BI 3034701, a GLP-1/GIP/NPY2 triple agonist, has moved into Phase 2. What the heck is an NPY2? | XCancel

BI 3034701, a GLP-1/GIP/NPY2 triple agonist, has moved into Phase 2. What the heck is an NPY2?

Jen Can NuSH

@JCanNuSH<br>2h

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I’ve been trying to understand the new triple agonist that has started Phase 2s from Boehringer-Ingelheim and Gubra. As has been reported, it’s a GLP-1/GIP/NPY2 receptor agonist.

It's the first multi-receptor agonist for obesity to include NPY2. There's obviously excitement for a new pathway, but why and is that excitement warranted?

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But what is NPY2?

Well, let's start with what Boehringer-Ingelheim has told us:

BI 3034701 is a potential first-in-class GLP-1/GIP/NPY2 receptor agonist designed to address obesity through three pathways, where neuropeptide Y2 (NPY2)-driven central control of hunger, appetite and food intake is complemented by GLP-1/GIP-mediated satiety, weight reduction, and metabolic regulation.

As BI stated, NPY2 stands for neuropeptide Y2, but, more precisely, it stands for “neuropeptide Y type 2 receptor” (NPY2R), and, just so you are aware, sometimes literature JUST refers to this as merely Y2. 🤯

NPY2 receptors are most likely to be found in the central nervous system, particularly in the hypothalamus and the area postrema, but they also occur elsewhere throughout the body.

There is no NPY2 peptide. The actual peptide secreted by the body is NPY, but there are multiple NPY receptor types. Think of NPY as a master key, but the different receptor types (Y1, Y2, etc.) can also be selectively opened by special truncated forms of NPY as well. In this case, NPY2 can also be selectively opened by certain NPY fragments, like NPY3-36.

To complicate things even further, NPY receptors can also be activated by PYY (peptide YY), a hormone primarily secreted by the small intestine and colon. Like the NPY fragments that can activate specific NPY type receptors, special truncated forms of PYY can also selectively activate certain NPY type receptors. Most of the NPY2 molecules that have advanced into clinical trials have actually been built as analogs of PYY3-36, one of PYY's fragments.

"The NPY-Y receptor system in the gut–brain axis. The graph shows the major sources of NPY, PYY and PP along the gut–brain axis and the Y receptor subtypes... The arrow symbols denote stimulation, the tack symbols denote inhibition" from https://www.researchgate.net/publication/230860853_Neuropeptide_Y_peptide_YY_and_pancreatic_polypeptide_in_the_gut-brain_axis

So when we say BI is making an NPY2 receptor agonist, what we’re really saying is that they have made a molecule that selectively activates (agonizes) the neuropeptide Y receptor type 2 (NPY2R) without meaningfully activating the other NPY type receptors.

Is NPY a nutrient stimulated hormone (NuSH)?

NPY is not a hormone. As a neuropeptide, it is used to signal across short distances, which is in contrast to PYY, which is a hormone and is therefore able to reach distant targets across the body. PYY is a NuSH. While NPY receptors are primarily in the brain, they also occur elsewhere in the body, which is why there's a hormonal form (PYY) and not just a neuropeptide.

What does NPY2 do that might make it useful for obesity treatment?

Well, just as there’s an NPY2, there’s also an NPY1 (neuropeptide Y type 1 receptor, aka Y1). NPY1 and NPY2 are two important signaling mechanisms used by the body to maintain energy balance/weight, although there are certainly other important pathways as well, like leptin and ghrelin.

NPY1 acts like a hunger switch for your brain. When your body senses low blood sugar or a negative energy balance (like in weight loss), it stimulates the release of NPY. This activates NPY1 receptors to stimulate hunger and cravings and can even modestly reduce energy expenditure.

However, NPY also activates NPY2 receptors, and NPY2 sends a signal to reduce further NPY release to limit excessive hunger signaling. Research also shows that NPY2 activation also slows gastric emptying, which can also influence satiety.

As a potential weight loss treatment, agonizing NPY2 receptors can help counteract the body's defense mechanisms against fat loss - such as increased hunger, cravings, and reduced energy expenditure - by engaging natural 'brakes' on NPY signaling. By selectively targeting NPY2 we can enhance satiety and dampen hunger signaling without directly triggering the hunger pathways NPY1 activates.

What are the potential negatives of NPY2?

Unfortunately, NPY2 also appears to have emetic effects - “emetic” meaning vomiting. So, like GLP-1, nausea and vomiting are issues that any selective NPY2 treatment will have to navigate. Since NPY2 also reduces motility, it can also lead to (or worsen) constipation.

So, what other NPY2 molecules have made it to clinical trials and what's their status?

Up until now, most (if not all) of the research has been on single agonists for...