Thalia Therapeutics Plc (THAT) Earnings Call Transcript & Summary

Good morning, and welcome to the N4 Pharma Plc investor presentation. [Operator Instructions] Before we begin, I'd like to submit the following poll. I'd now like to hand you over to CEO, Nigel Theobald. Good morning to you, sir.

Good morning, and thank you to everybody for joining us today. We're delighted to be able to talk you through our latest progress update and the strategy for the company as we move forward. And I have Fiona McLaughlin and Mark Edbrooke with me today who will each talk through different parts of the planned program. So just to give you a bit of an overview of N4 and some of you may well know us from before and others might be new, so just a flavor of who we are and what we're doing. First off, we are working in the rapidly growing area of RNA therapeutics. This is a market that's worth around $18 billion by 2028, according to research. But it still faces big issues and mainly the issues it faces are on how it's going to deliver those drugs to the right tissue in order to actually meet and succeed and beat that market forecast. And what we've been doing at N4 is we've developed a platform which we call Nuvec, and this has the potential to really revolutionize gene therapy and gene delivery and particularly by solving the challenges of both manufacturing and how you target delivery of RNA therapeutics. At the moment, what we're doing is we're focused in the near term on how we can monetize the Nuvec platform, and I'll go through the strategy a bit more in more detail soon. Looking at partnerships. And in the longer term, we're looking at progressing our own RNA therapeutic assets and taking those into clinic ourselves. So this year, we've achieved a lot of key milestones in '25. We've had some positive in vivo efficacy data for our IBD product called N4 101. We also successfully raised GBP 1.7 million in April this year, which has given us the funds and the launchpad to actually start working on our expanded commercial data program, which we began in May of this year. We are currently focused, as I said, on expanding that data set so that we can drive the platform because the platform needs to be in a good state when we're talking to potential partnering and license partners. So we're building those partnerships in the near term while simultaneously building our pipeline, as I mentioned, of our own RNA therapeutics. So just a brief overview of the Board. We have been strengthening the Board over the last few months. Myself and Luke have been with the company for some time. Chris Britton has also been our Non-Exec Chair, having previously been just a non-exec for the last couple of years. And we've recently recruited Alastair Smith, previously of Avacta; and Dr. Mike Palfreyman, who is based in the U.S.A., who has a big background of both corporate and investor-related deals in the U.S.A. in the biotech space. So the Board is now looking a very strong Board. And what we've also been doing is significantly improving the leadership team, building out the expertise around the areas that we need. So we have Dr. Fiona McLaughlin, who's our Head of R&D; and Dr. Mark Edbrooke, our Head of Strategy, who are with us today. They'll be talking through their own background so I won't sort of go into that now. We also have Dr. Simon Bennett, who's heading up our business development team and he is out there talking to and establishing partnerships, conversations and Dr. Margaret Courtney, who is looking after the chemistry and all the manufacturing and control aspects of the program in terms of how we make the Nuvec system itself. So our strategy. Our near-term focus is on partnering, partnering the Nuvec platform whilst we then build in the background a novel drug pipeline for ourselves, and I'll go on to explain why we're doing that relatively in the biotech world shortly. So longer term, we're going to be creating significant shareholder value through the commercialization of our novel platform and also our own proprietary RNA therapeutic assets, all of those using the Nuvec platform themselves. So in the near-term, our resources at the moment are focused on validating and monetizing that platform through -- having some commercial partnerships or academic partnerships where we can expand and evolve and move the value of the company forward. And the most important thing there is through our conversations with potential partners, we know that if you're going to be a successful license deal, the platform itself needs a whole series of robust preclinical data sets which supports the claims that we're making. If we make a claim when we sit down in front of somebody, we want to be able to show them exactly how we make that claim and why because we -- whilst we strongly believe those claims, we need to have the data that backs up every little part of it. So the strategy is expanding that commercial data room now. So we support those performance claims, particularly looking at things like dual loading of different nucleic acids on the same particle, the targeting capability, our ability to deliver orally. Also our safety and manufacturing profile and go through the appropriate pharmacokinetics because you don't have the basics, then you won't -- we won't be doing a deal. So we'll be looking to secure those partnerships and each one of those will give them nonexclusive access to the Nuvec platform. That will be third parties licensing those in or doing collaboration deals with us. And there'll be upside value based on any successful product that gets developed or product that gets launched, so it could be an upfront fee and then milestone and license payments throughout. But we're also looking to develop, as I mentioned, our own assets. So particularly, we have N4 101, which is currently in preclinic at the moment. And the key thing there as well as being a unique position in the IBD market, it really showcases all the key benefits of the Nuvec platform, and Fiona is going to go through those in a short while. And then finally, as I mentioned, we're developing a pipeline of novel proprietary RNA therapeutics and drug concepts that we can then take through preclinical phase and that all leverages the Nuvec benefits, showcasing exactly what the platform can do as well. So we're well placed to deliver, well I think, significant value into '25, '26. Continuing that focus on advancing Nuvec, our platform, consistently meeting performance benchmarks and moving the milestones forward, and we'll come on to those in the end as to how -- why we think that will move the value of the company forward. And as I mentioned, we're looking at RNA therapeutics, which is a big market with its own delivery challenges, having a very strong differentiated position in that market. So, so far in '25, what we have done is we have got positive data for N4 101 in our IBD program. We have successfully raised some money, and we've launched the expanded commercial data program. So we've had a very busy '25 so far but that's continuing as we go through the rest of the year. And I wanted to explain a little more about the biotech business model to you. Some of you may well be familiar with it, but others may be less familiar with the biotech model. The model is based around doing R&D, being an R&D-led company to build valuable therapeutic assets. It's not about PE ratios, short-term profit, revenue generation in the first 12 months, et cetera. It's about building shareholder value through long-term strategic commercial partnerships and ultimately acquisition. And the typical biotech business goes through these sorts of phases. And you'll see companies that start out where we are at the sort of platform stage right through to companies that have got a whole range of assets that might be valued over GBP 2 billion, GBP 3 billion. And when assets get sold in this business, they get sold for huge sums of money. So you start out with the sort of technology partnering approach, developing and building the Nuvec platform, which is what we're doing at the moment. And this is an entry point to the market. And the reason we do this is because it reduces the financial risk for a small biotech like ourselves but it strongly enhances our market credibility. So we're all the time out there talking to people, getting articles in key publications from the biotech world. What you then do as a biotech business, as you move beyond that technology partner, you start to create your own assets. And those own assets will have much higher value and much higher returns because they -- through licensing them to pharma companies to ultimately develop and bring to market. And the first one that we've been exploring here is N4 101, which is our orally-delivered IBD product. Once the company has established itself with its own set of assets in sort of preclinical and early clinical phases, what it then does is it looks to commercialize products by itself, so it takes over full ownership of that program. Now that gives much, much higher rewards. I mentioned the sort of billions that people have valued that, but it does come with significant upfront investment. So you need to move through these phases in order to be able to hit some of those key strategic and commercial goals as you develop your own products. So what we're doing at the moment, N4 is we have a hybrid approach. We're both doing the platform technology development and partnering work, alongside developing our own asset portfolio, looking to take those into preclinic. So it both minimizes the risk involved and accelerates the growth of the company. So as I said, the partnering approach, why are we doing this? So it gives us this rapid return. And what it will do is, it will give initial revenue generation through some licensing fees and service payments as we start to develop that platform and license the platform and get collaborations with people. It does mitigate our risk. It lowers the risk by having collaborations with established partners. And that also enhances our credibility in the market, both with leading academics that we might work with and also working with some key companies in this space. The other thing it does is it gives us access to technologies that we might not actually have ourselves. So if we start partnering with people that have got specific assets, specific targeting elements that you can add to Nuvec, specific RNA compounds that they want to investigate, we can get access to those by working with other people. So it establishes ourselves with a real foothold as a competitive operator in quite -- what is quite a competitive market by working with established industry leaders. So the partnering approach is really valuable to getting the biotech company moving. But then as it moves forward, its own asset creation and out licensing, we begin to see it builds and grows as a company in the biotech space. So we're looking at identifying key therapeutic areas that have got both high demand and unmet needs that can have products developed using the Nuvec platform. That will allow us to cultivate further relationships with some of the major pharma players who will look at those therapeutic assets, I think, with real interest while we're developing them. It also allows us to build really a much stronger IP portfolio. We have a very strong one at the moment, but as we move forward, we want to continue to build that. So we have strong patent protection, both with ourselves and our licensing partners. And that allows us to clearly communicate the value proposition that we bring, both of the particular assets and the company itself. So what we'll then be doing is looking to efficiently and effectively move these assets through the preclinical phase and into Phase I clinical trials with partners. And the other thing that we will be doing is doing a thorough analysis of the market opportunity. So when we're talking to people, we not only say what we do but also why we see that as a strong value proposition for them to then partner with us. And finally, once we've got the partnerships in place, we'll be looking at the regulatory strategy so that we can bring these products through the clinical phases and ultimately, a very clear time line for both licensing and divestment of some of these assets that we'll be developing. So it's a classic biotech model, one that's been operated very successful by platform companies that have evolved and moved through from being just platform companies moving from low tens of millions of valuations into the 100 million valuations and ultimately into the billions once they achieve a whole range of product portfolio themselves. So that gives you an overview of the strategy of the company. And I'm now going to hand over to Dr. Mark Edbrooke, who is our Head of Strategy. And he's going to talk a little bit more about the RNA therapeutic field and the revolution that's going on in that space at the moment. Over to you, Mark.

Thank you very much, Nigel. So hello, everybody. Welcome. My name is Mark Edbrooke, and I have been in the drug discovery pharma business for quite a long time. So this is a summary of what I'm going to cover in the next 10 or 15 minutes. I'll describe who I am and then describe the world of RNA therapeutics that Nigel has been referring to a number of times. I'm going to refer to them as RNA therapeutics or nucleic acid therapeutics because, of course, RNA and DNA are made of nucleic acids. And then I'm going to describe some of the recent successes in this field with this particular drug modality. I'm going to -- I think it's a sensible idea to at least briefly describe how do these drugs work. How does this therapeutic modality actually lead to drugs? How they get into cells and do their job? And then that will lead on nicely to Dr. McLaughlin about the potential for Nuvec and how Nuvec can help with these types of drugs. So just as a quick background to me, I'm a molecular biologist by training. I worked at GSK for 25 years and then jumped ship to AstraZeneca for 3, but I've been an independent consultant now for the last 7 years. When I was at GSK, I set up their therapeutic RNA or therapeutic oligonucleotide unit, ran that and designed the strategy and got the funding for that to run that. At AstraZeneca, I also worked on oligonucleotide therapeutics and mRNA therapeutics with companies like Ionis and Moderna and Regulus, and now currently a consultant and my clients include venture capital companies, small biotechs across the globe, universities in U.K. and mainland Europe and rare diseases charities. So as Nigel has mentioned, the world of RNA therapeutics and nucleic acid therapeutics has really taken off in the last, particularly the last 5 years or so since 2020. And nucleic acid therapeutics include a broad term which I call oligonucleotides, which is oligonucleotides are just types of nucleic acids. It also includes siRNA, which are small interfering RNAs and I'll come back to that in a minute, and also includes mRNA and mRNA vaccines. And of course, I'm sure you're all familiar with mRNA vaccines in the last 5 years or so. What I'm not going to mention again is that not only does it include these larger sort of overall scope type modalities like oligos and sRNAs, but it also includes named patient drugs. And I'm not going to go into those in any more detail. But I'll come back to it in a minute as to how we design these types of drugs. But really, all you need is we're living in the genome world now where you sequence people's genetic material, and you can identify all the different genes and also the potentially mutations that are causing diseases in those individuals. And now we have the potential to design individualized drugs to specific named patients, so n-of-1 drugs. And there are a number of oligonucleotide or nucleic acid drugs which are approved for individual patients. And though it's not relevant to what we're doing here, I mean it could be, obviously, Nuvec and what N4 Pharma are doing could be applied to rare diseases. What it does help us is that it means these compounds are going into humans and children, obviously, in most cases, incredibly rapidly and allowing us to understand how they're manufactured, what's the toxicology, tolerability, all those sorts of things, and it helps expand the field tremendously. So even though these are n-of-1 individualized drugs, it helps the field tremendously. Also, it shows that in these particular cases, you can take an idea, develop a drug and start to treat humans in 2 years, which most of the time, we won't be doing that but it just shows that the capability is there. This slide is just a summary between 2020 and 2023 of the types of nucleic acid drugs that have now been approved. The 2 orange horizontal lines are the DNA vaccines, so that's from Pfizer-BioNTech which is the third line down, and the fifth line down is the Moderna vaccine. We're not going to be focusing on those, but we're going to be focusing on most of the other types of modalities of drugs that are listed in the sort of green and the blue, which is the oligonucleotide drugs. So those are siRNAs, if you look at the 1, 2, 3, 4, seventh or so column across from the left. So siRNAs and antisense oligos, which are ASOs. So the Nuvec platform can be used for these types of compounds. Just to show you what the most recent approved siRNAs actually look like, so here are some pictures of the actual drugs themselves. These are the 5 that have been approved in the last 5 years. If you look at the bottom 2, so fitusiran and vutrisiran, they've both been approved in the last few months. So this is a field which is expanding tremendously. And the top right-hand one, so inclisiran is a drug which is potentially a replacement for statins. So this is -- these are really, really important drugs. But going back to something that Nigel said at the beginning, delivery of these drugs, these are nucleic acids, they're small pieces of RNA and DNA. They're heavily charged. They don't get into cells relatively readily. So we do need to work out how to deliver these to specific cells and specific organs and tissues. Now interestingly, this set of approved siRNAs, all of these are targeted to just one organ, the liver, and they're actually all targeted to one cell type, so hepatocytes in the liver. That's because they're relatively difficult to deliver. And that's where Nuvec and N4 Pharma should be able to help because it will expand where these types of compounds can be delivered to in the body. This is the antisense oligos. So the previous slide was siRNA and I'll show the difference between siRNA and antisense in a minute. These are antisense oligos that have been approved in -- again, in the last 5 years or so. Again, 2 or 3 of them are in the last 12 months. But I've actually also put on here nusinersen, which is the one in the middle at the bottom. That is for a relatively rare disease called spinal muscular atrophy. But I think the important thing is that this drug has now been dosed to more than 14,000 individuals, which is an important thing because it shows that these types of compounds, these oligonucleotide or nucleic acid therapeutics have been delivered to thousands of patients safely and shown to be efficacious and safe. And I think that's, again, another important milestone for this field. This is a new therapeutic modality. We need experience in the field to show that they have been delivered to humans safely. Again, this is a snapshot about FDA approvals. If you look at the column on the right-hand side, that's the approvals in 2023. So there's what, 45 -- sorry, 55 drugs that have been approved there. But interestingly, if you break them down, you find that 4 of them are nucleic acid or nucleotide-based therapeutics. So we're getting on towards 10% of all the FDA approvals in 2023 with this type of therapeutic modality, which shows how it's expanding. It's moving on from where we were 5 or 10 years ago when there was like just 1 or 2 approved compounds in this modality. And just to give you a feel as to who is interested in the RNA therapy or the nucleic acid therapy landscape, if you look at the top 2 lines, you've got antisense oligos. So I've mentioned those a number of times already. And RNAi is actually siRNA, it's another name for small interfering RNAs. So those top 2 rows, if you look at the right-hand side, you've got some of the marketed drugs, which I've already shown you some pictures of. So small biotechs are involved in this area like Sarepta and Ionis and Alnylam. But you've got some big drug companies here. You've got big pharma, you've got Biogen and Novartis and Novo. But if you look at the Phase III, that shows you some of the things that are coming through in the pipelines of some of these other companies. You've got AstraZeneca, GSK, Novartis, Amgen, Regeneron and Takeda. They're all interested in this field, nucleic acid therapeutics. So it's a field which is expanding tremendously. So I'm just going to give a couple of slides on how they work and how they get into cells. So how do nucleic acid therapies work? They're just short pieces of RNA or DNA that, in effect, large small molecules. They're not biologics. They're not the same as monoclonal antibodies. They're machine-based synthesized drugs, similar to small molecules but just a lot larger. And because they're nucleic acids, they're acids, they're negatively charged. So they're quite large and they're negatively charged. What happens is they get inside cells and they invoke a natural intracellular process, which leads to the silencing of genes. So you can turn -- in effect, turn genes off quite specifically using these drugs. And something I'm not going to mention again today but it's something which N4 Pharma clearly are thinking about is that you can potentially use these small pieces of RNA or DNA to turn genes on as well as turning them off. And turning them on is a modality which hasn't really been fully exploited yet, so therefore is still in its infancy. But as that takes off, I think we can move into that area as well. But for the time being, we're just thinking about turning genes off, so silencing of genes. And all you need, you can essentially target any piece of nucleic acid sequence. So you can target a gene or the messenger RNA or long noncoding RNAs or microRNAs. There's lots of different flavors of RNA inside your cells. All you need is a piece of target sequence and you can then go ahead and design compounds, nucleic acid therapeutics, which will target those specific pieces of sequence. How does it actually work? I mean, there are a number of different mechanisms. I've mentioned antisense oligos, which is the modality in box A. It's also similar to box C. We're focusing on box B, which is siRNAs. So that's the mechanism which involves RNA interference. What happens, you can, in effect, imagine that the blue box is a cell in your body. The siRNA is a double-stranded piece of RNA. It gets inside the cell. It enters a silencing complex called risk. Risk then is a naturally occurring process, which then leads to the degradation of RNA. Remember, your genes are made of DNA. They make RNA. RNA then leads to production of protein and proteins are what tend to cause diseases. What we are going to do and what has been done in the field is to degrade the RNA and that, therefore, shuts off the RNA and also shuts off the production of proteins, which cause disease-causing proteins. So that's how the process works. And so we're going to focus initially on siRNA, and Dr. McLaughlin is going to mention that later on. How do these nucleic acids enter into cells? They basically all use a process called endocytosis. Endocytosis involves a number of different overlapping methods. So there's clathrin-coated pits, there's caveolar pathway, there's macropinocytosis. But one of the pathways is receptor-mediated uptake. So on the outside of your cells, you've got all these receptors and receptors are always sampling. What's going on outside your cells? Because the cells, in order for them to survive, they're bringing in nutrients and things from outside the cell all the time. So they're sampling the outside environment. These receptors, they bind to specific things that they see going past. We can exploit that and it has been done in the past. We can add ligands to our drugs which bind to specific receptors. The receptors then take the drug into the cell. And that is part of what we're going to be doing. And again, Dr. McLaughlin is going to mention some of that in her presentation soon. So that is a way in which nucleic acids enter into cells. One thing I should mention, and I think Fiona will mention this, is that the molecules, the drug molecules get inside cells but quite often, they're packaged inside things called endosomes. And endosomes can then shunt your drug around the cell. We need to make sure that the drug gets released from the endosome. So you need endosomal release. And that is one of the things that it looks like Nuvec is good at doing is allowing for the release of the drug into the cell and therefore engaging the silencing mechanism that we want to exploit. So just to summarize what I've covered, we're talking about therapeutic RNA or nucleic acid therapeutics. That includes a number of different classes of molecules called antisense oligos or siRNAs. It also includes mRNA, for example. And it is now the newest modality, which is expanding beyond small molecules, proteins and peptides and monoclonal antibodies. There are many recently approved drug products. They can be easily designed. And because quite a few of them are now on the market and there's lots of clinical trials, we now understand the tolerability and the off-target properties of these compounds. It doesn't mean we understand all of them. Of course, not. But there are ways in which we can predict and monitor the off-target effects of these drugs. But as I mentioned, RNA therapeutics are relatively large. They're negatively charged. And so they need help to get into cells and to get to the silencing mechanism. And that is the tremendous potential of the Nuvec platform. So just to summarize, and Dr. McLaughlin will go through these aspects in a little bit more detail soon, the Nuvec has a number of multiple properties. One is it allows for the protection of the drug molecule. So the one thing we don't want, obviously, is the compounds to degrade or disappear before they get to their cell of interest, and Nuvec appears to be able to protect those. We have the potential to look at more than one payload at a time so you can put multiple cargoes into Nuvec, so you could target more than one thing at the same time. You have the potential for cell-specific targeting, which I've mentioned before, so you could have receptor-mediated uptake, which is potentially a tremendous benefit of this platform. And then also, I'm a biologist, but clearly, drugs need to be -- you need to be able to make them relatively easily and they need to be stable and you want relatively low cost of goods. And again, Nuvec has that potential as well. So that's all I was going to cover today. And so I was now going to pass you on to Fiona McLaughlin for the next stage in the presentation. Thank you.

Brilliant. Thank you, Mark. Great introduction to my slides. So my name is Fiona McLaughlin. I'm working with Nuvec as the Head of R&D. And what I want to do today is talk you through some of the well-established delivery platforms that are already out there and then really focus the majority of the presentation on the key benefits of Nuvec. So while doing the outline of the presentation, I'll start with just a brief biography to introduce myself. I'm going to talk through an overview of the landscape of nanoparticles as therapeutics. So that's what we call nanomedicine, specifically using in the therapeutic space. I'm going to talk you through just 2 examples of approved nanomedicines used for the treatment of cancer. And then the features that Mark just outlined in that last slide, I'm going to take you through some of those key features with exemplified examples that we have for our platform. And then in the very last slide, I just have an overview of summary of those Nuvec benefits, specifically when we talk about the delivery of RNA. So myself, I'm an oncology drug developer. I've spent over 25 years in this field. I've got a very strong track record of translating drugs from the preclinical setting into the early Phase I and Phase II clinical studies. I'm a molecular biologist and hematologist by training. Right now, I work as an independent consultant. But prior to that, I've worked in a number of companies from pharmaceuticals from GSK through a number of biotechs. And Nigel outlined to you the biotech model. What's been really interesting when you move around different biotech companies is you get exposed to a number of different modalities. So whilst I have primarily been in oncology, I've worked in small molecules, aptamers, biologics and radionuclides as well. So I've seen a lot of different technologies. Okay. So let's go back to nanomedicine. So the global nanomedicine market is huge. So it's projected to exceed GBP 562 billion in quite a short time by 2033. Now that nanomedicine market, of course, covers a real breadth of indications, therapeutics and also diagnostics. But if you focus on what a nanoparticle is, so it needs to have at least one dimension in what we call the nanoscale range, and then we think about the key features that nanoparticles have to have to become therapeutics. So the first thing is they have to be able to carry a high amount of drugs, that's the drug loading that Mark spoke about. You have to be able to transport that payload safely to the target without early release of the payload or the cargo as we call it. And then once we get to that site of action, we have to be able to fully release the drug so that it can work inside the cell. So I wanted to start with this schematic, which is a really nice outline of where this nanomedicine field has gone over the last 50 years, so quite a long time since the very first liposome structure was discovered back in 1964. You can see on the left-hand side of this schematic, really moving through into the first major milestone in 1995, which was the first liposome approved by the FDA. And this was a liposomal form of a chemotherapy drug. It's called Doxil, and I've got one slide, just going into a bit more detail on that drug. So it took quite a long time, as it often does in a field like this to go from the initial discovery through clinical validation. In the last part of this slide, we're looking at now moving into targeted nanoparticles. The example given, BIND-014 with a PSMA, so prostate cancer-targeted polymeric nanoparticle. What you can really see here is the breadth of the different types of particles. This takes up to 2011, that was 50 years after the first discovery. And then, of course, in 2020, you've seen, as Mark said, huge advancements in the field, in particular, driven by the use of lipid nanoparticles in the delivery of mRNA vaccines for COVID-19. So that's the nanomedicines and where they are in terms of approval. If we just take a step back now and look at the types of particles that produce those therapeutics, they can be broadly classified into 4 different types. So on the top left, you can see the lipid-based nanoparticles. These are probably the ones that most people have heard of and are more familiar with. They're extremely good at delivering, for example, poorly soluble drugs to a target site. On the top right, you can see what we call polymeric nanoparticles. These have been used in many indications, including, for example, those cases when you might want a slow controlled release of the blood into the circulation. In the bottom left, you can see what we call carbon-based nanoparticles, graphene and carbon nanotubes. These can be really good for the various good conductors and used in a number of diagnostic and imaging implications. And then lastly, we come into the inorganic nanoparticles. So this will include gold nanoparticles, you may have heard of iron oxide. But really importantly, this is where the silica nanoparticles and Nuvec, this is the category that they fall into. So just looking at this slide, again, you can see so many different structures that obviously all with different properties. And that leads to a real breadth of opportunity for different nanoparticles to be used in different indications. So just to take you through, as I said, 2 examples of approved drugs. These are both happen to be in oncology. The first on the left-hand side is called Doxil. It's a liposomal form of a very old and well-characterized chemotherapy called doxorubicin. And what happens with Doxil is it improves the circulation time of the chemotherapy in the body, giving it a longer time to be active in the body. But really importantly, it reduces the major problem with doxorubicin is the cardiac toxicity. Doxil isn't specifically targeted to the tumor. It's passively taken up by the tumor. But interestingly, the properties of Doxil mean that the distribution of the drug in the body is different to the naked drug. And what that does is it means that the liposome can distribute to the hand and feet causing a hand-and-foot syndrome, which is a side effect, which is specific to the liposomal form of doxorubicin. Second example is called ONIVYDE. It's a PEGylated liposomal drug called irinotecan, which is another -- it's basically an inhibitor of DNA division in cancer cells. It was first approved 10 years after Doxil to treat second-line pancreatic cancer, which, as you all know, is an incredibly difficult to treat tumor. Interestingly, though, first approval in second line. But 10 years later, after many, many different clinical studies, it actually got extended approval to treat first-line metastatic pancreatic cancer, that's cancer that spread, in combination with the chemotherapy regimen. So continuing to expand the utility of the drug and also the revenues from the drug moving forward. But again, just to note, ONIVYDE is also passively taken up into tumors. And so you can see here that there's scope to improve upon these, if you like, first-generation nanomedicines with, for example, targeting to a specific tumor type. Okay, so on to Nuvec. So Nuvec, I'm sure you're all aware is what we call a smart drug delivery system for siRNA. These images here are our Nuvec images so specific to our technology. We described Nuvec as a unique mesoporous silica nanoparticle with a hollow core and external spikes. So I'm just really quickly going to just take you through these figures. So the first one on the left just shows you a high-resolution image of what a Nuvec particle looks like. You can see it's got a really nice size distribution, which is similar and side length are similar in each of the molecules. If you go to the middle image, what you see here is a slice through that Nuvec particle. You can see it's hollow in the middle. And then in the last image, what we've done is we've taken those spikes and then that's a 3D reconstruction so we can see and we can measure the size of the spikes on the particles. And this is -- I'll come on to this incredibly important point. So when we think of the key features of Nuvec, one of the really important ones is called functionalization. What does that mean? It means we can add on a number of different modalities to help us with things like targeting. So you can see those modalities on the left-hand side. So that can include small molecules. That can be small molecules for therapy or small molecules for targeting. We can add antibodies or fragments of antibodies or we can add small peptides, for example. And then really importantly, we've actually already functionalized Nuvec for targeting. This was in the recent study in inflammatory bowel disease, where we use Mannose to target to a receptor on a macrophage that we have in the IBD mouse model, and I'm going to show you one slide with some data from that model shortly. So functionalization is a key feature of Nuvec. Second very important feature is these particles have a very large surface area. So to try to put that into context, if we take something like 2 grams of our Nuvec, actually the surface area of that is equivalent to a basketball court. And if we look at the surface of Nuvec compared to, for example, a non-spike, so we call that smooth particle of an equivalent size, we've increased the surface area approximately tenfolds. That's important because that really increases the amount of drug that we can load onto the Nuvec particle. So this is data from a study that we conducted with our collaborators at the University of Queensland. Incredibly important proof-of-concept study because it demonstrates 2 features of Nuvec. One is the oral delivery, and secondly is the targeting directly to a cell and immune system that we call a macrophage. So here, we have Nuvec loaded with dual cargo so siRNA and mRNA that Mark outlined to you. We have the plus and minus models that we functionalize the molecule with for targeting purposes. And then we administer this orally in a mouse model of inflammatory bowel disease. And then we look at markers of inflammation in the colon. So on the right-hand side of the graph, if you look at the -- we're measuring a molecule called TNF, which is a marker of inflammation. You see it's very nicely upregulated when we induce the disease in the mouse. That's TSS in the red. We can knock down that level of inflammation with dual-loaded Nuvec. But if we add dual-loaded Nuvec with [indiscernible] to target to the specific cells that make the TNF, you can see we have a very significant reduction in this marker of inflammation. So proving the concept we can orderly deliver and that we can get efficacy in a mouse model. So just I'll go through these slides quite quickly but happy to take questions after. So Mark mentioned this endosomal release. So not only do we need to be targeted to the cell, we need to release the cargo inside the cell. In the middle image, if you just focus on the bottom right, in red, you can see that's the delivery of our cargo to the cells, if you can see there's a uptake green staining, which is a marker of the rupture of the endosome. And the graph on the right-hand shows that you get a very high amount of endosomal rupture when you deliver the cargo after 24 hours in a cell. Another really important feature of Nuvec is the stability not just of the Nuvec particle but the ability to protect the cargo that's attached. I mentioned to you that within the inorganic group of nanoparticles. So silicon, the silicon-oxygen bonds are incredibly strong, and that gives you resistance to degradation. It could be important, for example, in the guts where you have a very acidic atmosphere. So if you look on the graph, what we show here is a control with an agent called lipofectamine. It's a lipid agent that's used to take DNA into cells and we compare that with Nuvec, so these are both carrying a DNA cargo. If you look at the bottom panel, we add an enzyme that we know can degrade the DNA. And if you see in the left-hand column with lipofectamine, the cargo is almost entirely degraded, that's the DNA, whereas on the right-hand side, you can see that Nuvec, the DNA loaded onto the Nuvec spikes is protecting the cargo from degradation. Okay, last slide. So this is a really important slide. So summarizing the key benefits of Nuvec. So we're [indiscernible]. So I'll just speak through the slides. We're competing the key benefits when we compare with both what we call AAV viral vectors. Viral vectors in the middle and then in the right-hand side with lipid nanoparticles. So there's some key points that I want to pick out. And then again, we can discuss this after the presentation. We know that Nuvec has the capacity to carry multiple different loaded nucleotides, both RNA and DNA, whereas viral vectors and lipid nanoparticles both have a significantly limited capacity to do so, okay? Now in terms of cell targeting, I've already shown you one example. We know we can target Nuvec to specific immune cells. And whilst you can have some degree of targeting with viral vectors and lipid nanoparticles, we believe that there are other issues, for example, and the fact that viral vectors can promote an immune response in the body. Manufacturing, we know that both viral vectors and lipid nanoparticles are expensive to manufacture, whereas we believe Nuvec is relatively straightforward and certainly very scalable. The main points. And then the last point that I'll just mention is the fact that we do not have any issues with our IP, whereas the lipid nanoparticle field is really covered with legal disputes over who owns what and the ability to get novel IP in that space is very difficult. And there are, as I mentioned, some significant regulatory hurdles in using viral vectors in the body. So some really key and significant commercial advantages to developing Nuvec to deliver RNA compared to viral vectors and lipid nanoparticles. So with that, I will pass on to Nigel.

So thank you very much for taking us through that. I'll just go through a little bit more about what we're doing over the next 12 months. So as we build this commercial case for Nuvec, we're going to be reaching certain key milestones as we go through this program, and that does 2 things. It demonstrates to the industry why Nuvec is important and has certain advantages, but it will also build the steps and the value of the company. People should see that when we hit these milestones, that it actually means something for the conversations that we're underway with different partners. So Fiona has talked through some of those key benefits. And I just wanted to surround a little bit about -- so what does that mean? So it's all very well. We can talk about oral delivery. We can talk about endosomal release on the science side. But what does that mean to people and why is that important? So let's take oral delivery first. There's no orally approved siRNA delivery product out there. And having more effective localized treatment in the GI tract is really important. At the moment, if you want to treat IBD, for example, you inject something. You inject an antibody that knocks down TNF alpha into the body, and then it's got to get all the way through the body and end up in the gut. If you can actually orally deliver it and get it straight to the gut and actually have localized and effective treatment, that's a huge benefit to people developing products in this space. Mark was talking about endosomal release, and lipid nanoparticles have very low endosomal release. So if you can get better endosomal release, your drug can be far more effective and a lot less of that drug is actually needed. So if there are potential side effects of the drug, then you can have less of it and more effective delivery of the drug. When you have high loading, you get more drug on each of the particles, so that's both better for the patient. And it also allows target proteins to be suppressed in those cells for longer. If you only have a small amount of drug in there, it's only going to have a small response. You want that suppression, that silencing of the gene to carry on for as long as possible. The dual loading element actually means you can actually put 2 or more drugs onto a particle, and really importantly, you only need one toxicology package. So that significantly reduces the amount of R&D work and the costs involved in taking a product forward. CMC manufacturing is, again, really important. We've shown that Nuvec is scalable, sterile and has a reproductible process. Without those things, people are not going to partner with us because they want to know that when we finally get to a product, it's going to be easy to make. The targeting element, as the team has said, is very, very important. It's a bit of a holy grail for RNA therapeutics. So we don't just want drugs going to the liver, which is where they currently are because people are using lipid nanoparticles and that's where lipids go. Being able to target specific cells, specific organs means you can actually deliver the RNA to that cell rather than having going around the whole body. So that's where oral delivery comes in. It's a form of targeting because we're targeting the gut. And then we have specific targeting agents within the gut as well, showing that certain cells are targeted. Toxicity is also really important. You don't want high toxicity at the therapeutic doses. And we believe if you don't have the toxicity, then we're going to have better tolerability than both lipid nanoparticles and viral vectors. So these are all really key benefits. But the other thing that's also really important is we have to be able to demonstrate the pharmacokinetics and the biodistribution of the Nuvec system because we need to show that it's suitable for going into clinical studies. So all this work is a program that Fiona is putting together that we will be releasing information as we go through these, hitting these different milestones, showing that we are actually hitting these targets for our development and hopefully increasing the value of the company as we go through that program. And that will allow us to, we think, both our strategic near-term and long-term goals. Firstly, securing partnerships and collaborations with different organizations and ultimately building our own portfolio of therapeutic assets. So we do believe Nuvec is a transformational opportunity and it can create significant shareholder value going forward. So just to summarize where we are. So we're operating in this rapidly growing RNA therapeutic market. It's already big and it's going to be much, much bigger and carry on growing as the years go on beyond '28. But as Mark was pointing out, developers in this space, people developing RNA drugs still face significant challenges, both in manufacturing and delivering the drugs to the right tissue. And Nuvec can step in and achieve those aims. So our delivery platform has been designed to solve those problems, and we believe it's got the potential to really revolutionize RNA delivery and can become a delivery platform of choice for the industry. And what we're doing now is we're focusing on generating the marketing data across our platform to allow us to really secure our first significant commercial deal under that partnership approach using the Nuvec platform, which will be a major inflection point for the company. So we believe that we are very well positioned now to deliver some long-term significant shareholder value, both through developing our platform and also through a pipeline of RNA therapies. So that's where we are today. And we've had a few questions pre-submitted and some that have come through today, so I'll just read out a couple.

First one, which I'm going to hand over to Mark. What therapeutic value does dual loading provide and which indications do we believe are going to benefit most from this capability?

Well, thank you, Nigel. I think the key thing is we live in a genomic world now. So we can -- genomes are being sequenced all the time. Thousands and thousands of genomes will be sequenced. We now know what the genome looks like for lots of different individuals. We know there's 30,000 genes or whatever. The simplistic way to approach drug discovery is to target one specific gene or one specific gene product. But it's much more complicated than that. We all know that gene products and genes interact with each other. And it's perfectly logical now to try and target more than one thing at the same time. It's just really difficult to do that. I think the therapy areas which would benefit most would be -- I mean, clearly, things like infectious diseases. If you're trying to inhibit things like HIV, you use a cocktail of drugs to try and prevent escape from resistance of the virus or of bacteria away from the drug. So hitting them multiple times is one obviously area. There are other areas like cardiovascular and cardiometabolic diseases where you have a complex interaction with all sorts of different gene products. It would be logical to try and target more than one thing at the same time to change triglyceride synthesis or LDL or whatever. And another obvious area, and I could pass this on to Fiona, is oncology is that we are -- there are -- all the main companies are working on multiple drug targets within cancer, and it's an obvious thing that we could do here. We could take siRNAs, which are relatively -- as I said, relatively straightforward to design new ones and load them on to Nuvec. You could load 2 or 3 at the same time. And it does appear that -- and this is a technical point is that when it comes to silencing, you use one drug to silence one particular gene. If you put in multiple different siRNAs, they don't seem to block each other. They don't compete for each other. They all seem to work. So if you put in multiple drugs at the same time, they all seem to do what they're supposed to do. So there is great potential for hitting multiple targets at the same time.

Okay. Thank you, Mark. A question again. How are we prioritizing target partners for the Nuvec platform? And are there any discussions currently underway? So I'll take that one. So there's 3 main categories of partners that we're looking at talking to. The first is the biopharma companies, those that have their own nucleic acid therapies and compounds. And they are looking for improved delivery systems because they may well have come across issues where existing systems that they're using aren't working for them. The second group of people are other platform technology companies who are interested in expanding with complementary delivery systems that they're already working on. And finally, we're looking to talk to major academic and translational science groups focused on preclinical exploration. There's a lot of people out there that have got a very strong credibility in the industry. And if we can get collaborations with them, it will help in that platform advancing stage and improving our credibility and foothold in the market. And we're currently in early-stage discussions with several potential people, but the focus there is on building the technical due diligence so that we can advance those conversations through to a partnership deal. Another question, one for Fiona this time. Will N4 Pharma remain focused on inflammatory diseases? Or do you anticipate expansion into oncology, rare diseases or infectious diseases?

Yes, absolutely. We're working on other indications that we can go after right now. Oral delivery gives us the opportunity for a proof of concept. Within oral, of course, we can think outside inflammation as well and we can think of, for example, oral tumors. So one of the things we're thinking about right now is esophageal cancer, which has an incredibly high unmet need. There's not really much to treat that. The other one is a tumor called GIST, which is a gastrointestinal stromal tumor. There are small molecules to target that but resistance always is an issue with small molecules and you can get resistance within months to years. So being able to come after the resistant genes with an siRNA approach is something that we're really interested in. But we're also not only thinking about oral delivery. We are also exploring other methods of delivery that will include intravenous, intratumoral, for example. But we have to start right now by just making sure we finish the job, if you like, on the IBD modeling proof of concept. And then we really do want to probably work with the groups that I just mentioned, those academic experts in thinking about how we deliver outside of the gut.

Okay. Thank you, Fiona. I think that answers some of the other ones when people were asking about how do we plan to go beyond the gut, so I think you've answered that one as well. We have another specific question, which I think is interesting, Fiona. What size distribution of nucleic acids do we think we can deliver?

Well, I mean, the early work that was done with the academic lab in Queensland, of course, was working on plasmid DNA so that's a full plasmid, that's a full DNA sequence. We've delivered mRNA, full-length mRNA of IL-10 in the current IBD module. And now as Mark said, we've been focusing now on siRNAs, which are much shorter of up to 25 base pairs in length. So the beauty of the spikes is that you can actually almost wrap a large plasma DNA or mRNA around the spikes. And we've shown that in some of the, what we call, the topology work that's been done. So it seems like we can go the full range to very small siRNAs right up to full-length messenger RNA and plasmid.

Yes, excellent. We're coming to the end of our hour now so we've just got one other question that's just popped in today. So there are certain cancers that do not respond to chemotherapy like kidney cancer, for example. And the way those are treated, the most targeted therapies and immunotherapy are the frontline treatments beyond surgical intervention. Is Nuvec a technology that's going to have the potential to enhance the effectiveness of these treatments?

Yes, that's really good question. So the key point is one that Mark made in the beginning is that with something like an siRNA, you can go after so many different proteins in the cell such as transcription factors, which are often oncogenes that we can't go after with many of these drugs. So in kidney cancer, what we're referring to is we have tumors that we call cold tumors, so they don't respond to the immunomodulating agents that are out there like the PD-L1 antibodies that many people have heard about. So if you could actually come after a protein that, we call it synthetic lethality. So you need one protein to be switched off before another one works effectively. If you could have that type of approach in something like a kidney tumor, then absolutely you can enhance the effectiveness of current chemo and IO drugs.

Great. Well, I think we're at the end, just gone past the end of our hour. So I just wanted to thank everybody for attending this morning, for putting in some questions both before and during the session. And hopefully, we've given you a good overview of the company, those that know us before, but those that are new to us as well and why we think we have significant potential to move way beyond the valuation that we're currently at and ultimately build a really strong successful company in the RNA therapeutic space. So again, thank you very much for joining us today, and there will be a copy available and we'll get it on our website, et cetera, in due course, and we'll answer as many questions as we can that we weren't able to go through today. Thank you, everybody.

That's great. Well, thank you very much for updating investors today. Could I please ask investors not to close the session as you'll now be automatically redirected to provide your feedback and all the management team can better understand your views and expectations. On behalf of the management team of N4 Pharma Plc, we'd like to thank you for attending today's presentation, and good morning to you all.