My name is Liisa Bayko. I'm one of the SMID Cap biotech analysts here at Evercore and we're ending our day today at HealthCONx wit This is a company that's working on a lot of different things, including hepatitis B, which I think we're going to get into, and some work in MASH as well. So looking forward to our conversation. I think I have a different name here.
Thank you, Liisa. My name is Hardean Acharya. I'm the Chief Medical Officer of Aligos, and very excited to be here today.
Yeah, great. Thank you. So let's start with a company overview and then we'll sort of dive into each of the different programs.
Sure. So Aligos Therapeutics was founded in 2018 as a company to bring better therapies in liver and viral diseases to patients. And since then, Aligos has built a rich pipeline of three potentially best-in-class therapies, one focused on chronic hepatitis B virus infection, that's our CAM-E, which we think might be superior to standard of care NUCs. The other one developed for treatment of MASH, we call it Aligos 009. And last but not least, a pan-coronavirus inhibitor.
Okay, great, so let's go into your Hepatitis B program. This has been such a tough area for so long, Hepatitis B. I mean, NUCs work to some extent, but sort of getting beyond that is where the challenge has been, so tell us about your approach with CAM-E. Why do you think this can kind of take treatment to the next level? What's the vision?
Of course. So NUCs have been around for over 25 years and no other treatment has been brought to the market since then. NUCs work to some extent because they lower the viral load. And ever since, you know, the famous REVEAL trial, we know that viral load is associated with outcomes for patients. Our CAM-E, in the data that we have to date, substantially lowers the viral load much more so than NUCs. And moreover, it also reduces S-antigen E-antigen core-related antige n in the E-positive patient population. So why does that work and how does it work? Well, it utilizes two mechanisms of action. The first mechanism of action of the virus is to use pre-genomic RNA in conjunction with polymerase and then builds a capsid around it to build a nucleocapsid with core protein.
And NUCs act on inhibiting the reverse transcription from the RNA to the relaxed circular DNA. Now, in the first mechanism of action, what CAMs do is they add a conformational change such that the nucleocapsid is empty. The core protein assembles really fast without a chance, so to speak, to add the important polymerase and the relaxed pre-genomic RNA. But what is even more exciting is that at higher concentrations, we engage the second mechanism of action. And the second mechanism of action, those nucleocapsids that do contain the relaxed circular DNA are inhibited from replenishing the nuclear cccDNA. And we know that the cccDNA in the nucleus is really the reservoir of the virus. That's how the virus stays alive in the liver cell.
So if you do that, you have existing cccDNA. So tell us about kind of what happens with that. Does that sort of expire over time?
Yeah, over time, in some % of cells, the cccDNA, which is like a standalone pseudochromosome in the hepatocyte, will be disappearing if it doesn't get replenished. Not every cccDNA molecule lives forever and hepatocytes are also constantly turned over. And when hepatocytes turn over, often the cccDNA doesn't make it. So there is this mechanism that the virus has figured out to replenish the cccDNA, and that is by infecting not only other hepatocytes, but also sort of infecting itself. And we engage into the second mechanism as well. And we see that by lowering antigens in addition to just the DNA level. And we also know from newer presentations by Hosaka and others that the correlated antigen level actually is a predictor of the risk of hepatocellular carcinoma.
In addition to suppressing the viral load, we can help patients in many other ways to reduce the morbidity and mortality of this disease.
Okay, and so walk us through a little bit what you've seen with your new data.
Sure. At AASLD, we recently showcased our data of the monotherapy cohort in our phase one study. This is a cohort where we dose patients for up to 92 weeks in the E-positive patients and 84 in the E-negative patients with 300 milligrams given daily. The phase one trial actually goes up to 96 weeks, but we made the data cut such that we had these data to present, and we were very pleased to see continued suppression. On the E-negative side, we were fully suppressed by 24 weeks. That means that at 24 weeks, there was a sustained response in all the participants to fall below the limit of quantification, which is 10 international units per milliliter, and that response was sustained also at 48 weeks, and in fact, at 48 weeks, 90% were below the limit of detection, so that's a much higher bar
That is a cutoff of.
This is on top of NUCs?
This is monotherapy.
Monotherapy.
So without NUCs.
Okay. And what would you expect to see with NUCs?
Exactly. So in the E-negatives with NUCs, we would see somewhere between 17% and 21% responders at 48 weeks based on the data that has been published comparing TDF versus TAF, and in our case, it was 100%. On the more difficult to treat E-positive side, those patients responded to about 60% at 48 weeks, and we know from historical data that very few patients, if at all, respond at that timeframe.
Okay. So what do you expect if you kind of look at a combination of NUCs and CAM-E? And when are you going to do that?
Sure. We've actually done that in one part of our phase 1 trial. We've seen that the combination of a nuke, in addition to the CAM-E, doesn't add anything. In fact, the viral suppression with the CAM-E is much superior to that of NUCs. We think that our CAM-E would actually replace NUCs as the backbone of therapy because they would cause greater suppression of the virus and also have a different mechanism of action, which would not only lower the viral suppression, but also engage the cccDNA pool that is the reservoir of the virus.
Okay. If you were to treat for long enough with CAM-E and you talk about diminishing this reservoir, do you think you could ultimately get to some sort of functional cure, and as we talked about, replicating hepatocytes don't always have a copy of the cccDNA.
Sure.
Tell us about how you think about that.
We think about it as a monotherapy as the first line treatment, so basically, everybody who's being treated with NUCs now could potentially benefit from being treated with our CAM-E, and when we talk about functional cure, it certainly makes sense to, number one, lower the viral load as much as possible, and number two, also reduce the cccDNA reservoir. Now, that might be a combination therapy in the future, but we would see our CAM-E to be the backbone of such a combination therapy.
So you don't think alone you could maybe get to that functional?
Perhaps if the patient is being treated for many years with that.
That's what I was thinking.
Of course, we're not that far out yet. Our next step is to do a phase 2 trial where we're actually comparing NUCs directly to our CAM-E in a superiority design, and the primary endpoint is 48-week suppression, so we feel confident that we can show that our CAM-E will be superior to NUCs.
Okay. Interesting. So have you done any modeling? A lot of people do modeling of this kind of these viral decay curves and stuff like that to kind of test the hypothesis of if eventually you could do something.
Very good question. We're doing that too, especially with our statistical experts. And we use the model to inform the design of our phase two study. And we haven't publicly talked about exactly what the phase two will look like. But what we have said is it will be a superiority study where we compare the standard of care to our CAM-E for 48 weeks. And we will do that in E-positive patients and in E-negative patients.
Okay. And what would be the next steps from there?
We are confident that we will be showing superiority in our phase 2 study. Of course, we engage FDA on a periodic basis. We are already in discussions with FDA. The normal route is then to proceed with the phase 3 trial and bring the CAM-E to market. If there are opportunities to accelerate that process, we will certainly take those opportunities.
Okay. I mean, people stay on NUCs for a pretty long period of time. What's the benefit of sort of having greater viral suppression? Is it just less progression to cirrhosis and things along those lines or?
Yeah, exactly. NUCs certainly have helped. They have changed the field. Before NUCs, patients didn't have much to choose from. But despite NUCs, patients, if we look at all comers, still progress to hepatocellular carcinoma, to cirrhosis, to liver failure. In fact, recently at AASLD, we saw a poster that very nicely outlined those rates of progression up to 4% looking at all comers. And this is because even though they're on NUCs, the virus is still replicating. cccDNA is still there. And we know that the more we can suppress the viral replication, the better it is for patients. But the type of suppression that we see and the degree of suppression with our CAM-E is just not achievable with NUCs the way we know them. So we think there's a benefit for all patients.
You talked about 60% of the E-negative patients, right?
E-positive.
E-positive, sorry, that actually go below the level of quantification or detection?
60% at 48 weeks, we reported go below the limit of quantification.
Okay okay.
Now, interestingly, we followed these patients further, and at 84 weeks, it was all the patients.
Okay.
So you can see that if we just follow them long enough.
Okay. That was my next question. I wanted to understand what was going on with these other 40%, but you just sort of eventually caught up. Okay.
Exactly.
Interesting. How many people were in the study?
So we have about 20 in our monotherapy cohort. And that was the data that we reported out on.
And how many E-positive and negative within that?
Roughly 10 to 10.
And so in the CAM-E space then, who are the other players and sort of what are their?
Yeah, we're in a unique position right now to be ahead of other players. Maybe the closest would be Assembly Biosciences. They're at the stage of doing their dose ranging study, which is a 28-week study that was, I think, started with the first patient in June. We're at a point where we will finish our 96-week phase 1 and start our phase 2 this coming year. So we don't really have that much competition at this stage.
Do you see any potential synergy or idea to combine with other new mechanisms? For example, I cover Enanta and they're working on a core inhibitor, for example. Would that be something that would be complementary?
Potentially. I mean, our first goal is really to establish superiority to NUCs and then replace NUCs as the backbone. Now, above and beyond that, in the future, we see this as possibly the backbone in combination with other mechanisms of action. And to investigate that, we're also starting an exploratory study with Xiamen Amoytop Biotech in China where we're combining our compound with pegylated interferon. That study will also start next year. And the goal there is exactly as you said, to start exploring possible combinations.
People hate pegylated interferon though. Do you think that how long would you have to take pegylated interferon for?
This is more a proof of principle study. We don't think that this will be the future of therapy. But it's the only other approved drug that exists as of today that has had any impact on functional cure. For that reason, we and others like to combine it with pegylated interferon.
Okay. Okay. What would be some replacements to pegylated interferon then if this is just proof of concept?
There are multiple agents to choose from. Broadly speaking, people think that maybe some agent that modulates the immune system would be beneficial. Maybe some that could reduce the antigen load when we go into the treatment. There's pretty much consensus also talking to our KOLs that there should be one agent that really suppresses the viral load as much as possible. That's where we're focused at the moment.
Okay. Any specific compounds you think about there?
For suppressing the viral load, it would be.
No, no. I mean for the immune system.
We don't have any specific one in mind. But we're open to different combinations.
Okay. Okay. Let's maybe move on to your MASH program, 009. Tell us about how that molecule is different from Rezdiffra. You know, I cover Madrigal, so obviously always looking at the space very with great interest. And I know you're a bit earlier, but you got some differentiated chemistry. Maybe you could talk about that.
Absolutely. Absolutely. It was designed in-house to have superior pharmacodynamics and pharmacokinetics, so what that means is this compound has up to 50-fold higher potency than Madrigal. It also has improved PK with less variability, and our hypothesis is that with higher potency, less variable PK, a compound could potentially be more efficacious and also have a more favorable side effect profile. In our phase 2a HALO study, we have demonstrated that there was no difference between placebo and active doses in, for instance, diarrhea, one of the key side effects of resmetirom. From an efficacy standpoint, we have seen substantial reductions in fat. We reported on a placebo-adjusted median reduction of 46%. If we look at the publication in Lancet from 2019 with resmetirom, and we tried to put it side to side, it would equate to about 26% placebo-adjusted median reduction.
So you can see that we are more potent, potentially more efficacious, and also have a side effect profile that, as far as we know today, could be superior.
Okay. Tolerability has been pretty good so far, actually. I think some of the side effects are quite early, but I hear you on the fat part. I mean, more efficacy is clearly.
Sure. And mechanistically, it makes sense if a compound is more beta-selective and has less ups and downs in its pharmacokinetics, then you would hypothesize there is a benefit to the patient.
Yeah. Yeah. Okay. So what are the next steps for that program then?
For us, that was an exciting time to get those positive readouts. At this point, we're in active discussions with potential partners. The next step would be a phase 2b study. The goal of a phase 2b study is to confirm the superior safety that we've seen so far and also to evaluate the histological improvement. We've seen in our study that up to 70% of patients had more than 30% relative reduction, which is the threshold that is often used to predict histological improvement. We're confident that we can see that on biopsy studies as well. The biopsy study would be the next one.
Okay. Okay. Great, and let's talk a little bit about your COVID program.
Sure. Our COVID program is designed to be ritonavir-free. And if we look at, for instance, PAXLOVID, ritonavir is needed as a booster because it inhibits cytochrome P450. And without ritonavir, PAXLOVID wouldn't actually be able to work. Now, the downside of this booster is that it lends itself to drug-drug interactions. And especially that patient population is often on different types of drugs, right? Patients at risk for COVID. So this is a great benefit. The other key point is that ritonavir causes also a bunch of side effects like nausea, vomiting, diarrhea, in some cases hepatotoxicity. And so far, our drug has proven to be safe, both in our phase one studies.
We're just now getting ready for a variety of other studies, including a hepatic impairment study, a kidney impairment study, and also starting a phase 2 study that is funded in part by the UK Government.
Okay. And what's your kind of development strategy here? Is this something you seek to partner? Are you going to take it to a certain point?
Yeah. At this point, we're very fortunate that the majority of our funding comes from the NIH and other sources. So that is great for us. But at some point in time, we might be willing to talk about other options of partnership. For us as a company, we are really focusing on our CAM-E because we have the good problem that we have three potentially best-in-class assets. And as a company, we want to focus on one to take it all the way forward. That will be our CAM-E. For the other two, we will look for other options as we move forward.
Okay, so you opened a China office, I noticed.
That's right.
can you kind of give us the purpose of that office and what you're doing there?
Yes, so in line with what I said about focusing on chronic hepatitis B, China, of course, has a lot of patients and a strong need for better drugs. We have an active collaboration with Xiamen Amoytop Biotech, and we're also going to start a phase 2 study, so for us, it makes sense to have an office with boots on the ground in China so that operationally, we're very well positioned to make sure that everything runs smoothly and we can execute on our next milestones.
Okay. And you're confident in IP and all of that with respect to your CAM-E there and the COVID component?
Yeah, we're very confident. In fact, our composition of matter IP doesn't expire until 2040. And we see this as an important differentiator versus other compounds as well.
Okay. Great. In the time that's remaining, maybe tell us about your cash runway, and then let's just talk through sort of upcoming catalysts for 2020.
Sure. Sounds great. We report that we have $75 million as of the third quarter of this year, which we expect will be enough for the end of 2025, and there are a few catalysts coming up next year. Of course, this is really an execution year for us. We'll be executing on the phase two study in chronic hepatitis B. We'll at some point announce the first patient dosed. We'll also start our collaboration study with Amoytop, which is our compound together with pegylated interferon, and we will report the data, the 96-week data from our phase one study, and that's noteworthy because most phase one studies never have two years' data, and whereas some CAM-Es failed in the past because of viral resistance breakthrough, we never saw that, and we have two years' data to prove it.
So we have de-risked the asset more so than is maybe commonly done in a phase 1 trial.
Okay. Well, great. Thank you so much for your time today.
Thank you very much.