This call. Nina Mojas, President, Global Product Strategy. Professor Seng Gee Lim, Director of Hepatology, National University Health System, Singapore. Kaivan Khavandi, SVP, R&D, Head of Respiratory, Immunology & Inflammation, Head of Translational Development and Sciences. Melanie Paff, Vice President, Medicine Development Lead, Hepatitis B Program. Pedro Zarazaga, SVP, Global Product Strategy Specialty. Please note on the next slide our cautionary statements. Also note that, during this presentation, we will also make the slides available. With this, I'd like to hand over to Nina to kick us off. Over to you, Nina. Right. Thank you, Constantin, and greetings from Barcelona. Thank you. Chronic hepatitis B remains a large, lifelong infection, largely untreated at the moment. Majority of the infections happen vertically, so from mother to child, at birth or in early childhood and as you can see, about 95% of these infections lead to chronic hepatitis B. At the moment, the standard of care in hepatitis C varies globally, but nucleoside analogues are the backbone, and the benefit of nucleoside analogues is the suppression of hepatitis B virus DNA. These treatments do very rarely achieve so-called functional cure. They are also lifelong therapies with no defined endpoint. The unmet need in hepatitis B is durable loss of hepatitis B surface antigen, and with the full suppression of hepatitis B DNA, they refer to as functional cure. Achieving functional cure will transform hepatitis B treatment into finite treatment, which is highly desirable and, at this point, not available. Next slide, please. Nucleoside analogues and the impact and current standard of care. As you can see on the slide, nucleoside analogues do lead to complete suppression of HBV DNA. The benefit of that is significant, 41% reduction in hepatocellular carcinoma. For those patients who are treated with nucleoside analogue in this study, if they achieve so-called functional cure, the reduction of risk of hepatocellular carcinoma goes further down by 76%. Next slide, please. When we look at the opportunity, as I mentioned, this is highly undertreated disease. You can see the global gap between number of infected individuals, number of diagnosed individuals, and those who are currently on treatment. U.S. and China, we are looking at about 120,000 in the U.S. and about 6 million treated patients at the moment, of which in both regions, about 70% have hepatitis B surface antigen below 3,000. In the U.S., standard of care are nucleoside analogues. Patients who are treated are largely patients who originate from immigrant backgrounds, so originating in Africa and Asia. In China, hepatitis B is very high national health priority. In China specifically, nucleoside analogues are used in addition to interferon. Next slide. Looking at the three key markets for us, thinking about bepi, about 80% of the opportunity are between United States, China, and Japan. All these geographies have accelerated regulatory processes, Breakthrough designation in the U.S. We are expecting approval in October, PDUFA 26th of October. The market in the U.S. is highly concentrated in five states that are marked by high immigration. We are looking at states like California, New York, Texas, Florida, and New Jersey. Patients who are treated are highly motivated. They have access to treatment and are very much willing to look for finite treatment. In China, you have seen our announcement that we have signed a collaboration with Sinopharm. Sino is market leader in hepatology in China with very broad commercial footprint, with access to more than 5,000 medical centers. Japan, SENKU designation as well. We are looking at accelerated review period. Again, Japan is second market in terms of number of treated patients with very high government incentives for treatment. With this, I will pass on to Professor Lim to walk us through B-Well 1 and 2. Thank you very much, Nina. I'm going to go through the presentation I did this morning for the EASL conference, and excuse my voice. I've got a bit of laryngitis. The title of the talk was Can you go back one slide? "Clinically Meaningful Rates of Functional Cure in Virologic Suppressed Patients with Chronic Hepatitis B infection Treated with bepirovirsen plus interferons. B-Well Studies, Pre-specified Sub Clinical Trials." Next slide, please. I think Nina has already covered that chronic hepatitis B affects more than 240 million people and causes more than 1 million deaths annually. It actually is the most common cause of hepatocellular carcinoma globally. Functional cure is now the new treatment goal of chronic hepatitis B, that's defined as shown in the slide, more than 24 weeks of sustained HBV DNA, below the lower limit of quantification and HBeAg loss after finite therapy with or without anti-HBs. Bepirovirsen is an antisense oligonucleotide that targets all the HBV transcripts, reducing HBV DNA and HBeAg levels. This is the first therapy in global phase III trials with functional cure as a primary outcome. Here I'm going to show you the key primary efficacy and safety results of the trials. Next slide, please. Next. The objectives of the B-Well 1 and B-Well 2 studies are shown here. The primary objective was evaluated at week 72, which was the functional cure rate in those with a baseline HBeAg level below 3,000. The key secondary outcome was also evaluated at week 72. This is the functional cure rate in those with a baseline HBeAg level below 1,000. In addition, also was assessed the sustained HBV DNA below LLOQ off all HBV treatments in those with HBeAg levels below 3,000 and below 1,000. Next slide. B-Well 1 and B-Well 2 were replicate studies which were identical in study design. Patients could be enrolled in the studies if they had chronic hepatitis B, were on stable nucleoside analogues, had HBeAg levels between 100 and 3,000, had DNA suppressed below 90 IU/mL, had ALT levels below two times upper limit of normal, did not have cirrhosis, or did not have interferon therapy more than 12 months. Upon enrollment, patients were stratified by HBeAg levels above or below 1,000 and were randomized two to one to receive bepirovirsen or placebo as two loading doses, followed by weekly injections for 24 weeks on the background of nucleos(t)ide analogue therapy. Upon completion of treatment, they were followed up for an additional 24 weeks on nucleos(t)ide analogue therapy, after which they were assessed at week 48 for eligibility to discontinue nucleosides. The eligibility criteria is shown in this slide. They had to have DNA less than LLOQ and HBeAg not detected between week 24 and week 46. ALT had to be below 2 x upper limit normal and had to be HBeAg negative. Those who were eligible to discontinue nucleosides, then stop therapy and were monitored for 24 weeks, after which they were evaluated for functional cure at week 72, which is the primary outcome of this study. Next slide, please. The baseline characteristics were similar across groups. Average age was around 50 years. They were predominantly male, mainly Asians. The mean HBeAg level was between 900 and 950. Patients with HBeAg below 1,000 comprised 60%-65% of patients, and most of these patients were HBeAg negative. Only 8% were HBeAg positive. Next slide, please. This is the primary outcome. Functional cure was achieved in 91% of bepirovirsen recipients and no placebo recipients, shown in the pooled study results on the right-hand side. Next slide, please. For the key secondary outcome, for HBeAg levels below 1,000, slight differences in B-Well 1 and B-Well 2, but the pool results showed a 26% functional cure rate in bepirovirsen-treated patients and none in the placebo. Next slide, please. This treatment effect was seen across all regions, regardless of HBeAg level. There were minor differences in efficacy rates between different regions, largely due to differences in baseline characteristics between study populations in those countries. Next slide, please. The key secondary outcome of HBV DNA below LLOQ of all HBV treatments was seen in 23% of bepirovirsen treated recipients and none in the placebo. This 23% constituted 19% of patients who had functional cure and 4% additional patients who had DNA below LLOQ but did not achieve functional cure, and none in the placebo group. Next slide, please. Sustained HBV DNA below LLOQ of all HBV treatments was seen in patients with HBeAg levels below 1,000 IU per mL. There were slight differences in B-Well 1 and B-Well 2. The pool results showed a 31% HBV DNA below LLOQ, comprising 26% of patients who had functional cure and 5% of patients who had DNA below LLOQ who did not have functional cure. None in the placebo group. Next slide, please. This is the patient disposition of all patients in the B-Well 1 and B-Well 2 study. I will point you to the pie chart on the right-hand side. I've already shown you how 19% of patients achieve functional cure, but an additional 30% of patients achieve S antigen levels below 100 IU per ml with our functional cure. These comprise 12% of patients for S antigen levels between 10 and 100 IU per ml, and 18% of patients who had S antigen levels below 10 IU per ml. S antigen levels below 100 IU per ml are thought to be clinically significant because these patients may have a future possibility of S antigen loss. Next slide, please. This is the on-treatment safety profile, which is consistent across B-Well 1 and B-Well 2, and I will point you to the full results on the right-hand columns. In blue are the bepirovirsen results, show that AEs leading to permanent discontinuation of study treatment constituted only 3% of patients, and SAEs related to study treatment only constituted 2% of patients. There were no fatalities, no fatal SAEs related to study treatment. Next slide, please. On-treatment AEs reported in more than 10% of patients is shown here. Most of these were injection site reactions comprising injection site erythema, pain, pruritus, or bruising. There were also safety signals in the ALT and AST increase and platelet count decrease. Four participants had permanent discontinuation for a liver-related event. However, two of these four patients actually achieved functional cure as well. Transient ALT increases after bepirovirsen initiation were associated with S antigen reduction. There were platelet and eGFR declines, but these resolved once treatment was completed or paused, and there were no clinically significant bleeding events attributed to bepirovirsen. Clinically significant changes in eGFR were not associated with markers of renal injury. Next slide, please. To conclude, functional cure rates of 19% treated with bepirovirsen among those with a baseline level of 3,000 IU per ml, and 26% bepirovirsen-treated patients among those with baseline S antigen levels of 1,000 IU per ml was achieved, and none was placebo. In addition, sustained HBV DNA below LLOQ off all HBV treatments was seen in 33% of bepirovirsen treated patients in those with a baseline level of S antigen below 3,000 IU per ml, and 31% of patients with a baseline level below 1,000 IU per ml, and none with placebo. Bepirovirsen is a first-in-class 24-week finite therapy achieving functional cure in virologically suppressed patients with chronic hepatitis B infection with an acceptable safety profile. This will definitely change the landscape of chronic hepatitis B treatment for the future. You can access the full paper in the New England Journal of Medicine as from today, 20th of October. Thank you for your attention. Thank you, Professor Lim. My name's Kaivan Khavandi. I lead specialty R&D at GSK, and I'm joined by Dr. Mel Paff from R&D, who's the medicine development leader for bepirovirsen. Next slide, please. The key point that's important to consider for a moment is the clinical impact these data show bepi could have. When we think about clinical importance, we typically consider the target value for an effect size and how this translates to improvements that matter for patients. This is sometimes conflated with the proportion of patients who respond to therapy when exposed, and so I wanted to cover both. It's now accepted that functional cure is the very highest bar of efficacy to aim for in this disease. It's the single greatest predictor for prevention of hard endpoints, hepatocellular carcinoma, and mortality. As the term suggests, this allows patients to come off all treatments with a finite management, and you'll appreciate that curative intent is a rare goal for a medicine in any portfolio. There's clearly no question of the clinical importance of functional cure, and this is reflected in management guidelines and regulatory processes. It also comes with a high burden of proof. To demonstrate this in an RCT, as shown in this slide, requires undetectable DNA and loss of surface antigen once off all treatments for six months within a study. Bepi met this high bar in the B-Well studies. The comparative arm emphasizes this high bar, which we label in the presentation as placebo, but which actually represents the standard of care. Nucleos(t)ide analogue treatments for 48 weeks before coming off treatments, compared to a similar group who received bepi for the first 24 weeks. It's 48 weeks of active treatments with NAs that we refer to as the placebo group. In that comparative group, you see 0% achieve the primary endpoint of functional cure in the ITT population, those with surface antigen of 3,000 or less. Further, 0% achieve functional cure in those with baseline surface antigen of less than 1,000. Finally, 0% achieved response for HBV DNA at the lower limit of quantification at 72 weeks. Zero is all round for the comparator arm, which is the standard of care. In comparison, in the ITT group, bepi achieved 19% cure. In the pre-specified population with surface antigen less than 1,000, bepi achieved 26% functional cure. If we relate this to real-world numbers, the majority of the treated population with chronic hepatitis B have surface antigen less than 3,000, and over 40% have surface antigen less than 1,000. When we consider the pie chart that Professor Lim presented, an additional 30% of patients achieve surface antigen levels below 100 of bepi, a threshold of reduction now accepted in guidelines as partial cure on the basis of the strong longitudinal data that shows protection from hard endpoints and which standard of care is poor at achieving. That allows us to appreciate the breadth of benefit across patient groups. One in five and one in four patients achieve the highest bar of efficacy, cure, depending on baseline surface antigen levels in the most commonly treated patient groups, and one in two patients receive a response expected to predict protection from long-term outcomes by achieving surface antigen less than 100 IU per ml. These data are clearly recognized and reflected in the impressive regulatory Breakthrough and Priority Review designations achieved in filings across multiple authorities. If we go to the next slide, I'd like to take a moment to consider that this is a monotherapy. It's quite remarkable that a single product can confer such protection. How can it do that? It's a single therapy. It unlocks a three-pronged efficacy benefit. It does this in a large part because bepi targets a highly conserved region across all HBV genotypes and present across all HBV RNAs. As such, it targets protein-coding RNAs, pcRNAs, that stop translation of HBe antigen. It targets pre-genomic RNA, pgRNA, which prevents the translation of HBV polymerase and correlated proteins, knocking down HBV DNA. The RNAs that translate HBV surface proteins or antigens, which really stops this latent substrate that's responsible for reactivation and relapse when, for example, the immune system is tested. Last but not least, it directly acts as an innate immune stimulator, which when combined with the strain that residual HBV antigen burden places on T-cells, prevents the immune exhaustion that's problematic in hepatitis B. This gives the system a chance to recover, and therefore, sustain the durable clearances that we observe. From a portfolio and competitive perspective, the efficacy of bepi truly resets the bar when we consider what could add meaningful benefit beyond bepi. You'll appreciate it's not typical to have a first-in-class program for a major public health challenge with a finite and curative solution. For this reason, we see the hep B portfolio positioned with bepi as the anchor. To this end, Mel will later cover one such program that does offer real promise alongside bepirovirsen in those with surface antigen levels not studied in B-Well. First, Mel will help put these data in the context of standard of care and clinical management of these patients. Thank you, Kaivan. I want to talk a little bit about the established standard of care that we have in hepatitis B now. You'll note that both nucleoside analogues, which are used around the world, and pegylated interferon, which is primarily used in China, neither of these drugs were designed for functional cure. Nucleoside analogues were specifically designed to stop viral replication, so it's not surprising that the functional cure rate is extremely low. As Kaivan stated in our trial, after six months of therapy, you can see that the functional cure rate in the placebo or the nucleoside analogue, comparator was 0% in our trial. Pegylated interferon, on the other hand, is primarily used in China, and it's a treatment for 144 weeks, for S antigen loss. It has a fairly low functional cure rate, around 2%-8%. The issue that you have with pegylated interferon is the unfavorable safety profile and the limited tolerability. Patients have a problem staying on this drug because it basically makes you feel like you have flu-like symptoms. There's quite high dropout rate, and compliance is a problem. We contrast that to what is the expectation of a standard for tomorrow. Clearly we're looking for a functional cure as the gold standard. We're looking for a finite duration of therapy. Patients don't want to be on nucleoside analogues for the rest of their lives. We're looking to lower that risk of cirrhosis and liver cancer and all of the associated reduction in morbidity and mortality. We're looking for a larger eligible patient population, and I think it's really important for us to point out the burden that these patients walk around with, the psychosocial burden of having this chronic infection and the lifelong medication. Could we go to the next slide, please? In addition to the information that Nina shared earlier, I want to point you to an analysis that was recently reported this past year that looked at the clinical outcomes of surface antigen loss. This was a retrospective cohort study using an electronic medical record database over a seven-year period, and it showed significant association between HBsAg loss and the reduction in the risk of liver cancer and even all-cause mortality. 89% reduced risk for liver cancer and 62% reduced risk for all-cause mortality. Next slide, please. One of the questions that we get a lot is: What about the ongoing development? What is GSK interested in from hep B, from a portfolio perspective? We'd like to draw your attention today to another study that we have going on right now in phase IIb with an siRNA that was in-licensed from Janssen. In this particular study, you can see from the graph, we're looking to expand the patient population to all treated patients, 100% of treated patients, not just the 70% of patients that are below 3,000. Daptom or siRNAs have classically shown a very strong and robust response to lower even very high levels of HBsAg to a low level. Unfortunately, by themselves, they don't seem to be able to achieve functional cure. What these siRNAs can do is bring the HBsAg down to a sweet spot where we know bepi works best. Our intention with the B-United Study is to test six months of daptomycin therapy, allowing the S antigen to come down to this low level. Following that with six months of bepi, again, to achieve functional cure, on the backbone of nucleoside analog treatment. After week 48, those patients will continue on their nucleoside analog for another six months, and those that are available to sustain their nucleoside analog will then stop, and functional cure rate will be called at week 96. We're very excited about this study. It has the potential to show both the increase in functional cure rate overall, as well as opening up a treatment for functional cure to patients that now have no ability to get functional cure. We're very excited about this. Can we get to the next slide? I think in summary, what we've shown today is that bepi is clearly a clinically significant functional cure medicine. It's achievable, it's durable, and we additionally have almost half of the patients who receive a clear medical benefit after one year of treatment. What we want to do is to think about the things that we have heard today around the EASL Conference. Physicians that we've talked to and that you've seen in print have said things like transformational, generational change in treatment, historic. The editorial from the New England Journal said remarkable results. I think this also reflects the innovation that we've seen by regulators and their recognition of that innovation. You can see both in the U.S., China, Japan, we have things like Fast Track, Priority Review, Breakthrough, SENKU designation. It's not a regular occurrence that you get this across so many regulators, and I think it's a recognition of the innovation that we bring. We'll stop here and then move to question- and- answer. Thank you very much, Mel. With this, we are ready to take your questions. Please use the raise your hand feature if you would like to ask a question, and kindly limit yourself to one question so more of you have the opportunity to ask questions. With this, we are ready for the first one. First question comes from Peter Verdult. Thanks, Constantin. Can you hear me? We can hear you. Go ahead. Good stuff. Thank you. Thank you to the speakers. Thank you for your time. Look, we also checked in with Professor Wong at Stanford earlier today, who's also at EASL. He definitely thinks the data's exciting, but he did say it's not groundbreaking. A couple of follow-on questions. You on the presentation talked about an applicable population as defined by B-Well as about 70%. He was saying, look, in that the B-Well study probably only represents 30% to max 50% of treated patients. I just wanted to square the circle there. That's a clarification. My real question is the interesting stuff. The sequencing and the combination study with siRNA is definitely interesting. What about some of the other questions from B-Well? The one I'm really interested in the trial design patients were allowed to stop their nucleoside therapy. I think that finite treatment is a real selling point. Within B-Well, can you tell us how the patients that stopped their nucs after 48 weeks, how did they do to those that continued? That'd be my one question. Thank you. Patients were eligible to stop treatment if they had HBV DNA negative and S antigen was undetectable, ALT was below two times upper limit of normal, and they were e antigen negative. They had to fulfill all those criteria for them to stop nucleoside analogue therapy. In other words, they already had to have S antigen loss. Does that answer your question? Peter, I assume this has answered your question. If not, raise your hand again, and we can have a follow-up. Sorry, I was muted. Yeah, I'll get back in the queue. Thank you. I'm happy to address also the nuc-treated population. The average that we have shown you today, meaning 68% of the treated population is less than 3,000, and 45% is less than 1,000, is the average across the five major markets, meaning U.S., China, Japan, EU5, and Germany. There is variability from market to market. For instance, in the less than 3,000 population, the average across those markets is 68%. However, Germany is a little bit lower at 54%, and Japan is a little higher at 86%. What we're providing is the average. Can I just follow up on that issue about whether this is breakthrough or not breakthrough, which I think is a matter of opinion. I think the breakthrough part is the fact that 90% of patients achieve functional cure. That's never been achieved in any treatment program before, nucleoside analog or interferon. If you don't call that breakthrough, I'm not sure what else you would call it. Thank you. Next question comes from Sachin Jain. Sachin, go ahead. Hi there. Thanks for taking my question. Thanks for presentation. I've got a question around testing and monitoring. The editorial calls out need for stringent safety monitoring, referencing every one to two weeks. I just wanted to clarify what the safety monitoring requirements were in the study, what you expect from the label, and how onerous that will be. Around hep B, the surface antigen testing, obviously approval's in October, minority of patients are currently tested in the U.S. is our feedback. How quickly do you think that can mobilize post-approval? Thank you. Let me take the question on safety monitoring. Patients were injected weekly, so they were obviously monitored weekly for safety features. I think there's two safety features that were important. One was the ALT rise. I didn't show you in the presentation, but ALT abnormality was seen in about 45% of patients. ALT more than 10 x was seen in 6% of patients, and 20 x was seen in, I think, 1% of patients. However, if you had an ALT rise more than 3x baseline, you had an 85% chance of getting a cure or S antigen loss. If you had ALT less than 3x baseline, then your chance of getting S loss was only 35%. It seems that the ALT rise is associated with efficacy. There were no drug-related liver injury problems that were contributed. From the ALT viewpoint, it seems to be an efficacy feature. As far as the other safety issues concerned, they comprise three issues: thrombocytopenia, renal function abnormalities, and complement abnormalities. These three features are actually features of class effect of antisense. They're not related specifically to bepirovirsen. Thankfully, all these features resolved once bepirovirsen was stopped, and including the renal function and the thrombocytopenia and the complement activation process. None of them were clinically significant. There were no bleeding events, and renal abnormalities resolved once the bepirovirsen treatment was discontinued or paused. Also, there was no markers of renal injury that were related, particularly things like proteinuria. I think safety monitoring needs to continue, but as far as the long-term safety is concerned, it seems to be a transient effect related to study treatment. Maybe I can address the difference between a clinical trial and a real-world setting. When you go into, especially a phase III clinical trial, you don't know the outcome. Of course, we're going to measure and we're going to monitor more than you would in a normal setting once you know the outcome. I wouldn't be concerned about the clinical trial monitoring that takes place right now. As we submit this data to regulators around the world, the regulators will decide what monitoring should or should not be in place. In my experience as a drug developer, that may be a little different from region to region, but they will approve what is appropriate for the safety and efficacy for patients. As far as HBsAg testing goes, you are correct that quantitative HBsAg is used primarily outside of the U.S. However, quantitative S/Antigen is readily available inside the U.S. as a laboratory-derived test. We use laboratory-derived tests all the time. That's not a problem. It's available on Epic. You can order it, you can get it. I think one of the things that we are going to see, much like you do in many diseases, the patient wants to know whether the medication is working, and this quantitative test is going to be able to give them that immediate feedback of how they're doing on therapy, which is going to provide extra motivation and compliance for them to finish the full six months of therapy. I think what's going to happen in the future in the U.S., now that we have a reason to use quantitative S/Antigen, you're going to see a significant uptick in that. Yeah. Sachin, I would just add on the testing. Testing in the U.S. is available. This is not some kind of novel test that is not available. Just from the execution perspective going into the launch, it's clearly our priority to make sure that physicians, whenever they want to use it, will be able to use it. It's just that the testing so far was not needed for diagnosis, treatment, or anything like that, and therefore it's used less or less available. Going forward, this is something that from the commercial execution perspective, it's a priority. This is going to be changing. Thank you. Next question comes from Graham Parry, please go ahead. Great. Thanks. I was just going to follow up on the testing question. Can you just confirm the frequency of liver testing during the trial, and why you think the regulator wouldn't require you to have the same level of testing? That may have masked the additional ALT elevation. On commercial strategy, can you just talk us through how you're thinking about pricing commercial strategy, just given the very large number of untreated patients, both across the U.S. and China. Just given the large numbers of untreated patients and even undiagnosed patients, can you just talk us through how to access that and how you're thinking about pricing? Thank you. Graham, I'm happy to take the testing question. I think what will happen, again, discussing the ALT, the platelet, the eGFR. I suspect what will happen around the world is that we will want to monitor those patients on a weekly basis for the first 12 weeks, and then it will loosen from there on out. Again, as I said, we can't really comment on exactly what the monitoring profile will be because the regulators will decide that on a country-by-country basis. I'm going to make a quick point to put the safety data in context. These isolated ALT increases within the range of the fold increases in question without associated increases in bilirubin or evidence of liver injury. In this setting, it tracks with efficacy and is all mechanism. You've got a boost in immune competence. It clears infected hepatocytes, and you have an associated increase in ALT, which for those of you who are familiar, will remind you perhaps of the eGFR dip you get with SGLT2s, which is a marker of benefit and efficacy. Finally, I think the adverse events should be put in the context of a finite treatment where if any effects are resolvable or reversible, that's a very favorable setting for benefit versus risk. I will touch base on pricing. Our approach here is to access patients who are on treatment, who are being treated, who have desire to be treated, who are willing to go through it, for whom physicians would recommend treatment. At the moment, our initial commercial approach is not focusing on going after whole pool of diagnosed and let alone those who are infected but not diagnosed. From that perspective, I think I mentioned before in terms of pricing for the U.S., we are looking at a price range that is similar to Hep C space that we have seen. So far we have a very clear understanding that this is very acceptable price level from the payers in the U.S. Next question comes from Ben Jackson. Great. Thank you for the question. I guess, can I ask for some further color on this 30% of patients that are achieving the antigen levels below 100 without the functional cure? You've made reference to the current antigen testing frequency in different regions. Does this mean that this kind of supportive data is more impactful in different regions, particularly ex-U.S.? How meaningfully could this mean that uptake is diverges between different regions as a result of that data? Thank you. Sorry, just to get some clarification, you're asking about HBsAg levels below 3,000 or below? Below 100, to be clear, how meaningful is that data, is there a disparity by region about how important that data is? I think in terms of the effects of bepirovirsen, I think we don't know whether bepirovirsen treated patients with S-antigen levels below 100 are the same as nucleoside analogs treated below 100. We'll need some long-term follow-up to determine whether that's the case. However, these patients are all off nucleoside analog therapy, and after six months off nucleoside analog therapy, they seem to have S-antigen levels below 100. That's definitely a good sign. Some of these patients will continue to have S-antigen loss. I think that's definitely a beneficial effect of patients below 100 IU/mL. Whether there's any regional specific differences, not as far as I know. I think, across the regions and across clinical studies, the 100 IU/mL cutoff seems to be holding on quite well. I'd like to also point out from an R&D perspective, when we were designing this clinical trial, you'll note that the inclusion criteria only allowed patients to come in that were greater than 100. There was a reason for that. Patients who have less than 100 more naturally have a chance over several years to achieve functional cure, and we were concerned that that would overly bias the outcome. I think that in itself, is evidence of this effect. Just one final point, that both the EASL and the AASLD guidelines were updated in the last 18 months and acknowledge that surface antigen less than 100 represents partial cure and is clinically important as a treatment goal. Thank you. Next question comes from Zain Ibrahim. Thanks a lot for taking the question. My question is on the efficacy and the potential breadth of label that you might receive, given that the ITT population efficacy looks really good at 19% functional cure rate, and then in the less than 1,000 is 26%. In that intermediate sort of patient subgroup, 1,000- 3,000 international units per milliliter, the functional cure rate was about 5%, 10% or 7% pooled. Just your thoughts on whether the data set you have you think is sufficient to get a broad label covering the ITT population or whether that might be more focused on that less than 1,000 unit subgroup, and even if you have a sort of broader label, how uptake could look. Yes, thank you for the question. I believe that what we'll see in this population, and this is the biology of the virus and the biology of the disease. As you go from 3,000 down to 100, it is a continuum of efficacy. The lower the S antigen has been seen as probably the strongest predictor of response. What we want to be able to say about this is that when we designed the clinical trial, we specifically stratified on 1,000. That 1,000-3,000 group will contain people who are 1,050, and it will contain people that are 2,998. It will be up to the physician to have a discussion with their individual patient as to whether the risk-benefit of this drug is available. I suspect from the feedback that we have heard from patients, a 7% functional cure is about what you see with pegylated interferon. If you had a finite therapy that gave 7%, patients would be highly motivated to take that. Very clear. Thanks a lot. Thank you. I see we have, well, one more question in the queue. Zach, please go ahead. Thank you. This is Zach Dunn on for Seamus Fernandez from Guggenheim. Appreciate the question. I guess I want to follow up on the 1,000- 3,000 group, because then at least based on the China functional cure rates, you're kind of falling in that peg interferon level. I guess when you compare then the side effects, can you provide any maybe qualitative color on those grade 3 adverse events? Are they evenly split between the two groups? If we can just kind of hear a little bit more on the risk-benefit in this 1,000- 3,000 population, or does it really seem that this drug will most likely be used in 1,000 and below? Thank you. Thank you for your question. I don't have any visibility date on the data comparing below 1,000 and between the 1,000 and 3,000, so I can't really give you an answer. I cannot be sure that these AEs are related to efficacy. The primary AEs we're talking about, particularly the complement platelet reduction and the renal function, were class effects of the antisense. This might be a random effect on patients. As far as the ALT increase, maybe we can speculate that that's more likely to occur in a 1,000 and below population, mainly because S loss rates. Are related to the level of ALT increase. If your ALT increase is more than 3x baseline, you have an 85% chance of S-loss. If your ALT is below 3x baseline, your chance of S-loss is actually only 35%. Most of the patients who achieve S-loss were below 1,000 IU per mL. I suspect the ALT rises will be seen in that population. As for the other AEs, they're probably going to be more random. Next question comes from Christopher Lovienko. Hi, good morning. This is Chris on for Steve Scala. Thanks for taking our question. Can you provide any comments on timelines for gaining payer reimbursement in the U.S., and what sort of prior authorization criteria do you expect for bepi in the U.S.? Thank you. The timelines for the U.S., we are expecting approval probably by the end of this year, and then the traditional negotiation with payers that will be ramping up during 2027. Regarding the prior authorization question, we are expecting, of course, antigen levels as per label, as be part of it, and also new treated restrictions. Those are the main two that we are expecting right now. Next question comes from Colin White. Hi, it's Colin White from UBS here. Thanks for taking my question. My question was just around how we should expect bepi to launch in each of the three major markets which you outlined. Is there expected to be a large bolus of eligible patients that physicians would want to treat with bepi soon after launch? Are there other factors that you think might lead to a more gradual launch in any of those markets? Thanks. Yeah, good question. A question that we are also thinking about, and as you can imagine, we don't have full clarity. We do expect certain bolus, as there are already number of patients who are being treated for years, and some of them waiting to be treated. We probably do not expect that bolus to be. Not the scale of Hep C that we have seen, just because we will continue to have probably significant number of patients that will maybe choose to wait or be suggested to be treated by their physician as they get more experience with bepi. It's very difficult for me to give you very specific trajectory. Bottom line, we do expect some bolus. We will need to see what that looks like. Again, not expecting that massive rush to demand treatment as soon as the approval happens. Thanks. Next question comes from Emmanuel Papadakis. Thanks. Maybe just a couple. I'll take a follow-up question on the one that was just asked, and more from a reimbursement angle. Which is also, to an extent, the question that was asked earlier about prior authorizations. To what extent do you expect there to be broad, unfettered reimbursement rapidly after approval, particularly in the developed markets, U.S. and Europe? Then the other question I was going to ask was B-United. If you could just remind us your expectation for functional cure rates, what's your ambition in that study? It's phase II, so is that potentially pivotal or would you then need to initiate a phase III? Thank you. Yeah, Emmanuel, I'm not sure if there is too much to add on what has been said. We do expect certain requirements, certain prior authorizations. Again, I'm not sure there is more than what we have said already. I don't know. I'm looking at Pedro. Anything more to add? Obviously, as we mentioned, U.S., China, Japan are the focus markets because of the prevalence and because of the willingness or readiness to treat. I would focus on those at the moment. Thank you. Next question. B-United. B-United. Yeah. For B-United, a minor correction. B-United is not a pivotal study. It is a phase IIb study, and we're expecting the data from that about middle of next year, and we'll see from there. I don't think we're ready to give guidance on what the expectation is. I think that the point you made, Mel, earlier is the key one, that it broadens the eligible patient population to those with circumstances not studied in B-Well. Thank you. Next question comes from Shyam Kotadia. Hi, yeah. Shyam Kotadia on here for Rajan Sharma from Goldman Sachs. Sorry, just a clarification question for one that was asked earlier. At week 48, where you had the patients that discontinued NAs therapy and those that continued it. Could you clarify what proportion actually discontinued it, and if there was any differences in the functional cure rates at week 72 for those that discontinued NAs therapy versus those that continued on it from week 48? Thank you. I think, overall, 24% of patients discontinued nucleoside therapy, and 19% had S antigen loss. 34% of patients had DNA undetectable without functional cure. An additional 1% of patients actually had DNA relapse. The number of patients that didn't achieve a benefit is only 1% who stopped nucleoside analogues. Again, to remind you, the definition of functional cure is that you must cessate your nucleoside analogue. We'll provide you with the slides obviously later, but if you go back to the pie chart slide, you will see that there are some patients that wind up being S antigen below 0.05, and that does sometimes happen. You have to completely cessate nucleoside analogue to meet the strict medical definition of functional cure. Yeah. It sounds like there is confusion about this. Just to reiterate what Mel just said, patients who did not stop nucleoside analogues at week 48, by default, will not be defined as functional cure. All those that are in the 19% defined as functional cure, these patients all stopped their nucleoside analogue backbone therapy. Those who continued might end up having undetectable surface antigen, but they are not falling into the category of functional cure. We have time for one last question. Last question comes from Zain. Please go ahead. I think I still have my hand up, but I'll take the question. It's on the discontinuation and dose. The dose discontinuations and dose interruptions in the trial, just in terms of how feasible you think that is to manage in the real-world setting. It sounds like given the expectation for weekly monitoring, that should be reasonably manageable to implement. Just your thoughts on that discontinuations and interruptions would be helpful. Very strict criteria for dose interruption and discontinuations. That's in the setting of a clinical trial. I think for guidance purposes, probably it'd be better to err on the safety side. The actual patients who discontinued permanently were actually quite few. For ALT abnormalities, only four patients discontinued. For platelet abnormalities, only eight patients. For complement activation without any clinical effects, nine patients. These were relatively infrequent, I would say. I cannot give you the numbers for dose interruptions. They're probably going to be higher and likely that the adverse events were not as profound. I think you're right. There needs to be some element of monitoring for these patients, for safety reasons. The weekly monitoring phase definitely needs to be done for the first 12 weeks. Very helpful. Thanks a lot. Thank you. With this, I'd like to hand over to Nina to close this call. Yeah. Thank you very much. We are at the hour. I really appreciate the interest. I just want to transmit the excitement here at EASL is actually very high. These data, as Kaivan said, and Mel, are called transformational at number of occasions. From this point on, we have next six months where we expect regulatory approvals in our major markets, and we are looking forward to sharing those updates as we get them. Thank you. Thanks, everyone. Thank you. Talk to you soon.