Okay, great. Well, good morning, everyone. Thanks everyone online and in the room for joining us, and welcome to the Cantor Global Healthcare Conference. Really a privilege to be here and grateful to be joined for our first presentation, Fireside Chat of the conference in our first session here by Aligos Therapeutics. Welcome to Lawrence Blatt, President and CEO. Looking forward to the conversation. This is a company that we picked up coverage of recently, very excited about in the HBV space. We will talk about that, the progress the company has been making, and really the outlook for the lead programs. Looking forward to the conversation. Larry, thanks for being here. Would love to open up maybe just with a broader, high-level strategic question about the HBV landscape. Give us your perspective currently on where we are today. There has been some progress and some successes in late stage. This has been a field you have been working in for a long time. Where are we today? What are the unmet needs, and where does Aligos see the sort of current deficiencies in the therapeutic landscape? Yeah. Well, thank you, and thank you for having us at the conference. It is a very exciting time right now in HBV research. We have spent more than a decade now working on new therapeutics. There were a lot of ideas over a decade ago, and now some of those are rising to the top, and some of those are being weeded out. The first thing that we should note is that patients on nucleoside analogues, while they do have benefit, they are still at risk for progressing to end-stage liver disease and hepatocellular carcinoma. So there is an unmet medical need in that the NUCs are not completely suppressing the progression of the disease. The goal of therapy, again, is to block the progression to end-stage liver disease and liver cancer, and there is a number of approaches you can take to doing that. I think a lot of people have talked about the idea of functional cure, and the reason we call it functional cure is because you cannot actually get rid of the virus. What you do is you are shifting the balance in that state when, prior to that, the virus is controlling the immune system, so the virus is an immunosuppressant, to where the immune system controls the virus. There were a number of approaches that people took, and they were all centered around HBV surface antigen. People believe because HBV surface antigen is immunosuppressive, if you lowered HBV surface antigen, you can get immune reconstitution, and patients would cure themselves. That largely turned out not to be true, so that is why we do not see siRNA monotherapy progressing on for FDA and worldwide regulatory approval. But there was one therapy, and is one therapy, that is both a drug that can knock down S- antigen through an antisense oligo mechanism but also is a immune activator. It's a Toll-like receptor 8 activator, and that's bepirovirsen from GSK. There's two other ASOs in development, one by AusperBio and the other by us, and maybe we'll have time to talk about that. The thing about the ASOs is that they only work in a subset of patients. So patients have to have baseline HBV surface antigen at a threshold of 3,000 international units or less, and this comprises something like 30%-40% of HBV patients. And in that population, GSK reported in the phase III study a 19% functional cure rate, meaning 81% of patients did not have a functional cure. So if you think about 20% of 30%, that's 6% of HBV patients, or even if you say it's 40%, it's 8% of HBV patients can ultimately get a functional cure. So the question is: What can you do to help the greater than 90% of patients that are left out there? And that's where Aligos comes in. And we have really a two-pronged strategy. One is through a capsid assembly modulator mechanism that's very new, very novel, that works on components of the HBV life cycle that nucleoside analogues don't work on. And for that matter, neither do ASOs or siRNAs. And we believe that those components will lead to better disease outcomes in those patients. I'll pause there. Sure. That was a lot to cover. No, it's a great overview. And as you mentioned, we'll talk about your CAM-E, and we'll maybe start there, but would love to cover, obviously, the ASO work you've been doing. Yeah. There's been some progress there recently too into the clinic. Yeah. We'll cover all that, but maybe we start with the CAM-E. Yeah. Just at a high level, then we'll dig into the weeds on some of the data you've already presented, but what are the specific features of this molecule, pevy for short,- Yeah. that make it potentially superior to the legacy NUCs? Yeah. First, let's talk about what a NUC does and what a CAM-E does. NUCs are chain-terminating analogues. When HBV is replicating, it's actually a retrovirus, just like HIV, and nucleoside analogues are added to the elongating DNA chain from the RNA substrate. It stops the reaction, so you get a short genome, and the virus doesn't replicate. That doesn't really affect other components of the HBV life cycle. HBV is a very complicated virus. It deposits into the nucleus of host cells, something called the cccDNA, which is basically a chromosome. So it deposits its own chromosome into the nucleus. If that wasn't enough, it also integrates a portion of its genome into the genome of the hepatocyte. Those are very important steps that need to be reconciled. What is interesting about pevy is pevy can block three of those steps. Pevy blocks replication very efficiently. The way pevy works is it's a capsid assembly modulator. Notice I didn't say inhibitor. It modulates the assembly of the HBV capsid, which is the protein shell that goes around the virus. That protein shell is made up of the HBV core protein. Pevy binds to that core protein, changes the conformation slightly, and forms empty capsids, so it doesn't have the pregenomic RNA. If you don't have pregenomic RNA, you can't make DNA, so therefore you block replication. What happens if pevy isn't 100% efficient and some of those viruses are actually made? Pevy actually blocks the second step, and the second step is that once the DNA is contained inside the capsid, it can recirculate, uncoat, and travel back into the nucleus to form new cccDNA or new integrants. Pevy can actually block the transport or uncoating of that capsid so that DNA is sort of stuck in the cytoplasm. By blocking that second step, pevy can lower cccDNA, and that's very important because cccDNA is the reservoir of the virus. As long as you have cccDNA, you will have HBV replication. Pevy also blocks the transport of what we call double-stranded linear DNA that's made in about 10% of virions, and that's the form of HBV DNA that integrates. Pevy works on replication, which we know is involved in disease pathogenesis. Pevy works on lowering the reservoir, which obviously is important for disease pathogenesis, and pevy blocks the form of the virus that integrates, which is very important because we know that integration can cause directly HCC. Integration can transform a cell into a cancer cell. One of the things empirically that you showed in phase I that I think is interesting now in light of the phase III ASO data was the- Yeah. reduction in S- antigen. Yeah. Can you help us understand the mechanism behind that and the implications obviously- Yeah. in a world where ASOs maybe are more effective in low S- antigen? Yeah. patients? Yeah. As I mentioned, pevy can block the transport of what's called rc or relaxed circular DNA into the nucleus. cccDNA has a half-life. It's not there forever, so it has to replenish. If you block the transport of the rcDNA into the nucleus, eventually cccDNA is going to go down. As cccDNA goes down, there's less mRNA for S- antigen made, and therefore S- antigen goes down. In our clinical studies, we've actually demonstrated prolonged reduction in S-antigen 24 - 48 weeks after we've stopped pevy therapy, and the only explanation for that to occur is that we've knocked down cccDNA. Got it. We're fundamentally changing the disease burden in HBV. I think it's also interesting that's the goal of many experimental gene therapies is to knock down cccDNA, and we're doing it with an oral pill. We're pretty excited about that kind of data. I want to circle back to a question you asked just before we got into this, and that is why is this different than the legacy CAMs? As you're aware, there were many CAMs in the clinic prior to pevy. I think there's a total of six actually. None of those previous CAMs could go forward for FDA approval, and there's a number of reasons for that. The first was that when they were given as monotherapy, they evoked drug resistance. If you have drug resistance to your CAM, you can potentially make the patient resistant to any CAM. You have to be really careful about that. People learned early on that those CAMs needed to be given with nucleoside analogues. The second thing is those CAMs did not evoke that secondary mechanism, so there was no knockdown of S- antigen the way that we see it in our clinical studies. What did we do that allowed us to, one, overcome drug resistance and two, overcome the need or the ability to evoke that second mechanism? We did two things. One is the drug is extremely potent. The EC50 of our compound is picomolar, as opposed to hundreds of nanomolars for some of the other compounds that were in the clinic. This is important because the concentration of drug required to evoke that second mechanism is 10 to 100 fold higher than the first mechanism. It takes more drug to block the transport of the rcDNA than it does to block replication. If you start out at 100 nanomolar against the primary mechanism, you are going to need mid micromolar levels to get to the secondary mechanism, and no one could achieve those levels in the liver. By having a more potent drug, we lowered the bar for how much we needed to get in the liver. The second thing is that CAMs generally had low oral bioavailability, something like 5%-20%, and that was true of our initial molecules. What we did was we created a phosphate prodrug. That is why we are called pevifoscorvir. That phosphate prodrug actually drives 80% of the drug in when you take it orally, and there is about a 20:1, 30:1 liver to plasma ratio. We have this super potent CAM, high oral bioavailability, and we reach concentrations in the liver that are in the excess of the EC99.9 of that second mechanism. That is how we were able to achieve what we were able to do. This elegant mechanism, this has culminated obviously in you running a pretty robust test here in phase II, which is- Yeah. ongoing. It is a superiority study versus- Yeah. NUCs. You are going to get a clear answer of whether or not- Yeah. this therapeutic hypothesis translates. You have two different cohorts, the e- antigen positive and the e- antigen negative. Right. What are you hoping and expecting to see, I guess, just in those two different cohorts in this study? Yeah. So again, it is a phase II study. There is a number of things that we would like to see in the study. The first is that we would like to see greater statistically significant suppression of HBV DNA down to the FDA stated regulatory approval endpoint, which is below 10 international units. That threshold has a couple of important cutoffs or points. One is there is a recent study that demonstrated that patients who were fully suppressed on nucleoside analog, so those that went, in the case of that study below 12 international units, had a protective effect against getting liver cancer over five years versus patients that were above that threshold. So that is an important outcome-driven threshold. We would hope to show that we have a superior rate of patients reaching that endpoint. But there is another very important point about our study. We should think about the DNA endpoint, because that's the regulatory approval primary endpoint. But let's take a step back and ask the question, why is that the regulatory approval primary endpoint? That's because when nucleoside analogues were approved, that's the only thing you could measure. Nucleoside analogues don't lower antigens. They don't lower RNA, so you can't measure them and approve the drug based on them. But that doesn't mean that those markers aren't important for the disease pathogenesis of HBV. We know that baseline S- antigen levels are associated with worse outcomes. So the higher your S- antigen level, the worse you do on outcomes. The higher your HBV RNA, the worse you do on outcomes. So pevy will differentiate itself, one on DNA, but also on the fact that it's reducing antigens and reducing RNA. Now, if you think about a world where ASOs are driving functional cure, and of course, we have our own ASO. It's interesting to note that on our clinical study that we reported the phase I-B data, no patient on the study entered into the study with an S- antigen level that would allow them to have participated in an ASO study. In our HBV e- antigen positive cohort, 40% of patients at the end of the study actually had S- antigen below 3,000 international units and then would have qualified for that. So that's a way to drive more patients into ASO therapy. Indeed. You've completed the interim analysis. You didn't reach futility criteria, which was terrific. You're moving- Yeah. towards the final analysis in the e negative cohort. You ultimately over-enrolled the e positive cohort- Yeah. as well. Can you just refresh us on what you learned from those interim updates? Yeah. On those analysis and how the trial's now set up for success in the final read? Yeah. It's important to note that when nucleoside analogues were approved, the HBV DNA assay, the latest approval came with an assay that went down to 29 international units. Right. That's above that 12 threshold that I talked about earlier. When we designed the study, we didn't have a database to compare the control group to. We looked at the Gilead phase III data comparing TAF to TDF in that 29 assay. It also qualitatively went down to 10. We had some idea, but not really a good idea quantitatively. We purposely built in an interim analysis to get an understanding of what the TDF group was going to do. There's an inherent problem in that, and that is that from the phase I data, the interim analysis was done at week 12, and from our phase I data, we know that on pevy, actually all but one patient was already negative by week 12. But we know from historical data on TDF, essentially no one would've been negative by week 12. The interim analysis had to project out how many patients on TDF would be negative by week 48, and to do that, you have to do a very complicated linear regression, and sort of guesstimate, I would call it, how many patients might be negative, and that analysis is inherently fraught with error. Now let's walk through the outcomes of what could have happened in the interim analysis. As you mentioned, we didn't reach futility, and that would've meant that NUCs were performing better than pevy. Another subtle point though is that part of the interim analysis pre-specified endpoints was that if NUCs were performing identical to pevy or near identical, we would not add patients because that would mean that you couldn't add enough patients to make a difference. It's only if there was a difference between pevy and NUCs in favor of pevy, would you have added patients? And that's, in fact, what they did. And so we added, actually, we went at that time, I think we were at 72 patients. We went up to 100 patients. We've actually over-enrolled that cohort to, I believe it's 114. Then we said, okay, look, the e-positive patients, they're going to be harder to estimate because they start four logs higher than e-negatives. You're going to see almost no knockdown in the NUC group, so it's going to be even harder. That interim was, I think, a 24-week cohort. 24 weeks, but still. Yeah. It was going to be another difficult linear regression. We had a conversation with the DSMB, and we said, "Look, what if we over-enrolled this study, and that way we'll build the power in?" They said, "That's fine. You can do that." We thought we were going to go up to 130. We actually went to 139. The reason we over-enrolled the over-enrollment is that once a patient has qualified in screening, you can't say, "No, you can't be on the trial." You get a little bit more patients. We think the study is adequately powered to see differences. Again, this is the first time anyone has run TDF with this 10 international unit assay in a controlled clinical study. This is going to be interesting data. The data from this will tell us how to power the phase III. Indeed. In addition to the assays, do you think your phase I population here is a good benchmark and similar demographic to what ultimately you enrolled in phase II? Because you have obviously an impressive phase I data. Yeah. We obviously don't know what happened in the pevy group in the interim analysis, but do you think it would be sort of a similar effect that you'd expect basically? It should, yeah. Okay. Yeah. The patient population is, I would say pretty similar, actually. Okay. The big thing that we had to do in the phase II enrollment was stratification by baseline HBV DNA levels. That is because if you were to skew one of the groups, say, with significantly higher DNA compared to the other group, you could skew the data. For example, if the NUC group had more high viral load patients than the pevy group, and pevy reached statistical significance, the criticism would have been, "Oh, of course it did. You had whatever, a log, half log less DNA." We stratified to make sure that there was equally balanced baseline HBV DNA between the groups. Other than that, this is a typical, and I would say much, much less restrictive population than the ASO populations that are being studied. Yeah. No question there. Just to put a bullet on the HBV assays because they're so critical here, and they've changed over the years. Yeah. Is what you're doing in the phase II, the assay, the limit of detection that you have, is that ultimately going to be what carries forward into phase III? Yes. Globally, are regulators aligned these days- Yes. on what they're looking for? Yes. Globally, the guidelines are the same everywhere. You have to use the most sensitive assay available at the time that you're running the clinical study. Okay. Let's devote, I guess, the last bit of time we have, I'd love to ask you about the ASO just because- Sure. there's been the progress that you mentioned. Yeah. From GSK's molecule in phase III. There's an incremental sort of increase in the functional cure rate, but of course, in only a subpopulation. When you start slicing and dicing the numbers,- Yeah. it leaves, as you mentioned, 90% or maybe more of the HBV population potentially unaddressed or inadequately addressed. Talk about your ASO-675 and- Yeah. maybe just off the top, remind us where that is currently because there's been some fast progress, I think- Yeah. in China with some clinical development. Where is that at today and what? Well, let's start at the beginning. Where did it come from? Yeah. As our name implies, Aligos, we have an oligonucleotide capability. We changed the O to an A so that we can be listed first at conferences like this. We have an oligonucleotide capability. We were approached by Amoytop, who are the leading interferon purveyors in China. They are selling pegylated interferon for HBV about three years ago. They said, "We want to form a partnership with you where you guys discover and help us to develop an ASO for HBV." We entered into a sponsored research agreement with them. That agreement has some pretty interesting conditions. One of the conditions is, they have greater China, we have rest of the world. But it has a co-development but not co-pay. That is an interesting thing. Part of the price, if you will, that they paid was that any data they generate in China is available to us for worldwide regulatory authorities filing outside of that territory. What is interesting is we did all the early development of pevy in China anyway. Now we are doing the early development of 675 in China. It is really not different than if we were to have done it ourselves. Likewise, any data we generate, they can use in the Chinese region. What happened was GSK data had been developing as we were discovering this molecule, and it was very clear that you needed to have two properties of the ASO. One was the classic ASO mechanism whereby you knock down messenger RNA. We actually optimized this compound to have greater potency in the ASO arena. So in head-to-head comparisons preclinically, we have a log or more greater knockdown of the HBV S- antigen, including in mouse models of HBV. But at the same time, you want it to modulate Toll-like receptor 8. What you don't want to do, though, is overdo that. Because if you look at the history of TLR8 agonists, there have been a number of small molecules in the clinic, and too much of that is not a good thing. So we very purposely designed in, we actually discovered what moieties modulate TLR8, and it's in the primary sequence of the ASO. These are non-canonical bases that are incorporated into the oligo? Yeah. Okay. And that's independent of the knockdown. You have to sort of tune each step. You got to do these, yeah. There might be trade-offs, and you have to sort of co-opt. Exactly. Right. You might optimize this and make that worse. Yeah. It was a lot of iterations to do that. But what our goal was to not go crazy on that. Yeah. We wanted that to be very similar to the GSK molecule. I see. That's what we achieved. 675 has preclinically greater ASO capability, but similar TLR capability. That compound went through GLP tox last year, and entered the clinic recently. I think you saw our announcement. First it'll be in volunteers, and then they'll quickly move into HBV patients. We're making our way through the volunteers now. We're working very closely with Amoytop, so we have a joint development committee. We're meeting with them weekly, so it's not just throw it over the fence kind of stuff. We're working hand-in-hand with them on manufacturing, and every aspect of the program. They've been a great partner, I have to say. They move really fast. Just to show you why it's great to have a partner in China, they were able to get what's called Green Channel for this, and that's a regulatory pathway that gets you faster through the IND process. Instead of waiting two or three months, they waited less than 30 days for that approval. They're working closely with the Chinese regulatory authority. Just likewise, they're our partner for pevy as well. What does this mean? It means that we're very well set up for combination therapy in the future. Yes. What we believe is that no one has combined pevy with an antisense oligonucleotide. We have done it in vitro and in vivo in mouse models, and we have shown it is synergistic in its effect. If you are lowering cccDNA and you are lowering S- antigen by a different mechanism, non-ASO mechanism, we think that is going to be additive to synergistic, and we think we are going to drive more patients into functional cure with that combination. We will be exploring, along with Amoytop, those combinations after we get through the phase I study and define the dose of the 675. It is really a two-pronged approach for us. It is chronic suppression by blocking replication, by blocking integration, by blocking cccDNA establishment and replenishment. For qualified patients, including those on pevy t hat lower their S- antigen to a point, they go on the combination of pevy plus our ASO. Yeah. Now the thing is, if you are on the combination of pevy plus ASO, if you meet the criteria for functional cure, you will stop. If you do not, then you will stop the ASO but continue on pevy. This is really a strategy to take over the dominant player in the HBV market. It sounds like the strategy with ASO is to enroll sort of the subset of patients with a particular S- antigen threshold. That is not something that you would look to sort of shift the paradigm on right away, but what you could do through the combo is open up, expand that population, right? Yeah, either expand it by lowering S- antigen with pevy. Yeah. Or find out that with pevy you don't really need to have that reduction. Yeah. Okay. Very interesting. Yeah. So we'll look forward to that. Just on, lastly here in the last minute, the timelines and sort of what type of data, I guess, once you're in HBV patients from that phase I study would be emerging that we would look for just knockdown. Yeah, knockdown of S- antigen. Compared to the GSK. You're going to be looking for similar knockdown. Yeah. It's well-documented what you need to see. These are patients that should get a fairly high rate of S- antigen below detectability, certainly when you get into the longer term phase II studies. The phase I studies only being one month of therapy. There you'd be looking for log reductions in HBV S. Very good. We'll be excited to follow the progress of the ASO and pevy, obviously as the phase II is prosecuted here and some exciting data catalysts coming up ahead for the company. I appreciate you being here, Larry. Thanks so much for the conversation. Thank you so much. Thanks, Aligos, for being at our conference this year. Yeah. Thanks everyone in the room and online for listening. Thank you.