Medivir AB (publ) (MVIR) Earnings Call Transcript & Summary

Good morning, and welcome to Medivir's R&D day. It's nice to see that so many of you have decided to come and listen to us live, but I know that we also have a lot of attendees that have connected through the web. I hope that we can offer you an exciting day, we think so. It will be a mix of educational and new data presentations. So I think the combination will really teach us a lot about liver cancer, a lot about MIV-818 and the opportunities that we see there and with other assets that we have. Let me first say that it's good to take a look at this note and the forward-looking statements that are included in that. This is a slide that we always have, by the way. So the agenda today really starts with Dr. Evans, who will provide us with a lecture on primary liver cancer, and I'll come back to that later on. I think it's a great introduction of the day. Then Christina Herder, who is our EVP and Chief Operational Officer, will talk about the market for liver cancer drugs, which I think is very good to give us an understanding about the size of the opportunities that we have ahead of us. Then we will make a break and after each presentation, you will get an opportunity to ask questions, so please don't interrupt the speakers during their presentations. And those who join over the Internet will also be able to submit questions by e-mail, and we can take those if we have time, which I think we will, so please submit e-mail questions as well. Then after the break, we will have the focus on MIV-818, so Fredrik Öberg will start out presenting the background from our nucleotide prodrug pipeline where MIV-818 comes from and the scientific basis for the program, and then Karin Tunblad will talk about MIV-818 and the Phase IA study and the Phase IB study, so I think you will find that quite exciting. And then I will provide a brief summing up of our program and where we are. And then we will have time to mingle, and you will be able to interact with the staff of Medivir and have nice interactions, I believe. So with that short introduction, I think that we should move on to Dr. Evans' presentation. And let me see here if we can move on, and Dr. Evans is obviously very well recognized professor and scientist. He is -- let me take a look here so I don't state the wrong things, he is a Professor of Translational Cancer Research and Director at the Institute of Cancer Sciences at the University of Glasgow and he is also Head of the Glasgow Experimental Cancer Medicine Center. So he has a lot of formal appointments, in addition to this as well, and I'm not going to go through them all. I can say that he has been running a tremendous amount of clinical trials and also has published close to 200 scientific publications. And he's a little bit special in the sense that his kind of expertise goes all the way from preclinical research into clinical research and through translational research, which is obviously very important because that kind of research may help us to use preclinical research in a better way to predict the outcome of future clinical studies. And if we get better understanding on how to do this, we will save a lot of money, a lot of time and potentially move much quicker to approved medicines. So Professor Evans is a true expert, and we are very happy that he has taken time to come here, I know that he has a very busy schedule, and to provide us with his perspective on liver cancer. So please, Dr. Evans. We are very much looking forward to your presentation.

Thank you. Thank you, Uli, and thank you for the very kind invitation to come back to Stockholm. I was actually here 3 times last year, giving different talks on liver cancer, and so it's always a pleasure to come back. But certainly, even though I've been here 3 times last year and probably about nearly 10 times in my life, the only words I can say are, "hey and tack." So my apologies, I can't deliver this in Swedish. But I will talk about something, which has caught many healthcare providers by surprise, and that's the prevalence and the big clinical burden that we currently placed in oncology of hepatocellular carcinoma. And I will also mention intrahepatic cholangiocarcinoma as another liver predominant separate primary tumor as well in the course of the afternoon. And I have many things to -- as a medical oncologist interested in drug development, I have many things to disclose, and these are just some of the things I admit to in public. And I can talk about more of these. I will make mention of some of these compounds belonging to some of these entities in the course of the afternoon. And I also realize that I'm speaking in a room with no clock, which is always a danger, so you might have to make some very rude signals if I go away over time, which is quite possible. Now. Up to now, liver cancer has crept in under the radar. It has not been considered to be a major problem and that's wrong, completely entirely wrong risk perception. And if there's one take-home message from today that you will take away is, this is a big problem and it's going to become even bigger. And the perception that this is not something that we should be spending much time on as oncologists mainly comes from the perception that it's predominantly a disease of the Far East. And again, that is not true. This is the fifth commonest cause of cancer worldwide and is the third commonest cause of cancer death. Not many people have appreciated that, given the much greater emphasis that we place on certain tumor types when you think of the amount of investment that goes in the management, say, of leukemia, but yet this is a vastly greater incidence and prevalence in the world. Now it's quite true to say that it's predominantly a much higher incidence in the Far East, this is the number one cancer in China, and they have a 1/4 of the world's population. There's 1 billion people and hepatitis B is endemic in rural China. So in some parts of the world, this is their big cancer problem, a bit like lung cancer is in Glasgow and some parts of the western world. So this is their equivalent. And this shows that the number of new cases, yes, are greatly increased in the Far East where it's predominantly related to viral hepatitis, but has much higher incidence rising all the time in the west as well. Now the challenge we have with this disease is that the vast majority of these patients have got 2 diseases in the same organ. They have the chronic liver disease, which predisposes to their liver cancer, and they also have the primary liver cancer. And in fact, in -- certainly in Europe, more than 90% of patients with primary liver cancer have got cirrhosis as well. About 20% to 30% of our population are due to hepatitis. 10 years ago it was mainly alcohol related liver disease. Most of the patients I now see in the clinic have nonalcoholic fatty liver disease, obesity, diabetes, hypertension, so different lifestyle choices at -- in the 70s, 80s and 90s. But when you think of the prevalence of excess weight, obesity, diabetes, type 2 diabetes and high blood pressure these days, this is going to become an even bigger problem, even if we eradicate hepatitis B and C, which we're not likely to anytime soon. So this is a really big problem. And if you just think of the hepatitis B worldwide burden, there are -- apparently 380 million people are hepatitis B infection worldwide, that's a lot. And hepatitis B is actually recognized as a carcinogen by the WHO. The carrier rate in endemic -- in China to be about 20%. Hong Kong, for example, has got a very high incidence. And they have a much higher risk of developing HCC. And that is even greater, again, with some things like aflatoxins, which are found in moldy peanuts, which is a stable diet in some parts of the world in rural Far East, where this is an endemic disease. Now. So the first take-home message is, this is a prevalent disease, it's a big problem and it's not exclusively a disease of the Asia Pacific region. And for a long time, this and still is the treatment algorithm we use. And I'll talk you through a bit of this because it sets everything else into context. So there will be some kind of diagnosis early stage. Remember what we said, this is a disease of 2 organs in the same -- 2 diseases in the same organ. So what you might want to do based on the anatomy, you may not be able to based on the synthetic liver function; and what you might be able to do based on the synthetic liver function, you might not be because of the anatomy. So there will be some with -- who will be candidates for surgery, a partial removement of the liver, partial hepatectomy. Now clearly, you can do that if you've got a well-defined abnormality, but you must have still sufficient nonmalignant liver to be able to survive and, of course, these patients have cirrhosis. So in those cases, transplantation is indicated. Approximately 10% to 15% of patients will have surgery with or without transplantation and, again, the recurrence does occur despite that. There will be some who will be not suitable for surgery for nonliver reasons, that is, they have comorbidities, they may be unwell for the reasons, and they sometimes get ablation. So about 20% to 30% form in that early treatable, potentially curable group of patients. Then we have the intermediate group, who have historically been treated by transarterial chemoembolization, catheterizing the hepatic artery, chemotherapy directly into the liver and embolizing some of that. Now the downside of that, of course, you damage some of the nonmalignant liver. And you have to be quite careful on how you choose your patients for TACE, it can't be done in those with vascular involvement, not recommended for those with disease outside the liver. And then there's those who historically would be candidate for new agents, systemic treatment. And we're well used to moving this algorithm from left to right. People may start off having surgery, then they might be recur, they might be a candidate for TACE, or they might be just candidates for new agents de novo. And clearly, TACE is a procedure we still do for patients with liver-only disease. But if you look back at the meta-analysis that said that this gives you survival advantage over best supportive care, it's driven by a couple of -- only 2 of those studies in the meta-analysis, which predominantly had patients that -- and the criteria of whom we perform TACE these days. A lot of it is because we can rather than we should. And at some point, we need to have a conversation and we are, and we haven't found the answer yet. At what point do you move from TACE to systemic treatment even if everything is confined to the liver? And at what point, when you do repeated rounds of TACE, should you stop doing it because the last TACE was probably one too many and you've damaged too much of the synthetic liver and they're no longer capable of tolerating systemic treatments? So if we did have a liver activity prodrug or other forms of systemic therapy that could replace TACE with the morbidity associated with that, then I think that would be an advantage as well. Now the world changed in -- I'm just going to go very quickly, I've mentioned all this on the surgery. The world changed with this trial in -- published in 2007 now, which was the SHARP study. This was a randomized trial of placebo versus sorafenib as first-line treatment of people who are not suitable for surgery or TACE or had relapsed following surgery or TACE. And they had well preserved liver function. Cirrhosis is described as A, B and C; A being well preserved liver function, B being impaired, and C being you're more likely to succumb to your cirrhosis than you are to the cancer. And clearly, if you want to demonstrate a drug's activity against the cancer, you want to exclude those patients who will, irrespective of how good your treatment is of liver cancer, still succumb at the same time because their liver is failing due to cirrhosis. They are, obviously, excluded from the clinical trials and rightly so. So these are patients with well-preserved function, about 600 patients, and well done to the international community for doing this so quickly. This was a non-Asia Pacific trial. It was entirely in the west. There was a repeat study done, which reported afterwards in Asia Pacific patients with a similar outcome. Subsequent trials have all been done with a mixed economy of patients from all over the world. Now this for a long time was as good as it gets in primary liver cancer. And again, I stress this is primary liver cancer, not metastatic disease to the liver. This is primarily liver cancer, HCC, hepatoma. This is the first and, for a long time, only positive trial in the first-line setting in this disease. Sorafenib, hazard ratio, yes, encouraging, but if we look at the median survival of placebo, 8 months; median survival with sorafenib was around 11 months. Now a word of caution, every time we've repeated that trial since 2007, and we view sorafenib as the control arm, it's always done better than in this because -- this was the first drug in this disease. And as people get more experience of managing the disease, people get more experience on managing the drug, then the outcome is obviously better, including patient selection. And it's been a challenge actually for the clinical community because you make assumptions for the control arm of your study based on this. And of course, it's inappropriately low because we've always done better. And therefore, sometimes the statistics has gone against us. I'll show you some data on where we really are with sorafenib these days. And that was as good as it gets. Now that doesn't say we're short of molecular targets in this disease. And I'm not -- you'll be relieved to know I'm not going to talk through all of these, I'm just going to pick out on some. Yes, there's lots of drugs, but a lot of these have actually failed, either head-to-head versus sorafenib or in combination with sorafenib against sorafenib. And I can remember one of the ones we did, which was combining an EGFR drug, erlotinib, with sorafenib. And yes, we got higher responses, but shorter duration of treatment and really bad skin toxicity. Sometimes when you try and give doses you would of the drugs in other diseases to these patients because of the liver function, which often is involved in drug metabolism, it may be more challenging. And I think we've learned that. Now I will talk about this drug because this shows what we can do. So this was a drug I first got involved with, again, about 15 years ago when we called it E7080, and I confess I still call it E7080, and it's now known as lenvatinib. So we did the first in-human testing like we are with MIV-818 right now. And we took it all the way through and is now licensed -- the second drug license for first-line treatment of HCC. Note here that this is not another me-too version of sorafenib, this is not a different flavor of sorafenib. This is a different drug, overlapping therapeutic targets, but also has different therapeutic targets, most notably our friends here, FGFRs, fibroblast growth factor receptor family. We know that FGFR19 (sic) [ FGF19 ] binding to FGR4 is an important player in at least a proportion of these patients. Now that's -- I'm not going to say any more about that because clearly, that's not the source of today's discussion. But this led to a noninferiority trial. Now a word of caution for nonmed biomedical statisticians amongst us. A noninferiority doesn't mean that you've just gone for something, which is a little bit less robust. If you go for a -- if you want to show there's something superior, you calculate the sample size required to do that; if you want to show there's something is definitely nor worse, your study is actually bigger and the statistics is actually more stringent because to say that something's definitely not worse, you actually need much more confidence. If, for example, you're doing a trial of treatment versus no treatment, you definitely want to show there something is not worse. So here, rather than compare with a placebo, which wasn't possible to do in 2018 when this was reported, this was a noninferiority comparison of sorafenib and lenvatinib. A word of caution, the doses of lenvatinib are lower here than in the recommended based on our Phase I work because of the metabolism within the liver. Now I showed you patient characteristics. I'm not going to talk through this, it's not relevant for today. Only to highlight, this is a typical liver cancer population. So this is a typical population with HCC. The peak age is around in the early 60s. They're predominantly male, and we have a predominantly male audience here today. So this is a disease where 85% of the patients were male, it's about 3:1, it's about 75% male, 25% female at the moment. As some of our lifestyle choices in the West take on, maybe that balance will change. But at the moment, it's predominantly a male disease. And again, I can comment that most of these studies, about 2/3 of the patients came from the Asia Pacific region and there are good performance data. But we haven't cherry-picked the best actors here. These are patients that, again, predominantly 70% of them either have extrahepatic spread or they got involvement of the blood vessels in the liver. And just some imbalances for the people who are HCC experts, the sorafenib had a bit of slightly better prognostic group because they had more hep C patients, which do better with treatment and well -- as well as a lower AFP level. But again, that's not relevant for today's discussion. And this shows noninferiority. It'd be difficult to wedge apart those 2 growth curves. So this meets its primary endpoint. Only after you've met the primary endpoint with noninferiority are you allowed to interrogate the secondary endpoints. Now these secondary endpoints, with what we call progression-free survival, superior with lenvatinib compared to sorafenib. In other words, the period that you keep the disease stable for was better as well as the time to progression because obviously survival may be driven by noncancer-related things, so the time to progression. So yes, we have noninferior survival but superiority of time to progression and also progression-free survival and objective response rates. Now us oncologists are very keen to show what we call a waterfall plot. This is what we mean, so the educational bit. So this is a waterfall plot, here they are, probably going to take out the planes on the London airport to this thing rather than show the -- but this is a waterfall plot here. And as you can see, so the way we call responses in cancer medicine, if you do a CT scan before and a CT scan afterward and you shrink it, that's called a response by arbitrary amount. So if you stay, we'd add up the size of all the lesions on the CT and you start at 0. If it shrinks below that line, that's an objective response; if it's above 20%, that's progressive disease. And of course, when people report stable disease on CT scan, maybe it's just you haven't waited long enough for the scan for things to get bigger. But as you can see, with a waterfall plot, you can see that everything is below the line in the majority of patients and gives you better visual representation of what's actually happening on the CT scan. So that's why we show waterfall plot. Now again, you may see some of those related to the updated MIV-818 data. And so it's important to explain what a waterfall plot is. Now on that basis, in 2018, this became license. We have 2 recognized first-line treatments in this disease. We have sorafenib and lenvatinib. And -- I didn't dwell on the statistics when I showed you that non-inferiority curve, but sorafenib was coming out 12, 13 months; levatinib 13, 14 months; that is the median survival in this disease. Yes, we do better with sorafenib than we did in SHARP in 2007, but the median survival of this disease in the first-line setting is around 13 months, and therefore still better than placebo, but after 15 years of clinical trials in this disease, that's as good as it gets so far. And I think there's plenty of potential development in the future. Undoubtedly, we need better drugs. If we get better drugs to get rid of what we have now, better drugs to get rid of TACE and RFA and everything else. Now at the same time, we wait 15 years for another drug to be licensed and you get 3 or 4 at the same time. These are second-line treatments. And I can remember when we started using sorafenib, we were approached to do some second-line treatment studies, and I said, "No, no thanks. I don't think we'll ever manage to get patients into second-line treatment." But now here we are already in a short space of time, not only we're trying to think what's the best first line, but what's the best treatment for second or subsequent lines of therapy. I didn't show the data suggests that there was an imbalance in the lenvatinib/sorafenib in favor of sorafenib having more second-line therapy, that's a discussion for another day. So this is a positive second-line study. The patients had tolerated -- which is an issue, tolerated or benefited and stable disease with sorafenib who then went on to regorafenib or placebo in the second-line setting and there was a survival advantage. And here, we can see that median survival with sequential drugs, sorafenib followed by regorafenib, pushes overall survival out to about 24 months, I think, in this disease. And if you look at the lenvatinib data and those in the trial who got second-line treatment, with 2 lines of tyrosine kinase inhibitors, yes, you're getting out to about 24 months, but a word of caution, in my practice, and it's pretty well reflected in everybody else's, about 20% to 30% of patients, certainly in the western countries, go on to second-line treatment. These are often not fit enough to, often get one go at it. And so there's a big drop off between first- and second-line treatment, but still a very big clinical and problem of unmet need. And at the same time, this shows cabozantinib, another tyrosine kinase inhibitor. Now there's a lot of names being thrown around here. But if you think sorafenib, lenvatinib, cabozantinib, regorafenib, they're all variations of tyrosine kinase inhibitors, they're all variations of drugs that hit some of those molecular targets I showed at the front; angiogenic, fibroblast growth factor. They are all of the same class of drugs with some subtle differences and some overlap of targets as well as overlap of toxicities. We've not dwelt on toxicities today, we can come back to that if anybody is interested. And also, ramucirumab, which is an antibody this time that targets some of the angiogenic growth factors, has also had a positive second line study in selected patients with high alpha-fetoprotein. So we now have 2 positive drugs in the first line, 3 in the second line, but mostly attacking similar but overlapping and some subtle differences in the molecular targets and, again, with a median survival of 13 to 14 months and some proportion of patients get to second-line treatment, surviving in a median of about 24 months. So plenty of room for improvement in something that's a big public health problem globally. Now you can't go to -- talk to an oncologist these days without immunotherapy raising its hand. And of course, we all like to think we've been involved in immunotherapy from the start, but I think most of us have jumped on the bandwagon over the last 10 years. The very first -- I mean, I could ask you when the very first immunotherapy trial was done, and it was actually in 1880s when somebody called William B. Coley, who was an American New York surgeon, noticed that patient's Erysipelas skin infection, had a very bad skin infection, when it got better, the tumor improved. And in the 1880s and 1890s, he was injecting bacterial toxins into patients to try and induce an immune response to treat the cancer. Now bear in mind, this was about 60 years before penicillin was invented. That's very brave drug development. We don't do that these days. Immunotherapy has moved on. But it's an interesting anecdote. When you have time, go and look at William Coley on the Wikipedia page, it's actually -- it's a fascinating read. So this is the hallmarks of cancer. You won't go to any oncologists' lecture without them showing you The Hallmarks of Cancer, Hanahan and Weinberg. And they're 2 iterations, and the big difference in the second iteration is that they actually have drugs that target all of the processes built and overlapped on the hallmarks of cancer. So every malignant tumor will have an aberration in these hallmarks of cancer as part of the carcinogenic process. Which one is the causative lesion may be different from one to another. And of course then, we have to introduce the old tumor heterogeneity concept because no one breast cancer is the same as another, not one lung cancer is the same as another; and even within the same patient, there may be different molecular profiling in different metastatic deposits, we think. And therefore, all of these are a very complex algorithm of potential aberrations occur in cancer cell. We want to find what's the driver abnormality, not the ones who come along for the ride, the guy behind the steering wheel with his foot on the accelerator, not the one clinging to the roof rack at the top and, therefore, not so much consequence. Finding what the driver is and its different, different bases. But one of the hallmarks of cancer is avoiding immune destruction. If your immune system was doing its job properly, it should eradicate the cancer cell because it's a foreign protein, but it's not, you have tolerized to it. Now everybody says, "Well, okay, this is not chemotherapy, this must be a very elegant way of eliminating cancer cells." Well, actually, it's a very complex process because the cancer cells have to be released, they have to be presented to the immune system, they have to be -- the immune system has to be primed, the T cells then have to traffic to the tumor, it's no good having them in the bone marrow and not traffic into the tumor, they have to be able to infiltrate into the tumor and overcome these checkpoints. Now you'd be forgiven for thinking that immunotherapy begins and ends with T cell checkpoint inhibitors. Now checkpoints are on cells for good reason. If we didn't have checkpoints on cells of the embryo, the human race would die out because the immune system would destroy us. And therefore, checkpoints are there for a good reason, but they're present in cancer cells for the wrong reasons when they acquire these checkpoints. And if you want to know the importance of this, the Nobel Prize for medicine in 2018 was awarded jointly to somebody who described CTLA-4 and PD-1 as the 2 checkpoints that currently are the major focus for immunotherapy advances and here we are. So these are CTLA-4 and PD-1. A lot of focus has been on there. And clearly, they've transformed the drugs, things like melanoma skin cancer, lung, breast -- sorry, renal and bladder, to a certain extent. And then there are some immunologically cold tumors where you have no benefit, colorectal, a small proportion of pancreas cancer, for example. Now most of the efforts have so far been on CTLA-4 and PD-1, including in liver cancer. Now we know that the liver is an immunogenic tumor. It has plenty of reasons to stimulate the immune system. And these are just some of the salient features. I'm not going to suggest this, but this is the poster child of messed up metabolism and inflammation in organ. You've got a cirrhotic, inflamed, burnt out liver which then becomes malignant. So this is in the background of inflammation in its broadest sense. Now this is one of the first studies that I was involved with, immunotherapy in liver cancer, and it was a drug of nivolumab, Bristol-Myers. This was in patients who had failed sorafenib or were not suitable for it. And I think what we do see, and this is what we call a swimmer's plot. I have to introduce a swimmer's plot. You've had your waterfall plot, now we have to do the swimmer's plot. We love our plots in oncology. So in the swimmer's plot, you imagine you're looking down the top of the swimming pool, and they're all in their lane swimming out, and as you can see, you're getting responses fairly early on, but they're durable. Now one of the differences that we see with immunotherapy is that responses can be durable, including when you stop giving the drug, so they don't always relapse like they do with the target -- tyrosine kinase inhibitors like sorafenib, lenvatinib, cabozantinib, regorafenib, et cetera. And we are seeing some encouraging results. Now a word of caution, this is a nonrandomized Phase II study, there's no comparator trial. And when it was randomized against sorafenib in the first-line setting, it did not meet its primary endpoint. It was published last year at ESMO in Madrid in September. There was a trend, but it did not reach its primary endpoint. The p-value, which we always aim to be less than 0.05 was 0.07, didn't quite get there. So what was going on there? Well, this now is pembrolizumab, another anti PD-1 antibody, this time from Merck. And again, similar encouraging results in a nonrandomized Phase II in the second-line setting. And here, we have a randomized trial of pembrolizumab versus placebo, best supportive care. Now they hedged their bets. They went for 2 primary endpoints, progression-free survival and overall survival. And if they'd gone for one of them, they would have got a positive study, but when you go for 2, you don't go for 0.0, 0.05, you are setting the bar higher and they missed out on both. Again, as you can see, in any of the study, we're quite happy the curves are beginning to separate, and maybe this is positive, but it did not meet its prespecified primary endpoint. So here, we have 2 first line -- sorry, 2 second-line T cell checkpoint inhibitors, nivolumab was then taken in the first-line, pembro in the second line, that shows a trend, but not -- does not quite reach the primary endpoint for superiority over those tyrosine kinase inhibitors. So what's going on there? Well, most of us assume that these drugs are probably insufficient on their own; that we need to sensitize the cells, cancer cells to T cell checkpoint inhibitors. And there's a way you can do that in the laboratory and we and others have been trying to do that, both in liver and in pancreas cancer. So I think this brings up the need for combinations that these drugs, unlike melanoma, are probably not going to transform liver cancer on its own. And right on cue, we have some fairly fresh data which is this study, again, another one that, I and my colleagues are involved with, taking the combination of atezolizumab, a PD-L1 antibody from Roche with bevacizumab, an antibody targeting VEGF, one of the vascular androgenic growth factors, overlapping targets and with drugs like sorafenib and lenvatinib, which have got a broader spread of targets compared to sorafenib head-to-head 2:1 randomization. This has not yet been published, but this was presented in the public domain at ESMO Asia in Singapore in November, and again at ASCO GI in January in San Francisco. And there are 2 co-primary endpoints, and this is overall survival, certainly a 6-month survival, and we don't have the median survival for the experimental arm as of yet, it's predicted to come out around 18 months maybe. And here's the median survival. Again, 13 months of sorafenib, always better than the original SHARP study. And we also got confirmed progression-free survival, primary -- co-primary endpoint. Again, superiority at the 6-month PFS and overall survival. So it does look that we now, again unpublished, and therefore a word of caution, but presented in the public domain and fairly robust data, that we have a combination of a targeted antibody with a checkpoint inhibitor that has now shown superiority over sorafenib, which is the first time we've managed that in approximately 13 to 15 years of trying. Nevertheless, we have still got a significant problem in that there'll be some patients who would be ineligible for this because one of the major challenges of bevacizumab is hypertension, high blood pressure, plus the fact that it can increase the risk of bleeding. Now of course, given that these have got chronic liver disease, portal hypertension, they may have esophageal varices and therefore, a word of caution that these patients will need mandatory endoscopies beforehand to make sure that they don't have any undiagnosed varices, which could lead to fatal bleed. It was a very low percentage in the trial, but once you start moving things outside of a trial context, then I think you need to be careful. And again, there'll be some patients who can't take an immunotherapy drug because of risk of immune-mediated toxicities, which we haven't discussed, but I'm happy to take questions about that. So where do we go -- where do we think for the potential for a systemic anticancer therapy, or SACT for short, is in the landscape of liver cancer? Well, we've got first- and second-line agents already approved, but still relatively disappointing overall survival, plenty of potential of improvement. We're now beginning to think, well, can we give these in combination with TACE versus TACE alone? Certainly, that was done with sorafenib, U.K. academic study resoundingly negative. But now that we have better drugs, can we give it with TACE? Do we give it after RFA or surgery? A word of caution, if you've had a liver transplant, then clearly we can't give this regimen, you can't give a checkpoint inhibitor to somebody who has been transplanted because of the risk of immune-mediated transplant rejection. Therefore, a word of caution there as well. Can we begin to move patients with more active drugs from right to left in that algorithm, drive them from advanced disease through to potential surgery? Can we begin to combine them with these local regional therapies? And I suppose the intriguing thing for Medivir is, if you have a liver activated prodrug and getting high activity within the liver, let us say, for sake of argument, can you replace TACE and would this be a partner with the potential for combining these drugs in the future? I just throw that out for consideration. So where do we go in then next? If we've got now a number of agents all coming together, how are we going to fit who should get what first-line treatment, who should get what second-line treatment? And I think we've been slightly late to the party with liver cancer and compared to, say, lung, breast, even pancreas, I think these multi-arm molecular stratified studies. In other words, if you have one target, HER2 -- Herceptin in breast cancer, you do a study looking at that target, you get your results. Yes, you can do that. But if you've got multiple targets and different subgroups of the different segments of the orange, would it be far more efficient to do these all at the same time? So working out what the pathways are in the lab and in the animal models, looking at vulnerabilities if you have a particular activated pathway to the range of drugs that we have and then planning one of these multi-arm molecular studies, whereby we allocate, maybe there's a Wnt group, maybe there's an FGFR group, maybe there's an immune sensitive and immune resistant group, and then we interrogate each of those with different drugs at the same time so that we begin to become -- precision medicine is the buzzword at the moment that we begin to look at tailoring the treatment through to the type of liver cancer we're treating. This is a heterogeneous tumor group with a heterogeneous etiology and probably heterogeneous biology as well. One of the challenges we've had historically in liver cancer is that this is a disease that's been made -- diagnosis made radiologically without resorting to biopsies for some very well-characterized reasons, and a lot of the tissues that we have, have come from those who've had a resection, and therefore how representative is this of advanced disease. So I think as a community, we need to think about doing more biopsies for these patients so that we can learn more and try and become better at the treatments that we actually have as well as developing new treatments. And of course, there are challenges in doing repeated biopsies. There's practical challenges, there's potential morbidity to the patients, and there's potential challenges as well in terms of resource. But an alternative is the so-called liquid biopsy, even I can take blood these days. And so you take blood and you begin to interrogate the molecular profile in the circulating blood, cell-free DNA and circulating DNA. There's international conferences on this these days how representative this is and what goes on the tumor. And this may be a way, in real-time, sequentially to be able to tailor our treatments to the patients. A lot of this is speculating for the future based on scientific validity right now, but this is the way the field is going, not just in liver cancer, but in oncology, in general. And therefore, we'll just end with intrahepatic cholangiocarcinoma. Again, this is a worldwide incidence. And you'll see -- I'm sorry, I haven't got Sweden on here, by the way, Denmark and Finland, my apologies, that's a bit of faux pa, isn't it? There are some parts of the world who've got a very high incidence, for instance, Northeast Thailand has got the world's highest incidence. And one of my other jobs is I sit on an advisory board for one of the universities in Thailand who've got a program on immunotherapy in cholangiocarcinoma. I'm due to go out to there in a few months' time, not sure that's necessarily a good idea. My wife is not too chuffed on the fact that I might be doing that in the current context, but we will all see how it goes. So it's been nice knowing you. But yes, it's not a joking matter, all seriousness aside, we have got big public health problems that restrict travel for academics at the moment. But also a big problem is the incidence in Thailand of -- and some parts of the world of intrahepatic cholangiocarcinoma. This is a cancer of the bile duct. There's an extrahepatic, i.e., there's a portion of the bile duct outside of the liver, the gall bladder and the extrahepatic; and there's a portion which is within the liver. Historically, we've grouped these altogether for chemotherapy trials and rightly so because it's a relatively uncommon tumor. But actually, most of the standard of care has been set by the U.K. So just to beat the drum for the U.K. at the moment. We did a study led by John Primrose and John Bridgewater, which is now published last year in Lancet Oncology, that if you remove -- and most of these are inoperable, but if you operate on cholangiocarcinoma and give them chemotherapy, it is better than no chemotherapy in terms of reducing the risk of recurrence, delaying recurrence, improving survival. And the standard regimen worldwide, this is one of the few study -- this is one of the few tumors where everybody in the world agrees on what is standard of care. It's gemcitabine and cisplatin, it's better than gemcitabine alone, median survival is still 11 months. And this was led by a colleague, Juan Valle, Manchester, and the U.K. Group published many years ago now -- 10 years ago, actually, in The New England Journal of Medicine and that's the standard of care. And there's some modest benefit to second-line treatment with FOLFOX, another U.K. study presented at ASCO last year, but the benefits are modest. So this is a disease that is increasing in incidence and crying out for new drugs. There's been some focus on molecular profiling, the intrahepatic cholangio is a different disease than those where bile duct starts from outside. And this shows, again it's one of Juan's review, this shows the profile of biliary tract cancer, and currently, we are looking at fusions of FGFR, it's about 5% of patients; IDH mutations, probably about 20% of the intrahepatic, but again, can you imagine trying to interrogate all of these even in your molecular arm multi-stratified arm studies? That's going to be an impossible study to do. And most of these are very small. For instance, these are single figure percentages of a relatively uncommon tumor. This shows what you can achieve, sorry, more waterfall plots of some of the FGFR targeting, but this is 5% of intrahepatic cholangios. What do we do for the other 95%? There's room for new drugs, and this is not the sole answer. Interesting and clearly going to make a mark in a small proportion of patients. So any questions? Obviously, we're done with the concert. We're bang on time.

Any questions from the floor?

What's your view regarding any diagnostic tools to move the disease from intermediate, advanced stage to an early stage?

Good question. I think what you're getting at is screening. Certainly, in my part of the world, screening is patchy. Now that's partly a resource and patients who've got hepatitis B and C, yes, there's probably recommendations now that we should be screening these folks. I see people presenting with HCC often at the advanced disease stage, who've been in screening programs. Sometimes the first presentation of their underlying chronic liver is when they develop HCC because they've been unaware that they may have got hepatitis C years ago. There is a proportion of patients whose liver disease is driven perhaps by significant addiction problems with alcohol and their health care behaviors aren't necessary with those who comply with screening programs. And then we have the enormous burden of type 2 diabetes, blood pressure, slight obesity with a bit of abnormal liver function tests. And the resource required to do screening programs for all that population is quite substantial. So clearly, we can identify more patients who, as you rightly say, are in that early group of patients with screening programs. Despite screening programs, we still get them in the advanced disease, and the vast majority of our patients are not in screening programs.

So you don't predict any like PSA diagnostic in prostate cancer, where a lot of males run to their...?

Well, I don't treat prostate cancer these days, but my colleagues who do would probably want to have a debate with you, whether we should be doing PSA screening, but I'm not an expert, so I hesitate to speak for areas outside my expertise. If you're asking should we be using alpha-fetoprotein? That's quite difficult because currently in those screening programs, they do have an AFP measure and they have ultrasounds. And if the AFP goes up, then you begin to start looking at cross-sectional imaging. Now if you can just do mass AFP testing in the community, then the problem with that is that AFP can go up for nonmalignant reasons, goes up in liver disease. And there is a proportion of patients with primary liver cancer, who do not have an elevated AFP. So there's no perfect screening test.

Could hep B vaccination have any relation to the development of cancer?

It can certainly reduce the incidence. Now I think it was a paper not many years ago, probably about 20 years ago now in New England Journal of Medicine, looking at the Taiwan experience of immunization against hepatitis B neonates because of the maternal-fetal transmission. And clearly, if you bring in hepatitis B vaccination, the number of patients who get hepatitis B decrease and therefore, the risk of liver cancer decreases. But I showed you the figures of existing hepatitis B. So even if we stopped hepatitis B transmission overnight now, I think it will be decades before the incidence of liver cancer decreases as a consequence. Certainly, the decrease of hepatitis B-associated HCC may decrease, but we're already seeing a rise for nonviral hepatitis, which is certainly in the west, and we export our bad habits around the world is driving a commensurate increase. So I think if you said, is this problem of liver cancer going to go away if we just stop transmission of hepatitis B and C by vaccination antivirals? I still think we're going to have a big problem.

And one question, which relates a little to the study. I thought I would take it now. In the Phase IA and Phase IB study of Medivir, you're also having liver metastasis. But as I read in clingov documents, in Phase II, you're not planning to have liver metastasis, you're just planning to have HCC and ICC. Will IA and IB be good enough when you're having liver metastasis in that going on to Phase II?

Yes. So I think just to bring to everybody's attention how we do drug development. So the first question is the dose, dose schedule and pharmacokinetics. Pharmacology is a little bit sort of forgotten about sometimes in all this trendy molecular biology and immunology but it's still a hallmark of what we do. So we have to establish the dose, and we have to establish the pharmacology, the pharmacokinetics of the drug. Now we can do that in patients where they've got liver metastases or primary liver cancer. When you then move on to the next stage and you begin to go to stage 2, you're asking more specific questions that you think you've established a dose. What is the signal that we're getting in a specific indication? Now if resources aren't unconstrained, I'm sure -- well, I can't speak for Medivir, but if I had -- if I was in charge of a pharma company with unlimited budget, you might want to explore HCC, intrahepatic cholangio and liver metastasis. There are hard diseases that have liver predominant or liver-only metastasis, colorectal being the obvious example, where even now we give systemic therapy with or without surgical removal. If you can downstage patients with metastatic colorectal, you can sometimes render them accessible for hepatectomy, that's a well-trodden path with the chemotherapy regimens we currently have. So you're quite right, we shouldn't forget about liver metastasis. But I guess, ultimately, it's not a question for me, it's a question for colleagues at Medivir, you have to have a certain resource to prosecute a certain number of indications that you can take all through for your ultimate Phase III trial.

And for Medivir, obviously it's a great opportunity to move forward with primary liver cancer, where we would have an orphan drug development program, which is much faster, much quicker, much cheaper. And over time, one can look into other indications.

And if you're looking at liver metastasis, I can speak as a noncolorectal oncologist, but I know what my colleagues get up to. Yes, they are colorectal cancer with liver-only disease and they give chemotherapy and surgery. Doing trials in that space hasn't been so easy. Certainly doing trials or surgery with or without chemotherapy wasn't easy because we tried to do it and everybody ended up giving chemotherapy. When you introduce a new therapeutic, you could do, and they are -- those trials have been done and ongoing. They're pretty big trials these days because of the bunch of superiority looking over existing available therapies. But it's by no means we should exclude that group of patients for future horizon scanning or where we might go with novel therapies that target liver disease.

Okay. Let's thank you for a fantastic presentation.

And I should end with an apologies that I have clinic tomorrow morning. So I will be leaving you before the end of the session. Sorry.

Thank you. So we will now have Dr. Christina Herder presenting you with a little bit about the market opportunity because I'm sure that you're excited about that. We have heard about the unmet medical need, but also the commercial potential is important to look at.

Absolutely. And you have already sort of indicated which market I will talk about, and that is the HCC market that we'll focus on today in the liver cancer, even if you saw the other opportunities around the cholangiocarcinoma as well as other more solid tumors that give specific -- the colorectal that give specific liver metastasis. So already great introduction by Professor Evans, and I think you will recognize a couple of things, even though I've tried to make it into more and understand what the market opportunity is. So looking again at the incidence of HCC, so a number of cases per year, and you see here that in U.S. and EU, it's quite limited. So it's around 40,000 up to 80,000 cases per year in these regions. But as Professor Evans already indicated, the large market is actually in Asia. But for us, I think it's important to see that for a small company like Medivir, the orphan status in these nearby western areas is something that we are interested. We could actually proceed and do clinical development in these areas and potentially also get to the market ourselves. But when we look at the Asian market, it's something where we would like to have a co-development partner to work with. And for advanced liver cancer, you have a 5-year survival rate of 11%, as Professor Evans said, it's actually the third leading cause of cancer-related death in these regions. And the current treatment options are not really providing us with enough survival benefits and that's why we think this is an interesting area for us. And then the next overview really shows a table of all those drugs that you've already been introduced to and that is the currently marketed drugs. And as you see -- heard already, it's only 2 of them that are in the first line of treatment. And the one that has been longest is NEXAVAR, it's called the sorafenib, is the generic name, and that was introduced already in 2007. And as you see, there have been a number of new drugs on the market for the past 3 years, but it's only 2 of them that are first line or standard of care, as we call it, and the other ones have not really shown that efficacy that is needed to make it into first line, so they are all second line. So this is an overview of those drugs that you have been introduced to. And again, you see that the mechanism of action is, there's kinase inhibitors, it's the majority of them. And even the PD-1s or the OPDIVO and KEYTRUDA that might have not been successful in reaching first line treatment that you just heard of. So if we take it more from the historic perspective, NEXAVAR was really the kinase inhibitors, that was the first drug to the market and that was in 2007, and it has been standard of care in the first-line setting. And it didn't have very large effect, but that was the only thing that was available. And some of the more recent drugs have failed to show that, and a good example is the PD-1 inhibitors that everybody actually expected them to take the market. But again, they had very initial good data in their Phase II studies, but then they failed to have an effect that was better than sorafenib when they came in the Phase III study, so they ended up as second line. And I think by listening to Professor Evans, we also do understand why this was not successful because they are really going into treating one of the genetic causes of the cancer, and they didn't really manage all the underlying causes of cancer. So it's a very heterogeneous type of cancer in the liver and that could be due to the many different ways. And it has been the viral infections that were discussed with hepatitis B and hepatitis C and aflatoxins and other lifestyle factors that we will have as human beings and this is related things or genetic factors. So that was the historic view. Really, the market is now changing into -- be more combination therapy, and this was based on the data that was presented by Roche towards the end of last year when they had the combination of their 2 drugs, they are called the TECENTRIQ and Avastin. And it's a PD-L1 inhibitor and it's -- the other one is an anti-VEGF inhibitor. And you saw that data also from Professors Evans, they really showed a significant -- statistically significant and clinically relevant effect in both the 2 endpoints, progression-free survival and overall survival. And this is the first time some -- either monotherapy combination has been able to show that, so that is a breakthrough for the market. And we expect that this will approve -- both these drugs have been approved for other cancer forms prior, so we think that they will be on the market during this year, so they will change the landscape. They -- also they were the first of several other things that are ongoing. So if you look at different sources of what clinical trial is ongoing, there are about 10 different combinations now in the clinical development or about to start clinical development and they look very much the same. It's one PD-1 being combined by some other things. So it could be the multi-kinase inhibitors, like the sorafenib and lenvatinib, or anti-VEGF or CTLA-4. So this is really what it looks like, and they're going to come along. So one of the interesting thing for us at Medivir is, of course, to understand what does this make our compound, why do we think that this would have a place on this very busy market or changing market eventually? And a couple of things that my colleagues Fredrik and Karin will present later on is that we have a very unique profile. And we're very different from all the other proved or all the other drugs that are in development. We are actually having more mechanism that actually affects all the tumor types, not just a specific type of tumor. So we would introduce DNA breaking through our small molecular -- molecule, a lot of the other ones are antibodies or large biological molecules, but we are a small molecule. And we would do that irrespective of the course of the tumor cells. And we can also see later on that the nontumor cell, the normal and the slowly dividing cells will not be affected by our compound. So it has a very -- which is very good. We introduce good efficacy without having a lot of safety problems. So the whole concept is that our molecule will actually be directed to the liver, so it's a prodrug that is orally taken, and then it's actually having its effect directly in the liver. So that is the beauty of this compound. And as we can see, it's likely to be effective also as add-on therapy to all the other compounds that are in development. That's why we think it's so exciting. So to talk about the market, I would also look at what does the global market today look like. So in 2018, we had a market, if you add the different territories with the U.S. and the EU and also Japan and China and overall Asia, you actually saw that the total sales at that time in 2018 was about USD 1 billion, but we expect it to triple within 5 years. And these are these new and better compounds that are coming to the market. So we think that we will be around USD 3 billion in 5 years, actually. But then one could wonder how will that change the market? And this is a very complex slide. So I'm sorry, but I'm not going to go into the details, but we'll look at the larger scope of this. And you can see that you have both, you have the sorafenib or NEXAVAR is the red dotted line, both -- this is U.S. versus EU. And this is number of patients that are treated with each drug. So it's not a number of -- it's not a market value, it's the number of patients. And you can see that already in U.S. LENVIMA has taken over, over NEXAVAR. And LENVIMA is the dotted line, very dotted lines, black or very dark brown. That is not the same if we look at LENVIMA because it is not expected to take over from NEXAVAR here because it's much more dominated by the price. But I think the overall picture if you look at this is that if we look 7 years from now, in 2027, there will be a lot of products on the market, and they will all have their space on the market. So there's room for many drugs. And if we think MIV-818 to be possible to combine with many different drugs, and I think Fredrik will, later on, show some examples of our preclinical data, we do think that there is some room for MIV-818, and it would be an important tool to treat HCC patients with. So with that, I will leave the floor open for questions.

Any questions for Christina? I think you've noticed, there will be a lot of patients that will be in need for therapy. And even if -- I think this is particularly important because it shows that the multi-kinase inhibitors will continue to be the drugs that people use most of the time for their patients or that doctors use most of the time for their patients. So that's one important take on from this slide because -- and the reality is that, obviously, the other drugs that come out, the immuno-oncology drugs will be much more expensive. So therefore, fewer patients will be treated with those, in particular, in Europe. Do you have a question?

I assume this is for the advanced stage...?

This is for the advanced stage because, as you saw, that's where you use systemic drugs.

Well, if we assume that there will be some significantly improved diagnostic tools and you move the disease to an early stage, do you think your drug will be possible to use as a neoadjuvant treatment prior to surgery?

Yes, I think you saw the slide that Professor Evans has. He already indicated that a systemic agent would actually be possible to be used throughout, and depending on, of course, what -- how you diagnose these patients, but you will still have some surgery, but I think there will be the possibility to use it in different stages.

And just to add to what Christina said, it's obvious that with a liver-directed therapy, as we would have with MIV-818, it would be quite interesting and relevant to use that for patients that only have cancer in the liver and nowhere else, so...

I fully agree. I mean, especially if it works, the transporters and the CTLA-4s, et cetera works in your direction. And if you could reduce the tumor size, it should be easier for the surgery as well. So that's a very interesting angle.

And I think we have discussed different ways because one way is to find a program where we think that we can come faster in the market, and then there should be a sufficient number of markets. But I think we have indicated there are other things like the -- we have also discussed the liver metastasis with the colorectal cancer, the cholangiocarcinoma, where there is basically not so much good data anyway. But I think we will see that this is -- we have discussed and agreed that this is the fastest way and there's a sufficiently large number of patients out there. So it's interesting for us to take it to the market, but it could definitely grow the market from there.

All right. So thank you, Christina. And I think it's time for a quick break before we move into the discussion on MIV-818. [Break]

So thank you for coming back after the break. It was nice to see the discussions that happened between participants. So I think you got an idea, at least, about the great potential of new drugs for primary liver cancer. So now after the break, we'll move into a discussion around our nucleotide platform and MIV-818, in particular. So Fredrik Öberg will start, he's Chief Scientific Officer at Medivir, has been with the company for some time and is, in my view, a very strong scientist. He will give you the background around the platform itself and also talk about the science behind 818. And then Dr. Karin Tunblad will give us the news about the MIV-818 program and about the Phase Ia study, in particular, where she will provide you with very interesting data, positive notes, as I would say. So I think that you can wait with questions after Karin has completed because, then I think, Fredrik's and Karin's presentations come together very closely. So let's do it that way. So Fredrik, please.

Thank you. So what I'll try to do is I'll first cover the nucleotide-prodrug platform in a few slides and then I'll come on to MIV-818 and try to describe to you sort of the basic science why we think that MIV-818 is interesting and likely to work the way we predict. So the nucleotide prodrug concept of the platform, as we call it, it is a way of making drugs that we can, in a way, fine-tune some characteristics of, some aspects of. And we're not only looking at MIV-818, it's the most advanced program, but we have followers that are also within this platform. The idea is that once in the cell, these prodrugs get metabolized and an active metabolite is formed. It has a potential to generate various drugs with sort of tweaking or fine-tuning various aspects of their function. And we've just listed those that we're having our pipeline down in the table below. So what exactly do we mean by the prodrug platform, prodrug concept? So I've indicated here a few areas in which we think that we have evidence that we can tweak or we can fine-tune aspects, both with respect to delivery of the drug. It delivers a nucleoside monophosphate. So in the case of MIV-818, it's the troxacitabine monophosphate that's delivered into the cell. It's not reliant on some of the early enzymes that many nucleosides are reliant on to become activated. It generates rapidly the active metabolite in the cell and thereby, increases the effectiveness of the drug. We can also see that we can modify cell permeability and increase that in the cases of nucleosides, which have poor permeability. The platform is not restricted to troxacitabine, but we'll be focusing on that. So we think that we have evidence that we can use this for other nucleosides as well with other characteristics. Usually, there's a lot of resistance development for nucleosides, that's well known, and by using a prodrug, we can bypass those resistance mechanisms. And therefore, we think that resistant or refractory tumors can be sensitive to prodrugs, nucleotide prodrugs. We can also use it to -- as commented, to tweak or fine-tune tissue targeting, manage stability in different tissues or different biological matrices. So one interesting aspect of this is the MIV-828, which is not in the clinic yet, which is then designed to be an intravenous-dosed nucleotide prodrug and with plenty of evidence in preclinical models in AML that is effective, and it also is effective in eradicating some T-cell lymphomas. The opportunity for this drug is really where the design has gone into or most work has gone into the design is to overcome resistance mechanism and also to generate something that's more tolerable than current treatments. So we think that it overcomes many of the resistance mechanisms that we have tested and it also eradicates cancer stem cells, which we believe could be a possible way of getting more durable responses. So that's one example. But of course, we're now at this meeting and also our current efforts are focused on MIV-818. So in this case, we're delivering troxacitabine monophosphate in the center of this scheme here. The prodrug moiety, the prodrug part is indicated by an orange and a green symbol here. And those are the regions where different parts can be modified in order to achieve this more fine-tuned type of characteristics. The monophosphate is delivered into the cell where it's possibly related to the active metabolite. In this case, troxacitabine triphosphate. This triphosphate is then incorporated into DNA by DNA polymerases and creates double-stranded DNA breaks and eventually cell death. So this is the sort of basic mechanism of the nucleotide prodrug. For the development program of 818, we set up certain criteria. So what we were looking for really was a prodrug that's stable in the gastrointestinal tract. We're aiming to give this drug orally, and therefore, it has to be stable in the GI tract. It's also stable in human blood, and therefore, it can be transported through the portal vein to deliver. We have also the criteria that should increase the potency or effectiveness in killing hepatocellular carcinoma cells and increase the cell permeability. Cell permeability for troxacitabine is quite poor, and be rapidly converted in the liver and trapped there. So the active metabolite, which is charged, should not be released into -- systemically to cause adverse effects. So that was the idea. So I'm going to show you a short movie describing this, and the prodrug then here is the nucleotide, the phosphate and the nucleotide ring illustrated and the prodrug part to the right. And what happens is then that we put this prodrug into a capsule, which is taken orally. It's taken up in the gastrointestinal tract, distributed rapidly to the liver where the tumor is. The tumor in the tumor cells, the prodrug is cleared off phosphorylated to triphosphate, which is the active metabolite. This metabolite, as you see there, is charged. So when entering a tumor cell and becoming converted to active metabolite, it gets trapped in the cell. When the cell divides then, it gets incorporated by cellular DNA polymerases into DNA. This causes DNA double-stranded breaks and cell death. So that's the principle of the nucleotide prodrug. Of course, a key element of this is that we generate enough active metabolite in the liver, and troxacitabine has been in the clinic. It was dosed intravenously through lung infusion. So how do we compare our liver targeting to troxacitabine? Troxacitabine had clinical effects, but there were dose-limiting toxicities. So in the left figure there, with those rats, both IV and orally with troxacitabine. And what we measure then is troxacitabine in plasma. So the green curve on the left there is troxacitabine in plasma when given IV, and red is when given orally. The dotted line is the limit of quantification. So what we're looking at here is measurement of the active metabolite in the rat liver. So this is a limit of -- our detection limit, essentially, the way we can quantify the active metabolite in liver. And we cannot find active metabolite in the liver. It's -- there is a low amount there for sure, but too low to be quantified. On the right is MIV-818 dosed orally, which is the way we dose it into patients, but in this case, a rat. The yellow indicates the active metabolite in the liver. The red then is the troxacitabine that leaks out into the plasma in the rat. And as you can see, we generate quite substantial amounts of active metabolite in rat liver this way, significantly higher. So at least a 100-fold higher active metabolite in the liver compared to troxacitabine self-dosed either orally or IV. So this is fundamental of why we think that we can generate efficacious doses in the liver of the active metabolite. So Professor Evans showed the complexity of hepatocellular carcinoma and the pathways that are involved, the mutations that are involved and also the different drugs that target these pathways. And I would make the case then that by its mechanisms of action, by being incorporated into DNA by DNA polymerase, MIV-818 represents a completely different mechanism. So irrespective of mutations and heterogeneity, which we do know that we have in HCC, this mechanism is very broad and general. It will kill all proliferating cells, provided that we get efficacious doses to the liver. That also means that the resistance mechanism that we know appear, receptors that are targeted, for instance, by sorafenib, they become upregulated or mutated and you get resistance to sorafenib. These types of mechanism resistance will not affect MIV-818 efficacy. And that means also that in terms of combinations, we think that MIV-818 is very complementary to these other more targeted therapies. We do have some preclinical evidence that targeting the liver or targeting HCC with MIV-818 works well or it enhances the activity of both these multi-kinase inhibitors, like sorafenib or lenvatinib, but also immune therapy like anti-PD-1, and obviously also drugs that inhibit DNA repair mechanisms, which is what you would expect. So we think that in this scheme of -- the heterogeneic scheme of pathways involved in HCC, MIV-818 has a place. So evidence of efficacy then, we've seen this in many different models. I'm showing you one here. So a preclinical model of HCC in the mouse. So in this case, this human HCC cell line is transplanted to a mouse and the transplant grows to about 200 cubic millimeters and then you start treatment with MIV-818 orally. The gray zone here are the 5 days that we treat with MIV-818. We've tried many different treatment schedules. And it turns out that a 5-day treatment in a cycle is the most effective way of antitumor activity. And you see the 2 doses there. You can also note that even if we just treat for 5 days, we have a prolonged antitumor effect, maybe up to 2 weeks, after that treatment. We've also looked at primary cells from hepatocellular carcinoma patients. So this is a study with -- from 15 different patients where we compare the effectiveness inhibiting proliferation of these cells from the patients, treating either with MIV-818, sorafenib or lenvatinib. And the more direct potency is clearly favorable to MIV-818, although I should say that the biology of both sorafenib and lenvatinib is mainly based on anti-angiogenic activity, which we don't see here. So a question is, of course, if we see this in vivo as well. So we have done a similar experiment using hepatocellular carcinoma cell line HepG2 transplanted into mice and dosing 5 days when the tumors have reached 200 cubic millimeters. And then the graph or the curve to the left in the vehicle are treated just with the formulation, then we see a slight effect of sorafenib by itself, a fairly good effect of MIV-818 and an enhanced effect with the combination. And we see this in vitro as well, that there is a synergy between these drugs. So if we take out the tumors from these animals and we take a closer look at the sections of the tumors, we can focus on the right-hand side here. So vehicle is the tumors from mice just treated with the formulation that's used to give the drug. If we treat with MIV-818, we see the red stain here. That's representative of DNA damage. So DNA damage repair is -- pathways are induced by MIV-818. If we treat with sorafenib alone, we don't see much DNA damage, but we see this green stain, which is representative of low oxygen tension, hypoxia. And this is what to be expected because it's anti-angiogenic. You reduce the vascularization of the tumor and you get hypoxia. And to the lower right, then we have the section from a tumor where the treatment is the combined treatment. And there we see the DNA damage and the hypoxia. And we also see DNA damage in the hypoxic regions of the tumor, which is what we were hoping to see. So in summary, the nucleotide platform gives Medivir an efficient way to generate a pipeline of new medicines, in addition then to MIV-818. And regards MIV-818, it has demonstrated efficacy in multiple preclinical models, both in terms of antitumor effect, but also of the markers that we would like to see in terms of DNA damage and also activity in hypoxic regions of the tumor. And as I described to you, I think the unique mechanism of MIV-818 allows it to be independent of other resistance mechanisms, but it also provides a very good combination partner for either double or triple combinations that we're seeing evolving in the HCC space. So I'll leave the word to Karin to move into the clinical phase.

Thank you. So for the clinical development of MIV-818 to treat advanced hepatocellular carcinoma, we have just completed the first part of the Phase I study, and that's the Phase Ia study. And this was an intra-patient dose escalation study with the main objective to evaluate safety and tolerability, and we also wanted to define the starting dose for the Phase Ib study. And the Phase Ib study, that's the classical 3 plus 3 inter-patient dose escalation study, where we also want to evaluate safety and tolerability, and we want to define the recommended Phase II dose to continue the treatment of MIV-818. But when we have that dose defined, we plan to add MIV-818 to standard of care, and that should be first-line approved standard of care to treat advanced hepatocellular carcinoma. And that study will have a similar design as the Phase I monotherapy study, and it will also evaluate safety and tolerability when MIV-818 is added to standard of care. In that study, we also want to define a recommended Phase II dose for MIV-818 when it's added to first-line standard of care. And we then plan to perform a Phase II study. And that will be a controlled study. That's a placebo-controlled study. That means that we will compare MIV-818 when it's added to standard of care with placebo added to standard of care. And with that design, we have the possibility to have this as a registration study. Of course, provided that we show good efficacy and also an acceptable safety and tolerability. So the unique mechanism that we have talked about previously of MIV-818 that enables us to do add-on treatments with several approved therapies. It could be either monotherapy or it could be add-on to either first or second line treatments. So that means that MIV-818 could be used to treat both early and late-stage advanced HCC. And also, since HCC is a rare disease, it's probable that we will get an orphan drug designation status for this compound. And that means if we get that, we will get an extra 10 years of market exclusivity in the EU and an extra 7 years in the U.S. And since this is a serious illness, we also have the possibility to get Fast Track Designation with the FDA, and that would enable us to get more frequent meetings with the FDA, and that should also speed up the development of MIV-818. And in EU, it's possible to get a conditional market authorization based also on a reduced clinical package, which we plan for now in the Phase II study. And that would also be a good advantage for us. So now on then to the Phase Ia study. So as I said, the primary aim of this study was to assess safety and tolerability, where we escalated the doses of MIV-818. And we included patients with hepatocellular carcinoma, intrahepatic cholangiocarcinoma or metastatic liver disease. And in this study, besides looking at safety and tolerability, we also wanted to define the starting dose for the Phase Ib study. Some secondary and exploratory objectives were to look at the overall response rate, that's the efficacy of the drug. And we also wanted to look at the pharmacokinetics. That's the exposure of the drug in the plasma, both of MIV-818 and also some of the metabolites. And we wanted to assess some pharmacodynamic effects on MIV-818 on markers such as DNA damage, similar to what Fredrik just showed from the preclinical models. So when it comes to the design, this was an intrapatient dose escalation study. And for safety reasons, we started very low with a single dose. That dose was then increased, and we also increased the number of treatment days for up to 5 days per week in each 21-day cycle. And with this approach, that also meant that we minimize the number of patients that were actually treated with noneffective doses, so we could quickly increase the dose. And that also meant that we could quicker come to a recommended Phase Ib dose, which will be the classic 3 plus 3 design. The measurements that we took for tumor evaluation that was done using computer tomography every 6 weeks. We looked at safety throughout the study. Blood samples were collected both after single and repeat administration throughout the study, and liver biopsies were collected after 2 cycles of treatment for biomarker analysis. We included 3 sites in this study, 2 were in the U.K. and 1 was in Belgium. So the patients that we included in this study were 9 in the number and all those 9 were evaluated. There were 8 males, 1 female. And they had a median age of 57 years and range between 50 and 84. And all these patients were non-Hispanic whites. The diseases they had were hepatocellular carcinoma in 2 patients, 1 with intrahepatic cholangiocarcinoma and 6 that had liver metastatic disease. So as said, the main aim of the Phase Ia study was to look at the safety and tolerability. And that means that we increase the dose until adverse events were observed. That's the goal or the aim of the study. And we used the common terminology criteria for adverse events scale to assess the adverse events, and this scale uses standardized criteria for classification of adverse events of drugs that are used in cancer therapy. And those grades are in the range of 1 to 5. And grade 1, it's a mild adverse event, it's showing mild symptoms and no intervention is needed. For grade 2, it's a moderate adverse event with minimal local or noninvasive intervention that is needed. Grade 3 is severe, but it's not immediately life-threatening. And here, hospitalization or prolonged hospitalization is needed. And then we have grade 5, which is death that is related to AE. Did I mention grade 4? Yes, it's life-threatening, and then it's an urgent intervention that is needed. So this table shows all adverse events of grade 3 and grade 4 that were reported from all patients included in the Phase Ia study. I should mention here that most of the AEs were of grade 1 and 2, but those are very mild, so those are not in this table. And I should also mention that most of these adverse events were observed in the patients that received the higher doses. And also when you look at the number of patients, you should be aware that 1 patient could have several of these adverse events. So it doesn't -- if you add the patients up, you will get a higher number than the number of patients that actually experience these adverse events. And the adverse events, they could come either from the treatment or they could come from the disease itself, that does not tell that from this table. So on the top, you can see some hematological effects like anemia, neutropenia and thrombocytopenia, and those are known effects from troxacitabine published data. Also from published data on troxacitabine, we know that you can have hand-and-foot syndrome with rash. We observed that in very few patients and only of the low grades 1 and 2. So that's why you don't see them in this table. In one of the patients, we had some bilirubin and liver enzyme elevation. And there was also 1 patient having a spinal cord compression that was related to the disease of that patient, and also some esophageal bleeding and that was related to bleeding from a tumor in that patient. One important thing to note is that all of these adverse events were reversible with the exception of bone pain that one patient experienced and also the spinal cord compression. So what about the exposure then. So this slide shows some exposure data from 2 of the patients, patient #5 and #7. So patient 5 was an HCC patients and patient 7 was a liver metastatic patient. And both these patients received doses in the upper range of what was dosed in the Phase Ia study. And the data that you see here is from MIV-818 in black and also troxacitabine, which is a metabolite of MIV-818. And on the top, the top 2 panels, you see data from day 1 in cycle 2. And on the bottom 2 graphs, you see exposure after repeat dosing, for 4 days in patient 5 and for 5 days in patient #7. So if you first look at the black curves, you can see -- which is MIV-818, you can see that we have a rapid absorption and also fast elimination. And that means that we have a very low exposure to MIV-818 systemically in plasma. And that's what was -- really what we expected based on the profile of MIV-818. And you can also see since we don't have any exposure on the first day at 24 hours when we give this repeatedly, we will have the same exposure as we did on the first day. If you look at the orange curve, that's the troxacitabine. You can see that we have a longer half-life on that. So that's staying longer than MIV-818 does in plasma. And that means that we also have some accumulation when we have repeat dosing of MIV-818. So you can see after repeat dosing that we have a little bit higher exposure than we had on day 1. So again, based on the reported data for troxacitabine in patients, solid tumor patients that have been treated with troxacitabine, we know that levels of about 100 nanomolar, you can see that in this graphs, that's tolerable if you have that as a continuous concentration for 4 days. And we clearly do not have that high concentrations over 4 days. So that means that the levels that we see here, both from MIV-818 and troxacitabine, supports further clinical development of MIV-818. So this table shows the biomarker data of DNA damage. And this is similar type of data as Fredrik showed for the preclinical models. So these are the biomarker data collected from liver biopsies in these patients. And the top or the patients with the lower numbers received the lower doses of MIV-818 and the patients with higher numbers generally received the higher doses of MIV-818, and these biopsies were taken after 2 cycles of treatment. So what you can see in the middle column, it says percentage tumor cells. For some of these samples, there are no values. And the reason for that is because either the biopsy was never collected or it was -- there were no tumor cells in that sample. And in that case, we cannot evaluate if we have DNA damage in the tumor. But for the remaining samples, you can see that we have DNA damage. So here you can see that we have DNA damage in all of the tumors where we actually had samples and at the same time, you can compare that with the normal liver tissue, where we see no or very limited effects. And that's really what we want to see. So we have a liver tumor targeting of MIV-818, where we see DNA damage in the tumor, but we don't see it in the healthy liver issue. And the reason why you see a range of percentage, for example, is because you can have different DNA damage in different regions of the tumor. So this slide shows basically the same data as you had for the previous slide. It's just that it's only showing data from a couple of patients. So these are images of DNA damage that were taken from these biopsies. So if you look at the further left image, where it's a pre-dose, this is data from patient #2, where a pre-dose tumor tissue was collected, and we were looking for DNA damage. And here, the DNA damage is seen as brown staining. So you can see that in the pre-dose sample, there is some, but very limited DNA damage. What we then did was that we dosed MIV-818 for 2 cycles, and we took another sample, where we first looked at the normal liver, as you can see in this panel, where there, again, is very little or non-DNA damage. However, in the tumor tissue, we see clear brown staining, indicating that MIV-818 is really targeting the liver tissue and doing the -- and causing DNA damage. And similarly, in patient 4, we did not have a pre-dose tumor tissue to look at. But you can see here in the normal liver, very limited DNA damage, while we see clear DNA damage in the tumor tissue of the patient. So this, again, is evidence of DNA damage in tumor, but not in the normal liver. And also, as Fredrik mentioned, from the preclinical study, we also saw DNA damage in hypoxic liver regions, also from -- in the patients. And that's really good because those regions are normally quite difficult to treat with chemotherapy. So the effect of this study was measured using the RECIST 1.1 criteria. And this is normally used to evaluate the effects of solid tumors in cancer treatments. And both tumor shrinkage and time to development of this disease are important endpoints and are normally used then in clinical trials. And the RECIST was evaluated using computer tomography scans, and they were performed after 6 weeks. In this study, the investigators selected up to 5 target lesions that were selected to evaluate the response. And I think, also Jeff Evans mentioned this earlier today of the types of responses that we can see, it's either a complete response, which means that all the target lesions disappear. You can have a partial response and that means that you have at least a 30% decrease in the sum of diameters of the target lesions from the baseline. You can have a stable disease, that means that the tumor does not shrink enough to become a partial response, but it does not increase sufficiently either to be a progressive disease. And the progressive disease means that you have at least a 20% increase in the sum of the diameters of the target lesions from the lowest observed value and that's, in this case, the baseline. So this table then shows the change in the liver tumor burden after treatment of MIV-818. And I think it's important also to remember that the patients that were included in this study are really advanced disease patients. So these are patients that have failed and progressed on other previous treatments and where there were not really many options more. So what we can see here is that 5 of these patients received a stable disease. And those were generally the patients that received the higher doses. Four of the patients showed a progressive disease, and those were generally the patients that received the lower doses. So based on this, we believe that the stable diseases that we do see in this -- in 5 of these patients is an indication of an effect. And it's also encouraging that we do find both of our HCC patients, #5 and #9, as being stable disease, since we are actually aiming to develop MIV-818 to treat HCC. So some conclusions from this Phase Ia study is that we did see some adverse events, but they were generally mild and very few were severe and they were all reversible, except for that -- the pain that we saw. There were only low levels of MIV-818 and the exposure to troxacitabine was acceptable. We could see that the liver biopsies showed selective DNA damage in tumor tissue and there were really no impact on healthy liver issue. And 5 out of the 9 patients that were included in this study did show a stable diseases. So what we have done then, after this study, we have decided to continue the development of MIV-818 and that will then be in the Phase Ib study, and this is a classic 3 plus 3 dose escalation study within -- between patients, and we will include HCC, intrahepatic cholangiocarcinoma, and liver metastatic disease patients in this study. And we currently have patients in screening to be included in this study. The starting dose have been set based on the Phase Ia data to 40 milligrams being dosed 5 times in each week. And if you recall from -- also from Fredrik's presentation, this is really what we saw from the preclinical studies that a 5-day dosing is much better than a shorter period of dosing. So we did end up with actually being able to do 5 days per cycle in the Phase I study. We have included 6 sites in this study, 5 of these are open now. There are 4 sites in the U.K. and 2 in Belgium. And the objective here is to look at safety and tolerability and to establish Phase II starting dose for monotherapy and also to use this dose to guide us to go into add-on treatments, which we think will be the fastest way for us to reach the market. We will, of course, also evaluate efficacy by the RECIST criteria, and we will look at both exposure that's pharmacokinetics and also biomarker responses. And we expect to have data to be communicated from this study during this year. So when it comes to drug substance, we have produced GMP material. We have done that at a large-scale European manufacturing. And we believe that we have an efficient synthesis that is in the final optimization and that's done from commercially available starting material. And that means that we will use commercial-grade material in the Phase II study. And that's, of course, needed if we want the Phase II to be -- to have the possibility to be a registration study. And we also believe that we have an optimized process that will enable us to produce at a competitive price at a commercial scale. And when it comes to the drug product, we have -- what we have for now is that we have a long shelf life at room temperature. And we have a strong patent situation for MIV-818. We have patent granted in most of the major markets up to 2035, and there are some additional countries pending. We also have a combination patent with sorafenib and some analogs granted in the U.S. and some, as you can see, some other countries pending. And then we have a combination patent with PD-1 or PD-L1 monoclonals that's been submitted where it's pending worldwide. Yes, I think that's it.

So I think we are open for questions to Fredrik and to Karin if you have any. Yes, please.

Some disparate questions. First, you said something about the possibility of increasing permeability, correct? How do you go about to achieve that?

So depending on the chemistry of the prodrug, that would affect cell permeability of the whole compound. So there is some leeway to manage that within the design of the prodrug.

Is there any measurement of percentage-wise, how much is entering the cells and how much is outside?

I mean, during the development, we routinely check that, if we want to achieve a greater permeability. But the permeability is really dependent both on the nucleotide or nucleoside part and the prodrug part. And we can modify -- actually, we can modify both, but we are mainly talking here about modifying the prodrug part. So I couldn't give you a figure, but if we see we have a nucleoside that is poorly permeable, we would manage that by making compounds that we think will be -- have better permeability and test that simply.

And what I'm aiming at is, if you have a cancer cell that divides, if you get sufficient of your prodrug intracellularly, you would, in theory, kill off all those cancer cells?

As long as they divide and replicate, yes, in theory.

That's the exciting part with MIV-818, isn't it?

Then a question on the adverse effects. I mean, one could expect some impact on the blood-creating tissues. So bleeding and lowering of red and white blood cells is to be expected. But pulmonary embolus, why do you think we had 2 such instances? I mean, it -- really one expects the opposite.

So we should ask Linda to answer that question because she is our MD.

The 2 pulmonary embolus result in the study, they are related to the disease, patient with tumor burden in the pelvis. They frequently develop embolism or blood clottings, and if such blood clottings start to move, they move up to the lungs. It is one picture we see. So it is disease related and really not related to the drug.

All right. Because that is -- if it's a normal occurrence with this type of cancer, it's okay. But if it's a side effect, then it would be very unwanted adverse event.

Yes. These 2 cases here, they are -- the investigators, they rate the adverse events. This is possible or related to the disease itself. And this means that the investigators -- it is possible not or not related to the study drug.

Any other questions?

Yes, we do have 2 questions from the web, from Joseph Pantginis from H.C. Wainwright in New York. First, regarding the Phase I study design, did the regulators have you start very low under the predicted therapeutic window?

Well, I'd say that the reason why we started low is because we have different metabolism of MIV-818 in toxicology species that we used and we had in man. So therefore, it was quite difficult to translate and actually come up with a good starting dose. And that's why we wanted to have an extra safety margin. So that's why we started really low. And that's also the reason why we have this interpatient dose escalation because we wanted to start low but come up to effective doses as quickly as possible, not to actually give patients noneffective doses.

Okay. Question number two. Do the PK data shown on Slide 29 approach predicted therapeutic levels, of course, noting the stable disease is achieved?

Again, that's quite difficult to answer because we have these differences in metabolism. And as Fredrik said, what we are looking at is really to have the active metabolite inside of the cells and that's the troxacitabine triphosphate. We cannot measure that in plasma. It doesn't -- we can't find it, and we shouldn't find it because it's too [ polarous ]. It doesn't go out of the cells. So what we really can use here is we have troxacitabine data that has been published. So we know where the safety margin is. And we want to dose in this study as high as possible for -- to reach the level, which is the most -- the tolerable level, really. So I think in this case it's the troxacitabine levels that we go for.

And obviously, we were below the limit that we did not want to exceed throughout. So that's very nice.

Yes. Yes.

Well, thank you very much. It's a very intriguing and interesting molecular mechanism of action of this because you have 1 -- 818 is the prodrug and then its form this TRX, and who is entering into the cell?

Okay. So maybe I was a bit unclear there. So what's entering in the cell is MIV-818. So in the cell then, this is rapidly converted to troxacitabine monophosphate. And then from there, it's phosphorylated by cellular enzymes.

Yes. And the longer half-life of this -- now we're going into pharmacokinetic details. The longer half-life of TRX, which sounds like a dinosaur, which is good, right? Because it should kill the cells. But it's -- what is causing the longer half-life for it? Is that -- when it's circulating around the body with a very long half-life, is that taking up efficiently into the cells as well?

Well, first of all, I mean, troxacitabine, as I said, has been dosed in clinic, and their half-life has been reported to be about 7 hours. So that's clearly longer. So it has its own PK regardless of MIV-818.

It's clearly an elimination rate limited metabolite.

Yes. Yes. Yes.

Is it taken up by the cells?

Well, it -- yes, it is. And I mean, as Fredrik said, the reason for why we are doing this prodrug is mostly to increase -- one reason is to increase the permeability so the permeability of MIV-818 is better. If you look at Caco-2 cells, it's better than it is for troxacitabine. But troxacitabine is, of course, also taken up, because otherwise, troxacitabine would not have shown any effect in the clinic, which it has.

Is it passive diffusion or is it any carrier-mediated processes.

Don't -- that I cannot answer.

I won't go further into details.

Thank you.

Now this Phase Ia study was, of course, very small. You had 5 patients that were stable but none that diminished the size sufficiently to be other than stable. Was that due to short treatment or -- and this is combination with another question? You showed some slides of staining tissue. Do you see any cancer tissue that does not take in the drug, that is, for whatever reason resistant to uptake? And we have to consider there are differences within the cancer.

So should I first answer that and then Linda can speak to the efficacy? I think that we should remember, what we're doing is taking a snapshot at cycle 2 with this biopsy. And from that, we can only say that within the tumor, we show or we find DNA damage response to a varying degree across different regions of the tumor. That is not possible to say if there are any regions that are resistant or not. That will require a completely different study, I think. But based on what we see in preclinical models, we don't really see regions that are resistant. We do kill off the tumor in the mouse. So if we can reach similar levels of active metabolite, we believe that we will have sort of monotherapy effect across the tumor. Having said that, all cancers develop some kind of resistance. That's a rule. So eventually, there will be some tumor cells that develop resistance. That's just a fact of oncology.

But because there are systems that spit out drugs that are taken up by cells, there is a pumping mechanism that ejects drugs. Do you have any knowledge about MIV-818 in that sense?

No. I mean, we have not found really that type of resistance in preclinical studies. It remains to be seen how that translates into the clinic. But it is difficult to generate resistant cells to MIV-818 in vitro.

If I can add, the active metabolite of MIV-818 is a polar metabolite that is trapped in the cell. So it cannot be kicked out easily. You also asked another question about, if we -- why we didn't cure an inpatient. The reality is that these patients are extremely sick, as you heard, 3 months expected survival. The tumors are growing rapidly. I think that -- what we saw an indication of is that we slowed down probably the progression of tumor growth in these patients, which is, I think, very and -- very interesting observation. And you may add to that, Linda.

Yes. I would like. As a former clinician before I joined Medivir, that having stable disease is disease control. Then you can -- really can control the tumor within the area we showed -- the 2 lines we had between response and progressive disease there is an area you really control the tumor. And I would say that we saw 5 patients with stable disease and 3 of the patients with progressive disease were very close to having stable disease. So I think it is very, very encouraging data in these patients that are very, very heavily pretreated. They have -- do not have any more options that the physician can pick from the pharmacy to treat them there, then they have to rechallenge them with the same drug again. And then usually the patient, they will have a very short response when you rechallenge the patient.

I can take one more question. Do you want to ask something?

Yes. I would like to come into the regulatory strategy and what time line you see in terms of orphan drug applications, et cetera, et cetera?

Perhaps I should answer that. So first of all, it's important to realize that in the western world, the U.S. or Europe, we are going for an orphan drug -- what should I call it, orphan drug strategy? And that's because we have a much lower amount of people suffering from primary liver cancer in Europe and the U.S. In Asia, it's going to be a completely different approach because there none of the liver cancer diseases are orphan in type. So there we will need a partner that help us to develop it for that larger population, that helps us to commercialize it. In the western world, we think we can do it on our own. So that's our strategy. We can move forward with an orphan drug using all the helps that we can get from the regulatory authorities, that are really very, very interested in helping a company like Medivir to go quickly to the market, effectively to the market. So as you have heard repeatedly today, we hope to be able to design a Phase II study that can be registrational. So that in itself provides us for a very fast path to the market. We're going to do a couple of Phase Ib studies, the ongoing one and the one where we add MIV-818 on the top of standard of care, then we can move into the Phase II study. And the first Phase Ib study we will have completed this year. We will be able to move into Phase II pretty soon thereafter. And I don't give a specific timing of that now. Obviously, the Phase II study will be sized so that we size it properly for high significance on the primary endpoint, so it will be based on the expected delta from standard of care. But it's not going to take a very long time. It will be a relatively inexpensive path compared to a regular drug development program. We are very excited about it. We'll come back to you repeatedly with what's happening on our development plans in the future, fast and relatively inexpensive, that's what we're looking for. Yes?

Just one last question. Given that liver cancer is rather seldom occurrence in our part of the world and it's not in the focus of clinicians, as I believe it is in China, for instance. So one would expect patients to be diagnosed at an earlier stage in China. Is that the case? And it could be interesting for the company with earlier treatment with our drug.

Yes. Honestly, and I think they will be detected earlier in the western world because we have a better health care system here. So -- but there will be a lot of liver cancer patients in China. Yes, for sure. But regardless of where they are in terms of disease progression, I think, within the western world, we will be able to detect them quite early. So I'm not so worried about that. Eventually, of course, if we want to move earlier than surgery. Then there are other kind of diagnostic methods necessary. But that will also come first in Europe, I think before we see it in China. So maybe we can move to the summing up because the mingling part of this day is awaiting us. So let me say, first, a few words on the new Medivir, because we are clearly different than we were a couple of years ago. We are now a pretty small company, having our personnel focus very much on the nucleotide-prodrug platform, and in particular, on MIV-818, which is the most exciting program that we have. And I personally -- I'm very, very excited about it. But we also see the opportunity to move forward with MIV-828 when we get financial resources to do so. Currently, it's at the clinical candidate stage. And we have not yet moved on with preclinical development of MIV-828. But this is what Medivir is really focusing its personnel and monetary resources on. In addition to this platform, we also have a number of other clinical programs that do not emanate from the nucleotide-prodrug platform. And those programs we intend to find partners for so that they can help us to really take them forward and generate increased shareholder value. We cannot do all of that. These programs are too expensive. They are not orphan programs, most of them. And they require major financial investments that we don't have access to today. So we want to find partners that we can get help from to move these programs through Phase III to the market and eventually to commercialization. And we are working very hard on that. Obviously, you have seen these programs before. These are our partnering opportunities for clinical programs. We have remetinostat, we have birinapant and we have MIV-711. And all these programs have pretty good IP exclusivity, which is important. And they hold a lot of promise that we hope to transform to revenues for Medivir. The first of these prodrugs, remetinostat, for a rare skin disease, cutaneous T-cell lymphoma, where we have pretty ideal drug to treat that condition. Remetinostat is formulated as a gel which is applied on to the skin. And it's stable in the skin, but when it's absorbed into the blood, it's broken down. Therefore, we will have an effective therapy topically that will not cause systemic problems in terms of side effects. So we have very, very nice data from Phase II with remetinostat for this orphan indication. We have decided with the FDA exactly how the Phase III program is going to look. It's going to be one clinical study. We know what the endpoints are being -- going to be. We know that we don't want to do this alone, we want to have a partner to do it. We also see additional broadening opportunities for -- to look at the complete potential of remetinostat. We have had already, last year, a presentation from studies in basal cell carcinoma, which looked very good, and we hope to see the total study for BCC presented sometime this year by the principal investigator. And she is also conducting another study in squamous cell carcinoma. So we expect to see additional data coming out over time. And again, we think that those data will demonstrate the full potential of remetinostat beyond, not only being an orphan drug but also broader drug. Now birinapant. You know that we had a clinical setback last year. It did not turn out to be effective when given together with KEYTRUDA in one type of cancer in the colon. And that was a setback, but we have an ongoing study in head and neck cancer, investigator supported. And we will see if we can find partners for birinapant. I should mention that this is a compound that has an interesting mechanism of action. It's a SMAC mimetic. And from time to time, you see reports that may lead to a lot of interest around this type of drug. So we hope to find a partner that can take birinapant forward as well. And then, of course, we have MIV-711. And you may remember that we sent out a press release just before -- well, just recently about an article that came out in a very prestigious journal, within a company editorial talking about the MIV-711 data, our Phase II data that it could be first step to a drug that would be disease modifying for this condition. It's a huge opportunity for someone who has a lot of money. So we're looking for that partner that can help us to run a Phase III program with MIV-711. Finally, you may recall that when we started rebuilding Medivir, we had a lot of preclinical research going on. And we packaged those research activities into multiple different projects if you wish. And our attempt has been to partner those early-stage projects with companies that have an aggressive preclinical research activity so that they can develop them further and give us also the potential to get revenues from these assets one way or the other. So most -- and most recently, we struck an orphan -- sorry, an option deal with a very strong early-stage biotech company that -- and it is just what we think the first of many such deals that will sort of monetize what used to be preclinical research at Medivir. And you may also have seen that we succeeded to get the Chinese partner to take on Xerclear and provide us with revenues from the commercialization of Xerclear for labial herpes. So we have a lot of things going on. Christina is in charge of that. And we hope to be able to come back to you with more announcements around deals from Medivir. So with that, if you don't have any questions, I thank you for your attention, but let's see first, are there any questions? [indiscernible] do you have any?

[indiscernible]

Okay. Yes, please?

That option deal you're mentioning, is that something you have -- press released anything about?

No, we haven't.

May I then ask you -- somewhere I read about MIV-708 as a veterinary product? I haven't heard anything.

So Christina, can you talk about that a little bit?

Yes. MIV-701 is for veterinary use. It is in development for doing that. It has not started. But to develop drugs for veterinary use almost takes as long as it does in humans. So we don't expect to hear so often from it, but we hope that it will proceed and that it will be very good for pets. That's what it's really for, for dogs and cats.

But the reason why we haven't spoken about it is that is so far away from our core business. But we think this is a nice additional thing that came out of a drug that could not be developed for people. So why not.

Okay. And the second question, you had, about a year ago, a package, as I can recall it, of around 6 preclinical drugs that you tried to get financing for. I guess one of them is 828, and possibly, one of them is 838. But the other ones, are they all prodrugs? Or are there other types of drugs?

There are other types of drugs. So it's -- different types, but they've all been within oncology.

So just to make it very clear that we like the nucleotide-prodrug platform. And ideally, we would like to develop it ourselves. It's the rest of the programs that we want to monetize through partnerships. So thank you very much for your attention, and we can mingle. Thank you.