for joining us. Appreciate it. So, maybe we should just get started with a quick snapshot of Arbutus and maybe what investors can look forward to over, you know, the next twelve to eighteen months. Sure. So Ed, thanks for having us today. We're happy to be here. We appreciate the invite. Arbutus is a company that's exclusively focused on developing a functional cure for hepatitis B virus. Hepatitis B virus, obviously, for those in the audience, is a virus that infects the liver, and our goal is to develop a finite therapy that delivers functional cure, gets patients off of all therapy for hepatitis B, and gets them undetectable for hepatitis B virus and surface antigen. Okay, fantastic. So, in checking your updates, I noticed on your website you have a rather new stated strategy, and I'll just read that out quickly because I think there's a lot in there to unpack. Developing, the strategy is to develop a combination therapy that includes antivirals and immunologics to provide a finite duration treatment for people with chronic HBV that results in at least a 20% functional cure rate. The combo, the finite treatment, and the functional cure, can we dive into that and explain why this was your chosen strategy? Sure. So, while the language on the website might be relatively recent, Ed, the strategy has been in place for a long time here at Arbutus. In fact, Mike and I, when we initiated and founded the company, this is the strategy that we wanted to pursue. It's actually a three-pillar strategy to deliver functional cure for hepatitis B. We need to suppress HBV DNA, we need to reduce hepatitis B surface antigen, and we need to boost the immune system. Okay? So a three-pronged approach, and our pipeline of drugs, which includes an RNAi therapeutic called Imdusiran, and a small molecule, PD-L1 therapeutic called AB-101, excuse me, will deliver on that message. At least we hope, we hope that it will deliver on that strategy. So, Imdusiran lowers hepatitis B surface antigen. It also has an impact on HBV DNA, and then AB-101, that PD-L1 small molecule, could potentially boost the immune system. From a combination approach, look, this has been known in the field for quite some time. We think we need combination therapy in order to deliver it. The current standard of care is our monotherapy. They don't work very well. And what we've seen from across the competitive field is that monotherapies typically don't deliver the full package of functional cure that we ultimately need here. With regards to finite duration, that's really in relation to current standard of care for hepatitis B patients. So current standard of care, there's actually two approved products for hepatitis B currently. One, nucleoside analogues. These are... There's a host of nucleoside analogues that are available, and they do a nice job of lowering HBV DNA, but they don't have an impact at all on hepatitis B surface antigen, very little, if any at all, right? And the problem with these nucleosides is they very rarely result in a functional cure for patients, which means HBV DNA undetectable, surface antigen undetectable, with or without circulating hepatitis B surface antigen antibodies for twenty-four weeks off all therapy. Okay, so no therapy at all. Finite duration, and getting them to undetectable and on with their lives, okay? Nucleosides, you typically have to take for the rest of your life, okay? And if they result in a functional cure at all, it's very low. It's in the single, low double-digit percentages, right? And then the second therapy that's available for hepatitis B is something called pegylated interferon. We'll talk about that a little bit more today. The approved regimen is for naive patients only. It's for 48 weeks, okay? And that leads to functional cure somewhere around 5% of patients, right? The challenge with that is that taking pegylated interferon for that long is challenging for patients. We have embarked on a strategy that reduces the duration of that interferon piece, and we'll talk about that data as we continue to move forward here today. But our goal is to put our two molecules ultimately in combination together, Imdusiran plus an immunobiologic, right? Whether it's AB-101 or something that's available on the market currently to deliver a finite duration of therapy, and ultimately, we wanna increase that functional cure rate to something that's meaningful for physicians and patients, okay? As I mentioned, that, you know, low single digits just doesn't cut it for patients, right? So we wanna increase that number to something meaningful. We had to put our stake in the ground somewhere. We chose 20%. That seems like a reasonable path based on the patients and physicians that we've talked to, being something that's meaningful for them. But obviously, we'll iterate on that and continue to develop that as we move forward. Right. Right. Okay. And then before we get into some of the data, your lead drug, Imdusiran, is obviously an RNAi inhibitor therapeutic. Wanted to just give the opportunity to quickly go over how that mechanism works and how it differs from others in the field. Sure. So, so Imdusiran is a GalNAc-conjugated single-trigger siRNA, okay? It blocks all HBV RNA transcripts and suppresses viral replication and production of all viral antigens. So it does quite a bit towards those three pillars that we talked about earlier. The main thing that it does is lower hepatitis B surface antigen to levels that are quite meaningful. So in some of the previous data that we saw with Imdusiran monotherapy in combination with a nuc, we saw a reduction in surface antigen of about one point eight to two logs, regardless of the duration, you know, dosing that we tested or the frequency of dosing. So it was leading to very good reductions in hepatitis B surface antigen. Some of the other products out there, outside of the RNAi class, don't really target surface antigen at all, and that's one of the key components for us, why we wanted to stay focused on the RNAi space, because it really does exactly what we need it to do, which is hit that second pillar of reducing hepatitis B surface antigen. Great. And so besides the HBs surface antigen- Mm-hmm. Any other key takeaways from your phase 1b results before- Yeah We move on to the current studies? Good point. So we also did show that it does reduce HBV DNA, and we also showed that imduceran alone does contribute to an HBV-specific immunology, okay? Which is important, right? We don't think in and of itself it's sufficient, but in combination with that immune booster that we were talking about, think of it as sort of priming the immune system for that immune booster that's coming. Right. That's what we garnered from the phase 1 study, so very interesting stuff, and we're excited to see where the data takes us. Great. All right, so moving on to your current programs, imduceran is now in long-term follow-up, in two combination phase 2a proof of concept trials, IMPROVE 1, which is with a short pulse of interferon, and IMPROVE 2, with the immunotherapy VTP-300 from Barinthus Biotherapeutics. Yes. What is the rationale behind those two studies before we get into the data? Yeah, so the rationale fits right with the strategy, Ed. We have a goal of, again, three pillars: reduce HBV DNA, suppress surface antigen, and boost the immune system, and that's exactly what these phase 2a studies were designed to test. In IMPROVE 1, the immune booster that we chose was interferon, as you mentioned, short courses of interferon, and in IMPROVE 2, it's VTP-300, with or without nivolumab, a monoclonal antibody for PD-L1, as that immune-boosting component, so that was the idea here, really, reduce surface antigen, and the two studies are set up exactly the same way. You reduce hepatitis B surface antigen with imduceran, right, for twenty-four weeks, and then you give the immune booster. In the case of IMPROVE 1, either 12 or 24 weeks of interferon, with or without continued dosing of imdusiran, so 4 arms total, right? And in the case of IMPROVE 2, we re-randomized after that 24 weeks to, for patients to either continue to get imdusiran or to add in VTP-300, which, as you mentioned, is an immunotherapeutic from Barinthus Biotherapeutics. It's really a prime boost, you know, therapeutic that, you know, that primes the immune system. Great. All right, so then, in early June, at the EASL conference- Yeah Arbutus presented really some compelling and robust end-of-treatment data from both of these trials. What were some of those results, and how does this, you know, move you closer to that three-pronged strategy? Yeah, good question. So yeah, we're really excited about the data we presented at EASL. Let's start with IMPROVE 1. That data was really interesting, mainly because it's a little bit further advanced than the IMPROVE 2 trial, okay? So if you hear me being excited about that particular trial, it's because it's more advanced, it's further along. There's some interesting things that are potentially coming with both trials, but that one in particular, okay? So in the best-performing cohort, remember I mentioned there are four cohorts of patients, right? So let's focus on the best-performing cohort. That was the six doses of Imdusiran cohort with 24 weeks of interferon, okay? So continued dosing of Imdusiran during that 24-week interferon treatment period. And what we saw at both end of treatment, and the effect maintained twenty-four weeks after end of treatment, and I'll explain what end of treatment actually means. So end of treatment was when the imduceran and the interferon dosing were complete, and then we carry on the nucleoside, which these patients came in on a nucleoside, and they continue on a nucleoside for twenty-four weeks. It's called a consolidation period, okay? So at the end of treatment, when we stopped dosing imduceran and interferon, we had overall 33% of patients who were undetectable for surface antigen, okay? Then we left them on their nucleoside, and we assessed them again at the end of treatment. We again had 33% of patients undetectable. So all those patients maintained their response through that twenty-four-week nucleoside consolidation period, okay? Then we stopped their nucleoside, and we're going to assess them for functional cure. Remember, the definition I mentioned earlier for functional cure is off all therapy for twenty-four weeks, okay? Now, very interesting and compelling to us was the fact that if you look at some predictors of response, one of the things that's really important is baseline surface antigen, okay? So in patients who had baseline surface antigen less than a thousand international units per ml, those numbers went from 33%- 67%, okay? You remember, we set our bar at 20%, right? Now, that's a functional cure bar. We're not there yet, right? This is just end of the nucleoside discontinuation piece. We have to wait for 24 weeks and see what happens. So we're excited, you know, we're excited to see that data when it comes. You know, hopefully, we'll have it, maybe at AASLD, depending on what gets accepted and what can get presented, but it's certainly coming in the fall here. Great. Okay? All right, so, as you mentioned, there's this robust, sustained, HBs surface antigen loss. Yeah. How does this compare with many other agents? Have we seen anything like this before? We've seen data from some competitor companies that look interesting. I would argue that ours looks a little bit more interesting. I think it's a challenge to sort of compare across, Ed, to be completely honest with you. The studies are set up differently, and, you know, in some cases, patients stay on their nucleoside, and sometimes, in some cases they don't. Looking at different time points gets challenging, as you can imagine. But if you take the time to lay things out, I think we compare very well to the most advanced competitors in the field. Hopefully, we continue to do so as we progress towards functional cure. And then, switching to the IMPROVE 2. Yep I n Group A, what proportion of patients were able to discontinue the nuke treatment, and how long have they remained off treatment? Yep. So let me set up IMPROVE 2 one more time. So we do imdusiran plus a nucleoside analog for 24 weeks, then randomize into either a VTP-300 containing arm or continued imdusiran dosing. So A, VTP-300 active, B, placebo, right? So in the VTP-300 active arm A, we had 84% of patients who were able to stop their nuke, okay? And in arm B, which was imdusiran alone, we had 53% of patients that were able to stop their nuke, okay? And that happens at week 48. Okay, so as I mentioned, this study's a little bit further behind than IMPROVE 1, right? So we're gonna have to continue to follow those patients and see sort of how things progress. What we presented at EASL was that there was a difference between the two arms when we looked at the data, okay? Interestingly enough, as I mentioned, we did amend this study and add an arm C, which includes low dose nivolumab in combination with the boost component of the VTP-300 regimen, and we're anticipating presenting some end-of-treatment data for that arm in the fall as well. Would you expect that at AASLD, or could that be somewhere else? I can't commit to you, Ed, only because we don't know sort of what may or may not be accepted, right? Yeah. So, look, we have historically targeted the major liver conferences, EASL and AASLD. And until we know, you know, I can't commit one way or another, but it will be in the fall here, for sure. What kind of data can we expect from? Well, that'll be end-of-treatment data for that arm C. So, week 48. For all the patients in that cohort? Yeah, for the patients that are in that cohort, and then, you know, we'll go from there. Yeah. Okay. So, as you're nearing the completion of both of these trials, now, how do you move forward in deciding and determining how to progress into- Yeah phase 2b? That's a great question, Ed. So yes, our next step is likely a larger phase 2b study. When we set out with these trials, look, we didn't have any false belief that we were gonna take every regimen we took into phase 2a to understand what the concept was into larger stage studies. So the goal was to really assess what regimen might work best and then progress back into phase 2b. So, you know, until we have all the data here in hand, it's hard for me to commit one way or another about what our plans are going forward, but we are spending a lot of time thinking about that, a lot of time thinking about how we can best accelerate that. So as the data continue to mature, we'll update everyone on the progress there. Okay, great. And then turning to AB-101, your PD-L1 inhibitor, obviously, you've talked about how that fits into your overall strategy. But just remind us, that mechanism and how it works with imduceran. Yeah, that's a great question for Mike, Ed, so I'm gonna let, I'm gonna let Mike talk about that. Yeah, and so, you know, just as Mike said, you know, a big piece of our strategy is immune activation in conjunction with imduceran, which knocks down S antigen, which is really the agent that everyone believes is causing this immune exhaustion phenotype you see in HBV patients. So what you wanna do is re-engage the host immune response, and, you know, it's been pretty clearly shown that the PD-1, PD-L1 axis plays an important role in immune tolerization in chronic hepatitis B patients. You know, PD-L1 expression is upregulated on HBV infection. PD-1 is upregulated in HBV-specific T-cells and B-cells, and, you know, we've shown, at least in preclinical models, that a combination of a PD-L1 compound plus an siRNA that knocks down S antigen, you know, shows immune activation present in those animals. And then, there's been some sort of clinical data that's helping support the concept of checkpoint blockade. There was an early Gilead study with nivolumab that showed some S antigen decline in a number of patients. In fact, one went to functional cure. And then, there's some data from companies like Ascletis that showed an antibody, a PD-L1 antibody, showing some S antigen reduction. So all in all, we believe that sort of that body of data is supporting the checkpoint axis as a potentially important contributor to immune exhaustion, and if you can break that, that, you know, axis and so to speak, then you can get that immune activation that you need in conjunction with the S antigen decline, where you're taking off the brakes from the immune system. So basically that's the mechanism, that's the rationale that we have for AB-101. If you then look at AB-101 itself, it clearly is not an antibody, right? It's a small molecule. And why is that critical? So I think the whole field has been a little skittish about checkpoint blockade as far as antibodies are concerned, because as you know from the oncology space, you actually turn on the immune system or really juice up the immune system a lot for a very extended period of time. And certainly clinicians in the HBV field are a little concerned about that in the hepatitis B space. And so when we thought about this problem, how are we gonna check, you know, address this checkpoint axis, we sort of gravitated to this concept of a liver-targeted small molecule strategy, that is where AB-101 ultimately was born from, and the rationale there is simply that we could enable oral dosing there. We could control the PK/PD relationships. We could reduce the potential systemic exposure, and therefore reduce potential systemic activation of PD-1, PD-L1 by doing a liver targeting or a liver-centric agent in that, and so we were able to, we believe, really fine-tune or tune the activity that we're looking for in a small molecule PD-L1 agent, so all in all, as I said, that led to AB-101, which is currently in our phase 1 clinical development program. Right. Okay, so Mike, as you mentioned, there's obviously some preclinical evidence with AB-101, as well as some clinical evidence from analogs, others in the field. But with AB-101 directly, you're now in phase 1, and I believe you've completed the SAD portion, and the MAD portion is coming up. What are you looking for with that next coming readout? And when would you expect to be able to start dosing HBV patients? So yeah, you're right, Ed. You know, so we, we've completed the SAD portion. What we can say is that we have safety that we're very excited about. So all these concerns about immune activation, you know, that one would typically see with the checkpoint blockade agent and the side effects, we do not see. So we're pretty excited about that. And one of the other things that we were really looking at is this whole concept of receptor occupancy. So is the molecule actually getting to the target that we want? And in fact, we've demonstrated that. We've, you know, commented on that in a press release, that, in fact, we're getting good receptor occupancy with AB-101. Everything is aligning up pretty well with regard to this molecule from a safety standpoint, as well as from the targeting of the biomolecule that we're looking for. You know, now it's moving into multiple ascending dose. Obviously, we'll get more data on safety there, get more data on the receptor occupancy piece, and then, you know, hopefully, fingers crossed, we'll be moving into the chronic hepatitis B patients in the not-too-distant future. Okay. And from there, is it still too early to be able to think about when you might be ready to start actually combining imdusiran with AB-101? And what sort of gating data or results would allow you to move that forward? We've been thinking about it, you know, exactly how we would progress this forward, the combination, because we're very excited about that, that combination. Look, we need to get the chronic hepatitis B patient data, right? Dosing for at least 28 days, see the safety. The safety needs to be there as well, because Imdusiran is a very safe drug, so we want to, we don't wanna impinge on that, and we wanna see that we're actually engaging the target, doing what we want to do with the immune activation, well, with the target itself, the receptor occupancy where we want it to be. Then, you know, frankly, it'd be nice to see what impact we're gonna see on biomarkers, you know, viral biomarkers. We've seen some, as I mentioned before, some of the antibodies, you see some level. We're excited to see if, in fact, we can see that with a small molecule. We're optimistic, but, you know, we - the data's gonna have to speak for itself. Right. And as we take a step back and look at the overall space, I believe at the moment really there's only one asset currently in phase three development. That's GSK's bepirovirsen. How does that mechanism and the data that they have differ from Imdusiran? And as the landscape continues to evolve, how would you think it would best fit in that landscape? Yeah, a good question, so if you look at the two molecules, Imdusiran is an siRNA agent. It's a GalNAc conjugated siRNA agent, so it's trafficked to the liver, it binds to the asialoglycoprotein receptor on the hepatocytes and gets taken into the liver, forming a RISC complex with a host mechanism to be able to basically clip or cut any viral message that's produced from cccDNA-