Hello, everyone, and welcome back to the 5th Annual H.C. Wainwright Viral Hepatitis Conference. My name is Patrick Trucchio. I'm a Managing Director and Senior Healthcare Analyst at H.C. Wainwright. It's my pleasure to introduce our next speaker, Mark Eisner, CMO of Vir Biotechnology, a clinical stage biopharmaceutical company focused on discovering and developing medicine for serious infectious diseases and cancer. And Vir has been, of course, a longtime leader in this area of viral hepatitis. So, pleasure to have you back with us at the conference this year. Maybe we'll start first with HDV and Delta virus. And we did have some interesting background at the conference on this, but maybe you can just to level set everyone, maybe you could just give us some background on HDV, including the viral life cycle and how chronic infection with HDV relates to HBV. Sure. Thanks, Patrick, and nice to be here with you. So, HDV is a disease that has a very high medical need. It infects patients who have hepatitis B virus infection because it's a replication deficient virus that requires the hepatitis B surface antigen to form its own viral envelope as part of its life cycle. So, it can either affect people with prior hepatitis B chronic infection, or occasionally it can be at the same time a concomitant infection. But in either way, it does require hepatitis B co-infection for its own viral life cycle. I think it's notable from a clinical point of view that it actually is a very rapidly progressive disease. It can progress to cirrhosis, hepatocellular carcinoma, or liver cancer very quickly in the majority of patients within a 10 year time period. So, it's much less of an indolent infection compared to hepatitis B infection. Right. That is interesting, and maybe you could talk more about the differences in the therapeutic approach to HDV versus HBV? Right. So, you know, in terms of the standard of care for hepatitis B right now, the majority of patients are treated with NRTIs to suppress the viral replication. It's really a chronic suppressive therapy because there's really no meaningful opportunity for functional cure for most patients based with the standard of care today. For HDV, there really is no approved therapy in the United States. In Europe, bulevirtide is approved, which is being used more and more for hepatitis delta infection. So, in terms of what we're trying to do with delta is to develop a new and novel approach to treating hepatitis delta infection to be a chronic viral suppressive approach. You know, we have two drug candidates: tobevibart, which is a monoclonal antibody against surface antigen, and elebsiran, which is an siRNA that targets all of the viral RNAs that arise from the HBV genome. Together, we are trying to achieve long-term suppression of Delta virus. Got it. And how do the goals of chronic treatment of HDV influence the design of clinical trials? That's an excellent question. So, we are pursuing the combination of tobevibart and elebsiran because we have shown that we can achieve very deep levels of viral suppression. We can achieve ALT normalization in many patients and that we can achieve, you know, approximately three log reduction in surface antigen. So, it's a very, very effective antiviral. So, for clinical trials, you know, we're planning trials that include our combination regimen versus bulevirtide as a current standard of care with, you know, endpoints that include the composite endpoint of HDV, sorry, target not detected by PCR and normalization of ALT. But, you know, our current initial goal will be a 48-week treatment period where we show viral suppression. Got it. No, that's helpful, and just, you know, talking about these endpoints, and I think that tracks with the regulatory bar for approval of novel HDV treatments, but maybe you could talk more about that and just how we should think about it, you know, relative to the Vir program? No, great question. So, the FDA guidance for industry for hepatitis Delta infection encourages a composite endpoint of virology and biochemical ALT response. So, for the virologic endpoint, they recommend less than limit of quantification and target not detected, which means no amplification by PCR at all. So, no detectable hepatitis Delta infection. So, that's the virologic endpoint. Then they recommend normalization of ALT as part of the composite. So, that would be their preferred endpoint. We also feel that, and this is based on our own opinion and also treating with many experts in the field, that, you know, suppression of the virus below target not detected is really, really critical. And, you know, our original SOLSTICE interim data, and we'll talk about this a little bit more, showed that we can achieve very deep levels of viral suppression. As the study goes on, we anticipate deeper and deeper levels. I think one of the key differentiating factors for our combination therapy will be the potent antiviral aspect of the regimen. Right. Great. And yeah, just in, you know, talking about Delta relative to HBV, what struck us is just how the outcomes are so much worse and so much quicker in these patients. You know, maybe they won't live for five years. So, there's no treatments right now in the U.S. that suggests us a very significant unmet need. And bulevirtide is the only treatment approved in the E.U. So, maybe you can talk about that treatment in more detail and how should we think about the unmet need in HDV post the potential approval of bulevirtide in the U.S.? Sure. So, yeah, well, as you said, bulevirtide has been approved in the E.U. for the treatment of hepatitis delta infection. It blocks the entry of delta virus into the hepatocytes. So, it has that effect. So, it's not actually a directly acting antiviral, but it does block the entry of the virus into the liver cells. It is a daily self-injection. So, there's quite a high treatment burden. And, you know, experts tell us that compliance or adherence is a challenge for patients. It does achieve about a 12% Target Not Detected at 48 weeks. So, it's not a very potent effect, but it does, you know, reduce the viral replication in at least that percentage of patients. And it can normalize ALT in about half of patients. So, it's definitely a step in the right direction. It's definitely an effective drug. You know, and I think the other important thing about that is it's making Delta a more prominent, you know, disease on people's minds, physician and public health officials' minds that needs to be addressed. I think the unmet medical need still is pretty significant, though, because number one, you know, we're aiming to have a treatment that's two subcu injections every month as opposed to injecting every single day, which I think is a real challenge for patients. And we're also aiming to have treatment that has a much higher degree of viral suppression than bulevirtide can currently achieve. Right, and maybe you mentioned the phase 2, the SOLSTICE program. Maybe you can talk more about the data you've seen so far in this program in HDV. Sure. So, we presented very, very exciting data at the EASL conference last spring. And the things I would highlight there are, again, the very potent antiviral response, so very rapid and deep suppression of the HDV RNA, achieving 55% target not detected at 24 weeks. Again, that was preliminary data, if only 11 out of approximately 30 patients reaching 24 weeks, reduction in ALT in about half the patients, and also reduction of the surface antigen by about three logs, which we think is quite exciting. So, we're very excited about that data. And we're also extremely excited to be able to present an update on the data at the Liver Meeting, the AASLD, in November, where we're going to have a complete data set at week 24 for the virology, ALT, and surface antigen, along with other measurements. Right. And so, you know, understanding that, you know, we're waiting that data, and, you know, we'll all want to, you know, be very interested in seeing what's in that data. But how should we think about that update relative to what you've already generated? And, you know, how should we think about, you know, what you're looking to see there? I mean, and my understanding is that the program is expected to move forward to phase three. Does this data just kind of confirm that and enable us to move ahead to phase three? And what learnings might you take into the phase three? I know there's a lot of questions there, but maybe we could go one- by- one. I really appreciate the question. I think it's right on point. First of all, you know, as we're going to have a more complete data set, complete at week 24 and more patients subsequent. So, I think what we'll be able to show is the, you know, the continued increase in the proportion of patients that reach Target Not Detected over time. And that, I think, is one very important factor. I think we'll be able to show you, you know, it's basically an evolution of the data set. And to your point, we've already made the decision to go forward into registrational trials. We've made the decision to go forward with the combination therapy. That's what the FDA has given us a fast track designation for, the combination. So, we're moving forward with that plan. We hope to be able to update everyone, you know, in the near future on more specifics about the trials that we're talking about because we are gaining and incorporating the regulatory feedback. You know, we will be able to share more information on that in the very near future. Right. No, that makes a lot of sense. And maybe you can just clarify just in terms of the development timelines for HDV treatments and, you know, in light of the fact that there's this significant unmet need for effective therapies, but also relative to HBV, where I think investors are used to these studies taking much longer. Right. So, to your point, I mean, HDV, Delta is an orphan disease. It's, you know, a rare disease. It's a very high unmet medical need. So, I think the program can be smaller and more streamlined. You know, the FDA guidance and EMA as well recommend a 48 week treatment course. So, that's important to note. But we also, I mean, we already have fast track designation. We're pursuing other accelerated pathways both in Europe and the U.S. So, we will be able to take full advantage of any ability to accelerate and get more real-time regulatory input as our program evolves. So, we do think that as opposed to hepatitis B, there will be a faster approach, more limited number of patients needed, more streamlined. Whereas B, you know, I think you can see what GSK is doing with Beppi. They're two quite larger phase three programs. So, it's a much more traditional kind of approach for a disease like HBV, which is much more common. Right. It's a good segue then to HBV. So, maybe tell us more about Vir's combination approach and what's differentiated about it? Sure. So, we are pursuing, well, we're going to be presenting data from the MARCH study at the AASLD, and we'll be excited to show everyone what our end-of-treatment data look like for our doublet of tobevibart and elebsiran, again, the antibody and surface antigen, the si RNA, and then the triplet that includes those two drug candidates plus pegylated interferon alpha as an immunomodulator. So, we'll have the end-of-treatment data for those two parts of the regimen. The off-treatment functional cure response will come a bit later in Q2 next year. But back to what we're trying to achieve. Ultimately, we're trying to achieve functional cure of patients with hepatitis B. Because the hepatitis B virus is integrated into the host genome and has the cccDNA, you know, we talk about functional cure, which in Delta, actually, the viral RNA is not integrated into the host genome. It's a different scenario. Functional cure we define as off-treatment, 24 weeks off-treatment responses where you have continued HBsAg loss, you have continued suppression of the HBV DNA, and off all treatment, including NRTIs. That will be the goal of, you know, our program and I think what others like GSK are trying to achieve as well in terms of functional cure for HBV. Right, and maybe you could talk a little bit more about the phase 2 MARCH program, what you've seen so far in this data. Sure. So, it's a multi-center trial with multiple treatment arms, so the most important of which it will be presenting data on are the doublet of tobevibart and elebsiran and the triplet, including pegylated interferon. The 1001 study we have already shown data for elebsiran, the siRNA, along with pegylated interferon. And there we showed approximately 26% S loss at week 48 end-of-treatment and 16% at 24 weeks off all treatment. You know, so there was some drop-off, which is expected between end-of-treatment and 24 weeks post-treatment. What we'll be showing you at the Liver Meeting is the end-of-treatment data for the doublet and the triplet. The full functional cure 24-week post-treatment results will come next year, approximately Q2. And how do you envision, you know, the Vir's combination approach, I think, is very unique. How do you envision this differentiating from others in the field? Will it, you know, will you be able to treat a broader, you know, we talked earlier with, you know, in one of the sessions about how, you know, in the Beppi program, they're, you know, stratifying by surface antigen. You know, we'll have to see, I guess, you know, how the Vir program develops. But would this maybe be relevant in a larger patient population, or is it just it's going to have a greater, you know, functional cure rate? I mean, what's been seen so far, I think, has been very impressive. So, I think just maybe trying to understand, you know, expectations around these next two data sets that I think are really going to define this program. Sure. So, in terms of the, you know, the patient population we can treat and the relationship between baseline surface antigen and that, you know, we will be presenting information to address those points directly at AASLD because, as you're alluding to, you know, GSK with Beppi is including patients with under 3,000 baseline surface antigen, and they're stratifying for above and below 1,000, so we will be able to present those data. I think the other question for our regimen is, you know, the doublet versus the triplet that includes immunomodulator with pegylated interferon, so we'll have the end-of-treatment data for that. I think where the another whole set of questions around that is in terms of durability, will the immunomodulator contribute to better durability, and those data will come next year. But I think because we have, you know, the dual mechanism of action with blocking viral entry with the tobevibart blocking the surface antigen, also, you know, binding virions as well and helping the immune system eliminate the viral particles directly. And the siRNA, elebsiran, where we're directly targeting degradation of the viral transcripts, so a direct-acting antiviral, you know, that two components of the mechanism of action, I think, are quite unique. And the other thing about tobevibart, because it has Fc modifications to stimulate T-cell responses. So, that's another aspect of the mechanism of action that we think could potentially contribute to the efficacy of the regimen. Just in terms of the key milestones that Vir hopes to achieve over the next 12 to 18 months in the HBV program, we've been talking about these next important data readouts at, you know, at The Liver Meeting this year and then next year. It sounds like the middle of, you know, around the EASL timing. So, I guess first, is that kind of a good way to think about it, you know, as it's been in the past? And then at which point do you think you would have enough information to move ahead to phase three? Can you maybe do that after the, you know, this next data readout, or would you need a little more information next year? Yeah, I mean, those are really good questions. So, the end-of-treatment data, I think, will be very important for everyone to see because it'll show you, you know, what we're able to achieve in terms of, you know, the 48 week period. Of course, you know, every regimen that's ever been studied has had a drop-off between end-of-treatment and the, you know, the 24 weeks, 48 weeks following that. So, the question will, of course, be the durability of functional cure, including the S loss component off-treatment. And that will, of course, have to wait till second quarter next year. And we haven't completely decided how we would disclose this information. I mean, EASL is a possibility, you know, but there could be other possibilities. In terms of our ability to make a decision, I think that's really going to be based on, you know, how confident are we in our ability to extrapolate end-of-treatment to functional cure 24 weeks later? And that's still a subject of active debate internally. We'll be seeking some external guidance on that from experts in the field. And I think that's something that, you know, we haven't fully wrestled to the ground yet. Right. No, that makes sense. And is there anything you think investors are missing regarding Vir's viral hepatitis treatments? Yeah, that's a really interesting point. I mean, I think for the delta program, the hepatitis delta program, I mean, we're generally very confident in the regimen, how potent an antiviral effect we're seeing. I mean, these are really spectacular data. And, you know, whenever we talk to external stakeholders, you know, I think there's a general acknowledgment that this is a really powerful antiviral regimen as a combination. I think where people see the challenge is, you know, hepatitis delta, because there hasn't been an effective therapy, at least in the U.S., there is no approved therapy, it hasn't been as emphasized, you know, hasn't been, you know, on the radar of primary care physicians. It may not be as, you know, emphasized even by hepatologists because there's really very little to offer patients. By the same token, there currently isn't a systematic reflex testing for Delta, in other words, where, you know, if you get a positive result for B, you automatically test for Delta. That's happening in the E.U. now. We expect that to start to happen in the U.S. once AASLD revises their guidelines and hopefully will include that. It's like there are a lot of disease areas like that, right, Patrick, where, you know, until there's an effective regimen, you don't even know fully how many patients there are, and it doesn't get on the clinician's radar. We believe there's 100,000 patients in the U.S., 200,000 in the E.U., but I would not be surprised if that's an underestimate once we have effective drugs on the market that clinicians can use. There'll be more of an impetus to screen patients who are otherwise at risk for the disease. And I would expect the disease prevalence to increase as that happens. So, I think that's an area where maybe investors and other external stakeholders are still trying to digest and understand. And, you know, I think, you know, we're trying to help with that. In terms of B, I think it's a different scenario. I mean, there's more than 250 million chronically infected patients with hepatitis B. Globally, there's more than 1.5 million in the U.S. I don't think there's any question that it's a very high burden of disease, that there's a lot of patients who need better treatments. But there, it's been a kind of a probability of technical success challenge, if you will, where, you know, multiple treatment regimens have failed to really live up to their expectation, and, you know, I think it's, you know, what we're hoping is that we can show, you know, a high degree of efficacy at end-of-treatment, get people excited, and that that will be followed up, you know, with good functional cure data. Of course, that will be dependent on how the data evolve, but that would be our hope, how we would see that evolving. Right. Terrific. Well, we'll have to end the conversation there, but Mark, thank you so much. It's always a pleasure to catch up with you and the team at Vir. And we'll look forward to these next data readouts. It should be a very exciting next, you know, couple of months, the next six months. So, thank you again, and thanks everyone for attending the conference. Have a great rest of your day and conference.