All right, let's get it started. Good afternoon, everyone. Thanks for joining us for Jefferies' London Healthcare Conference. My name is Clara Dahm, one of the biotech analysts here at Jefferies. It's my absolute pleasure to welcome Dr. Lawrence Blatt, CEO of Aligos Therapeutics, to give us a presentation here. Welcome. Thank you. Thank you to the Jefferies team for inviting us to present today. I'm going to walk through our portfolio at Aligos today. While doing that, I'll make some forward-looking statements. We have a large phase II pipeline at Aligos. Our lead program is in hepatitis B. The molecule is called pevifoscorvir. We call it pevi. Previously, you might have heard of ALG-000184. I'll talk a lot about that molecule today. In addition to that, we have a drug, purpose-built beta thyroid agonist, ALG-009, that's completed phase II- A testing. I'll talk a little bit about the results there, as well as some preclinical results we have in obesity. In addition to those molecules, we have a protease inhibitor for coronavirus. It's a pan-coronavirus protease inhibitor. Right now, here in the U.K., it's undergoing a phase II study that's being funded by the MRC. In addition to that, in our preclinical portfolio, we have an antisense oligonucleotide targeting hepatitis B virus, as well as an antisense oligonucleotide targeting hepatitis delta virus. So I'm going to dig deeper into chronic HBV infection. I think most people know that HBV is the largest chronic viral infection in the world that causes morbidity and mortality. 250 million patients living with chronic HBV. In Western Europe, there's 14 million patients. In the United States, it's around 2- 2.5 million patients. In mainland China, 70 million patients living with HBV. Like MASH and other chronic liver disease, HBV causes end-stage liver disease and liver cancer. The primary goal of therapy is to prevent end-stage liver disease and liver cancer. Now, currently on the market, there's two different modalities available. One is the standard of care, which are nucleoside analogs. These drugs work by blocking the copying of the viral genome. HBV is a retrovirus, just like HIV. The nucleoside analogs are reverse transcriptase inhibitors. Unfortunately, while patients are on nucleoside therapy, they still can progress to end-stage liver disease and liver cancer. A recent study in Taiwan demonstrated over a five-year period, patients with nucleoside analog therapy, 4% of them went on to get hepatocellular carcinoma, 5% went on to get end-stage liver disease, and 1% died or had a liver transplant. There is also another drug available, pegylated interferon. It is not widely used in the West. The response rates are low and causes significant toxicity. Now, to put a finer point on the unmet medical need, this study was out of Korea, and it looked at the number of patients achieving full viral suppression on nucleoside analogs or standard of care therapy versus patients that were partially suppressed. Here they defined full suppression as patients going below 12 international units of HBV DNA. What they saw was if you can achieve below 12 or full suppression at one year, you had a protective effect against getting hepatocellular carcinoma over the next five years. Likewise, if you had suppression below 12, even in two years, that was still a protective effect for patients that did not achieve full suppression. Let's think about how HBV causes end-stage liver disease and liver cancer. The first issue, and that was highlighted in the Korean study, is that replication of the virus or the virus making copies of itself causes an inflammatory response as well as tissue damage. This leads to inflammation and a wound healing response. Instead of normal hepatocytes being deposited, you get scarring or fibrosis and, in later stages, cirrhosis of the liver. This can be transformative, causing hepatocellular carcinoma. In the first order, blocking replication completely would lead to less inflammation and less tissue damage, less scarring, less end-stage liver disease and liver cancer. HBV has another way that it can cause end-stage liver disease and liver cancer, and that's through, one, integration of the viral genome into the host chromosome, and two, by establishing an extra chromosome called cccDNA, which acts as a reservoir for the virus. When HBV integrates, it can either activate an oncogene, directly transforming the cell to a cancer cell, or it can cause the production of HBV antigens, including HBsAg, which is a potent immune suppressive agent, and that sets up the cancer environment. Lastly, HBV can integrate into a normal housekeeping gene in the liver and destroy that hepatocyte and cause end-stage liver disease and liver cancer. What you really want to do is block both the replication of the virus as well as the integration of the virus and the establishment and replenishment of cccDNA. Pevifoscorvir belongs to a family of drugs called capsid assembly modulators. Unlike nucleoside analogs, which only block the replication of the virus, capsid assembly modulators, when designed in the right way, can block both the replication of the virus by blocking the encapsulation of the pregenomic RNA, as well as the establishment and replenishment of cccDNA by blocking the transport of that HBV DNA into the nucleus and thereby also blocking the integration. If we go back to the chart that I just spoke about, the capsid assembly modulator has the potential to block all of the disease processes that lead to end-stage liver disease and liver cancer for HBV. Our drug, pevifoscorvir, or pevy, initially started its life in the laboratory of Raymond Schinazi at Emory University. Ray discovered very potent capsid assembly modulators that were picomolar potent. Mostly we talk about nanomolar potent molecules. The molecules we licensed from Dr. Schinazi were picomolar potent. When we began to look at them for pharmacological properties, we noted that the compounds that we got from Ray's lab had poor pharmacological properties. They had rapid metabolism and low oral bioavailability. Our laboratory further modified those compounds to block metabolism, and we increased oral bioavailability from 5% - 80%. That became what was known as 184, or now pevi. In early phase I clinical studies, we showed for HBV DNA reductions starting at 10 mg all the way to 300 mg in 28-day studies, full suppression of HBV DNA. What was more interesting, at the higher doses, we were able to show reduction in HBV surface antigen, which was indicative of the second mechanism blocking the establishment and replenishment of cccDNA. This to date is the first and only capsid assembly modulator that has been in the clinic that has demonstrated effects on cccDNA. I'll show you more of that data as we go through our clinical trials. Following the 28-day study, we set up a long study, a two-year study in HBV patients. We have several cohorts to look at here. The first cohort we did was a combination of pevi plus a nucleoside analog and tenofovir. The reason we did this initially was that the capsid assembly modulators that had been in the clinic prior to pevy had caused drug resistance as monotherapies. In our case, we also did a monotherapy arm. I can tell you in advance, there was no drug resistance that occurred to pevy. In addition to the monotherapy and the combo arm, we had another arm that had nucleoside analog or tenofovir therapy for the first 12 weeks. Those patients were switched to the combination of tenofovir plus pevy. Now we can look at the quantitative HBV DNA reduction results. In the orange line, we can see the tenofovir, the standard of care therapy that gives you something like a 3.8 log reduction in HBV DNA. In contrast to that, the pevy monotherapy arm or the pevy combo arm had a log and a half to log 1.8 greater log reduction in HBV DNA compared to tenofovir. You can see that our drug is much more potent at reducing HBV DNA. Now, it's very interesting to note that when we combine pevy with tenofovir, you do not see any additive effects. That is because pevy is completely blocking the encapsulation of the pregenomic RNA, leaving nothing for the nucleoside analog to do. If you look now at the individual patients in monotherapy, we divide these patients between E positive. These are earlier patients with higher baseline DNA, higher baseline S antigen, higher RNA, and E negative patients, which are more advanced patients that have partial immune response to the virus. These patients typically have lower baseline DNA, lower S antigen, but a higher degree of integration. What we can see very clearly is that pevy rapidly drops HBV DNA in both patient populations. By week 48, 60% of the E positive patients are below 10, which is the limit of quantitation for the assay. By 96 weeks, 100%, including those patients starting very high at a billion copies. This is rarely seen with nucleoside analogs. I'll show you that in the next slide. For the E negative patients who started at a lower baseline, about 5 and a half logs, by week 6, all but one of the pevy patients were below 10 or negative for HBV DNA. One patient took out to week 20. By week 48, all patients treated were below the quantitative limit or negative for HBV DNA. In fact, they not only were below the quantitative limit, the qualitative or limit of detection of the assay was reached in 10 of 11 patients. By the end of the study, week 96, that response was maintained. 100% of patients E negative, 60% E positive. Now, how does that compare to standard of care nucleoside therapy? In the phase III study comparing tenofovir, two forms of pro drug, either TAF or TDF, Gilead reported not only below the cutoff of 29, which at that time was the provable endpoint, but also below detection, which was 10. At week 48 in E negative patients, they had about 20% below 10. In our studies, we have 100% below 10. By two years, they had a third of patients below 10. In our study, 100% of E negative patients. E positive, they did not report anyone below 10. At week 48, we had 60%. At week 96, they had between 9-14% below 10, where we had 100%. You can see there is a big delta between the response rate. Recall the Korean data where going below 12 was protective against liver cancer. In our case, we're going below 10 and even below 4 in some patients. Now, what about antigen reductions? The only way that our drug can cause antigen reductions is by reducing HBV cccDNA. That is by the mechanism that I showed earlier. In this study, we had E positive patients reduce HBV S antigen by about a log and correlated antigen and E antigen by over two logs. The reason that S antigen line is flattening out about week 36 is because what's happening is the S antigen from the cccDNA is being exhausted, and the remaining S antigen comes from the integrated HBV DNA in the chromosome. For the core and E antigen, we're approaching the limit of detection. That is why the line is flattening out towards the end there. Now, what about the safety of this drug? The drug is incredibly safe. We had no patient dose-reduced or come off therapy for any adverse event. We did have some patients have elevation of liver test ALT. That is very commonly associated with reductions in antigens. These were deemed to be transient flares. The ALT went up and down while they remained on therapy. In this study, we just recently reported what happens when you stop therapy. This is really important data. First of all, you cannot just abruptly stop HBV patients because we know from nucleoside analog therapy, if you stop abruptly, patients can have a severe immune response to the reactivation of the virus, and patients can die. Instead of stopping abruptly, we offered the patients nucleoside analog therapy. Nucleoside analogs do not suppress RNA. They do not suppress antigens. If we had not lowered cccDNA, you would have expected full recovery of the antigens and the RNA to baseline. That is, in fact, what did not happen. In this study, in the E negative groups, the RNA only slightly rebounded in two patients. The remaining patients had no rebound. The patients that had slight rebounds were less than half a log of increase in RNA. In addition, the antigen reductions we saw were maintained over eight weeks. Again, the only way this could have happened is if we reduced cccDNA. In the E positive patients, we saw a slight rebound in RNA, so about half a log to a log rebound in RNA, but not to baseline. This also tells us that we reduced cccDNA. The S antigen, E antigen, and correlated antigen did not rebound, indicating that we knocked down cccDNA. This finding was highlighted in the meeting highlights at the AASLD summary slides at the end of the meeting. We were very happy to see that. Currently, we're in a phase II clinical study of pevy. This is a worldwide study being conducted in the U.S., Canada, Europe, and Asia. What we're doing is comparing pevy to TDF, one of the standard care nucleoside analogs. This is a randomized blinded study. They either get pevy plus a placebo for TDF or TDF plus a placebo for pevy, divided into E positive and E negative patients. In this study, we have an interim analysis that will look at quantitative reductions in HBV DNA. That will help us to see if we're on track and determine whether we need to adjust the sample size or perhaps try to convert this into a phase III study. A lot of you have probably heard about drugs, antisense oligos that are focusing on patients for functional cure. That is defined as patients losing S antigen, HBV DNA, and normalizing ALT while they go off therapy. I want to point out that that therapy only works in patients with a baseline S antigen of 3,000 international units or less. That composes or comprises 30% of all HBV patients. 70% of all HBV patients are not even eligible for that therapy. In that 30% of patients, they are getting between a 20%-25% response rate. That's something like 6% of HBV patients will have a functional cure, leaving over 90% of patients needing better chronic suppressive therapy. That's where pevy comes in. We see pevy becoming the standard of care for chronic suppression. Because we can suppress HBV cccDNA and integration, it's the choice molecule to combine with therapies that are aimed at functional cure. pevy would be used in both of those circumstances. We have a number of milestones coming up for the company. We already met the first two. We announced the initiation of our phase II study in August. We've just presented the data that I showed you, especially the off-treatment responses at AASLD. Importantly, early next year, we'll be announcing when we'll do the interim analysis from the phase II. That will give us good confidence around the HBV DNA reductions. In 2027, we'll have the top line readout of the primary endpoint for that study. Looking forward to those milestones. Now, briefly, I want to talk about ALG-009, our beta thyroid agonist for MASH. What we've been able to do is to look at the competing beta thyroid agonists that are out there and to address the pharmacological weaknesses of those molecules. ALG-009 was developed in our lab. It has around clinically 100 times the potency of resmetirom. Its alpha to beta selectivity is 5 to 1. Resmetirom is about 2. It has linear and non-variable PK. Resmetirom has highly variable PK. That's why the approved dose is 80-100, which gives about three times the exposure. We also do not have any CYP liabilities. That's one of the issues we see with resmetirom. Now, I should say resmetirom has done a fantastic job at validating that beta thyroid agonists are active in MASH, both in reduction of fat and reversal of fibrosis. We did a phase II-A study with this molecule and demonstrated by MRI- PDFF, a non-invasive test for fat in the liver, almost a doubling of the fat reduction reported for the equally 12-week phase II study with resmetirom. This drug is currently ready to go into phase II-B and perhaps even to acceleration now that the FDA is relaxing the need for biopsy in this patient population. In addition to that, that was I had the wrong slide. In addition to that data, we have data recently demonstrating that ALG-009 can be given in combination with incretins and activate the metabolic pathways that block the metabolic adaptation. Many of you are aware that when incretin therapies are given, you get rapid weight loss. The body gets into a starvation mode and adapts to where it's no longer burning fat. That is the plateau region in the incretin therapy. This happens either with mono agonist or dual agonist. What a beta thyroid agonist has been shown to do, and we'll be reporting the full report on this at the upcoming Hep-DART meeting where we have an oral presentation, is that when you give ALG-009 in conjunction with either a mono or dual beta thyroid agonist, you can actually increase the weight loss period and block the metabolic adaptation and increase weight loss. That is some pretty exciting data of a new use for beta thyroid agonist. With that, I thank you for your attention. I hope I haven't gone over. There's no clock here. So I don't know how long I've been talking. Thank you. Any questions? We have three minutes for questions. OK. Yeah, thanks. Just maybe previous capsid assembly modulators, I mean, we've seen the data from them, but they kind of rapidly develop resistance. So based on your finding, I think pevy actually shows data against those variants. How does that variant really inform your opinion with that feature? I couldn't hear that. What was the question? Say it one more time. Oh, I'm sorry. You can go ahead. No, so previous capsid assembly modulators, they have as monotherapy, they develop drug reactions. How does your finding that pevy seems to have activity against those variants, how does that inform your opinion? Yeah, yeah. So that's true. In our study, the resistant variants to the other capsid assembly modulators are actually naturally occurring variants that occur in the population of HBV patients. In our study, those variants were present at baseline in some of the patients in our study. We knew that we would be active against those variants because we tested them in vitro prior to going into the clinic. In fact, when we did our study, none of those variants emerged. You might ask why is that the case? The reason is that the binding mode of pevy avoids those amino acids that change in the resistant variants. That is a typical way that you can block drug resistance for antiviral agents. The implications for that are that we can do monotherapy. That is a very important point because if we could not do monotherapy, the endpoint of chronic suppression would not be available to us. The FDA guidelines are very specific that if you want to get approval for chronic suppression, you must do monotherapy. That is actually a big deal for pevy. The previous capsid assembly modulators tried to go forward with chronic suppression but needed nucleoside analog combination therapy to block the drug resistance. Incidentally, the previous capsid assembly modulators had additive effects with nucleoside analog, indicating they were not completely blocking the encapsulation of the pregenomic RNA. In our case, there is no additive effect of the nucleoside analog. Thank you. Yeah, Thank you. Thanks, everybody.