Peptides:- What you need to know.

Dr Gavin Nimon: 0:29

Some of the most important medicines we have are peptides: insulin, oxytocin, the drugs we use for osteoporosis, for anemia, for diabetes, and more recently, the GLP-1 receptor agonists, medications to aid weight loss. But then there are another group, those currently unapproved for use in Australia, but which students and sometimes patients ask more and more about. What actually is a peptide? What is it used for? Why in Australia does the Therapeutic Goods Administration and the Medical Board of Australia have concerns about these? Today, we speak with Ian Mosgrave, a molecular pharmacologist and toxicologist, about peptides. G'day, and welcome to Aussie Med Ed, the Aussie-style medical podcast. Our pragmatic and relaxed medical podcast is designed for medical students and general practitioners, where we explore relevant and practical medical topics with expert specialists. Hosted by myself, Gavin Nimon, an Orthopaedic surgeon, this podcast provides insightful discussions to enhance your clinical knowledge without unnecessary jargon. I'd like to start the podcast by acknowledging the Kaurna people as the traditional custodians of the land on which this podcast is produced. I'd like to pay my respects to elders past, present, and emerging, and recognizing their ongoing connection to land, waters, and culture. Once again, welcome to Aussie Med Ed, a medical education podcast designed for general education and health professionals, medical students, and general practitioners. Our aim today is a narrow and deliberate one. By the end, you should be able to say what a peptide actually is, when and for what purposes peptides are used in medicine, and how the different peptides are classified, and how a peptide medicine is developed, approved, and regulated here in Australia. This is not medical advice. It's not a treatment recommendations, and nothing in it is directed at an individual's circumstances. And when we use the term unapproved today, we're talking about regulatory status in Australia. It doesn't automatically mean that every product use or access pathway is unlawful. If you have a health concern, please see your own medical professional for further information I'd also like to say that everything we say today is the Australian position as it stood at the time of recording. Other countries and other jurisdictions may have a varied view, and if you're listening from outside Australia, please take the science as general advice and check the regulatory position that applies where you are. Finally, we can form and take a lead from the Australian regulators, the Therapeutics Goods Administration, which has made unapproved peptides products a compliance priority and is working with AHPRA and the national boards on the safety concerns arising from their use.

Dr Ian Musgrave: 2:53

My guest today is Dr Ian Musgrave, senior lecturer in pharmacology at Adelaide University. Ian is a molecular pharmacologist and toxicologist whose work spans

Dr Gavin Nimon: 3:03

neuropharmacology, natural product pharmacology, and drug safety, including the forensic and safety implications of herbal medicines. He's the education officer of the Toxicology Special Interest Group of the Australasian Society for Pharmacology and Toxicology, and a regular science writer for the Conversation. Ian, welcome to Aussie Med Ed.

Dr Ian Musgrave: 3:21

It's a pleasure to be on.

Dr Gavin Nimon: 3:22

Well, thank you very much for coming on. Look, we're gonna talk about peptides today from an Australian perspective. Pepts have … They're having a moment at the moment, both in medicine and in the public conversation. I wanna start by outlining that some of the most important drugs in medicine are peptides. Can you talk about those for us, please?

Dr Ian Musgrave: 3:38

Okay. Peptides are short strings of amino acids. They're basically mini proteins. To quote the chemist Derek Lowe, for a chemist, peptide has a pretty clear definition. They're any relatively short chain of amino acids. And when they get longer, we go ahead and call them proteins. However, exactly where that dividing line is a matter of personal preference. And many of our natural hormones are peptides. For example, insulin is the most famous, discovered in 1921. This is an essential hormone containing glucose metabolism. Others you may have heard of include glucagon, angiotensin II, erythropoietin, and oxytocin, to name a few examples your listeners might be familiar with. And of course, peptides are widely used as drugs. Again, you'll be familiar with insulin as the life-saving drug for type 1 diabetes. Oxytocin is used for induction of labor, and erythropoietin is used to treat anemia We also use peptides derived from venoms because venoms are believed to evolve potently to interact with physiological systems. Example includes ziconotide, which is derived from cone shell venom for pain, and exenatide derived from Gila monster venom for type 2 diabetes. But unlike the majority of medicines you may be familiar with, peptide-based medicines can't be taken orally. They are rapidly broken down by the digestive system and so must be given by injecting. For example, a pain-relieving peptide ziconotide must be given by infusion into the spinal cord. And so it's approved for certain types of chronic intractable pain. So unlike paracetamol or ibuprofen, which are small molecules that can be taken orally.

Dr Gavin Nimon: 5:16

Now

Dr Ian Musgrave: 5:17

they've been spending a lot of time trying to develop oral formulations for insulin, and they've done some very clever chemistry around, uh, nanoparticle delivery systems, which unfortunately none of which have been successful in being approved yet. But that's something we look forward to in the future.

Dr Gavin Nimon: 5:33

So Ian, some people might assume that because a peptide is similar to something the body naturally makes, it must be safe. But that's not necessarily the case, is it?

Dr Ian Musgrave: 5:41

As a toxicologist, I will repeat the toxicologist mantra, it's the dose that makes the poison. Insulin, again, is life-saving, but if you get the dose wrong and get too much insulin, it can result in hypoglycemia, neurotoxicity, organ failure, and death Erythropoietin is another natural hormone. It's a critical medication in some forms of anemia, and side effects of erythropoietin include high blood pressure, joint muscle pain, fever, nausea, and injection site irritation. There's also serious risks involving blood clots and heart attacks and strokes. So even though these are perfectly natural, under particular conditions, they can also be very dangerous.

Dr Gavin Nimon: 6:20

Now, obviously these peptide medicines had a long history. I believe there's even Nobel Prizes that resulted from them.

Dr Ian Musgrave: 6:26

The, the history is far too long to recount, but well, of course, we start with insulin. Insulin was the first peptide hormone that was effectively discovered in 1921, and it was used as a therapeutic in 1922. But there's been an explosion in peptide therapeutics since then, and this has been fueled by molecular biology. In the old days, we had to take secretions and squirt them over tissues to find out if they actually did something. Now, molecular biology has expanded our ability to identify peptide hormones, work out what their targets are, and work out ways to, to make them therapeutics. As an example, since 2000, there have been 37 peptides licensed as therapeutics, and the fastest increase has been in the GLP-1 receptor agonists, starting with our friend exenatide, the Gila monster venom derivative in 2005. And now there's at least seven therapeutics in this space. So there's been a, a literal explosion in this area because they've been so effective in controlling type 2 diabetes and also because they have effects on weight. You start off with clinical observations, then you can use animal models to work out which tissues can secrete these peptides, and then you can derive tissue culture models to develop targets for these peptides.

Dr Gavin Nimon: 7:50

Right. Why can't they be taken by mouth? What's the problem that occurs when you take them by mouth?

Dr Ian Musgrave: 7:56

Because the digestive system breaks them down. They treat them exactly like steak, egg white, or any other protein you take in, broken up into singular amino acids, which while tasty are not very good for being hormones. As I mentioned for insulin, there's been some very clever packaging that we've tried to put peptides into nanoparticles to get them through the digestive process and get them to be absorbed, and then release their peptides i- into the bloodstream. Although this has been successful in some experimental models, it hasn't got to the point of being available as a, as therapeutics. I- in part, I think also because there's issues around people trying to replace the broken islet cells with stem cells and other approaches which can provide a more permanent solution to insulin deficiency rather than moving it from being injectable to oral.

Dr Gavin Nimon: 8:52

Right. Now, you mentioned that one, exenatide I think you were thinking of, was diverted from a peptide found in, from memory, the Gila monster venom. The newer GLP-1 medicines aren't made from that venom. Is that correct?

Dr Ian Musgrave: 9:05

That's correct. Exenatide was the one that was derived from the, the venom, and since then they've been able to m- provide modifications of the original GLP agonists so that they can now have something that's closer to the human hormones and be very effective. But then again, the, the venom has been the, the proof of concept that this will work, giving people the ability to investigate this further.

Dr Gavin Nimon: 9:33

How can you actually classify these peptides then? A- apart from knowing the level of the string of amino acids to divide them into peptides, is there another sub-classification system for those?

Dr Ian Musgrave: 9:43

Because the, the peptide hormones do such a wide variety of things, there's no simple classification. But you could broadly classify them into things like metabolic and endocrine regulators, that includes insulin and semaglutide, growth hormone, so growth hormone-secreting drugs, things that do tissue repair, and regenera- regenerative peptides.

Dr Gavin Nimon: 10:07

Right Okay. So it's really based upon function that the peptides do?

Dr Ian Musgrave: 10:12

Yes. Yeah. There, there's, there's just such a huge variety of peptides that it's, that unlike, for example, the HMG-CoA reductase inhibitors, which you'd all classify as statins, which all share a similar structural basis, or all the angiotensin-converting and enzyme inhibitors, which also share a similar structural basis, and we can all call them rils, perindopril and enalapril, et cetera. The diversity of peptides is enormous. For, for the chemically-minded, we can also base them on whether or not they contain multiple cysteine residues which fold them up into particular three-dimensional shapes. For those of you who are not chemists, this is probably not very helpful.

Dr Gavin Nimon: 10:55

Right. Now, the TGA has raised concerns about unapproved peptide products. Why are we hearing so much about these now?

Dr Ian Musgrave: 11:02

This, it's not really sudden. It's been something that's been happening for quite a while, but there has been an explosion over the past four years. But the, the use of peptides goes back some time, back to the '20s and '30s with monkey gland extracts, and has accelerated since then. So again, these are generally grouped under performance and image-enhancing drugs, where they can either improve your ability to re- recover from injury in terms of athletics or improve your endurance in athletics, improve weight loss, muscle definition, and things like that.

Dr Gavin Nimon: 11:44

Ian, we should probably clarify these are claimed or perceived benefits. For many of these products, the clinical evidence in humans is limited or absent. Is that fair?

Dr Ian Musgrave: 11:53

Yeah, people have been using weird and wonderful substances for weight loss and health improvement for, for almost as long as there's been humans. Back in the turn of the 19th, 20th century, the f- the favored drugs were strychnine and, uh, cocaine. We've moved on a bit from that, and of course I meant the monkey te- testicle. Recently though,

Dr Gavin Nimon: 12:16

there was a

Dr Ian Musgrave: 12:17

use of a industrial chemical which is basically an industrial poison and can cause your organs to liquefy because it causes your body to go into therma- thermal deregulation. So people will take all sorts of wild and wonderful things in the hope that they will get that bit of extra muscle definition or lose a bit of weight and, and things like that. So peptides have been one more arm of the desire to look better, move faster, excel at sport, and so on.

Dr Gavin Nimon: 12:54

So for many of these unapproved peptides, we don't have a good clinical evidence in humans showing that they provide the benefits being claimed.

Dr Ian Musgrave: 13:01

That's correct. For the majority of the ones, they either, either have not been proven or have been proven not to work in the first place. But they still remain popular despite actual evidence that they don't work. Talking about getting a drug approved, we have to look at an evidence portfolio. So for example, in Australia, for a drug to be approved to be sold as a medication, it needs to have a portfolio of evidence and be listed on the Australian Register of Therapeutic Goods. Now, for drugs, for example like insulin, in your portfolio you need to present a series of evidence. Of this evidence will say start off with basic proof of concept, tissue culture. Does it do things in tissue culture that would be consistent with an effect? Does it work in animals? And then you have to go and show that it works in humans, and not only that it works and is not harmful And this is typically clinical trials. You will first have a, a phase one clinical trial where you're doing things like dose ranging. Phase two for more, where you use larger populations to see how they respond to the drug. And finally, phase three clinical trials, which gives you a proof of both efficacy, does it do what the s- it says it does, and safety, are there serious adverse effects? What adverse effects are they, and are they dangerous to small populations? Now, there's so much drug development goes on, and the majority of drugs which you can show work in tissue culture or work in enzymes look very promising, and then you can put them into animals and make sure that they do as advertised in working in animals. And the big jump is from animals to humans, 'cause quite often it's not translatable. The big lesson, for example, from clinical trials for cancer is we should be able to cure cancer 10 times over if humans responded to our anti-cancer drugs in the same way mice do. But they don't. The, the reasons for this are largely complicated, and I won't go in, into that area of drug development. But the going from does it work in animals, and it c- it may very well work in animals, to does it work in humans, is that's the big transition. If you just say, "Oh, it's worked on mice, it must be really good for you," for the TGA, the FDA, the EU medicines group, and NICE in the UK, it doesn't fly. You have to show that it works in people, that it produces significant clinical benefit, and that benefit doesn't come at a cost of adverse reactions. Right. Again, th- th- this is where a lot of these things come from, is that you can show that it works in a tissue culture, you can give it to animals and you get a response which is vaguely in the area that human … it might have a human response, and they go ahead with that full steam, and never checking that it actually works in

Dr Gavin Nimon: 16:27

humans.

Dr Ian Musgrave: 16:28

And a- again, if you haven't got the phase three clinical evidence and doesn't pass review by the TGA or the FDA or the equivalent overseas groups, it's not getting licensed. And if it's not getting licensed, it doesn't go onto the Australian Register of Therapeutic Goods, and you can't sell it or use it.

Dr Gavin Nimon: 16:48

So the concern isn't simply how the peptide is made, it's whether the final product has been properly manufactured, purified, and tested to appropriate pharmaceutical standards. I mean, how do they make these substances in the first place then?

Dr Ian Musgrave: 17:00

Um, peptide synthesis, uh, can be done in a number of ways. You can have, say, solid construction where you add one amino acid at a time to a growing peptide chain that you've stuck onto a, a solid support. You could even make a, uh, a DNA con- construct, inject it into E. coli and get them to pump out large amounts of peptide. Human recombinant insulin is made that way. So Making peptides is relatively simple. Making pure peptides that are of sufficient quality to inject into people is an entirely different story. So for example, I use beta amyloid in my experiments, or I used to use, I might be in that area just at the moment. But different suppliers will supply peptides which are allegedly of the same sequence but have entirely different in terms of stability, their ability to fold up into the right three-dimensional shape. The counter ions, they use them to keep in shape, and we know there are some, some suppliers that supply really good peptides, and other suppliers where they're basically selling you expensive water.

Dr Gavin Nimon: 18:13

So if a product is manufactured outside appropriate pharmaceutical quality controls, there's an additional risk from the contamination or manufacturing impurities, quite apart from the effect of the peptide itself.

Dr Ian Musgrave: 18:23

Oh, certainly. When we're talking about peptides that are made for people, so a human recombinant insulin, they go to a lot of effort to make sure that the human insulin is purified out from all bacterial products, and they test it to make sure there's no lot of polysaccharide or other contaminants in it. So when you're injecting recombinant human insulin, you're injecting recombinant human insulin and no peptide fragments or at least copiopathic levels of peptide fragments or other levels of contaminants. This is not the case in the illicit peptides which people are buying online. They don't have this safety mechanism. Any drug, whether it's a peptide drug or a standard small molecule drug that is sold as a medication must not only pass phase one, phase two, phase three clinical trials, but it also must be made under a licensed manufactory. The licensed manufactory must hold a certificate that produce these drugs according to good manufacturing process. And so this ensures that whatever drug is coming out is free from impurities as part of the manufacturing process, or that the impurities are below any potentially dangerous level, and that you get… When it says f- 500 milligrams of paracetamol, you get 500 milligrams of paracetamol. You don't get any other chemical byproducts. It's free from heavy metal contamination as part of the processing line. It's sterile, and so that you are not taking in infectious material. So when you buy a standard pharmaceutical, be it an over the counter medication or prescription medication, it's manufactured to these tolerances, so you're not exposed to dangerous byproducts, microorganisms, heavy metals, and you get the right amount of drug. Whereas with the stuff you buy online, there is no such guarantees. Not only do they-- you have no human or limited human safety data, you don't have any guarantee of purity, uh, or, or microbiological safety. One of the recent ones in Australia, which was associated with six cases of liver failure, had two times the amount of peptide in it that was stated on the label. In a study out of Belgium, they, they s- saw huge variations and the purity ranged. And in the best case, you're getting a small amount of real peptide and a lot of mannitol. Mannitol is one of the carriers that they often use in these peptide pr- products. I- in the worst case, you're getting a, a whole range of other things, fragments of, of peptides, possibly other counter ions that is a part of the product. In the Belgian study also, they looked at heavy metals and found that there was a, a substantial number were contaminated with levels of lead and arsenic above the regulatory limits. So you're in for a, a whole world of pain through heavy metal contamination

Dr Gavin Nimon: 21:33

Right. So even putting manufacturing quality aside, for many of these unapproved peptides, there's limited or no good clinical evidence in humans for the benefits being claimed, and they haven't conducted appropriate human trials.

Dr Ian Musgrave: 21:44

In general, they haven't. One very famous one used for, for weight loss has not only been tested in clinical trials, it failed them utterly. So it doesn't work. We have very good evidence that it doesn't work. Another one, which is b- is very popular, was put through clinical trials, and they never reported. The trials were abandoned, the reports were never released, which is a big red flag, which suggests that either it either completely failed to do, do as advertised, or it possibly had adverse effects that were unacceptable. So again, this is a, a, a really big red flag. At least one actually does what, as advertised, but has serious side effects which would prevent it from ever being regulated or used o- in Australia or other jurisdictions, including cancer induction.

Dr Gavin Nimon: 22:37

So there are really two separate issues here, whether there's good evidence of benefit, and whether we're adequately understanding the safety and quality of the product.

Dr Ian Musgrave: 22:44

Yeah.

Dr Gavin Nimon: 22:45

So those uncertainties around evidence, safety, and manufacturing quality help explain the regulator's concerns.

Dr Ian Musgrave: 22:51

Yes. That, that, that's quite correct. And worldwide there is a, a great deal of concern about the unapproved products, where there is either no or limited evidence of efficacy, and they are produced under conditions where there is no guarantee of sterility or content, or that you'll be free of contaminants, including heavy metals.

Dr Gavin Nimon: 23:15

Could placebo effects, lifestyle changes, or other treatments also explain some of the benefits people perceive?

Dr Ian Musgrave: 23:21

Oh, most definitely. Placebo effect is involved. Although it can be quite difficult to work out what's going on. Quite often these people are doing not just these peptides, but also a range of other dietary and other interventions, and they may perceive, say for example, some weight loss due to a completely different treatment that they're on to be due to the peptide they've just taken. This is why we do double-blind placebo-controlled studies in the first place, to eliminate that. But a lot of this, people will swear by these things, and yet there is no actual evidence that they do anything.

Dr Gavin Nimon: 23:59

I believe that there not only is the manufacturing issue, but storage can be an issue.

Dr Ian Musgrave: 24:03

Um, it's hard to tell, because typically they're presented as lyophilized vials, and they, that can be quite stable. But then again, that's another thing that they haven't shown stability studies. So we don't know exactly how stable they are But given there's so many other problems with them, I think stability is, doesn't rate highly.

Dr Gavin Nimon: 24:26

So have adverse events associated with unapproved peptide products actually been reported in Australia?

Dr Ian Musgrave: 24:31

Yes, they have. There's been a series of cases just recently where six cases of liver damage were traced back to use of these illicit peptides. So as well as those, the TGA has reported a range of adverse events associated with illicit peptides, including severe allergic reactions which have required hospitalization, and inflammation and other health complications that have required medical attention. So there is clear evidence that there is significant and serious health effects occurring for Australians who are using these illicit peptides. There's a concern at multiple levels, but not just from the regulator, but also from professional societies that have to deal with the fallout from these health issues.

Dr Gavin Nimon: 25:18

So Ian, what's the main take home message for a medical student or junior doctor when a patient asks about an unapproved peptide product?

Dr Ian Musgrave: 25:24

The first thing I would say is that do not use any materials you buy on the internet. They are not approved by the Therapeutic Goods Administration. There is no guarantee of their purity. There is no guarantee even that the peptide itself will be there, let alone that it's safe from contamination with heavy metals, bacteria, or other byproducts. These things carry significant risk. Do not purchase them. Now, if one of your patients had a vial of this, of these peptides, what would you say to them?

Dr Gavin Nimon: 25:57

Yeah, thanks, Ian. It's not really something I've come across, but I have had people ask me about peptides. First of all, if someone did tell me they were taking one, I'd really wanna know what they were taking and record it in case an issue arose, and so we knew how we could treat it. I'd wanna find out what they were taking for that reason, but also find out what condition they were trying to treat and offer them actual appropriate treatment that I could offer, and keeping them in the loop so that they didn't, I didn't put them off coming back. I'd want to explain to them what the evidence actually shows for their condition and point them towards reliable information. I'd wanna be specific about what their concerns were and what had made them go down the pathway of taking a peptide, and also would want to monitor them for side effects should they occur, and watch out for anything that might occur, and get it treated. So they'd be my initial thoughts, having learnt about these peptides. But certainly, I'm sure this is an evolving area, and there may be even some advice given through the appropriate authorities that we could give to these patients in this scenario, for those patients who are already using one of these products.

Dr Ian Musgrave: 26:52

Good. That sounds like good advice to me as a non-medical practitioner.

Dr Gavin Nimon: 26:57

Well, I really appreciate you coming on to explain what these peptides are. I didn't really quite appreciate it with the manufacturing process, and learning about the chances of contamination and other issues that can arise is really important to know. So once again, thank you very much, Ian, for coming on to explain this to me, and it's just nice to know what we're talking about when these m- are mentioned in medical circles and in the media.

Dr Ian Musgrave: 27:20

Thank you. No worries. It's a pleasure to be on and to chat about this ra- rather important area at the moment.

Dr Gavin Nimon: 27:26

Brilliant. For those listening, I'd like to emphasize the importance of getting reliable health advice and following the current guidance from the TGA and the relevant professional regulators. Everything you've heard today is for general education. We've discussed what peptides are, how they're used in medicine, and some of the evidence and regulatory concerns around unapproved peptides in Australia. The evidence and regulatory position can change, so check current TGA guidance and speak with an appropriate health professional if you need advice regarding your own circumstances. I'd like to thank Dr. Ian Musgrave for coming on the podcast today, and once again, I hope you found this useful. If so, please leave a review, subscribe to the podcast, or like it. And once again, I hope you've enjoyed the podcast, and until next time, please stay safe