Do we have any measurable data on animals then? That n subjects were injected with aggregate containing solutions and a non acceptable percentage suffered serious damage and/or developed an immunological adverse response?
In addition is there actual measurable data that gives us a cause and effect correlation between factors that cause aggregates and their end result? P.x. physical stress causes % much aggregates +/-5 Celsius that much etc
I really appreciate the intelligent, sincere questions you're asking, instead of the insane, confrontational, baseless responses I sometimes get from others.
Sharing what I've learned helps me organize my thoughts on this subject, and forces me to stay sharp. I'm not looking to "win" an argument. I'd love for someone to demonstrate the contrary, ie, aggregates are harmless. But at this point, if that was proven or even strongly hinted at, it means the FDA, Pharma, and nearly every scientist involved in protein based drugs is wrong.
It's a very complex topic, and there's a ton of scientific literature available, much of it is impenetrable for most people, as the audience is other pharma scientists.. So I'll go over the docs I've collected and choose the ones that will answer them in the clearest way possible.
All peptides are unique in terms of aggregation and the impact of that aggregation.
It all falls under the category of "Managing known risks that are difficult to quantify:"
In the meantime, let me try to sum up what applies generally with certainty,
What causes aggregation?
Dozens of factors. From PH, concentration of the peptide, the interface between the protein and other surfaces (including air), physical shock, heat, contamination and the nature of the peptide itself, Some are naturally prone to forming aggregates, others not so much.
Why should we care?
From most certain to least certain:
-Aggregated peptides don't work.
When they clump up, it's just wasting peptide that should be doing something, resulting in unintended underdosing.
-Local immune reactions.
The immune system, especially in subcutaneous tissue, recognizes these clumps like they would dirt getting into a cut. They attack the foreign material causing pain and inflammation. The bigger they are, the worse this site reaction is.
-Immunogenic reaction
Vaccines are a type of peptide/protein drug that are designed to make this happen intentionally, "Spike" proteins are attached to small molecules or plastic or other foreign matter designed to attract the immune system, like large aggregates do, and with a vaccine, where this effect a desired, the immune system learns the "shape" of the protein so it can recognize it and get rid of it quickly in the future,
When this happens due to aggregation of a peptide drug it's undesirable, and the short version is the drug gets removed from your body faster than you want it to, reducing, or even eliminating its effectiveness. Like a vaccine, this can be short term (requiring a "booster shot"), and the drug will be fully effective after a break, or the "immunity" to the drug can last a lifetime. This has happened with numerous drugs, in some cases leading to death because there were no other available treatments.
Individual factors also play into this, with some people reacting and developing immunity and others not.
This happens with growth hormone. The treatment protocol when GH stops working is to take a break, see if the antibodies go down and try again. The other thing that's tried is using a different brand. Since all pharma brands are Somatropin, the only differences are the excipients (used to control aggregation) and, by extension, how much aggregation a formula has. The hope is a different brand will trigger less of an immune response.
-Aggregates cause "cross immunogenicity" to your body's natural proteins.
Since the immune system "learns" to recognize certain proteins as the enemy, the random proteins formed in aggregation can resemble a protein that's naturally present in the body. Then your immune system starts to attack it. You don't need to be a scientist to know that's bad.
It's not mere theory. It's happened in clinical trials for protein drugs, turning healthy volunteers critically ill and causing them to suffer for a lifetime. This was what set off alarm bells about immunogenicity and aggregation. From then on, many steps had to be taken proving aggregation and immunogenicity would not be an issue before allowing any human trials of new peptides. If ANYTHING is changed in the manufacturing process or even packaging, like using a different pre filled syringe, that can induce aggregation, the FDA requires it be proven safe from immunogenicity again. That's how important it is,
- Aggregated proteins cause neurodegeneration and other diseases.
This is the most speculative risk. We know people with severe neurodegeneration have bodies filled with aggregated proteins. Just like pharma proteins aggregate, so can natural proteins, The amount of natural aggregates in our bodies are kept low by various mechanisms, including the immune system. That amount stays low and stable in healthy people,, then if something happens, and they start to increase unchecked, numerous organs develop disease, especially the brain.
There are several suspected causes. One that's been discovered is that certain aggregates, "fibrils" can, on rare occasions, form into a shape that can reshape other proteins into itself, like a mold, which then reshape more proteins, and so on, until there are so many they start doing severe damage. It takes years or decades for this to be noticed, and only during an autopsy,
The speculative risk here is: "What if one of the random aggregates formed from a UGL produced or unapproved peptide combination is one of these "self replicating fibrils?".
One of the safety measures required when developing a new peptide is running a computer simulation that calculates all the possible aggregates that could form from a protein drug breaking down, its excipients, and packaging. Then the relative risk to health from all those millions of possibilities is assessed, and if any are high risk something has to be done to remove the possibility of them ever forming. If it can't be eliminated, the project is cancelled.
Now, add multiple peptides in a single vial or syringe, and the possibilities go from millions to trillions of aggregates, none of which have been assessed for risk,
So that's why I advocate minimizing aggregation where we can, using simple steps, like the right dilution ratio, pharma BAC, not combining, and filtering. It's not about eliminating risk, but reducing it.
I'll post some of the studies regarding demonstrated harms in animals and human cells in vitro (petri dish) shortly,
If anyone has a question regarding anything I've asserted here I'm happy to go into more detail and provide the research papers I used to come to my conclusions.
