I don't need to be in the video. Let me get this. Yeah. You do have slides, right?
Just a few.
All right. OK.
All right. We'll kick through them really quickly.
OK. Thank you, everybody, joining us again for the Citizens JMP Life Sciences Conference. My name is Roy Buchanan. I'm a biotech research analyst. And we're happy to have Arbutus Biopharma with us, as usual, the whole team, a subset up here. Mike McElhaugh, he's the Interim President and Chief Executive Officer. Mike Sofia, to his right, Chief Scientific Officer. And then Karen Sims, to his right, Chief Medical Officer. So thank you for joining us. And I think Mike McElhaugh is going to run through some slides to start.
Yeah. Thanks, Roy. I'll try to make this relatively quick here. Arbutus, as you know, Arbutus is a company that is exclusively focused on delivering a functional cure for patients suffering with chronic hepatitis B. We believe we have the team in place to be able to deliver on that vision. We have Mike Sofia, who was the developer of sofosbuvir in a previous life, which was able to deliver a cure for hepatitis C. We have a portfolio of internally discovered assets with distinct mechanisms of action. I'll get into what those compounds are here in the next slide or two. And I do want to mention our patented LNP technology. As many of you know, that is the subject of ongoing litigation with both Moderna and Pfizer in relation to their COVID-19 vaccines. Moving on to the next slide.
We take a three-pronged approach to therapeutic success in hepatitis B. We believe we need to do three things. One, suppress HBV DNA. Two, reduce viral antigens. And three, boost the host immune response. And we can solve for suppressing viral DNA using available nucleosides. We can reduce viral antigens, mainly hepatitis B surface antigen, using our RNAi technology. And we are looking at various ways to boost the host immune response, namely through our own internal PD-L1 inhibitor, oral PD-L1 inhibitor, AB101. This is our pipeline. As I mentioned, we have two programs in our pipeline, one imdusiran, also known as AB729. That's an RNAi inhibitor, currently in phase II. It's in multiple phase IIa studies. I'm sure we'll get into some details from Karen in the near future here. We also recently kicked off a combo trial looking at imdusiran plus durvalumab, which is a PD-L1 antibody.
We're excited about that study that just recently started enrolling. Karen will speak to that as well. Then we have AB101, which is currently in single and multiple ascending dose phase I trial. We're moving that forward as quickly as we can. That's our oral PD-L1 inhibitor. Before I get into this slide, I want to mention, Roy, as you know, we have an ATM program in place. Through that ATM program, over the past several months, we've been able to raise a fair amount of capital that helps us execute on our mission. We believe that we currently have sufficient runway. As you can see from the top of the slide here, we have a cash balance of $138 million as of the end of the first quarter, which gives us cash runway through the second quarter of 2026.
We will, of course, always take advantage of all the tools available to us as our business and as our pipeline continues to evolve to make sure that Arbutus is appropriately funded over time. But at this time, we don't anticipate the need to further utilize the ATM this year. If you focus on the bottom part of the slide here, you can see the key milestones for the year. You can see two boxes have already been checked for the first half of the year. That's the initiation of that durvalumab trial. There we go. And also the preliminary data from the AB101 trial. We also have two ongoing phase IIa studies with imdusiran, end of treatment data anticipated at EASL this year, which I'm sure we'll talk about more in detail. That's coming up here.
So we'll be all checked off on all four of our first half milestones for 2024. So, Roy, maybe with that, I'll kick it back over to you for any additional questions you have. And we can get into the chat.
OK. Great. Thank you, Mike. Appreciate that, especially the cash update. That's important. And maybe I missed it when I stepped away for a second. But sorry. The slide.
You just stepped up, by the way.
I guess the company's theory, I'll put it that way, for a functional cure, just how do you envision getting to a functional cure? What do you need? Is that in agreement, in your view, with the consensus, I guess, in the field, the KOLs?
Yeah. It's a good question, Roy. And yes, I think the answer to that question is yes, it is in alignment with the rest of the way the field thinks about things, including specifically the KOLs. As we've talked about, and I can put the slide back up, our goal here is to suppress HBV DNA, reduce viral antigens, and boost the host immune system. So you'll see a variation of this slide in just about everybody's deck at this point. I think Mike and I joke because we're the first ones who actually put it into our deck. So yes, we do think it's consistent. We do think that this can deliver a functional cure for hepatitis B patients.
OK. Great. And so on the right, the immune system, you're actually testing three of those in addition to the RNAi. And so you're really OK.
That's correct.
So maybe let's start with the RNAi and imdusiran. That's a cornerstone or keystone for your platform. Just how is it different than other RNAis? There's other Vir has one, et cetera. I guess GSK has one now. How is yours different?
Mike, Karen, one of you guys want to take this one?
Yeah. Sure. So when you look at RNAis, currently, the GalNAc conjugation strategy is the modality of choice for delivering RNAi to the liver. And all of them have that. When you look at the differences between RNAis, what you see is imdusiran both has some unique profile characteristics. Number one, we have the lowest dose that is out there. So we basically go with 60 milligrams q8. All the other ones are either 2 or 400 milligram doses. I mentioned we do q8. Everyone does q4 once every month. We do once every two months. And the others is that we have a single trigger siRNA that basically knocks down all viral transcripts. So everything the virus produces, we can knock down with one trigger siRNA.
We look at now the GSK, formerly J&J, or Arrowhead, they had two siRNAs that they needed to do what we can do, as well as you look at the Dicerna/Roche siRNA. They use a siRNA, although single trigger, but they only focus on what is known as the S transcript knockdown. They don't address the X transcript, which is the protein that's involved in transcription of message from cccDNA to form other viral proteins. So there's the differences, generally, sort of from the basic understanding science standpoint.
OK. Great. Thank you, Mike. Then I've got an unfair question, but I'm going to ask it. Because you don't know until you see the data. But so out of the three other immune modulators up there, do you have one you think is going to come out on top, one you like better? Could you see a scenario where both interferon and vaccine are being used in different patients? Or how do you think about that?
Roy, as you said, you caveated appropriately. Obviously, we can't preempt the data. I think we're excited about all of the data that we have upcoming. We're excited about all the programs we put in place. And we'll see what happens as far as what combos need to be put together. But we think we have an appropriate path forward here.
Yeah. OK. I guess if you didn't think it was worth a shot, you wouldn't be testing it. All right. Like I said, unfair. So yeah, maybe let's move to EASL. That's coming up pretty soon here. And you've got a couple end of treatment readouts, correct? Maybe just walk us through what we're going to see at EASL, the two trials, and the data we can expect.
Sure. Karen, why don't you hand it over?
Yeah. Sure. I can take that one. So all of our phase II trials are designed in a similar way, really, to try to look for that optimal immunomodulator piece, as Mike mentioned, to drive patients towards functional cure. So the 2 trials that we'll be sharing at EASL are the top one here, the interferon trial, the 201 trial, end of treatment data, and then also the imdusiran trial in collaboration with Barinthus Biotherapeutics with their VTP-300 therapeutic vaccine. Both of the trials are designed in a similar fashion. The goal is to drive down surface antigen as low as possible with imdusiran initially and then come in with the immunomodulator, either interferon or VTP-300, and really try to find that next level of viral suppression and then hopefully functional cure as we follow these patients out over time.
So for the 201, the interferon trial, we'll be looking at end of treatment data, meaning all subjects will have completed the interferon treatment period. They would have been randomized to either 24 weeks of interferon or 12 weeks of interferon. So everyone having completed that treatment period plus additional follow-up on Nuc therapy alone after that treatment period. And for this trial, as for the 202 trial, these subjects are all assessed for their ability to stop Nuc therapy at the end of the follow-up period. And so as data accumulates with those subjects as well, we'll be sharing that. For the 202 trial, we'll be sharing, again, end of treatment data for the first two groups of that study.
So for that trial, again, we started with imdusiran to drive down surface antigen, then added either the VTP-300 immunotherapeutic regimen or placebo for the first 2 groups in that cohort. So again, we'll be seeing full end of treatment data, so week 48 data for those subjects. And as you recall, we presented that data preliminarily at AASLD with a very small number of subjects at week 48. So now we'll have essentially the full complement of subjects having completed the treatment period. And again, those subjects are assessed for their ability to stop Nuc therapy at the end of the treatment period. And we do have an additional arm we added to that study with low-dose nivolumab. And that data will be coming at the end of the year for preliminary end of treatment data there as well.
OK. Great. And I'm sure you don't want to preempt the EASL data. But it sounds like probably you have some patients stopping Nuc therapy in the trials. You have some, at least?
Absolutely. Absolutely. I think even at AASLD, we shared that we had some initial subjects stopping therapy back in the fall. So yes, we've certainly built upon that. So we do have additional subjects in both cohorts that were able to stop therapy.
OK. Great. And then I guess just remind me what the criteria are for stopping?
For stopping? So sure. So their DNA needs to be suppressed. They need to have an ALT value less than two times the upper limit of normal. They need to be e-antigen negative. And then they need to have surface antigen less than 100 IU/mL.
OK. All right. Maybe let's discuss for a bit the durvalumab trial. Because you mentioned the knocking down, the S antigen. And I think you're going to explore some timing aspects in that. So maybe just walk us through what that trial is designed to do and why durvalumab and not nivolumab like in the other trial?
Yeah. Sure. So again, another trial looking, again, for that optimal immunotherapeutic. For this one in particular, we chose durvalumab. But maybe I'll start with that because we do have a proprietary oral PD-L1 inhibitor, AB101. And so we really wanted to focus on the PD-L1 component of the checkpoint axis. And durvalumab is a commercially available anti-PD-L1 antibody, whereas nivolumab is a PD-1 antibody. And we believe there are some differences in terms of the actual checkpoint inhibitor target that we focus on in hepatitis B. So we selected durvalumab for that reason. The trial itself, you're correct. We are looking at different ways to administer the durvalumab in terms of the optimal timing of it. So right now, we don't know yet whether early checkpoint inhibition versus late checkpoint inhibition may make the difference in helping subjects move towards a functional cure.
So in that study, we'll be looking at two doses of durvalumab but changing the timing of the administration of those doses in the context of ongoing surface antigen reduction with imdusiran. So the goal is really to look for that optimal timing. And based on that data, hopefully, we can translate that to our AB101 oral small molecule program when that's ready to go into combination with imdusiran. So the goal is really to inform that upcoming combination trial with AB101 and imdusiran.
OK. Great. And sorry to kick back. But maybe a little more detail on just what your expectations are for the interferon trial versus a vaccine trial and just how those treatments differ, I guess, and what you expect. And the prior interferon trials have been kind of odd. I think it was Vir showed some confusing results with interferon. Just what are your expectations? And yeah, in that regard.
Yeah. Sure. So again, unfortunately, I can't share the upcoming data. EASL is under embargo for that. But I think the two approaches, again, both looking for that optimal immunomodulator component, they both act differently. There are completely different mechanisms of action. Interferon can act as a direct-acting antiviral as well as providing some immunomodulatory activity. And usually, that activity occurs fairly quickly. A therapeutic vaccine, however, needs to basically take some time to boost the immune system of the host, which then in turn can cause changes in hepatitis B parameters. So in terms of how the data may differ, the interferon effect may be a little quicker, perhaps, than the vaccine effect. That may take a little bit longer.
On the flip side, though, the idea with this particular therapeutic vaccine is that hopefully, that immunostimulatory component will be maintained over time with the activation of the host immune system. So although it may take longer, it may perhaps be a more sustained immunomodulatory effect. But again, we really need to see the data from these studies as they emerge. And certainly, the Barinthus data as well. They're exploring their VTP-300 in their own studies as well, with or without checkpoint inhibitors. So I think they're both important approaches to take. And kind of as you said, we have to wait and see how the data evolve. Did I answer everything?
Maybe I can yeah, that was great, Karen. Thank you. Maybe one additional thing to add with regards to interferon. I think it's important to remember that it's what people know. So although interferon may not be the ultimate goal at the end of the day, physicians have lots of experience with it. Patients understand what they're getting. And that is going to be dependent, of course, upon the level of functional cure rate that one can achieve. So you can see a path forward for an imdusiran/interferon combination depending on how the data evolve. And I think that's important to not lose sight of because people tend to sort of just brush interferon aside. But the fact of the matter is, people have experience with it. They know how to deal with it. They know what the side effects are.
If you're going to dose for like 24 weeks, for example, it's pretty tolerable.
That is one thing you asked about, the differences between the trials. We are focused on shorter treatment durations, 12 or 24 weeks with interferon, whereas the Vir data looked at 44 or 48 weeks of interferon and did see some, as you said, kind of inconsistent results between end of treatment and follow-up. We're hopeful that the way we've designed the trial to lower surface antigen first and then come with a more focused, shorter duration of interferon may make a difference for how subjects respond.
Yeah. OK. So what's your bar for a functional cure rate for the different regimens? Maybe just define functional cure for the audience.
Sure. So I can handle that. So functional cure is undetectable HBV DNA, undetectable surface antigen, with or without detectable antibodies, six months post-cessation of all therapy. So that's the definition of functional cure. And then as far as what level makes the most sense, honestly, Roy, depending on who you speak to, it could be anywhere from 15%-25% being meaningful. We've set sort of our stake in the ground at 20%. We think anything beyond a 20% functional cure is meaningful for patients and physicians.
OK. And that's triple what interferon gives today, correct, I guess?
Yeah. That's about right. Yeah.
OK. Do you guys plan to present individual patient traces at EASL? I like how you guys do the S antigen.
Yes. Wait and see.
What? OK.
We have to wait and see. Yeah.
OK. Well, I'll put in a plug.
We usually try to be very transparent with the data we share. We have done that in the past, presenting individual tracing. Yeah, we're putting the presentation together. Less than a month, you'll know.
Yeah. I'd like to see it. Not that I can make any conclusions. It's still unclear why some patients have high baseline levels and low levels, correct? Is it integrated DNA or any hints?
I think it's dependent on each individual's immune response to the virus, how they handle it. So that's the challenge, is each individual has a unique immune system. And therefore, they will respond differently to the virus and manage the virus uniquely. Because functional cure is essentially immune control over the virus. You're not eradicating the virus. cccDNA still exists in the cell. But you've got now immune control over the virus. So in the cases where you see all these different levels of S antigen or response, it kind of relates, I think, to the immune component of the individual, the immune system of the individual, and how that immune system responds to the virus.
OK. And segueing on that, you guys have shown, I guess, maybe hints of immune reactivation, T cell, with imdusiran. Maybe talk about that a little bit. And what more do you hope to show over the next, I don't know, year or even at EASL or wherever?
Yeah. So I can jump into that one. Sure. As you said, we've shown some preliminary immunologic activity with imdusiran in our 001 trial. We have a very active immunology group under Mike's direction that is working with patient samples from all of our trials. So we collect PBMCs. We collect blood for cytokine analysis. So we're certainly actively involved in looking at how imdusiran interacts with the immune system and in combination with these known immunomodulatory approaches. And I think the importance of T cells and the rest of the immune system beyond just B cells and antibody responses, I think, is pretty widely embraced in the hepatitis B field right now, that you need activation of multiple prongs of the immune system to push patients towards functional cure.
That certainly, I think, is reflected in our choices of what we're testing in terms of immunomodulatory approaches, in terms of trying to target different components of the immune system in a more broader immune activation than just a B cell and an antibody approach.
OK. Great. All right. Maybe move on to AB101. That's your small molecule PD-L1 inhibitor. Maybe just describe a bit more about the mechanism, how that works. Was it discovered in-house? And yeah.
Yeah. So yeah, AB101, we're very excited about this molecule, the target. PD-L1 is highly expressed on hepatocytes in chronic hepatitis B patients. And so if you can reduce the number of PD-L1 receptors on the surface or block them in some way, the theory is that you can get that immune reconstitution happening. So AB101 is a small molecule. It has a very unique mechanism of action relative to an antibody. So antibody basically binds to the receptor and blocks it. And it has a very, very long duration of effect. And so that's one of the concerns in hepatitis B, is that are you juicing up the immune system and all of a sudden, you can't turn it off? And so some of the immune-related adverse events associated with checkpoint blockade with antibodies is a concern in a therapeutic area like hepatitis B.
So our approach was saying, can we use a small molecule strategy that we can control the PK? We can control the dosing. We can control generally PK/PD relationships with a small molecule. And in addition to that, enable a liver-centric or liver-targeting strategy. So you eliminate or very much reduce the peripheral exposure to other organ systems. So that's where AB101 came into play. It is an internally designed and developed molecule. AB101 is very unique in its mechanism of action. So unlike antibodies, which bind and block, this small molecule basically binds to the receptor, causes dimerization of the receptor on the surface of the cell, PD-L1, internalization, and ultimately, degradation of that protein inside the cell. So now you completely eliminate surface PD-L1. Now, related to the safety issue, you can reconstitute that pretty quickly.
So if you wash out drug, which ultimately happens within a couple of days, it's full reconstitution of PD-L1 on the surface of the cell. So we've now shown, at least preclinically, that you can actually reactivate PBMC T cells from chronic hepatitis B patients with this small molecule PD-L1 inhibitor and that you can show effect in an animal model equal to an antibody reducing in a particular animal model, the MC38 mouse tumor model, reducing tumor growth there. So it works. The end result is very similar to an antibody. But I think the safety profile and the mechanism by which it works is very different.
OK. And I know you always get this question. And I wasn't going to ask it. But the mouse tumor, are you planning oncology?
Look, we certainly are aware of that. We're focused on hepatitis B as our target area. And right now, that's the focus of the company and where we want to take this molecule.
OK. Fair enough. Just had to ask. All right. Anyway, it's in a phase Ia sorry, phase Ia/Ib in New Zealand, three-part study. Maybe just describe that study and what the goal was. And the FDA wanted some data or something. So maybe just describe that and why you went to New Zealand.
Yeah. Sure. I can take that. So it's a pretty standard first-in-human trial in terms of antivirals and hepatitis B, although this one is a little bit different. As Mike said, it's not a direct antiviral. It's acting primarily on the immune system. So the study design starts in healthy subjects. There's a single ascending dose portion in healthy subjects, which then moves into a repeat dose portion in healthy subjects. And then there is also a chronic hepatitis B patient portion of the study. All of these are included under the same umbrella protocol. So we can move through each phase of the study relatively seamlessly. In terms of the placement of the study, we did have some interactions with the FDA initially. Decided to pursue a different jurisdiction for this study just based on some of the FDA feedback.
But we feel that we've incorporated the majority of the feedback into this redesigned study. Really, just for timeline considerations, we're looking for alternative jurisdictions to place the study. It is progressing quite well. We're very happy with the results. We shared some preliminary results from the single ascending dose of the study just in the last couple of weeks.
OK. Right. I think you reported receptor occupancy 50%-100% at the 25-mg dose. So this is parts 1 and 2 in healthy volunteers. You have an update coming in the second half. Just what can we expect to hear at that time?
Right. So second, as you said, we reported data from the single dose portion, very well tolerated, the receptor occupancy data, as you stated. We were quite happy with the 25 milligram single dose. We will be reporting data from the multiple dose portions of the study in healthy volunteers in the second half of the year as the study evolves. So that is in progress.
OK. And then the third part's in hepatitis B patients.
Correct.
I think that can start this year. Is that more 20?
It really depends on how the study progresses. We need to make sure we have sufficient safety PK/PD data to feel comfortable with a starting dose in hepatitis B. But assuming that the study moves as it has been, that will start as soon as possible once we have sufficient data.
OK. Thank you. Looks like we're over time, unless there's any burning questions in the audience.