GSK plc ($GSK)

Dear ladies and gentlemen, welcome to this GSK EASL presentation on bepirovirsen and our B-Well 1 and 2 pivotal Phase III studies. My name is Constantin from GSK. I'm also joined by Nick from IR, and I'm delighted to introduce the following speakers for today's 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 and Inflammation, Head of Translational Development and Sciences; Melanie Paff, Vice President, Medicine Development Lead Hepatitis B Program; and Pedro Sarrazaga, 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. Great. Thank you, Constantin, and greetings from Barcelona.

Thank you. So chronic hepatitis B remains a large lifelong infection, largely untreated at the moment. Majority of the infections happen vertically, 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 B varies globally, but nucleoside analogues are the backbone and the benefit of nucleoside analogues is the suppression of HBV DNA. These treatments do very rarely achieve 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 (HBsAg). And with the full suppression of HBV DNA, referred to as functional cure. Receiving 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 and 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% are 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, 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. Geographies have accelerated regulatory processes, Breakthrough Therapy designation in the U.S. We are expecting approval in October, the 26th of October. The market in the U.S. is highly concentrated in 5 states that are marked by high immigration. So 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 Sino Pharma. Sino is market leader in hepatology in China with very broad commercial footprint with access to more than 5,000 medical centers. Japan, accelerated review 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. And with this, I will pass on to Professor Lim to walk us through B-Well 1 and B-Well 2.

Thank you very much. So I'm going to go through the presentation that I did this morning for the EASL conference and excuse my voice, I've got a bit of laryngitis. So the title of the talk was clinically meaningful rates of functional cure and viral loss in suppressed patients with chronic hepatitis B infection, B-Well clinical trials. Next slide, please. I think 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, and that's defined as shown in the slide, more than 24 weeks of sustained HBV DNA below the lower limit of quantification and HBsAg loss after finite therapy with or without anti-HBs. Bepirovirsen is an antisense oligonucleotide that targets all the HBV transcripts, reducing HBV DNA and HBsAg levels. And this is the first therapy in global Phase III trials with functional cure as a primary outcome. So here, I'm going to show you the 2 primary efficacy and safety results of the trials. Next slide, please. The objectives of the B-Well 1 and B-Well 2 studies are shown here. The primary objective was evaluated at week 72, which is the functional cure rate in those with a baseline HBsAg level below 3,000. And the key secondary outcome was also evaluated at week 72. This is the functional cure rate in those with a baseline HBsAg level below 1,000. In addition, we also assessed the sustained HBV DNA below LLOQ off all HBV treatments in those with HBsAg levels below 3,000 and below 1,000. Next slide. So B-Well 1 and B-Well 2 were replicate studies, which are identical in study design. Patients could be enrolled in the studies if they had chronic hepatitis B, were on stable nucleoside analogue therapy, had HBsAg levels between 100 and 3,000, had HBV DNA suppressed below 90 per ml, had ALT levels below 2x upper limit of normal, did not have cirrhosis and did not have interferon therapy more than 12 months. Upon enrollment, patients were stratified by HBsAg levels above or below 1,000 and were randomized 2:1 to receive bepirovirsen or placebo as 2 loading doses followed by weekly injections for 24 weeks on the background of nucleoside analogue therapy. Upon completion of treatment, they were followed up for an additional 24 weeks on nucleoside analogue therapy after which they were assessed at week 48 for eligibility to discontinue nucleoside analogues. The eligibility criteria is shown in this slide. They had to have HBV DNA less than LLOQ and HBsAg not detected between week 24 and week 46. ALT had to be below 2x upper limit of normal and they had to be HBe antigen negative. Those who were eligible to discontinue nucleoside analogues then stopped 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 Asian. Mean HBsAg level was between 900 and 950. Patients with HBsAg below 1,000 comprised 60% to 65% of patients and most of these patients were HBe antigen negative, only 8% were HBe antigen positive. Next slide, please. This is the primary outcome. Functional cure was achieved in 19% 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 HBsAg levels below 1,000, slight differences in B-Well 1 and B-Well 2, the pooled 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 HBsAg 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 off 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 HBV DNA below LLOQ but did not achieve functional cure and none in the placebo group. Next slide, please. Sustained HBV DNA below LLOQ off all HBV treatments was seen in patients with HBsAg levels below 1,000 IU per ml. There were slight differences in B-Well 1 and B-Well 2. The pooled results showed a 31% HBV DNA below LLOQ comprising 26% of patients with functional cure and 5% of patients with HBV DNA below LLOQ who did not have functional cure and 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 studies. I would point you to the pie chart on the right-hand side. I've already shown you how 19% of patients achieved functional cure, but an additional 30% of patients achieved HBsAg levels below 100 IU per ml without functional cure. And these comprise 12% of patients with HBsAg levels between 10 and 100 IU per ml and 18% of patients with HBsAg levels below 10. HBsAg levels below 100 are thought to be clinically significant because these patients may have a future possibility of HBsAg 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 pooled results on the right-hand columns in blue. The results show that adverse events leading to permanent discontinuation of study treatment constituted only 3% of patients and serious adverse events related to study treatment only constituted 2% of patients. There were no fatalities and no fatal serious adverse events related to study treatment. Next slide, please. On-treatment adverse events reported in more than 10% of patients are shown here. Most of these were injection site reactions comprising injection site erythema, pain, pruritus or bruising. There were also safety signals in ALT increase and platelet decrease. Four participants had permanent discontinuation for liver-related events. However, 2 of these 4 patients actually achieved functional cure as well. Transient ALT increases after bepirovirsen initiation were associated with HBsAg reduction. There were platelet and eGFR declines, but these resolved once treatment was completed or paused, and there were no clinically significant events attributed to bepirovirsen. Clinically significant changes in eGFR were not associated with markers of renal injury. Next slide, please. So to conclude, functional cure rates of 19% treated with bepirovirsen among those with a baseline level of 3,000 and 26% bepirovirsen-treated patients among those with baseline HBsAg levels of 1,000 were achieved and none with placebo. In addition, sustained HBV DNA below LLOQ off all HBV treatment was seen in 23% of bepirovirsen-treated patients with a baseline level of HBsAg below 3,000 and 31% of patients with a baseline level below 1,000 and none with placebo. Bepirovirsen is a first-in-class finite therapy achieving functional cure in virologically suppressed patients with chronic hepatitis B infection with an acceptable safety profile. And 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 from today. Thank you for your attention.

Thank you, Professor Lim. My name is Kaivan Khavandi. I lead Specialty R&D at GSK, and I'm joined by Dr. Melanie 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 bepirovirsen 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 is 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. So 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 HBV DNA and loss of HBsAg once off all treatments for 6 months within a study. Bepirovirsen 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, nucleoside analogue treatment for 48 weeks before coming off treatment compared to a similar group who received bepirovirsen for the first 24 weeks. So it's 48 weeks of active treatment with nucleoside analogues that we refer to as the placebo group. And in that comparator group, you see 0% achieved the primary endpoint of functional cure in the ITT population, those with HBsAg of 3,000 or less. Further, 0% achieved functional cure in those with baseline HBsAg of less than 1,000. And finally, 0% achieved response to HBV DNA at the lower limit of quantification at 72 weeks. So 0 is all around for the comparator arm, which is the standard of care. In comparison, in the ITT group, bepirovirsen achieved 19% cure. In the prespecified population with HBsAg less than 1,000, bepirovirsen achieved 26% functional cure. If we relate this to real-world numbers, the majority of the treated population with chronic hepatitis B have HBsAg less than 3,000 and over 40% have HBsAg less than 1,000. And then when we consider the pie chart that Professor Lim presented, an additional 30% of patients achieved HBsAg levels below 100 on bepirovirsen, a threshold 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. So 1 in 5 and 1 in 4 patients achieved the highest bar of efficacy, cure, depending on baseline HBsAg levels in the most commonly treated patient groups and 1 in 2 patients received a response expected to predict protection from long-term outcomes by achieving HBsAg less than 100 IU per ml. These data are clearly recognized and reflected in the impressive regulatory Breakthrough Therapy and Priority Review designations achieved in filings across multiple authorities. Now if we go to the next slide, I'd like to take a moment to consider that this is a monotherapy. And so it's quite remarkable that a single product can confer such protection. How can it do that? Well, it's a single therapy, but it unlocks a 3-pronged efficacy benefit. And it does this in large part because bepirovirsen targets a highly conserved region across all HBV genotypes and present across all HBV RNAs. As such, it targets protein-coding RNAs, pre-core RNAs 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. And of course, 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. And 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 bepirovirsen truly resets the bar when we consider what could add meaningful benefit beyond bepirovirsen. 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 hepatitis B portfolio positioned with bepirovirsen as the anchor. And to this end, Melanie will later cover one such program that does offer real promise alongside bepirovirsen in those with HBsAg levels not studied in B-Well. But first, Melanie will help put these data in the context of standard of care and clinical management of these patients.

Thank you, Kaivan. So 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. So nucleoside analogues were specifically designed to stop viral replication. So it's not surprising that the functional cure rate is extremely low. And as Kaivan stated, in our trial after 6 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 HBsAg loss. Now it has a fairly low functional cure rate, around 2% to 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. So there's quite a 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 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. So if we could 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 HBsAg loss. This was a retrospective cohort study using an electronic medical record database over a 7-year period, and it showed significant association between HBsAg loss and the reduction in the risk of liver cancer and even all-cause mortality. So 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 hepatitis 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. 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. However, what these siRNAs can do is bring the HBsAg down to a sweet spot where we know bepirovirsen works best. So our intention with the B-UNITE study is to test 6 months of siRNA therapy, allowing the HBsAg to come down to this low level, then following that with 6 months of bepirovirsen, again, to achieve functional cure on the backbone of nucleoside analogue treatment. After week 48, those patients will continue on their nucleoside analogue for another 6 months. Those that are eligible to stop their nucleoside analogue will then stop and functional cure rate will be called at week 96. So we're very excited about the 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. So we're very excited about this. Can we go to the next slide? So I think in summary, what we've shown today is that bepirovirsen 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 1 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 of Medicine said remarkable results. I think this also reflects the innovation that we've seen by regulators and their recognition of that innovation. And you can see both in the U.S., China, Japan, we have things like Fast Track, Priority Review, Breakthrough Therapy designation, accelerated review 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. So we'll stop here and then move to question and answers.

Thank you very much, Melanie. With this, we are ready to take your questions. With this, we are ready for the first one. First question comes from Peter Verdult.

Can you hear me?

We can hear you. Go ahead.

Thank you for your time. We also checked in with Professor Wong at Stanford earlier today, who's also at EASL. He definitely thinks the data is exciting, but he did say it's not groundbreaking. So a couple of follow-on questions. He on the presentation talked about an applicable population as defined by B-Well is about 70%. He was saying that in that, the B-Well study probably only represents 30% to max 50% of treated patients. So I just want to square the circle there. That's a clarification. My real question is the interesting stuff. I mean the sequencing and the combination study with siRNA is definitely interesting. But what about some of the other questions from B-Well? So the one I'm really interested in: in the trial design, patients were allowed to stop their nucleoside analogue therapy. And I think that finite treatment is a real sort of selling point. So within B-Well, can you tell us how the patients that stopped their nucleoside analogue after 48 weeks, how did they do compared to those that continued? So that would be my one question.

So patients were eligible to stop treatment if they had HBV DNA negative and HBsAg was undetectable, ALT was below 2x upper limit of normal, and they were HBe antigen negative. So they had to flow through all those criteria for them to stop nucleoside analogue therapy. So in other words, they already had HBsAg loss. Does that answer your question?

Peter, I assume this has answered your question. If not, raise your hand again, and you can have a follow-up. With this, we...

Sorry, I was muted.

Yes. And I'm happy to address also the treated population. So 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 5 major markets, meaning U.S., China, Japan, EU5 and Germany. But there is variability from market to market. So 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%. So 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. But I think the breakthrough part is the fact that 19% of patients achieve functional cure. That's never been achieved in any treatment program before, nucleoside analogue and interferon. So if you don't call that breakthrough, I'm not sure what else you call it.

Next question comes from Sachin Jain.

I've got a question around testing and monitoring. The editorial calls out need for stringent safety monitoring referencing every 1 to 2 weeks. So I just wanted to clarify what the safety monitoring requirements in the study were, what do you expect from the label and how onerous that will be? And then around hepatitis B surface antigen testing, obviously, approvals in October, a minority of patients are currently tested in the U.S. is our feedback. How quickly do you think that can mobilize post approval?

So let me take the question on safety monitoring. Patients were injected weekly, so they were obviously monitored weekly for safety features. I think the 2 safety features that were important were, one, the ALT rise. And I showed you in the, I didn't show you in the presentation, but ALT abnormality was seen in about 45% of patients. ALT more than 10x was seen in 6% of patients and 20x 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 HBsAg loss. If you have ALT less than 3x baseline, then your chance of getting HBsAg loss was only 35%. So it seems that the ALT rise is associated with efficacy. There were no drug-related liver injury problems that were called. So from the ALT viewpoint, it seems to be an efficacy feature. As far as the other safety issues are concerned, they comprise 3 issues: thrombocytopenia, renal function abnormalities and complement abnormalities. These 3 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, including the renal function and the thrombocytopenia and the complement activation process. None of them were clinically significant. There were no bleeding effects and renal abnormalities resolved once the bepirovirsen treatment was discontinued or paused. Also, there were no markers of renal injury that were related, particularly things like proteinuria. So 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.

And 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. So 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. So I wouldn't be concerned about the clinical trial monitoring that takes place right now. 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 United States. However, quantitative HBsAg is readily available inside the United States 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. And I think one of the things that we are going to see, much like you do in many diseases, is the patient wants to know whether the medication is working. 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 6 months of therapy. So I think what's going to happen in the future in the U.S., now that we have a reason to use quantitative HBsAg, you're going to see a significant uptick in that.

Yes. Sachin, I would just add on the testing. Testing in the U.S. is available. This is not some novel test that is not available. And 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. But going forward, this is something that, from the commercial execution perspective, is a priority, and this is going to be changed.

Next question comes from Graham Parry.

Great. I was just going to follow up on the testing question. So 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 because that may have masked additional ALT elevation. And then 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 U.S. and China? But 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 think about pricing?

So 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. But 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. Isolated ALT increases within the range of the fold increases in question without associated increases in bilirubin or evidence of liver injury, and in this setting, it tracks with efficacy and it's all mechanism. So 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. But finally, I think the adverse events should be put in the context of the finite treatments, 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 will recommend treatment. At the moment, our initial commercial approach is not focusing on going after all pool of diagnosed and let alone those who are infected but not diagnosed. So from that perspective, I think we mentioned before in terms of pricing for the U.S., we are looking at a price range that is similar to the hepatitis C space that we have seen. And so far, we have a very clear understanding that this is a very acceptable price level from the payers in the U.S.

Next question comes from Ben Jackson.

I guess can I ask for some further color on this 30% of patients that are achieving the HBsAg levels below 100 without the functional cure. You've made reference to the current HBsAg testing frequency in different regions. Does this mean that this kind of supportive data is more impactful in different regions, particularly ex U.S.? And how meaningfully could this mean that uptake diverges between different regions as a result of that data?

Just to get some clarification, you're asking about HBsAg levels below 3,000 or...

Below 100, to be clear. And how meaningful is that data? And is there a disparity by region about how important that data is?

I see. In terms of the effect of bepirovirsen, I think we don't know whether bepirovirsen-treated patients with HBsAg levels below 100 are the same as nucleoside analogue–treated patients below 100. So we'll need some long-term follow-up to determine whether that's the case. However, these patients are all off nucleoside analogue therapy. And after 6 months of nucleoside analogue therapy, they seem to have HBsAg levels below 100. So that's definitely a good sign. Some of these patients will continue to have HBsAg loss. So I think there's definitely a beneficial effect of patients below 100 IU per ml. Whether there's any region-specific differences, not as far as I know. I think across the regions and across clinical studies, the 100 IU per 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. So I think that in itself is evidence of this event.

Just one final point that both the EASL and the AASLD guidelines were updated in the last 18 months and acknowledge that HBsAg less than 100 represents partial cure and is clinically important as a treatment goal.

Our next question comes from

So 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 it's 26%. But in that intermediate sort of patient subgroup, so 1,000 to 3,000 international units per milliliter, the functional cure rate was about 5%, 10% or 7% pooled. So 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 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, is that as you go from 3,000 down to 100, it is a continuum of efficacy. So the lower the HBsAg has been seen as probably the strongest predictor of response. So what we want to be able to say about this is that when we designed the clinical trial, we specifically stratified on 1,000. But that 1,000 to 3,000 group will contain people who are 1,050, and it will contain people that are 2,998. So 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 acceptable. I suspect from the feedback that we have heard from patients, a 7% functional cure is about what you see with pegylated interferon. And if you had a finite therapy that gave 7%, patients would be highly motivated to take that.

I see we have one more question in the queue. Zach, please go ahead.

This is Zach on for Seamus Fernandez from Guggenheim. Appreciate the question. So I guess I want to follow up on the 1,000 to 3,000 group because then, at least based on the China functional cure rates, you're kind of falling in that pegylated interferon level. So 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 2 groups? And then if we can just kind of hear a little bit more on the risk-benefit in this 1,000 to 3,000 population? Or does it really seem that this drug will most likely be used in 1,000 and below?

Thank you for your question. I don't have any visibility on the data comparing below 1,000 and between the 1,000 and 3,000. So I can't really give you an answer. But I can be sure that these adverse events are related to efficacy. The primary adverse events we're talking about, particularly the complement and platelet reductions and the renal function, were class effects of the antisense. So 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 the 1,000 and below population, mainly because HBsAg loss rates are related to the level of ALT increase. If your ALT increases more than 3x baseline, you have an 85% chance of HBsAg loss. But if your ALT is below 3x baseline, your chance of HBsAg loss is actually only 35%. So most of the patients who achieved HBsAg loss were below 1,000 per ml. So I suspect the ALT rises will be seen in that population. As for the other adverse events, they're probably going to be more random.

Next question comes from Christopher Lobianco.

This is Chris on for Steve Scala. 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 bepirovirsen in the U.S.?

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. And regarding the prior authorization question, we are expecting, of course, HBsAg levels as per label as part of it and also nucleoside analogue–treated restrictions. So those are the main 2 that we are expecting right now.

Next question comes from Colin White.

It's Colin White from UBS. My question was just around how we should expect bepirovirsen to launch in each of the 3 major markets which you outlined. I mean, is there expected to be a large bolus of eligible patients that physicians would want to treat with bepirovirsen soon after launch? Or are there other factors that you think might lead to a more gradual launch in any of those markets?

Yes. Good question and 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 a 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 of the scale of hepatitis C that we have seen just because we will continue to have probably a 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 bepirovirsen. So it's very difficult for me to give you a very specific trajectory. But 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.

Next question comes from Emmanuel Papadakis...

Maybe just, well, a couple. I'll take a follow-up question on the one that was just asked and more from a reimbursement angle. To what extent do you expect there to be, 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? And then the other question I was going to ask was B-UNITE. 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 Phase III...

Yes, 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, U.S., 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 will focus on those at the moment.

Next question.

B-UNITE...

Yes. So for B-UNITE, I just want to make a minor correction. B-UNITE is not a pivotal study. It is a Phase IIb study, and we're expecting the data from that about the 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.

But I think the point you made, Melanie, earlier, is the key one, that it broadens the eligible patient population to those with HBsAg levels not studied in B-Well.

Next question comes from Shyam...

Shyam K on here for Rajan Sharma from Goldman Sachs. Sorry, just a clarification question for one that was asked earlier. So at week 48, where you had the patients that discontinued nucleoside analogue therapy and those that continued it. Could you clarify what proportion actually discontinued it? And if there were any differences in the functional cure rates at week 72 for those that discontinued nucleoside analogue therapy versus those that continued on it from week 48?

Overall, 24% of patients discontinued nucleoside analogue therapy and 19% achieved HBsAg loss. Four percent of patients had HBV DNA undetectable without functional cure and an additional 1% of patients actually had HBV DNA relapse. So the number of patients that didn't achieve a benefit is only 1% among those who stopped nucleoside analogues.

And again, to remind you, the definition of functional cure is that you must stop your nucleoside analogue. Now if you go back, 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 having HBsAg below 0.05, and that does sometimes happen, but you have to completely stop nucleoside analogue to meet the strict medical definition of functional cure.

Yes. It sounds like there is confusion about this. Just to reiterate what Melanie just said, patients who did not stop nucleoside analogues at week 48 by default will not be defined as functional cure. So 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 HBsAg, but they are not falling into the category of functional cure.

We have time for one last question. Last question comes from...

I think I still have my hand up, but I'll take the question. It's on the discontinuation 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. But just your thoughts on those discontinuations and interruptions would be helpful.

The criteria for dose interruption and discontinuations are set in the setting of a clinical trial. I think for guidance purposes, probably it will be better to err on the safety side. But the actual patients who discontinued permanently were actually quite few. For ALT abnormalities, only 4 patients discontinued; for platelet abnormalities, only 8 patients; and for complement activation without any clinical effects, 9 patients. So 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. But I think you're right, there needs to be some element of monitoring for these patients for safety reasons. So weekly monitoring definitely needs to be done for the first 12 weeks.

Thank you. With this, I'd like to hand over to Nina to close the next call.

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 Melanie, are called transformational on a number of occasions. And from this point on, we have the next 6 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. Talk to you soon.