Hello, welcome to the Vir Biotechnology's AASLD late-breaking Data update call. As a reminder, this conference call is being recorded. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. I will now turn the call over to Sasha Damouni Ellis, Executive Vice President, Chief Corporate Affairs Officer. You may begin, Ms. Damouni Ellis. Thank you and good afternoon. With me today are Dr. Marianne De Backer, Vir's Chief Executive Officer, and Dr. Phil Pang, Vir's Chief Medical Officer. For the Q&A portion of the call, we will also be joined by Dr. Ed Gane, Professor of Medicine at the University of Auckland, New Zealand, and Chief Hepatologist, Transplant Physician, and Deputy Director of the New Zealand Liver Transplant Unit at Auckland City Hospital, and Dr. Jordan Feld, the R. Phelan Chair in Translational Liver Research and the Toronto Center for Liver Disease, Toronto General Hospital. Before we begin, I would like to remind everyone that some of the statements we are making today are forward-looking statements under the securities laws. These forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, future results, performance, or achievements to differ significantly from those expressed or implied by such forward-looking statements. These risks and uncertainties and risks associated with our business are described in the company's reports filed with the Securities and Exchange Commission. I will now turn the call over to our CEO, Dr. Marianne De Backer. Thank you, Sasha. Good afternoon and welcome. I'm Marianne De Backer, CEO of Vir Biotechnology, and I'm pleased to welcome you all here today. I'd like to start off by sharing some of my insights here on the ground in Boston at AASLD The Liver Meeting in 2023. I've spent the last few days interacting with key opinion leaders, with patient advocacy groups, and with industry peers, and I can sum these interactions up into a few observations. First of all, there's a shared sense of excitement and optimism for new potential treatments, especially for our antibody tobevibart, our VIR-3434, and our siRNA elebsiran, also known as VIR-2218, and their potential ability to combat both chronic hepatitis delta and chronic hepatitis B. For chronic hepatitis delta, the common themes here were around obviously the limitations of current therapy, leading to potential warehousing of patients in certain geographies. Also, the limited screening and diagnosis infrastructure and the need for patient advocacy groups, for clinicians and us as an industry, to work together to raise awareness and to solve these challenges. Turning to our hepatitis delta data, Dr. Tarek Asselah delivered the SOLSTICE Trial late-breaker oral presentation here at AASLD in a very well-attended general session. And in his words, "These early results that we are showing are unprecedented," with 80% of the participants having undetectable HDV RNA at week 12 of combination therapy. Our Chief Medical Officer, Phil Pang, will give more details on these data later in the call. With regard to chronic hepatitis B, I was personally heartened to see that the rooms were overflowing with clinicians eager to understand the latest data. From our own meetings with physicians, what truly resonated is that our goal of 30% or better functional cure for hepatitis B is well aligned with their expectations. They seek a regimen that is safe, well-tolerated, and doesn't leave irreversible side effects. Physicians also noted that, you know, there's clear progress that we are making in our pursuit of a functional cure, and we're certainly intrigued by the MARCH Part B data that suggested that VIR-3434, as part of a combination regimen, may stimulate an immune response against hepatitis B virus. We look forward to the additional data also on that to come next year. With that, I'll now turn over the call to Phil, who will be sharing our latest AASLD data with you. Thank you, Marianne. Let me begin, as Marianne said, with our chronic hepatitis delta data. As the most severe form of viral hepatitis, among those patients with chronic hepatitis delta and cirrhosis, there is a 50-50% of them develop liver cancer, liver decompensation, require transplantation, or die within 5 years. There are nearly 12 million people in the world living with chronic hepatitis delta, of which approximately 300,000 are in the United States, the U.K., and the EU4. These numbers are likely an underestimate, given that the lack of highly effective therapy means there, there is lack of a desire to be diagnosed. As Dr. Gane pointed out on slide seven in his editorial in The New England Journal of Medicine. There is now at least a glimmer of hope for patients with chronic hepatitis delta, but it is early days... The only currently available therapy requires lifelong daily subcutaneous injections. In his own words, "If undetectable HDV, HDV viremia is required for clinical benefit, then only 12% of patients in the 2 mg group and 20% of patients in the 10 mg group had a clinical benefit, and this was after 48 weeks of therapy. Therefore, there is much room for improvement." At Vir, we have challenged ourselves to develop a potentially game-changing chronic suppressive therapy that addresses efficacy as well as safety and convenience. Looking back, as we shared at EASL in June, we had the first preclinical data in hepatitis delta models, demonstrating the potential of both VIR-3434, our vaccinal antibody, and VIR-2218, our siRNA, to suppress HDV RNA. On the right is shown their additivity in an in vivo mouse model. So today, reprising Dr. Tarek Asselah's presentation, we will discuss the initial clinical data for these drug candidates. Shown here on slide 10 is the design of the initial cohorts of the SOLSTICE study. As we progress from left to right, 5 patients received VIR-2218 monotherapy, illustrated by the green block, for 3 doses over a 12-week period. Another 6 participants received VIR-3434 monotherapy for 3 doses, again over a 12-week period. Then, based on their week 12 results, of these 11 participants, 6 transitioned into cohort 2C, which is our combination therapy, according to the criteria shown here. Specifically, those participants not achieving ALT normalization or a virologic response at week 12. Next slide. The top-line virologic data for these participants is shown here on slide 11. What you can see is, as highlighted in the red box, the first red box, among those who received VIR-2218, the median HDV RNA decline was 1.4 logs. Among those who received VIR-3434, shown in the middle of the table, the median HDV RNA decline was 2 logs. And importantly, among those who transitioned into combination therapy, the median HDV RNA decline was approximately 4.3 logs. In the second red box is highlighted those who achieved undetectable HDV RNA. This is the goalpost described earlier by Dr. Ed Gane, and it is notable that, as shown on the far right, 80% were undetectable at combination week 12. To give you a little bit more color, shown here on slide 12 are the HDV RNA declines observed for individual participants receiving either 2218 or 3434 monotherapy. Noted by the stars are the six individuals who opted to transition into combination therapy, either because their ALT had not normalized or because they had not re-achieved a virologic response. The HDV RNA profiles for those who received combination therapy are shown on the next slide, illustrated here. To orient you to this slide, on the Y-axis is HDV RNA in log units, and on the X-axis is time. Shown in orange is the monotherapy curves, and then the moment at which they transitioned and started to receive combination therapy at study day 113. On the right, in blue, is the RNA declines observed when combination therapy was initiated. Most striking is the individual who had an approximate 5-log decline in HDV RNA within just 8 weeks. Next slide. Shown here on slide 14 are the ALT profiles for the participants who received monotherapy or transitioned into combination therapy. For those who received monotherapy with VIR-2218, as you can see, as denoted by the asterisks, 2 of 5 experienced an ALT flare. The specifics of their ALT increases are described in the footnotes. In contrast, I draw your attention to the middle curve, where those who received VIR-3434 monotherapy did not show any ALT increases and in fact show a slight decline over time. And perhaps most striking is that among those who received combination therapy, no clinically significant increases in ALT were observed through week 20, despite 2 of these participants having surface antigen levels greater than 10,000 IUs per ml. So in conclusion, this early data demonstrates the initial tolerability and initial potent antiviral activity of VIR-2218 and VIR-3434 as combination therapy after only 12 weeks of treatment. To reiterate, after 12 weeks of monotherapy, VIR-2218 and VIR-3434, when given every 4 weeks, achieved reductions of 1.4 and 2 logs. In contrast, combination therapy achieved a 4.3 log decline, which is the fastest decline in HDV RNA observed with any therapy to date. There were no SAEs to date, and the majority of AEs that did occur were transient or grade 1 or 2. As noted earlier, ALT elevations did occur in two participants who received siRNA or VIR-2218 monotherapy, and both of these had baseline surface antigens greater than 10,000 IUs per ml. In the combination arms, no clinically significant increases from baseline were observed through week 20, and this was also replicated in the VIR-3434 monotherapy arm. This was irrespective of baseline surface antigen or HBV RNA. I want to close out this chronic hepatitis delta section by highlighting the fact that these participants, as noted earlier in the combination group, have received dual therapy for only 12 weeks and that dosing was required only every 4 weeks. Consequently, it's a very exciting time for us and our clinical investigators. I will now switch gears to chronic hepatitis B, where the goal is different. For chronic hepatitis B, the goal post is not about suppressing the virus, but about achieving a functional cure, which is defined as lifelong control of the virus after a finite duration of treatment. A functional cure is strongly associated with a significant reduction in the risk of liver cancer, even among those on nucleoside reverse transcriptase inhibitors. As noted on this slide, to remind you, only 3%-7% of patients are able to achieve a functional cure after 48 weeks of peg interferon alone. So what we believe here at Vir is in order to achieve our goal of a 30% or better functional cure rate, you need a combination regimen of both antivirals and immunomodulators. This is what our vaccinal antibody cocktail of VIR-3434 and our siRNA VIR-2218 are designed to be. In the end, to achieve a functional cure, we've hypothesized you need to awaken the immune system. Next slide. Our preliminary data, which was shown at EASL and before that at AASLD in 2022 and 2023, is illustrated here on slide 19. It suggested for the first time that when VIR-2218 plus peg interferon is given for 48 weeks, that about 30% of participants achieved an HBsAg loss at the end of treatment, and about 16% had sustained surface antigen loss 24 weeks after the end of treatment. The number of participants in these studies is small, but this is the first sign that siRNAs can have a potential impact on functional cure rates. Vir was also the first to demonstrate the additive impact of combining a monoclonal antibody with an siRNA. This combination of VIR-3434 and VIR-2218 resulted in the largest declines in surface antigen ever observed after just 12 weeks of combination therapy. With this background in mind, we set out to answer the following questions as part of the phase II MARCH Part B trial. First, does VIR-3434 enhance end of treatment response rates? To remind you, the end of treatment response rate was 5.6% with VIR-2218 plus peg interferon alpha after 24 weeks. Second, the question is, are there signs that VIR-3434 is immunostimulatory? In other words, do we see signs of a vaccinal effect? To remind you, a vaccinal effect describes the ability of antibodies to engage immune cells through their Fc domain and stimulate an ongoing and proliferative immune response. The Fc domain of VIR-3434 has been specifically enhanced by a set of mutations that bolster its inability in vitro and in vivo to engage dendritic cells and therefore theoretically act as a therapeutic vaccine. With that background in mind and these questions in mind, I'm excited to share the latest data from MARCH Part B, which was highlighted by Dr. Ed Gane today, during the late breaker poster session. The phase II trial design is shown here. We are evaluating 24 versus 48 weeks of VIR-3434 alone, VIR-3434 with 2218, with and without interferon alpha. Today, we will be sharing the end of treatment and early post-treatment data from the 24-week cohorts. On slide 23, we see the participants' baseline viral characteristics. These participants in the trial had an approximate median surface antigen level of 3,000 at baseline, irrespective of the cohort, and the other thing to note is that the majority of them were HBe antigen negative at study entry. Here are the end of treatment results on slide 24. In gray are the study results from two prior studies. The prior study evaluating 2218 with interferon alpha for 12, 24 and 48 weeks, and the data from MARCH Part A, which evaluated shorter durations of VIR-2218 with 3434. In color, green, purple, and blue, is the new data from MARCH Part B. What you can see is that, as noted earlier, 5.6% of patients in the VIR-2218 peg interferon arm had an end of treatment response with that combination, and that we see nearly a threefold increase in that response rate to 15% and 14.3% with VIR-2218 plus VIR-3434 without and with peg interferon alpha. We also observed in the purple for the first time, end of treatment surface antigen loss with an interferon-free regimen of years. Next is slide 26, where we characterize the anti-HBs antibody response of the participants. On the Y-axis is the anti-HBs antibody titer, and on the X-axis is time. Shown are three cohorts for 2218 with interferon alpha for 24 weeks for the duo of VIR-2218 and VIR-34 34, and finally, for the triple cocktail. To remind everyone, an anti-HBs antibody titer is a measure of the participant's own immune response to HBV. Comparing the gray cohort on the left, which is VIR-2218 plus pegylated interferon alpha, as noted, to the blue cohort on the right, which demonstrates the addition of VIR-34 34 to that regimen, there is a marked difference, with 53% versus 11% mounting an anti-HBs response greater than 10 IUs per mL. This data is suggestive, but not definitive, that VIR-3434 can act to awaken the immune response in a patient with chronic HBV. Notably, as marked on the slide, the two trial participants who have maintained HBsAg loss through post-treatment and end of treatment week 12 have the highest anti-HBs antibody titers. To summarize, the clinical data supports the ability of VIR-3434 to enhance end of treatment responses, and more importantly, is that while the number of participants are small, this immunology data is the first evidence that when part of a combination regimen, our vaccinal antibody, VIR-3434, has the potential to play an important role in facilitating a functional cure. I want to close out with two reminders. The first is to remind you, as shown on this slide, that what has been repeatedly observed with peg interferon immunotherapy is the majority of the benefit occurs after the first 24 weeks of treatment. Thus, we may be seeing just the beginning of the potential of our regimens. And on the following slide, slide 29, I want to remind you that there are ongoing cohorts evaluating and asking to answer this exact question, which is: What happens when VIR-34 34 and VIR-2218, with and without peg interferon alpha, is given for 48 weeks? With that, we will now start the Q&A section. As a reminder, we have Dr. Ed Gane and Dr. Jordan Feld with us for this portion of the call. Operator, please open up the lines. At this time, I'd like to remind everyone, in order to ask a question, press star, then the number one on your telephone keypad. Please limit questions two per person so that we're able to get all the covering analysts. We'll pause for just a moment to compile any questions. Again, if you'd like to ask a question, please press star one on your telephone keypad now. Our first question comes from the line of Eric Joseph with J.P. Morgan. Please go ahead. Hi, good afternoon, and thanks for taking the questions. Some very interesting data here. Just looking at the comparisons of the doublet 2218, 3434 without interferon versus the triplet with, you have similar clearance rates of S- antigen, but some differentiation in terms of a seroconversion and perhaps also time to rebound. I guess, having seen these data side by side, what are your thoughts on sort of the opportunity to perhaps move forward an interferon-free regimen, perhaps employing a longer course of treatment with the doublet regimen? Thank you. Thank you for that call. Thank you for that question. I'll answer briefly, and maybe I'll then turn it over to Ed for some additional commentary. So I think it's a little bit too early to say. I would not rule out VIR-2218 and VIR-3434 for a longer course of duration, because I do think we know that often with immunomodulators, the biggest impact is seen after 24 weeks. So I think we'll have to wait for the data to see whether an interferon-free doublet is possible, if given for longer. And really, the question will be: How much more effective will the peg interferon alpha-containing regimen need to be, given the fact that there is obviously more tolerability issues with interferon alpha? Dr. Gane, any other commentary you might want to add? Thanks, Phil. No, I agree with your thoughts. I think this is really exciting data. To see rates of surface antigen loss during treatment with only 20 weeks of a non-interferon-containing arm is really a game changer, I think. But this is short duration, and I agree we need to see the results of the longer duration arms in Part B of the study. So 48 weeks of an interferon-free regimen to see whether what we're seeing here does translate to off-treatment surface antigen loss. Regardless, I think the triplet it's almost certainly be increased efficacy as well. But this is, I think, really, really important data from this meeting. And just picking up on your belief that 34 34 proceeds with a vaccinal type of activity, can you characterize that a little bit more, in sort of how long-lived the effect or that activity might be perhaps, you know, beyond the half-life or this, the, the presence of the antibody? I guess, is there at all a memory component here, or is it sort of, you know, limited to the, the some quantity of antibody being present? So I'm going to take that one. This is Phil. I think that it's too early to say. I think that when you get titers, as we did in one patient, to over 1,000 IUs per mL, that's obviously very strongly suggestive. And if you note, that was actually increasing over time, suggesting that there is probably a CD4 component that is enhancing a B cell response. We do have PBMCs from some of these patients, and we hope to be able to answer some of those questions, as soon as that data becomes available. But you're right, that's the question we'll have to answer. And I think that right now, we're excited by the preliminary data but know we have further to go. Okay, great. Thanks for taking the question. Our next question comes from the line of Roanna Ruiz with Leerink Partners. Please go ahead. Yep. Afternoon, everyone. So first, for the SOLSTICE data, we noticed that two patients had ALT elevations, and they also had baseline S- antigen levels that were pretty high, around 10,000. I was curious, what might be causing these ALT elevations in these particular patients for the 2218 monotherapy arm? And do you have any theories about that, and what can we extrapolate from there? Thank you, Roanna. I'm gonna turn that over to Dr. Jordan Feld to answer and speculate on. Thanks. It's an important question. That's notable that the ALT elevations are seen only in the siRNA group alone. So, and that was actually something that was seen in the REEF-D trial as well, the Janssen siRNA study. And in that study, what they identified was that the ALT elevations, which were quite significant, were only noted in patients with surface antigen levels above 10,000 and high delta RNA levels. And that's really the same thing recapitulated here. And I think one of the things we saw after REEF-D is we wondered whether adding an entry inhibitor to this might actually prevent this from happening. The exact mechanisms are obviously still speculative on why this is happening, but one theory is that the siRNA is impacting the ability of the virus to get into liver cells by affecting the subviral particles, which are the non, the incomplete virions, just the surface antigen themselves. So what we had actually speculated that by adding an entry inhibitor, you might prevent this. And then it's very interesting here to see that when you see the combination with 2218 and 3434, effectively, the monoclonal acting like an entry inhibitor here, you don't see those ALT elevations. So obviously, we need more data. This is a small study, but it's very promising and I think suggests that the mechanism of why this, what's driving this might be becoming clearer. Got it. That's helpful. And then also a question on the MARCH trial data. I was curious, what anti-HBs response threshold at the end of treatment would you think is clinically meaningful for predicting durability of HBe antigen suppression in post-treatment? So, Roanna, I'm gonna try and answer that first and then turn it over to Ed for further commentary. So as you know, predictors of off-treatment response are still not really in existence or robust, simply because there's been so few people who have had an off-treatment response. Predicting those who would is early days. As you recall from EASL, what we did show was that among the patients with PEG interferon alpha plus 2218, those who had an anti-HBs titer less than 100 were more likely to relapse, and those greater than 500 were more likely to sustain. But of course, that was based on a handful of patients. So I think that that's the best evidence we have to date, and we'll have to continue to work forward from that point. But I'll turn it over to Ed, since he obviously has seen a plethora of data from other, other studies as well. I don't know, any, any commentary? Well, yeah, just, in the pegylated interferon-containing triplet arm, certainly the appearance of really high levels of neutralizing antibody, should be associated with more durable, surface antigen loss, and we know that from pegylated interferon-only studies. That's in difference to some other agents in development where, surface antibody levels at the end of treatment by themselves were not predictive of, sustained loss, in particular the antisense oligo. So I think this is a different treatment. It's got an immunomodulator involved, and I do believe that the surface antibody appearance and high levels, at the end of treatment should be predictive. Great. Thanks. Our next question comes from a line of Phil Nadeau with TD Cowen. Please go ahead. Hi, good afternoon. Congrats on the progress, and thanks for taking our questions. One on HDV and then one on the combo in HBV. First, on HDV, what are the next steps in combo development? Do you think that you could take 3434 + 2218 right into a pivotal study, and if so, when could that begin? Phil, this is Phil, and thank you for that question. I think it's a little bit early and premature to be saying when and when we'll be starting our pivotal study. I can only say that from a regulatory perspective, given the high unmet need, it is well recognized by regulators that an accelerated path is possible. We saw that accelerated path in the EU for bulevirtide, and we are obviously in constant dialogue with regulators to see where we can go and how fast we can move, given the unmet patient need. Actually, I was just talking to Dr. Feld here earlier, and he was talking about how some of his patients were already gonna be asking for when they could get into a study to enroll. So that's obviously also exciting to hear. I don't know, Jordan, any other color you'd like to provide? I mean, it's literally a daily occurrence in clinic where we have delta patients coming in, and they are asking us, especially in North America, where we don't have access to bulevirtide yet, it's really frustrating for these patients. Some of them are interferon-experienced. They've, in some cases, been on interferon for more than a year, sometimes two years, without responses, and now coming back to clinic and asking us, "When are we gonna have trials available, and when are we gonna have cures?" therapy, recognizing in some of these families, they've lost family members to delta, so they're really, it's very top of mind. They've already got cirrhosis, and concerned about their future. Ed, anything else you'd like to add? I would just echo, this is a huge unmet medical need. I'm at the other side of the world in Australasia, but we have large numbers of Delta co-infected patients, most of whom have failed interferon, and whom we have no treatment. We don't have access to bulevirtide. And the possibility to get on an effective and well-tolerated regimen such as this would be incredibly important. Great. One question on the chronic hepatitis B data. We thought one of the most intriguing data points was the fact that two patients, at least through 12 weeks post-treatment, remained clear, and that seemed to correlate with levels of antibody titers. We're curious to hear from Dr. Feld and Dr. Gane, what implications do they think that data point has for the ideal regimen in order to drive higher functional cure rates? What does that say about what needs to be in that combination and, I guess, basically, what mechanisms should be in the combo to drive the highest functional cure rates possible? This is Jordan, Jordan Feld here. Yeah, I think it's a good question. I mean, obviously, what's exciting about this is with the sRNA approach before, we have not seen durable off-treatment responses. So this is where I think this is differentiating for me, is that you're seeing you're seeing S antigen loss that's persistent off therapy. And when you look at what are the components here, obviously, you've got three things. It's not entirely clear with small numbers what's clearly required. But I do think it suggests, with the high antibody levels that you're seeing, this is some evidence that the vaccinal effect might be in play, and we're gonna be trying to study that a little, in a little more detail by looking in the liver and actually looking carefully at T cells and how they're responding and how antigen presentation is changing, in the presence of 3434. And, you know, we have data over many years that interferon is relevant. It's just we still struggle to completely understand exactly how it works and why it works and when it works. These data are promising. I would hope that if you extended the duration of the interferon free arm, you might see the same thing. Obviously, we need more data here to know that, but that's what I'm hopeful for because interferon is challenging, but if it's necessary, I think if we can get good HBsAg loss rates, people will take it. And just to add to that, Ed Gane here, I think the 48-week arms of part two of MARCH are going to be incredibly informative. Because if there is a vaccinal effect, and we do see restoration of immune responses and protective levels of surface antibody in the interferon-free arm, that would bode well. I guess it's a delta between that and the triple therapy arm. And if we are seeing really significant improvements, I think then we also have a track going forward for triple therapy. Most patients can tolerate 24-48 weeks of pegylated interferon, but if we don't need it, we won't use it. That's very helpful. Thank you. Our next question comes from the line of Paul Choi with Goldman Sachs. Please go ahead. Hi, this is Khalil calling in for Paul. Thanks for taking our questions, and congratulations on the data. So a couple quick questions from me. One, for the two patients that did maintain HBsAg loss, has there been any additional follow-up done, in the time since that you'd be able to share now? And then secondly, I think regarding the HBsAg curves, what do those look like over time? And if it's flat by week 20 or 24, does it make sense to continue treatment for a longer duration? Thanks. So at this time, we don't have data past post-treatment week 12, and as emphasized earlier, it is early data, right? Normally, you look at post-treatment week 24, but, you know, we wanted to share as much as possible with you all as soon as we could. So that's the data we have, with regard to that. And can you remind me, what was your second question? Yeah, of course. So I was asking about the HBsAg curves over time. In prior releases, you had those curves where you would show what those levels looked like over time, and we were just wondering what they looked like for this latest release and whether they were flattening out towards 20 and 24 weeks, or what it looked like. Yeah. So I can say they do look like they're flattening. Well, actually, I don't think that that's accurate. I would say that they are flatter, with the greatest declines having occurred in the first 12 to 20 weeks. But they continue to decline after week 20 and continue to go down in those patients who have not achieved surface antigen loss. Obviously, in those who have, they got there earlier. So I would say that there's, the surface antigen curves suggest that longer durations would certainly have the potential to increase, surface antigen loss over time when given for longer, as well as obviously, the immune response also seems to be starting up just around week 20, so that would also be an important thing to follow with longer durations of therapy. All right. That's helpful. Thank you so much. Our next question comes from the line of Gena Wang with Barclays. Please go ahead. Thank you for taking my question. So I have two. So the first question, I think a question I'm already asked: I wanted to understand or anything we understand that why peg interferon alpha could have immune-modulating activity earlier than the 34 34 if we look at the, 12 weeks post-end of a treatment data. And the second question is for the, for two doctors here, but so if in the future turn out to be 24 weeks, treatment, that-- sorry, 48-week treatment, that interferon, peg interferon has to be one essential component, what kind of a cure rate you will be looking for that you think a patient will be willing to adapt to this regimen, say, if, if we are talking about cure rate, 24 weeks off treatment cure rate? Then a related similar question is, if turn out, you know, 2218 plus 3434, 3434, like, peg interferon-free regimen, what kind of rate will be threshold for doctors' adoption after, say, 48-week treatment? Thank you for that, question, Gena. I'll turn it over to Ed to answer the second part, which is, you know, what kind of functional cure rates would be considered meaningful with 48 weeks of interferon and what would be considered meaningful with an interferon-free regimen? And then have Dr. Feld answer those two aspects as well, and then we can get back to the first question. Thanks, Pang. I would have thought in patients with chronic hepatitis B monoinfection, 48 weeks of an interferon-containing regimen, you'd be looking at a functional cure rate of, I would have thought at least 25%. And for interferon-free, I think at least 15%-20%. I think that's in the right range that I would expect to see, too. I mean, when you talk to these patients, there are a lot of patients that are quite motivated to look at curative regimens, and they're always asking us, "Why can you cure hep C and not cure hep B?" So this is coming up pretty regularly in clinic, and I guess when we hearken back to the days of hep C, we were putting people through 48 weeks of interferon plus ribavirin, which significantly worsened the side effect profile for cure rates much lower than that. Really, initially, we were starting in the 10%-20% range, and over time that increased, but it was only eventually that we really got to these remarkably effective regimens that we have now, and so I think people will be willing to tolerate 48 weeks of, of therapy. I mean, for me, I think 30% is for sure will get people signing up. 25% is probably in the right range, to think about many patients. And then, eina, could you clarify your first question? I don't think I completely grasped it. Oh, sure. So, just wondering, you know, when we look at the 12-week post-end of treatment, so if we look at the 15%, like if we only look at the S- antigen less than 0.05 international unit per mL, so like 15% drop to zero. While for the peg interferon regimen, the triple combo that still maintained a 9.5% from 14.3%. So just wondering, like what could be... like mechanistically, like what would make us believe, say, if we wait, like treat for a longer period of time, for 48 weeks, then the 3434 immune-modulating activity will also show up and again maintain the cure rate post-treatment? Yeah. So, Gena, I think we need to just wait and see what the data suggests. I think that the best data that we have today is that when you look at slide 27 and you look at when the anti-HBs antibody response is coming up, it's usually coming up around week 16 to week 20. So the idea would be that if you were to have continued therapy beyond week 20 to 24, that you would have the potential to increase the immune response. Of course, that's a speculation, and I think we'll just have to wait to see what that data is, and certainly of course, adding interferon seems to bolster that even further. So I think it's about the kinetics. But let me ask Dr. Jordan Feld to add to that. I would just say that the importance of interferon here can't be underestimated, and the timing is relevant. When you look at interferon treatments for hep B, we know that if you go to 48 weeks, and in truth, if you even go longer, you actually enhance responses, that every study that's looked at 24 weeks only of interferon has been suboptimal. So I think what you're seeing here is that if you did extend this further, you would expect even just the interferon alone to add to this, and then you're adding in these, of course, these two novel mechanisms. Very helpful. Thank you. Our next question comes from the line of Rohit Bhasin with Morgan Stanley. Please go ahead. Hi, this is Rohit on for Mike. Thanks for taking our questions. Can you just talk about how this data changes your expectations for the 48 weeks data and, after seeing this data, your confidence level of hitting the bar of a 30% functional cure rate? Thanks. Yeah. So maybe I'll provide some color from the company perspective and then turn it over to Doctors Feld and Gane. So I think as you may recall, you know, the first question was: Do siRNAs have a role? And I think we've demonstrated that when you take an siRNA and add it to interferon, you do get increased rates of response, albeit the numbers are small, and that was actually, I think, recapitulated by some of the data seen here by other companies here at AASLD. So I think that question is moving forward in the right direction, showing the value of 2218. Then the next question is, what is the value of 3434? And I think that has been an outstanding question. Is there any evidence of a vaccinal effect, and is there any ability to actually achieve surface antigen loss even on treatment? I think both of those questions have now been now started to be answered here at AASLD, where we see an end-of-treatment response 3 times higher by the presence of 3434 at the end of treatment, and also the beginning of an anti-HBs or a seroconversion response. So I think all of those point that I think we have a excellent cocktail of 2218 and 3434, with and without interferon. And the immunology data from interferon suggests that when you give an immune modulator, most of the effect happens after week 24. So I think all of those things make us hopeful. But of course, in the end, the data is the data, and we need to wait to see what happens, because in the end, you can always also be surprised. So, we're excited to see what happens with the data, and looking forward to it just as much as you are. Ed, anything else you'd like to add? Just to say that for, you know, for 20-week data, we're seeing a drive down of surface antigen titers, even in the with an siRNA to almost 100%, less than 100, with the addition of a monoclonal antibody. That's incredibly fast suppression. You wouldn't expect that with an siRNA alone. And you would hope that with that really deep suppression of surface antigen maintained throughout the next 24 weeks, plus the immunomodulatory properties of both the VIR-3434 and or the addition of interferon, you would see increased surface antigen loss maintained, attained and maintained post-treatment. Our next question comes from a line of Patrick Trucchio with H.C. Wainwright. Please go ahead. Hello, everyone. Thank you for taking our question. This is Luis Santos for Patrick. Congratulations on the great data. There were a lot of good questions already. I think one of that that is pending for me is, do you need to see or do you expect to see, would you like to see a 30% functional cure in an all-comers trial versus a trial that is enrolling people with lower antigen? In other words, if the trial is enrolling patients with low antigen, do we need to see a higher regulatory bar versus an all-comers trial? Thank you so much. So from a regulatory and drug development perspective and turn it over for a more clinical perspective from our key opinion leaders here today. So from a regulatory perspective, I don't think there should not be any regulatory difference to whether or not they would prefer to see it in low surface antigen patients or in all comers. Generally, the regulators are most concerned about the efficacy or rather the risk-benefit profile. And so what they want to do is obviously demonstrate, they want you to demonstrate efficacy in the setting of safety. And I think that whether or not it's with a subgroup, such as those with less than 3,000 or 1,000 or in all comers, really is something that is often left up to the sponsor. So from a clinical, development perspective, of course, one pathway would be to have a phase III study only in those with low S-a ntigen, and then you would be able to really understand all the nuances of who those patients are that would respond or not respond. The other approach is, of course, to run a larger study in all comers and still obtain both sets of data. And I think that that's definitely a matter of discussion and something we are thinking deeply about. Ed, any commentary you'd add to that? Well, I think, you know, we're at the beginning, maybe, of the pathway to a functional cure for hepatitis B. I think if we identify a combination or a therapy which can achieve a significant rate of functional cure in a subpopulation, then, and the other population is futile, then, of course, you would progress that treatment regimen in that population most likely to respond. So I think we need to wait and see the data, but there is, I think, worth in developing a regimen which has high efficacy in a subpopulation. Of course, that's the first step. What we'd love to have is a functional cure available for all patients with chronic hepatitis B. Dr. Feld? Yeah, I mean, I would agree fully with what Ed said. Obviously, it makes sense to try to target your therapy to the group that for whom it's most likely to work. But I would still say this is an area where we're learning a lot. I was a bit surprised, for example, to see the REEF-D data, where they showed that in patients with this is the Janssen data, where they showed that patients who were effectively immune tolerant, very high S- levels, e-antigen positive, that they had 19% of patients lose S with an siRNA based regimen. It was transient, but we wouldn't have expected any of those patients to lose S if you had taken it sort of at face value, that this is just bringing down antigen levels. So I think we really need to understand this a little bit better, and then once you have the data together, you might want to, you know, identify a population who's more likely to respond. But I would actually, I'm cautiously optimistic that it may go beyond the low S-level population. That's, that's great. And will we, will we learn that from this trial? In other words, will we be able to segment this, the patients in this trial so that we can actually make good conclusions on this front? So this is Feld. I'll try and answer that question. The answer is, we—that's our intent. We are enrolling larger cohorts in the 48-week arms, as opposed to the smaller cohorts shown here. And we have every intent to be able to try and tease apart that data. But of course, we need to wait to see. Right now, we have about 50% of our patients have a baseline surface antigen, less than 3,000 in our longer treatment arms. And so we look forward to being able to understand that result or understand that data by that cutoff, as the data emerges. Sounds great. Thank you very much. There are no further questions at this time. I would now like to turn the call over to Marianne De Backer for closing remarks. Okay, thank you, operator, and thank you all again for your interest and participation here today. I hope you all agree that, you know, we have shared some very interesting data, and this gives us added confidence that we are on the right track to address the high unmet needs that exist for both, you know, patients living with chronic hepatitis delta and those living with chronic hepatitis B. I would also like to thank all our investigators, obviously, the site study staff, and the participating patients and their families for all their support in making, you know, these data a reality. And a very special thanks to Dr. Gane and Dr. Feld for joining us here today and answering some of the questions that people have about our data. We are looking forward to sharing additional data with you as it becomes available in the course of 2024. Thanks again for joining us here today, and operator, you may end the call. I'd like to thank our speakers for today's presentation, and thank you all for joining us. This now concludes today's call, and you may now disconnect.