Okay. Good afternoon, everyone. Thanks for joining us for the fireside chat with Barinthus. I'm Dr. Wang, one of the pharma team's senior analysts. I'm joined by Barinthus CEO Bill Enright. Bill, just for those who are unfamiliar, about a year ago, you guys rebranded from Vaccitech to Barinthus. Why the change, and what drove the focus towards chronic hep B and celiac disease? Oh, thank you. Thanks for having me. Yeah, so Barinthus was started as a spinout from the University of Oxford and really started as a universal flu vaccine company. And so the previous name made a lot of sense. We pivoted a while ago to therapeutics. And so the Vaccitech, known for it, didn't really fit with us anymore. So Barinthus is the mythical navigator who took King Arthur to the Isle of Avalon to be healed after he was wounded in battle. And it kind of fits with our English roots and guiding the immune system, which is to heal, which is kind of what we're focused on right now, is kind of rebalancing the immune system. Great. And so you have two kind of platform areas that you're focused on. Can you just kind of walk through, I guess, just give a high-level view of the two programs, and then we'll dive into the specific questions? Sure. Sure. The initial technology that we spun out of the University of Oxford is a viral-based platform. The scientific co-founders at Oxford, they spent the last 30 years really looking at lots of different platforms to try and stimulate CD8+ T cells, more specifically. They looked at all these different combinations, different combinations of viral platforms, viral platforms in combination with RNA, in combination with DNA, in combination with protein. They did this all empirically in phase I clinical studies and showed that you get the highest magnitude of CD8+ T cells lasting for the longest period of time, starting with an adenoviral vector and then coming back as a second dose with a pox virus called MVA. That's really the focus of that platform. Then subsequent to that, we acquired a company that was spun out of Johns Hopkins, Bob Seder's lab, and the NIH. And this is a synthetic nanoparticle technology platform. It self-assembles, peptide-based. And that allows us to go after other arms of the immune system, kind of, again, focus on rebalancing the Treg to T effector ratio. Great. And I guess with HBV first, VTP-300, your main knowledge layer there. Can you just describe the program, what its key attributes are, and where it fits into a potential regimen for HBV? Yeah, I mean, HBV is a pretty complicated area. Initially, people thought that you could control the disease with antivirals, so NUCs, entecavir, and tenofovir are the most commonly used. And it turns out that you get very little functional cure with those, maybe 1% to 2% functional cure rate. And so the virus, it pumps out this decoy protein called surface antigen. And really, that kind of exhausts the T cells over time. And so you get a depletion of antigen-specific T cells that can actually fight off the disease. So people thought if you knock down that surface protein, then the body would be able to take over. So a number of things were developed, siRNAs, antisense, and some monoclonals. And they do a really good job of knocking down the surface antigen. But as soon as you stop giving them, the surface antigen levels rebound again. And so what you really need to do then is stimulate the body's immune system. And that's where VTP-300 comes in. So it allows us to stimulate the host immune system so we can actually, again, rebalance and take control. And so you're getting those exhausted T cells healthy, and you're stimulating de novo T cells that are antigen-specific and disease-specific so that you can control the disease. Great, so it sounds like it makes sense in a combination regimen. Can you talk about how you've kind of shaped your development profile or program to evaluate different combinations? Yeah. So right now, we've got two programs, two clinical trials that are enrolling. One is called HBV 003. And in that, we're targeting people with low levels of surface antigen, so relatively low levels, 200 international units per mL or less. By the folks that are coming into our study, that's about a third of the patient population in chronic hep B. No real good data out there broadly, but from an enrollment criteria, that's about what it is. And the goal there is, again, to use VTP-300 in combination with low-dose nivolumab to get those patients that are already low and keep them low, get them to functional cure. You want to get the surface antigen levels below the limit of detection and then get them off their NUCs and see if they can maintain those low levels of surface antigen for at least six months, which is what a definition of functional cure is, and in the other study, we've got a collaboration with our Arbutus, where in those patients that have higher levels of surface antigen, so siRNAs, their imdusiran, they've demonstrated in several studies previously that if you start with patients that have 5,000 international units per mL or less, and you do a six-month course with imdusiran, you can get 95% of those patients down to below 100, so we pretreat with imdusiran, and then we come back with VTP-300 with or without nivolumab to see whether or not we can drive those patients to functional cures. Great. And so you'll actually be presenting some data from both studies at AASLD next week, both selected as late breakers. Let's just start with VTP-300. I guess, what data have you shown so far, and what's new that we'll see next week? Yeah. At EASL earlier this year, we shared data on the first 21 patients that reached day 169 in 003. What we showed was that we got about 20% of those patients got to nondetectable levels of surface antigen. We got about 70% of patients getting to less than 10 international units per mL. About 80% of patients were eligible to come off their NUCs. This is a significant improvement over current standard of care and available therapies that are out there. We're looking at best-in-class therapy right now. At AASLD this weekend, we will have a late breaker, and we'll add more patients to that day 169. As I said, we had, I think, 21 patients out there. We'll have close to 40 patients at day 169. Then, obviously, we'll be able to follow them longer, see whether they actually get to functional cure, whether they're able to seroconvert, those kind of things. Got it. Can you put into context some of the durability data that we've seen so far with your program versus some others in the space? Yeah. Well, we'll continue to add to that with these data coming up at AASLD. Because, again, that's what ultimately you'd like to see is functional cure data, which means that you need to get to that undetectable level and then another six months after that to make sure that that response is durable. So that's what we'll start seeing at AASLD. Great. And then beyond that, I guess, within identifying responders versus non-responders, what kind of work have you done there, and is there kind of a common identifier of responders? Yeah. We're continuing to look at that and evaluate from an immunological perspective and looking at other immunology markers and things like that. So that's an ongoing effort. Got it. And then the other study, IMPROVE, what can we expect to see there next week? Right. So in the IMPROVE study, there's three cohorts. So essentially, we're pretreating with imdusiran for six months. And then we come back with either VTP- 300, a placebo, or the VTP- 300 in combination with low-dose nivolumab. At EASL earlier this year, we shared data on the first two cohorts, which was the VTP- 300 or placebo, because we added the third cohort later. And so we didn't have enough data on that cohort yet to share. But now we'll be able to see the group C cohort as well. So we're looking forward to seeing those data on the VTP- 300 plus low-dose nivolumab arm as well. Great. And then with that group C cohort, I guess, what would you consider a success there? Yeah. I mean, again, what we're trying to drive towards is increased number of patients that get to functional cure. So we want to be in the, well, greater than 20%, hopefully as high as we can get as far as patients getting to functional cure levels. Got it. Got it. And then, I guess, how long will you continue to follow these patients on for? I know durability is the focus here, especially when we're considering the definition of functional cure. So when can we expect the next updates after AASLD? Yeah, so we've been pretty good about cadence. On On a regular conference basis, EASL and AASLD are kind of split six months apart. So we've been kind of reporting at both of the major liver conferences, and I imagine we'll continue to do that. Near final data on both of these studies will be at the next EASL conference. Great. And can you talk about next steps? I guess, what does future development path look like for VTP-300? Is it in combinations with the program? I guess, how are you guys thinking about it so far? Yeah. So I think VTP-300 plus low-dose nivolumab right now is standing out as the arm that looks like the highest commercial opportunity, at least in patients that have starting surface antigen levels less than 200. And then we can expand that opportunity further by adding a surface antigen reducer. Whether that is imdusiran or others remains to be seen. The Arbutus collaboration is just a clinical collaboration. So we're not tied up from an IP perspective. We're sharing in the clinical costs of that study. And then we agreed to additional conversations if the data are positive. So we'll see how this works out as we get more of these data. Got it. And what does the potential registrational study look like for the VTP- 300 and low-dose nivo combination? And is this something that you can take forward yourself, or is this something you'd ideally look to partner? Yeah. I think we're going through those discussions as we speak. I think, ideally, we would have loved to take this forward. But I think HBV continues to be a complicated area. And so from a geographic perspective, a lot of this disease is in China and Southeast Asia. So I think we would look at least to potential regional partners here to help move this forward in registrational studies. But we'll see how this develops. Great. And then that's actually a good segue. As we're thinking about the commercial opportunity, obviously, this is a kind of global issue. But I guess, specific to the developed world, can you help frame some of the market opportunity here? Sure. I mean, this is a huge unmet medical need, as I said. Right now, on the NUCs, you're getting 1%-2% functional cure rates with pegylated interferon, maybe 7%-9%. So getting up to 20%, 30% is a huge improvement in standard of care. Over 200 million or over 250 million people chronically infected with HBV around the world. As I said, many of them are in China. So maybe it's in the 90 million-100 million range in China and Southeast Asia, 16 million-20 million in Europe, Western Europe, a couple million in the U.S. So that's kind of how it breaks down. So the real opportunities in all of these, Gilead did very, very well in HCV. And this market is much larger than HCV. Got it. And I guess, what does the market look like with a cure rate in that 20%-30%? How, I guess, what level of adoption do you expect? Yeah, so we're looking at peak sales of greater than $1.5 billion a year. Great. And just longer term, as we're thinking about improving functional cure rates above that 20%-30%, I guess, do we know kind of have a sense of what's needed to kind of get to the next level? No. I mean, we and others are evaluating that. I mean, we need to look at whether repeat dosing will help drive that down even further. So there's other ways and other combinations that may allow us to get to higher functional cure rates. But I think, at least, we can get a toe in the market here with the combinations that we have now. Great, and switching to your other side of the platform, the SNAP-TI, can you talk through that platform, I guess, what drove that acquisition and how you've kind of designed your lead program around it? Sure, so yeah, very interesting technology platform and amazing group of chemists out of Hopkins and Bob Seder's lab at the NIH, and really, I guess, the initial drive was to develop a synthetic adenovirus, so adenovirus is the one that gives you the highest T cell response of any platform out there, and so how could you do that synthetically and not worry about the biologics, and so these guys developed a pretty interesting way to essentially manufacture any sequence of peptides that you can think of, so peptides have been studied for a long time. The problem with peptides has been the things that have the best activity are highly charged or hydrophobic, and you're not able to make them, and so you can't use them. And so they found a way to kind of mask the charge and hydrophobicity issues and allows you to make essentially any sequence of peptides. And so we can control the size of the nanoparticle. So if we want to target things that are internal to cells, or you make them small, if you want to do antibody work, you make large particles. There are a lot of different things you can do to the particles and controlling all these different parameters. We can put temperature-sensitive linkers and all kinds of things. And we use these in combination with immunomodulators. And so we can covalently link to immunomodulators for other things as well. So that's really the gist of it. We chose celiac initially because the antigens are well known in celiac disease. And also, you can do challenge studies. So you can get to an early efficacy signal. So the program that we've got moving forward in the clinic that we announced is now in the clinic a couple of weeks ago. That is designed as a SAD-MAD, which is kind of typical in this immune tolerance space. So the first portion is a single ascending dose study. So we'll look at three different doses with six patients in each of those dose groups. And it's a double-blind placebo-controlled study. And so we will be able to get early efficacy signals, particularly in the MAD portion, where that includes a gluten challenge. Great. And can you remind us timelines around that? When we can expect the SAD data, the MAD data? So as I said, we just got this trial off the ground. So we're pushing on the enrollment right now. But we hope to have data from the SAD portion available in the first half of 2025 and data from the MAD portion in the first half of 2026. Great. What would you like to see, I guess, from the SAD portion to kind of give confidence ahead of the MAD portion? So obviously, safety and tolerability is the key thing. This is a first-in-human study for this technology platform. And that's the key driver. But we will look at some transglutaminase antibodies and see whether we can detect a signal. We'll be pleasantly surprised if we see something in the SAD. But looking forward to seeing the MAD data in particular. Got it. And can you talk about some of the preclinical work that you've done here to kind of give confidence to this program? I guess, what have you shown in preclinical studies? Yeah. So there's not really a good preclinical celiac model. So people use a multiple sclerosis model, an EAE mouse model. And we've had several people tell us that that is the best EAE data that they've ever seen. And so you can do the studies in a couple of different ways. One is you give the drug at the same time as you're giving the animals the disease. And you show that essentially the animals don't get the disease. And we've done that pretty clearly. That's kind of the low-hanging fruit experiment. The tougher experiment is actually give the animals the disease and then treat them at peak disease and see whether you can actually impact that. And that's really where I think we've outshone the competitors in that kind of a model. And it's really through this mechanism where we're really changing the ratio of the T effector cells to the pro-inflammatory, sorry, the Tregs to the pro-inflammatory T effector cells. So we're able to show that we can increase the Tregs. And you do that by transdifferentiation of the T effectors as well as stimulation or decreasing of the T effector cells. So you're really changing that ratio. Great. Can you talk about some of the competition in the space in celiac disease? I know there's been some mixed results here. Yeah. I mean, there's a number of different companies out there that are applying different techniques. Some directly trying to target the liver through either liver receptor cells or glycosylation approaches. And I think some of the survey work is showing that the concept of an antigen-specific approach to these immune tolerance diseases is possible. And we think we've developed a better way to do that with these nanoparticles. They're able to get to a broader range of APCs where you can affect the T cells and that rebalancing that needs to occur. And the other thing is we're doing this in combination with an immunomodulator. One of the issues with these technologies is you're actually using the antigen that you're trying to prevent having an immune reaction to. And so you get some sensitization. And so sometimes patients get worse before they get better. So the immunomodulator actually helps us to avoid that issue. And so one of the things that we're able to do is administer IM, where most of these other technologies that we're aware of have to deliver IV. So I think from a patient-friendly and commercialization perspective, that's a huge benefit as well. Got it. And can you talk about some of the commercial opportunity here? How large is this market? So again, this is a huge market. It's estimated that about 1% of the global population right now has celiac disease. And that's diagnosed, confirmed celiac disease. That's not gluten intolerance and some of the other social things where people are having gluten issues. And it's growing at about 7.5% a year. So a big problem and getting bigger. So real opportunity for us. Got it. I guess, where else would it make sense to apply this platform? Are there other indications you're looking at? Yeah. No, that's a great question. I mean, the mechanism of action we think is particularly important in a number of immune tolerance indications. We've got some pretty interesting preclinical data in type 1 diabetes and vitiligo in MS that we shared at ASGCT earlier this year. So I think that this field is advancing rapidly. And this mechanism is potentially useful in a number of different pretty large indications. Great. And just to wrap up, can you just remind us of kind of key catalysts to watch in the next months in 2025 and the cash position and runway? Sure. So from a milestone perspective, as we mentioned, we've got late-breaking oral presentation and late-breaking poster presentation for both of the phase II HBV studies coming up this weekend. And then we'll have near-final data from those programs in the first half of 2025. We expect data from the SAD portion of the celiac study coming out in first half 2025 as well. So those are kind of the near-term clinical milestones. From a cash position, we just announced earnings last week. We had $106 million in cash with a $15 million receivable. So this technology platform, the viral-based platform, was actually involved. We were co-inventors and involved in the early development of the COVID-19 vaccine that AstraZeneca sold around the world called Vaxzevria. So this is kind of the source of royalties as they stopped selling that vaccine. They didn't want to continue to make the different strains and variants and things. So we get an additional $15 million from that, bringing that to almost $60 million with the royalties from that program. So again, nice validation on the technology and helpful non-dilutive funding. Yeah. Great. Thanks so much, Bill, for joining us. Appreciate it. Thanks a lot, Evan.