Cagrilintide; a science-based perspective

[nurseratchit]

Rather than add to the already contentious and argumentative thread concerning Cagri and fibrils, I thought I would repost @TessaM ‘s well reasearched piece that is buried within that thread for those who are just trying to make an informed decision for themselves and not get caught up in the back-and-forth.

I apologize for any of my previous comments that may have muddied the waters. I have read many thoughtful posts on various subjects by Tessa M, and she has a gift for explaining complex and nuanced topics in an accessible manner.

Some final thoughts shared by TessaM in response to another user on Roundtable that she gave me permission to share here:

• Member comment:
  I think it’s a lot of information to try to decipher and align the points of argument for a novice. It’s a he said she said game and impossible to really determine who’s right and wrong for some of us.
• TessaM’s response:
  That's totally fair. For things that aren't in my area of expertise, yeah: I trust the experts. But here? We're a bunch of anonymous nerds pontificating about grey-market drugs based on incomplete trialsand without access to any of the preclinical data. There's no way to assess credentials here, no peer review process, nor any of the typical vouching mechanisms people should use as a gauge for the trustworthiness of information outside their fields.
• So if you're not sure: play it safe. Don't use it. I'm a big fan of the precautionary principle here. These drugs might be life-changing in their effects, but these are NOT chemo meds or blood thinners or something that's actually life and death. We don't need them to survive. So when in doubt? Err on the side of doing nothing for now.
• And I believe this about ANY of these peptides, especially ones in the earlier stages of clinical trials. This community tends to push the envelope a lot, and even encourage it, but it's totally valid to set your risk bar around 'post-P3,' 'pharma dispensed', or etc.

 

[hexagonal]

Effect of β-amyloid on blood-brain barrier properties and function - PMC

The deposition of beta-amyloid (Aβ) aggregates in the brain, accompanied by impaired cognitive function, is a characteristic feature of Alzheimer’s disease (AD). An important role in this process is played by vascular disorders, in particular, a ...

pmc.ncbi.nlm.nih.gov

I've seen this shared as proof that the underlying thesis that fibrils and oligomers can't pass through the blood brain barrier is false:

Aβ peptides which are in different states of aggregation (monomers, oligomers, and fibrils) can pass through the BBB at different rates and affect the state of endothelial cells in different ways. Oligomers have the greatest damaging effect. The clearance rate for the release of oligomers from the brain into the bloodstream is higher than for fibrils and monomers. With regards to the entry and passage of Aβ in different aggregative states through the BBB, data are not yet available. Disturbance of the redox status and mitochondrial respiration of BBB endothelial cells is an important component of the damaging effect of Aβ peptides. Despite the similar binding constants of the Aβ40 and Aβ42 isoforms with RAGE, the rate of their entry through the BBB from the blood into the brain differs. A potentially promising line of investigation would be to consider the passage through the BBB and the effect on endothelial cells of pathogenic Aβ isoforms with post-translational modifications, such as isomerization, since this may be an important factor in the development of AD pathogenesis.

Much of the study seems to be about them going the opposite direction, though some of it seems to discuss entering the brain, but mentions that different types pass through at different rates, so I also have no idea how cagrilintide compares to what was studied.

https://pmc.ncbi.nlm.nih.gov/articles/PMC11257072/ seems to be a mechanistic study that indicates that amyloid oligomers can accumulate at the BBB and disrupt it's ability to block passage as well.

(Edit: Trying to do some research of my own here and I can find references to other types of amyloid related fibrils traveling through the bloodstream without being broken down as well: https://my.clevelandclinic.org/health/diseases/17855-amyloidosis-attr )

I don't understand these well enough to have any idea if they're relevant to what's being said here, so would love if TessaM could weigh in.

 

[Dee X]

Effect of β-amyloid on blood-brain barrier properties and function - PMC

The deposition of beta-amyloid (Aβ) aggregates in the brain, accompanied by impaired cognitive function, is a characteristic feature of Alzheimer’s disease (AD). An important role in this process is played by vascular disorders, in particular, a ...

pmc.ncbi.nlm.nih.gov

I've seen this shared as proof that the underlying thesis that fibrils and oligomers can't pass through the blood brain barrier is false:



Much of the study seems to be about them going the opposite direction, though some of it seems to discuss entering the brain, but mentions that different types pass through at different rates, so I also have no idea how cagrilintide compares to what was studied.

https://pmc.ncbi.nlm.nih.gov/articles/PMC11257072/ seems to be a mechanistic study that indicates that amyloid oligomers can accumulate at the BBB and disrupt it's ability to block passage as well.

(Edit: Trying to do some research of my own here and I can find references to other types of amyloid related fibrils traveling through the bloodstream without being broken down as well: https://my.clevelandclinic.org/health/diseases/17855-amyloidosis-attr )

I don't understand these well enough to have any idea if they're relevant to what's being said here, so would love if TessaM could weigh in.

Paging @TessaM

 

[TessaM]

I don't understand these well enough to have any idea if they're relevant to what's being said here, so would love if TessaM could weigh in.

This is talking about amyloid-beta protein, not amylin -- amylin's full government name is islet amyloid polypeptide or IAPP. Amyloid-β was the OG amyloid discovered, so it got the name before they realized there were many other kinds of amyloid as well.

Re BBB, quoting from PNN over on RT:

Also there was a question/comment from a member before who was still concerned that cagri fibril might somehow finding its way to the brain. Here was my take on it:To summarize:

• the propensity to form dimers are DIFFERENT between amylin, pramlintide, and Cagrilintide. In fact that's the whole point of the molecular backbone modification on the older pramlintide. Then take it one step further when the Pramlintide molecule is modified with salt bridges (among other modifications) to become Cagrilintide.
• unlike true fibrils, peptide dimers are not a "forever molecule", they can still revert back to monomer form
• when a dimer revert back to the monomer form, it gets bound to albumin. This albumin binding is very important not just in terms of prolonging half life, but also it very much stabilizes the cagri molecule in physiological pH 7.4. a Cagri molecule that is bound to albumin simply cannot for any dimer even if it really wants to.
• and then there's the last hurdle: these large dimers, even when present in significant amounts in your plasma (which is very unlikely in this case, but let's play devil's advocate), will have to still pass the formidable Blood Brain Barrier. This barrier allows small (and preferably lipophilic) molecules to pass. Generally, molecules up to 600 daltons are able to pass with simple diffusion provided they're also lipophilic enough. The less lipophilic, the smaller they have to be to squeak through.
• but we know large molecules can sometimes pass the BBB, and they do that through specific receptors/transporters in the BBB, specific gates for specific molecules. The largest peptide that I know to pass the BBB is CINC-1 at 7800 daltons. Cagri is about 4409 daltons so if you make a dimer of that, you can do the math. To top it off, Cagrilintide is NOT very lipophilic. How do I know? Hint: what do you use to dissolve your cagri?
• And lastly, I am not aware of a specific BBB receptor/transporter for cagri DIMER

Articles about BBB and molecules that cross it:
Overview of Blood Brain Barrier (BBB)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494002/
CINC-1 passing the BBBhttps://www.jni-journal.com/article/S0165-5728(01)00256-9/abstract

 

[clevesand]

I don't want to read any of the threads. Can someone just tell me if I should still be squirting this stuff in my stomach?

 

[hexagonal]

This is talking about amyloid-beta protein, not amylin -- amylin's full government name is islet amyloid polypeptide or IAPP. Amyloid-β was the OG amyloid discovered, so it got the name before they realized there were many other kinds of amyloid as well.

Re BBB, quoting from PNN over on RT:

Thanks for helping clear up my misunderstanding!

Is there any concern around research that indicates IAPP can have an impact on amyloid fibril formation and weaken the BBB?

https://www.pnas.org/doi/10.1073/pnas.1610371113

Islet Amyloid Polypeptide: A Partner in Crime With Aβ in the Pathology of Alzheimer's Disease - PMC

Diabetes affects hundreds of millions of patients worldwide. Despite the advances in understanding the disease and therapeutic options, it remains a leading cause of death and of comorbidities globally. Islet amyloid polypeptide (IAPP), or amylin, ...

pmc.ncbi.nlm.nih.gov

(Interestingly, it seems like pramlintide might actually be neuroprotective based on that second link - perhaps something cagrilintide would share?)

Do you have a hypothesis on why NN is going through the trouble of producing cagri at 4.0 pH with a special pen that keeps them separated, and why they have spent so much time testing for ways to prevent fibril formation?

 

[rkl123]

Thanks for helping clear up my misunderstanding!

Is there any concern around research that indicates IAPP can have an impact on amyloid fibril formation and weaken the BBB?

https://www.pnas.org/doi/10.1073/pnas.1610371113

Islet Amyloid Polypeptide: A Partner in Crime With Aβ in the Pathology of Alzheimer's Disease - PMC

Diabetes affects hundreds of millions of patients worldwide. Despite the advances in understanding the disease and therapeutic options, it remains a leading cause of death and of comorbidities globally. Islet amyloid polypeptide (IAPP), or amylin, ...

pmc.ncbi.nlm.nih.gov

(Interestingly, it seems like pramlintide might actually be neuroprotective based on that second link - perhaps something cagrilintide would share?)

Do you have a hypothesis on why NN is going through the trouble of producing cagri at 4.0 pH with a special pen that keeps them separated, and why they have spent so much time testing for ways to prevent fibril formation?

I'm not the original poster but my own hypothesis is time frame (i.e. imagine your reconstituted vial needs to survive a year in a warehouse ). Very slow reactions are a lot more problematic over long time scales.