Hi, good morning, everyone. I just want to say, I'm not here to announce that I'm going to the, I'm a Celebrity, Get Me Out of Here. I wanna quash those rumors straight off, okay? Thank you very much for coming and attending the Capital Markets Day for hVIVO. The company formerly known as Open Orphan. I really appreciate that you guys are really busy, and you've taken the time out to come and listen to us. Today is really about the company, so I'm not gonna be doing too much of the talking. I think it's better to look under the hood a little bit of hVIVO and see what we actually do and who are the people who do the work. I think that from that point of view, hopefully you'll gain some more insight into the company than you may maybe have previously had from me talking to you for 20 minutes or the CFO talking to you for 20 minutes. I'm Yamin Khan. I joined as a non-executive director of Open Orphan back in October last year when Cathal Friel, the Chairman, invited me to join the board. One of the first things he told me was that he hated CEOs and I had no ambition to be a CEO. Four months later, I announced myself as a CEO of the company. The share price plummeted on the same day. Not all down to me. On the same day, Vladimir Putin decided to invade the Ukraine, so it wasn't a great day for anyone really. Since then, thankfully things have settled down. We've only had, what, four new chancellors, I think, to date and three prime ministers and, no, sorry, yeah, two prime ministers, and a new king. On the upside, I've been informed that we only have two more chancellors left till Christmas, so I think we're good to go. Today's agenda really focuses on the company overall. I'm gonna focus a little bit on the overview of the company, but then I will hand over to the very talented Andrew Catchpole. He's our chief scientific officer, who's been with us for over 10 years, and to be honest, he's been overseeing the majority of the challenge trials we have been running. He'll be able to give you on how we do challenge trials, why we do the human challenge trials. After that, we have Douglas Thompson from Pneumagen, CEO of Pneumagen, who are our current customer. Pneumagen are a fairly small biotech company working in influenza and going great guns. You know, I think it's good for you guys to hear why does a customer come to us and ask to do a challenge trial, for one. Then secondly, you know, why do they choose hVIVO as a vendor, a partner for them. After the break, we have. It's a great pleasure for myself to have Professor Peter Openshaw here, professor of experimental medicine at Imperial College London. For those of you who are not aware, Peter is very highly known within the academic circles on challenge trials. I think a key message you need to kind of understand really is that a lot of the work that we do for commercial companies is really underpinned by the research that happens at the academic level, conducted by people like Peter. Based on that, we actually, you know, hope to find new targets, new antivirals or vaccines against viruses. It's really great that Peter is here to kind of give his take on human challenge trials. We will have a fireside chat to talk about the impact of the COVID pandemic on the challenge trial market. After that, Eglė will talk about how we actually go about selling hVIVO to our customers. You will effectively get a sales pitch as if you were a biotech or a pharma company, and how we sell the challenge study market. You've noticed I've said challenge trials more than hVIVO, and that's intentional. Our strategy when you go out to our customers is not to sell hVIVO as a company. It is to sell human challenge trial as a concept to develop their drugs much more faster and less expensive. Because we know that if we're able to convince a customer to conduct a challenge trial, we are the world leader in doing human challenge trials. They'll come to us. It's not about saying how wonderful hVIVO is. It's more about showing the customers the benefits of conducting human challenge trials, okay, in their drug development cycle, and then saying, "Okay, once you agree to do a human challenge trial, well, we are the world leader in that." Stephen Pinkerton, sitting here, he's our new CFO, joined recently in the CFO role. He's been with the company for a number of years, and he's gonna give you a brief outlook on some of the key financial performance metrics. Finally, we'll have some closing remarks, and then we'll have lunch, which I know why you're all here anyway. Who are we? We are the world leader in human challenge trials. This is not something we say lightly. I know a lot of companies use this in a subjective manner that we are the world leader, but we are quantitatively the world leader in the sense that we have more challenge models, in that we can conduct challenge trials in more indications than anyone else. We have conducted more challenge trials than anyone else. We've done 66 human challenge trials to date. Our next competitor that as far as we know have done three or four challenge trials, okay, per company. We've inoculated with the virus over 3,500 healthy volunteers. Our next competitor has done about 200 or 300. When we say we are the world leader, we truly are the world leader. There's nobody there who is dedicated to conducting human challenge trials. There's two other companies, commercial entities doing human challenge trials, but they are phase I units who happen to do human challenge trials. We are the only company across the globe focused on human challenge trial as its core business. Our roots go back to the 1940s. After the Second World War, the Common Cold Unit was set up in Salisbury, south England, which was really set up there to study initially the rhinovirus, the common cold virus. They were challenging healthy volunteer with the common cold and then observing them and see how the common cold progressed within those volunteers. Two of the leaders in the Common Cold Unit in the late eighties established the company known as Retroscreen, which rebranded into hVIVO in 2015. As you all know, Open Orphan acquired both hVIVO and Venn Life Sciences in 2019, and then following in 2021, we spun out Poolbeg to a completely new independent entity. You know, recently, I'm sure you've seen the news, we've now rebranded ourselves back to hVIVO. hVIVO has always been the operating brand for us, okay? All our customers, all most of our employees, all our academic partners, all know us as hVIVO. I think the biggest impact of the name change is for people like yourselves, investors and shareholders, and the people associated with the markets. The key thing for us is that we are creating a market. People ask me, "What is the market size of the human challenge trials?" It's very difficult to measure because every time our scientists, like Andrew, speak to our customers, they're trying to convince them on why a human challenge trial would benefit their product development cycle. This is the management team, so I'll quickly introduce some of the key people here. Starting from the left, we have Stephen Pinkerton here, who took on the role as CFO very recently. Eglė Pavydė, sitting here to my left, has joined the business development team, so we've increased our sales team as we are addressing a bigger market now. Adam French is here. He's heading up the clinical operations, and he will be taking people around a tour of the facilities after lunch. If any of you are, I think some people have already signed up, but if you're interested in having a look around the screening facilities and the laboratories and so on, please let Adam know. He'll be more than happy to add you to the tour. Andrew Catchpole has been with us for over 10 years, and he is the CSO of the company. I know you all guys love numbers, so I thought I'd start off with a slide on the numbers. We have a very strong financial footing, okay? We are projected to hit GBP 50 million of revenue this year. We're still lined to hit between 13%-15% EBITDA margin, and as of beginning of September, we had GBP 20 million in cash. I think on any sort of measurement, I think we have a very strong financial footing right now. We also believe we are really well-positioned for future growth. We had GBP 80 million of contracted order book. You got to remember that this order book includes clients, only includes clients that have contracted and have paid the upfront payment to reserve their slots within our quarantine facility, okay? That results in over 80% of the 2023 revenue already being contracted. In fact, some of the revenue for quarter one 2024 is already contracted too. We've never had this length of transparency going forward with regards to potential revenue recognition. One of the key things for me, especially that I like, is that four of the top ten pharma are key partners for us right now. We're doing repeat business with these customers. That gives us a lot of confidence because if the big pharma keep coming back to us again and again to do human challenge trials, we must be doing something right. They're getting good benefits, good return on investment on the money and the time they're spending on doing human challenge trials. As we look forward to our human challenge trials, we know that the size of the human challenge trials is increasing. People are now looking to get more out of the data from human challenge trials than ever before. The average size right now of a typical human challenge trial goes between GBP 5 million-10 million, and the great thing for us is we aim to recognize the revenue under a 10-month period. It's good for us that we can recognize the revenue. It's good for the customer that they can get efficacy data, in other words, whether the drug is effective or not in their target patient population under 10 months. If they ran a field study, there's no way they will be able to do that in such time frame. Andrew will go into a bit more detail about that. We're also future-proofing ourselves. We've added new screening facility in Manchester, so now we can screen up to 1,000 healthy volunteers every week. We've added new models already this year, so we have malaria that's already announced. Next year, we are looking to announce at least two new models, including the Omicron model. We're also adding new revenue streams, okay, based on the current infrastructure, okay. We're not adding any more resources, any more infrastructure. Based on the people we don't put into human challenge trials, we're looking to allocate them into field-based phase II, phase III trials. The key thing for us is the FluCamp branding that we use to ensure we meet our recruitment targets. Strategy for growth going forward, both on revenue and also on EBITDA margins. We talked about the new revenue streams with the current infrastructure. With the increase in volume of work, we're gonna increase our efficiency and improve our EBITDA margins. You will already see this from last year to this year and hopefully next year as well. We are building a library of challenge models. It's really key for us that we continue to keep on top of that. We don't want to rely on one indication for the rest of the time. We will continue to build a new variety of challenge models. Influenza, for example, is not one challenge model. Influenza itself has different variants, and each variant is a challenge model in itself, and that's something we will continue to build on, both at an opportunistic level, but also at a strategic point of view. Finally, at some point in the future, we will potentially be looking to open a second challenge unit ex U.K., potentially say maybe North America, but that's something in the books. My personal goal when I joined the company was to build the backlog. I felt our backlog was too small for us to have a healthy, sustainable growth in revenue. We've got to a stage now where we have good backlog, we have good operational team able to execute and recognize the revenue from that. Okay? Stop being a lumpy business and this volatility that we've seen historically. Okay? Once we have that sustained growth in revenue and EBITDA, we can then look to expand and potentially go into M&A activities. The market dynamics are very attractive. Clinical trials are generally increasing mainly because of COVID, but especially vaccine trials against viruses and antiviral medication. Okay? We've seen year on year increases in the number of clinical trials taking place. The number of antiviral and vaccines against viruses in preclinical right now is more than it's ever been. I think Ed, sitting somewhere here, Ed has projected that the clinical trial market will go up to GBP 700 million in around five, six years. We will see this growth in the market. I think when you see these numbers and you look at our future projections, you might say maybe we are potentially underpromising. I'm okay with that. I think, you know, people might say my projections are a little bit boring, but as long as we are able to deliver what we're promising, that's the key goal for me at the moment. One more point. If you look at the key pathogens that are currently being researched with a number of products, you know, the ones in bold are where we have active models right now. This is where if you look at some of the other indications, not every indication is suitable for a challenge model, but as we move forward, we'll continue to expand on those. I will now hand over to Andrew Catchpole, our Chief Scientific Officer. Thank you. Thank you. I'm delighted to be here today and to give you a little bit of insights about how we actually run challenge studies. Let's start with the basic question, what do we really mean by a challenge study? The definition of a challenge really is the deliberate exposure of humans to a known pathogen. Conversely, what happens with traditional field trials and antivirals is that you have to recruit people who become infected in the community. That's natural exposure or a field trial. What we're doing is we're recruiting typically healthy individuals, and we're deliberately giving them the disease. That's really what we mean by a challenge study, is that we're deliberately exposing them to the pathogen. It's not a new concept, though. Even though it may not be a household name, challenge studies, and people don't. Doesn't roll off the tongue and you know what we do. It is really an old concept and has been used for many centuries by medicine actually. In this, I just got here some very famous examples on this timeline. Edward Jenner, way back in 1796, did a challenge study of sorts where he was testing for smallpox. He famously gave a boy, James Phipps, he gave him cowpox and then challenged him with smallpox and proved that he could prevent him from getting the disease. Very early concept of vaccination and challenge by giving someone exposure to something they think is going to protect them and then exposing them to the disease. Even way back in 1796. We've got rabies being looked at by Louis Pasteur, yellow fever in the 1900s, Walter Reed, and even influenza, which wasn't even discovered what influenza was as a causative agent until the 1930s. In 1937, it was discovered that if you keep passaging it and growing it in eggs and then take it out, put it in another egg, put it in another egg, and keep doing that, you actually weaken the virus. You can take that virus, give it to a person, and then challenge them with something natural, and then you've actually protected them. It's the first concept of how to weaken a virus and turn it from a pathogen into a vaccine. Way back in the 1930s. As Mo mentioned, in the 1940s, the Common Cold Unit started up in the U.K., which was totally designated for doing challenge studies and in a very constructive and ethical manner and actually ran for many decades. This has really underpinned in this country a really strong history of doing challenge studies, which is totally unprecedented worldwide. I think this is actually massively contributing to hVIVO's success because before you do any clinical trial, you have to go to the ethics board and the MHRA. You submit your package and say, "I would like to do this trial." The regulators look at it from a regulatory perspective. Do you have everything? Do you have all the safety data to be able to go into humans? Every clinical trial, and challenge studies are no exception to that, is looked at by an ethical review board. It is ethical to do. Of course, we're giving people the disease, so this is a slightly different concept to most people. In the U.K., we've got decades of experience of our ethics committees looking at this. The concept of giving someone a disease to actually test something is not new, and that really has a lot of advantages. Some other countries where the ethics review boards have never come across this concept gives a lot of barriers to them to even be able to start doing challenge models and get the permissions to do them. I think this long history in the U.K. is really the underpinning of why we're successful here. What do we really mean, and how does that actually work, though? This schematic then describes essentially what we're doing. In stage one, this person standing up is depicting that they're healthy. They're completely healthy. We're recruiting them, and we're medically screening them. It's one thing to say you're healthy, but let's test and have a look. We have a look at their blood, we look at their lungs, we look at their heart. We make sure they are truly healthy. Then if they meet all our eligibility criteria, we recruit them onto the study, and then we inoculate them. They come into our challenge unit, which is a dedicated challenge unit, so it's an individual room. Think of like a clinicalized hotel room with an en suite bathroom. These individuals are not leaving that room. All their food is brought into that room, all the medical staff go into the room, and the bathroom's there. If they need to be quarantined for two weeks, they're literally in that room for two weeks. A lot of the skill set on the recruitment isn't just are they medically fit, but from a mental health perspective, do we think they're going to be able to be in that scenario for two weeks? It's a very specialized type of clinical trial, and our expert team, this is why we are dedicated to doing challenge studies. This is why we believe we have an advantage over our competitors, which do the odd challenge study amongst doing all types, other types of clinical trials. 'Cause it's a really big skill to be able to identify and to also then keep the volunteers engaged and able to stay in that quarantine. 'Cause it's not a locked door. It's not a prison. They are free to leave. If they do leave, of course, that impacts the scientific integrity. We have very few people leaving, and it's always, like, for a family emergency outside. It's a big skill set from our clinical staff to be able to take them on that journey. Once we've inoculated them, we can then follow the disease course. They gradually get sick until depicted here by the person in the bed. We're making them sick, and then we're recovering them, and actually, they only leave the quarantine when they've completely recovered, and they're not having any symptoms anymore. We're literally following the whole disease life cycle. Before they're sick, until they're sick, and then recovering them, and then they can go home, and then we typically call them back about a month after we gave them the virus just to double check that they're truly back to full health, and then we can discharge them from the clinical trial. That's what we mean by a challenge study. Now, if we think of this green line is like the placebo arm. If we're doing a vaccine study, we typically have two arms. Some people get the vaccine, and some people get the placebo. This is what a vaccine would, we'd expect to look like. If a vaccine is efficacious and doing its job, it should truncate the disease. If you get sick, you get sick only with mild symptoms, and you only have it for a short period of time, as depicted here. You clear the disease much quicker. That's really what we're looking for a vaccine. It'd be lovely if the vaccine stopped you getting the disease entirely, but that's typically not realistic. Most vaccines are significantly reducing the disease burden as opposed to stopping you get any disease at all. As Mo mentioned, we have a number of different challenge models for different pathogens using essentially the same type of skill set but for different viral pathogens. Here, we've got here the number of clinical studies that we've run for these different pathogens. The main pathogens we've worked with are RSV and influenza. I know Peter's going to talk to you a little bit more about how much of a disease burden RSV really is. We've run similar numbers on both of those, so 27 and 31 clinical studies. Also rhinovirus, which is the common cold virus, but actually has a really big impact on asthma exacerbation, so it has a very significant disease burden in its own right. Of course, SARS-CoV-2, we've run a clinical study in that, and now we're developing an Omicron model and malaria and going into asthma and COPD. I mentioned to you that challenge studies is where we're deliberately exposing someone to the pathogen and having a healthy volunteer. The converse of how it's traditionally done is what we're calling field trials, where you recruit someone, you give them the vaccine, you send them out into the community to live their normal lives, and then only when they become exposed to the pathogen can you actually tell anything about the disease whatsoever. I've just got some comparators here about why we believe challenge studies are so effective in testing vaccines and antivirals. You can see, you can do them all year round. Now, if you think about influenza, we all know you have flu seasons. Now, if you're trying to do a vaccine study, that means you need to recruit people, and you can only test if it's working when there's flu. You chase a disease around the globe, they have to have hundreds of different sites, and they can only do flu in the northern hemisphere in the flu season, in the winter. In the summer, there's no flu around, so they can't do anything, can't learn anything about their vaccine that time. They can only start when there's a flu season. Now, because we're giving them the virus, we can conduct these type of clinical studies all year round. If someone comes to us at Christmas and says, "I want to do my clinical study in six months' time," we can start in the summer. It's no problem for us. We can do them all year round. We have a lot lower numbers, which means you can do them a lot quicker. Our duration, so the period in the quarantine from the first volunteer to the last volunteer in a clinical trial is typically only about three months. You compare that to field trials, and they're typically over two years, and they're also at the complete mercy of how much disease is around in the community at that time. If we're talking influenza and it's a low flu season, then instead of two years, you're probably looking at three or four years. They really can't predict how long it's going to take to do the clinical trial because they're at the mercy of how much viral diseases are circulating at that time. We can completely control the timings. Of course, timings and time to market for a vaccine or antiviral is means massive differences to profits on the different vaccines as they come to market. A little schematic here to really illustrate that. On these two studies, on the left-hand side, we've got the challenge, and on the field trials are on the right-hand side. In these two illustrations, essentially what we're saying is, if this was a vaccine trial, you'd need to vaccinate way more people, so everyone in gray has been vaccinated. If we want to learn if a vaccine's actually working, you can only tell if a vaccine's working if someone actually becomes exposed to the virus. The majority of people on a vaccine field trials go about their daily business but never become exposed to the virus in the community, so actually, you can learn nothing from those individuals whether the vaccine's working or not. Whereas on our trials, everybody is exposed, so if you can only learn if a vaccine's working from the infected individuals, you can see how challenge studies are so effective. In the pink here, I've illustrated the number of infected individuals, and you can see you get the same number of infected individuals in a challenge study as you do a field, but you start with a much less numbers of people. Some published examples of exactly that. Vaccitech is a biotech company testing an influenza vaccine. On the left-hand side is the Vaccitech numbers, and in the green on the right-hand side is the equivalent numbers we would need to do exactly the same trial and have the same number of people infected in a challenge study. You can see Vaccitech recruited 2,152 individuals but only got 58 of them infected. It's 58, not 2,000, which tell them anything about the efficacy. To get 58 people infected on a flu trial with our models at 69% infection rate, you only need 84 individuals recruited to your study. You can see the recruitment numbers are vastly different. You'll probably all be familiar with the Pfizer BioNTech COVID vaccines, of course, most of us have probably had one. On that efficacy trial, 43,000 individuals were given the vaccine, but of course, they were also given advice to stay at home and stop themselves being exposed. Most of them were not exposed to the virus. When we look at the data, 170 people of that 43,000 became infected with COVID. Actually, the number of people where they learned about does the vaccine work or not was the 170, not the 43,000. With our COVID model that we developed with Imperial College, that had an infection rate of approximately 50%, so if we were to have 170 people infected, we would only needed to recruit 361. Very different leagues of numbers. You can see this is really the key reason why challenge studies, you can get efficacy data and understand if the products are working so much faster. Speed, of course, is so important when you're talking about preventing a pandemic or even just time to market. A little bit more detail now about how we actually do it. I thought this might be of interest to you. Of course, the two really key things about for viral disease, if you're trying to see if a product is working, whether it be a treatment from an antiviral drug or whether it be a vaccine, is you measure how much virus someone is shedding, so we can take a swab, we can do a PCR, and we can get a quantitative measure whether they're actually shedding any virus. Secondly is the symptoms, of course. The symptoms are actually self-reported by our volunteers. We give them a symptom diary card, and we ask them to complete that at very structured times each day, so three times a day. On the right-hand side is an example of that. They would list all the potential symptoms you may expect. Runny nose, stuffy nose, coughing, malaise, tiredness, all of this is listed, and then they score themselves. If they haven't got that particular symptom, they would score zero. Then depending on how bad they felt that symptom was, they would score one, two, or three. Three being really quite bothersome, it's stopping me in my daily activities, whereas one, yeah, it's there, but I can just ignore it. We use that, and then we total up that score, and you can plot that score over time to track the disease, which is essentially what's been done in this type of graph on the left-hand side. Another thing we do is, we know we're all familiar, when we get a really bad cold, we're blowing our noses all the time. It sounds crude, but it's a really effective way of measuring how much disease. These people are in a quarantine room, so we're providing the tissues. We pre-weigh the tissues, we give them to them at the beginning of the morning, and we have the lovely job of weighing them when they come back. It's a crude but very effective way. If you can measure essentially the nasal discharge in that, it's very correlative to how much disease they've got. That's an example here on the left-hand side, where the people who got placebo, their nasal discharge is in the gray. As you can see, they were shedding a lot of nasal discharge, blowing their nose a lot. Whereas those who got an effective vaccine in the orange there, they were blowing their nose, but very, really they weren't having much nasal discharge at all. Going from quite sophisticated state-of-the-art PCR machines to collecting tissues and weighing them. It's not always a glamorous job. As Mo mentioned, we've got a lot of experience in doing this, and that's absolutely pivotal when we're trying to design these studies. There are very subtle nuances you need to understand when you're designing a challenge study as opposed to a normal field trial to make them successful. One way we do this is, 'cause we have a large body of data we've collected over the years, so the placebo data, so those people who didn't get an active drug but were still on a trial and exposed to the virus, we collect, and we pool them together, so then we've got a big body of data. By doing that, we can really truly understand what's going on and look at it in more depth. This is an example of that, where we've basically combined all that individuals' data, and on the left, top left here, we've got those who were given the virus, but they did not become infected. Now, although we exposed people to the virus, people have underlying immunity. We do not expect 100% of people we give viruses to get infected. Indeed, if they did, we'd probably be giving them so much that we'd be overcoming the immune response, and it'd be an artificial model. We're trying to give them the minimum amount of virus to actually cause infection, and then it's like it is naturally. The rest of the individuals who did become infected are just like you would expect when, you know, the wife may have typically a mild cold and the man's always got man flu. He's always dying, right? It's like my wife tells me whether I'm probably not shedding very much virus, but I always feel terrible. Hence people have a very different severe. At the bottom right, you can see those people, those bars are the symptoms that I talked to you about on the symptom diary cards. High bars means they have lots of different symptoms. They would be coughing, they would be sneezing, they would have headaches. The green is how much virus they're shedding. A good correlation between when they're shedding loads of virus, they've also got peak symptoms. As we move across, you go up to just mild disease. If we're then testing a vaccine and thinking about what we want the vaccine to do, but really what we're trying to do is to take those people in the red box, and if we can make them into the blue box and then turn their quite severe disease into a mild disease, then that's really a successful vaccine. You extrapolate that into what happens into flu in the community. If we can vaccinate the elderly and prevent them from going into hospital, but just make it a mild disease, then that's success. That's what we're looking for. This takes understanding this great body of data to be able to design those studies and get those endpoints exactly right, so that we are truly giving the efficacy of these products and not throwing out the baby with the bathwater because we designed the study wrong. Having this body of data is critical. When you do that, you can get great success. What we've got here is some studies which we're really proud of. These are a great breakthrough in RSV vaccines. Each of these studies have been tested by hVIVO. Starting off at the top, it was Janssen's RSV vaccine. In the middle, we've got Bavarian Nordic's RSV vaccine, and in the bottom, most recently, Pfizer's RSV vaccine. This is a classic example of what one often sees in this market, is that someone tests a vaccine like J&J here, and they sure saw great efficacy. In each case, gray is the placebo group. You can see they're showing great disease, and the colored one is the vaccinated group. You can see much lower disease. Up the Y-axis is more disease. You can see much lower disease. Each of these vaccines, very, very efficacious. J&J came to us. RSV has been a really tricky pathogen to get vaccines for. It's been studied for decades and very little success. This really showed the first glimmer of hope to the market. Then what happened is it ignited the market to then, "Okay, maybe this can be done. This is a challenge which can be done." Shortly on the back of that, we were then asked to test Bavarian Nordic's vaccine, and then Pfizer also came to us because their shareholders go, "Well, is your vaccine in development as good as J&J's, which is in the public domain?" It can create business when you have success as well. Most importantly, it didn't just give them the confidence to then take these products into the field. For RSV, it's very difficult to go into the field because you're typically trying to vaccinate the extremes of the age group, so these very young babies and also the elderly. They're difficult populations, you know, to put experimental vaccines to. You do want some confidence that your product's going to work, and that's what the challenge study can do. It meant that these products then were fast-tracked within their own organizations and prioritized. Importantly, this was also recognized by the FDA, and each of them got what we call breakthrough designation, which is a badge of honor effectively from the FDA, which means that their future clinical trials, their phase II and phase III, which are pivotal trials needed for licensure, they get fast-tracked reviewing of those packages. They can save many months on getting that product to market because of the breakthrough status, which was given to them because of the efficacy data from doing challenge studies. It has benefits for our clients later on as well. Last sort of data slide here, just 'cause I like the images and totally stole the technology from Peter and his Imperial team, so he's gonna go into this much more detail for you. What I've described to you is really our core business is helping our clients discern whether their products are efficacious or not. If it's a treatment, does it stop the disease and get you better? If it's a vaccine, does it prevent you getting ill or at least less severe ill? What we're seeing now is an increasing trend of our clients realizing that from challenge studies, you can actually learn so much more than those basic concepts rather than just looking at symptoms and just looking at the viral load. These people are in the quarantine. It's so easy to take samples over such a defined timeframe. You can learn so much about what the vaccine's doing to the immune response and also what the virus is doing to the immune response, and this is an example of that. Each dot is a component of the immune system that we're tracking over time, and as it goes up the Y-axis, it's differentiating that those who are infected look statistically different from those who are not infected. That's what this is showing. Over a very short time course of up to 57 hours, you can see we're able to discern different parts of the immune response, which are clearly differentiating from infected and non-infected, translate that to your vaccinated population, and it gives the clients great insight about how their vaccines are working and really at the molecular level. Excuse my voice. This is essentially an add-on revenue stream. They don't need to do this, but if they want to, it's an add-on revenue stream that we offer our clients to give them really great insight. This is important because a lot of vaccines work, but it's hard to demonstrate to the regulators exactly why they work in some instances. They are required, as they move their products forward, to get this sort of data to prove biologically how they're interacting with the body, and human challenge studies really enable you to do that quite elegantly. A new change that we've seen is what we're calling clients coming to us for end-to-end business. What do I mean by that? Well, typically, the historical model was our clients would come to us and say, "Can you test my vaccine? I know that you've got..." If we use SARS or COVID as an example, everyone's familiar with the variants. I know you've got the Alpha strain, but my product really, I really want to test it against the Omicron strain." Previously, what would have happened is, "Okay, I would have to use the Alpha strain 'cause that's what you've got." Now, that would alienate some clients because if their product is very specific to the Omicron strain, they wouldn't come to us because we can only test against the Alpha strain. As Mo mentioned, this is the same for all viruses. This is the way they evade immune responses, that they change and gradually have different strains. Similarly for influenza, we had a specific influenza challenge strain. Now, some products are agnostic, and they don't mind which strain it is. They work against all of them, and we have those clients. Some clients have products which only work against specific strains to ask specific questions. Now what we're seeing is clients coming to us and say, "You guys have got massive experience in doing challenge studies. You also make your own challenge strains, which is also a completely unique skill set. Our competitors don't make their own challenge strains. So can you custom-make me a challenge strain which matches my product?" That's what we mean by an end-to-end service. At the right-hand side where we would normally contract our clients, come in, test your product in the model we already have. Now we're contracting our clients on the left-hand side, where they're paying for the whole end-to-end process for us to collect clinical sample, this case, an Omicron sample, grow that up to a medical-grade virus and release it, test that virus in some individuals to understand how much we need to do, how much virus you need to give to cause infection, and then do a challenge study to compare their vaccines. Instead of us having to invest GBP 2 million to develop a new model, we're waiting for customer demand, and then they're funding this. It's not only a new way of getting expansion of models, it's also a massively higher revenue stream. You can see that demonstrated. On the right-hand side are some of what we've announced are three key clients here. You can see the value of these studies are much higher because of it, so GBP 14.7 million and GBP 10.4 million, for example. That's where we end it there. Thank you very much. Thank you, Andrew. What we'll do is we'll go straight into the next presentation, and following that, we'll have a Q&A session. Okay. I'm very pleased to introduce Douglas Thompson, a very Scottish name. He's a very Scottish person. You'll see when he starts to speak. He's the CEO of Pneumagen. He's had lengthy experience of being a CEO, a chairman, non-exec director, also a business development director. He's had successes previously with 4D pharma. He has an extensive network of people he can tap into with regards to bringing products forward. I think he is, I'm not gonna say it, but, you know, he's very frugal in the sense that he has a network of consultants he uses on and on rather than building a huge salary-based of permanent staff to run his studies. It's very elegant way of doing things. He's really here today because Pneumagen is a current client of ours, and I thought it would be good for you guys to hear why a biotech such as Pneumagen would want to conduct a human challenge trial in the first place. Secondly, why would they choose hVIVO? I have warned him to only say nice things about us for the purposes of this presentation. Douglas, thank you. I'm tempted to start with och aye the noo and so on. Happy to hear, and thank you to Mo for the kind introduction. I'm not sure whether you mean to say frugal or you mean tight. But we'll do our best. As Mo said, a little bit about Pneumagen at the beginning to give you some context for where we are is also the quid pro quo of coming in, presenting and saying nice things is that I get to say a few things about Pneumagen as well. Into why challenge studies. Why a biotech company such as ours would think about a challenge study as being the route forward for our clinical development program. From there, why did we choose hVIVO for the study that's running at the moment that we've already announced. As I said, this is the structure of the talk. Pneumagen, Neumifil was our lead program. We are undertaking a challenge study at the moment, and I talk about the design of that study in one of the slides. The challenge study model was the route for us to go. The next couple of slides are about Neumifil and Pneumagen. We were originally a startup from the University of St Andrews in Scotland, back in 2016. We were working on a broad-spectrum antiviral and not a vaccine. It's not a vaccine approach, though still the challenge model is adaptable to that sort of approach. When Andrew was talking, he was talking more about the vaccine approaches, but clearly antivirals and the type of drug that we're developing can also be tested in the challenge model. Our ultimate label is looking at prevention of exacerbation in patients with respiratory disease, but this challenge study is an important step towards that particular study, improving the output that actually can translate into humans, and what we've seen in animals happens in humans as well. I think I've jumped forward. We've got a very experienced team, very experienced board, a scientific advisory board. We've raised around about GBP 80 million of equity funding to 2022. We have a lot of IP, including owned patent families, and we have composition claims that have gone to grant. Neumifil, which is our lead program, is a broad-spectrum antiviral product. We're not constrained. Andrew was talking a lot about vaccines and how you have to match the antigen to the vaccine, and actually your challenge has to match. We don't have that issue because we're working on a broad-spectrum approach. We've shown data that works against flu, RSV, rhinovirus, and SARS-CoV-2 and coronaviruses in preclinical efficacy. We've demonstrated that across a number of different in vivo and in vitro systems. We've completed a phase I study, and the product was safe and well-tolerated. It's delivered intranasally, as you can see here on the right-hand side, and that study was run here in the U.K. as well. That was a phase I unit at HMR in London. I think I keep on pressing the button. We're now. We initiated the challenge study in August 2022. We're well into that now, and we're hoping to complete that in the middle of 2023 and have the full readout then. Why do a challenge study? We could have continued on. It's not actually required for us to do a challenge study ahead of doing a phase II in patients. We could have just gone straight to that, and missed out the challenge study. The market recognizes the value of challenge studies. That's the broader market, but also pharma, an ultimate acquirer potentially of our business, recognizes the value of challenge studies and what they can bring, quickly bring a proof of concept in humans. It mitigates the risk of later clinical development. We are going on to do a phase II in patients. That's what happens after this phase II challenge study. We can go into that with some confidence knowing that our product actually works, and we have efficacy in a population. When we go to phase II in patients, we're testing it in that population rather than does it work at all. It translates our preclinical safety and efficacy into humans, and it demonstrates we can look at drug mechanism of action. We can begin to look at how does our drug work. We have an understanding of that, but this challenge study gives us more information. Andrew again talked about getting that understanding of the virus kinetics, the virus, and begin to look at how our product may be working in that setting. We're doing a first challenge study. There's clearly future challenge studies and more, and Andrew didn't really talk to that. You don't have to do just one. You can go on and do another challenge study where you may be looking at different dosing regimens, different dose levels. You may also look at, you mentioned briefly, COPD, asthma, so there could be backgrounds here where you're looking at other disease backgrounds other than healthy subjects. The focus I know has been very much around healthy subjects. That's what our first study looks like as well, but you can go beyond that. Doing a CHIM, I mean, when we presented this to our board and said, "Why did we want to do CHIM?" Not all of them were familiar with challenge studies, and that is one of the challenges, if I can say that, of challenge studies. Not everybody's aware. Sometimes you talk to people outside of the space and you say, "We're gonna do a challenge study," and they say, "What does that mean?" You say, "Well, we're gonna infect people," and they think you're off your head. It does need a bit of education. You need to talk people right through, and some of the work that hVIVO were doing is important in that respect of giving certainty that challenge studies will work and deliver something of value. Recruitment. Mo and Andrew in particular talked about field studies. You know, you look at the difference in numbers of trying to recruit thousands of people into a field study. You can go quite quickly in a healthy subject challenge study. Our study is 100 subjects, so that's 60 on active and 40 on placebo. It's... Very quickly, we can get through that study and generate some valuable data. We might have to do a field study in the future, but we can go into that with some confidence that our product actually works. Even with 100 subjects, you can get statistical power, you know, into the thousands again, which you see in the vaccine-type studies, and we can get a meaningful outcome to our endpoints. One of the important points, and Andrew sort of touched on this as well, is you have certainty. You know when you've infected somebody. You know they're going to get ill, and you can follow them. You go into a field study, a lot of the people you're dosing, yeah, you'll get safety data out of them because they're not, they're being given the drug, but you're not gonna get any efficacy. They're basically dead to the study from a point of view of you being able to get useful data. We know we're infecting these people. We know the infection rate. We know what we should be seeing. Understanding of the infection kinetics and symptomology, we can begin to define our endpoints clearly because we know what happens on placebo. Also, if we see something strange happen, we can, from the experience that hVIVO will have, we can begin to understand whether that's drug-related or virus challenge related. Again, that gives us some clarity. We're also looking in our study at cytokine development as well because we can, because we know when these people are being infected, so we can take samples and we can look at that. That wouldn't be possible realistically in a field study. CHIMs do. I mean, this was talked about, I think, by Mo. There is a deep regulatory understanding here in the U.K. U.K. is, to me, the world-leading, probably explains why hVIVO were here, and hVIVO have probably been part of giving that experience. There's no doubt the MHRA has great experience in looking at challenge studies. I think Andrew also touched upon about ethics as well and beginning to look at the ethical background to doing challenges. If you go to the wrong ethics board, it's never seen a challenge study, so they'll go, "What the hell are you doing?" You know, "You're infecting people, and you're paying them," and all these problems begin to come. The U.K. has a very strong background in this space, and I think it will be one of the things that will have to be overcome as we move into different territories, beginning to explain why a challenge study makes sense, what the ethics behind that is. You know, I think we've shown here in the U.K. it can be done, and it can be done safely, and you can get useful data, but not every regulatory environment has that confidence in it, and the U.S. being, you know, one where I think there is more work to be done. Hopefully, as they see more and more challenge studies coming through, and that data is presented to them, that'll give the regulatory authorities, not the MHRA, more confidence in CHIMS and what they can achieve. There are multiple disease models. I talk about, you know, we're doing a healthy subject study, but again, Andrew and Mo have talked about the number of other disease models that we can be looking at. For all those reasons, it really makes you know, a really powerful argument to use that for a small biotech company. A little bit back into Pneumagen for a second and Neumifil. This is our study design, which again, we worked with the group at hVIVO to develop the study design and the synopsis. Again, I'll talk why hVIVO in the next few slides, but that was a big part of it. That knowledge of running challenge studies, what is feasible, what is gonna happen. Understanding of the placebo environment. You know, what's the infectivity data gonna look like and what sort of endpoints can we see 'cause we are looking at both infection rate and symptomology, and that's gonna be important to us particularly as we move forward in further development, understanding the symptomology is key. As I said, 100 subjects. We are actually using H3N2 in influenza, and we're giving both a single and a multiple dose in the study, so we've two active arms and one placebo arm. Everybody gets three doses. Some get placebo, placebo, and so on. This study is running at the moment, so I can't tell you anything that's going on 'cause it's all blinded. I'm sure it's going really well, and the guys in here might, if I put them up against the wall, may tell me something that I don't wanna know. But we'll get to the study next year, and we'll have the full data set. Coming back to CHIMs, and again, I think this was picked up particularly in Andrew's slides where he showed the RSV vaccines all being tested at hVIVO. There is a good acknowledgement within mid-cap pharma to the value of CHIMs. We see that, and that's important to us 'cause when if we as a selling company ultimately want to transact on our assets and our business, do they value the data that's been generated in the challenge study? The answer to that is yes. We've seen that again and again. J&J, Pfizer, it delivers proof of concept. It translates the animal data into humans. We can do dose ranging. We can do dose schedules as we're doing in our study. We can look at different doses. Interestingly, talking to a pharma company just recently, they were very pleased that we were doing a single dose in the study as well because they felt that was an important aspect to understand. You can use it to update vaccine antigens. You know, we've seen that in COVID and in influenza as we begin to go through that. I mean, much of the data slides that Andrew showed I think were vaccine-related, but you can test other things, monoclonal antibodies. You can test antiviral small molecules as well. There's big pharma recognition of CHIM value, and I've got one slide here, and Pfizer completed the acquisition of ReViral for $525 million, and that was largely based upon the CHIM data. They had gone into a phase II, a further study beyond that, but they weren't very deep into it, and it was largely around the CHIM data that the asset was sold. As I said, in the press release from Pfizer, it significantly reduced viral load in the phase II RSV human study. That was clearly a big part of why they put that price tag on the RSV study. This was said to me recently at BIO- Europe, the partnering conference just last week I think it was, "All roads lead to hVIVO." I thought that'd be an interesting point. That's both seen as how pharma sees it. They see it as being the premier challenge group in the world but also that the data coming out of it is solid and strong. When we come to present our data, because they're also customers and clients of hVIVO, they look at the data, and then they look at the results rather than starting to worry and have a discussion about the CRO itself. That's all challenge studies. Why hVIVO? I think I've kind of touched upon a lot of this already. We did a competitive bid process at the end of last year. We conducted site visits. We didn't just look at hVIVO. I'm sorry, Mo. We did look at somebody else. We did face-to-face meetings. We did desk research. We looked at the facilities and logistics. Just to pick up on one particular point, particularly that track record, I mean, I think Andrew touched upon this. We've talked about the number of studies done by other groups and how many people have actually seen the viruses. There is no comparison between hVIVO and others. I think Andrew also made the point, which I was gonna make, that a lot of other sites are sites that do challenge studies, but they do a lot of other things. It's not that they are so focused. They're not solely focused on doing challenge studies, and I think again hVIVO's focus on that gives it an advantage. We saw the strong capability of the senior team. We were very impressed. I won't pick out anybody here, but we were very impressed when we did meetings face-to-face with the team, you know, about their knowledge and the input to our study. This is maybe a slightly unusual one for us. No national barriers to supply. Our supply chain is all U.K. We manufacture at Fujifilm up in the northeast of England. Our clinical site for phase I was HMR in London. Our clinical site for phase II is also. Given all the turmoil there's been, that's probably was probably a good choice, but it's obviously not gonna apply to every company. MHRA regulatory submission, we've talked about that already, about the benefits of being able to work with a regulator that's seen a lot of challenge studies and, you know, isn't put off by the concept. Specialist challenge CRO, I've mentioned that. Multiple challenge studies conducted. There's a lot more than the H3N2 that I'm talking about here, but there's been seven studies conducted, as I understand it, in H3N2. They've got a good understanding of the infection. They understand what it does in placebo, so when we run our study, we add to that, but we also get the benefit of that depth of knowledge. Deep understanding performance of the challenge strain. Viral loads and such, well, I've talked about this already, about how we powered the study. We took up trade references from pharma, and this was a comment. They strongly recommended us, hVIVO, as our challenge CRO. That was not the same pharma as the previous one, so it isn't the same person saying the same nice things about you. A number of different pharmas all have very positive comments to make. That's it. Thank you for your time. Thank you very much. I think I would hire you to do all our sales pitches if I could afford you. All right. You've heard from our Chief Scientific Officer. You've heard from our current client. I think I'll open up the floor for any questions for these two guys. Thanks, Phil. Is that on? Can you hear me? Yeah. Morning, everyone. Edward Thompson from Lytham Capital. Thank you for the board, for your time today. I know you're very busy. Question for Douglas just on the competitors that hVIVO compete against. Was there any weaknesses that hVIVO had in their offering that you saw did give some competitive advantages to maybe consider other rival challenge study providers? Yeah. It's a good question. Mo wants me to answer no. I'm not even looking at him. I think one of the things that can be done is that if you wanna do a combined safety and challenge study, that's difficult to run at hVIVO at the moment because they don't run just safety studies and safety and tolerability studies. We did a safety and tolerability study at a phase I unit here in the U.K., but some other groups do offer you the chance to do a phase I study and then go straight on into a phase II challenge study as part of the same protocol. That, you know, is a potential area. Having said that, the gap between us finishing our phase I study and starting our phase II study was two and a half, three months. It wasn't a big impact on us 'cause we were able to turn around. Again, with the support of the regulatory team at hVIVO, we were able to get that study started pretty quickly. That, that's an area where I think there could be an opportunity. Offering essentially, you know, safety phase I data and potentially follow on phase II studies. You can do it right as the same protocol. Yeah You don't have to then resubmit to the MHRA. You can submit the whole protocol and say, "Right, we're gonna go straight on into. We do a safety readout halfway through the study for safety, and then you're going into the phase II study." It save you a couple of months, which, you know, can be important. If the FDA was probably more receptive to challenge studies and there was an easier path to use them for study data. Mm Regulatory packages, would the appeal from a company perspective be mainly to do a challenge study in the U.S. or maintain a challenge study in the U.K.? Yeah. I mean, I think the FDA is receptive to data once you've generated it. I think what's been the difficulty is actually running challenge studies in the U.S. I think the FDA has been more reluctant to actually sanction those type of studies. In fact, Mo may be able to talk to this, but I don't think there is a CRO now in the U.S. that's routinely running human challenge studies. I think that's probably more where the issue is. If you've got good data from a study, and you go to the FDA with it, I think they'll be receptive to it. I don't think that's a pushback. Having said that, you know, they like field studies, 'cause that's kind of where they are. Just to add to that. We've had clients which are U.S.-based, which have done challenge studies with us, submitted their data to the FDA, and the FDA have seen the value of it and actually asked them to do- Mm They want to do more further challenge studies before they go to the field to answer more questions. They are receptive and they even encourage expanding what you do with the challenge study. There's a slight difference of approving them to be done in the U.S. from them actually accepting the data. They're very receptive of the data, and there are regulatory agreements between the FDA and the MHRA about cross-fertilization and accepting the working practices as well. That does make that relatively straightforward. Thanks. Last question, then I'll drop out. Is it clearly one of hVIVO's selling points they point to is their volunteer network, the ease of being able to do recruitments. Yeah. How much was that an appeal, and how did you find where in the buildup of conducting the challenge study, the ease of finding patients and setting it up? I mean, it's any study, whether it's a challenge study or another type of clinical study, recruitment is normally the problem. It's normally what slows the study down. You just can't get people onto study quickly enough. Mm. It was a fairly key part of what we looked at when we were assessing. You know, the group having now opened Manchester, and I know hVIVO have also done a lot of other actions, which Mo can talk to if he wishes to, as to how to improve that throughput of studies. That was fairly crucial to us. You know, we want to start and finish the study in a defined timeframe, not end up bleeding into the second half of 2023. Okay. Anyone here that's interested in participating? Yeah. Sam is here. He'll be more than happy to sign you up for doing a trial. Melvin? Thank you all. Thanks. Hi, Melvin. Thank you, Andrew and Douglas, for the presentation. My question particularly to Andrew, and probably Doug. Grateful for having your inputs as well, is you said 3,500 patients have come through. I mean, how many patients have prolonged illness, not been, not got well in the time schedules that we expect? You know, and any can you focus on answering on the negative bits, if you know what I mean? Yeah, that's an excellent question. These studies are safe by recruiting the volunteers which we would naturally expect to clear the disease. We're not weakening the virus in any way. I think that's a misconception sometimes. They're wild type viruses just like you'd get exposed to in the community. That's why recruitment is doubly difficult because you're not just trying to find someone willing to do it, and medically, they have to be the healthiest of the healthy. Because of that, we have a really excellent safety track record. I mean, you're only as good as your last subject, right? If we did have someone who had a very severe reaction, it would have likely shut down us doing challenge studies. We haven't had anybody with that. These individuals do clear the infection without even any antivirals given to them. We're not even medicating them to get them well. They clear it naturally themselves. I think, I mean, so that's really where we are. It's got an exceptionally good safety record. The longest protracted symptom we've ever had on any of the challenge studies was with COVID. We're all familiar that the impact on loss of sense of smell can be protracted with a lower frequency of individuals on the COVID studies. Yes, that's our longest by a long way. That's an exceptional virus, which is a very unusual symptom. For RSV, flu, rhinovirus, they're all cleared and completely back to health 100% within- No patients kinda rush to the ICU of a hospital or whatever? No, we've had like 'cause we monitor these subjects really very closely, looking at blood levels, the whole lot. Sure, we've had some people checked out for strange blood results. Yeah They've all been then returned and cleared absolutely. There's no long-term impacts. These are safely done when they're done in the right hands. Douglas, any words from you? Yeah, I mean, I would say there's always potential for people going to ICU in a study, 'cause sometimes people get unwell even on studies. Certainly in our experience, no evidence of drug-related issues in particular. Yeah, we wouldn't be running the study if we didn't think it was gonna be safe. Thank you. One more question. Annie, Julie. Thank you. Just sort of following on a bit from Ed's question on the regulatory environment for doing these sorts of trials. You talk about expanding into other geographies with another trial center. I mean, is that gonna have to be chosen with the regulators in mind as who's actually gonna let you do these challenge studies? And sort of how far have you got in terms of identifying geographies that would or wouldn't allow you to do them? Absolutely. That's the key fundamental. There's two, I'd say. It's the regulators and the ethics committees, 'cause they are independent. Some countries, the regulators are quite open, but their ethics and their community perception of their ethics is not. It is becoming increasingly accepted. I mean, even within Europe, there are countries which you can't do this and some which you can, right? They're becoming more and more on the list of countries which accept doing challenge studies. For example, it was very difficult in Germany in modern times, but now there are malaria challenges run quite frequently in Germany. They're done frequently in the U.S. still, to quite a large degree. I mean, the U.S. government has actually funded them being done on an academic level. There are wider and wider exceptions. There are some geographical regions where the whole ethical concepts is still very difficult. For example, in India, it's technically illegal to give someone a virus. On the Hippocratic oath, thou must not do harm. They perceive that literally under that. There are some challenges in terms of expanding that level of acceptance in terms of culturally as much as anything else. It's not just regulatory-wise. I think it's probably more culturally than regulatory. I know that Peter's work with HIC-Vac is fundamental to that, and he will talk more about that later. Perhaps you can have a few words on your input on that. Yeah. I think, well, I will talk more about the consortium that we have that tries to promote the use of human challenge internationally, and particularly in developing countries for pathogens of high global impact. Absolutely agree that, you know, the attitude of the population to these studies does vary from nation to nation. It's very culturally dependent. In the U.K., we have a very, amenable population who understand these things and actually step forward in large numbers to volunteer. Thanks. I just also want to just level the expectations here, right? We're not looking to expand internationally tomorrow, okay? This is something a long-term goal for us. U.S. is the target market, at least from a commercial point of view, not for the what Peter's mentioning. There is a CRO in the U.S., a small CRO currently doing challenge trials, for example, against noroviruses. It is being done. There are a number of academic sites in the U.S. currently conducting human challenge trials. The data we have used for, I think it was Pfizer, Janssen, and Bavarian Nordic, was all produced here, submitted to the FDA, and they were granted breakthrough status. This is not something alien. We appreciate they're not as receptive as the U.K., but to be honest, no country in the world is. The U.K. regulations are very favorable for conducting challenge trials. This is a long-term goal for us to be able to do this, and North America, particularly U.S., seems to be the ideal target. I don't want to, you know, blow this up too much. We have sufficient capacity to, you know, meet our revenue targets going into 2024, 2025 right now. Okay. Depending on the demand, and if we continue to see the surge in increase in interest in challenge that we've seen in the last eight, 12 months, then we may accelerate that. One fi nal question. Yeah. Yeah. Hi, it's Christian Glennie from Stifel. Just wondering about the challenge of, I can say, of recruitment of volunteers in terms of, you know, what is typically the number of people, sorry, not patients, but people you need to screen to be able to get 100, say, in this, you know, Pneumagen example. Can you have that on your slide later? Yeah. I won't talk to the numbers 'cause I'll steal her thunder in a slide later. I'll talk generically for you. There's another key element that we're not just trying to. Obviously, they need to be willing to do this, and I say that because it sounds obvious that they come to us, but of course, a key part of doing any clinical trial is informed consent. We spend a long time going through exactly what's going to happen to someone. They may not be, you know, once they've gone through that process, which is key, they have to be truly informed about what's going to happen. Of course, some people may choose it's not for them, and that's the right thing if they choose that. You'll lose some on that. Really, when we're working with viruses, a major recruitment barrier is that all of us have been exposed to flu, whether we think we've had flu or not. If I take your blood and test you, most of you would not be eligible to go on our trial. Maybe even as much as 80%, 85% of you, because you've already got too high antibody levels that you would be protected if I tried to give you that virus. You wouldn't get sick. As I showed earlier, you can't learn anything if you don't get sick. That already eliminates, for some viruses, 80, 85% of the individuals. Even if they're perfectly healthy. Yes, we are going from many thousands down to these hundreds. Although you end up recruiting small numbers, it's a very large funnel. That is, I think, why being in London and having a screening center in Manchester is not by accident. You know, these are large populations, and actually in London particularly, fairly transient changes of population, which is key. If you were trying to set up a challenge unit in a small geographical area, you'll never get enough volunteers. Has there been any shift in trend in terms of, you know, people coming forward to, you know, as a result of COVID maybe? Yeah. That's been favorable? Yes. When COVID, we in development with Imperial College and Peter and Chris' teams, we set up the COVID Challenge model, and that hit the general press, not the scientific press. That actually gave massive awareness that you can actually do this. We saw huge influx of people volunteering, not just for COVID, but in general. What we actually saw was a massive influx, artificially high, and of course, that's come down to a more plateaued level now. Immediately after, there was probably a little bit of a depression because when we were allowed to go back to living our normal daily lives, people wanted to do that, lead their normal daily life. The thought of doing something medical was lower. now we're seeing it coming back out to more normalized levels, where we've still got a wider exposure and people knowing about it and knowing that this is done and seeing it in the press. We're now above where people are starting to then truly think about, "Okay, I've got back to life normal. I can reconsider doing this again now. If I may add to that, I think our SARS-CoV-2 Challenge study was also a good example because for that study, we had around 26,000 people signing up for the study, like voluntarily, and it was only 36 subjects who were included in the study. It was like for picking who goes, you know, to the moon. We needed also to select the healthiest of the healthiest. Yeah, that's also, you know, a good example of numbers. Of course, we don't need that huge numbers to recruit for the study, but it's also, you know, the willingness to participate in such study, even at those times when there was no, you know, a drug or no vaccine available. Yeah. One key aspect which really, really helps build recruitment is having a full order book. What I mean by that is if in any six-month period we're contracted to conduct a study for RSV and flu and rhinovirus, then we take an individual, and we're screening them against all three of those pathogens. They may not be eligible for flu because they've got too high antibodies, but they may be just fine for the rhinovirus trial. You lose less volunteers because you're able to put them into a different range of trials. If we're only doing influenza and they're not good for influenza, you've essentially lost that person to challenge studies. Having a full order book really enables us to maximize recruitment as well. Okay. I think time for a quick break. Can we say reconnect at 10:55, please? Thank you, everyone. All right. Thank you for coming back promptly. We're honored to have Professor Peter Openshaw, Professor of Experimental Medicine at Imperial College London. For those of you who don't know, a lot of the work that we do with our commercial partners really is underpinned by the work that you know, Peter and his team and his other colleagues do. We collaborated very successfully with regards to the COVID challenge trial with Imperial College as well as other institutions. Peter is very experienced in especially in studying influenza and RSV, which is the two mainstays of challenge trials. He's also a chair of the consortium called HIC-Vac, which is an MRC sponsored group promoting the use of human challenge trials in the clinical development of products as well as on an academic level. It's an honor to have him here. He's spending this afternoon with JVT. He has, you know, high networks and is, you know, I'm really pleased personally to have Peter present to us, thank you. Well, thank you very much. Let me just see if I can operate this device. Yes. I was going to, I hope, explain some of the science that we've learned from doing challenge studies. You know, what motivates us as academics to become involved in human challenge. I must say that it's been hugely rewarding for me as a medical academic to move from doing basic studies in preclinical models in mice, and so on, trying to understand the immune system in its most fundamental research terms into doing human challenge, where we can actually do experimental studies in human biology, looking at the immune system, looking at the immune responses. Just to give a bit of background. I've been a member of NERVTAG since its inception. I was chair of NERVTAG at one stage, which is a committee that advises government in the U.K. I'm the director of this network, the HIC-Vac network, which is funded by the Medical Research Council, in order to try to promote infection studies, deliberate infection studies for pathogens of global, high global impact. Member of the U.K. Vaccine Network. I guess also just to highlight, I've advised many companies, in terms of providing scientific advice, but I'm not a paid advisor to hVIVO. I have no financial interest in hVIVO, so I'm really here as an independent scientific expert. This is HIC-Vac, this consortium that we set up with money from partly from the overseas aid budget, actually, because I think the government was wondering how to use the overseas aid budget for things that would actually be onshore. It was partly for that reason that we've developed this very big worldwide network of investigators, over 300 different investigators around the globe. Actually, tomorrow we've got our annual meeting down in Leatherhead, where we've got a lot of the key people coming together for a two-day festival of science based on all of those studies that we've been doing. It's gonna be very exciting indeed to see what sort of progress we've been able to make. My interests, I guess, I've been funded full-time to work on RSV and other similar pathogens since about 1985. My background is as a chest physician. I did straight clinical medicine for about five years after qualifying before I went off and did a PhD actually on T cell responses to RSV in mice. Had about 20 years of working on mouse models and now human models of disease. I think each of these pathogens is unique unto itself. Each has different ways of overcoming the barriers to infection. Each has individual ways of becoming a successful pathogen and continuing its global spread. In terms of volunteers, back in the early 1990s, we did some very amateurish experimental infections around the lab. This was in an era when there was much less regulation, and basically we took some virus out of the freezer, and we asked people around the lab, "Would you mind having the virus in your nose?" Quite a lot of postdocs and others volunteered. I was looking at the sort of nasal mucus production that we were getting in some of the slides here. I mean, I remember one of our postdocs actually got 20 grams of mucus per day, which was assiduously weighed by the graduate student day by day in terms of wet weight. You know, we did those studies. They were very small scale, but I think it was useful to us to be able to see how they could be done. When we started back in 2008 to do more systematic studies, I think the advice that we got through our discussions with people at hVIVO were instrumental in making sure that we were doing the studies in a way that sort of was closer to having some sort of regulatory standard. This is Max Habibi, who was one of my PhD students at the time, who's pretending to inoculate another PhD student with virus just for the benefit of the photograph. We can do a lot of monitoring, not only of the blood, but also of the airway. Because we're embedded within a chest clinic, we can do bronchoscopies, we can get samples from the lower airway, and we can discover an awful lot of science by taking this very intensive approach to sampling. Also doing a sequential nasal sampling, which was really developed by my friend and colleague, Trevor Hansel, over many years, refining the way in which you can collect nasal fluid very atraumatically. Chris Chiu has really been transformative since he joined the group. He joined on a fellowship, which sent him over to Emory for a while. He came back with expertise in, you know, T cell memory studies in particular, and has allowed us to do studies on influenza and RSV. Just, you know, some interesting contrasts between these two. Influenza, I'm sure you've all heard about influenza. You all know what influenza is. It tends to be a relatively rapid takeoff in the studies that we did, and doesn't have this interesting lag phase that we've seen with RSV. During this period, the first couple of days after we put RSV into the noses, there seems to be a sort of negotiation going on between the nasal mucosa and the virus. You know, which one's gonna become dominant, which one is going to defeat the other. That lag phase is the sort of thing you can only study in human infection challenge. You wouldn't be able to do that in a field study, and it's the crucial event that determine where infection goes. You know, is it a mild infection? Is it an asymptomatic infection? Is it no infection, or is it a more established infection? All of that is decided in these very early stages before you could ever get any samples if you were waiting for people to present to you with disease. Absolutely crucial in studying the immunology. We've been able to do very detailed studies of, you know, the dynamics, and you saw those nice volcano plots with with different numbers going up and down. This is showing what happens to a number of different, what we call immune mediators over time. These are the interferons, which were actually described first in the U.K., some years ago, which are very important in defense against viral infection. These are more inflammatory mediators, things like tumor necrosis factor, which more represent the severity of disease and which are to do with the sort of pathogenesis of why people get severe. In this particular graphic, basically it shows that if the virus suppresses the baseline immune response in people soon after its entry, then it becomes successful and becomes an established infection. Whereas if there's a slight sort of response from the host, even a very mild response during that interval between inoculating the virus and the establishment of infection, then the immune system can defeat the virus in that very early stage. Here's one of our volcano plots. This is actually from whole blood, from the peripheral blood, and I think it shows the enormous advantage of being able to control when the virus goes in, when the sample is taken, and it's only by doing these very, very well-timed studies that you can really get a lot of information about, you know, the role of different cells, the role of different immune mediators, in defense. It's absolutely fascinating to be able to see this in real time. You'd never be able to do that just from waiting for people to turn up with flu. In terms of, you know, what determines the severity of infection, I think one of the things that surprised us was that it's these neutrophils. Neutrophils are cells in the blood that are typically raised in people with bacterial infections. We wouldn't have thought that those were of any great relevance, but it turns out that the status of your neutrophils in your nose prior to inoculation, so before the virus is ever put in, is really important in terms of determining the outcome. This sort of stuff is crucial for scientific discovery and can only be done through doing experimental infections of this sort. I think hVIVO, to give them credit, have been absolutely vital in global terms in being able to drive these studies and work with academics to develop protocols that have enabled all of this science to be discovered. Switching into RSV. One of my big regrets about RSV is the name. Respiratory syncytial virus, I think anyone in marketing would say that's a disaster. It's a terrible name. It was actually described by a research group led by Dr. Savage, and for some years, I've been trying to get RSV renamed the Savage Agent, but so far we haven't. We're stuck with RSV. It's a virus arguably of almost equal importance to influenza, but it is often the real hidden pathogen. It's very hard to diagnose RSV infection, particularly in these older adults, the frail elderly, who have a lot of RSV disease, but often by the time you take samples, the virus has been gone and went. It's disappeared. What you see is the inflammation which has resulted from the virus infection. It's this sort of insidious respiratory disease which has become much better known in the last five or 10 years because of investigational studies. You know, originally it was just known as a wheezy baby's virus, but actually it's a really important virus in older adults. Here's the same mock study of infection. We originally started just looking in completely healthy younger adults because we were very afraid of seeing severe disease. Having got a lot of experience of doing that, and with all the experience coming from hVIVO, we've finally plucked up courage to go into older adults. These are still healthy, but they're up to the age of 75 in this study called InflamAge that was co-funded by the Medical Research Council and by GSK, because they were really keen to know what was happening with this disease in older adults. We've published some of this already, and it's been very revealing in terms of looking at the severity, looking at virus replication, trying to work out what it is about older adults that makes them more vulnerable. Age, of course, is an absolutely key determinant. We all know that age is one of the major risk factors for for COVID-19, but we don't know why. We don't know why it is that babies and young children often get infected with no symptoms at all. They may pass it on, but they don't develop any symptoms. We don't know enough about the immune system across the whole range of age in order to try and discover, you know, what is the reason for this variability. This is just a bit more detail of the initial studies that we did in collaboration with hVIVO and in collaboration with many other academic units as well. People have said that the reason we could do this study was basically that all the planets were aligned. You know, the funding was there, the will was there, the support was there from a very high level within the U.K., and we had a production facility. We had hVIVO to do all the proper, you know, meticulous stuff that they do, and a database of 26, nearly 27,000 individuals from whom we could then select volunteers who would be eligible for this study. That was absolutely crucial, and we were able to inoculate with virus and then move up through the protocol. The thing which astonished us all was how little virus was needed in order to cause infection in this study. We started with this dose because we thought it was such a low dose, nobody would get infected. We thought we'd probably have to go up, what, 100, 1,000-fold, something like that. You know, we just didn't think that this very, very low dose would do anything. It was astonishing that actually we got 53% infection rate just with the smallest dose that we could measure in the clinic. When we looked at how much virus they produced, it was vast compared to the inoculum. We worked out that you'd only need a particle about the size of a red cell of nasal mucus in order to produce this inoculum dose. That was one of the things we learned. Just enormously infectious. It all came from these very careful, meticulous studies where we weren't just asking them if they'd got any problem with smell or taste. We were actually doing very detailed monitoring using smell cards and so on. We weren't just asking, you know, "Do you feel a bit fuzzy-headed?" We were doing battery of testing to see if there was any detriment in terms of their psychological performance. A lot of very detailed stuff. Chest CTs, lots of blood sampling, lots of nasal sampling. That produced this first published study of SARS-CoV-2 challenge, which has been a real landmark and I think a wake-up to the public and to regulators and to politicians about the potential of human infection challenge to yield, you know, vast amounts of scientific data, some of which may be important in terms of how we manage infections. Here's another nice little volcano-type depiction where you can see some mediators going down early and then a lot of these other mediators going up. Many of these are the sort of mediators you'd expect in a viral infection. This type of output you can only get from human challenge, and it's enormously revealing to us as scientists to be able to see what happens over time. There are many initial conclusions. We're still analyzing a lot of these, and I must say that we're still analyzing a lot of data that we gathered during the 2009 swine flu pandemic. We're still publishing results from that, from those studies that we did way back. I think, you know, these studies are going to continue to generate absolutely vital data, and it's a resource that we can go back to again and again when new questions arise, new products arise that we want to get some information about. We can look back at our data, and you can look back at your databases, and we can try and come up with with answers that point us in specific directions. We can look at genetics. We can look at so many different aspects, all of which informs about the biology. Very important to acknowledge the teams and the funders that have been vital in doing all of these studies. Thank you very much for listening. Thank you, Peter. Any questions for Peter while he's here? I didn't expect many questions for you, but okay. Okay, we'll move on to the fireside chat. You wanna take a seat. I've put together kind of a list of questions that I thought that you guys might be interested for this panel to discuss, but I'm also open to add any new questions. If you, I'll start it off, and then if you have any kind of burning question that you want to kind of address to this forum, I think it's really good. You know, I'm always available to you guys all the time, it's not really. I mean, I can answer your questions, but I think it's really good that you've got a client here, and a leader in academia, you know, and a chief scientific officer especially that you don't normally get to kind of talk to. Anything for them I think would be really good. Maybe I'll start up. Maybe with you, Peter, first. When the COVID pandemic hit and the fact that we were able to get vaccines to the market in such a short timeframe, you know, two or three years, even less than that, whereas historically, it's been taking over, you know, 10 years, do you think that process, that speeding up, expediting this drug development has had an impact on the usage of challenge trials? I think there's been many factors that were important in allowing that very rapid development of vaccines. I must say that on the advisory committees, on the planning committees, on the Academy of Medical Sciences task force, we were not anticipating that vaccines would be anything like that rapidly developed. We were absolutely thinking that the pandemic was going to be over before we would have a vaccine. I think, you know, we started seeing early data within a few months that made us think that maybe vaccines could be developed. The crucial elements, I think, were big amounts of money going into vaccine development, which really allowed, you know, almost in parallel development of the different stages that you'd normally go through. Huge amount of commitment from all levels, you know, support from government, support from regulators, all of which, you know, set the green light ready to go as soon as the data came through. I mean, I suppose there's a broader question about, you know, would challenge studies have accelerated that process, the main topics that we're going to debate at our conference in Leatherhead of human challenge in in. I don't know whether you. I mean, as you saw that we've developed the COVID model together, that was set up and funded by government because, to Peter's point, it wasn't expected necessarily that this first wave of vaccines would be successful. In that scenario, then what do you do as a government? You're then faced with a need and answer. We've got five, six, seven other potential vaccines. How do I select which one to procure in advance of having field trial data, which may take some time? Challenge studies were seen as a way to help select that process. Now, we are all very fortunate that by the time we had run ahead of those by that COVID challenge model, that actually had got the evidence that these first wave of vaccines were very efficacious. But we should think of, remember the context that we developed that model was when there wasn't any vaccines rolled out at all. I do think, you know, they would have really demonstrated had they had their place if the first wave of vaccines hadn't been successful. Don't get me wrong, I'm very grateful that they were. Carl has a question. Hi. Karl Keegan at Singer. Following on from your data, Professor, on SARS-2, what was the sort of strength of the pushback from your ethics committee? You think that the data that you showed, which is so, you know, very clear, do you think that the ethics committees now going forward are more amenable to these type of studies, in that you've sort of shown in a very sort of serious pandemic situation they work and are safe? You know, I think in the U.K. we've been very, not just fortunate, but actually forward planning in terms of making sure that the ethics committees are not there to basically just have a firewall, assess the data, and say no. The ethics committees are there in part to discuss with us how we can safely and ethically perform these studies. I think it's, you know, there is a question, you know, if we can do these studies, and we can do them safely, is it ethical not to do these studies? They're so revealing. They're so important in terms of the information that we can gather, you know, that actually there is an ethical imperative sometimes that we do go ahead and we do these studies because they save lives. Douglas, for you in a different sense, do you think that because we had the COVID pandemic and we ran the COVID trial, did that make your job a little bit easier in trying to convince your board and your shareholders to actually approve and give you the go ahead to do a challenge trial? Secondly, going forward, would you recommend other companies in your situation to do a challenge trial too? Yeah. I mean, I think as I said in the presentation, I would absolutely recommend them doing a challenge study. It's a very efficient and effective way, sorry, relatively low cost, that's not a negotiating point, to get to efficacy data. So I think it's, you know, instead of running a field study over a couple of years, you can get to an endpoint in 9-12 months. So yeah, I think that point's already been made. I'm not certain that COVID had much of an effect. It had an effect upon our approach to the regulator, everything, you know, even our phase I study was approved much faster than normal because of COVID, and we put the word COVID in the headline. It went through much quicker than it would normally perhaps have been reviewed. I think that has been a help, but I'm not certain that, you know, having a challenge study, and in fact our phase I had started before you'd run the challenge study, certainly from my board, I don't think that was much of a factor. Challenge studies per se, yes. You're doing one specifically in COVID, less so perhaps. I mean, just picking up on your point about timing, you know, vaccine studies normally taking 10 years. I mean, I think Peter showed a slide there about RSV. We've been working on RSV vaccines for a very long time. Yes. Yeah. It's not just how quickly we can put things through the regulatory process and so on. Do we actually have the right science to be able to take it forward? I'm with Peter, I'll be honest, as somebody who comes out of the vaccine industry, I didn't think we'd see a vaccine for SARS, or at least that quickly. Yeah. Yeah. RSV for that matter. Peter had that. RSV as well, so. Yeah. It's a great step forward. Yeah. Thanks, Phil. Thank you very much. You've all touched upon the benefits of challenge trials in your presentations. I guess playing devil's advocate, with much bigger populations which potentially give you a more representative sample, whether that be age, sex, race, et cetera, is there an argument that challenge trials you lose some of the richness of the data, or would your point be that actually that's captured in later trials anyway, and you're looking for something more specific? Yeah, that's an excellent point, if I may start on that. Challenge studies are never going to entirely replace field trials unless it's a really exceptional example where you physically cannot do it in the field, which is very unusual. For the pathogens we're working with, they're never going to completely replace it. For example, what we've seen in some of like some RSV antivirals, so they're in this case trying to treat RSV, is that instead of going into these very complex field trials in babies without really understanding, you know, what is the best way to dose? Do I give this massive bolus dose, or do I give tiny bits every day? You know, they don't want to go into those really complex field trials in a really vulnerable population without really knowing, in a human population, those answers. They use the challenge study to whittle down those essentially research questions, so that when they are going to late-stage trials, they're only testing what they believe to be the best possible way of using their drug. In the case of a vaccine, it might be the best possible dosing regimen or the best possible amount of antigen in the actual vaccine. It means when they're doing those phase II and phase III trials, which are crucial 'cause as to your point, you need to get it across as wide a demographic as possible to be representative, and some of that demographic is going to be too frail to be in a challenge study safely. You're going to have to still do those phase trials, but at least what you're then testing in those phase trials are an optimized product rather than spending two years and then realizing, "Actually, my product didn't really work. Maybe if I tweaked this," and then you go back and do another two years, and you can do that five times, you've lost 10 years. If you can hone it down in the challenge study, you can get there quicker. I think, you know, these studies are so useful in terms of demonstrating, you know, how effective the treatment could be under ideal circumstances, under sort of laboratory conditions. You know, the vaccine efficacy in a field trial is another matter and depends on lots of other factors to do with vaccine transport, delivery, administration, all the rest of it. It's not going to answer those questions. We have to be clear that we're only going to be doing challenge studies on, in a population at low risk. We're not doing these studies in people who might end up in intensive care. Yeah. Mark. Thanks very much. You've talked about developing new challenge agents for various variants, whether it be flu or SARS-CoV-2. What are you actually looking for in terms of a dose and infection rate when you're developing those? Because clearly, if you have 100% infection, you're probably dosing too highly, and if you have 0% infection, it is a hopeless. Are you looking for that 50% because you've talked about one of the flu variants having 67% infection rate, and you've talked about one of the SARS-CoV-2 having 52% and 49%? That's an excellent question. The answer to it is it depends on what scientific question we're trying to ask. If we're doing a question maybe without a product like a lot of what Peter and Chris' work in exploring the response to infection. Actually, if everybody gets infected, you're not gonna learn anything about what prevents people from being infected, so that doesn't help you. You need a mix. From our perspective at hVIVO, it's a combination, and you've hit the nail on the head actually. Particularly for vaccine studies or for products which we're administering prior to the actual exposure to the pathogens we're trying to prevent the disease, like Neumifil, for example, if we give such a large amount of virus that it's going to overcome any product or any immune response, then A, it's really artificial, and B, you're not gonna learn anything whatsoever. We're trying to give the minimum amount of virus to cause a reproducible infection now, and then you can come back to the economics of it. If the infection rate is only 20%, then clearly you have to still put, you know, five times more people in there to get your answer. It becomes economically not viable, and it becomes. A lot of the benefits of doing challenge are it's cheaper and it's quicker. You need to be around that 50% really to make that speed and cost benefit still hold true. We're mainly targeting somewhere between 50% and 70% infection rate. I'd love to be able to design the studies and pick 70%, but that requires colleagues like Peter feeding me much better and us having a greater understanding of the immune response. We don't understand nearly enough about the immune response right now to be able to select a volunteer and know who's gonna get infected or not. We really don't. We are targeting the 70%. We may achieve 50%, and then we power against it. Clearly, I mean, if you're getting an infection rate, infectivity rate of 50%, it is commercially better for hVIVO because you're gonna be recruiting more patients into the study to get the end result. No. I mean, I think it becomes. It will put our clients off as well. Yeah ... because a lot of the benefits of them doing the challenge study suddenly disappear because, you know, our costs are our costs, and, you know, most of our clients won't be able to bear that cost, particularly if it's small biotech, or won't be able to tolerate the timelines if it's larger biotech and pharma. It's in our interest to have as effective models as possible as well because then, if we can make these as efficient as possible, we attract more and more usage of challenge models, and that's really where the business comes from. Not doing a really expensive one for a client because they can't afford it. We need to make it affordable for all and do more and more of them. Ed. Hello again. Peter, Douglas, you've both spoken about the value add of challenge studies, but exactly to the point of the fireside chat, where do you see the demand for challenge studies evolving in looking ahead, and over to you of where you think, you know, the impacts ethical changes or regulatory changes might have on the demand? Do you want me to go first? Yeah. Sure. Well, first there's a lot of viruses out there that we don't have challenge models for. On the list that Mo put up, I think there were four or five that you were covering, and within that, there was influenza and RSV and different strains. I think there's a lot of opportunity there. There's, you know, from a point of view of hVIVO, there are bacterial vaccine challenges which I don't think hVIVO have currently got on the list. If I was looking at hVIVO, I think there are plenty of opportunities out there to have a look at. I think generally there's been more. Well, one good thing from COVID, if I can put it that way, is that there's a lot more interest in infectious disease now. There's a lot more funding coming to infectious disease even for early-stage companies such as ourselves. There is more customers of hVIVO now than there perhaps would have been a few years ago. I think there is also that opportunity there. Mm-hmm. Yeah. I think, I mean, it is a growing field, and that might be a surprise to some people that there's such growth in this area. I mean, as a chest physician, I would say that I really want to see more studies in rhinovirus. Mm-hmm. You know, rhinoviruses are a major problem. I know I've had a couple of rhinoviruses over the past few months from my grandchildren. You know, they've severely impacted my own asthma. In the clinic, my patients with asthma, chronic bronchitis, and, you know, pediatricians who are seeing people with cystic fibrosis, the major reason for exacerbation of those diseases. Mm-hmm is these days infection with rhinovirus, but with other viruses as well. There's not enough going on in terms of, you know, how do we tackle rhinovirus, and I hope that that's gonna be an area for future growth. But there are many, many other pathogens out there which it might be possible to do infection challenge. You know, we still lack vaccines for things like gonorrhea. Gonorrhea is developing multi-drug resistance around the globe. It's a major concern. You know, how is that gonna be tackled? If we could use challenge studies to try to understand better you defend yourself against a bacterium like the gonococcus, and I think there is the potential to do that. You know, maybe challenge studies will find a niche in other areas. Both of you point there to expansion of challenge studies into additional indications. What about actually the demand within already approved indications for challenge studies? Well, the two trends that we tend to see on that is that, for example, back in even 2018 there was a classic example. Twenty fourteen, sorry, the classic example where we had, if you look at our revenues over a year, there was a big spike, and that spike at the time was because there was an academic paper two years prior which said the particular path of the influenza molecule, the stalk of the key outside protein could be a good target for an antiviral. This had not been considered before. What happens is a lot of people just then start developing products specifically targeting that new discovery as a new target, and then within, we had four or five customers who all had different antibodies which bind that, which wouldn't have existed three years ago because it wasn't even thought of as a target. What you see is one way you get is getting a new target becomes available, normally from academic research. That then gets developed, either academics spin off a company with a product or big pharma and biotech develop products against that new target. That's one way, and we have seen that. An example of the RSV vaccines as well. When you have something successful go through, others realize, "Actually, this is a potentially area where we can cure this disease or help in this disease," and they put investment into it. You do breed your own success in that. Another trend we're seeing much more recently is as there becomes more adoption by big pharma and biotech, particularly on vaccines, there's a trend to doing larger trials, and that takes a much larger infrastructure. Rather than doing. Traditionally, if you look back five years ago, they would've come to us to do the minimum possible studies, so maybe 20 in placebo, 20 in the vaccine before they move on, and now we've got contracted on our books some trials which are 250 individuals because they're trying to get much more clarity of the data, answer more questions, look at endpoints which are lower frequency to see, to de-risk further and further their field trials. So that's one trend we're seeing. Also, the other impact of the pandemic is it really brought home a phenomenon which some people have forgotten about, which is you cannot rely on a seasonal virus to be there when you want it to be there. The pandemic completely messed up the flu seasons. There was virtually no flu last year. You imagine trying to run a flu vaccine trial in the field when there's no flu. You can't do anything, right? It really brought home the fact that you are so dependent on what's circulating. What's a new trend we're seeing is, okay, this strain of flu I managed to see in my field trial, but I want to claim to the regulators that my vaccine or antiviral works against all flu, and the regulators go, "Fine, prove it." They can't prove it in the field 'cause it's not circulating anymore, so they use the challenge study to fill the gap with a specific strain that is now very infrequent in the field, so they can get a broad label claim, and that massively improves its regulatory and improves the market value of that product. I think another point to make is that the first product to market may not be the best product to market. There may be other coming along through the pipeline which are gonna be much better. But in the presence of an already partially effective intervention, it's very hard to design even very large scale studies to answer the question, is this superior, let alone non-inferior? By doing these challenge studies comparing, you know, product A, product B, product C, you can actually get a lot of information about the relative efficacy in relatively small studies. Apologies, Carl, but we're gonna have to move on. Douglas, Peter, and Andrew will all be here hopefully for lunch, so you can approach them directly then and hopefully they will be able to answer your questions. We're gonna move on to a sales presentation from Eglė Pavydė. Eglė is based in Lithuania. She joined us a few months ago. Very impressed. Half a year already. Oh my gosh, half a year. Wow. Time flies by. An amazing addition to our BD team, and the real focus here of this presentation is really kind of to show you how we as a company make our sales pitches to people like Douglas doing sales pitches. Thank you. Thank you. Hi, everyone. It's a pleasure for me to be here, and I will try to explain how we explain challenge studies to our clients. Oh, sorry. I will start with the service offering, basically, and I'm sure that you've seen this slide already many times, but the core focus here is basically to show the integration that we have of our subsidiary, Venn Life Sciences. We work very closely because Venn Life Sciences starts with our clients from even earlier part, so from discovery stage, and then moving forward, it was actually a question about that, about not integrating phase I, phase II studies with us. Basically, Venn Life Sciences can do that, and we already have proposals in our pipeline where we will do a combined phase I, phase II study for our clients while then we'll select a vendor, a specific site for the phase I to be conducted. Most probably in the U.K., we will continue with the challenge study. There is a lot of integration and cross-selling in that regard. I will start very shortly with Venn, as mentioned. They start with the clients quite early from the discovery stage, do preclinical consulting for them, writing their dossiers, helping as well with phase I studies, and then we can very much cross-sell between those two subsidiaries. Moving forward to hVIVO, as already Mo emphasized, I think is his, in his presentation, we are a full scope human challenge CRO, and we are a world leader in human challenge studies. This is basically the services that we provide to the clients, and they are very continuous and very seamless. We start from the study design, we help with the regulatory interactions with the competent authorities even before the submission of clinical trial application with the scientific advice. Andrew is the one attending those scientific advice meetings with the regulatory bodies and helping clients to explain what we are planning to do. Then moving forward to the clinical conduct of human challenge studies, which is highlighted here. Also right now in our clinical part of services, we are looking much more adding some other, studies, such as phase II, phase III vaccine studies, also non-first in human, healthy volunteer studies and mild condition patient studies. I will talk about that in a moment. Our laboratory is designed to support everything that is needed for a challenge study, but all those assays are absolutely suitable for all other kind of studies, so for example, phase II, phase III studies. Therefore, we are also looking to expand that piece as a stand-alone for our clients. The benefits of human challenge studies were already touched, but I want to emphasize that they are also our unique selling proposition. As Mo mentioned, I think we not only want to present hVIVO and and say we are the world leader, but we really want to promote the human challenge studies as itself. Andrew touched a bit on the scientific piece, but from the clinical development perspective, it was also mentioned that it requires fewer subjects in the study, so therefore, it is a significant time saving, and then there's no seasonal dependence. From the regulatory perspective, there was some case studies shown that our clients obtained breakthrough designations which helps them to shorten their path to the market. Then there is a financial benefit, when especially for the smaller biotech companies, when they obtain their phase II- A efficacy data and they can show to the sponsors that the drugs works, of course, is a significant valuation uplift. For me as a BD person, I'm very happy that I have all these colleagues, you know, something to catch their attention. If I'm speaking to scientists or regulatory or clinical colleagues or even the folks who are, you know, most interested in money, I have some things for everyone to say and to hook their attention. We are a partner of choice for the Big Pharma and biotech clients. As you can see, there is a nice mix between the Big Pharma as well as the stars in the biotech industry, and also it serves very much to us as a reference. When you can show to the client a case study from a Big Pharma client who successfully conducted their study, there's much more confidence for those smaller biotechs to invest this money in their challenge studies. I will touch a bit our strategy for growth, but in a nutshell, we recently strengthened our BD function in different ways, not only adding myself to a team. We have a very diverse pipeline right now. We have new challenge models coming in or new challenge models recently set up. We have also new service offering to our existing clients, and we also looking at ways to increase the cross-selling and upselling between the subsidiaries hVIVO and Venn. Looking at our business development department, I joined the team half a year ago, and right now, me and Rich, we basically are split by geography. My colleague Rich, who's with the company, I think seven years already, he is now more focusing on U.S. and Canada, where he is very strong at, he is from U.S. I'm focusing on Europe and Asia Pacific. Asia is something new in our portfolio. There was not too much clients or too much interest in that region, and I think there is quite a lot of opportunities there for us, and we also see a growing pipeline from Asian clients. From the business operations perspective, the scientists are the one who are shining bright in the client calls. Recently we had some additional scientists assigned to us to include those in the interactions with clients and also in the proposal preparation process because our proposals are really scientifically oriented. From the business operations and marketing perspective, we just added a new FTE to help us with prospecting activities and lead generation and also revised our marketing structure to focus more on business-to-business marketing. From the legal and finance perspective, we've added additional resources to speed up the process of proposal preparation and also contract negotiation. I mentioned already a bit on the field studies. For those, we have a principal investigator assigned within our team who will be helping us on those opportunities. We are really a sales-focused organization, and I'm enjoying hVIVO so far very much. I was very happy actually to prepare this slide for you, and I was happy to see how the numbers diversify, because we basically do not depend on anything looking at our pipeline. It's very diverse, and it means that we don't depend on a single client type, we don't depend on a single region where the opportunities comes from or on the model or on the investigational medicinal products. If you look at the distribution by client, we have a good mix between pharma and biotech. There might be a question why we have a bit less of proposals from pharma, but basically those opportunities, I would say, they are with a higher probability. Pharma clients usually have a financing secured to finance their studies while the biotechs might still be looking for funding. It's a really good mix in that way. From the distribution by region, for sure, most of our proposals right now come from U.S. and Europe, but there's a portion, as mentioned before, from Asia, which is growing right now, and we want to increase that even more. From the model perspective, again, there is a very nice mix from those already established models, so influenza and RSV and HRV, but there's also a nice portion of the new ones, so SARS-CoV-2, asthma, and even other models looking beyond and discussing whatever models we could add to the portfolio for the clients. By the IMP, we talked a lot, I think, today about vaccines, but again, there is a good mix between the vaccines, antivirals, antibodies, immune modulators, and other molecules in the pipeline. Also there were some questions on the new models in development. We have currently existing models, and asthma and malaria are the newest ones, additions. We have Omicron under development. We will start challenge studies on this one next year. There is also a new influenza model being developed, and we are also looking quite extensively into dengue. Maybe worth mentioning, these are the list of viruses of models that we could add to our portfolio. It doesn't mean that we will add them all, but if there is a significant commercial background to do that, we will definitely look into it, and we will follow our customers' demand. Talking about the expansion of services, so for hVIVO, I want to emphasize that it will definitely remain a challenge-focused CRO. From the existing resources that we have, we can see that we can increase the efficiency in our work by adding some additional services, such as phase II, phase III vaccine field studies, non-first-in-human healthy volunteer studies, and mild condition patient studies. For Venn Life Sciences, our subsidiary, we see a huge trend on the need of advanced therapy medicinal product consultancy as well as medical devices. Just to touch a bit more on those field studies that I mentioned, we have this huge apparatus of FluCamp that was already mentioned around the recruitment of healthy volunteers. The recruitment of healthy subjects in general in the CRO industry is the number one issue or problem that either CROs or pharma might face. Having this huge numbers of volunteers that we screen and having a small portion of volunteers which are CRO suitable for our challenge studies, we want to use those 85 or 80 percent of subjects which are not suited for the challenge studies. We can easily recruit them to the vaccine field studies, phase II, phase III, and act as a site, a high recruiting site in such case. This is definitely something that we are discussing and already have opportunities on our pipeline on that. Very shortly about this integration between our laboratory and Venn Life Sciences. Our lab can work starting from preclinical all the way up to phase III trials. Therefore, we see this good match between Venn Life Sciences when we offer services around preclinical, non-clinical testing together with our laboratory. First of all, we are trying to increase our brand awareness for laboratory as standalone services, as well for Venn Life Sciences for those new areas, so ATMPs and medical devices. We also want to increase leads coming for standalone laboratory services. Therefore, we added this lead generation person to our team, and we are working very closely right now actually with the Venn Life Sciences team to increase the cross-selling and upselling because Venn hooks those clients from the early stage, and therefore we can move forward with the seamless extension moving forward. Thank you very much, and if you will have any questions later on, I will be happy to answer. Thank you. Great. Our final speaker for today is Stephen Pinkerton. Stephen has been working in the financial industry for over 25 years. He joined hVIVO as a Commercial Financial Director in 2017. He's worked across transforming the business with regards to putting together budgets, reporting, and also building up our costing models for our sponsors. Recently, he took over the role of Chief Financial Officer, and this is his first capital markets day, so be gentle. Thanks, Mo Khan. Just making sure I know how this works. Left and right, yeah. Left and right. Right. That's all. Well, good morning, everybody, and thank you. I'm delighted with this appointment, and I do work with a really great team. I've known them for six years, or most of them for six years. They are a great team, and they deliver differently. Mo, thank you for giving me almost the last watch. I'm a sailor by heart, so for me, the last watch is when I'm crossing the sea and going over to France, and I'm having to be awake to make sure I don't hit any ship tankers and things like across the sea. Thank you for that. I've been asked to keep the presentation fairly short because actually the team have already done a fantastic job in explaining the numbers and the performance. We can just look at the graphs pretty much because actually you've heard all the explanations for the performance that we're projecting. This is our contracted order book. It is a record. It is fantastic result. You can see we've gone up 500%, from the end of 2019, we've gone from GBP 12 million to GBP 18 million. The core drivers for that has been already explained by everybody in the team today, where we have end-to-end models in play. The market is expanding. We have more clients on board and this is great. It's giving us more visibility on 2024. I think the other thing to highlight on the contract is, Andrew highlighted that when we contract a client, we ask for a reservation fee, and it's about 15% of the value of a contract, of any contract. That secures the commitment of the client as well as a slot, a time period when we're going to deliver the study. It also adds to our cash flow, so we do have a healthy cash balance, as you know. I think, you know, one of the questions we often receive, you know, is that trajectory going to continue? Maybe not quite as aggressively, but we do expect a trend, a positive growth trend and largely because the market is growing. As explained by Eglė, we have improved our BD, increased our BD resources. Eglė has already started selling to clients. She's been here for six months, and she's already sold two, three studies coming on board. I think that's a fantastic result and clearly we're beginning to capture that market more. This is our revenue. Obviously, if you've got a record contracted order book, it really means that actually revenue is down to delivery, operational delivery, right? It's not so much about the sales because we've already got the sales. 2022, we're looking to grow from GBP 22 million in 2021 to GBP 39 million in 2022, and we're going to go up to GBP 50 million in 2022. Now, as at the end of September, we're bang on track on our forecast for delivering that GBP 50 million. Of course, we do need a strong, solid performance in Q4. Adam is in the audience, and he's certain I'm quietly positive about it. Mo is determined. 2023, the market consensus is GBP 55 million. It is reasonable growth. Now we'd rather, as Mo would say, sort of under-project and over-deliver is what we're really after doing here. The... It's good to note that 80% of that is already in the bag 'cause we've sold it already. It's just down to delivery for the rest of the period. What else do I want to say? I think another thing I wanted to just highlight on this slide is just for example, the volume of work that's going through the business. In 2020, we did 127 volunteers. In 2021, 312. In 2022, we're going to do about 400 volunteers are gonna go through our unit. One thing to highlight, as Mo has mentioned, we don't have a capacity issue to deliver that growth of GBP 55 million, and we don't see we have capacity issue for the next couple of years without it. You know, for 2023, 2024, 2025, I think we have enough capacity to deliver that revenue in our existing facilities. Core to delivering all this revenue is obviously recruitment, and we have touched on what we're doing with recruitment. We've invested in the CRM. We've expanded our reach by having Manchester office and we've also improved the facilities in Plumbers Row, so we can get a much higher throughput. This slide gives you a flavor of just gives you a sense of the work activity that's going in the business. The many clients where we're sort of servicing in per quarter. In 2020 Q1, we had two. We're now growing up to about 16- 14 clients at any that we are working on and delivering revenue. The graph below highlights that how much revenue we are delivering, more than. How many clients we're delivering more than GBP 1 million per quarter. You could see in 2020 Q1, about one client, and we were delivering revenue for GBP 1 million, and then we're now delivering around six clients. We're delivering quite a lot more revenue going through. I like this graph. This gives you a sense of the mix. We could see from the government revenue is declining and is being replaced by big pharma. What I think is also interesting in this slide is the fact that you can see biotech is still holding its proportion of revenue. The implication on this graph, if you're looking at 2023, for example, is that our revenue is growing. It is also growing not only just because of big pharma contracts but also because biotech are coming on board. I think the other thing to note to mention is that our studies are increasing. When I joined hVIVO, our studies were typically 44-60 volunteers. I think we've only got one study that is around about 80 volunteers at the moment. Every other study is closer to 100 or 100 plus going forward. That's because people are beginning to understand what challenge models can deliver. They're looking for more information, right? Pure 60-volunteer study just delivers you know efficacy, whereas the other study, greater volunteers delivers you a hell of a lot more information, and that's what clients are looking for. Spend a little bit more time on sustainability. Our EBITDA margin, you can see it's going from 7.4%- 13%-15% is our expectation in 2022. There are some core drivers for this. I mean, the first note on 2021, 7.4% is slightly understated in the sense that we had COVID studies. Obviously, if you remember COVID, there was a lot of issues around COVID, and we had one-off COVID costs. That amounts to about 1.5%, impacting that 2021 revenue. That's not repeating. So obviously we benefit from that in 2022 because we don't have a COVID study or the COVID regime happening in 2022. The other drivers for performance in the EBITDA are what I would call operational leverage. We have two things we've touched on. One of them is recruitment. Recruitment is an expensive part of any study and is incurred by any CRO. with more studies on board, more viruses, the volunteer has a much greater chance of getting onto a study. Volunteers also have a very prescriptive time when they want to get onto a study. You know, they have semesters when they can do, you know, when they're not at work, not at university, and they wanna come on, onto a study. They will choose a slot. We have many slots now. We have a lot more studies on the go, so that we are able to leverage our recruitment costs across more clients. The other item on operational leverage is our clinical facilities, where we have at a typical unit, if we have. Invite 12 volunteers onto the entire unit. We need around 6 clinical staff to manage that unit, staffed at any time, whether it's about eight volunteers or 12 volunteers. If we have 20 volunteers, the incremental spend on our staff, we only had to have maybe eight or nine staff, clinical staff to manage those number of volunteers. We get that leverage as well. The last thing I wanted to highlight is that we used to be known as, before we even joined Open Orphan, as a lumpy bumpy business. We would have to scale up, and we have to scale down. That includes. You train all your staff, you lose them. You recruit, you pay recruitment fees, and you lose them again. We've kept on doing that. Now, with a very solid trajectory of work, we're able to stabilize our staff and stabilize our resources. We still have an element of scalability in that, but it's not as extreme as we had to do in the past. That will deliver us strong profitability gains. I think that's pretty much all I wanted to say. Let me just check. Yeah. I think that's it. I think, thank you, everyone, and I'll hand over back to Mo. Thank you very much. Before I conclude with my closing remarks, I wanna open up to the floor for any final questions for the whole panel. Yes. Thank you. David Herrmann. I'm from AozoraStep Capital. Just a question on the EBITDA margin. What is kind of the maximum EBITDA margin you can achieve, given, you know, the capacity constraints that you might face? How much is that in comparison, I think like you mentioned 400 volunteers you had this year and something like 16 active clients. Like, what is kind of the highest margin you can achieve, versus capacity? Well, first thing I want. I'm sorry. Yeah We don't really have a maximum. We do want to grow our margin more. I think we aspire to try and getting closer to 20% as much as possible as a business overall. With steady growth and those. At the moment, what I'm seeing is we're getting the utilization. We're getting good improvements on our margin from utilization. That's just using the staff that we have at the moment and the facilities. What we haven't started seeing in our metrics yet is what I'd call the efficiency, the operational leverage. There's a little bit of glimmer of that coming on board, but it's not there sufficiently. We're not an Ergomed plc. I think, you know, 20% is quite strong. We're not a subscription business, so we do have a cost base to deliver, a solid cost base. I mean, as I said to you, we aspire to 20% but, you know, at this stage, you know, we're very comfortable with the 13%-15%, and we expect to grow on that as well. In terms of capacity constraints? We don't have capacity constraints at this stage. Certainly our revenue projections and our business projections for the next two, three years, we have sufficient capacity. We've got 43 beds. We're something like, which is more than sufficient capacity, you know, capacity for our growth, certainly for 2023 and 2024. Great. Just on the, I think, like, you have something like 20- Just, I was gonna add just to that one point. We did set up new facilities, and Mo's mentioned that earlier today, as that we are able to set up new facilities should we need to do so. Should there be extreme demand or unexpected demand that we don't expect but currently, we would be able to set up new facilities. We have done so in the past. In fact, that's why we have 43 beds today, 'cause we've kept one of those facilities that we set up within four months. Yeah, because I think you have something like GBP 20 million in cash at the moment as well. Yes. Is that kind of like, do you have some current liabilities that are coming up? Or what's kind of the some CapEx plans or? Our CapEx spend is low. We have other facilities that have been well established. Effectively, some of our CapEx spend is maintaining those facilities or replacing lab equipment. There's no significant spend. I mean, I think in the half year we spent something like GBP 700,000. For the full year, we're looking at maybe GBP 1.2 million for this year in terms of capital spend. I mean, I would expect a similar level. Now obviously we're improving things and ticking it over more than having to go out and spend vast amounts of CapEx. Is it the amount of cash you have I mean, versus market cap is quite high, right? It is. That's why I'm just wondering, do you have any plans what to do with that cash or? Well, we have it on deposit. We're earning interest. We don't have any plans for it at this stage. Do we? No. I think you have to be aware of where we're coming from. What position we were 18 months ago, right? We're building the foundations currently to be able to grow and hopefully get into the M&A activity. Right now, because of the model we run, we have a large amount of upfront payments. This is a lot of accrued revenue. It's not cash. It's non-refundable in the sense that if the client was to cancel that project, we have the right to keep that money. Okay? It's not recognized revenue as per project. Okay? As we move forward, and we are able to run these multiple challenge studies concurrently and be able to recognize the level of revenue we're recognizing right now, then that's gonna drive future M&A activity and what we do with the cash. My goal first was to build the backlog. Like I said, that was really important. Then to be able to operationalize multiple studies because historically, we've never run more than one study at any given time. Operationalize multiple studies concurrently, which we're doing right now. Once we have that sustainable model in growing the revenue and the EBITDA, then the third step, I know it's boring, but the third step is to then look at M&A opportunities, whether it's a phase I unit, for example, someone, I think Douglas kind of mentioned that's a potential target. Whether it's a separate challenge unit, whether it's another consulting firm that aligns well with our event subsidiary. We are actually. We will be actively looking at that. But right now, as of today, the goal is to be able to have a model that gives us sustainable growth in revenue and also EBITDA margins. Okay. Great. Thank you. Okay. Thanks. Hi, I'm Seb Jantet with Liberum. Eglė, a quick question for you on the pipeline slide. Is that showing the pipeline by number of opportunities or by value of opportunities? By number of opportunities. By number. If we looked at it by value of opportunities, how would that look? You know, I mean, I guess what slightly surprised me was the 30% pharma, 67% biotech. I'm guessing if I looked at it by value, that would look very different. Yeah. I looked at it by value and then the pharma piece gets a bit bigger, for sure. Yeah, you're right. At the slide, it was shown by the number of opportunities. Are these risk-adjusted at all, or is there a kind of cutoff to get in the pipeline? I'm trying to get a sense of how early stage some of these are versus, you know, whether you've actually done RFPs for some of them and so on and so forth. These shown on the slide were only the ones that are proposals submitted. Right not the ones that are in discussion phase or, you know. Okay. All right. Thank you. Andrew, quick question for you. I'm going back to this slide you showed at the start where you're working for big pharmas and you're starting to actually develop bespoke models for them. Who owns those models at the end of that process? Are they yours? Can you then go and, you know, commercialize them with other people? That's the model which we need to get to. So it depends on the contract. On the slide, it was three listed contracts. Two of those, we would end up owning the model and be able to use it for others. The other one was a very, very bespoke and was done just for that client. Presumably there's a commercial trade-off then if you end up having the ownership of the model and the ability to kind of commercialize it versus what you might charge someone for having an exclusive model. It's very unique. Equally, they get a trade-off because they get data they wouldn't be able to get otherwise. They're tapping into a skill set from us. Under that scenario, you know, we have access to the viruses. We're sourcing the virus to make to match to them as well. Essentially, we have all the IP in it, all the know-how and the ability to do it. Yes, they're funding it, but they would not be able to get this data otherwise. Under those circumstances, yes, we're not doing it cheaper for them because we're allowing it. We're allowing to do others to use it for others. It's not we're discounting or anything like that. No, it's just the fact that they need to get a particular means to an end. We have the skill set to do it, so we're win-win and matching in that sense. Brilliant. Thanks. Anyone else? Yes, Julie. Thank you. Julie Simmonds, Panmure. Just wondering in terms of the proposals that you get from the pharma or biotech companies, how much help they need in terms of t urning them into a proper challenge study, and how often do they come to you asking for things you can't provide, and what would those be? Yeah. Basically, as mentioned, why we include our scientists in the proposal preparation process or even initial discussions with the clients, is due to the fact that we do everything from them from the very scratch. We are not a CRO when the client comes with a synopsis, study synopsis, and we just need to quote for that, but we really work with them to design the study. We even show them sometimes the ideas comes during those conversations, you know, what additional groups we could add to the study, what, you know, what can we check in those challenge studies. It's definitely very from scratch, I would say, working with them. Your other part of the question was when we cannot do something. Yeah, is there anything you can't do? Actually, the recent congresses I've attended, you know, speaking with clients, I've seen a lot of interest in new challenge models. There's a variety of those clients who comes to us and saying, "We need this model. Can you develop it for us?" We need, as mentioned also in my slides, you know, a strong commercial background to do so. We won't develop one for one single study, you know, a model, but if there are two, three clients that we could work on it, we would definitely go forward and do it. What is very nice with my scientific team, each time I can bring to them the craziest project, and they are considering it. You know, is there a way to do that? How we can do it? There is very nice approach from the team, you know, that we can do very much, but of course, there are certain things that we are saying no. This is where working with some of the clients really early on matters because, for example, if a small biotech isn't talking to us, they go to their investment and get an investment to do a study which they think is gonna work and then come to us to be told, "Actually, that doesn't work in a challenge model." They then need to get new investment. That doesn't help anybody. Mm-hmm. That's why we do go to these conferences with the scientific team and the BD team to talk to our customers very early, so they're actually designing the study and then going to raise the money for it, so they know that they're designing the right study and getting the right funds for the study. Biotech, sorry, Big Pharma are a little different. They're so used to doing it all in-house and giving it to you, so that's a bit more diplomatic, shall we say? We say, "You could do it like this, but" and then point out the alternatives and normally coax them around to where it needs to be. That's a case of matching the skillsets, you know. They know about their product, but we know the nuances on that. The Big Pharma we have repeat business for, we're now very used to that model. When we first start with Big Pharma, yes, there's an educational piece about you need to tweak what you're doing to get the right answers. Thank you. Carl? I can't say no to him again. Second time lucky. It comes back to this, the challenge agent itself. Aside from the bespoke models, is that like a real intangible value or a sort of a barrier to entry that you have internally to know how? Then flipping over to Eglė, is that like a real selling point for you as a USP when, I guess Douglas could comment that, you know, your ability to work with the right challenge agent and get it just right, like, you know, Goldilocks, not too hot, not too cold. Mm-hmm. Is that something that perhaps we as sort of on the sales side have missed that intangible value? That's an excellent point, and it definitely is a barrier to entry. There are many people around the world who can grow a virus in an academic lab. There are not many people around the world who can take that and make a medical-grade version that the regulators and ethical review boards would be happy to inoculate someone. It is a really unique skill set we have within hVIVO of being able to make challenge viruses and putting together those different, sometimes competing problems of making a virus that reflects what's in the community, keeping it pathogenic, but also abiding by all the regulatory standards because they're unlike a vaccine, where you can pick up a regulatory book, it tells you the pathway you have to follow. There is no regulatory book that tells you how to make a challenge virus, which means it's gained knowledge. You know, it's not sitting out there by the regulators about how to do it. You have to interact with the regulators and say, "We're doing this. This works well, doesn't it?" Re-bring the regulators on board with you. Because we've been doing that for so long, we can now do that. It's not something someone could just start doing and expect it to be successful. Know-how is definitely a barrier to making new challenge agents. Financing is also a barrier. It costs to make a new challenge virus can cost as much as GBP 2 million, depending on the virus. You've got to do a small study to characterize it, which means we've got to work out what is the dose that we need to give before we can then test products. These are the things that are expensive to do, which is why the end-to-end sales, when the customer's paying for it, is ideal. That's not always possible, which is why having some of the GBP 20 million in there, I'm always asking Stephen, "Can I use some of it for a new model?" He says, "Show me the return on investment." If we have two or three clients which are interested in it, that's all it would take to make that profitable. Yeah, I think from what Andrew mentioned and what I mentioned before, about the new models and adding those, I think many of clients who are working in a space with the models which are not yet developed or not well developed, they see the challenge data coming from other companies working on those developed models like RSV, influenza, and we want the same for their company. Therefore, right now, we really see a huge interest in different models which we haven't seen an interest before. For us, it's only to decide how much of a commercial benefit we risk and how much to invest in those discussions. Cool. I think everyone's getting hungry, which is good. Right. Just on closing, hopefully, we've kind of sent out some key messages to you guys as to, you know, why hVIVO is a good investment case. We are the world leader in what we do. I think that's as undoubted with regards to the number of challenge trials we have, we've done and the models we've done. We know the market is increasing. I mean, we know there's more research in antivirals and vaccines against viruses. On top of that, the number of challenge trials and the size of the challenge trials is also increasing. Even if the overall infectious disease market was stagnant, I still expect to see a growth in the challenge study market because the reason why people are doing challenge trials is expanding every day. We have a scalable infrastructure. We have already invested this year in expanding our screening facilities, our beds, our laboratory services to cater and meet the growing needs of the market. We've invested significantly in our FluCamp initiative to be able to meet the needs of our clients who need all these healthy volunteers to come in and take part in these clinical trials. I think as Douglas and others have mentioned, patient recruitment or subject recruitment is the single biggest challenge in clinical research, okay. 80% of the trials that fail in or delayed in the timeline are delayed because of poor patient enrollment. The capacity in itself is not a rate-limiting factor for us. We've shown previously that we've been able to set up a new capacity within a four-month period. It generally takes us six months from award to the study being ready to go into quarantine because you have to get regulatory and ethics approval. Okay, from that point of view, I don't see capacity as a limiting factor for us and our growth. We have a strong customer base, and I think we've shown already that from a regulatory and a financial point of view our customers have benefited. I think Andrew showed three different customers who got breakthrough status based on challenge study data. Douglas showed a company that was bought for half a million pounds based on human challenges. We're already seeing the fruits of the data produced through challenge studies. I think having the big pharma come to us again and again gives me a lot of confidence that what we're doing, we're doing right. We know big pharma are wealthy institutions, but as Douglas knows, they're very frugal. They don't like spending a penny. They do lengthy due diligence before they commit funds. The fact that they keep coming back to us year on year, I think, like I say, means we have a very good, robust model when it comes to challenge trials. The new end-to-end programs that are running, two already signed up, more being negotiated, are key messaging that, I believe. This year, I was especially pleased that we were able to do some cross-selling between the two different entities, Venn Life Sciences and hVIVO. Two of the customers from Venn Life Sciences were converted into challenge study customers, which was really good to see. As we move forward, we're now seeing full service being provided across the two companies on single challenge trials. Venn Life Sciences is providing different phases compared to hVIVO, as Egle mentioned. I mean, financially, I think, I hope you all agree we are in a very strong position. We are reiterating our guidance for GBP 3 million of revenue this year, 13%-15% EBITDA margins. We've got healthy cash position, and we're giving, I think, good growth projection for next year. Again, I would like to say that's our minimum. We wanna do better than that. I think the underpromise and overdeliver is a key sentiment for me. I think historically, we may have been guilty of overpromising at certain stages. I think I've heard this comment that, "Oh, your share price is depressed because of the baggage you carry." Okay. A lot of nodding here. I'm fully aware that we wanna overcome that. The only way I can do that is to be able to set the right expectations and deliver on those expectations. We will be growing our revenue and EBITDA year on year. We've shown that last year. We'll show that this year as well, come end of January. Positioning for growth, yes, especially considering what we currently have with regards to the amazing management team we have in place. The key focusing in sales, especially with the scientific team, moving and educating and coaching our potential customers in that. My final message really is I know all of you guys and us too, we focus on the EBITDA and the margin and the profits and so on, but I think sometimes we forget that we do actually make a difference. We as a company have made a difference. This was an article in The Guardian, published on Monday this week, where the author mentions how human challenge trials are a way of moving and accelerating drug development. She mentions that the fact that these human challenge trials have given us hope finally for some RSV vaccines. We have ran all of these human challenge trials for the RSV models. I'm not saying without these human challenge trials, there'd be no RSV vaccines, but I can say hand on heart that we have definitely accelerated that process. Through the use of human challenge trials, we hope that infants and the elderly will be able to get access to safe and effective RSV vaccine for the first time in their lives. That's all we have. Thank you for your time. I hope it was useful. I hope you've had some good insight, not just me selling hVIVO to you, but also from a operationally scientific point of view. I'd like to extend my thanks again, especially to Douglas and Peter for their attendance and for their contributions to the meeting. I hope they will stay here for lunch, and hopefully you guys as well. Thank you very much and have a great day.