In Novo’s Own Words: Degradation of Amylin Analogs Such as Cagrilintide (and How to Test For It)

[JohnnyGobbs]

I feel like I fairly thoroughly argued against this post in the other thread.

To summarize it from that thread, it is obvious the centrifuge test was meant to be a proxy for potential long term degradation - that was the whole point. A 45 hour test is not useful for any sort of commercial applications otherwise, since no one prescribed cagrilintide would be taking it within 45 hours of formulation, or using it in a centrifuge at high heat. It is an attempt to recreate the sort of results they expect cagrilintide might have when reconstituted against the long term. And, ultimately, they could have gone with that formulation at a pH of 7.5 and not had to develop a whole new pen that kept cagrilintide and semaglutide separate, significantly increasing their cost, but instead decided that doing so was necessary.

The rest is basically a bunch of extrapolation from that premise which I would argue is untrue. It also says absolutely nothing about the tests in the patent, which were significantly less extreme, and also showed fibril formation at 7.5 (and even 4.0 depending on the buffering agent used.)

I do not think it is a persuasive argument in favor of not seeing any fibril formation for our use cases.

Agreed. You won that shit dawg but it was a good back n forth. lol

 

[PopTart]

I don't take Cagri, but I don't think it's dangerous, and it makes me sad that so many people are unnecessarily fearful

I started Cagri 5 weeks ago and will continue using it. I’ve had great success stacking it with tirz. I was unable to arrive at the same conclusions as the OP after reading ALL the referenced docs.

 

[echohunter]

I started Cagri 5 weeks ago and will continue using it. I’ve had great success stacking it with tirz. I was unable to arrive at the same conclusions as the OP after reading ALL the referenced docs.

Can you please elaborate why?

 

[hexagonal]

You argued against my conclusion, but did not provide your own complete interpretation of the paper. As I've said multiple times in this forum and others, I don't take Cagrilinitide, I'm a Mazdutide girl. My only goal when reviewing the original research was to understand the intent and meaning of the authors. After reading it I came to the conclusion that the study goals and outcomes weren't consistent with what you were asserting about the risk of fibril formation.

This is simply untrue, and I am unsure how you can come to that conclusion.

As I have repeatedly stated, my complete interpretation of the paper in regards to fibrils is exactly what is stated in the paper: Cagrilintide, as formulated, is susceptible to forming fibrils at 7.5 pH. This is what is in the table of the paper.

I've tried to be very diplomatic prior to this, but I'm afraid I don't see another way forward besides being very blunt here: I find this accusation incredibly hypocritical when you are arguing that you do not find cagrilintide to be dangerous based on the paper. The only data within that paper shows conditions in which fibrils form - it does not provide any evidence that fibrils will not form under regular circumstances.

There are two things that are categorically true in that paper:

1) They found that it is possible for cagrilintide to form fibrils under certain circumstances at a pH of 7.5
2) They do not provide any evidence that cagrilintide will not form fibrils under other circumstances at a pH of 7.5

We also ultimately know that they opted for a pH of 4.0 for the final product.

I do not understand how you are comfortable taking a leap of faith about cagrilintide's safety with no supporting evidence but find my assertion that is based on some general knowledge of why such experiments are performed is a bridge too far.

It may exist, but I have found absolutely nothing in the text of the paper that supports this assertion, and you have not provided any external sources that support your claim either. According to the study authors "Propensity toward formation of fibrils upon exposure to mechanical stress was assessed". They did not include "as a proxy for long term degradation" after that statement which they were perfectly capable of doing.

Neither do they claim that cagrilintide is safe a a pH of 7.5. If we are judging things by only going what the authors have stated, it is incredibly irresponsible to assert anything about the safety of cagrilintide at a pH of 7.5

Again, I want to be clear: my understanding of the purpose of that test is not based a complex logical argument, it is a direct result of my textual analysis.

I will copy my original comment in full to make it more accessible, but I honestly think the most responsible approach to settling this debate isn't through argument. These theories do not belong on forums and should not be pushed in the community and promoted on Facebook without support from:

1) The study authors
2) Someone with specific knowledge that qualifies them to interpret these results
3) Real world tests of Cagrilinitide's behavior under stress

How you can take the stance outlined here and make any assertions about the safety of a compound is beyond me. There is a reason I am being careful to make no such assertion: Because laypeople making any sort of assertion about the safety of a compound when none of us truly understand it is dangerous and irresponsible.


I have also linked and discussed the patent both here and in the other thread and discussed how fibrils are shown to form in a significantly less torturous test as well.

I do not know if these fibrils are dangerous. I know even less about oligomers. The only thing I am confident in saying is that none of the textual evidence supports the idea that fibrils do not form in normal circumstances at a pH of 7.5, and that it does support the idea that they form in a variety of circumstances in general, including at a pH of 7.5

 

[hexagonal]

Agreed. You won that shit dawg but it was a good back n forth. lol

I'm honestly not trying to win - if anything, I hope that cagrilintide isn't forming any fibrils for people, particularly if the fibrils (or oligomers) are actually dangerous. I'm just concerned that I feel like the paper and patent are quite clear that fibrils can and do form under certain circumstances and do nothing to rule out the possibility in "normal" circumstances, yet people are using them as an argument to state that they believe pH 7.5 cagrilintide is safe.

 

[Hapkidobigdad]

I'm honestly not trying to win - if anything, I hope that cagrilintide isn't forming any fibrils for people, particularly if the fibrils (or oligomers) are actually dangerous. I'm just concerned that I feel like the paper and patent are quite clear that fibrils can and do form under certain circumstances and do nothing to rule out the possibility in "normal" circumstances, yet people are using them as an argument to state that they believe pH 7.5 cagrilintide is safe.

So here’s my question. How many 250 microgram doses does it take to cause end organ damage and is that damage overly evident or is it insidious surprising us with early onset Alzheimer’s in a decade?

 

[aloil]

So here’s my question. How many 250 microgram doses does it take to cause end organ damage and is that damage overly evident or is it insidious surprising us with early onset Alzheimer’s in a decade?

No one knows. Maybe 1, maybe a million. Novo clearly thought it was worth it to go to the trouble of keeping it at pH 4.0 but even if it's a real risk you might get lucky. Not everyone who smokes gets lung cancer.

It seems reasonable that any effects of the fibrils might have a similar timeline to infectious prion diseases like BSE (mad cow disease). If so it could take years to decades for symptoms to develop. On the other hand, end organ damage due to oligomers might be relatively rapidly noticeable in someone who already has chronic disease in that organ.

I don't work in either infectious disease or pharm so that's just a guess based on enough knowledge of the fields in question to be dangerous. Since none of us are likely to be experts (and if anyone was we'd have no way to verify that) all we can really do is make semi-educated guesses and assess the risk based on our own priorities and risk tolerance.

Personally, even a theoretical risk of developing a neurodegenerative disease in a decade is enough to make me uninterested in trying cagri, but I'm willing to accept a risk of developing thyroid cancer due to GLP1s. Other people will make different decisions. I think all of us will make better decisions if we talk about this kind of thing so that people are aware of what the risks may be and can decide for themselves if they are concerned.

 

[hexagonal]

So here’s my question. How many 250 microgram doses does it take to cause end organ damage and is that damage overly evident or is it insidious surprising us with early onset Alzheimer’s in a decade?

No idea. I have zero understanding of if there is any actual concern around fibrils (or oligomers). I've seen the long reddit post arguing that there's no actual risk from the fibrils, and maybe they're right! But I am not able to parse through it or the referenced sources and come to any sort of conclusion. I just don't have the knowledge and expertise to do so.

I am unable to make any sort of comment, in good conscience, on the safety or danger that these might have in the human body.

All I feel comfortable doing is pointing out that I believe the paper and patent are quite clear on the fact that Novo's scientists found fibrils in cagrilintide in certain situations. And, that despite the additional R&D work, effort, and cost, they are delivering CagriSema with a dual injector pen, where Cagrilintide is kept at 4.0.

 

[penewbie]

I'm trusting Novo Nordisk risk-assesment and analyses rather than my sketchy, friendly, Chinese drug dealer.

If the Amylin analogue was the only decent weight loss drug on the market I probably would have been willing to take the risk, but, there's so many highly effective, highly safe alternatives, it just doesn't make sense to me. The benefits of Cagri clearly do not outweigh the risks.

No Cagri for me.

 

[Dee X]

Hi, that would be me! Notice how SW posted at the beginning that anyone who disagreed with him had "ulterior motives"? Yeah, that's his MO. I was "reliably named"... by, uh... <checks notes> ... Megalith.

So, every vial of cagri you buy... don't forget to send $0.05 to my agent I guess?

Anyway, attached is a write-up that might help people not be freaked out. If you're still freaked out, ofc, don't take cagri. But if you have, the tl;dr is no, you haven't in fact given yourself Alzheimer's or ruined your pancreas even if its pH tested a bit high. Our bodies have lots of ways to deal with both oligomers and fibrils.

Hey, thanks for posting this in here too

 

[nurseratchit]

Hi, that would be me! Notice how SW posted at the beginning that anyone who disagreed with him had "ulterior motives"? Yeah, that's his MO. I was "reliably named"... by, uh... <checks notes> ... Megalith.

So, every vial of cagri you buy... don't forget to send $0.05 to my agent I guess?

Anyway, attached is a write-up that might help people not be freaked out. If you're still freaked out, ofc, don't take cagri. But if you have, the tl;dr is no, you haven't in fact given yourself Alzheimer's or ruined your pancreas even if its pH tested a bit high. Our bodies have lots of ways to deal with both oligomers and fibrils.

Thank you for your brilliant research and posting here also.

 

[peptideusername]

oligomers

 

[nurseratchit]

Do you lie about people on other platforms too or just this one?

In response to @nccane on that other platform, someone had this to say:

That's how I conduct myself on other platforms. But when people completely ignore the science and just talk shit like you've done? Don't play innocent and pretend that you didn't provoke it when it comes back to you.

Yet, in most evidence-based server, you have remained strangely quiet.

 

[nurseratchit]

Just a reminder or maybe you don't know much this forum yet, but people here don't care about safety.

They're gonna complain if the product they receive is not 99% pure, or is under filled. But they're gonna use 3 months old BAC water punctured a trillion time to reconstitute and use the same vial to draw and inject from every week. Reconstituting in a non sterile environment without swabbing the vials and things like that. Of course no filtration, no usage of any sterile standards cuz we have one life to live they say

People are cheaping out sooooo much on safety but they're gonna complain as soon as they receive a subpart product. It's almost like they think a quality product can replace safety procedure

It's just mind blowing to me, that people think this way here, so of course when you bring anything about safety that'll complicate their stone age reconstitution process, you're not gonna be liked

Why exactly are you here?

 

[peptideusername]

She's an oligonner now.

 

[exploitedworkerbee]

I wonder if cagri is more or less risky than those mail order bath salts I got into for a spell during grad school. If that stuff didn’t get me I can’t believe this stuff will.

 

[clayd]

NurseRatchit's got the fibril fever.

Tessa posted this in multiple places. There are conversations going on in tandem. This isn't the first time fibrils + reconstitution pH were discussed and heavily debated in peptide communities since this info came out 3+ years ago and Cagri early this year.

but still nobody seems to have the answer. surprised there's not one or 2 people out there with some access to testing equipment or a microscope or whatever who can say "looky what i found"

i mean i know this is specialized info but the internet always seems to find some highly trained individual who can help clear things up

 

[Ladylaw]

 

[49metal]

OK. If I were to credit this warning I would need to target a pH of 4. I already reconstitute Cagri using Hospira Bacteriostatic 0.9% Sodium Chloride which has a pH 5.0. The resulting reconstituted Cagri has a pH of 5.0-5.25. I have Acetic Acid 0.6% Solution with a pH of about 3.0. I'm confident I can use it knock the pH of my reconstituted Cagri down to 4.0.

Now, assuming I do this, does 4.0 really address the issue? Or will I be made to understand there are yet more reasons I can't shoot my Cagri?

 

[zpped]

OK. If I were to credit this warning I would need to target a pH of 4. I already reconstitute Cagri using Hospira Bacteriostatic 0.9% Sodium Chloride which has a pH 5.0. The resulting reconstituted Cagri has a pH of 5.0-5.25. I have Acetic Acid 0.6% Solution with a pH of about 3.0. I'm confident I can use it knock the pH of my reconstituted Cagri down to 4.0.

Now, assuming I do this, does 4.0 really address the issue? Or will I be made to understand there are yet more reasons I can't shoot my Cagri?

If you believe in the warning, it's already too late to change the ph. The ph would have been wrong even before it was lyophilized.