Vir Biotechnology, Inc. (VIR) Earnings Call Transcript & Summary

Hello, and thank you all for joining us today for the Vir Hepatitis Portfolio R&D Day. My name is Heather Armstrong, and I'm the Vice President of Investor Relations at Vir. Joining me today are George Scangos, Ph.D. and Chief Executive Officer; Jordan Feld, M.D., M.P.H and R. Phelan Chair in Translational Liver Disease Research and Professor of Medicine at the University of Toronto; Phil Pang, M.D., Ph.D. and Chief Medical Officer; Carey Hwang, M.D., Ph.D. and SVP of Clinical Research and Head of Chronic Infection also at Vir. Not presenting today, but available for the Q&A portion are Howard Horn, Chief Financial Officer; and Kate Morse, Head of Global Product Strategy. [Operator Instructions] The materials we will reference on today's conference call can also be found under the Events section of the Investors page of our website. Before we begin, let me remind you that some of the statements we will make on this call are forward-looking statements. These include statements that are not historical facts. These forward-looking statements, risks and uncertainties and many other factors may cause actual results to differ from current expectations. Other risks and uncertainties are described under the caption Risk Factors and elsewhere in Vir's SEC filings and reports. We undertake no duty or obligation to update any forward-looking statements that we will make today. And with that, it's my pleasure to turn the call over to George.

Well, thank you, Heather, and good morning, everyone. Hello. Thank you for joining us today. We're very happy to be here to talk about our hepatitis portfolio this morning. So Vir -- we can go to the next slide, please. Vir was founded a little over 5 years ago with the goal of developing medicines to prevent and treat major infectious diseases around the world. So I think it's a real testament to the team's experience and dedication and hard work that we've progressed as much as we have in a relatively short period of time. The first success that we've had was not COVID, but it was actually in Ebola. Our team developed an Ebola antibody that's now known as Ebanga. That's one of the approved medicines for the treatment of Ebola. And I was just reading the past couple of days, there was a new outbreak of Ebola in the Congo. And I think it's gratifying to have a drug that can significantly reduce mortality in those patients. And of course, we brought forward sotrovimab, our anti-COVID antibody, which has helped millions of people with COVID around the world. If we can go to the next slide, please. We are -- have a lot more to do, and we aspire to really save a lot more lives. We're in a really fortunate position at a time when, let's say, the interest in biotech stocks has waned where a lot of money has moved out of the sector, leaving a lot of companies in the industry having to make hard choices about how they spend their money, how they preserve their cash. We are in a position to have enough cash to take all of our major programs through significant milestones in the next year or 2 years, 3 years. And that includes, of course, sotrovimab, our next-gen COVID antibodies, our flu antibody, our HIV program, and of course, our hepatitis B and hepatitis delta programs, which will have -- all of which will have multiple potential value drivers in this year and next as well. So we're here today, of course, to discuss hepatitis B, hepatitis delta. If we can go to the next slide. We can just give you an overview of that program. It's in the middle box on this slide. And you can see here multiple trials. As a small company, we've put together a program that has the breadth and depth of companies that are much larger than Vir. We believe this is a highly competitive program and has the potential to lead to a functional cure for hepatitis B. So we're going to focus on those programs for today. And so with that, I will turn the call over to Jordan Feld, who's kind enough to join us today and give you a little overview. So Jordan, over to you.

Great. Thanks, George, and thanks for the invitation today to be here. It's really a pleasure to be here, and it's exciting to see what Vir has done in the time that you have started working in different areas of infectious disease and a lot of progress. And what I'm going to do today is really give some background, really, to set the stage for discussing where we're going in hepatitis B. And I'm really going to focus on why it is that we need new therapy for hepatitis B. It might seem obvious, but I think it's important to really stress this point and stress some key aspects to it to help us really set the stage for thinking about moving forward. So when we think about viral hepatitis, I think this is one of the relatively underrecognized huge public health problem. So when you typically think of the big 3 global public health problems, we typically come with TB, HIV and malaria. And certainly, these are major public health threats. But if you actually look at what's happened with viral hepatitis through improvements in therapy for those other big 3 and aging of the population and continued spread of hepatitis B and C, what we've seen is that hepatitis B and C combined now have overtaken any of those big 3 in terms of the overall public health burden that they cause. And it's estimated that by the year 2040, if we don't do something pretty significant, we will actually be in a situation where chronic viral hepatitis will cause more deaths than all 3 of those "big 3" combined. And that's really quite devastating. And when you look at this in a little detail, what you see is that it's really hepatitis B that's driving this. So we all know about the remarkable progress in hepatitis C. And you can see that when you look at deaths and millions from 2015, it was estimated that hepatitis B primarily through driving liver cancer is the biggest burden here. And when we look around the world, I think most people are aware that the heaviest burden of hepatitis B falls in Asia and Sub-Saharan Africa with an estimated somewhere between 250 million and 300 million people living with chronic infection, but up to 1/3 of the world's population with past exposure to this virus. But it's important to recognize that as the world has become much more global, and we have all seen much more movement around the world that places like my home in Toronto that is a very multicultural city with people born from all over the world now actually has moved into this light green of being an intermediate prevalence region for hepatitis B. And this is primarily because we have a very large foreign-born population, many people hailing from HPV endemic regions. And that's true for many large urban centers in Europe and North America and just really highlights that this is a global problem and needs to be tackled as such. And because of the progress in hepatitis C and B, the World Health Organization has really moved to this very ambitious goal of actually eliminating viral hepatitis as a public health threat by the year 2030. And what you can see here are their targets for 2030 of making sure that we're vaccinating 90% of people for hepatitis B and that, in fact, 90% are getting the birth dose vaccination. We're cutting down on problem. We're getting good safe injections. We're improving harm reduction. And I want to highlight the bottom that we're getting people on to treatment, and they set intermediate goals for 2020. These were targets were set in 2015, and you can see that there was a goal that 5 million people should be on hepatitis B treatment by 2020. Unfortunately, we're not quite there. I'm going to show you some data about that. Now of course, the reason that people are thinking about the idea of having actual elimination of this as a public health problem is for hepatitis B largely to do with the vaccine. So people often talk about the first cancer vaccine as being the HPV vaccine, but of course, it was really the hepatitis B vaccine. And it's been a remarkable success story when you look at Taiwan, the first country in the world to introduce universal hepatitis B vaccination, and they did this way back in 1984. And you can see that when they started, they had a more than 10% prevalence of chronic hepatitis B. And by instituting universal birth dose vaccination, their chronic viremic prevalence has plummeted, which has been really a model for the rest of the world. But what we've seen is, although we've seen increasing vaccine coverage, it's really plateaued. So you can see that in 2012, it was about 79%. In 2014, 82%, really not increasing. And concerningly, the big missing target here is that 38% of the world is getting a birth dose coverage, which is really critical for reducing new infections. And when you look at the impact of the vaccine, you might imagine that this has had huge impact. But when you actually look at age standardized rates in terms of the effect of the vaccine on liver cancer rates and end-stage liver disease, and you compare 1990 to 2010, you can see that there's actually been very little movement. So this is a problem, and this is partially because the population has grown and there's been some spread of infections or the population's aged as well as grown. But really, this highlights the need for having better therapy because even with what you would think is the perfect therapy, a vaccine, to prevent infection entirely, we're still seeing this enormous burden of liver cancer and end-stage liver disease from chronic viral hepatitis, and particularly hepatitis B. So the bottom line when we think about the vaccine is that although it's clearly effective and very safe -- there we go. The coverage is a problem. It's good but far from perfect. Birth dose is really a problem. An incomplete or absent vaccination has major health consequences. And so I think it's fair to say that the vaccine is necessary, but it's not sufficient to eliminate HBV, and we really are going to need to focus on therapeutic approaches. And of course, the vaccine is not helpful for anyone who's already infected, and that's really critical to consider. And when we think about chronic hepatitis B infection, I am going to go through quickly the natural history of this relatively complicated scenario. Most people that acquire chronic hepatitis B infection are affected at or near birth, and they go through this period of the so-called immune tolerant phase. I still like that term, although some people now call this chronic hepatitis B infection without hepatitis. And what you see here is the reason I like the term is that you've got high levels of virus but normal liver enzymes, and this is really a marker that most of the damage caused by hepatitis B is immune mediated, and there's good evidence for that. And here, we're seeing normal liver tests and really very little immune activation. And then people transition at some stage into the so-called immune active phase where you start seeing these flares of hepatitis B with fluctuating levels of virus and intermittent flares of ALT. And it's here where the liver damage happens. And eventually, people get into a stage of immune control, which is sometimes referred to be an active carrier state where people control viral replication, and it may stay that way for a long time. And the serological profile of these people is initially E-antigen positive. And the E-antigen serum conversion, which I think is underappreciated, it's importance in the natural history. Once that occurs, you do see a very significant change in the natural history. And then if people stay in an inactive stage for a long time, they may eventually clear surface antigen. And when -- but what happens after E-antigen loss, well, we do know that people can go on to have active E-antigen negative chronic hepatitis B with flares of HBV DNA leading to flares in ALT and progressive liver damage, and this happens at much lower viral levels. And the challenge for this is that it can be difficult when you see a person at a given moment in time, are they between these flares? Or are they in an inactive state? And we really don't know this when we see a person at a given point, and this has really important implications because if they're inactive, we're going to do nothing. And if they have chronic active disease that's intermittently flaring, we're going to treat them. And so this really does have important implications for management. But I would also highlight that even these people would stay inactive are a group that we really need to think about therapy for because, really, we don't know when this is going to happen. So the consequence of this is that this is a very dynamic disease for people who remain surface-antigen positive, and they really need long-term follow-up, which can be very challenging both for patients and providers. And really, from the patient perspective, they usually feel perfectly fine throughout this complicated natural history. It's usually entirely or close to entirely asymptomatic. Even when people have significant flares of hepatitis, they don't walk into our offices with any indication that they've got hepatitis B. So we really have to screen them. And even when their livers look damaged like this with clear evidence of cirrhosis, they may would well feel perfectly fine. And this is really a challenge for us because it means that we've got to do screening and especially if we want to expand this out of specialty providers. And when we look at that natural history and think about when we treat, so we typically will treat people when they're in this immune active phase, whether E-antigen positive or negative, but it can be more challenging to define exactly in the E-negative category exactly what constitutes active disease. At least right now with our current therapies, we don't treat inactive carriers, but that might change if we had better treatment. If we think about people who are at risk of having active disease, we do tend to put them on therapy. But again, what the definition of that varies and can change over time. We try to prevent reactivation when people are getting immunosuppression, so we put them on therapy in that setting. And at least for now, we don't treat people in that immune-tolerant phase mostly because our treatments are relatively ineffective. And at least in the short to medium term, they have a good prognosis. But again, these 2 areas where I've highlighted as no treatment currently are areas where we might change if we had better therapies. And so if you look at the current guidelines across the different professional society, you can see that they're relatively complicated, particularly if you don't do this all the time, and they do require a sequential and a follow-up of people to know whether someone, whether they're E-antigen positive or negative in these different thresholds of where treatment begins. And this can be really a challenge for making sure that people are on the right treatment. And so what happens? Well, when you look at the world, we recognize that we have a huge problem with underdiagnosis and undertreatment. If you look globally at this, if you take people who are surface-antigen positive, you can see about 1/3 or so would be treatment-eligible according to current guidelines, but only 10% are diagnosed and a fraction of that are actually on treatment. And even if you look in a high-income country in the U.S. at the insured population, so this is not the under -- uninsured population, which, of course, is an even bigger problem. But again, you can see only 20% of those living with chronic hepatitis B are diagnosed, and a tiny fraction are ever treated. So this is really where we're starting from and why we need to make big gains in terms of using even what we have now, but I would make the case that if we had better and curative treatment, some of this would improve significantly. So if we actually go back to those World Health Organization targets and you look at where they were starting from, so this is what they were trying to get to in 2020. And then by 2030, it's important to recognize that the baseline for HBV treatment was less than 1% of those treatment-eligible were on treatment, really quite concerning. So...

Jordan, this is Heather. I just wanted to interrupt briefly. It seems we're having a little bit of technical difficulty with the audience being able to see the slides. We're looking into that. But the good news is we have a PDF version available on the Vir website under Investors and Events and Presentations. So Jordan, this doesn't affect your part of the presentation at all. I just wanted to let the audience know that there's a version on the Vir website, again, under Investors and then Events and Presentations. So sorry for the interruption, Jordan. Go ahead and keep going.

So just to make sure, I'm not doing anything wrong, am I, with the slides? Just, if I need to do something...

No. You're not doing anything wrong at all.

Okay. So I think what I highlighted here is it really does -- when we think about the challenges with underdiagnosis and undertreatment, I think one question that comes up is, should we actually just be treating everybody? And I think this is an important consideration. There is some push to treat everyone who's surface-antigen positive, particularly in low and middle-income countries where diagnostics actually might be more expensive than treatment and follow-up can be difficult. And if you think of the rationale, it's likely more cost-effective than our current guidelines. Even our current drugs are safe. Resistance is rarely a problem. And it may be difficult to sort of prove that in a cohort study that people need -- that are going to benefit from therapy might have a trouble designing a trial to show long-term outcomes like liver cancer appearance are benefited, but you might see those at the population level. And then, of course, there's also the transmission benefit by putting everybody on therapy like we typically do with HIV and hepatitis C. So I think it's important to think about that it's not who we're treating now that we would treat if we had new therapies, but with the right therapy, I suspect that the indication would move to treating everybody who's surface-antigen positive just as the needle has really moved with hepatitis C where we used to only treat those with significant fibrosis, and now we treat pretty much everyone with chronic infection. So if we're going to do that, then let's think about what our goals of therapy are? Well, we can certainly learn from the natural history, and we can see that it is true that people with inactive chronic hepatitis B have a very good long-term natural history, you see on the curve on the left. But in terms of really reducing the risk of liver cancer, it's getting rid of surface-antigen. And I'll show you a little more data to highlight this point, but you can see it's only this group who's surface-antigen negative that has a very low or negligible risk of liver cancer, which is still globally and particularly in high-income countries the driver of mortality from hepatitis B. So how do we want to do that? Well, our current therapy is very good for certain things. It suppresses the virus. It normalizes liver enzymes in most people, prevents fibrosis progression and can even promote regression even in people with established cirrhosis can even remarkably prevent and reverse hepatic decompensation, which is amazing when you see it in real time. But importantly, although it reduces, it does not eliminate the risk of liver cancer. And that means that not only are our patients in long-term screening, this is a major concern for them. It's anxiety provoking, and of course, for those who do develop liver cancer, often even with our best surveillance programs in place, cancer is diagnosed at a stage where our treatments are not affected. So we need to do better, and that's really the case for thinking about new therapy, particularly when you see that suppressive therapy is not a cure because what you see is that when you compare people with inactive disease on their own. So these are the real inactive carriers compared to people who have complete viral suppression on a NUC. So they're suppressed just where we're getting undetectable HBV DNA and normal ALT. And you can see that their risk of liver cancer is still quite a bit higher and markedly statistically significantly higher than people who have naturally inactive carriers. So even though we think we're replicating the inactive carrier state, we're not doing as good a job in either the non-cirrhotic and even more and concerningly in the cirrhotic population. So really, this makes, again, the case that surface-antigen losses are goal. You can see that when you actually do clear surface-antigen, what we see is that you see the risk of future liver cancer is extremely low. Sorry, I'm having -- there we go. Okay. And when we look at what our current treatments do in terms of achieving this goal, well, let's first look at how often does spontaneous surface management clearance happen? You can see it's about 1% a year in this very large analytical study over a pretty long-term follow-up and not surprisingly associated with lower DNA levels in E-antigen negative disease in older populations. Well, does our therapy do much better? The truth is not much better. You can see that here are our NUCs, even our potent NUCs, and you can see very low rates of surface-antigen loss. Interferon is a little bit better, but it's got its own challenges. And even when you combine interferon with a potent NUC, you're really only looking at still an under 10% probability of getting surface-antigen loss. So this isn't a great improvement over the natural history in terms of S loss. And I suppose the only upside to that is it gives us lots of room for improvement with our new therapies. So the problem with the current state of affairs, if I were to summarize it, is that we have massive underdiagnosis. We've got relatively complicated treatment guidelines. People who need treatment are often not on treatment, and people need to be followed very long term to figure out whether -- even if they don't meet guidelines now, whether they need them in the future. Once we start our therapy, this is usually lifelong treatment for most people. We can rarely stop, and we know adherence drops off. We occasionally see people losing prescriptions, running out -- their insurance runs out and having severe flares of hepatitis because they stop their treatment. Despite our treatment, even if we get people on the current therapy, they remain surface-antigen positive in large part. Their cancer risk goes down, but it's definitely not eliminated, so they have to remain in long-term cancer surveillance and still at risk. There's significant cost to lifelong therapy. And I don't think we should underestimate the issue that there's still stigma associated with being surface-antigen positive. This is a very real issue. Our patients tell us they want curative therapy, and they want a curative therapy even for those who are at low risk of bad outcomes. So when we tell inactive carriers, "Don't worry about this. You're probably going to have an active disease long term," they still say they want to be surface-antigen negative. So there's really an incentive to improve upon what we have now. And so how are we going to do this? Well, we'd like to try to actually cure the infection and get rid of all traces of hepatitis B, ideally eliminates cccDNA, the long-term replicative intermediate of the virus. This is going to be hard to do, and getting rid of integrated DNA might be an even bigger challenge. So I think most people have settled on functional cure of getting rid of surface-antigen. There is some interest in this idea of a partial care sustained off-treatment in active disease, but I would make the case that this probably isn't good enough. And it's not just my opinion, when you look at consensus from the ESL/AASLD endpoints meeting a couple of years ago, what you see is that the vast majority of participants felt that this functional cure of getting surface-antigen loss with undetectable DNA in normal liver test was a challenging but achievable goal, which really was the right target. And probably getting sterilized and cure was not achievable. But I do want to highlight a couple of caveats about that. So although surface-antigen loss is definitely the preferred endpoint, it may mean different things with different targets. So what we really want to do is what sort of natural clearance does, achieving cccDNA loss or silencing. And that's really what we want to do. But when we target the transcripts or eliminate -- or just get rid of the protein product of surface-antigen, does this actually affect cccDNA transcription? Will it lead to the same degree of immune control? We don't really know that. We think so, but we don't know that. And if we use other approaches, it really may depend on the mechanism, what it means. Immune targets are probably what we want, but they're harder to assess, and flares can be a bit scary. And I think an important point to highlight is that we have the risk of false negatives. Because of integrated DNA, you could have someone who still has low level surface-antigen positivity even if you've effectively silenced or cleared all of the cccDNA from their liver. And this puts us at risk of throwing away a good drug. It's also important to remember that this is slow. So we need probably long-term therapy for most of our approaches unless we really think of new approaches. And I think it's important to understand what surrogates mean, what is meaningful in terms of surface-antigen declines, whether it's log declines or absolute levels. And we probably need better biomarkers because our current ones are imperfect. So just to really compare this, and I think it is worth thinking about a contrast against hepatitis C where hepatitis C, we're starting it with ineffective, poorly tolerated therapy. Whereas with hep B, we have very well tolerated, pretty effective therapy. So we have a higher bar. We've only got a single viral enzyme as opposed to many targets in the HCV life cycle. With hep C, we didn't have this long-lasting reservoir, where with hep B, we have cccDNA and integrated DNA. And with hep C, the immune system was less important. Whereas with hep B, it's clearly more important. So we have to worry about flares, particularly in relatively healthy people. So the bottom line is it's not going to be as easy to cure hep B as it was to cure hep C, and this is important to think about as we move to the world of therapies. And so when we look at the viral life cycle, I've kept this slide intentionally complicated to highlight that the viral life cycle of HBV is complicated. But through really an improved understanding of this life cycle and I think really impressive scientific progress in molecular biology and virology, there now is ability to block and interfere with this viral life cycle at many stages from the earliest stage of blocking viral entry, targeting cccDNA either for destruction or inactivation, a lot of work on targeting the viral transcripts, either through silencing with siRNA or antisense oligos, targeting packaging with the capsid assembly modulators. Importantly, our NUCs target DNA synthesis, and you can see here why this doesn't affect surface-antigen numbers because it's well downstream of the production of the surface-antigen protein. There are approaches to target assembly or export, and then we can think about stimulating either the innate or adaptive immune response. And all of these approaches are being tried in various different ways. And just a little bit more detail on the immunotherapy side. You can try it on the innate side with cytokine therapies like our old friend, interferon, toll-like receptor agonist, RIG-I agonist, which I'll briefly mention, or on the adaptive immune side of looking at therapeutic vaccine or checkpoint inhibitors, which have been so effective in cancer therapy. But another consideration here is just by bringing down the protein levels, there is a hope that this will lead to a block of the immune exhaustion and immune restoration, which will actually lead to an antiviral target really leading to immune restoration. So this is attractive immunotherapies. But I think we do have to be mindful here that flares can be good, but they can also be a little bit scary and harder to manage, clinically. So of course, we have lots of potential combinations, and this slide was a veil that doesn't look as good without it, but we usually are thinking about viral control with blocking HBV-DNA replication through either our NUCs or some of the newer agents, trying to reduce the protein levels and get a reversal of immune exhaustion and then bring in an immune punch either an innate or an adaptive immune punch as sort of the knockout punch. But of course, you can mix and match these in multiple different ways. And then even if you find the right compound and the right combination, it's not -- it doesn't end there. You've got to make sure that you're thinking about the right therapy or combinations in the right population. So is it the group with the highest need like people with cirrhosis or the group that might be easiest to show an effect like those who are inactive carriers? What about immune-tolerant patients, NUC-suppressed or not NUC-suppressed? And then we have to think about the endpoints, I already talked about S-antigen, looking at other end points, many combinations. And of course, safety is a concern. And I just want to highlight that as an example, the RIG-I agonist and Inarigivir, which looked promising, looked very promising until it didn't. So in the background, you can see that this looked effective, but then were reported to cause liver injury and actually led to liver transplants and one death and halting development. So we've got to be mindful of this and really do it in a cautious and careful approach to make sure that we do this safely. It's not just hepatitis B. We can also think about delta. Delta is the worst form of viral hepatitis, only occurring as a co-infection with existing hepatitis B. Fortunately, there is decreasing global prevalence due to hep B vaccination but also unfortunately because of mortality from this most severe form of chronic viral hepatitis. But it's important to recognize that the attribute -- that the population attributable fraction of bad outcomes from among people who are already surface-antigen positive, so those with hep B, is really overrepresented by the delta group. So you can see that despite accounting for a small proportion of those with hep B infection, 18% of hep surface-antigen positive people who have cirrhosis or co-infected and about 20% of those who have liver cancer are co-infected. So really a disproportionate burden from HDV, making it really an unmet medical need. And we know that despite the fact that this is causing a huge burden, it actually is a relatively small population of only about 12 million people estimated globally, but the truth is we don't really have great estimate. So there are some delta hotpots like Mongolia highlighted here, but the reality is we have pretty questionable data and a wide range of estimates. And there's efforts to improve the quality of data here, so we understand the burden better. But the challenge here is we don't have any approved therapies currently. People use interferon, but you've got to use it long term with high dose. It's not well tolerated and doesn't work very well. And unfortunately, the NUCs are totally ineffective because delta only cares about surface-antigen. The good news is now that we're targeting surface-antigen, any therapy that reduces or clears surface antigen or blocks HBV entry should also work for delta because delta wraps itself in the surface-antigen envelope to get into the cell. So this is a nice sort of byproduct of focusing on B, which will hopefully get us a cure for this more orphan but quite devastating disease for those who are living with it. So to summarize -- sorry, here's the pipeline for delta where there is a lot of therapies of looking at either viral entry or immunomodulatory therapy for HDV, but really to -- sorry, just to finally to summarize that despite an effective vaccine, the burden of hepatitis B is still quite enormous globally, and it's important to not lose sight of that. I think sometimes people forget about this because most of the deaths are happening after long-term infection from liver cancer, and sometimes people even forget that it's related to hepatitis B. Our current therapy is very safe and effective, but it's not curative. It means we have a high barrier -- or a high bar to improve upon it, particularly because the science is complex, and cccDNA and integrated DNA are very challenging. And even our endpoint of surface-antigen loss is imperfect, but it's probably still our best available endpoint, combination therapy is likely going to be necessary. I don't think we're going to get there with the only antivirals unless we have some significant breakthroughs, and we'll probably need a combination of antivirals with immunomodulators. But it's going to be important to think carefully about study design to get the right population, the right mechanisms of action, really think about safety. And this part is going to be challenging. But I am cautiously optimistic that we are going to make really good progress, and I think we already have in the last couple of years with some really good promising options in the future. And this will hopefully benefit those living with HDV as well because surface-antigen is really the key. So there's lots of potential, but I really want to stress the point that it's important to be a bit patient here. This is not quite like hep C where it was relatively easy and the development happened very quickly. I think it's going to take a little longer with hep B, But I am optimistic that if we stay the course, we will actually get there. Thank you very much. And I'm going to pass it over to Dr. Phil Pang to now talk about Vir's pipeline.

Thank you so much, Jordan, and I really appreciate you taking the time to share with us that information about hepatitis B. I know there were some issues with the slides, so thank you all for bearing with us. And just to orient everyone who's following along either on the webcast or on the slide deck, we are now on Slide 48. I'm Phil Pang, I'm the Chief Medical Officer. So as Dr. Feld has outlined, the unmet need in HBV is enormous. It's real. It's not just a number. And what he's also outlined is that what we have today in terms of our antivirals simply does not solve the problem. And Dr. Jordan Feld just concluded, what was also clear is that HBV functional cure will be challenging. And so what you're going to see in the next half of this presentation, what Carey and I will be talking about is how is Vir going to answer that unmet need? Our answer is that we believe by having the broadest and most relentless pursuit of a functional cure for HBV, we will get there, and we will specifically get there, but -- and we will be the first to get there by combining antivirals with multiple immunomodulators. Next slide. Specifically, our goal is to be the first company to transform the current and, frankly, measly 3% functional cure rates we see today into something much greater, maybe tenfold greater, somewhere around 30 or more percent. We also believe that one can get there only by combining antivirals with multiple immunomodulators. And the reason for this is that first, we don't believe that stacking more antivirals on top of one another is enough. As Carey will explain and Jordan alluded to, chronic HBV is due to a dysfunction of the immune system. And so you need to address that dysfunction by removing tolerogens and stimulating the immune system. Importantly, our broad portfolio includes looking at 5 complementary immunostimulants. And as importantly, our broad portfolio will be evaluating 3 different patient populations. And so I want to connect the dots back to what Jordan just said, which is about having the right combination and the right population. And our broad portfolio looking at 5 complementary immunostimulants in 3 different patient populations allows us to have the confidence to believe that we can get there. Another exciting takeaway from today is that -- is the additive data that Carey will be sharing with you regarding 2218 and 3434 in hepatitis B. Now the reason why this makes us very excited about our hepatitis delta program is exactly what Jordan said, which is that hepatitis delta uses surface-antigen to complete its life cycle, which means that if you knock down surface-antigen, you are very likely to knock down hepatitis delta virus. And that is a disease for which there is not in the United States any approved suppressive therapy. Specifically, what excites us in the delta field? As I alluded to, we have clinical data on the additivity of 2218 and 3434, the antigen used by delta in its life cycle. We know that entry inhibitors can make a huge difference in delta, and VIR-3434 is also an entry inhibitor. We have not seen any concerning safety signals in our HBV trials to date with 2218 and 3434, making us believe based on both the mechanism of action and their preclinical safety that both drug candidates have the potential to be used even in the sickest of patients such as those that are hepatically impaired. And finally, we believe it will allow for convenience. It may be possible with these drugs to get to once monthly or even less frequent dosing. Next slide. I want to just double-click a little bit and get a little bit more detail. So what do we mean by combining antivirals with immunomodulators? And really, I think this can be encapsulated with the phrase, our goal is to stop and clear, to stop the virus with antivirals and clear already infected cells through immune-reconstitution. This differentiated and broad program is evaluating drug candidates therefore that have multiple mechanisms of action, as shown here. Each of our drugs is not just one and not just the other. We will be able to block entry. We will be able to block replication, reduce tolerogens and stimulate immunity. And that is how we intend to get to a functional cure. Next slide. Finally, as Dr. Jordan Feld already talked about and Carey will allude to, HBV is a heterogeneous disease. Not all the 200 million people in the world with hepatitis B are the same. We want to find the population with the maximal chance of making an impact in patients' lives, and therefore, the maximal chance of success. Next slide. Finally, I want to return to this idea of hepatitis delta and really hone in on why we are so excited. Again, remember, hepatitis delta virus is a co-infection that occurs only in those who are infected with hepatitis B. It requires the surface-antigen to complete its life cycle. We have -- Carey will be sharing with you the additive data between 2218 and 3434 in knocking down that surface-antigen, which has been shown to directly correlate with hepatitis delta viral load. So I want to close by sharing with you 2 thoughts. Imagine a treatment that could be given once a month and prevent hepatocellular cancer and has the potential to be used in the sickest of patients. That is why we are pursuing hepatitis delta. And until there is a 100% cure rates for hepatitis B, we feel that these are excellent and complementary programs. Carey, over to you.

Great. Thank you, Phil, and thank you, Jordan, for the great introduction. So I'm Carey Hwang, I'm the Head of Chronic Infections here at Vir. I'm really excited to be here today to discuss our comprehensive hepatitis program. What I'm going to do today is discuss the HBV unmet need, review our preclinical and Vir clinical data of our current Phase II program, introduce our programs in additional hepatitis populations as well as delta, discuss the HDV unmet need and then our expected clinical data milestones for 2022 and 2023. So as have been stated so eloquently before, HBV remains a significant global health threat with approximately prevalence of 300 million persons worldwide and about 1.5 million new infections every year, and unfortunately, still approximately 900,000 deaths per year due to complications due to hepatitis B. Despite chronic NUC therapy, the unmet need remains for hepatitis B patients. Clinically, about 40% of patients will develop clinically significant progression of disease, including cirrhosis as well as hepatocellular carcinoma and liver failure. Hospitalization rates are also higher for patients with hepatitis B, along with ER visits and outpatient visits, increasing the cost of health care. And as what's been also described, there has been 6 sigmas also associated for these patients, with the fear of infecting others as well as the fear of progression of their own disease. Existing standard of care is not optimal. There are limitations with NRTI therapy. It's not curative. Even though it does decrease the risk of hepatocellular carcinoma, it does not eliminate that risk. In addition, it requires lifelong daily pill burden as well as adherence, and experience rates are very difficult to sustain for that such a long period of time. In addition, interferon alpha has low functional cure rates of approximately 3% to 7%, that has poor tolerability and also is contraindicated in hepatically-impaired patients. The chart on the left highlights the significant opportunity in hepatitis B. As we've been discussing, hepatitis B afflicts a large number of patients worldwide. However, only a small fraction or possibly 2% are actually on NRTI therapy today. Achieving functional cure will completely shift this paradigm for patients, potentially offering a finite curative regimen to approve their outcomes. Vir's differentiated regimens are well positioned to potentially reach these meaningful functional cure rates in the different HBV populations, and this will be a significant opportunity worldwide if we can achieve this. Vir's approach to functional cure is based on the premise that immune dysfunction is the basis of chronic HBV and that a functional cure will require regaining immunologic control. Therefore, our hypothesis is that knocking down HBV antigens or remove the block on the immune system and in the setting of immune modulation result in immune control. Why do we believe that a functional cure is a result of immunologic control? Because if you immunosuppress a patient that has been functionally cured, their HBV actually reactivates, strongly suggesting that their immune system was what resulted in their functional cure. We know that high-antigen loads can drive T cell dysfunction resulting in tolerance. In the last panel, in the presence of high-hepatic antigen levels, T cells become nonfunctional or exhausted, and this results in antigen persistence within the liver. In the right panel, with low-hepatic antigen levels, T cells can remain functional and are able to clear antigen within the liver. This is evidence of the importance of reducing collagen as part of our strategy with therapies such as our siRNA, VIR-2218 to enable the immune response to regain control of infection. As additional proof of principle for a hypothesis, an HBV model demonstrated that activation of CD8-positive T cells and functional cure was achieved when tolerogens were suppressed within siRNA, followed by the administration of a therapeutic vaccine. The same was not observed when the therapeutic vaccine was not given in the context of VIR-2218 -- of siRNA. So what you want to take away from this slide -- study, is that it strongly supports the hypothesis that reducing tolerogens, followed by an immune-stimulant can result in functional cure. This is the same strategy that we are employing with our collaboration with Brii. Now that we have taken a look at some of the evidence supporting our hypothesis, I want now to turn our attention to our robust pipeline with VIR-2218, being evaluated in combination with different immuno-modulators. We currently have 4 Phase II clinical trials ongoing combining VIR-2218 with pegylated interferon, VIR-3434 in combination with TLR8 agonist GS-9688 as well as nivolumab and another trial evaluating VIR-2218 in combination with a T cell vaccine. So let's first turn our attention to the combination of VIR-2218 with pegylated interferon alpha. Our trial consists of 5 different cohorts. Cohort 1 evaluates 2218 monotherapy, and Cohort 2 evaluates a 2218 lead-in for the first 12 weeks, followed by concomitant administration of 2218 with interferon through week 24. In addition, we have additional arms, which are evaluating the concomitant administration of both 2218 and interferon together from Day 1 through 24 weeks of treatment. And then we have also amended the protocol to add additional arms, Cohort 4 and Cohort 5, in which we extend administration of interferon up to week 48 in Cohort 4 and extend administration of 2218 and interferon to week 48 in Cohort 5. In both Cohorts 4 and 5, if participants achieve S-antigen loss on 2 consecutive visits, then they are eligible to stop their therapy and to be followed. So I'll be describing the data from Cohorts 1 through 4. So in this -- in Cohorts 1 through 4, the mean change in S-antigen level on treatment through Week 24 were similar in Cohorts 1 and 2, with approximately 2 log decline in both of those arms. Cohort 1, as a reminder, was 2218 alone and Cohort 2 was a 2218 lead-in, followed by co-administration with interferon alpha. However, when we look at Cohort 3 and 4, when we co-administer VIR-2218 with interferon alpha from Day 1, we observed faster and deeper declines in S-antigen levels. And then, more importantly, 3 participants, one each in Cohorts 2, 3 and 4 achieved S loss. Now let's take a look at these 3 participants who achieved S loss. These participants had baseline HBS-antigen levels between 130 and 160 IUs per ML. And 2 of these 3 participants achieved seroconversion with anti-HBS antibody by week 24. This provides proof of concept of our hypothesis as we did not observe HBS-antigen loss in our VIR-2218 alone arm and only in combination with interferon. This shows that combination with the immunomodulator has an enhanced effect. And we will have additional follow-up from this study from these participants and other cohorts later this year. What I want you to take away from this trial is that the combination of VIR-2218 and interferon demonstrated a proof of principle that an immunomodulator combined with VIR-2218 can result in enhanced responses in S-antigen levels and that we are also able to achieve S loss. This strongly suggests that the siRNA can unlock the potential of immunomodulators. As I've mentioned, this trial has been expanded to evaluate 48 weeks of treatment with data expected later this year. So now we will turn our attention to our unique combination with VIR-2218 and VIR-3434. We are really excited about the potential of VIR-3434. VIR-3434 is a monoclonal antibody that's directed against the antigenic loop of surface-antigen. It has 2 modifications in the Fc domain. The first modification is an LS modification, which extends the half-life of that monoclonal antibody. The second modification, the GAALIE or XX2 modification is an engineered Fc domain, which enhances dendritic cell activation. So in this cartoon, as we work from left to right, the vaccinal antibody forms immune complexes with S-antigen. These immune complexes then bind the dendritic cells, selectively binding Fc gamma receptor IIa and IIIA, which facilitate activation of the dendritic cell. This results in generation of effector T cells, which we hope to see that they will provide durable HBV-specific immunity over the longer term and then eventually contribute to functional cure. Two animal studies in oncology and flu demonstrate the powerful effects of antibodies with the GAALIE modification and proof of the vaccinal effect. An oncology model on the left, the presence of the GAALIE mutation was able to clear long tumor lesions in those mice that received antibodies with GAALIE. And as you can see in the other animals that had control, they have multiple lesions that were still present. On the panel on the right, this is a flu model looking at an anti-HA antibody with different modifications to the SC domain. And as you can see, with the GAALIE mutation, these animals, after a flu challenge, were able to regain their weight very rapidly compared to those animals that did not. And importantly, all the animals who received the GAALIE mutation survive the infection. These 2 examples provide further proof of the activity of the vaccinal effect of these antibodies and the potential for this application to hepatitis B. Shown here is the clinical trial design of our initial study with VIR-3434 in the clinic. This is a single-ascending dose trial evaluating Part A in healthy volunteers and then Part B, C and D in virus-suppressed patients as well as viremic patients. In dark gray are shown the doses that have -- or the cohorts that have already been dosed, and in green are the ongoing dose cohorts. We have dosed up to 3,000 milligrams IV in healthy volunteers without any safety signals, and we have also dosed 300 milligrams without signals observed to date. So the key takeaways from this slide are that increasing doses of VIR-3434 correlate with a maximum decline in S-antigen levels. As a reminder, these participants in these different cohorts were randomized 6:2 to receive either 3434 or placebo. In terms of the mean reduction seen at the highest dose evaluated -- that we have data for with the 75-milligram dose cohort, we were able to observe approximately almost a 2-log decline at nadir and then also persistent response after Day 29 of approximately 1.5-log decline in S-antigen levels. I'd just like to briefly comment on the 2 participants in the yellow -- shown in the yellow that's named 1 and 2 will appear to have less response compared to the other participants in that dose cohort. When we analyze the 3 3434 concentrations in those participants, those levels were either undetectable or much lower than what we had expected and likely suggested a dosing error. So the important thing to note from the data from the SAD trial are that in single-ascending dose even at 6 milligrams, almost all participants achieved at least a 1-log decline in their S-antigen levels. And as I mentioned, the 75-milligram dose had possibly 2-log decline. This allows us to evaluate even higher doses that we are actively looking at with 300 milligrams to see if we can get even additional decreases of S-antigen levels in this population. However, the data here really support evaluation of the combination and moving forward with the combination of the looking at 2218 in combination with 3434. So we are really excited about the initiation of the MARCH trial. This is the first study that's combining both 2218 and 3434. Part A of the trial shown on the left is what's rapidly -- designed to rapidly assess the safety of the combination of 2218 and 3434 together as well as to evaluate the PK as well as the S-antigen suppression with this combination. In regimen 1, we had a 2218 lead-in for the first 16 weeks, followed by concomitant administration of 2218 and 3434 for 4 weeks through week 20. And in regimen 2, we had concomitant administration of both agents for 12 weeks. Next, I will share some of the initial data from Part A of this trial that we haven't shared previously. So [ primary ] treatment data from Part A with the 2218 lead-in, followed by 3434 show the following: number one, at the end of treatment at week 20, we have approximately a 3-log decline in S-antigen levels from baseline; and number two, looking at week 16 time point, data show evidence of additivity between VIR-2218 and 3434, with addition of VIR-3434 at week 16, resulting in an additional 2-log decline in S-antigen losses. Importantly, we also saw no safety signal from these 2 agents were combined together, and there were no discontinued issuance or other clinically significant findings that were observed. So in the system point of points I made from the previous slide, we expect to present more complete data from Part A of the MARCH trial at a scientific meeting later this year. And this is due to the impact of the war in Ukraine and effect on our clinical trial operations in that region. However, Part B of the MARCH trial, which, again, is evaluating the combination of 2218 and 3434 for 24 and 48 weeks as well as in combination with interferon will be starting in the second quarter of this year as planned. So now let's pivot back to VIR-2218 and its combination with other immunomodulators. We have 2 Phase II trials ongoing with collaborations with both Gilead and Brii. Both trials are evaluating our hypothesis of reducing tolerogens and then adding an immunomodulator to enhance the immune response. In the case of the Gilead trial, we are adding VIR-2218 to reduce the tolerogens and then looking at adding a TLR8 agonist as well as a checkpoint inhibitor to improve HBV-specific T cell responses. With the study with Brii, we are combining VIR-2218 with a therapeutic vaccine. And in this case, again, VIR-2218 would be reducing the tolerogens while the therapeutic vaccine would improve responses to achieve immune responses in that case. So this is a study designed for the Gilead trial. Virologically suppressed as well as viremic patients are being evaluated in this trial and looking at different regimens with both a VIR-2218 lead-in, followed by co-administration with the TLR8 agonist and anti-PD-1 antibody as well as concomitant administration of all 3 agents together. And with the Brii study -- so here, we are evaluating 3 different cohorts here. There's a single cohort that's looking at VIR-2218 alone, and then subsequent cohorts of evaluating a 2218 lead-in, followed by administration of the therapeutic vaccine and then another arm using interferon alpha as an adjuvant. So this portion wraps up our comprehensive review of our current robust Phase II clinical program with both VIR-2218 and 3434. So now I would like to focus on additional opportunities for our program, leveraging VIR-2218 and 3434, specifically looking at viremic populations within HBV as well as the new opportunity in hepatitis delta. So we are eager to expand evaluation of 2218 and 3434 into other HBV population that are currently not indicated for treatment. Current trials at Vir have focused primarily on the virologically suppressed HBV population. However, other viremic populations who may are currently not indicated for treatment based on guidelines may actually benefit from treatment and could also have a higher probability of achieving functional cure as they may have a more intact immune system. Vir will be initiating a platform trial in the second half of 2022, which will allow efficient evaluation of these additional patient population as well as different regimens. And so these initial populations will look at inactive carriers as well as other viremic patients not currently on NRTI therapy. So I now want to pivot to a very new opportunity, an important opportunity in terms of pursuing hepatitis delta in a population with a very high unmet need, as previously discussed. Approximately 12 million people worldwide have HDV. However, HDV has a 3.9-fold higher risk for HCC compared to the hepatitis B population. Vir's answer to hepatitis B is to leverage both 2218 and 3434 with their complementary mechanism targeted against the virus and also differentiated by its potential for more convenient dosing and tolerability as well as the potential ability to treat hepatically-impaired patients. This opportunity is independent and in addition to our robust portfolio of hepatitis B. HDV is the most aggressive form of hepatitis, with faster progression and higher proportion of patients that progress towards hepatocirrhosis and hepatocellular carcinoma. An early treatment and diagnosis is critical for this population to prevent that progression of the disease and as well there are significant costs -- health care costs for this population. There are currently no approved therapies in the United States. Pegylated interferon, efficacy is very limited and is also contraindicated in hepatically impaired populations in which this population has a higher proportion. In addition, nucleoside analog therapy has little or no activity against HDV replication. Bulevirtide, which has conditional approval in the European Union, is probably less convenient in terms of required daily subcutaneous injections. So the left part of the chart really highlights that only approximately 5% to 10% of patients with HDV are actually diagnosed today. As we've been discussing, while HDV co-infection is a small proportion of those with hepatitis B, it has an enormous impact on the progression of disease in those patients that proceed to HCC and liver failure. Our Vir regimens are very well differentiated due to this potential for more convenient dosing as well as the additivity -- potential additivity of their different mechanisms and also the potential to be used in sicker patients. We believe that such a regimen will drive increased diagnosis as well as treatment rates in delta, addressing this significant unmet need. As shown on the left graphic, both VIR-2218 and VIR-3434 have multiple mechanisms of action directed against both HBV and HDV. So this is a prime opportunity for Vir to really explore both disease states. The combination of 2218 and 3434 leverages the independent as well as the synergistic -- potentially synergistic mechanisms by both knocking down S-antigen levels through production of S-antigen with VIR-2218 as well as removing S-antigen with VIR-3434 from both HDV [ variant ] as well as preventing infection of new hepatocytes. We expect to initiate a proof-of-concept study in this population in delta in the second half of this year and hope to see initial data from that proof-of-concept in 2023. As you can see, this slide really demonstrates the breadth and robust clinical development program that we have at Vir for both VIR-2218 and 3434 as well as the combinations that we have currently evaluating different immunomodulators both within the current clinical trials as well as our announced clinical trials today. We will be expecting 5 key readouts from our trials in 2022 and 4 key readouts from our trial in 2023. In the first half of 2022, we will be presenting additional data from our 2218 and 3434 monotherapy trials at EASL. In addition, in the second half of this year, we will present more complete data from MARCH Part A, which is the combination of 2218 and 3434. We also expect to see initial data from the Brii collaboration study where VIR-2218 is being combined with a T cell vaccine. For 2023, we expect to see additional new data from MARCH Part B where we are evaluating 24- and 48-week treatment of Vir -- the combination of 2218 and 3434 with and without interferon. And then we will also expect to see initial data from our platform trial evaluating viremic patients in the second half of 2023. Additional data readouts are the Gilead trial, the combination of 2218 with the TLR-8 agonist and anti-PD-1. And then as I mentioned, we hope to see initial data from our proof-of-concept study with hepatitis delta. So as you can see from this session today, HBV and delta remain diseases with really high unmet needs for patients. The key takeaways -- the 3 key takeaways for our broad strategy in HBV and HDV are the following: Vir's goal is to be the first company to have achieved a functional cure rates of 30% or greater in the HBV population. We have a differentiated HBV cure pipeline, combining 2218 as a mechanism to reduce tolerogens and combining that with multiple immunomodulators. And number three, we will leverage both 2218 and 3434 to expand into new populations within HBV as well as in delta where this population has very few treatment options available. So let me end by saying that in my career, I've been involved in both hepatitis C and HIV drug development and witnessed -- really witnessed the amazing impact of the therapies in both of these disease areas, both with the cure of hepatitis C as well as the transformation of HIV into a chronic disease. The impact those therapies have had on patients was immense and unmeasurable. I couldn't be more excited about the potential of VIR-2218 and VIR-3434 and Vir's distinct approach to achieving a functional cure in hepatitis B as well as controlling hepatitis delta as part of chronic therapy. And with that, I will turn it over to Heather for the Q&A session. Thank you.

Thank you, Carey. And thank you to everyone for your patience as we sorted out the slides. It's the never-ending trials and tribulations associated with technology.

We will now turn to the Q&A portion of this event. [Operator Instructions] So the first question that came in is, can you comment more on the MARCH trial? What were the 3434 dosages showing in the graph? Is it 18 or 75?

Thank you, Heather. So the answer is, is that the graph you saw, all the patients received 2218 and then followed by 3434 at a 75-milligram dose.

Thank you, Phil. So the next question, when looking at the 3 different patient populations, NRTI suppressed by [ remit ] or inactive carriers, which proportion of each patient type do you anticipate being included in your Phase II trials? How would you anticipate functional cure rates to differ between the 3 groups, if at all?

Thank you, Heather. So I'll begin answering, and then I will actually be happy to turn it over to Jordan to see what his thoughts are as well. So the first answer is we're actually going to be running 3 separate trials in those 3 separate populations. So each trial will enroll only that patient population. So when we released the actual trial on clinicaltrials.gov, you'll be able to see the exact numbers in each one of those trials. But we will be able to answer for each one of those trials what the actual -- what happens to those particular patients. In terms of the probability of success in terms of functional cure rates, frankly, it's very hard to speculate, but I can tell you why we chose these 3 different populations and why I think each one is somewhat unique. Obviously, in the NRTI-suppressed patient population, there's great data coming out of [ Mindie Nguyen ] at Stanford, basically showing that the longer you've been infected with HBV and the longer you've been on chronic suppression, the more probability you have to be able to be closer in some sense, depending how you define closer, to a functional cure. But one could also argue looking at Antonio Bertoletti's data coming out of -- coming out of Singapore, which is that patients who have been more chronically infected for longer also have a more [indiscernible] immune system. So there's data on both sides suggesting why a viremically suppressed population would be both good or bad to look at, but also suggest why they shouldn't be the only population you should look at. With regard to the inactive carriers, really, they're a distinct immune population also in the sense that these are patients who have managed to really bring down their HBV-DNA to quite low levels but have not been able to make that final step into getting into surface-antigen clearance. Again, so maybe they're closer in a different way, and we want to test that population. Finally, with regard to the viremic patient population, often, these -- who are qualified for nucleotide therapy, these are patients who are having active immune signals, which suggests that their active -- their immune system is still active, and therefore, we might be able to help them cross the barrier into cure. So these are the reasons why we're going after these 3 patient populations. But until we test it, I think in the absence of a immune animal model, we're going to have to figure out the answer empirically. Jordan, do you have any thoughts you might share with us?

No. I think -- I mean I think you really hit on the high points here. I think it's important to think about the fact that these really are very different groups immunologically. And I think it's also important to consider that they're starting out often with very different S levels. So where you're -- sort of the threshold from where you're starting is quite different. I mean I'm really interested to see what happens in the inactive carrier population. This is a group that I think is sort of often ignored because people feel like their need for therapy isn't as great. I would make the case that this is a group -- it's a huge population of patients. As I mentioned, they want to get rid of S, and we have to follow these patients long term because we really don't know if and when they'll become active and also what their risk of cancer is. They're starting very low. They've already got an immune system that is controlling virus well. I think the real question here is whether that S is coming off of integrated or cccDNA and whether the therapies are going to have any differential ability to control S from those sources. But I would be -- my sort of A priority expectation is that you're going to actually see the best effects in that group where you sort of just need to push them over the edge to get to functional cure. And I -- but I would agree with Phil that really the empiric data will answer the question.

Great. Thank you. The next question relates to HDV, and it's a 3-part question. So the first is the prevalence of HDV seems to be very low in HS positive patients or S-antigen positive patients. Is the level of S-antigen correlated to the chances of the patient being infected with HDV? The second part of the question is, is there a preference of HDV to different HBV genotypes? And then the third part of the question is, are there other prerequisites for a patient to be infected by HDV?

So I'm going to start the answer and then again turn it over to Jordan. I think there might be a slight confusion in terms of how we think about the disease. HBV -- chronic HBV is required to have delta. So in some sense, it's almost impossible to be surface-antigen negative and be infected with delta. There may be a confusion between E-antigen and surface-antigen, but you need to be surface-antigen positive. If the question is why is only "5%" of the world's population have delta and not 90%, I think part of that, frankly, is the fact that most people don't get tested. The reality is that being tested is not a part of most standard workflows in the primary care or even in certain liver clinics. But also, the question is, for many people, they're like, why bother to test? There's nothing I can necessarily do for these patients. Now that paradigm is changing as we speak, but it hasn't been there. So when we look at prevalence estimates, we're looking at prevalence estimates from years ago, not prevalence estimates from 2022 after new tests have finally come on market and new drugs are finally being developed. So I would say the reason why it's 5% is probably it's underreported and will continue to climb as effective therapies are made available, and there's an incentive to treat. Jordan, any thoughts?

Yes. I think some other important considerations about the epidemiology of it is really that it is -- this is geographic. So you do see hotspots in the world where there's a lot of delta, but those things can change. And actually, I think there was a really nice study done from Hopkins a few years ago where they had looked back in the '90s that their prevalence of delta among their hep B infected population founded to be extremely low. And then they looked 20 years later, and they found that there was a lot more delta. And particularly in North America where a lot of delta is among people who acquired infections through injection drug use, it's introduction of delta into the population then it circulates. And that's a bit the same in other regions when -- if you go to a place like Mongolia, there's a lot of delta. Most parts of China, the estimate is that there's not a lot of delta. I think Phil is right that there's probably under testing. But the other thing that happens is because delta is so severe, many people unfortunately don't live and they die at younger ages. So I think as we test at younger ages we'll find more of it. And I would also argue that the epidemiology will shift. Just to sort of the other points there, I don't think there is any effect of the HBV genotype that's known on supporting delta infection. And there's no minimum amount of surface-antigen. So even people with very low levels of surface-antigen that are circulating can support delta infection. And interestingly, it can be supported even from integrated S-antigen that's coming off integrated DNA that's been shown nicely in vitro.

That's helpful. Thank you. The next question also relates to HDV. For chronic HDV being a rare disease, is there potential for an accelerated approval pathway with FDA? And if the Vir program is successful and approved, should we assume the pricing for the treatment would be more aligned with a rare disease rather than one that is more prevalent such as chronic HBV?

Maybe I'll turn that one over to Carey from a regulatory perspective. And then just before I do so, comment on the fact that, frankly, right now, it's too early to talk about pricing. While I have extraordinary faith that we will achieve both the functional cure for B and chronic suppressive therapy for delta, I think it'll be more germane once we get there. Carey, as far as the regulatory paths, we're looking for, for orphan and accelerated approval.

Yes. I mean we will be looking at all the different pathways to try to facilitate our program, moving it forward as fast as possible because I think the unmet needs of this population are so great. So whatever discussions and pathways that we can try to utilize to get this therapy to patients, we will try to pursue.

That's helpful. Thank you. So the next question relates to HBV. The bar for success appears low in HBV in terms of generating a functional cure. Can you discuss the bar for success for a functional cure in HDV? And what rate would be needed for the program to be considered successful? Actually, I lied. That was actually an HDV question.

So why don't we take that in 3 parts, Heather? I'd like to give an intro, maybe have Jordan weigh in and then have Carey weigh in. So first off, just to explain, the biggest difference probably -- well, there's many differences. But one of the biggest difference in practice between hepatitis delta and B is for B, there's actually suppressive therapy. Whereas for delta, there's no easily available, well-tolerated, well-known, well-studied suppressive therapy for delta. So the first difference is that there is actually a market need and especially a medical need for suppressing delta irrespective of a functional cure for delta. So there are 2 ways to address the unmet need in delta, either suppress or cure. So we believe that, obviously, that the bar is quite low for both of those categories given the fact that at least in the United States, there's no approved therapy. There is more cludex in the European Union, which is used as a daily injection. And this is, of course, an important recognition that without effective treatments, the bar is quite low. Jordan, do you want to talk at all about what you think the bar is in terms of rates that people have seen in the past? Or -- and maybe Carey can follow up if he has anything to add.

And I would agree with you entirely, Phil, that I think the bar is quite low for delta. I mean we really -- I mean if you look at it even -- when you look at what the white paper calls for what is an effective treatment for delta, they've actually just asked for a 2-log decline in delta RNA levels and normalization of ALT, which is really a pretty low bar, but that's actually what the regulators are looking for, and it speaks to the fact that this is an aggressive disease with no effective therapy. And although Bulevirtide is certainly a breakthrough, it's important to remember it's a subcu injection. It's given daily, and it blocks bile acid uptake, which is -- seems to be safe temporarily. But if you do that forever in a person on long-term therapy, that might lead to some concern. So I think really almost anything that actually gets to curative therapy for delta would be a real significant benefit, particularly if it's well-tolerated. And even chronic suppressive therapy, it doesn't require on a daily injection with its potential risk for side effects would also be a big advance.

Yes. So I just want to clarify as well, our program in delta is for chronic suppressive therapy. So one principle is that if you cure -- if you functionally cure hepatitis B, you'll also functionally cure hepatitis delta, right? But right now, I think there's still a long road ahead, and it's still challenging. However, for suppression of delta and preventing progression of disease, we believe that the combination of 2218 and 3434 can suppress the viremia and progress -- and prevent that progression while we still work towards a functional cure for both B and delta.

The next question is, in what HBV genotypes should we anticipate Vir's approach to be effective? And what proportion of each genotype would you anticipate being enrolled in your Phase II trials?

So let me try and answer that one, Heather, and see if Carey has anything to add if I've missed anything. So first, I want to clarify, there are about 10 different HBV genotypes. And our siRNA 2218 is actually designed to hit a conserved site that is active against all 10 genotypes in vitro. Similarly, VIR-3434 is a monoclonal antibody that has an engineered Fc region that is designed to act as a therapeutic vaccine -- allow it to act as a therapeutic vaccine. That, too, has been selectively -- was selected because it has reactivity against all 10 genotypes. So in sum, we would anticipate, if efficacy is demonstrated, for it to be effective against all the genotypes out there that we are aware of. In terms of what the enrollment impact would be in terms of our clinical trials, I want to stress the fact that as we mentioned, there are 3 distinct patient populations, the suppressed, the viremic and those who are viremic but are inactive carriers who would not be eligible for treatment. And of course, in the viremic population, you can actually genotype the patients, and those who are virally suppressed it's actually challenging to genotype. And most of our studies to date have been in virally suppressed patients. Therefore, the genotype is mostly guessed by where they have been enrolled. Most of our patients to date have been enrolled in the Asia Pacific region, and so therefore, have genotype B and C. We are now expanding to Europe, which has had obviously its own challenges with the war in Ukraine, but that will also expand the genotype population we explore. Carey, did I miss anything?

No. I think you've covered it all. Our initial trials were both in Asia Pac, but now we are expanding more globally with our future clinical trials.

So the next few questions are around the MARCH trial. Can you tell us what portion of MARCH Part A was enrolled in Ukraine or Russia? And how that data is being included or now not included in the trial going forward? And what regions have you shifted enrollment to following the war? And how will this impact the baseline characteristics of patients enrolled, if at all?

Carey, I think that one is entirely yours.

Yes. So actually -- yes, so we do have significant number of participants that were enrolled in the Ukraine region. And so that's why our clinical operations group has done an amazing job trying to work through those issues to follow up those patients and try to get that data. However, we don't know what's going to be happening in the future as the war progresses. So hopefully, by second half this year, we will be able to gather more complete data and gather some of that data from those regions. To the second question around where we are going, we are exploring and we are already planning to move into other regions of the world for clinical trials, and we are trying to accelerate those efforts now with an ability to move into Russia as well as Eastern Europe.

Maybe just to clarify, I think it was 18 out of 40 patients in the MARCH Part A trial that were enrolled in either Ukraine or Moldova. The reason why we include Moldova is the fact that the aerospace over Moldova is obviously impacted, and therefore, impacts the ability to execute clinical trials. So the data we're showing is an aggregate of what we have available. That is why we are saying that the actual scientific presentation with all the details will be delayed until the fall, so we can settle out some of those details. I will say thank you to our participants in the Ukraine, Moldova region. Believe it or not, there are still patients sometimes coming to clinic, which is just beyond my imagination right now. And so I just wanted to put a shout-out for those patients. Thank you.

So the next question about MARCH is, did any patients achieve surface-antigen levels below the lower limit of quantification and/or detection at the end of treatment?

I can take that.

Sorry, please go ahead.

Yes. So yes. So as I mentioned in the presentation, Part A of the trial was just really to rapidly assess the safety of the combination of 2218 and 3434. So the treatment duration was quite short. Now we are only 20 weeks with the 2218 lead-in and only 12 weeks with the 2218 and 3434 combination. So we are still following some of these patients out and then kind of seeing where they progress. But because of the short-term duration of treatment, the likelihood of achieving S loss in that short period of time is probably low. And we hope and expect to see more when we look at the 24- and 48-week treatment arms from Part B.

That's absolutely critical. Remember, the point of the Part A is to test short duration -- is actually not to test short durations but did test short durations of a low dose of 75 milligrams of 3434 in combination with 2218. And really, the goal was, does it show additivity, which is exactly what we were hoping for and exactly what we saw, and then translating that into how does it help us design Part B where we'll be looking at much higher doses of 3434 and for much longer durations of time. So that's what we'll be focused for now.

So the next question is, can you comment on the durability of VIR-3434 in the MARCH trial? Repeated doses of 3434 seem to sustain the reduction in S-antigen unlike a single dose, but also no further significant after giving the second to fifth dose of 3434.

I think it's a little bit too early to comment, Heather. I think that with an incomplete data set, with 18 out of 40 patients still, frankly, the data is a little bit messy. I would say that clearly, there's a continual decline after more doses of 3434, but the degree of that decline and these sort of things, we'll have to wait further exploration for their data, and we'll present that in the second half of this year.

For the 2218 plus 3434 Part A MARCH data, what is the log reduction profile for each -- profile each for regimen 1 versus regimen 2?

So as you can see from the graphic, we saw about a 1 log to 1.5 log decline on 2218 after only the first 16 weeks, and then we add to that more than 1.5 log afterwards. But the reason why -- I'm not trying to be coy or anything, but as I said, it's an incomplete data set. So I don't want to give you an exact number only for it to be somewhat tweaked as we go forward. That's why we like to say it's likely additive, and we'll have more details for you at the scientific presentation in the second half. And -- but we are very excited by that additivity not only because of its ability to help us design Part B of MARCH and understand better how we can put these 2 drugs together in an optimal combination, but as Jordan mentioned and as other people have shown, surface-antigen correlates directly with HDV viral load. And so it gives us very high confidence that, that is a high probability of success program for us.

So for MARCH Part A data, how many patients are represented by the data on Slide 77? Are patients still being enrolled in Part A? Or has that cohort completed recruitment?

Carey, do you want to address that?

Yes. So that cohort Part A has completed enrollment. If I recall correctly off the top of my head, there are 17, I think, participants that were enrolled. Something 20 -- let me double check.

Right. So basically, around 20 patients enrolled in the data that you've seen. It is incomplete because, of course, we have patients in different stages of the follow-up and even on treatment in terms of collecting the on-treatment data. So it's not 5, but it is closer to 20.

Right. We had 17 enrolled, and then I think around 12 that we have data for at the week 24 time frame -- the week 20 time point.

Thank you, Carey.

The next question is similar, although related to baseline characteristics. So the question is, on Slide 77, can you tell us more about the baseline characteristics of the patients enrolled? What rate of functional cure could an S-antigen decline be predicted to generate? And then when do you anticipate providing an update on functional cure rate for regimen 1?

Let me take that one up a level. So I think that I love the excitement around the data. But I think that being able to say that a patient who achieves a certain S-antigen reduction level, let's say, 10 versus 1 versus, frankly, 12 or 15, it's just not known. I want to remind people that when it comes to hepatitis B as opposed to delta, the critical aspect will be what happens off-treatment in terms of being able to have a sustained functional cure. And that we don't know. And the reason why we don't know that is not because there's not historical data with interferon alpha. But as Jordan pointed out, whether or not that translates for new mechanisms of action, we simply don't know. So I could certainly speculate, but it would be pure speculation. Certainly, if you were to take a natural history cohort and ask, is the functional cure rate higher in those with lower S-antigen than higher S-antigen, it's definitely higher -- the higher functional cure rate, the lower the S-antigen goes. It's also true that if you take those that gradient of patients and you treat them with interferon alpha, their cure rates go up as their surface and their baseline surface antigen goes down. Whether or not getting them there by adding an siRNA and a monoclonal antibody will act the same way, we simply don't know.

So the next is around the next data set. Do you anticipate full data set in second half of 2022? Do you expect that it will include all 30 patients from both regimen 1 and regimen 2 from Part A? And then what gives you confidence that you're seeing an additive effect of VIR-2218 plus VIR-3434?

So maybe I'll take the second question first. I think the data speaks for itself. I think that the curve we see shows a decline with 2218 monotherapy. And then clearly, something very different happens once you add in 3434. So I think the fact that it is additive, I think, is apparent from the data. As far as what the exact presentation in the second half of this year will be, I think we'll have to let the data evolve, see what data we have, and we're going to try and present as much as we can.

Are there patients in the MARCH trial who achieved S-antigen levels less than LLOQ so far?

Yes. We haven't discussed that. We haven't disclosed that. We'll have details on that in the second half of this year.

The next one is the combination of 2218 and 3434 reduced surface-antigens 3 logs. What level do you think you need to get to? And for how long to get to high levels of functional cure? In the 2218 interferon data achieving S-antigen loss, why did ALTs go up for the final time points? That was a 2-part question.

That was a 2 separate questions.

Two separate questions.

So I think that it is not entirely accurate to say ALTs went up at the final data point. I think it's more accurate to say the ALT is fluctuating. It has not gone -- there's certainly no safety signal. Now it certainly -- it goes up in the sense that as you give patients more interferon, their ALT tends to go up. So I want to make sure we're not conflating either a safety signal with what is expected for interferon alpha. And I also don't want to conflate what is expected with interferon alpha as a sign of a -- either a good or a bad flare. So I think that, that's just a statement I would like to make. As far as the first question, again, I think we need to allow the data to evolve and to see where things go. I think that -- I think -- and Jordan can certainly weigh in here. I think the duration of suppression you need to achieve a functional cure is unknown, and that's exactly why we're doing our clinical trials.

Happy to weigh in. But I think, Phil, you've really hit the nail on the head. I mean I made the point that I think it's hard to predict what threshold of surface-antigen levels mean. I think we think lower is better, but what level is required to reinvigorate an exhaustive immune system is known. And whether getting people to that low level for some period of time will lead to the same thing that we see in the natural history when people do it on their own, it's really hard to predict. We know the sort of magic number of 100 is a strong predictor of subsequent clearance in the natural history. My suspicion is you got to get significantly lower than that in people when you're using a therapy, but what that number is -- I think anyone that gives you a definite answer, you should be -- make it with some question marks because it's not clear yet from the data.

So for 2218 plus 3434, does current Part A data support 3434 every week -- every 4-week dosing? What full data will you be looking for from Part A to help further guide Part B?

So I think we have the data we need currently from Part A to design Part B. I would say that the data supporting a -- whether or not it has to be weekly or actually what we believe now is it can be monthly is a amalgam of both the data coming out of MARCH Part A as well as the monotherapy data coming out of VIR-3434 Phase Ib trial. So that Phase Ib trial data will be presented in this half at a scientific conference, and I think it will be more clear at that time. But we are pursuing once monthly dosing for 3434 both in our hepatitis delta and hepatitis B trials and feel confident that, that is a very reasonable thing to do.

The next question asks, to what extent are preclinical models of hepatitis predictive of clinical responses?

So I'm going to take that in 2 parts. I'm going to separate out hepatitis delta from hepatitis B. So as we talked about, there is both suppression and cure. And I think when it comes to viral suppression, the animal models are quite -- for delta, the animal models are quite good. I think that things that knock down delta in an animal model in terms of viremia are likely to work to suppress delta in a patient. I think for hepatitis B, I think the on-treatment response is likely predicted by animal models. But the off-treatment response is a function of immunology. And frankly, in my opinion, there are not very good animal models of hepatitis B immunology. And that is why we are taking -- and that's why we've really designed our platform to be one of the broadest, looking at 5 different complementary immunomodulators if -- do we believe that 2218 and 3434 is the best shot on goal? Yes, that is my personal belief, but it would be a mistake from a drug development perspective to say because I believe that we're going to exclude all other possibilities. And that's why we've initiated this broad program with 5 different immunostimulants in 3 different patient populations.

The next question asks, what surface-antigen level could be considered at HBV functional cure?

So the definition of a functional cure right now, there was actually a recent guidance issue. But in terms of what we think of as an HBV functional cure is the loss of surface-antigen 6 months after the end of treatment -- sustained 6 months after the end of treatment.

If people are interested in the level, that's usually using the standard threshold of 0.05 international units per ML as the -- that's the standard. It's only relevant because there are potentially more sensitive surface-antigen assays, which might pick up lower levels of that. But the nice thing about that 0.05 threshold, it's been around for quite a while, and we know that the natural history of people after surface-antigen loss, as I showed you, is extremely good. So I suspect that, that will end up being the final definition of functional cure long term.

The next question asks, have there been any trends [indiscernible] flares among chronic HBV patients following 2218 plus 3434 treatment to suggest immune reconstitution hepatitis?

So it's too early to say because we don't have all the data for all the patients. I would say that in general, the observation I would share with you all and point you to is the Gilead poster from a couple of years ago, which showed that while a flare is -- increases the probability of a cure, the sensitivity is extremely low, meaning the vast majority of people who achieved S loss did not have a flare even if the probability of success was higher. So that's the kind of data we're also looking forward to, and we plan to share at the scientific presentation later on this year.

So the next question asks, do you plan to seek FDA approval after completing the Phase II MARCH trial if data are overwhelmingly good?

I think I can't comment on regulatory actions, but I can tell you that certainly, if there's a medical need that we believe we can address, we will do everything possible to get it to patients as soon as possible.

So the next question asks, you have many combinations in development with multiple trials underway. At what point would you anticipate having a clear idea of which combination or strategy is the way forward? And when -- and would we have a better idea by the second half of 2022 or would it be more by mid-2023 when we would have a clearer picture of the strategy for Phase III?

I think the strategy -- just to be clear, I think the strategy for Phase III is actually quite simple. We'll take the best regimen forward and do our pivotal trials and get the exact rate of functional cure should we be able to achieve a functional cure. I think the question maybe behind the question is, how will we choose? And really, it's not -- it's relatively straightforward, but there's always nuances, which is, of course, we want the regimen that has the highest efficacy, that is also the most convenient and the most safe. And so not all the trials will read out at the exact same moment. And so we'll be looking closely at the cards and saying, okay, between those 3 factors, what time frame are we willing to consider waiting for more data? For example, if the 2218 interferon alpha data is overwhelmingly positive, certainly not going to sit on it. But at the same time, we recognize that it would be less convenient and less well tolerated than 2218 plus 3434. So that's certainly part of the strategy.

So the next question is, for the combo with immune modulators, what additional biomarkers will you be sharing? And what kind of data sets would suggest activity of immunomodulators?

So we are going to be looking at all the standard biomarkers, but -- and I would love, Jordan, your thoughts on this. My feeling is the standard biomarkers are standard only because people are looking at them, not because they're standard to have been able to show anything of importance. And the reason why I say that is because until you've achieved high rates of functional cure, you can't have a biomarker that predicts what the functional cure rate is. And since no one has achieved high rates of functional cure, you can't have a biomarker that's predictive of functional cure. So that's my feeling on biomarkers in general. In terms of immunology, the challenge here, and this is something that I really want to highlight that Vir is interested in, is we need the immunology not just from the peripheral blood, but from the liver. And those are studies that we are planning either as part of these studies or as supplemental to these studies -- as additional studies to be able to look at biomarkers of immune reconstitution in the liver. Jordan, do you have any thoughts on this? I know your center has been really pioneering some of that liver immunology.

Yes. I would really stress exactly what you said that I think a lot of people talk about immune reconstitution, and they use, I would say, very weak surrogates for that. People see ALT flares and see -- and they say, you see, we showed you that there's immune reconstitution. That could be anything from toxicity to active hepatitis to immune reconstitution. And even if it is immune reconstitution, whether it's effective immune reconstitution is unclear. So I think really the field needs a better look at immunology broadly. And I would agree with Phil's comment that you really need efficacy before you come up for predict cures. I mean we've really spent a lot of time trying to improve the ability to look in the liver using -- finding new aspirates where we're taking sort of a liquid biopsy of the liver. It's pretty well-tolerated, and we can look at immune cells in pretty good numbers as well as small numbers of hepatocytes in the liver to get an idea of what's going on. I think this has been underused. And frankly, even as Phil said, although the peripheral blood is not good, to be honest, most trials have not even looked in the peripheral blood at really showing that therapies that are bringing down the antigen levels are actually leading to restoration of immune function. So hopefully, we will see more of those data moving forward.

So the next question relates to 2218 and PEG interferon. So it said the combination resulted in greatest S-antigen reductions, with most patients having achieved S-antigen levels less than 100 IU per ML and 55% who achieved less than 10 at week 24. Question, what proportion of those patients at less than 100 and less than 10 would be expected to achieve a spontaneous functional cure based on the natural history of the disease? And after what time frame after having S-antigen below those levels would this be expected to occur?

So we can talk about the natural history, and Jordan, maybe you know the numbers off the top of your head, but I think that all we can say is that from my recollection of the graph is that patients who have achieved less than 100 can have functional cure rates spontaneously that are in the double digits, in the low double digits as opposed to the single digits, which we see normally for people who have a higher S-antigen. But I do want to caution that getting there with siRNA therapy isn't the same thing as getting there from the natural history. That's what we're trying to determine and improve. So I don't want to either undersell or oversell it. I want to really emphasize the fact that we've achieved something that most clinical regimens have not. We've achieved and the fact that we have shown that our medications are additive with one another, whether or not that's interferon and 2218 or 3434 and 2218, as you can imagine, the field has not always shown that. In fact, recent data showed that adding a capsid to an siRNA actually may be detrimental to the impact on surface-antigen that you see with an siRNA. So I just really want to caution people that we need to understand what the achievement is, which is we've demonstrated that activity. We are getting closer and closer to being -- trying to get as many patients as possible to less than LLOQ and have them in a sustained way. But that for HBV, the critical question will be long-term functional cure requires immune reconstitution. That is in contrast, obviously, to hepatitis delta where bringing on the surface-antigen, we believe, will directly correlate with suppression of the delta virus.

Thank you, Phil. The next question is, why study HDV separately rather than just include patients with HDV plus HBV co-infection in the HBV clinical trial programs?

So let me take that a little bit more philosophically and talk about it from a drug development perspective. So clearly, every delta patient we enroll will have hepatitis B. And so when you design a clinical trial, you're always asking yourself, what is the question? And how best to answer that question? In terms of answering the question is also what you expect the answer to be. So for delta, as we talked about, the main goal, not to say we are not interested in a cure for delta, we believe we can get there through curing B, but the immediate goal will be to suppress HBV-RNA. So we could certainly enroll a subset of patients in one of our trials. That's an option. But the problem is, is then you may not be enrolling patients in the correct sites or in the correct parts of the world to be able to enrich for that patient population. So really, it's a trial logistics and development question, which, of course, that sounds like a beer and a -- maybe a long bottle of wine type of question rather than a pity answer for you just because it is -- there's 100 factors that go into how we design a clinical trial.

But I would also add one more important consideration is that the natural history of those 2 infections is so different. So if you have HDV-HBV co-infection versus HBV mono-infection, I mean, they don't respond to NUCs the same way. The safety profile isn't necessarily the same and what might happen in one group versus another. So it's particularly in a small trial. If you have it sort of contaminated by having some co-infected patients in there, and they behave differently than your HBV mono-infected patients, you might come to the wrong conclusion about whether your therapy is effective for HBV. And I think especially as you are moving in the early stages of development, you don't want to contaminate your populations. It's difficult enough within HBV of all the different HBV populations. We don't think genotype matters, but it could. But even just thinking about the different phases of disease, different -- whether people are on therapy or not on therapy, to throw in delta into the mix would be, in my opinion, a big mistake early on.

All right. So the last question that has come in, how is Vir thinking about positioning all of these chronic HBV programs in the future? Do you envision certain populations being better suited for certain 2218-based combos? And also any insight on which might be best for which combo?

Thank you, Heather. So I think this goes back to one of the earlier questions. So I'll try and answer this in 2 different parts. As we stated, we are exploring many different populations with our regimens because they have very different immune profiles. And which ones will work best in which populations, we simply need to test empirically. But I will say that it is my hope that -- obviously, from an ideal perspective, we would eventually be able to get to what I would call a hepatitis C-like regimen where you can have a single pill once a day for every type of patient of the 290 million people infected, but I think we are not anywhere near that right now. So for us, I think being able to cure patients at greater than 30% rates and be able to identify which patient populations would most benefit from that treatment is our goal in the near term, in the next 1 to 2 years. And then beyond that, we intend to iterate upon any success we find to continue to be able to provide a benefit to patients.

Thank you, Phil. Any last comments before I turn it over to George for closing remarks? All right. George?

All right. Thank you, Heather. Look, let me thank all of you for your attention today. I want to thank Jordan for taking time out of his incredibly busy schedule to be with us today. Much appreciated, Jordan. And also our collaborators Brii, Alnylam, Gilead, and of course, the patients and the investigators who have participated in all these trials. I also just want to say that I think we remain committed at Vir to bringing forward medicines that will prevent and cure major infectious diseases. We focus on hepatitis today. I hope you got a good view of the programs, of the rigor, of the breadth and of the thinking that is behind this clinical program. And we look forward to, obviously, updating you in more detail at upcoming scientific meetings. And finally, I think this program is representative of the work that goes on at Vir. This is one of several programs or other programs, COVID, flu, HIV, that we believe have major potential where we have sound approaches, good clinical development plans and where we have a reasonable chance of success going forward, and we'll have data on all of those programs coming up over the next months and year or 2. So thank you all for your attention. And I think with that, we can sign off.