Welcome to Pharma Talk Radio. This podcast is focused on achieving oral delivery of peptides to formulation and molecule design approaches from the twenty twenty four pod Partnership Opportunities in Drug Delivery Conference. For more information on the pod conference, editorials, podcasts or webcasts, please visit drug desh Delivery dot org. Thank you and enjoy the podcast.
I'm le Pasha, I lead the Novel Delivery Technology Steam at Novatas down the road you're in Cambridge, and I would like to briefly introduce the panel here today that will be talking through the oral delivery of peptides via formulation and molecular designs.
This is the topic that we have for the panel.
So firstly, and it back from Astra Zanika heading the Advanced Drug Delivery Teams there, Andy Lewis at Quotient Sciences, the CSO from and Suman Lutra, director at Mark for the Discover Very Pharmaceutical Science Esteem. So thank you all for being here. Probably if you could share a bit on you know, the topic why we have here, so the purpose of this topic on what makes peptide so difficult to deliver or really speak to some of your experiences.
If you have an example of two, perhaps each of you can talk to that a bit.
Okay, I'll go first.
So, yeah, a question science is we're a CDMO, so we develop manufactured drug products, but we're different in that we're also a CRO so we've got two clinical trial units, and we've really pioneered the integration of drug product manufacturing and clinical testing so that you can optimize drug products in response.
To clinical data.
And as such, we've we've worked on quite a number of oral peptide programs.
Somewhere in the region.
Well it's over fourteen programs at the moment, eleven different peptide All of them have been permeation enhancer programs, so I think we've evaluated ten different permeation enhancers. It's given us a really privileged insight into the state of the art for oral peptides and how different companies are approaching the clinical development. Obviously we see the pre clinical data and obviously lucky enough also to see the clinical performance.
And I think for me it's really fascinating because I think, I mean, there's decades of work been done to try and understand the biopharmaceutics of oral peptizes. And I think we do know a lot more than we used to, but also there's still a lot to learn, and I think there's been some great advances, but the biopharmaceutics of oral peptized probably requires a.
Lot more work.
I think someone you want to talk of it.
Thank you, Lipa, and thanks for the invitation to share my perspectives here.
You know, many years.
Ago there was a lot of innovation that was happening in the OORO delivery of biologics.
It turned out to be quite challenging.
So the company, you know, the industry as all pivoted towards patient compliance through improvement and devices and administration, but there's still interest in taking those established mechanisms and enabling patient delivery through oral administration. So that's where the peptides come in. And of course at Mark we have a lot of interest in immunology and oncology and enabling AORO
delivery or peptides for those patients. So, as Andy mentioned, the biopharmaceutics principles apply for or delivery and the you know, the first one comes to mind for a formulator is what we test is stability, solubility and permeability. Stability is modulated through early measurements because peptides when they go to the stomach they see low pH and then they see
various prote ltd enzymes in the GI system. So we have screens that exist that we can measure and as a formulator we can you know, make changes to the formulation to avoid the degradation mechanism as well. Second is solubility, and as a formulator, again we have a lot of.
Tools to measure and influence solubility.
But the biggest hurdle for biology for the peptide deliveries permeability.
These peptides, on an.
Average twelve to fifteen more amino acids are about two thousand average daltons and they are high molecular weight as well as very polar, which makes them beyond role of five molecules that are not really onally bioavailable. So that's the biggest challenge we have. And as Andy mentioned, there are many techniques, formulation interventions and permeation.
Enhancers being the biggest one of them.
That's the chemical approach that's out there, but there is a ceiling to it. There are approved drop products, there are many in the clinic that just show us unmentioned yesterday point five point seven person or by availability.
So that's where the opportunity space.
Is to really lift that ceiling and reduce cost of goods and improve patient compliance through reducing image size.
So that's the opportunity I see for peptides.
Thanks and it would you like to add to them?
Absolutely? I love over old path sides.
It's the modality I've been at for the longest time with my career. I did my graduate work on oil delivery of path sites. I still remember the first time I did a study where I put panzoma PAP side in red intestine or homogene it was gone so quickly that I couldn't measure it. So the prime I agree
with your permeability is an issue God. Before that, we need to treat modern nature because she sees pap tides as food and papodi days is pancreatic path todays is, especially in the GI track, will chew them off faster than you can say peptide. So there's a design effort up front where we need to design metabolic liability out of pap tides, and we will discuss that here today, and then I absolutely agree we have an issue after
that that's permeability as well. And I've seen every time I've encountered an old path tie getting at the path today's issue before you can do your first PK studies. Even IVY, it's an issue, but getting at the path today's issue is the paramount to.
Teg Thanks for starting off with some of these challenges but also opportunities like you rightly mentioned things. So what we have heard in the last two days at this conference is also achieving this patient adherence but also being competitive in this field. It definitely needs drug delivery approaches beyond probably permation and answers like we do today. If Anatan Suman, based on your early discovery and drug delivery experience, you can share a bit of insights on how an
early molecular design approaches could look like. And perhaps also if you want to look at different delivery targets for a given peptide, if you can add a bit on that and share with the audience.
Here sold you one, Okay, go ahead. I mean this first the issue around how to design the molecule, and then there's the second question what to design it for. If you look at molecular design first and foremost right, there's two approaches to overcome both pats bases and permation. Right, you can insert non natural amino acids, you can libidate it to make it more hydrophobic, and you can cyclize. These are the sort of three key standard approaches to
molecular design. Right Now, there's the pros and cons. Right, you can actually design quite by available path sites. But then can you make a product out of it?
Right?
If you have ten non natural amino acids and cycles and stables, and you know they may become especially for more common diseases, they may become too expensive to produce. So it is really threading a needle between you know, the low buyo availability of linear liberated path sites and the higher bioavailable ability you can get with highly designed path sides versus your cost of goods. The linear path tize. You can also make the cells the other ones you need to synthesize.
Which is more expensive and nonetheless.
Of course what you wanted to sign for. We have touched about path today stability and permeability, but you can also design for maybe absorption and different paths of the GI tract. Right, You can get, for example, you have less pathadases in the barka maculsa. It's a route that we don't explore that often. You can use nanoparticles etcata. To get to the lower GI tract as well, so those are options as well.
So then you would like to add someone.
Yes, thank you for bringing up the point about you know, what are the molecular handles for designing the peptides. And I just want to add, you know, cyclization have life extensions non natural amino asseys methylation.
These are very you know.
Established tools in our medicinal chemistry tool set to to designs you know, stable and well we can call them permeable, but you know, as best as they can be in our chemical you know design process. But then there's also designing the molecule for the delivery system, making sure that you have the.
Right pH solubility profile and if.
You do need to modulate it, say for example through self emultifying drug delivery systems and making sure you know, those properties that make it enabled for that delivery system are also died in into the molecule design.
We also as.
Formulators, we layer in formulation engineering on top of the molecule design. And this is where you know, and I can curve with a net that our standard approved products in the market for peptides are you know, immediate released rug deglorary.
System with premation enhancers. But then there is an.
Opportunity that if we need to avoid the you know, either the stomach degradation or peptidase driven metabolic pathways in certain parts of the GI, what is that regional area in the small interest tine where you want to deliver it.
And it's not a simple delivery or just.
A peptide, because permation enhancer is a functional recipient, we need to make sure that we are targeting to deliver both the pe as well as the peptide at a defined region of the GI. So that's where the formulation
engineering comes in where the opportunity space is. One more thing I want to add here is we are talking about the molecule design and in the discovery space, and one important aspect of there is sitting in the discovery space where we are influencing the discovery of the molecules, we need to have an appropriate in vitro in vivo correlation, which is missing for these large molecules. And not only that, the pre clinical to clinical translation is also missing, which
makes a discovery engine of peptides very slow. So if there are opportunities for GUT on the chip based models to really expedite and be able to you know, screen molecules faster, that would help the field overall.
And one more common great point on the first camp propitcies. One thing that I've also seen that's quite important when you design molecules is to keep if you use excipients such as permation enhances to produce some early studies around how the molecule interacts with the permation and hands. But otherwise great outliner and the first camp propies I can.
Just add add to it as well.
I actually see in recent years, I think there's been a convergence of drug drug discovery and engineering and drug delivery. I think a third of the most recent programs that we've done the peptides have been specifically designed for oral delivery using some of these.
Strategies.
But you know, there's technologies such as phage display where you can create huge libraries of peptides and screen them for properties of interest. You know quite often that will be receptor binding, but you can also screen for stability to peptidases, etc.
Great thanks for sharing these insights.
I believe one of the point that you mentioned about this in vitro in we will connect or disconnect in the WABC it this is also an apportionatefy nicely highlight and probably speaks to some of these collaboration potential we're having. Building models specifically to address this kind of issue would be quite helpful in the industry.
And you rightly introduced.
A course sciences and also the rich experience that has come through with actually testing into clinic some of the peptides with permission and answers and other tools and techniques. If you can share, based on your experience what has worked well perhaps and also where you see things need to further improve, that'll be great.
Yeah, wells worked well well as a CDMO. I'm not allowed to tell you what the best permeation enhancer is, but I think what I can say is the answer is, and people have published this that some permeation enhancers seem to work well with some peptides and not others. And I think it's probably to the point and that was making in terms of the interaction between the permeation enhancer and the peptide, but potentially also you know how it's delivered.
You know again people, many people have published we need to deliver the permeation enhancer to the epithelium at the same time time as the peptide, so that that's a really really important consideration when when we're advancing or a peptides into the clinic. You know, bearing in mind we've got this functional and excipient, we need to deliver them at the to the epithelium at the same time. Compared to normal first in human study, we tend to use
more complex dosage forms. So for a small molecule first in human quite often people will use a drug in capsule, maybe enabled intermediate, but quite often the first in human study will be a tablet formulation. Many of these permeation enhancers need to be in the tablets in really high amounts, so that these are not your normal tablet formulations and
that can present analytical and manufacturing challenges. But also if you look at the published you know, phase one clinical studies on oral peptides, so the ribelsa swan and the merks PSK nine inhibita, you'll see that the formulations need to be optimized, you know, because of you know, what we don't know is what the best performing formulation is in humans, and so generally there needs to be an expanded singlear sending dose phase where people is fairly exploratory
exploring what is the best performing formulation for that peptide. And typically people will evaluate the dose of the peptide, the levels of the permeation enhancer, the ratio between the two.
Inter subject variability.
In intras subject variability is something that's really important to get a good handle on, potentially the site of delivery, so in terrat coating with and without terror coating.
Amongst amongst other things.
And I recently reviewed all of our oral peptide programs that we've done for a number of clients, and I compared to the pre clinical by availability to the.
What we achieved in humans, and.
What it certainly showed was which might be pleasing as a formulator. When you change the formulation, you change performance, right, And if you look at them as a hole, there isn't a great correlation. However, interestingly, dog by dog by availability seems to correlate fairly well with humans. So yeah, the data that we've got relatively small data maybe, but fourteen clinical studies seems to show that or dog if you can what you can achieve in a.
Dog, you can achieve in humans.
However, the best performing formulation is different.
So that's what we've found.
Yeah, that's a really good point pre clinical species because the delivery of peptides using chemical permation enhances is a functional mechanism which depends on the physiology, and the physiology between humans and preclinical species is different. Yes, I think as a formulator we need to pay close attention towards the castric volume, the pH the upper GI, the mucus, castric motility, transit time. All of those aspects pay play a very big role as we are screening molecules and formulations.
But yeah, I agree with you.
You know, I think categorically dog may correlate better, but then humans are still humans.
Can I just start of coming here? I think it becomes even more important to have that knowledge as we think outside the permation and here. So if you look across this conference, there's been many sort of innovative devices, etc. To get at all delivery of biologics, and having that understanding of the physiology and the biopharmaceutics becomes even more paramount there.
Great, that's a very nice segue because one of the aspects that I'm sure just as I'm curious about in this room others as well. So we talk about them now probably the near future. But when it comes to making a breakthrough in oral delivery of peptides, and coming back to your points and where probably we are doing smaller increments information enhancers and yet not there to do a justice to delivering peptides orally and with a higher biovailability.
If you, each of you have to think of a blue sky aspiration for delivering peptides orally, what is that technology which probably is out there yet not developed, but also something that is not out there. What you wish that it is available? What would that be for each of you? So know soonne if you want to get status.
So if you guys heard the keynote from Bob Linger yesterday, right, he has brought from his you know lab spuns the com various companies have spun off that brought the Runnie pill, the biograil, and there are a couple other options like that.
I just want to be cautiously optimistic of that delivery system because that's so far I think it's been in the clinic just as an empty pill to test the mechanism safety, not so much the delivery, and it's been claimed in pre clinical species that that gives about sub Q like biovailability. So double digits anywhere between twenty to forty percent has been reported, which is great because as as I mentioned right, the current standard threshold is less than one percent.
So I think that is a blue sky idea. We just have to be really you know, working towards that.
What is our patient population that we are trying to make it a better delivery system for over injectables and these are mostly chronic indications. So if we move from weekly monthly injections to daily pills and they are working through lack of a better work, you know, injecting into the GI on a daily basis, I think there are CMC regulatory hurdles that we need to demonstrate that these are safe for chronic indications.
So that's the blue sky right now.
As we see, there are other options that we haven't looked into, and I would be very curious to hear I know and had mentioned in trabuccal intrant nasal.
Are there other roots of administration that are not.
As invasive and can get us to better than one person by availability of captides.
Great to add more to that.
Sure, absolutely, I mean I think for the barcal route what you get away where is the enzymes. You still have the permeability issue, but muco adhesive patches for baccle delivery can still in some peptides be an advantage. We don't see any on the market though right Other things that have been explored pre clinical is nanoparticles, muke adhesive to the lower GI tract as well. Again less enzymes more but again still a permation issue. The item that I wanted to bring up we had earlier today we
had a session of novel exhibients. You know, we are still using them, I'm sorry, same old permation enhances. You know, there's a lot of exhibient innovation that potentially could be done there as well. So but the excipient chemist out there, that's an option as well, if you want me to go really blue sky. I've heard about this for quite a number of years now, like microbial drug systems that actually produce the pathtide of the biologic institute in the intestine.
I met a first time about seven or eight years ago.
I've not seen it.
Progress, but it seems like conceptually a really good idea, but that's very much out in the blue sky.
Thanks for sharing that. Anatids reminds a bit of this enviable you know, cell generating.
Systems don't get many bacterial toxins can transverse gut epithelia as well, So yeah, it's quite the idea, I think.
Ken. So, whoever can crack that nut, you know, will crack that market. I think.
Great.
Any anything that you would like to add to what you would wish to see running some clinical trials from say ten years from now.
Yeah, Well, the first time I saw the ingustible devices, I was kind of blown away, But then I was also I also kind of became a little bit It was kind of skeptical in that there's obviously going to be cost associated with manufacturing of them and how much patients would accept them. So they're getting great by availabilities, and it comes to that kind of cost benefit analysis,
particular patient groups, particular indications, et cetera. I think, you know, the premation enhancers they do suffer from from food effects,
which are you know, quite significant. I think technologies that can address that, and I think in fact, there was there was a talk earlier on a device that was that was there's been developed that again just kind of effectively controlling the location of the peptide as it's being delivered with permeation enhancers and also allows you know, these kind of patches that biodesi patches as well, I think are really really interesting developments that could address many of
the issues we've discussed.
Great now, thanks thanks a lot for sharing these insights. I think so given the promise and also given that there are immense of portunities in this field into where we all strive for delivering peptides differently in this case orally, it is important, really important to look at patenting opportunities, be it understanding the molecular designs space or novel excipience that could act as permission answers or devices that can
offer a breakthrough for example in this field. So something like this forum is actually good to keep continuing the discussion. Any last aspects that you would like to leave the audience with in terms of peptide delivery orally, I think.
What's missing right now, at least for the standard permation enhance the delivery route is the mechanistic understanding. I think we have some idea that how does those permation enhancers work, but perhaps more academic collaborations and really you know, trying to understand what is that mechanism happening at the cellular level, so you're able to perhaps combine the mechanisms to maximize the effect. I know many have tried, and there's a
lot of work going on. But if we can collectively, you know, fund that research and try and understand, I think it would benefit the you know, the promise of heptide delivery for all.
Great anything Elseangie, I would just say, advance into the clinic as quickly as possible, don't spend too long looking at in vitro models and you know, pre clinical animals.
I think there was some great it was.
There was a great work piece of work published by the guys at Medamine actually where they did do a really nice They did some petite engineering and then they screened a load of permeation enhancers, which I think is a good template and then get it into the clinic.
I think an End talked about it, I think yesterday. I think he was in the audience just a brief while ago. But yes, that's a good study, so I would say, I said before innovation on permation enhances, right, they're still not working great now the industry has come to be become more accustomed to novel excipients with the nucleic acid delivery, why not start there. I think there's still thing that things we can do on molecular design. I'm not a medicinal chemist, but we are doing the
same maybe five six seven design strategies. I think we need to think outside the box on the chemistry front as well, because it will make our job as formulatus easier when it gets to us. We will of course have to contribute as well with the delivery system, but I think the better the molecule, the better the outcome.
Yeah. Great, thanks, I hope you all agree with molecular design built into the peptides, coupled with a lot more innovation of opportunities would really get us to target a much higher oral delivery of peptide, much higher mark. Thank you all, Thanks so much for sharing your insights. It is a pleasure to interact with all of you. And if there are questions, I think it's another half an hour remaining, so grab one of us then. Thanks so much, Thank you all, Thank.
You so much.
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