NNC0165-1875
NNC0165-1875 (PYY1875), long-acting PYY(3-36) analogue
Written by Aaron CuhaReviewed Sep 2026
Also known as: PYY1875, Long-acting PYY analogue
The clearest test of stacking a second appetite hormone onto semaglutide, and it failed on both counts. The authors call the added effect modest and not clinically meaningful, and the higher dose was not tolerated.
Overview
Peptide YY is the gut hormone that tells your brain the meal is over, acting through a different receptor from GLP-1. On paper it is the obvious partner: two independent satiety pathways should add up. Novo Nordisk built a long-acting version and tested exactly that, first in rats, then in phase 1, then in phase 2 as an add-on to semaglutide 2.4 mg.
The rat result was encouraging. The human result was not. The published conclusion is that a modest but not clinically meaningful treatment effect was observed for the 1.0 mg dose against placebo on top of semaglutide, that gastrointestinal adverse events were common at that dose, and that the 2.0 mg escalation regimen was not tolerated at all.
That is the most useful negative result in this batch, because it tests the assumption the entire combination era rests on.
Mechanism of action
A long-acting analogue of PYY(3-36), the truncated form of peptide YY released from L cells in the distal gut after eating. PYY(3-36) is selective for the Y2 receptor, which is presynaptic and inhibitory on hypothalamic neuropeptide Y neurons, reducing the orexigenic drive. Because that is a separate pathway from the GLP-1 receptor, combining them was expected to be additive on appetite without being additive on side effects. The trials show the second half of that expectation was wrong.
Human evidence
Phase 1 and phase 2 completed and published together with the preclinical work, which is unusually transparent. The phase 2 add-on result is negative on efficacy and negative on tolerability.
- Phase 2, 120 participants, testing the analogue as an add-on to semaglutide 2.4 mg.
- The 1.0 mg dose produced a treatment effect the authors call modest and not clinically meaningful against placebo on top of semaglutide.
- Gastrointestinal adverse events were common at that 1.0 mg dose.
- The 2.0 mg dose escalation regimen was not tolerated, so the dose that might have worked could not be given.
- In obese rats already receiving semaglutide the analogue did produce additional weight loss, which is the gap between the species worth noting.
What this does not tell you: A 120-person phase 2 cannot rule out a small real effect, and the authors do not claim it does; they say the effect was not clinically meaningful, which is a judgement about size rather than about existence. The more informative half is the tolerability ceiling: when the dose that could plausibly work cannot be given on top of a GLP-1, the combination fails for a practical reason rather than a mechanistic one. Nothing here tests PYY analogues as monotherapy at higher doses.
Reading the research record
This trial deserves more attention than it gets, because it is the cleanest published test of the assumption underneath the whole combination era. The reasoning behind stacking appetite hormones is that independent pathways should add benefit without adding harm. Here the benefit was not clinically meaningful and the harm was dose-limiting.
That does not condemn every combination. Amylin plus GLP-1, in cagrilintide and semaglutide, produced large weight loss in phase 3, so the strategy clearly can work. What this result shows is that it does not work automatically, and that reading a promising rodent combination result as a preview of a human one is exactly the error this site exists to flag. Novo Nordisk published the rat data, the phase 1 and the disappointing phase 2 in one paper, which is more than most sponsors do.
The evidence, charted
Fig. 1 · evidence composition
3of 3 citations (100%) are in people
Every citation cited here is Human work; no other study type is cited on this page. This count is of our own citation list and understates any literature larger than the sources we cite.
Fig. 2 · evidence over time
Citations here span just two years, 2021 and 2025.
Too few distinct publication years on this page to plot as a timeline.
Fig. 3 · legal status at a glance
US
Not approved
UK
Approved
AU
Approved
CA
Not approved
Approved in 2 of 4, prescription route in 0, not approved in 2. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Fig. 4 · dose response
No human dose response curve exists
We draw this figure where the data supports it. For this compound in humans it does not, so the panel stays empty rather than borrowing an animal curve and implying it transfers.
Key studies & citations
- Human2025
Long-acting PYY(3-36) analogue with semaglutide for obesity: from preclinical assessment through randomized clinical studies
A programme spanning obese male rats, a phase 1 study and a phase 2 study. In semaglutide-treated obese rats the analogue induced additional weight loss. In phase 1 all doses alone and coadministered with semaglutide were tolerated. In phase 2, verbatim: a modest but not clinically meaningful treatment effect of PYY1875 1.0 mg versus placebo as an add-on to semaglutide 2.4 mg was observed. Gastrointestinal adverse events were common at 1.0 mg and the 2.0 mg dose escalation regimen was not tolerated. The authors conclude the treatment was not well tolerated.
Obesity - Human2025
A trial of NNC0165-1875 and semaglutide in people with overweight or obesity
The phase 2 add-on trial record, 120 participants.
ClinicalTrials.gov - Human2021
A trial investigating NNC0165-1875 in people with overweight or obesity
The earlier phase 1 record.
ClinicalTrials.gov
Frequently asked questions
Does adding PYY to semaglutide help?
Not usefully, on the published phase 2. The authors describe the added effect of the 1.0 mg dose as modest and not clinically meaningful, and the 2.0 mg regimen was not tolerated. So the dose that might have worked could not be given alongside semaglutide.
Why did it work in rats?
In semaglutide-treated obese rats the analogue did produce additional weight loss. Rodents tolerate gastrointestinal effects differently and cannot report nausea, which is the exact variable that limited the human doses. It is a good illustration of why animal results are kept in their own section on this site.
Does this mean combination drugs do not work?
No. Cagrilintide with semaglutide produced large weight loss in phase 3, so combining pathways can clearly work. It means it does not work automatically, and that the side effects stack along with the benefit.