposed Phase 2 programme in 2027.
That should begin answering much more meaningful questions about:
longer-term weight change;
dose response;
tolerability;
metabolic markers;
safety;
and whether peripheral restriction successfully avoids the problems associated with earlier CB1 drugs.
Why CRB-913 matters beyond one compound
Perhaps the most interesting thing about CRB-913 is what it says about the metabolic research landscape.
A major 2026 review identified several emerging non-incretin strategies, including peripheral CB1 inhibition, myostatin and activin pathways, melanocortin signalling, mitochondrial modulation, thyroid receptors and FGF-based approaches.
In other words:
The future of metabolic research isn’t simply “more GLP-1.”
GLP-1 will remain enormously important.
But researchers are increasingly looking at metabolic biology as a network involving numerous organs, hormones, receptors and signalling systems.
That could eventually produce therapies that complement incretins, improve body composition, influence different metabolic abnormalities or work through completely independent mechanisms.
CRB-913 is one of the clearest current examples of that expansion.
At Klarity Research, we’ll continue following these emerging pathways as new clinical evidence develops.
For educational and research information only. This article is not medical advice.