Hello, everyone. Thank you for joining us at the H.C. Wainwright Second Annual BioConnect Investor Conference at NASDAQ. For our next presentation, we have Arbutus Biopharma, and with us on the stage today, we have Mike McElhaugh. He's the Interim President and CEO, and we also have Dr. Karen Sims. She's the Chief Medical Officer of Arbutus. Perhaps we can start with a brief introduction with Arbutus for those who are not familiar. Sure. So I have this slide. We have a couple of slides we can run through here, Thomas. Yeah. Arbutus Biopharma is a company that is exclusively focused on finding a functional cure for hepatitis B. Mm-hmm. We think we have the team and the expertise internally to be able to deliver on that. We have significant history in hepatitis generally. Mm-hmm. and virology. We have a portfolio of internally discovered assets with different distinct mechanisms of action that we think can really be beneficial to patients with hepatitis B. Mm-hmm. We have two compounds. We'll get into those on the next slide. Financial position's in good shape, and of course, we have our patented LNP technology- Right which is the subject of some ongoing litigation with Moderna and Pfizer. Real quick, we can hit the approach- Yeah. - if that works for you. Mm-hmm. We think it's important, to actually hit three prongs as we think about how we might be able to deliver a functional cure for patients with chronic hepatitis B. One, we need to suppress HBV DNA. Mm-hmm. Right? We need and we can do that with existing nucleosides that are out there currently. Second prong is to reduce hepatitis B surface antigen, all viral antigens, but really surface antigen is the most important because that's what's responsible for causing immune exhaustion. Right. Okay? And we need to boost the immune system, and we can do that through a variety of ways, and we'll get into the specific trials as we, as we move forward here. Right. Well, you touched on it a little bit. Perhaps we can start by discussing what are some major classes of hepatitis B therapeutics, either approved or, you know, currently in use or in development, and how does imdusiran play into that? Okay, sure. So there are actually two classes of approved therapies for hepatitis B currently. Right. Mm-hmm. There are nucleoside analogues, which are given lifelong, daily drug given lifelong. Right. And those do a nice job of reducing HBV DNA, but they do nothing to surface antigen, and really, the functional cure level is extremely low. It's about low single digits, about 3%. Right. These patients take that drug for their lifetime. There's also pegylated interferon, which is approved for hepatitis B. That's a 48-week course of treatment. Mm-hmm. 48 weeks is a lot of interferon for a patient to tolerate. You see functional cure rates somewhere around 7% with interferon. As far as other mechanisms that are in development currently- Right I guess the best thing to do would be to pop to our pipeline slide, to hit a couple of important ones first. We think one of the important therapeutics as classes is RNAi or siRNA, and our lead candidate there is imdusiran. It's currently in phase 2a. Right. Karen can talk about those trials as we move forward here. Mm-hmm. There are other siRNAs in development. A couple of our competitors have siRNAs. There's also ASOs that are in development for chronic hepatitis B. Mm-hmm. There are capsid inhibitors in development. There are a whole host of different, viral-specific, targets and immune-boosting components- Mm-hmm that are currently in development. So it's a very active space- Right which is, which is good. And then we also have a PD-L1 inhibitor called AB-101- Mm-hmm. - that's currently in the clinic as well. Karen can talk about that as well. Right. The interesting thing about that particular therapy is that it's an oral small molecule- Mm-hmm as opposed to an antibody. Right. There are some distinct advantages to that approach, relative to the antibody approach. Once you give an antibody, it's on- Mm-hmm and it's really hard to turn it off. Right. We can fine-tune, or we think, we hope to be able to fine-tune the small molecule approach, to give us the, you know, the, the ability to sort of tune the response and eliminate—importantly, eliminate some of the side effects that you see with the antibodies, which is immune-related adverse events. And once those crop up, it's really hard to turn them off. Mm-hmm. But with a small molecule approach, you can kind of, you can kind of tune that and wash out drug, you know, stop giving the drug, and you get, you know, you get reactivation of the PD-L1. Right. Perhaps taking a step back, you seem to have, you know, a deep focus on hepatitis B. Mm-hmm. Can you discuss a little bit about the market opportunity there? What are some, what are the lead markets- Sure globally? What are some of the top markets? Yeah. So hepatitis B is a really big market. There are a lot of patients suffering with chronic hepatitis B globally, about 300 million patients- Mm-hmm so about twice the size of hepatitis C. There are pockets all over the world. There are about 2 million patients in the U.S., which is a really big number- Mm-hmm about 15 million in Europe, 90 million in China. Right. So it is definitely a major problem in Asia, but that's not to discount the other areas as well, which have lots of patients. Mm-hmm with lots of need. Yeah. And then with imdusiran, as you touched on earlier, different mechanisms. What are some advantages of RNAi therapeutic, and what are some potential disadvantages? Yeah. You mentioned there's a proprietary LNP technology. So maybe I'll let Karen talk a little bit here, and we can kind of tag team with each other. Does that make sense? Yeah, sure. Yeah, absolutely. Please. I, you know, I think as a class, the siRNAs are very attractive because they do have this very long duration of activity- Mm-hmm. which is, you know, quite different from other therapeutics. So with most of the siRNAs in the field, you can administer them on a monthly or bimonthly basis and get a quite prolonged duration of activity, mostly surface antigen- Mm-hmm. -reduction. They're quite well tolerated, I think, across the class. They have a very good safety profile. Imdusiran in particular is a little bit different. We're at a much lower dose level than some of the others in development. Mm. In our initial human clinical trials, we looked a little bit more at dosing intervals in terms of the frequency of dosing that's necessary- Mm. and have settled on an every eight-week dosing interval. Right. As to most others in the class are dosing every month. So a little bit different. We've also been very interested in the immunologic activity that's induced by imdusiran alone- Mm. or in combination with a NUC. So we've been looking at that on an ongoing basis through our clinical development plans as well. Okay, so with these different mechanisms, what do you consider to be the ultimate goal for hepatitis B therapy? And, how does imdusiran's RNAi mechanism fit into this vision? And also, are there some other competing RNAi therapeutics in the hepatitis B space as well? So maybe we can handle the, the back end of that question first. Yes, there are a few, other siRNAs- Mm-hmm. in development. There are at least, let's see, one, two, three- Mm. -three other RNAis in development. They're differentiated in certain ways. Sometimes they target—sometimes there's multiple triggers. Sometimes there's X-s paring. So X is a hepatitis B protein. So there are some differences- Mm-hmm. as far as what those siRNAs look like and, and potentially what the potential outcome could be when dosing with one of those siRNAs. Good. For the first part of your question, I think that the most interesting outcome, as it pertains to hepatitis B, is functional cure. Mm. So functional cure is defined as undetectable HBV DNA, undetectable HBV surface antigen, with or without an antibody response- Mm six months after stopping all therapy, okay? Including your nucleoside, so everything off of therapy. And as far as what imdusiran can contribute to functional cure, we think it can actually be a backbone of therapy for a functional cure. Obviously, it's gonna take a combination approach to deliver a functional cure for hepatitis B. We think we have two very good components in our pipeline- Mm-hmm. and we think imdusiran could stand as a backbone. Right. And you mentioned the six-month, You got a hand up over here. 2-3 years ago, Mm-hmm. Jane Yeah, good question. So I think you're referring to sort of, yeah, the 2015—let's say 2015, 2016 timeframe. Mm. when the siRNA showed some reduction in surface antigen, and there was some attention- Right Paid to the class, right? Unfortunately, all they showed at that point was reduction in surface antigen. Mm. As we've mentioned, that's one component of a multi-pronged approach that we think we need to cure hepatitis B. Mm-hmm. Right? So I think what happened was there was excitement around the siRNA class, understandably so, and it's an important component, right? But you have to get the rest of the components correct as well, and I think we've made a lot of progress since then in understanding what makes sense to combine with the siRNAs in order to deliver that. And you know, we've made some progress in the past, I'd say, probably a year and a half or so- Mm At the various liver conferences, and I think we're gonna continue to see, you know, growth as we continue here to EASL upcoming, to AASLD in the fall. Because those studies that were put in place after that sort of, let's call it a frenzy around siRNAs, are now reading out, and people are understanding what the, what the potential value is. Okay. Right, speaking of that, you mentioned this six-month mark. Mm-hmm. It seems to be a key period to show. Can you tell us what are some data that have shown imdusiran has been efficacious in clearing, you know, reaching the efficacy level six months out? And you mentioned EASL, AASLD, what are some upcoming presentations that investors can look forward to? I'll let you answer that one. Yeah, sure. Yeah, actually, it's a perfect slide. Yeah for this discussion. So, we are in multiple Phase IIa trials at the moment, so those are proof-of-concept trials looking for a signal of surface antigen loss, and then ultimately functional cure. Right. As was mentioned, these studies do take a long time to run, so we're just starting to get to that point now of having subjects at the end of all treatment, and subjects into follow-up and discontinuing all therapy. Right. You know, where we are, for example, with the study shown here, our studies are all designed a similar way, with the idea of using imdusiran to lower surface antigen as much as possible. Mm. Because, again, that's believed to be what's contributing to host immune exhaustion, so patient immune exhaustion, then adding an immunomodulator to try to boost the immune system and ultimately lead to functional cure. So what we've presented so far for the first two studies here- Mm. Our 201 study is a combination study with pegylated interferon alpha as the immunomodulator. Mm-hmm, mm-hmm. The second study shown here is a combination trial with Barinthus Biotherapeutics, formerly Vaccitech, with their therapeutic vaccine, VTP-300. So we presented preliminary data from both of these trials last year. Right. Early kind of on treatment data coming up, as you said, at EASL, we'll have end-of-treatment data for both of these trials, meaning all subjects having completed the treatment with the immunomodulator. So all subjects having completed 12 or 24 weeks of interferon for the top trial, or having completed the vaccine or placebo treatment period for the second trial. So that data will be coming out at EASL. Mm-hmm. That second trial with the therapeutic vaccine, we've also amended that to add in a low dose of nivolumab. Mm. - which is a PD-1 antibody, based on some data Barinthus has, suggesting that adding that checkpoint inhibitor to the boost component of the vaccine may allow more subjects to respond and perhaps have a more deeper, meaningful response. So we've also amended that into this trial, and we'll have data from that portion of the study in the second half of the year. So making progress. In terms of the functional cure piece, again- Mm. So subjects would need to complete the entire trial, then come off of therapy for six months. Mm. and then be evaluated for functional cure. Mm-hmm. We're not quite there yet with these trials. Mm. - but coming. Right. Coming. Yeah. So we should expect. I do recall last year around this time, so, you know, you have specific number of patients that have completed a six-month period, so we should expect just with more patients within a data set to report it? Right, exactly. So for example, last year with the interferon trial, we had about the first 12 patients of 43- Mm-hmm. through the interferon for 12 weeks of interferon, so now we'll have the full 43 patients. Right Completing all interferon, plus additional follow-up, and some patients that have already discontinued therapy, as we mentioned. But, you know, you have to kind of do the math in terms of, of adding the different treatment- Right - and follow-up periods together. Right. Similarly, with the 202 study. Right The study with Barinthus, we had, I think, about 12 or 13 subjects through the end- Mm of treatment, and now we have the remainder of the 40 subjects through that end of treatment period, plus subjects that have also come off of therapy in that trial as well. Right. So speaking of the second trial, in combination with the extension arm- Mm the combination of PD-L1, can you talk a little bit about the rationale behind that, and then how it interacts with AB-101? Sure. So yeah, we've, you know, as, as noted, too, we, we also have a third trial now with durvalumab, which is a PD-L1 monoclonal antibody. So the idea really is that, you know, we think the checkpoint inhibitor axis may play a very important role in maintaining that, immune exhaustion in hepatitis B patients. Mm-hmm. Mike Sofia and his group have done a lot of work looking at the basic science of this in terms of PD-1, PD-L1 expression- Right in human hepatocytes, in PBMCs from patients with hepatitis B, and we think it's quite important to target. I think others in the field are looking at checkpoint inhibitors very closely as well. Mm-hmm. In terms of how it interacts with AB-101, you know, nivolumab is a representative checkpoint inhibitor, but it's, you know, PD-1 versus PD-L1. Right. We think there's a little more evidence for PD-L1 being perhaps a more important checkpoint inhibitor in hepatitis B. So the idea with this third trial with durvalumab is to start testing the optimal timing of using a checkpoint inhibitor in the context of imdusiran lowering surface antigen. So one thing- Mm we don't know is, is it best to intervene in that early phase of surface antigen decline with imdusiran? Is it better to intervene when subjects are already at their nadir for surface antigen reduction- Mm-hmm and then add the immunomodulator? So that third trial is attempting to look at the optimal timing of checkpoint inhibition during treatment with imdusiran. And the reason we think that's important to look at now is our AB-101 program is in the clinic- Mm but it's still in phase 1. Right. It's in healthy subjects, Right single dose and multiple dose in healthy subjects. So if we can learn a little bit about the timing of checkpoint inhibition and then use that data when AB-101 is ready to be put in combination with imdusiran, I think that will give us a leg up in terms of designing that trial appropriately to get the outcomes we're looking for. Right. So clearly, the next question would be, where is AB-101 at? When will it be ready for- Mm you know, to be in combination with imdusiran? What kind of data should we expect from this phase 1 study with AB-101? Yeah, no, good question. So, you know, as you said right now, it's in a phase 1 study, so we have to, you know, make sure we understand the basics of how the molecule looks, right? The safety, the pharmacokinetic profile- Mm the pharmacodynamic profile. As is typical in this space, we start in healthy subjects. The study right now has completed several single-dose panels in healthy subjects, and we shared some data earlier this year about the levels of receptor occupancy we're seeing after a single dose. Right. Doses up to 25 milligrams, we see between 50% and 100% receptor occupancy in healthy- Mm subjects after one dose. So very pleased with how it's performing, with a, you know, very well-tolerated safety profile to date. Mm. So now we are in the multiple-dose portion of that study, and it's designed as an umbrella study, meaning we can progress seamlessly through single doses in healthy subjects, repeat doses in healthy subjects, and then ultimately move into patients with chronic hepatitis B as part of the same trial. Right. Really, it's just a matter of accumulating- Mm. enough of that information to move to the next step safely in terms of the- Right safety profile, again, PK/PD. So we hope to share initial multiple dose data from healthy subjects in the second half of this year. Okay. And then move that trial seamlessly into patients with chronic hepatitis B, again, with the goal of moving it as quickly as possible into combination with imdusiran. Right. Yeah. And then, perhaps, you mentioned a number of data readouts. Can you perhaps recap what are some upcoming milestones in the next 12 months, and how does it go in relation to your cash runway? Yeah. So let's handle cash and runway off the start. Right. So cash balance as of the end of the first quarter was $138 million. That gives us cash through the second quarter of 2026, so over two years of runway. We expect cash burn this year to be somewhere in the mid-$60s million. As far as milestones are concerned, you can see we've already been able to check off two of the, two of the first half milestones that we had planned for this year. That's the initiation of the imdusiran durvalumab trial that Karen just mentioned, and also presentation of single dose data in healthy cohorts for AB-101. Right. We have, as we mentioned, we have two data sets upcoming at the EASL conference. Mm. both end-of-treatment data cohort, excuse me, both end-of-treatment data sets- Mm. one for imdusiran plus interferon, and one for imdusiran plus VTP-300 from Barinthus. And then in the second half of the year, we expect end-of-treatment data from the follow-on to that, Barinthus study. Mm-hmm. That's imdusiran plus VTP-300- Right plus the nivolumab, and also preliminary data, as Karen mentioned, from the multiple ascending dose cohorts of AB-101 in healthy subjects. So it's still gonna be a productive start to the year. Yeah. We think that production's gonna continue as we move- Yeah - forward through the year here. Sure, sure. Yeah. Well, perhaps last question: as some of us may have seen, do you have any comments regarding Friday's this open letter from Whitefort Capital? Yeah. Do you have any response to that? Yeah. So we're, of course, aware of Whitefort's letter. We take our interactions with all of our shareholders to heart, right? Mm-hmm. It's important that we think about shareholder feedback as we think about our strategy and how we're gonna continue to increase value for the company. You know, I can't comment much further than that. Right. But we do take shareholder feedback seriously. We look to engage proactively with all of our shareholders, not just Whitefort. So yeah, we're gonna continue to evaluate and continue to move that forward, so. Great. Well, well, thank you, everyone, for joining this session. Thank you very much- Thank you John, thank you very much, Dr. Sims, for joining this discussion. You're welcome. Thanks all. Thank you.