Thanks, James and Mindy, and for the invitation, although you'll notice that I'm actually not the intended speaker. If I was a little taller and had blonde hair and a slight Dutch accent, you'd be seeing Harry Anson up here, but unfortunately he couldn't be here, and I'm stepping in for him to talk about emerging therapies and an update on hepatitis B cure. So here are my disclosures. And so what I'm going to start off with is just touching on goals of therapy, and Noor already did a nice job outlining this, and then really spend most of the time talking about new approaches to hepatitis B therapy, aiming for cure with both virological and immunological targets, and briefly touching on combination. Obviously there's lots of data, which is nice to see, and I can't cover it all, so I'm going to be focusing on things that have already advanced to human data, so there's at least early clinical trial data, and focus more on conceptual concepts around the targets rather than covering every single agent in development. So when we think about the goals of therapy, I think our ultimate goal would really be that we'd like to truly cure this infection and get rid of all the traces of hepatitis B from the liver, sort of like what we've achieved for hepatitis C, or at least what we believe to have achieved. But this is very difficult, and it may be impossible, at least with our current technologies, because of this long-lasting reservoir of covalently closed circular CCC DNA in the liver. And so that's really led us to sort of lower our bar a little bit and aim for this term functional cure, which really is based on the fact that the natural history gives us some keys to what does lead to very good clinical outcomes, and we certainly know that people that lose surface antigen, and particularly those that develop anti-HPS, really have a very good natural history. But it's also important to recognize that even people that are able to stay with very inactive disease, and I think Nora showed this, that the people that have, that remain surface antigen positive, but have low or undetectable levels of HPV DNA in normal liver tests, with normal liver histology, also tend to do well. And some people have referred to this as partial cure, if you can achieve this off therapy. And so when you think about these things, and you look at the natural history, we see that patients that have very inactive disease have excellent survival, and if you clear surface antigen, that particularly lowers the risk of HCC. And I think it's these type of long-term natural history studies which have led to these being the targets for therapy. But I would just highlight these data from the REVEAL cohort that showed that in long-term follow-up, patients you see in red, who remain surface antigen positive, but have undetectable HPV DNA, you see that these patients do actually similarly to those who clear S-antigen. And I think it's just something to think about when we're thinking about cure, and one of the questions, and this is sort of a confounder for the field, is about using surface antigen as our aim, as our target for therapy, is this question about integrated HPV DNA as being a source of surface antigen, and it's at least theoretically possible that some of these patients that remain surface antigen positive in the serum are deriving all of that surface antigen from integrated DNA rather than from CCC DNA. And achieving that may be just as relevant, and it's important because this could make us discard potentially very effective therapies if we don't keep this in mind. But is there any consensus on this, what should we be aiming for, should we be going for this sterilizing cure, I think most people think this is probably too hard to achieve, at least in the current status. And although I think a sustained off-treatment response would be considered an advance, most feel that this probably is not enough, and really the target is this aim of getting surface antigen loss, ideally with lower undetectable HPV DNA and normal ALT off-treatment. And that's felt to be a generally challenging but achievable goal, and in fact at the easel ASLD endpoints meeting, there's now been two of these, the majority of the attendees felt that this should really be the target for developing new therapies. So when we consider achieving this level of functional cure, and just comparing these viruses, because I often have patients say, how come you've cured Hep-C, why can't you cure Hep-B, and it is certainly a challenge, but there are some important differences. With Hep-C we were starting with ineffective, poorly tolerated therapy, whereas with Hep-B, as Nora showed you, we have well-tolerated, very effective therapy, so the bar is much higher. With Hep-C we had multiple targets in the viral life cycle, in HPV, although we've achieved targeting other approaches, there's still a single viral enzyme. With Hep-C there's no long-lasting reservoir or integration, whereas with Hep-B we have CCC DNA to contend with. And then finally with Hep-C, there seems to be limited importance of the immune system, at least with our current therapies, whereas immune control is very important for Hepatitis B, and this complicates things quite a bit, because it raises the issue of flares being potentially helpful in terms of leading to cure, but causing a little bit of fear among us is how do we manage these, and when do we know if they're so-called good or bad. So the bottom line is it's not going to be as easy to cure Hep-B as it was for Hepatitis C. So when we look at the viral life cycle, fortunately it's been fairly well-characterized and there are lots of potential targets, so we can target the entry of the virus, we can target CCC DNA, the long-lasting reservoir of the virus, the RNA transcripts, we can target packaging, we can target the DNA synthesis, which we've been doing for a long time, export of the virus, or alternatively we can try to gain immune control either through stimulating the innate or adaptive immune system. So I'll just go through these and highlight some key examples from each of these approaches. So blocking entry, just starting at the beginning, seems like a nice strategy, although when chronically infected patients, this may not be that effective. We know the vaccine works before infection, but of course not after infection. So Mercludex-B, which binds to the NTCP receptor and prevents HPV entry, unfortunately doesn't work very well for Hepatitis B, at least as a monotherapy, with very modest HPV DNA declines and no change in surface antigen, but perhaps it could be used as an adjunct. And I think these data in studying Delta Hepatitis with Mercludex-B in combination with interferon are very interesting. So the first thing that you see is that when Mercludex is used alone, it has much less effect than with interferon, and in terms of the HDV response, the only real benefit is seen in those patients who have combination treatment, and you see this decline in HDV RNA. But on the flip side, this is also relevant for Hepatitis B, as you see that there were a number of patients in this study who had a surface antigen decline of greater than one log, and indeed patients who went down to very low levels, and this only happened in patients getting combination therapy. So this wasn't only an effect of interferon, this was Mercludex with interferon. So I think this is certainly interesting. The mechanism of why these should be synergistic is not so clear, but I think these are interesting data and are worthy of some more exploration. So if we move on to targeting CCC DNA, I think this is what we'd all really like to do, and there's certainly some interesting preclinical technology that would suggest that this might be possible, either using CRISPR-Cas9 technology or zinc finger nucleases. This is still pretty early days here. This is difficult. There's certainly a risk of off-target effects, and it's not simple to deliver these where they need to get. But I think this certainly holds some promise for actually eradicating CCC DNA from the nucleus of infected hepatocytes. So the next step downstream is to target the viral transcripts that come off of CCC DNA, and this has been approached primarily using small interfering RNAs or siRNA, or alternatively with antisense oligonucleotides, which work similarly but use the RNA's H system in the cell to degrade the RNA, rather than the RISC complex, which is used for microRNA processing in the cell. And so the nice thing about hepatitis B is because of the overlapping reading frames in a fairly conserved genome, it allows for developing targets that target all of the viral proteins together, and also target the pre-genomic RNA, which is the replicative intermediate that leads to reproduction of the genome. So you can block antigen production, and the thought here is that by reducing antigen production, you may actually restore or reduce exhaustion and then restore immune function and lead to clearance. And in addition, you can get a direct effect on RNA replication by knocking down pre-genomic RNA. And indeed, oops, I keep pushing the wrong button, and indeed data are emerging showing that these approaches actually work. With some of the newer RNAi approaches, you can see the Arrow HPV, now JNJ3989, you can see that this did lead to surface antigen reductions when given, and you can see importantly in the gray bars, you see the e-antigen negative patients, and the blue bars are the antigen positive patients. And this is important because with the first generation of these molecules, there was a concern that this was only occurring in the e-antigen positive patients, where the majority of surface antigen is coming off CCC DNA, and may not be working against surface antigen coming off of integrated DNA. But seeing the effect similar between the e-positive and e-negative patients gives us confidence that this is working in both, off both types of S-antigen transcripts. Now importantly, you do see a reduction in these other markers, HPV RNA and correlated antigen, but perhaps not as profound as what we're seeing with surface antigen, and the reasons for that are not entirely clear. Now I think it's also an important question to ask, what does it mean when we see S-declines with different therapies? We want to see clearance of S, but when we directly target the viral protein, is that the same as blocking CCC DNA transcription and silencing of replication in that measure? And so one of the questions is, can we use data from previous studies to suggest thresholds of reduction of surface antigen, and you can see that when you get below a surface antigen titer in the serum of 100, you can see that patients are much more likely to lose surface antigen. So this has suggested that perhaps this would be a good target. But I would say that we should have a little bit of caution here. So you do see that with these data, with this J&J molecule, you can see that a high proportion of patients started above 100, and after therapy, the majority get below 100. But whether that means the same thing as patients who get to below 100 through a natural immune control is a very important question, and I don't think we really have the answer yet. And whether this will lead to reversal of T-cell exhaustion and restoration of HPV-specific immunity is definitely a testable hypothesis, but at least to date, has not really been well shown. So I think this is still an important uncertainty here, and I think we should be careful about jumping to conclusions of what the significance of these declines are, particularly on therapy declines. So let's move now to the next step of targeting packaging or encapsidation, and the approach to this is using capsid assembly modulators, sometimes called capsid inhibitors. But the reason that this term is preferred is that they don't all inhibit the formation of capsids. In fact, the majority of the agents in development are the so-called type 2 or class 2, which form normal capsids, but they don't have any pre-genomic RNA inside them. So they block encapsidation, but they don't actually block the formation of the capsids. And you can see that when you look at this sort of simple schematic, so this is going to work a little bit upstream of where nukes work, and so what you should see, and this is what's been shown, is that you see a reduction in HPV DNA. You also see a reduction in packaging of hepatitis B RNA, and that's detectable in the serum. Now another interesting potential mechanism, which has been certainly shown in vitro to be true, and possibly in vivo, but I think the data are less compelling so far, is that these molecules also have an effect of uncoating encapsidated virus that's entering the cell. And that's either of recycling of new virions that are forming, or a virus that's entering a newly infected hepatocytes. And with this approach, with cell turnover, you would actually eventually deplete CCC DNA. And this is certainly very promising. And what we see here is that you can see that these drugs work potently to interfere with replication, so you can see that at different doses, HPV DNA declines. And you can see a similar plateauing at the higher doses, but importantly, you might need higher doses, and actually the in vitro data would suggest you do need higher doses to get that secondary and perhaps more important mechanism. So that's why as long as the safety looks good, going to the higher dose might make more sense, even when the HPV DNA declines look similar. There are many other agents in development, and I'm just showing one here. And I think these data that were shown earlier this year at Eazl were compelling in that they showed that by adding a capsid with a nuke, you do actually get some synergy between these agents. So you see in green the patients who were on nukes alone, and then you see when the capsid was added, you get a deeper decline in HPV DNA, and you also get a decline in HPV RNA. And importantly, this does not mean that you've blocked CCC DNA transcription. What this means is you've blocked packaging of RNA. And that's expected for capsid assembly modulators, whereas you can see with nuke monotherapy, which happens downstream of RNA packaging, you don't see any significant decline. Now importantly, when you use a very low, a more sensitive technique to detect low-level replication, even in patients on long-term nuke monotherapy, you can see the majority were still detectable, and with the addition of a cam, you can see that most of them became undetectable. Now does this mean there's no replication happening? I don't think we can say that. We can just say that with this assay, which is more sensitive than standard assays, you can get a better block than with a nuke alone. So this is certainly promising, and there's gonna be some more data presented with this molecule and others at this meeting. So let's move down to targeting DNA synthesis. Well, we've already got nukes that do this very well, and although there are some other nukes potentially in development, this is not a major focus. So we can then move to the next step of actually assembling and packaging and excreting virions. And these data using nucleic acid polymers, which are molecules that, in a mechanism that's not entirely clear, block the secretion of the sub-viral particles. So not the intact virions, but the sub-viral particles. And what you see here is when combined with a nuke and interferon, you see that they have these very dramatic declines in surface antigen in the serum. And you can see that that actually translates into pretty impressive off-treatment responses with surface antigen loss and the development of anti-HBS in a high proportion of patients. One thing that's, I think, given a little bit of pause for thought about this is, first of all, the mechanism is not entirely clear, but the second is that most of the patients that achieve this S loss have fairly significant ALT flares. You can see that these ALT levels shown in the bottom graph are going up quite high. And so I think the question is, are these immune flares that are leading to immune control, which has certainly been proposed and might be possible, but there's, of course, other explanations. And until we understand how these molecules work better, we're a little bit uncertain about them. There is plan for a phase two study with the AIDS clinical trial group to try to get a little bit more deeply at understanding the mechanism and confirm these promising results. So next we move to the immune system of either the innate or the adaptive immune system. And so you can target on the innate side, which B tends to avoid stimulation of the innate immune system, a so-called stealth virus. And you can do this either with our standard cytokine therapy, like interferons, with toll-like receptor agonists, or with rig eye agonists have been proposed so far. And on the adaptive side, primarily people have focused on therapeutic vaccines or trying to take off some of the breaks that normally inhibit the adaptive immune response. And another important consideration is that a very potent antiviral strategy, which depletes viral antigens, might lead to immune restoration just through that mechanism by reversal of exhaustion. So this is attractive, but all of these immunotherapies cause a little bit of angst among hepatologists because they potentially can lead to significant flares, which although these might be therapeutic, they can also sometimes be pathologic and certainly can be hard to stomach as we watch patients go through them. So one interesting molecule on the innate side is this agent called in a Rig-A-Vir, which is a RIG-I agonist, and this has potentially a dual mechanism of action where it stimulates RIG-I, which is a normal, one of the, which normally stimulates the production of type 1 and type 3 interferons as a pathogen recognition receptor. But importantly, also RIG-I directly interferes with HPV replication by interfering of the binding of the pre-genomic RNA to the initiation sequence for reverse transcription. And so these data potentially, you have a dual mechanism of action, and you can see that when given to e-antigen negative and e-antigen positive patients, you can see both HPV DNA and HPV RNA declines, and you can see that the effects of this seem to be greatest in e-antigen negative patients and those with low surface antigen levels, and there will be some, again, more data presented to look more deeply at what's going on with this molecule and whether both mechanisms of action are indeed active. The checkpoint inhibitors and immunotherapy have really revolutionized oncology therapy with the idea that you take off the brake of the adaptive immune system, and this reversal of exhaustion potentially leads to a stimulation of the immune system and to immune control, which has worked very well for cancer targets and has led to some interest in the infectious disease area, both for Hep B and HIV, with the idea that if you can reverse exhaustion, you might be able to achieve immune control. And in this very small study, using very low doses of nivolumab, either alone or in combination with a vaccine, which probably wasn't terribly effective, you can see that the nivolumab, the PD-1 inhibitor, led to high receptor occupancy, and although you can see that the overall, there wasn't a dramatic effect across all patients, there was this one individual shown here who had a very dramatic response where this patient had exactly what we would hope to see with this type of therapy, with a stimulation of an ALT response, a surface antigen decline, and this person actually cleared surface antigen. And this has led to stimulation of more interest in approaching this type of therapy. Ultimately, it's probably gonna require combinations, and which combinations are we gonna use? Well, probably something that impairs viral replication, and I think the idea that we try to lower the antigen load and stimulate immune recovery seems attractive through one of the different mechanisms, and then possibly the knockout punch of an immune stimulant, but there's lots of potential ways to do this, and you can think of sort of a complicated matrix of combining them. So how should we do this? Well, firstly, does do all of the agents need to be active alone? I would challenge that a bit and say all of the agents need to be safe alone, and they need to have a rationale for being used in combination, but if that's the case, then it might make sense to combine even relatively inactive agents with more active agents. And then which one should we try together? Well, I don't know for certain. Obviously, there's lots of ways you could try this, but I think the key is that we look across the different molecules in development. And then we'll have other things to consider, the population, whether we've got the right endpoints, whether the same endpoints should apply to every mechanism of action, whether we use the correct combinations, and then ultimately safety is a major concern because we have very effective therapy right now, so we're not gonna tolerate very much of the safety risk to achieve a functional cure. So to summarize, we've got many virological targets, which is exciting, and it's really exciting to see the last couple of years with the development of these agents and the promise of more to come. We have fewer immunological targets, but there's more coming, and I think we're learning a lot about the immune control of hepatitis B, and this will help us understand how to develop new therapies. Combinations are likely required, but this is going to be a lot more challenging than it was for hepatitis C, so we need to be a little bit patient, and I really encourage both patients and to some degree investors to be a little bit patient and stick with us because it will take longer to get there, but ultimately, I think we will get there and achieve functional cure in a high percentage of our patients. Thank you very much. Thank you. Great, so we're gonna start the panel discussion. I'd like to invite all the speakers to come up to the table. We have two microphone on each side of the aisle. We'd like to invite the audience to come up to the microphone and ask a specific question, and please identify yourself. Stephen Wu from Los Angeles, California. For Dr. Nguyen, the presentation is wonderful, but in Hong Kong, I see the study, but the question for you is that Hong Kong mostly use the Baracuda, not the tenofovir, so we should not, you mention about the kidney disease get worse and osteoporosis. However, in Hong Kong, we study, do you see any difference? If it is, then it is valid. Thank you for the question. So the data from the published data, I don't recall a separate analysis between treated and untreated in terms of kidney disease, but in our U.S. data analysis, we did control for the use of agents, but in the U.S. data set, less than 10% of the patients were taking any medication, very small percentage, so I believe that the increasing in kidney or hypertension disease that we see are probably not related to the antivirals because the number of use are so little in the U.S., and like you mentioned, in Hong Kong, the percent, less than 1% for tenofovir. Okay, the next question is, we're talking about entacavir and also tenofovir, which increase or reduce the hepatoma. The next question for you is, is this patient belong to subgroup genotype B, genotype C, do you know of? So it depends on what study you're referring to, but most of them were done in Asia where genotypes B and C predominate, and in some of the studies in univariate analysis, the genotype is associated with HCC risk, but in a propensity-matched approach where you match on genotype, then genotype falls out and is not a predictor, and that's where the treatment effect is sort of evaluated. The next question, you know, the Asian actually has more central obesity as time goes by, you're going into the liver cirrhosis, and even more is liver cancer. Did you consider that part of the treatment that is related to that? So, I mean, I think you're highlighting beautifully the challenges in looking at the data on HCC risk using retrospective cohorts, and I have to commend the authors who've written these papers that they've done the best job possible with the quality of the data they have, but in the end, there are many factors that we know could be linked with cancer that are not captured, and I think fatty liver, and we recognize central adiposity, et cetera, is probably one of the leading ones that is not captured in current database. Thank you. I want to follow up on that a little bit. There's another factor is time. So, as we see with hepatitis C, the warehousing effect, when DAA first came out, we got a lot of sick people waiting for DAA, waiting to be treated, so we saw a lot of liver cancer and worse recurrence, et cetera, that have been proven to not be true after subsequent studies. So, in the case of entecavir and tenofovir, in our data set that we looked at the US data, when the difference between the approval and usage of entecavir and tenofovir were not very different, 2005 and 2008, we actually did not find any difference at all, and in the same consortium, we analyzed the Asian data, then there were difference in the Asian data that the entecavir patients were sicker and will follow for longer time, and they got more cancer, and so, when we adjust for the timing, we no longer see a difference. Just want to add one more thing is that, just to the audience, both entecavir and tenofovir reduce the development of a hepatocellular carcinoma, so it's not that one is causing cancer or vice versa. Yes, the microphone to you. Thank you, Carla Coffin from Calgary. Very good presentations. I have a question for Nora and for Jordan, so I'll start with you, Nora. In your HBRN studies, did you look at quantitative surface antigen in those individuals in the gray zone to see who might transition in long-term follow-up, or are you planning to look at that now that it's a FDA-approved assay? You know we're a little behind, so. But we did look at it, and it is actually associated, but we only had at baseline, and I think what really one's interested in is probably how surface antigen might change, say, over the first year, and how that might predict an outcome. We haven't done that, but similar to other studies, the individuals who tend to be in the inactive group and who remain there tend to have lower surface antigen. In the analysis that we did, it was under 1,000. Thank you, and so for you, Jordan, my question is related to definition of functional cure, and what would you see the role of surface antibodies or seroconversion, because as you know, in terms of people that reactivate, we generally have an impression if their surface antibody titers are higher, they'd be at lower risk of occult hepatitis B reactivation. Yeah, I think it's a good question. I think the data with nuke therapy suggests that it probably doesn't matter that much, that the probability if people clear S, which as Nora showed isn't common, but it happens, that it seems to be fairly durable whether or not they develop surface antibodies, and so I think probably as a, if it would be nice to see anti-HBS, I think we'd all be more confident that that was truly a functional cure, but I think we would be very happy to see S loss in the absence of anti-HBS as a first step if I can hedge my bets a little there. Thank you. Oh, Dr. Wei. Kim from Stanford. Dr. Felt, I don't know if this is an answerable question, but I want to see how you think about this question. So if you look at the NAP data, it's very impressive how quickly the surface antigen decreases and then people flare and get rid of, seemingly, a functional cure, and you think, is it relevant to consider the rapidity with which the surface antigen declines in terms of immune reaction or whatever, and whether you can induce a soft landing, if you will, reducing the surface antigen level in a way that you don't induce a lot of flare, but be able to get where we need to go. What do you think? Yeah, I think that's a great point, Ray. I think the idea that surface antigen decline means different things with different therapies and the speed, I focus sort of on the mechanistic side, but I think you're right, that the speed with which S antigen goes down may give you clues about how it's going down, and I think one of the big questions with the NAPs is that we don't really understand what that is. The rapidity of it and then the follow-up flares, it does sort of have an immune flavor that this is something that's happening that's pretty dramatic, whereas when you see very potent antiviral suppression, it takes a long time, and that's, I think, why one of the arguments would be to try to combine therapies where you have a very potent antiviral, and hopefully a reduction in protein production, and then bring on top, but I think that's the whole challenge with the immunotherapies, is how do you get just enough to get control without the risk of having these big flares, which, even if they work, are a bit scary. So we'll take one last question. Yes, sir? Yeah, go ahead. My name is Jackie Chen. Sorry. I'm a patient myself. My whole family are Hep B positive. I've been treated for like 10 years. I'm also a professor in pharmacology at the medical school here. I want to ask a question about the gray zone, that why you don't want to treat patient, for example, immune-tolerant patient. Why, what's the reason? Is there any disadvantage in addition to the cost, or are they going to cause any harm to the patient? Drug resistance? Why are you holding on treating those that are infected? I mean, this is very serious for a lot of us, that they could go into flare. They could have acute divert failure. But what's the reason that you are withholding the treatment for most of us here? So thanks for that perspective. I think that always we like to be reminded, as we're talking about guidelines and guidance of the patient, and really where they're coming from. And so I appreciate that. I try to really lay out the reasons that we are holding back. And the primary one is that we, in very young individuals, and I'm going to restrict my comments to those, say, under 30, where they're very likely to be truly immune-tolerant, and not somebody who's sneaking their way into being immune-active, okay? That true young individual, their natural history in terms of risk for liver disease, cirrhosis, decompensation, is zero, essentially. Liver cancer, not really seen in the first 30 years. It's sort of after. And what we don't know is if we suppress them for that 30-plus years, whether that would be different. So it's sort of that data gap that's holding us back, coupled with really not knowing how to treat, because our treatments don't really work that well. We don't suppress the majority of individuals. They have low level of iremia. They're hard to get down. It's the kind of patient I usually have on two drugs, because I can't get them suppressed on a single drug. And if we can't suppress them, then really, are we getting the cancer benefit, and are we setting them up for resistance, and or other complications related to being on long-term therapy? So it's that sort of balance of risk and benefit. We don't have clear benefit, and there's some theoretical risks, and some real risks related to doing treatment. But I'm gonna say that it is probably the question I get asked the most often, and I think everybody in this room who's doing work in therapeutics wants to move towards finding a therapeutic approach for the immune-tolerant patient. Yes, but looking at your data, I know that the suppression, the complete suppression for immune-tolerant patient is like 70, 80%, but the number goes up, and if you look at it in different direction, is that 70 to 80% of patient will benefit from being eradicated from the virus for the rest of their life, and that will prevent transmission, and they will benefit from going to a scary flare or other potential complication. You have to look at those. You have benefit, those 70, 80% of patient who are immune-tolerant. So, you know, with all due respect, I'm not sure we know there's benefit. I mean, I know we can suppress. I think that's the point you're making, and it's well taken. For sure, we reduce the risk of transmission, so that is an important reason to consider treatment in a subgroup of patients. What we're less clear about, to be honest, is suppression for 30 years or whatever number of years that that person is willing to take a pill is going to achieve the goal that we want, and what I'm hoping is that ultimately we're gonna have a much better therapy to offer them that will actually result in suppression and loss of surface antigen, which would really be the goal, the thing we should hope for for that group. The only thing I would add to that is I would say with the new therapies, this is a group where there is no approved or recommended therapy, so this is a group that should be studied and should be studied early. They also have some advantages in the sense that you can see the dynamic range of the effect of your agent, because even on patients on nukes, there's gonna be additional suppression which can happen with an antiviral, so I would hope that we start to see more interest in studying IT patients earlier. Just because I feel the passion from that question is that I really tried to emphasize age, and I think easel and apposal focusing on sort of 30 as being the time you should really think about treatment, I think that's probably the right place. ASLD guidance, we say 40, that's probably too late, I think. I mean, most people in the 30 to 40 we should be thinking about treatment. So really, remember age and bring that into the equation also when you're thinking about that IT patient. Great, please give a big hand. So we're gonna conclude the first session of the day.

therapy for hepatitis B

functional cure

covalently closed circular DNA

virological aspects

immunological aspects

capsid assembly modulators

RIG-I agonists