Yeah. All right. Good afternoon, everyone. Thank you for joining our third day of our Piper Sandler Healthcare Conference. Really excited to be featuring the team from Aligos Therapeutics. We have a lot to cover over the next 25 minutes. Let's get started. Maybe a great place to really start is talking about your hepatitis B program, as you've really shared groundbreaking data at the liver meeting that really caught the attention of many KOLs in this space. I guess the first question here is, on a high level, what were some of the key takeaways that were really groundbreaking in the space of hepatitis B that you presented? So first of all, thank you for inviting us to this fireside chat. We're very excited about the- Mm-hmm. data we presented at AASLD. This is the first time that a capsid assembly modulator- Mm-hmm. - has been shown to demonstrate activity in what's called the second mechanism, and that really involves, blocking the uncoating- Mm-hmm. - of the viral, core or capsid. Mm-hmm. and releasing the relaxed circular DNA- Mm-hmm ... into the nucleus that- Mm-hmm ... replenishes the- Mm-hmm ... cccDNA. Yeah. The reason other earlier molecules hadn't shown effects there is because it requires a concentration- Mm-hmm ... something like 100 times- Mm-hmm ... higher than the primary mechanism, which involves blocking the production of the mature virion. Mm-hmm. There's different markers we can look at. Mm-hmm. So for the primary mechanism, we look at HBV DNA- Mm-hmm. ... and HBV RNA, and we had already shown- Mm-hmm. ... that our drug was a very potent- Mm-hmm. ... DNA and RNA inhibitor. In fact, doses ranging from 10 milligrams-3 milligrams- Mm-hmm. ... 300 milligrams- Mm-hmm. ... we had the same effect- Mm-hmm. ... saturation of the DNA and RNA response. Mm-hmm. What was interesting, though, in our trials, we showed the higher doses- Mm-hmm. ... had effects on the secondary mechanism. Mm-hmm. What we showed at the AASLD meeting- Mm-hmm.. ... was log reductions. Mm-hmm.. ... in HBV surface antigen, log reductions in HBe antigen- Mm-hmm. ... and log reductions in HBV- Mm-hmm. ... core-related antigen. Mm-hmm. That is direct evidence- Mm-hmm. ... that we're interfering with the cccDNA. And this has really been the goal of- Mm-hmm. ... capsid assembly modulators from the beginning- Mm-hmm. ... of when they went into the clinic. Mm-hmm. But we are the first capsid assembly modulator to show these marked log reductions. Mm-hmm. ... in all these HBV markers, so I think people were very excited. Mm-hmm. The other thing that's interesting about the data that we presented is that our drug was equally effective as either a monotherapy- Mm. or in combination Mm-hmm. ... with the nucleoside analog- Mm-hmm. ... entecavir. That's important because there may be a regulatory path- Mm-hmm. ... or there is a regulatory path open for us to get the drug- Mm-hmm. ... approved as monotherapy. Team, at what junction can you engage with the agency and really ask, which would be groundbreaking to have the first to have innovation in the first-line therapy? So, Yeah, so, When are you planning to engage? What, how soon could you come back to us? So we- to discuss next steps? We have the data set now- Mm-hmm. ... to talk to the FDA. Mm-hmm. This is the data set we just presented. And we'll be engaging with the FDA- Mm-hmm. ... over the first half of next year. Mm-hmm. We hope to have feedback- Mm-hmm. ... on that in that timeframe. When we have that feedback- Mm-hmm. ... we'll report it. Okay, and based on what you've seen in the KOL work that you've done, what is the likelihood, given this groundbreaking data, that they could sign off on a- We think it's very high. Yeah. The primary reason we think it's very high is the FDA guidance- Mm-hmm. ... for HBV says that if you can, give your drug as monotherapy- Mm-hmm. ... you can get it approved, with the primary endpoint being chronic suppression of HBV DNA. So we would look for a label that had a primary- Mm-hmm. ... indication of suppression of HBV DNA, with superior claims- Right. ... on antigen reduction. So Nucs, Mm-hmm. ... do not- Yeah. ... improve antigen status. One very important endpoint that we're starting to see is we had, patients- Mm-hmm. ... very close to the lower limit of detection- Mm-hmm. ... of HBe antigen. In fact, one of the patients- Mm-hmm. ... is HBe antigen negative, and HBe antigen negativity is a positive prognostic- Mm-hmm. ... indicator for a better outcome. Mm-hmm. ... in HBV. So patients who are HBe negative- Mm-hmm. ... have a better, or slower- Mm-hmm. ... progression of their disease than patients that- Yeah. ... are HBe positive. There's a lot of clients who have obviously not looked at the regulatory path of the monotherapy arm since there's been no innovation done. Yeah. Could you maybe remind us, like, let's—the first question is, would you be asking for a phase II, a phase IIb study, or could you jump directly into a pivotal? And if you could just maybe remind us what the size of those studies are, and we talked about the endpoint- Yeah. ... and duration on- Yeah, yeah. ... that they would, you need to show. So it's likely the FDA will ask us to do a phase IIb study. Yeah. It would be unlikely that- Yeah.. ... we could go to phase III- Yeah ... at this point. Yeah. Even though we have 48- Yeah. ... week dosing, I think the patient population is probably too small- Mm-hmm. ... at this point. Phase II studies typically are something like 30-plus- Mm-hmm. ... patients per arm. And this would be a monotherapy. Mm-hmm. We would probably compare it- Mm-hmm. ... to standard of care, one of the nucleoside- Mm-hmm. ... or nucleotide analogs. The primary endpoint- Mm-hmm. ... would be, suppression of HBV DNA. We would be looking at secondary endpoints- Mm-hmm. ... on antigen suppression, HBe antigen- Mm-hmm. ... seroconversion, and negativity.... ALT Mm-hmm. normalization, that's a liver test that tells us how much- Mm-hmm. inflammation is occurring in the liver. And then a lot of experimental endpoints- Mm-hmm. In the study, looking at biomarkers. Mm-hmm. - and probably to add a number of patients- Mm-hmm. that would have paired biopsies. Mm-hmm. So that we could directly quantitate- Right. - cccDNA, we could look at, HBV transcripts- Mm-hmm. Importantly, look at the integration events. Mm-hmm. Because we believe that by suppressing- Mm-hmm - viral replication to the level we are, by suppressing cccDNA- Mm-hmm. ... we're going to have less Mm-hmm. - integration occurring, and that's also an important part of the pathogenesis- Mm-hmm. - of HBV, because the integration is- Mm-hmm. - thought to be involved in carcinogenicity of the virus. You know, that's very helpful. Obviously, the sign-off of the agency to move forward to a monotherapy study is a very stock-moving event, and a lot of clients will be very, very eager to look forward to that, and we look forward to all your communication. But there are also additional data catalysts, right, from this. So if you could just maybe talk about, you guys have really done a great job at every liver meeting to have data. Yeah. What is your hope for EASL to present? And, you know, what should investors be looking for as what's the type of data we will get, and what will they be seeing, you know, with the continued suppression of viral load reduction? So we'll have data flow, Mm-hmm. ... on this actually at 3 major meetings. Yeah. this year. Well, first, the APASL meeting- Mm-hmm. ... which is the Asia-Pacific, Society for- Mm-hmm. Study Liver Disease. We'll be doing updates- Mm-hmm. ... to what we did at AASLD. Mm-hmm. So you'll see, similar data- Mm-hmm. ... but some longer duration, Mm-hmm. ... dosing and, more endpoints. I think the exciting data, that we'll present at EASL- Mm-hmm. ... will be the longer-term- Mm-hmm. ... monotherapy data, both in HBe antigen negative- Mm-hmm. ... and HBe antigen positive patients, and so we hope to present that at EASL. Mm-hmm. Obviously, we don't know yet if those have been- Yeah. ... accepted, but generally speaking, we would, we would think that we would get acceptance of that. Then on into the fall, we have AASLD again. Mm-hmm. We would be presenting data close to 96 weeks, right? Mm-hmm. For the combo cohort. So that gives us a long safety- Mm-hmm. ... profile for the compound, more data on the reductions in the antigens- Mm-hmm. ... more data on whether patients lose- Mm-hmm. ... the antigen- Yeah. ... or not. So that's all important data that we'll be seeing. And then maybe another data point that I think we should also discuss is how initially, you know, you had considered partnering this asset, which then led into maybe keeping it in-house- Right. ... and led to a very successful, private placement- Right. ... transaction last month. Could you maybe talk about sort of what the sequence of events were and what happened? Because I think that's another very important data point that- Yeah, so, Like, strengthen. Yeah. At this point, you know, hepatology is actually a small number- Mm-hmm. ... of treating physicians- Mm-hmm. ... compared to, you know, other indications. Yeah. It is something that we can take pretty far- Mm-hmm. ... on our own, and even to approval. Mm-hmm. And you know, my favorite example of that- Mm-hmm. ... is the Vertex- Mm-hmm. ... who did this with HCV- Yeah. ... and launched an HCV drug- Mm-hmm. ... very successfully, HCV protease inhibitor. Mm-hmm. Built their company based on that and then- Mm-hmm. ... acquired another company- Mm-hmm. ... which got them into the cystic fibrosis- Mm-hmm. ... space. Not that we're gonna go into cystic fibrosis- Right. Yeah. ... but it's just, you know, what they could do with that leverage. So, at this point, you know, we would think about, perhaps global partnerships- Mm-hmm. ... regional partnerships. Mm-hmm. But likely, keeping the U.S. Mm-hmm. That's very helpful. Now, maybe the next half, would love to talk about your THR-β that's entering the clinic in Q1 with key data in the fourth quarter. I think, the everyone is very much... As the study is up and running, what is, what's left to do, like, between now and kicking off the study over the next quarter? Yeah. So we're finishing up- Yeah. ... manufacturing- Yeah. ... of the drug. We'll be submitting the- Mm-hmm. ... phase II protocol to the FDA- Mm-hmm. ... soon. There'll obviously be discussions with the FDA- Mm-hmm. ... about the protocol. I think we're really pleased to have, Matt- Yeah. ... working very closely with Stephen Harrison, who has a lot of- Mm-hmm. ... institutional knowledge about clinical trials. Mm-hmm. ... and NASH and things involving biomarkers- Mm-hmm. ... study conduct, inclusion- Mm-hmm. ... exclusion criteria, sites- Mm-hmm. ... that enroll and other sites that don't enroll- Mm-hmm. ... and CROs that manage these sites. So, having Dr. Harrison on board has been tremendous- Yeah. ... for us. And so it's really now very logistical- Mm-hmm. ... implementation- Yeah. ... on our part. No, that's great. Yeah. Matt, maybe for investors who haven't looked at the DAC or, or looked at the design, just briefly capture sort of the design of the study, like how many doses or dose ranges- Yeah. is being tested. So first, I wanna say what the premise- Yeah. ... behind our molecule is. Yeah. You know, like in HBV, we came in later- Mm-hmm. ... with our beta thyroid agonist. Mm-hmm. Our whole premise of our company is, we build better molecules- Mm-hmm. ... with our experienced chemistry team. Mm-hmm. And what we did, just like we did in HBV- Yeah. ... what we did in the beta thyroid space was we looked at the competitor compounds- Mm-hmm. We looked at the pharmacological deficits- Mm-hmm. ... compounds, and I would say they fall into three categories. Mm-hmm. One would be potency. Yeah. In that potency, I also include the alpha/beta- Mm-hmm. Selectivity ratio. Then it would be exposure. Mm-hmm. It's not enough to have a potent compound- Yeah. if you don't get the right exposure. Yeah. The last would be any potential for drug-drug interactions. Mm-hmm. What we did was improve on- Mm-hmm. Every one of those aspects. Yeah. So we have the most potent- Mm-hmm. beta thyroid agonist that's ever been in the clinic. Mm-hmm. You can see that based on our dose range- Mm-hmm. -which is, micromolar, sub-nanomolar- Mm-hmm. Dosing. And then, you could see that in the PK improvement- Mm-hmm. and the fact that we're giving the drug once a day. Mm-hmm. We don't have to give the drug every other day. We don't have to give the drug twice a day. The fact that we've dialed out a lot of the- Mm-hmm. ... CYP inhibition and different liabilities of the other drugs. So that's kind of the premise, that the better potency- Mm-hmm. the better selectivity, and the better PK is gonna Mm-hmm. -lead to greater efficacy. What we're gonna do in the phase II study- Mm-hmm. This study a range of doses. Mm-hmm. There'll be either 3 or 4- Mm-hmm. arms of dosing compared to placebo. Mm-hmm. We're working now with Dr. Harrison and- Mm-hmm. - eventually the FDA- Yeah. -to think about what those doses are gonna be. We have an idea- Yeah. -what they're gonna be. They would, they would be again, in the sort of ranging between around 0.3 milligrams, sorry- Mm-hmm. ... 0.3 micrograms, 300 micrograms, up to almost 1 milligram. Mm-hmm. Yeah. Is there in the study... And it's a 12-week study, right? The change. And these patients are identified based on NITs to have NASH, right? Is there a way, based on the NITs, to quantify and see like whether they would fall into like more the F1, F2 population, or more like- Mm-hmm. ... an F2, F3? Like, will you kind of get a sense for, at the end when you report the data, like, is this a representative population of a typical phase 2b or slash- Well, it definitely will be a representative- Yeah. population based on the inclusion Yeah. -exclusion criteria. We aren't doing, biopsies- Yeah. -in the study, so we won't have- Yeah. ... biopsy-confirmed- Yeah. fibrosis, but we will have FibroScan- Yeah. which gives us some indication of that. Okay. Some of the patients may have historical biopsies. Yeah. The key to remember in this study is it's not, the endpoint is not paired biopsies- Mm-hmm. It's MRI-PDFF. Mm-hmm. So, knowing where they are- Yeah. is somewhat important. Yeah. -because we want a representative population. We also don't want to have- Yeah. Anybody with clinical cirrhosis- Yeah. On the study. Yeah. or advanced disease. Yeah. But it isn't as important as a study that would- Yeah. have paired biopsies. Yeah, no, that's... But there will be some F ones included by the NIT- Yeah. -analysis, right? Yeah, there is. Like, there's no way to, like- Yeah. rule them out based on the No, that's right. Yeah. It'll be a mixture of F1s to F3s. Okay. But there is a requirement for a certain percentage of fat in the liver to- Okay. be on the study. Have you guys disclosed what the MRI-PDFF minimums are to get in? No, we haven't disclosed them. Okay. Look, what we want to do is wait for the FDA approval- Mm-hmm. of the protocol Yeah. and then disclose the protocol. Got it. It'll obviously go up on- Yeah. -clinicaltrials.gov. So I think once the data becomes available, you know, a lot of investors are gonna look for, you know, very much the results and specifically MRI-PDFF. Could you maybe talk about, you know, obviously you know the competitor data, but like, and we also saw that maybe, A, what do you want to see in MRI-PDFF to establish best in class? And then, B, maybe remind investors who weren't at AASLD, the NIT data that was presented for the class of THR-βs, how it really has a high predictability to pathological response. Yeah, so that's a great point. Yeah. So, so not for all classes- Mm-hmm. ... of drugs, but- Mm-hmm. -for beta thyroid agonists, reduction of fat- Mm-hmm. ... as measured by MRI-PDFF- Mm-hmm. -is a good, surrogate predictor- Yeah. ... of improvement in liver histology. And I, and I don't think that that's gonna be translatable- Yeah. to other classes Yeah. of drugs. I think it's just translatable right- Yeah. -to this class of drug. So, and what we saw at AASLD and prior to AASLD is that this is a clearly dose-responsive indication. Mm-hmm. The greater the exposure, the better the potency, the more reduction- Mm-hmm. ... in fat you're seeing. And more reduction in fat- Mm-hmm. ... was clearly correlated with- Mm-hmm. improvement in liver histology. And so people had focused previously on this, 30% reduction in fat. Mm-hmm. Really, it's when you get to 50%, 60%- Mm-hmm. ... 70% reduction in fat- Mm. is when you see these really marked improvements Yeah. in liver histology- Mm-hmm. -NASH resolution and improvement in fibrosis. Mm-hmm. What we hope to see on MRI-PDFF is, on average- Mm-hmm. ... a greater% reduction in fat. Mm, mm. And then looking at these different categories, we'd like to see a greater percentage of patients- Mm, yeah. at the 50% Yeah. ... mark, rather than the 30% mark. Yeah. So when you look at, but in our, a lot of these, and as I recall, with like, for instance, resmetirom, like maybe I think more than 50% of the patients had more than a MRI-PDFF greater than 50. So like, to be best in class across like more than 30 and more than 50, MRI-PDFF changes, like, how much better do you need to be? Is it like, is each incremental 5% difference? So it gets, the slope is very steep. Yeah. So, Matt, maybe you- Yeah. Yeah, I was going to say, that's an important point, is that the slope is very steep. Yeah. When you go from a 30% improvement- Mm-hmm. - to a 40-50- Yeah. - the percent histologic improvement- Mm-hmm. It goes up quite dramatically. Okay. So it's really a continuous variable. Yeah. So the more you defat- Yeah. In every given patient, the more histologic improvement you have. I see. You want as much as you can get. Yeah. It's not like it's a categorical variable- Yeah. - where you hit 50%, and then it kind of flattens out. Yeah. It's very steep, from 50 all the way- Yeah. up to 80-90% reductions. Yeah. Yeah, and, I think the other thing that I wanna focus you on is the pathogenesis- Yeah. - and why the beta-thyroid agonists are important. Yeah. Essentially, we think of a NASH patient, or MASH, I should now say- Mm-hmm. ... patient of having hypothyroidism- Mm-hmm. in the liver, and that's because there's a metabolic defect that actually produces an inactive form of T3. And therefore, there's no- Mm-hmm. hormone there to- Mm-hmm. - to bind to the receptors. What's really happening then in that, hypothyroid liver- Mm-hmm. is not just fat storage, but the conversion of fat- Mm-hmm. to lipotoxic species. Mm-hmm. MRI-PDFF is not- Mm-hmm. - measuring those specifically. Yeah. I think that's really important- Yeah. - to focus in, because this is why we believe that, a liver tropism, a liver targeted drug, like a beta-thyroid agonism- Mm-hmm. - is gonna affect the disease state- Mm-hmm. outcome in NASH very differently than a drug that just reduces fat. Mm-hmm. Yeah. In the liver. No, that's, that's very helpful. Team, obviously, there is next year, you know, we have the first approval for the class, right? For the THR-β class here on March twenty-sixth, upcoming. And like, as you guys are... Like, how are you thinking about, you know, in terms of how should the launch- should the approval and the launch be a translation- like, translation to your stock as well, or should they be not correlated? How do you foresee the success and the class building awareness? Well, certainly- Yeah. - getting the approval in NASH, is- Mm-hmm. de-risking the Yeah. this class of drugs. It's also de-risking NASH- Mm-hmm. per se, right? Yeah. Because we have not seen approval of NASH. Mm-hmm. So, it's good for the field, it's good for patients. Mm-hmm. ... and ultimately good for us. I think, you know, from where we sit- Yeah. Matt and I share this opinion. I think it's highly likely that- Mm-hmm. the FDA is gonna approve Yeah. - the drug. And that's, again, a breakthrough for the field- Yeah. and important for- Mm-hmm. - us, and, and- Yeah. - most important for patients. I'm sure that, you know, there's also a strategic interest on this class, right? As that it's been validated- Right. in NASH, and let's say it leads to also the first approval, you're gonna have quite a bit of optionality in regards to partnership interest on this. Yeah. So the first question is, like, is there enough evidence to actually contemplate partnership before the data, or no, like, ultimately you would see the value to be higher, to weigh to your phase 2, establish further the clinical differentiation and product profile, and then really wanting to transition this product into- Yeah. So, I think classically, you would have better valuation- Mm-hmm. for the program Yeah. - after the MRI-PDFF data. Yeah. Having said that, I've seen a lot of times when there's a first-in-class approval and- Mm-hmm. drugs coming along that have better pharmacological properties, there's exuberance- Yeah. - around the class. And people feeling like: "Oh, if I don't get this now, I'm gonna lose it. Yeah. So there could be some interest- Yeah. look, we have an ongoing dialogue with- Yeah. - potential partners on all- Mm-hmm. - of our programs, which I think is important because, you know, many investors might not know these deals take 6, 12- Yeah. 18 months to do. Mm-hmm. So having that relationship- Mm-hmm. Having that ongoing dialogue is very important. Mm-hmm. You can't just show up one day- Yeah - with your data set. So we Mm-hmm - continue to have those dialogues. And, you know, if there's a partner that- Mm-hmm makes us an offer where we feel is warranted. Mm-hmm the value they're offering- Yeah Is warranted, then we would consider that kind of offer. On the other hand, we're not gonna give this thing away. Yeah. Right. So we would wait for data- Yeah and very fortunate to have just raised- Yeah - $92 million. Yeah. Thankful and grateful to our investors for that. Yeah. and it gives us the firepower- Mm-hmm to really bring both the- Yeah - this drug, as well as the HBV drug- Mm-hmm - to fruition. Should also say, in the minute that we have left- Yeah We also have a coronavirus protease inhibitor. Mm-hmm - that's largely being funded- Mm-hmm - by the NIH. And that's an exciting program- Mm-hmm because it's active against every coronavirus. Mm-hmm. This is highly differentiated- Mm-hmm - from the protease inhibitors that are more specific to SARS-CoV-2. Mm-hmm. I think the importance of this is that it's not if we're gonna have another- Mm-hmm coronavirus jump from animals to humans. Yeah It's when. Yeah. This drug will likely be active against any new variant that comes from animal species. We have a rich pipeline- Yeah At our company, a lot of value creation- Yeah over the next year. Yeah. Probably the most important year- Yeah for the company. Everything we've done has been leading to- Yeah What's gonna happen this year. So quite excited about what's... this year. No, I think as you noted, you have a very, very busy 2024 with- We do. Some very major inflection points. As I said, I sat here last year with many of my companies who were at a low valuation, and within a year on data and achievement has changed substantially. So, like, this, that's why this is the beauty of biotech. So we're really excited for an amazing 2024, and just wanna say thank you on behalf of all of us here at Piper Sandler for being part of our conference, and I can't wait for a great year for you next year. Thank you. I'd like to say thank you to you.