Diving Deep into the Oral Delivery of Peptides: Four Perspectives

0:05 

Hello, everyone. 

 
0:06 
Thank you for joining. 

 
0:07 
It's great to have you with us. 

 
0:09 
Welcome to this monthly science exchange, which is part of Oxford Global's Biologics series. 

 
0:13 
Today's session will be on the topic of oral delivery of peptide therapeutics. 

 
0:18 
Now let me introduce you to our discussion group leader for today, Joel Richard, who is the Chief Development Officer at Enterome and he'll be joined on the panel today by Hans Mello, the Co-founding Chief Executive Officer at Menten AI, Jutta Eichler, who is the Professor of Medicine, Medicinal Chemistry at University of Erlangen-Nuremberg and Andrew Lewis, the Chief Scientific Officer at Quotient Sciences. 

 
0:42 
You are also welcome to use the chat function to pose any questions or comments you have over the course of the session. 

 
0:48 
Without further ado, I'll hand over to our panel. 

 
0:55 
So thank you very much Tom for this kind introduction and I'm really happy to be here this afternoon to moderate this discussion on one of a hot topics in the field of peptide and peptide delivery, which is actually the oral peptide delivery for therapeutics. 

 
1:24 
So I would like that before we go into the discussion, we have a, a, a short introduction of all the panellists and let's say the relevant part of their positions that are related to peptide and oral peptide delivery. 

 
1:48 
So I would like to to start with Utah. 

 
1:52 
Utah, please, would you mind introducing yourself? 

 
1:56 
Sure. 

 
1:56 
Yeah. 

 
1:57 
Thanks, Joel. 

 
1:59 
I'm Utah Eichler. 

 
2:00 
I'm working in an academic setting at the University of Erlang Nunberg in Germany. 

 
2:06 
And our research is more positioned at the at the fundamental at the discovery stage. 

 
2:14 
So what we do, we design based on structures of protein complexes, we design novel antiviral peptides and we generate those peptides through chemical synthesis, solid phase A peptide synthesis, which enables us to introduce a range of chemical modifications, all sorts of chemical modifications. 

 
2:38 
And I'll be happy to elaborate on that later on if there's interest. 

 
2:44 
And that may also be the interface to the to the field of all delivery of peptides because those chemical modifications may facilitate oral bioavailability. 

 
3:02 
Joe, your turn. 

 
3:02 
Hans, would you mind continuing? 

 
3:04 
Well, it's my pleasure, happy to be here. 

 
3:07 
My name is Hans Mell. 

 
3:08 
I'm Co founder CEO at Menten AI by training. 

 
3:13 
I'm actually computer scientist, PhD in machine learning from the University of Toronto. 

 
3:19 
But for the for the past few years, we've been building a company called Menten AI, where we focus on developing and applying machine learning AI as a tool to design cyclic peptides in particular. 

 
3:36 
And over the last couple of years, we we been really focused on membrane permeability as one of the key features that we think is key for for therapeutic. 

 
3:47 
This goes both for oral viability as well as cell permeability. 

 
3:51 
So happy to to discuss that, of course. 

 
3:56 
Thanks, Andy. 

 
3:57 
Now. 

 
3:59 
Yeah, thanks Joel and hi everybody. 

 
4:02 
I'm Andy Lewis. 

 
4:03 
I'm the Chief Scientific Officer at Quotient. 

 
4:06 
So my background is I'm originally trained as a pharmacist and got over 20 years experience in the Pharmaceutical industry in a range of different organisations of all sizes. 

 
4:17 
The majority of my experiences in in formulation and advanced drug delivery, including the number investigating number of alternative routes of peptides, peptides and proteins and I quotient we've got significant experience with oral peptides. 

 
4:38 
We, we're quite a unique CDMO in that we can do the drug product testing and the clinical testings. 

 
4:44 
We've, we've done over 14 oral peptide programmes and look forward to sharing some of our experience with that in this, in this webinar. 

 
4:54 
Thank you Wendy for the introduction. 

 
4:56 
So just a few words, a few words about me now. 

 
4:59 
So, so actually I've been involved in the field of peptides synthesis and delivery for more than 20 years now in various companies and bringing some of his products to the to the market. 

 
5:19 
I've also been involved in developments of oral peptides for let's say targets in the GI tract or systemic targets. 

 
5:34 
So we are all passionate about peptides I'm sure here because actually these are really amazing drugs that provide a real good balance between bio activity and low toxicity. 

 
5:54 
And we are of course going to to talk about the challenges for oral delivery of these peptides. 

 
6:02 
And as we all know they are mainly related to stability of the peptides in the cheques in the tract until they are absorbed. 

 
6:13 
And second point is about the crossing of the epithelial membrane of the intestine to reach the systemic receptors. 

 
6:25 
But before going to this, actually I would like that we spent a few minutes discussing about how do we position today the oral peptide products in the landscape of the peptides that are usually delivered using the injection And more particularly how do we position these oral peptide products versus long acting injections and delivery devices for injectables. 

 
7:05 
So I think it's an interesting topic to to discuss since well, actually why would fashion prefer to have let's say a daily pill with a peptide versus for instance, as we know one month, three months or six months injection. 

 
7:28 
So I would like that the panellists comment on this and and give their their input about this positioning of the oral peptide versus the over delivery forms. 

 
7:43 
Andy, what do you think? 

 
7:44 
Yeah, I can certainly start with that. 

 
7:46 
So yeah, suddenly the the OR at least in the Western Hemisphere, the oral route of delivery is, is I would say generally accepted to be most patient preferred. 

 
7:59 
It's the one people are most familiar with. 

 
8:02 
It makes it easier for people to start their treatments, you know, for injectable formulations if they're going to be self administering, they will need training and use of the devices etcetera. 

 
8:15 
Whereas orals, you know, relatively easy for people to start and also easier to maintain. 

 
8:21 
But you're right that many of the kind of, I guess, physical, chemical and biopharmaceutics challenges presented by peptides, their Rapids clearance, their instability meant that some of the first few generations of peptides were certainly injected and overcome with drug delivery strategies, which included and let's not forget advances in device development, you know, narrow gauge needles to make, you know, injections several times a day, less painful, easier to administer. 

 
9:01 
But then also those long acting injections And the those kind of original technologies, a lot of them mostly based around PLGA where where we're injecting implants like Zoladex or and then microparticle formulations as well are able to achieve once every month, three months, six months injection frequencies, but through really large gauge needles. 

 
9:35 
Quite often they would have to be administered by a healthcare professional, but they certainly addressed, you know, the, the, the the challenge with the kind of rapid clearance of peptides, I think advances in the last few decades, things such as peptide isolation of enabled, you know, once weekly dosing of peptides through through relatively narrow gauge needles. 

 
10:03 
And it's a really interesting proposition, you know, will patients prefer injecting once a week or taking a tablet every single day? 

 
10:15 
And I think, I guess really just two products that we can look at, but that and that would be Rybelsus. 

 
10:24 
So the oral semaglutide versus I think it's Ozempic the the once weekly injection of semi glutide and also my capsule which is oral octriotide and that also has injectable sustained release long acting injection formulations on the market. 

 
10:43 
And there's certainly a subset of of patients that that would prefer a daily tablet over the injections. 

 
10:53 
OK, Yeah, yeah, you're, you're surely all right. 

 
10:58 
Do do you have something to add answer and your town these aspects, would you like to comment further? 

 
11:04 
What is your feeling about this, let's say choice between oral, let's say delivery and and injection? 

 
11:19 
Yeah, happy to to comment just briefly on that. 

 
11:22 
From our perspective as a, as I guess a design company, we've seen obviously a lot of success over the last couple of years advances, you know Merck, PTSK 9 J&J and others, two guys Luna in. 

 
11:38 
So clearly the, the, the field is asking for orally deliverable peptides. 

 
11:45 
And so I I think more and more we'll see growth there which presumably should go hand in hand with patients acceptance, right. 

 
11:57 
Whether that pens hard or not that is beyond the scope of or work certainly very exciting. 

 
12:04 
We see a lot of interest. 

 
12:06 
Yeah. 

 
12:06 
I also believe I mean if you look at the development on the market that clearly demonstrates that there is a there is a need for it and or else there wouldn't be the the oral products on the market. 

 
12:19 
In the end, I think it will all come down to a compromise mise of different factors. 

 
12:26 
Important one, of course, as Andrew pointed out, it's adherence and preference by the patients, what's what's being preferred, but then also other factors apart from economic factors. 

 
12:39 
So which I cannot comment on because I'm not working in a commercial setting, but by your availability and I'm sure we'll get to that later on is, is a is a big point and you have to sort of balance that the benefits you get from all the delivery that may be set off by poorer by your availability. 

 
13:01 
But the the trend we are seeing is I think it's clearly pointing to to a strong preference for oral availability. 

 
13:13 
OK, great. 

 
13:15 
Thank you for your input. 

 
13:17 
Yeah. 

 
13:17 
So I think, yeah, there's there's this strong trend for for oral and yeah, you can see that there are so many products in in development for this new route of administration of peptides that there should be a really something really attracting here. 

 
13:39 
So, but yeah, so now let's come to maybe to the challenges that we all know. 

 
13:45 
So we know that well, there's a part related to the stability of the peptides in the GI tract and the other one related to permeation and bioavailability. 

 
13:59 
So of course, we are going to focus on peptides with systemic receptors. 

 
14:07 
There are peptides that are very successfully developed for let's say receptors in the GI tract. 

 
14:16 
And we are not going to focus on this type of peptides now. 

 
14:20 
We are more going to talk about the main challenge of crossing actually the intestine barrier to reach the systemic receptors. 

 
14:34 
And yeah, so until now, I would say the main technologies that have been successful are related to the use of formulations that involve permission and answers. 

 
14:53 
And I would be really curious to hear you about what do you think about the, the success of this technology 1st and we will go a little bit later on what the next steps would be in terms of improvement of oral bio availability if there's a need. 

 
15:17 
But before this, I would really like to hear you about, well, what do you think about the successes of the present permission and answers that have been used for Rebelsus or my capsule. 

 
15:32 
For sure, these are different ones, different technologies. 

 
15:36 
And yeah, would be also interested in hearing you about the limitations of this type of approaches. 

 
15:45 
So you time Libi, would you like to start? 

 
15:50 
Well, actually, as I, as I pointed out in my introduction, this is not my field of expertise. 

 
15:56 
Of course, I, I, I read about it, but maybe somebody else on the panel would be more like qualified to sort of give a perspective on these approaches. 

 
16:10 
OK, So Andy, maybe, yeah. 

 
16:15 
So I mean permeation enhances undoubtedly I guess the the best validated oral peptide drug delivery technology. 

 
16:25 
As you say, there's 22 products on the market. 

 
16:28 
There's others that are in late stage development. 

 
16:34 
What's what's clear is, is that that they're really important actually because what they demonstrated was they demonstrated that they're acceptable to the regulatory agencies. 

 
16:46 
They demonstrated that that path to market as well. 

 
16:51 
They demonstrated that you can get efficacious levels of a peptide, albeit with you know fairly low bioavailability. 

 
17:01 
You're talking about 1% or or less. 

 
17:06 
And I think to be honest with you, those two products have probably stimulated all of this, this this increase in, in interest in in oral peptide delivery. 

 
17:18 
I think Rybelsus in particular I think was, was I think that product innovative on many levels. 

 
17:26 
There was certainly the the approach that Nova took in looking at the drug delivery technologies and the permeation enhancers. 

 
17:33 
But I think up until that point, and I'd include my capsa in that companies really only been evaluating APIs that were already approved when Nova Nordisk developed ribosis semi glutide wasn't approved. 

 
17:52 
And I don't think even Lyra glutide, which was the peptide before and ahead in development was approved. 

 
18:01 
So I mean, the, the implication from that is, is that Novadordis were able to kind of take a bit of a step back and kind of decide, OK, what's the best peptide and what's the best permeation enhancer. 

 
18:15 
But if we just kind of focus on the permeation enhances to to start with, because I know we're going to talk about the APIs in a little bit. 

 
18:25 
There's, there's a lot around the kind of biopharmaceutics of oral peptides using permeation enhancers that that we still don't fully understand. 

 
18:34 
And Nova published some of this and in our own work, a quotient, as I said, we've we've performed 14 different oral peptide programmes with 10 different permeation enhancers and different 11 different peptides for different clients. 

 
18:55 
And we've had that unique insight into the kind of the preclinical data package and the clinical data package and the performance. 

 
19:05 
And once clear. 

 
19:06 
And so, so you know, from those figures, you can work out that we've, we've tried some of the same permeation enhancers with different peptides and it, and it backs up what, what, what Nova published as well that that's the optimum permeation enhancer seems to be different for different peptides. 

 
19:24 
And that could be the selection of the permeation enhancer. 

 
19:28 
So some permeation enhancers seem to work better with some peptides than other peptides for reasons unknown. 

 
19:35 
And, and the other thing is, is that actually the optimum formulation for the particular peptides with particular permeation enhancer seems to be different. 

 
19:46 
So in terms of the the dose of the peptide, the levels of the permeation enhancer, we've seen ratios of the permeation enhancer with the peptide to be the critical to performance formulation variable. 

 
20:02 
So yeah, there's a, there's a lot of unknowns. 

 
20:04 
We've seen people using combinations of permeation enhancers as well. 

 
20:07 
At least three of our clients have worked with permeate combinations of permeation enhancers and and I think the other thing that we've seen is that. 

 
20:19 
The preclinical models don't don't accurately predict, don't correlate well with human performance. 

 
20:30 
So typically when you advance into the clinic, you will need kind of a bit of an expanded first single ascending dose study where you're, where you're, you're, you're evaluating each of those different variables in order to identify the best performing formulation. 

 
20:51 
And, and again, I refer you to the publications. 

 
20:55 
I think Hans mentions the PCSK 9 inhibitor. 

 
20:59 
That Mark is in phase three at the moment they've published their first in human study. 

 
21:07 
You can see how they designed that, you know, they evaluated different permeation enhancers, levels of permeation enhancers, doses of peptide ratios, food effect, internal interest, subject variability really need study designed to achieve that. 

 
21:25 
And similarly Rybelsus, they published their their phase one and looked at similar variables. 

 
21:34 
OK, thank you. 

 
21:35 
Thank you very much. 

 
21:37 
I have some questions for you afterwards, but I would also like ants to maybe to add on this and yeah, to, to give, to give us his, his hint about, yeah, the national answers and what, what he thinks. 

 
21:53 
I, I think it's a it's a great technology that we can leverage. 

 
21:58 
I think that much of the challenge, as Andrew pointed is, is hard to know how they actually work. 

 
22:04 
The mechanism of action is very unclear, which makes it very challenging for, well, for researchers to figure out, OK, which one should we use? 

 
22:13 
You know, what's the right ratio? 

 
22:15 
How's it actually acting? 

 
22:17 
And I think those are the questions that if we could answer, it will really help understand how to, you know, make better combinations, improve by availability someone. 

 
22:30 
I think what's important also is to understand what these enhancers can and cannot do. 

 
22:37 
So what they clearly can do is improve by availability because that facilitate the passage through the epithelial layers. 

 
22:47 
But that of course, we should keep in mind. 

 
22:49 
I think that this is just one limitation or challenge to be met in the development of an oral orally available peptide drug stability being another one, molecular size being one that is also directly linked to the to the feasibility of of penetrating biological membranes. 

 
23:14 
And I think it should be considered all and discussed in context that of course, I mean, these enhances that they've been a game changer to, to facilitate the overall availability. 

 
23:25 
But it's, that's not all we need. 

 
23:29 
There's many other factors that come into play which also have to be considered in, in, in the development of a successful oral peptide drugs. 

 
23:41 
I, I believe, yeah, I'd agree with that. 

 
23:44 
And I and I think it stands whatever the delivery technology actually for oral delivery, you know, 1/3 of the peptides we've worked on have been specifically designed for oral delivery. 

 
23:59 
Welcome to yeah, welcome to this later Andy about actually this could be, I would say most likely the next steps and way to improve permeability of peptides for the membrane. 

 
24:17 
It's the design of the peptide itself. 

 
24:19 
And by the way, I don't think that rebels this would have been such a success if semiclative would have not show on for instance, this already long of life, you know, that made it possible to go to a a permanent permanent state, you know. 

 
24:40 
So yeah, I would like to come back maybe on what you you mentioned and the about the your experience or your recent experience about evaluating various permission and answers with various peptides. 

 
24:57 
So, so first, let's say, would you, would you confirm that the oral bioavailability would still remain within let's say the peasant range versus the administer dose or would would have you found any specific permission and answers that would really make it possible to go for instance to 10% of of bioavailability? 

 
25:34 
So this would be the first point. 

 
25:36 
And secondly, I would like also to understand, so you've got most likely a lot of data and so are you going to try to understand? 

 
25:48 
Yeah. 

 
25:49 
And it's related also to what the answer was, was just mentioning how can we improve the understanding of the important factors, maybe using modelling of interactions, things like this. 

 
26:07 
So yeah, understanding would be really helpful in designing maybe even next permission and answers and next peptides. 

 
26:18 
Yeah, absolutely. 

 
26:20 
I mean, yes, as a so 88 of the 14 studies that we've done evaluated the absolute by availability of the peptides. 

 
26:30 
So that's that's versus the intravenous and that the highest by availability we've seen is around 6%. 

 
26:39 
We've had a couple of programmes that got to like 5-6 percent. 

 
26:44 
I think we might be talking about other technologies later on, but you know some of the kind of microneedle technologies can achieve much higher bioavailabilities than that. 

 
26:53 
But yeah, what we've seen is with optimization of the formulation in humans, because we do see that there's a different formulation, the best performing formulation is different in humans to that in pre chemical animals. 

 
27:07 
But with a formulation optimization in humans, you can get high single digit percent by availabilities in terms of that the yeah, those the modelling and the kind of key factors. 

 
27:24 
As everyone said, there's a surge of interest in in oral peptides. 

 
27:28 
And I would love that we assemble some kind of pre competitive collaboration so we could pull all of the data. 

 
27:37 
And let's start to also I would add standardise some of the kind of preclinical or development test. 

 
27:49 
So you know, dissolution studies, for example, you know, how they're performed, how the preclinical animal studies are performed would grow greatly affect the data you're getting. 

 
28:01 
You know, and everybody's doing probably slightly differently. 

 
28:08 
But yeah, with a larger data set, it might be better to easier to kind of probe that. 

 
28:13 
We've we've done some recently for one of our clients which were published recently at age conference, we did some PBPK modelling on an oral peptide that they were developing and that used S snack as the absorption enhancer, the permeation enhancer, so the same one as Rybelsus. 

 
28:35 
What was different was they were targeting the small intestine. 

 
28:39 
So the tablet was enteric coated and we've published the preclinical data, I think the clinical. 

 
28:52 
So we did refine the model once we got the clinical data as well. 

 
28:59 
That's not yet published. 

 
29:01 
So I can't really talk about that yet, but it is in process and I'd certainly be happy to share with that once we've got approval to publish that. 

 
29:08 
But what I can say was the PBPK model was able to predict how changes in the formulation could influence the performance in terms of bioavailability. 

 
29:26 
It was interesting in that it seemed to find something different to ribosis, which is, but you've got to appreciate it as a model and you also got to appreciate in terms of PBPK modelling, you know, you can model the preclinical data, then you get the clinical data and you refine it and then you can, and then that will help you further help inform you in, in later development. 

 
29:53 
So it's, it's not predicted from a point that you know, if you provided any peptide with any permeation enhancer, we'll we'll be able to predict the clinical performance. 

 
30:05 
But it will help you PVPK modelling can help you actually within development make data-driven decisions as to where you go with your formulation development. 

 
30:20 
Good. 

 
30:20 
OK, thank you. 

 
30:21 
Thank you very much for for your input. 

 
30:23 
So, so of course this low bioavailability has a strong impact from an economic point of view because actually you need to administer very high doses, which might be sometimes 20 times or even more of a, the dose you administer by by injection. 

 
30:47 
And it has also an impact of course on the amount of API that you are able to produce to let's say provide the market with a with a product. 

 
31:02 
So, so of course for this, so now this is the reason why actually there's a strong need to really enhance, I would say the oral bioavailability which goes through the permission, but also the metabolic stability of your rather peptide drugs. 

 
31:26 
And so now maybe we're going to shift a little bit of the discussion around the, let's say the design of a, of a peptide and potentially the chemical modifications as well as the modelling and computational approaches that can be used to let's say help this design and produce efficiently a new structures. 

 
31:57 
So Utah, maybe would you like to to comment on this point? 

 
32:02 
Yeah, sure. 

 
32:02 
I'd love to the topic of course is or the question is the the metabolic stability which intrinsically is poor for peptides. 

 
32:14 
Normally the the peptide drugs we we know most of them are derived from endogenous peptides or protein fragments, meaning they are entirely composed of protein eugenic amino acids. 

 
32:27 
That means there will be a rapidly degraded in biological environments in in the in the blood. 

 
32:34 
They have proteases, but even more so. 

 
32:36 
And that's why this is even bigger issue and more severe issue when we talk about all availability a drug, any oral drug has to survive really harsh environments. 

 
32:49 
First in the in the stomach, highly acidic, then in the intestine, lots of proteases, digestive proteases and like a normal peptide composed entirely of of proteinogenic amino acids would would not survive that. 

 
33:08 
That's why they have to be protected against this proteolytic attack. 

 
33:14 
And there's and if we look at the current peptide drugs and in particular they're only available be it semi glutite or cyclosporine, it's like the classic example, which has been around forever. 

 
33:30 
It's a peptide, but it's it's highly chemically modified. 

 
33:35 
It's a cyclic peptide that hamburst attack of exo peptidases. 

 
33:40 
It it's MI bonds are methylated, which prevents attack of proteases on those peptide bonds and it has more chemical modifications that's a natural product of course. 

 
33:54 
So this has been this exercise of chemically stabilising peptides against proteases has been done before even we we came up with that idea by by nature by those fungi that produce cyclosporine. 

 
34:12 
But if we come now, if we look at our synthetic biosynthetic peptide drugs, what they're typically feature is the pegulation like a pack derived acylation and liquidation modification with with a fatty acid in order to cover to shield the molecule kind of stearically from the attack of proteases and also to make it more hydrophobic because that's another have yet another limitation of peptides in general as as peptide drugs. 

 
34:46 
So I apologise of being chemical here, but I'm a medicinal chemist and this is what we do. 

 
34:53 
But I think that's relevant also in the context here strategy used for some of your type, for instance, or Yeah, that's exactly, there's one, I mean one licence residue that is a pegulated antipidated. 

 
35:06 
And then another things what what what is typically done during the discovery and development process is the peptide is scanned amino acid by amino acid, where are the the hotspots for a proteolytic breakdown And those sites are being identified. 

 
35:25 
And then these amino acids are changed to non proteogenic amino acids such as D amino acids or other like in semaglutite, there's an amino isobutyric acid that replaces 1 amino acid and others as well. 

 
35:43 
So these are typically the strategies to to shear, to protect, but the peptide drugs from proteolytic degradation and they're, yeah, they are increasingly successful. 

 
35:57 
And apart from all formulation things, you guys probably know much better, more and can talk about it much better like nanoparticles, viral and bacterial vectors and that sort of thing. 

 
36:11 
But it's all about making them more stable because if they are not stable even when they're not stable, then even the permeation enhancers won't help much. 

 
36:22 
So this is two things that need to come together I believe. 

 
36:26 
OK. 

 
36:27 
And by the way, what about the use of non natural amino acids? 

 
36:33 
Yeah, that's I I was mentioning briefly and semaglutide, we have one amino isobutyric acid. 

 
36:40 
That's the same is true for turcic petite. 

 
36:44 
And then in decimal present for example, that's also an orally available drug vasopressin analogue. 

 
36:52 
And pretty much that's a classical example. 

 
36:54 
There's one cysteine is being replaced by an D amino cysteine. 

 
36:59 
So the amino group is just chopped off and an arginine is replaced by an D arginine and that does the job in terms of stability. 

 
37:08 
It's only very like specific, not that many selected modifications at specific well defined sites of the molecule that can dramatically enhance the proteolytic stability. 

 
37:26 
OK, thanks. 

 
37:27 
Hans, would you like to add on on this and also talk about maybe your your approach? 

 
37:34 
Yeah, happy to elaborate. 

 
37:36 
Yeah, I, I definitely think there's a lot of physical and chemical properties that need to be considered in order to whether you're designing or or screening for a oral Bible of peptide. 

 
37:52 
I agree with you that obviously stability is key for, for, for, for a peptide, but also what we've seen charge for example already is, is very, very important. 

 
38:05 
You may have a extremely stable hyperstable peptide that is just not soluble or it has some charge which is not amenable to permeability. 

 
38:14 
And so chemical composition becomes really, really important impact to on natural amino acids. 

 
38:20 
One of the beautiful things about peptides is that we have a very rich and diverse chemistry available to us that is not available to to proteins, for example. 

 
38:30 
And so chemical modifications, methylation, different cyclisation techniques can become very, very powerful. 

 
38:38 
And so a lot of the of the work, you know, done over the last decades has taken inspiration from nature and seen, OK, how does cyclosporine do the right, what kind of what properties are are present there? 

 
38:51 
Can we try to emulate that, simulate that, exploit that to our own purposes for all their designs? 

 
38:58 
And and so that is what we we find really exciting at the company right now. 

 
39:04 
We find that new tools, artificial intelligence is giving us a new options, new power can be a powerful tool in your toolkit to go after a lot of these properties and really try to understand sort of the underlying principles guiding a lot, a lot of these properties. 

 
39:24 
And then can we exploit that to then design. 

 
39:27 
And I think that that is what we're beginning to, to, to do and we're really, really excited about that. 

 
39:32 
So I'll stop here, but happy to come in more of course later. 

 
39:38 
OK, great. 

 
39:40 
Just one comment if I may. 

 
39:44 
And it's just loops back to what you said general about cost of goods. 

 
39:48 
So one of the the other considerations in designing the peptides is, is the synthetic route and making sure that it's for all delivery is going to be as cheap as possible. 

 
40:02 
Because because you should expect low buy availability that has impacts on cost of goods. 

 
40:07 
And so the the kind of simplest synthetic route is possible of the highest yield. 

 
40:14 
All of that sorts of stuff's really important from an industrial perspective. 

 
40:18 
Yes, you're right. 

 
40:19 
The more that you know, today, the synthetic routes that are used are actually employing a lot of organic solvents, you know, and which might be one of the of the main limitations actually for this type of processes. 

 
40:40 
So most likely to enable oral delivery, let's say for a larger number of peptides, most likely there are also some improvements of the synthetic processes for, for peptides that needs to be developed and implemented. 

 
41:04 
So I think it's a, it's also a key point because the environmental impacts actually might be quite high, you know, multiplying the production of peptides by a factor of 20 or more for each of these peptides as a as a strong impact on the environment as regards very, very solvents that are used and then that have to be destroyed. 

 
41:31 
OK. 

 
41:32 
So, and maybe can I, can I add on on this, just a thought as since you mentioned it. 

 
41:38 
Absolutely the that's always one big argument, the environmental impact of chemical versus biosynthetic generation. 

 
41:46 
And that's actually a big, big, big research effort not only in academia, but also in, in there there's an industry of developing peptide synthesis technology that is focused on reducing the, the, the impact simply by reducing the amount of solvent. 

 
42:07 
There's really ingenious technological developments out there into a conference earlier this year where I learned about this such as like recycling the solvent by evaporating and re condensing them and really which of course these processes again are energy intensive. 

 
42:28 
So they need a lot of energy and that's then about finding a balance there. 

 
42:32 
But this depression is fully being realised by by the people who develop these synthetic technologies and I think we will see a lot of progress in this regard in the in the years to come. 

 
42:47 
OK, thank you very much for for this comment. 

 
42:51 
So, so actually I've seen that we have some interesting questions coming on this topic from the attendees and I think we we may try to answer them. 

 
43:04 
And one of the attendees is asking actually what would be the average size, molecular weight? 

 
43:12 
Does it play a role actually on the potential for development of an oral delivery system with this bedtime? 

 
43:24 
Would you have some comments on this? 

 
43:29 
I can comment a little bit, but so we, we know from looking at mitral peptides, not always, but typically speaking the smaller the better in terms of permeability, right? 

 
43:45 
The other considerations, right, in terms of residues, you probably, you know, looking at 4:00 to 10:00 is easier to across membrane, you know, you got 1112 still do it. 

 
43:59 
If you get something like the 30 amino acid peptide, you'll need a really, really strong permission enhancer to to get some bioavailability. 

 
44:09 
It is possible. 

 
44:10 
It's obviously done and and there are certain rules, you know, that could be loosely used for guidance, but ultimately really comes down to the the physical, chemical properties of each peptide. 

 
44:23 
Yeah, OK, I can comment on some. 

 
44:27 
Yeah, I can comment on our experience. 

 
44:30 
So the average kind of molecular weight, so this is not just the amino acid chain, the average molecular weight of peptides that we've worked on across those 14 was, was between 4005 thousand kilo daltons. 

 
44:47 
And now this is much higher than I was expecting. 

 
44:50 
If you look at kind of marketed oral peptides from kind of 1015 years ago, they were much smaller around like one killer Dalton. 

 
45:00 
But what's 1 of the things that is driving that is that people are moving towards the long circulating peptides that are typically conjugated in some way as, as you're to said to, you know, maybe maybe they're lipidated or, or or pegulated or other kind of types of conjugate to promote their long circulation. 

 
45:25 
And I agree with with Hans, you know, there's a decent amount of data out there that shows, I think you have mentioned it as well, the larger a peptide gets that the lower the permeability. 

 
45:38 
But it's kind of interesting with the state of permeation enhancer technology is that we can, we can get decent systemic absorption around 4 to 5K Dalton peptides, No impressive, right. 

 
45:56 
OK. 

 
45:58 
That's another question. 

 
45:59 
I think which is interesting to to try to answer is actually one of the attendees is asking well or evaluation about the probability that novel peptide structure can really help in the oral delivery of of peptides. 

 
46:17 
So what what is of confidence actually in this approach about the the design of of a peptide specifically for oral administration? 

 
46:28 
I think this is the question, what do you think? 

 
46:34 
Who wants to stop on this? 

 
46:36 
Yeah, yeah, sure. 

 
46:42 
I, I'm not aware of any strategies that reliably allow for the design of all of the all the available peptides from scratch. 

 
46:53 
As I pointed out before, typically that involves subsequent later on chemical modifications and enhancement. 

 
47:05 
This help me enhances, yeah. 

 
47:14 
But what we can do, what we do know in terms of the ability of peptides to to translocate membranes, there is and probably Hans can can comment on that. 

 
47:27 
Also there is rules or at least there's there's evidence, empirical evidence what it takes for a peptide to or what, what is a useful strategy to implement to enable a peptide to permeate membranes. 

 
47:44 
One thing is typically alpha helices if that now we are talking about second secondary structure when an alpha helical peptide has a good chance to because of its empathic character to to penetrate, to translate, locate through biological membranes. 

 
48:05 
Which does not mean that any each and every peptide that falls into an alpha helical confirmation is able to do that. 

 
48:13 
But this is something a design principle that that could be that could be that could help in the design. 

 
48:22 
Another thing is or general empty patheti. 

 
48:26 
So to have a peptide that it's not entirely hydrophilic and not entirely hydrophobic. 

 
48:32 
So that we have those, those dual, you mean antiphilic, antiphilic nature or yeah, the that's, that's one thing, but that's not the only thing. 

 
48:42 
I mean it's nothing as I as I said at the beginning, there is no like reliable strategy that you can follow or maybe Hans can have has one which I'm not aware of that reliably will get us all the available peptides. 

 
49:00 
I believe that will be obviously a multi step process of of optimising and involving lots of chemical modification also prediction to in the end to come up with an orally available peptide. 

 
49:14 
So there's a, there's one question about relationship between flexibility and permeability. 

 
49:21 
So is there an influence of a constraints on the, on the peptide structure? 

 
49:29 
What's, what do you think about it answer? 

 
49:32 
Have you, have you had some modelling about visa specs? 

 
49:35 
I'm happy, happy to, to comment on that and maybe going back to, to cyclosporine as an example. 

 
49:42 
So cyclosporine is a very interesting molecule that exists into conformational state states. 

 
49:52 
It it has a open conformational stage which is insoluble, which which is soluble and in that state it it has a lot of hydrogen bonds exposed and so it it becomes soluble. 

 
50:05 
Now what's interested in cyclosporine is that it's what people call camelionic. 

 
50:10 
Upon entering or really making contact with, with a membrane, it changes to a close confirmation actually, and all of the exposed hydrogen bonds now become shielded inside a molecule. 

 
50:26 
And so that then allows it to transverse the the membrane. 

 
50:30 
And so, and, and it's a beautiful example of nature figuring out a strategy to accomplish just that, right? 

 
50:38 
How, how to remain soluble when it's important, how to change in order to, to go across the membrane and, and go back to, to do this other state. 

 
50:48 
So flexibility can be very, very, very helpful. 

 
50:54 
Now we, we, we know from cyclosport and from other examples that there are certainly underlying principles that while Judas right, they're, they're not determinant of permeability, they can certainly enhance some of the prediction capability. 

 
51:13 
So again, polarity very important. 

 
51:19 
We seen really what the most predictive I guess feature that we've seen. 

 
51:27 
It's not a single property or predictor or size or or even composition. 

 
51:34 
It's really about the energetics it makes both in, in, in, in solution and then as it interacts with the membrane. 

 
51:44 
And those are things that we we can model and we have some ways of doing that. 

 
51:49 
People have succeeded at doing that. 

 
51:52 
But we can use all other principles as guiding principles for for design. 

 
51:57 
So my Co founder, Vikram Mulligan, for example, published just two years ago, probably one of the the 1st and few papers using computational design to create permeable peptides, specifically cyclic peptides of a specific range attended with they saw the most success with six to to 8 mirrors in in size. 

 
52:24 
So while it doesn't, you know, give us high rules for how to predict permeability across the board, it does give us some insight as to what are the underlying principles and how to use those as guiding, you know, as signs for for design. 

 
52:43 
So hopefully that that is some thought for for people. 

 
52:48 
Yeah. 

 
52:48 
And, and again, if I could comment, I mean, I think it makes, I think if you're working in oral peptide delivery at the moment, makes absolute sense to, to design the peptide for oral delivery and consider also it's compatibility with whatever delivery system you're using. 

 
53:07 
So I think it's a sense to get, maximise the chance of success to get the best performance. 

 
53:13 
I think that's definitely the way to go. 

 
53:15 
And you know, I'm aware Med Immune published a few years ago, I think how they designed the GLP 1 analogue. 

 
53:24 
And you know, you can screen stability to peptidases in in vitro. 

 
53:31 
There's also obviously, you know, advances in peptide discovery where you can screen vast libraries and compounds as well for particular properties. 

 
53:41 
So things like phage display where you can produce, you know, thousands of different peptides and and screen particular properties. 

 
53:50 
I think that provides great opportunities to identify the peptides that are most likely to be stable, but also cross epithelial membranes. 

 
54:03 
OK, thank you. 

 
54:04 
Thank you Andy for for this additional comment. 

 
54:06 
So before going to the discussion about imaging technologies for oral peptide delivery, beyond the permission and answers, I would like to address maybe rapidly 2 questions. 

 
54:20 
And I think you already touched a little bit about this and the few minutes ago and bizarre questions related to the development and development tools that could be used for this oral peptides. 

 
54:37 
The first one is related to in vitro systems or technologies which will allow optimization of formulation of peptides beyond screening in vivo. 

 
54:48 
So you don't have to go in vivo to predict what would happen in in vivo. 

 
54:53 
And the second one is, and I think it's related to your population based PK, it's about how do you approach the scaling to human from the animal species. 

 
55:09 
So would you, would you like to comment a few minutes about, about this, Andy, I think you might have some experience in this field. 

 
55:18 
Yeah. 

 
55:20 
So I mean, typically our clients will come to us and they've identified formulation or drug delivery technology and then we'll help advance it into the clinics. 

 
55:32 
They'll have done the preclinical work, but typically they will have done some work with KAKO 2 monolayers to to evaluate different permeation enhancers, although really mostly they will have advanced those into in vivo screening and in order to identify kind of lead permeation enhancer systems. 

 
55:59 
There's also, you know, the ex vivo models like in us in chambers, so you can take bits of intestine and even different sections, you know, and evaluate permeation enhancers, but you know their their correlation with clinical performance of each of those is not great. 

 
56:21 
And even the preclinical animals as I said are not all not really particularly predictive. 

 
56:28 
So they're really, really useful studies to identify, I guess lead systems, which then I think would need to be, you know, you've got to make, make some choices and then optimise the formulations in humans. 

 
56:48 
I mean, similarly that scaling from from animal to to human is really challenging that there's, there's a lot to really be be understood about kind of oral peptide biopharmaceutics. 

 
57:05 
You know, those differences are not well understood. 

 
57:07 
So typically in the kind of first in human study, they, they usually follow, you know, pretty standard approach for a first in human. 

 
57:15 
So you, you'd start your going to a single ascending dose study, you'd start determine your starting dose based on the safety pharmacology predictions of receptor occupancy. 

 
57:27 
You know, there's a safety factor in there. 

 
57:30 
And I'd recommend also, you know, making sure that you know that that there's a justification there in terms of the bioavailability, if if relevant, you know that you start on a on a higher as higher dose as possible. 

 
57:47 
But yeah, the scaling is really difficult until you actually get into humans. 

 
57:52 
And the as I said once, if you build APBPK model on your on your preclinical data, once you get your human data, you can then refine it and then that can start to provide you the insights. 

 
58:04 
But at some point you're going to have to make, make a step into the clinic now, so you are talking about single ascending dose. 

 
58:13 
Do you go quite rapidly the clinic to multiple ascending dose or or multiple dose actually just to see whether you can get to a steady state in the the single ascending dose would typically be kind of a bit more expanded compared to like what you might be used to with kind of small molecular weight drugs. 

 
58:37 
So you would, you would certainly start usually with what would be, you know your, your best performing kind of formulation in preclinical animals in terms of levels of permeation enhancer. 

 
58:52 
But you're obviously you've got to start at a lower dose because it's a first in human study, assuming that you're using an Oval peptide that is. 

 
59:02 
And we're, so we would typically then start to increase the peptide dose until you start to see by availability because you usually you've got to start at such a low dose. 

 
59:15 
Quite it's not unusual that the first few dosing cohorts you don't see a great deal of bioavailability. 

 
59:21 
And then once you start to see bioavailability, we typically start to explore how adjustments to the formulation might impact, might improve by availability. 

 
59:32 
So that could be looking at increasing the levels of the permeation enhancer, that could be looking at the ratio between the peptide and the permeation enhancer, that could be evaluating a different permeation enhancer as well. 

 
59:48 
And, and then once you kind of achieving, it's usually once you start to achieve your kind of high highest bio availability that you make a decision, you know, probably coupled with some modelling as well to, to, to that you might have confidence that you're on multiple dosing, you'll achieve a pharmacodynamic effect. 

 
1:00:11 
That's that will be when we're going to into the mad phase. 

 
1:00:15 
OK, OK, thank you very much promise. 

 
1:00:19 
So I would like now we have still a few minutes. 

 
1:00:23 
I would like that we we shift a little bit to to the fracture and emerging technologies for oral peptide delivery. 

 
1:00:34 
So of course we have seen white early stage system based on nanoparticles, functionalised nanoparticles but make it possible to improve the interaction with the membrane of the epithelial cells and improve the crossing of the cells. 

 
1:00:54 
We have seen also some published technologies based on micro needle, anterior micro injection, different type of of systems. 

 
1:01:09 
There are some also computational technology. 

 
1:01:13 
So and what about the the AI actually AI technology, our AI technology can also help us. 

 
1:01:24 
So I would like to let you your comments on let's say this prospective technologies and well, give, give us your, your input about what you imagined about them. 

 
1:01:41 
So can we start maybe with Utah? 

 
1:01:48 
Yeah, again, I have to say that I'm, I'm not an expert and I'm not involved in this field. 

 
1:01:56 
But from my perspective, I think formulation is will be the focus will continue to be the focus to to work with existing molecules and existing Peps, the peptides and come up with innovative formulations such as nano particles. 

 
1:02:16 
You just named them to shield them again, shield them, make them metabolically more stable and also at the same time facilitate the the uptake. 

 
1:02:28 
That is one thing when it comes to discovery. 

 
1:02:31 
Of course, then, and probably Hans can talk about it, it will be a strategy would be to implement design strategies aimed at facilitating oral availability. 

 
1:02:48 
And we've already touched upon that. 

 
1:02:50 
And also if, when it going one step back, like if the discovery of new molecules of new of new peptides, then of course, if, if the goal is from this from the goal to have an orally available peptides, it would, it would be logical to implement this, this this goal into the strategies by making starting with not with endogenous peptides in the in the development process, but to start with already chemically modified peptides. 

 
1:03:26 
This could be done by specifically by using screening, specifically designed peptide libraries that are available synthetic peptide libraries D amino acid peptide library. 

 
1:03:37 
So this is also like an alternative strategy to to endow the the molecule itself before it gets modified, before it gets formulated and mixed with with other molecule enhancing molecules to to increase its intrinsic ability to to survive proteolytic environments and to translocate through membranes. 

 
1:04:12 
So this would be this would be my perspective what I would expect. 

 
1:04:17 
OK, thank you. 

 
1:04:19 
As would you like to add on this and we will and ask Andy this position. 

 
1:04:27 
Well, I think the the future looks, looks very bright for oral peptides. 

 
1:04:34 
There's emerging technologies from every angle with permission enhancer, better screen techniques, AI design technology to help. 

 
1:04:44 
And I, I think we will more and more see these technologies coming together to, to deliver better peptides. 

 
1:04:53 
And I, I certainly think there's a lot left to, to learn and I think cooperation across the board is necessary. 

 
1:05:01 
Whether you are a computational scientist or a formulation scientist, I think it's important to have a, a discussion. 

 
1:05:12 
That's my input. 

 
1:05:15 
What, what do you think and what, what would be a according to you technology game changer in the film? 

 
1:05:23 
So if I, if I just may refer to to some publications, some functionalised nano particles in animal models seem to improve by a factor 10 and you may reach the bio availabilities in the 30 to 40%. 

 
1:05:41 
So what do you think about this and is this the next game changer or or what? 

 
1:05:48 
I'm not, I'm not familiar with that publication. 

 
1:05:51 
I'd love if you could forward it through. 

 
1:05:52 
But yeah, if you could. 

 
1:05:54 
The higher the buy availability we can achieve, obviously it will enable the development of of many more compounds because, you know, it makes that reduces those cost of goods, makes it kind of a bit more financially viable to develop these these types of products. 

 
1:06:11 
So yeah, any of those, I know the micro needle technologies are getting, you know, those types of bioavailabilities and I think some of those are kind of progressing. 

 
1:06:23 
I think Ranny announced that that that got a collaboration I think to develop there with the GLP one analogue. 

 
1:06:33 
I mean that they're obviously the kind of long term safety of those types of systems. 

 
1:06:38 
And also I guess you know, this seems to be on the face of it quite a complex manufacturing process as well, you know, remains to be proven, but they are achieving high, high availabilities I think in permeation enhances. 

 
1:06:54 
You know, one of their drawbacks is that they suffer from significant food effects and even the volume of water that you take your tablet or capsule with has a significant effect on their performance. 

 
1:07:07 
So any technologies that could be developed that would avoid that would just make it easier for patients and and again, potentially be be game changing and you know, enable them to be to be used for a wider, wider range of products. 

 
1:07:28 
So you mean actually keeping on with the permission and answers and finding systems, but made for bio validity less dependent on drug, drug interactions or food effects or things like this? 

 
1:07:47 
Well, that would be one way to do it. 

 
1:07:48 
Whether that's feasible or not, I don't know. 

 
1:07:51 
But there might be some inventive people out there that can think of a way of doing it. 

 
1:07:55 
That would be one way. 

 
1:07:56 
But again, like those functionalised nanoparticles, I think the other one that we're not mentioned, although the the IT might be actually is, is those kind of receptor mediated trans epithelial strategies. 

 
1:08:09 
So, you know, it's possible to design peptides. 

 
1:08:13 
I know there's a lot of work obviously with different actual actually proteins based on, you know, bacterial toxins that that fascinating molecules that can, you know, interact with receptors and then effectively translocate parts of their polypeptides in, you know, across the epithelium. 

 
1:08:37 
So I think those are really interesting types of technologies and, you know, and if they can function without food effects, then, you know, definite advantage what's already on the market. 

 
1:08:52 
Yeah, So I agree with you. 

 
1:08:55 
That's OK. 

 
1:08:55 
There might be some very innovative new systems. 

 
1:09:00 
We need to be careful with the additional complexity they may bring. 

 
1:09:08 
There might be of course ways of dealing with this, but well, this might be another hurdle for development. 

 
1:09:19 
OK. 

 
1:09:20 
So would would you like to add any other comments any, any of you about the topic? 

 
1:09:30 
I think we have addressed all the all the key points and actually I think the discussion went very well. 

 
1:09:46 
We have addressed a lot of the, the key aspects of oral peptide delivery and I would really like to thank you and congratulate you for, for your, your input to this very interesting discussion. 

 
1:10:05 
So any, any other comment from you before we, we close the, the session, not from me. 

 
1:10:13 
Thank you for inviting me to the panel. 

 
1:10:16 
Thank you for the welcome pleasure. 

 
1:10:19 
Thanks for guiding the discussion, Joel, and thanks to Oxford Global for setting this up and putting it together. 

 
1:10:28 
Thank you. 

 
1:10:29 
And thanks to Oxford Global also for enabling us to have this very interesting discussion. 

 
1:10:36 
And I hope that the attendees have also got, let's say, the the most from this discussion as regards the development of new oral peptide delivery systems. 

 
1:10:50 
Thank you. 

 
1:10:51 
Thank you Joanne Dee hands and gift her for sharing your insights and your knowledge with us today. 

 
1:10:57 
And thank you for everyone that joined us to participate in the discussion. 

 
1:11:01 
I hope you we can see you at one of our future events and I hope you have a good rest of your day. 

 
1:11:06 
Thank you very much. 

 
1:11:08 
Thank you, Thank you. 

 
1:11:10 
Bye bye.