Hello everyone, and welcome to the first annual H.C. Wainwright Virtual Liver Disease Conference. My name is Patrick Trucchio. I'm a Senior Healthcare Analyst at H.C. Wainwright. This year, for the first time, we've combined our viral hepatitis and MASH conferences, expanding the scope to also include liver cancer. Together with my colleagues at HCW , we're pleased to be hosting some of the most innovative biotechnology companies in the world, alongside leading key opinion leaders in the areas of hepatitis B virus, HBV, and hepatitis delta virus, HDV treatments, as well as MASH treatments and liver cancer. It's my pleasure to introduce our next management team, Chief Executive Officer Lawrence Blatt from Aligos Therapeutics, a clinical-stage biopharmaceutical company focused on developing best-in-class therapies for liver and viral diseases.
Aligos is advancing its lead program, pevifoscorvir, or pevi, a next-generation capsid assembly modulator for chronic hepatitis B virus, CHB infection, as well as ALG-055009, a thyroid hormone receptor beta agonist for metabolic dysfunction-associated steatohepatitis, or MASH, along with additional discovery programs leveraging its expertise in antiviral and liver-targeted drug development. Maybe just to get started with HBV, can you give us some background on the disease, the unmet need, the treatment landscape, and kind of where you see things.
Yeah, first, Patrick, thank you for giving us the opportunity to speak at your conference. We really appreciate that. HBV is the largest, most prevalent chronic viral infection in the world that causes mortality and morbidity. The number of people living with HBV is about three times that of HIV, a very important disease. Just like MASH, infection with HBV can lead to end-stage liver disease and liver cancer. Perhaps later we'll talk about how that happens. Current standards of care are nucleoside and nucleotide analogs. Those drugs block the replication of the virus, but do not block the long-lived form of the virus, or what's called the cccDNA. That has marked implications for disease progression.
In a recent study conducted in Taiwan, it was noted that over five years of nucleoside analog therapy, 4% of patients still developed hepatocellular carcinoma, 5% suffered liver decompensation, so end-stage liver disease events, and 1% either died or underwent a liver transplant. Nucleoside analogs are beneficial therapies, but they're not arresting the disease entirely. If we can go to the next slide, I'll put a finer point on that. This was a study conducted in Korea, actually with one of the investigators who's participating on our clinical trial. They looked at outcomes in patients treated with nucleoside analogs. What they did is they divided the patients who, after one or two years, had suppression to below 12 international units. I'll just remind you, when the nucleoside analogs were approved, the threshold for the assays was much higher. Around 30 international units was the assay used when TAF was approved.
What they were able to show was that patients who were fully suppressed, those that went below 12 at either one year or two years, had a significantly better outcome than those patients that were partially suppressed. This tells us that deep and rapid suppression of the virus is needed to prevent liver disease and liver cancer.
Right.
Yeah, that's the landscape as we currently know it.
Great. Maybe you can walk us through some of the key differentiating features of pevi compared to first-generation capsid assembly modulators.
Yeah, so this compound, if we can go to the slide that talks about where this compound came from, this compound, the initial IP was licensed from Dr. Ray Schinazi's lab at Emory University. Your investors probably are aware that Ray has been involved in a number of developments in antivirals, including in HCV and HIV. Ray had discovered picomolar potent capsid assembly modulators. These are orders of magnitude more potent than the first-generation molecules. When we received the molecules from Ray's lab, we noted that they had poor pharmacology. They were rapidly metabolized. They had poor oral bioavailability. We further chemically modified the compounds to stabilize them from metabolism and maintain the picomolar potency. We went from 5% bioavailable compound to 80%. That meant that we could get very high concentrations of a super potent capsid assembly modulator in the liver.
Now let's go to the slide on mechanism of action for capsid assembly modulators. Capsid assembly modulators, in theory, have two potential mechanisms of action. The first is to block the encapsulation of pre-genomic RNA. When HBV replicates, the cccDNA drives the production of a full-length RNA. This is RNA corresponding to the entire genome. That gets encapsulated by the core protein into a capsid. Inside that capsid is contained some DNA reverse transcriptase. That reverse transcriptase turns that RNA genome into DNA. What our capsid assembly modulator can do is block the encapsulation of that pre-genomic RNA. There is a second mechanism for capsid assembly modulators that has not been achieved with other drugs, but has been with ours. That affects the establishment and replenishment of cccDNA. Our drug can block the transport of the rcDNA into the nucleus and thereby block the production of cccDNA.
We have now demonstrated, and we did a press release on a recent publication with a long-term cell culture model where we showed direct effects on reducing cccDNA in cell culture. We also have clinical data where we see antigen reductions. The antigen reductions can only be explained by reduction in cccDNA. I want to highlight our presentation at the upcoming AASLD meeting where we're, for the first time, going to present off-treatment effects. Our patients have been treated for 96 weeks. We've stopped the capsid assembly modulator. We're going to present data on what happens to the antigens, RNA, and DNA when you stop treatment with pevifoscorvir or pevi.
Right. Terrific.
We're the only capsid assembly modulator that has been shown to reduce antigens and evoke the secondary mechanism.
Right. That's really helpful. You know, just a follow-up on the 96-week data set, which showed durable viral suppression and multi-antigen reductions. How do you interpret those results in the context of long-term HBV management?
Yeah, if we can go to the slide comparing our data to what happens with tenofovir derivative drugs. When TDF was approved and TAF were approved, the cutoff was 29 international units. The limit of detection for that assay was 10 international units. In e antigen negative patients, those that start with lower HBV DNA, we had 100% of patients below 10. Whereas the TDF and TAF arms of the Gilead phase III, they had about 20%. Remember that graph I showed you of the Korean study where patients that didn't go below 12 had the potential to progress to end-stage liver disease and liver cancer. This has a direct implication on the outcomes for HBV patients. If you looked at two years, which is the other cutoff that we mentioned in the Korean study, only about a third of the patients were below 10.
Those are the patients that would have also done better based on outcomes of the Korean study in e negative patients. E positive patients are more difficult to treat. In the phase III study comparing TDF to TAF, they didn't report any patient going below 10. At week 48, we had 60% in our 96-week study. At week 96, we had 100%. That compares to about 10% of e positive patients treated with traditional [NUKES]. Going below that threshold of 10 and getting there faster has direct impact on outcomes for HBV patients.
Right. You have highlighted the absence of resistance despite baseline variance. I'm wondering how you explain this finding, and how does it inform the opportunity for monotherapy?
Yeah, so we've treated with monotherapy out for 96 weeks. As you alluded to, previous capsid assembly modulators, when given as monotherapy, rapidly developed drug resistance, meaning the drug was no longer effective against the virus. Those studies were done with sequence analysis. It turns out that in the HBV population, there are present resistant variants that, when treated with the previous capsid assembly modulators, would emerge as drug resistant. We had tested these variants before we ever filed our IND, and we knew that pevi was active against these variants. Our drug is active against resistant variants to the previous capsid assembly modulators. That has to do with our potency, as well as the interaction with the core protein and where we interact with the core protein, such that these mutations don't affect our activity.
What was very interesting in our study was, at baseline, a number of our patients had, in fact, these resistant variants present before they were even treated. These are naturally occurring variants. When we treated those patients, those variants were suppressed, and we had no viral breakthrough. In the e negative patients, by week 20, we could detect no more virus, including the resistant variants. This drug affects and is active against the resistant variants to other capsid assembly modulators. You mentioned, how does that affect the endpoint? This is actually quite a big deal. If we can turn to the regulatory guidance, the FDA has, for many years, issued regulatory guidance on how you can get drugs approved in HBV. It turns out that if you have a monotherapy, you can go forward with chronic suppression as the primary endpoint. Nucleoside and nucleotide analogs are monotherapies.
Because the previous capsid assembly modulators had to be given in combination with nucleoside analogs because of drug resistance, this pathway for approval was not open to them. We have had discussions with the FDA, representatives of the EMEA, and the Chinese Regulatory Authority. All have agreed and given us the green light that we can go forward with monotherapy superiority study for chronic suppression. Another important data point, regulatory data point, is, as you know, we've initiated the B-SUPREME Phase II study. That's being conducted in 14 different countries, and every one of those countries has given us regulatory approval to move forward with chronic suppression as the primary endpoint in the study. This seems to be universally accepted and is a pathway only open to drugs that can be given as monotherapy.
It is not a pathway open to drugs, for example, any of the oligonucleotide drugs like ASOs or siRNAs, because they have to be given at least in combination with nucleoside analogs at this time.
Right. That's interesting. I'm wondering, maybe we can talk about the Phase II B-SUPREME trial. What are the design features of this program? What are the most important objectives for HBe anti-negative versus e positive patients?
Before I do that, I want to show you the DNA data from those two groups. It'll make more sense about the study design. If we can go to the slide that shows the individual patients treated, what this is going to show you is what happened. Look at the E antigen negative patients first, that's on the right-hand side. You can see how rapidly they not only go below 10, but actually become target not detected. The dark green boxes are below 10, and the open green triangles are target not detected. We're driving the replication down to where you can't even measure any HBV DNA in this patient population. This is rarely seen with nucleoside/nucleotide analogs. Now, in the e positive patients, because they start so high, by week 48, we can get 60% target below 10.
You can see in later time points, they're starting to become target not detected. Let's turn to the study design. You need that information to understand the study design. This study has now been accepted by 14 different countries and, of course, all the IRBs and investigators. We're going to be looking at e positive and e negative patients. In the e negative patient population, we're going to have pevi plus a placebo for TDF or TDF plus a placebo for pevi. At week 48, for the e negatives, we're going to be looking at the number of patients that were below 10 target not detected. That would be below 4. For the e positive patients, same design with the TDF placebo in the 300 mg pevi arm and the pevi 300 placebo in the TDF arm.
In this case, we're looking for patients just going below 10 and target detected or not detected. Different endpoints. This has been approved by the regulatory agencies. The interesting thing is that we're also going to be measuring antigen reductions in this study. We're also doing paired biopsies to look at quantitative levels of cccDNA, as well as the degree of integration. Integration is a very important event in the HBV lifecycle. Integration occurs randomly and can activate oncogenes and cause liver cancer. We believe our mechanism is blocking integration because we're blocking production of double-stranded linear DNA in the virion. We're also blocking transport of the rc DNA, which can be converted to double-stranded DNA in the nucleus. We think we'll have a marked effect on integration. That's a very important marker. In addition, we hope to show, as we have in cell culture, direct inhibition of HBV cccDNA.
We've already shown in cell culture that we can lower cccDNA, and we have indirect evidence from the Phase I, 96-week study that we're lowering cccDNA. You'll see more of that at AASLD. Here, we're going to directly measure cccDNA. After 48 weeks, patients will all cross over to open-label pevi. That includes the patients that were treated with nucleoside analogs. This is going to be just like patients in the community that are on nucleoside analogs and have not achieved that below 10 international units. We believe they'll rapidly go down to 10, and we'll also see antigen reductions in those patients. A lot is going on in this study, very important study, and universal acceptance by regulatory agencies of this study design.
Right. Interesting. Can you discuss the role of paired biopsies in B-SUPREME and what you hope to demonstrate with cccDNA and integration analyses?
Yeah, so we're going to have biopsies at baseline, biopsies at week 48, and biopsies at week 96. We can actually quantitate the amount of cccDNA baseline versus week 48, and we'll be able to see the difference between what happens on TDF versus what happens on pevi with regard to cccDNA. In addition to that, we're going to do sequencing of the chromosome of these patients and looking for the junctions where HBV DNA meets host DNA. That's a way to quantitate the amount of integrants that form. What we hope to show, and we have in- vitro cell culture evidence, is that we will reduce the amount of integrants over that time course. There's no evidence over 48 weeks that nucleoside analogs can reduce integrants. This would also mark an important step in understanding the mechanism and differentiating our compound from current standard of care.
Right. You've alluded to the AASLD presentation. I'm wondering if you can tell us a little bit more what we might expect from this presentation of the final 96-week and off-treatment data and how those results inform B-SUPREME .
Yeah, we've already reported the full 96 on-treatment data. That's what I presented, 60% in e positives were below 10 and 100% e negatives. What we've never reported is what happens when you stop pevi. We're going to be reporting data on antigens, as well as DNA and RNA. This is going to give us some more insight as to whether or not we've knocked down cccDNA. I can't say any more because I can't preempt the data. That information is contained in the abstract. I'm really looking forward to our oral presentation at AASLD highlighting these data. In addition to that, we have more of the cell culture data that I talked about where we're demonstrating knockdown of cccDNA and prolonged in cell culture. We've already reported this. Prolonged, after you stop therapy in cell culture, prolonged down regulation of antigens and RNA and direct quantitative lowered cccDNA.
That was presented at the Berlin Hepatitis Conference that was held a few months back.
Right. I'm wondering how you're thinking about functional cure combinations and what role you envision for pevi as a backbone alongside some of these other RNA targeting drugs like siRNA and ASOs or other mechanisms.
Yeah, let's focus on ASO because siRNA, I don't believe, has a clear path right now to registration.
Right.
One of the things that happened with this ASO from GSK and also Ausper and now us, we have our own ASO, was serendipitously the molecule and sequence produced by originally Ionis and licensed at GSK was a toll-like receptor agonist in addition to activating the ASO pathway, which is through the RNase H activity. Now there's well-known what moieties can confer that toll-like receptor agonist. You have to think about bepi, which is the bepirovirsen, the ASO from GSK, as two mechanisms. Just like our molecule has dual mechanisms, that one has dual mechanisms. It turns out that the patient population eligible for that therapy are those with 3,000 international units or lower of HBV-S antigen. That only comprises 30% of HBV patients. That means 70% of all HBV patients are not even eligible to try that therapy. In addition, they get about a 20% response rate.
That means 6% of patients overall are able to have a functional cure with ASO. Imagine you're going to give a therapy that has fuller suppression of replication occurring and lowers cccDNA at the same time that you're blocking the s- antigen and other antigen messages through the antisense. At the same time that that antisense is activating the immune system, you can imagine that you're going to have a much better and higher response rate compared to bepi, which is being given in combination with nucleoside analogs, where all you're doing is blocking replication. By having these dual mechanisms, we're creating patient populations that might be more likely to respond to some of these other mechanisms.
As I mentioned, and we'll have data at the AASLD meeting about our ASOs, we have ASOs that we believe are superior to both Ausper and GSK with respect to both the TLR activity as well as the RNase H activity. We're envisioning combining our drug with ASOs. siRNA is a little more difficult to know what to do there. They're still struggling with what regimen is going to give them the same kind of response rate that you get with bepi monotherapy. We'll stay tuned on that. I think some of the newer therapies that are directly cleaving cccDNA in combination with our drug are very interesting because if you can lower the pool of cccDNA, you're going to make it easier for things like the precision molecule or the gene silencing molecules to do their job.
I think there's a vast role for our drug, initially for chronic suppression and then as the backbone of therapy for those patients that can have functional cure.
Right. It's really interesting, all these takeaways and learnings. As this pipeline kind of advances, I guess what I'm wondering, though, is as we think about it commercially and as we think about the opportunity for chronic suppression therapies in HBV, I guess what I'm wondering is just first, how can you frame for us the opportunity? I mean, you showed us that there's a large proportion will remain to be on these chronic suppression therapies. What is the opportunity there? Also, how are you thinking about this opportunity for pevi with your ASO and the combination for generating a functional cure? It seems like it's a very compelling, possibly a very compelling regimen.
Yeah, let's go back to the flowchart. What this flowchart is saying, 30% eligible for functional cure, 20% response, 6% HBV have functional cure. That means 94% of patients are in need of better chronic suppressive therapy.
Right.
That means it's most patients. What we've shown you is that our drug is active in all patients. In fact, at 96- week, we have a 100% response rate. Every patient is below 10 international units of HBV DNA. Clearly, going below 10 has been linked to outcomes in HBV. First, we'll become the standard of care for chronic suppression. What I see happening for functional cure is as more efficient regimens are put together and those that probably would contain pevi, you'll increase the rate of functional cure. Maybe you get it to 50%. You still need 50% of the patients on chronic suppressive therapy. We see our drug as the backbone of therapy. Just like now, every drug targeting functional cure is using a nucleoside analog in combination. All the siRNAs, the ASOs, all are done in a backbone of a nucleoside analog.
They should be switching to a backbone of pevi because, again, if you're reducing cccDNA, if you're more potently inhibiting replication, that has beneficial effects towards functional cure. The positioning, and that goes to the next slide, is we're really everywhere. Standard of care for suppression and act as the backbone of therapy for drugs that will be combined, including our ASO, for reaching functional cure. Our drug is not restricted. We have treated patients with normal ALT, elevated ALT, HBV e positive, HBV e negative. Our drug is to treat all patients. As I mentioned, we affect the entire HBV lifecycle. We have knockdown of DNA, RNA, and all of the antigens. This will be highly differentiated. We've also done work with potential payers and talked to them about our profile.
They're quite excited about the potential for this drug because they're paying for end-stage liver disease and liver transplants in liver cancer. That is a very expensive burden on the health care system. If we can block progression of disease, that's going to have a positive impact on HBV patients' lives, as well as on the cost of their care.
Right. Maybe just as a final question in HBV, if you can outline the key milestones for investors that they should be looking for over the next several months, next six months, year. Yeah.
We've already initiated the B-SUPREME study. We reported that in August of this year. We're going to have the post-treatment readout at AASLD. I would encourage you to look at that. Very exciting data. We have interim analyses planned for the B-SUPREME study that are going to give us some hint as to how the drugs are performing. The first interim analysis occurs at week 12 in the e negative patients. We'll be giving an update as the enrollment continues as to projections of when that would occur. Right now, we're projecting sometime in the first half of 2026 for that to occur. There will be a second interim analysis that will occur in 2026 when the e positives have reached 24 weeks. The top-line data readout occurs in 2027. The study is just underway. Enrollment is going nicely, but I can't project full enrollment yet.
We'll be updating more on the full enrollment. These are the milestones to look out for. Obviously, if the interim analyses are quite positive, that could trigger future studies like acceleration into phase III or even conversion of this study into a larger study.
Right. Terrific. Maybe just a couple of questions on MASH and ALG-055009.
Yeah.
The first question is just maybe you can kind of talk to us about this drug, the mechanism, and how it compares relative to first-generation thyroid beta agonists.
Yeah, so the thyroid beta hormone receptor , there's two isoforms of the thyroid hormone receptor, the alpha receptor and the beta receptor. They only differ by one amino acid, but they have marked biology separation. It turns out that the beta thyroid hormone receptors are present on the liver and also on adipose tissue. I'll mention something about that in a moment. We got into this at the beginning of the formation of our company back in 2018 when MASH was called MASH and most drugs were failing. We noted that the Madrigal compound looked pretty interesting in Phase II. We synthesized the compound, which is now called [resmetirom]. We found a number of pharmacological liabilities of that compound. The first thing is very impotent, very high nanomolar concentrations required to activate the thyroid hormone receptor. It didn't have the best alpha-beta split.
You don't want to activate alpha with your thyroid hormone receptor because you're going to cause cardio disease and other manifestations of hyperthyroidism. In addition to that, resmetirom has very hypervariable PK. If you give 10 subjects the same dose, you can see quite variability in the exposure. It has nonlinear exposure. That's why you see the approved dose of 80 mg- 100 mg. Most drugs, you wouldn't have that little of a gap, but you get a threefold increase exposure when you go from 80 mg- 100 mg of resmetirom. With the hypervariable exposure and the nonlinear exposure, some patients will be overexposed, some patients will be underexposed, and you would see toxicity as well as potential efficacy left behind. We made this molecule in-house with our chemist. It is 50-fold in vitro more potent than resmetirom. In clinical studies, it's 100-fold more potent.
It's more beta selective, and its PK has been optimized. In addition, resmetirom has some liabilities which cause drug-drug interactions, particularly liabilities around the cytochrome P450 system. We don't have those drug-drug interactions. Resmetirom has a number of warnings for co-administration of statins and other drugs that are given to MASH patients. The drug has been through Phase I and II clinical testing. In Phase I, it was well tolerated. It had a nice 20-hour half-life, indicating once-a-day dosing. No safety signals. It had great induction of sex hormone binding globulin, which is a biomarker for beta thyroid, and then corresponding decreases in atherogenic lipids. We then ran a Phase II-A study in MASH patients. We dosed from 0.3 mg to 0.9 mg. Remember the dose of resmetirom, 80 mg- 100 mg, we're below 1 mg.
In our study, we achieved the primary endpoint and saw up to 46% reduction in fat as measured by MRI PDFF. That's approximately double what resmetirom saw in a similar length of study. The drug was well tolerated and did not demonstrate GI toxicity. That's a very important differentiator in addition to the improved efficacy. More recently, and this is data that we will be presenting, and I'll just give you a little bit of preview, but at subsequent meetings, we've now demonstrated that because beta thyroid hormone receptors are present both on the liver and on adipose tissue, this drug has a role in obesity. It turns out that when you combine it with an incretin, either a dual or mono agonist, you prolong the period of weight loss, you block the plateauing effect, and you have a marked increase in weight loss drop in those patients.
That's something we'll be presenting at subsequent meetings. I'll give you more information when we get the acceptance of those abstracts. This idea around using beta thyroid in combination with incretin RAs has also been put forward by a SGLT2 competitor. They've shown some small four-week data that shows the combination of their beta thyroid hormone agonist with semaglutide gives you 50% better weight reductions. This is another new mechanism of action for beta thyroid hormone receptor. In addition to MASH patients, you can also use it in obesity.
Right. Terrific. What is the current status of partnering discussions for ALG-055009? What do you view as the most likely structure or timing of a deal?
Yeah, so we're now currently in discussions with multiple partners. There's a lot of interest in the program right now. I can't really project the timing of the deal because these things go at the pace they go at. We would hope to announce something in the first half of next year on a deal on this. Given we have what we call a high-class problem, we have two potentially best-in-class drugs. We have our pevi and we have 009. We also have a pipeline beyond that. We're just not able to prosecute all these ourselves. We're going to partner out the beta thyroid agonist, probably with a company that has other offerings in cardiometabolic disease, and gain benefit of that partnership through milestones and royalties.
Right. Terrific. That does bring us to the end of our time. Thank you so much to Lawrence and to Aligos for presenting. It's such an incredible pipeline. We're really looking forward to these next milestones. Thank you to everyone for attending our liver conference. Have a great rest of your day and a great rest of your conference.
Thank you.