Good morning, everyone, and welcome to the 27th Annual H.C. Wainwright Global Investment Conference, taking place from September 8th - September 10th. My name is Patrick Trucchio. I'm a Senior Healthcare Analyst at H.C. Wainwright. It's my pleasure to introduce our next speaker, Lawrence Blatt, CEO of Aligos Therapeutics. Aligos is a clinical-stage biotechnology company founded with the mission of improving patient outcomes by developing best-in-class therapies for liver and viral diseases. The company applies a scientific-driven approach and deep R&D expertise to advance a purpose-built pipeline addressing areas of high unmet need, including chronic hepatitis B virus infection and metabolic dysfunction-associated steatohepatitis or M ASH. With that, let's begin with a discussion of ALG-000184. This is Aligos's capsid assembly modulator for HBV. Maybe we could start there.
Perhaps you can talk us through or walk us through this drug and how it became part of the pipeline, as well as its mechanism of action and why you see it as potentially transformative in HBV.
Patrick, first I want to say thank you for inviting us to participate in the conference. It's a pleasure to be talking with you this morning. If we could move to the slide talking about how ALG-000184 was discovered, I can tell you that initially the IP around ALG-000184 came from Professor Raymond Schinazi at Emory University. You may remember Ray's name. Throughout the years, he's invented a number of drugs in the viral space, including FTC for HIV, as well as his company, Pharmasset, invented what became sofosbuvir for HCV. The class of capsid assembly modulator drugs has been known for over two decades. It was actually accidentally discovered at Bayer Labs when they were looking for better nucleoside and nucleotide analogs.
They discovered a class of molecules that bound to the HBV core protein and prevented the HBV pregenomic RNA from being encapsulated by the capsid or the multimeric form of the core protein. There had been a number of capsid assembly modulators that went into the clinic prior to Dr. Schinazi starting his work. He noted that they suffered from a couple of defects. One was that they weren't very potent. Ray's group at Emory developed picomolar potency, so 10 to the minus ninth potency capsid assembly modulators, which were orders of magnitude more potent than anything that had been in the clinic. When we licensed these drugs, we received them from Emory University, and we began to characterize these compounds. We found that although they were very potent, they needed improvement in pharmacological properties. They had some metabolic liabilities.
Most importantly, the pharmacokinetics or the exposure of the drug was not very good. Working with our chemists in the house at Aligos, we modified the compounds that we received from Ray's group and were able to block that metabolic liability and also greatly enhance the pharmacokinetic exposure. We went from drugs from Dr. Schinazi's group that had about 5% oral bioavailability to ALG-000184, which has 80% oral bioavailability. We were able to produce a compound that has both the attribute of being extremely potent but very well absorbed and exposes the liver to very high concentrations of the drug. We then moved this compound into the clinic, and we started out with short-term dosing, 28-day studies. We learned some very interesting things. We dosed the drug from starting at 10 mg and going all the way up to 300 mg.
For the primary readout of reduction in HBV DNA, 10 mg was as potent as 300 mg. What was very interesting is we started to see reductions in HBV surface antigen, or S antigen, in just a 28-day study at the 100 mg and 300 mg doses. That told us that we were evoking what's called the secondary mechanism of capsid assembly modulators, which is a mechanism that blocks the establishment and replenishment of ccc DNA, which you may know is the long-lived viral reservoir deposited into the host nucleus of cells replicating HBV. This was an important breakthrough because one of the promises of CAM s early on was that it could reduce ccc DNA . Given the potency and exposure of the first-generation drugs, they were unable to come up with that finding.
What you'll see as we progress in this discussion is that our drug, in fact, is evoking that second mechanism. We have log reductions in viral antigens, including HBs antigen, HBVe antigen, and HBV core-related antigen, in addition to very profound knockdown of HBV DNA.
That's a really helpful overview. We have a number of follow-up questions from that. I guess just first on the 96-week phase I-B data in terms of durability and resistance. How might this inform the path forward? What's your take on this data?
Yeah, so let's talk about resistance, which has been a problem with the earlier developed capsid assembly modulators. If we can go to slide Jordan on [JNJ 379], just to show what that looks like. It's actually the slide much earlier in the presentation. Basically, what you have is you have initial knockdown of HBV DNA, but then you see these patients where the virus is coming up. That's a hallmark of drug resistance. That really limited the utility of the early capsid assembly modulators because they couldn't be given as monotherapy. They had to be given in combination therapy. When we were developing ALG-000184, we tested in vitro the known resistant variants. It turns out that these resistant variants are naturally occurring, so they're contained within populations of HBV patients. When 379, for example, or the early assembly drug evolved resistance, it wasn't that these were new mutations.
It was the selection of these populations that made up the quasi-species of virus infecting those patients. Now let's go to our slide on resistance. In the 96-week study, we didn't see any breakthrough, and we went ahead and sequenced the virus. It turns out that at baseline, a number of patients had these resistant variants present in their viral quasi-species. In spite of that, following treatment of ALG-000184, the virus was contained, and these resistant variants were shown not to be resistant to ALG-000184. We talk about 1075. ALG-000184 contains a prodrug. 1075 is the parent drug that is released when ALG-000184 is given. We did not see drug resistance emerge, and we were active against known variants that were resistant to the previous capsid assembly modulators.
That has really opened the door for monotherapy of our drug, which means that we can go forward with a primary endpoint of HBV DNA reductions.
Right. That's really helpful. I'm wondering if you can elaborate more on this dual mechanism of action, specifically the blocking of pgRNA encapsulation and ccc DNA replenishment, and what better clinically.
OK, let's first, Jordan, go to the slide that has the livers on it that talks about pathogenesis of HBV. I'm going to address your question. I want to talk about why those are important endpoints to cover in the viral lifecycle. When HBV infects a liver, its replication or copying of the virus causes an inflammation of the liver. That inflammation leads to tissue damage, which evokes a wound healing response. Instead of depositing normal hepatocytes, the liver is then covered with scar tissue, initially characterized as fibrotic tissue. Later, as the fibrosis advances and the liver is covered in scar nodules, it is characterized as cirrhotic. At that point, the patient can decompensate, meaning the liver cannot function as needed, and the patient is in end-stage liver disease. This pathway causing tissue damage can also transform normal hepatocytes into hepatocellular carcinoma cells.
That's one way that HBV can cause cancer. The first thing that you want to do is you want to block replication of the virus. In addition to that, there's an independent pathway whereby HBV can cause liver cancer. HBV can make, in addition to the relaxed circular DNA, linear double-stranded DNA. That linear double-stranded DNA integrates into the host chromosome randomly, and that random integration can activate oncogenes. Independent of replication, HBV can cause liver cancer. Let's go to our slides looking at mechanism of action. First, we'll talk about what nucleoside analogs do. Nucleoside analogs are reverse transcriptase inhibitors. HBV is a retrovirus. Inside the capsid, it has packaged pregenomic RNA, which is a full-length copy of the genome in RNA form. Inside the capsid, that RNA is then reverse transcribed to form DNA. Nucleoside analogs can block that reverse transcription reaction and inhibit the production of DNA.
At the same time, once that DNA is made, it can recirculate back into the nucleus via the capsid chaperoning that rcDNA into the nucleus to form ccc DNA . Once that rcD NA is in the nucleus, the host polymerases can also make that linear double-stranded DNA. There are two ways that linear double-stranded DNA is made. One is inside the virion, the other is inside the nucleus. Nucleoside analogs only block the conversion of the RNA to DNA. They do have some effects on outcomes, but not completely suppressing the formation of fibrosis, cirrhosis, and liver cancer. In contrast to that, let's go to the next slide. Capsid assembly modulators block the encapsulation of pregenomic RNA. If you don't have any pregenomic RNA inside the capsid, you can't make any DNA, and that means you can also not make, you cannot make linear double-stranded DNA.
At the same time, the capsid assembly modulator at high concentrations can block the transport of that rcDNA into the nucleus and thereby prevent establishment and replenishment of ccc DNA . We have direct evidence in vitro that we're knocking down ccc DNA , and we have indirect evidence in the clinic that we are because our drug is able to reduce viral antigens, including HB surface antigen, HBV core-related antigen, and HBe antigen. Remember what I said about the viral lifecycle and how it causes disease. You have to block replication on the one hand, but on the other hand, you have to prevent formation of these integrated events. Our drug is able to block all of those steps in the lifecycle. We believe we'll have better outcomes for our patients.
Right. It's really interesting how this class of drug has evolved, and one for in particular. I wanted to ask you about how the regulators are viewing the program. They've endorsed the chronic suppression as an improvable pathway. What feedback has been most critical in shaping the phase II B- SUPREME design?
Yeah, so importantly, the FDA, as well as the EMA and the Chinese Regulatory Authority and regulatory authorities throughout the world, have written guidance on HBV. The guidance is divided into either monotherapy or combination therapy. If you have monotherapy in HBV, chronic suppression or patients that go below the limit of quantitation for the HBV DNA assay is accepted as a primary approvable endpoint. If you have combination therapy, you have to go for an endpoint of functional cure, which is the loss of HBV DNA, HBs antigen, and normalization of ALT following cessation of therapies. The other capsid assembly modulators did not have a path to regulatory approval as monotherapies because of the drug resistance problem that they had. What the guidance says is that if you can go for monotherapy, you can do a trial looking at the endpoint of DNA undetectable.
That's defined as below the limit of quantitation. In our case, that's now 10 IU at 48 weeks in either E- positive or E- negative patients. The trial should have an active comparator group. I'll show you in a moment what the design of our trial is. I want to talk about why this threshold is so important. If we can go to the, Jordan, the slide on the Korean study that is a hallmark in showing why going below 10 IU, in this case, they used 12 IU , matters. This is a group in Korea that's actually participating in our phase II study as investigators. What they looked at is patients who were on nucleotide analogs of whether they went below 10 IU either at one year or it took them for two years to do it.
What you can see is that patients on nucleoside analogs, so everybody has suppression of HBV DNA. Only those patients that go below 12 IU have benefit with regard to lack of progression to liver cancer. If you didn't achieve negativity or below 12 IU by the first year, you had a worse outcome for cancer over the coming years. The situation gets worse if it takes you two years to get to suppression. Let's just look at our data now compared to the standard of care nucleoside analogs. I'll just remind you of the 96-week data. We're comparing data from the TDF/TAF phase III study at Gilead, where they had a cutoff of 29 IU. At that time, 29 IU was the quantitative limit. The qualitative limit was 10 IU. We know about what they'll get with 10 IU.
In the E- antigen negative subjects, we had 100% at week 48 below 10, compared to the historical data of around 20% for TDF and TAF. If you look out 96 weeks, they were able to increase that to about 30% in the E- antigen- negative patients, whereas we remained at 100% at- 96 weeks. For the E- positive patients, more difficult to treat because they start with a much higher viral load at baseline, we had 60% negative at week 48 compared to not reported in the Gilead study at week 48. At week 96, they had around 10% go below 10 IU versus our 100% in our phase II study. You can see superiority on an endpoint that has clinical validation to predict outcomes in HBV. Going below 12 IU in the Korean study was indicative of lack of progression to liver cancer.
This is an important threshold that's now recognized as something you need to achieve in these patients.
Right. As we look ahead to B - SUPREME , just both from a regulatory and commercial standpoint, what would success look like in that program?
Yeah, so let's first look at the design of the phase II study so we can talk about what we're hoping to achieve. The phase II study that's ongoing right now, and we earlier this month announced the first patient in, enrollment is moving along, is being done in both E- positive and E- negative patients. It's comparing 300 mg of ALG-000184 plus a placebo matching TDF versus a placebo of TDF and a placebo of ALG-000184 in both E- positives and E- negatives. What we're looking at is superiority in the 48-week endpoint in the case of E negative patients below 10 IU and target not detected. In E- positive, they can be below 10 IU and target detected or not detected. Let's look at the data now to show why we have this subtle difference.
Jordan, if we can go to the slide that looks at the individual patients and where they ended up in our study. This is the 96-week data. Notice the E- positive patients start at much higher viral loads, so up to 10 to the ninth or a billion copies of HBV DNA versus the HBV E- negative patients that go as high as 5.5. What you can see, the closed squares, green squares, are when the patient goes below 10. The open triangles are when they become undetectable, target not detected. What you can see is that a lot of patients are becoming target not detected. Those in the E- negative group at week 48, 10 of 11 are target not detected, so even going lower than that 10 IU threshold. In our clinical study, the endpoint for E- negatives is below 10, target not detected, so those triangles.
In the E- positive, it's below 10 IU. They could either be detected or non-detected. We believe strongly that we'll show superiority in the DNA endpoint. In addition to this DNA endpoint and going below 10 IU and even to the lower threshold, one thing that our drug can do, and we mentioned, is the lowering of ccc DNA , resulting in antigen reduction. Let's look at that data as well. Here we have the HBV E- positive patients and the reductions in antigens. What you can see is a log reduction in HBV S antigen and multiple log reductions in E antigen and core-related antigen. You might ask the question, why is the S flattening out where the E and core continue to go down as you treat the patients? That's because HBV S antigen has two sources. One is the ccc DNA .
The other is HBV DNA that's integrated into the chromosome. That integration event is a truncated genome. It doesn't integrate core and E antigen, only S antigen. What we think is happening is we're exhausting the S antigen from the ccc DNA . The remaining S is from the chromosome. If that were true, we should see E and core go down even as S flattens out. That's exactly what we see. Notice then E starts to flatten out. If we go to the next slide, that's because E is approaching undetectability. We're having immune reactivation because we see E antigen going down and anti-E antibodies coming up. Success looks like superiority on the HBV DNA endpoints, as well as superiority on antigen reductions for these HBV patients. These are things that cannot happen with nucleoside and nucleotide analogs.
One other important thing that we're doing in the phase II-B study that we're running right now is we're doing paired biopsies in selected patients. We're going to look for integration. We'll quantify the amount of integration at the baseline. We'll look at integration events that occurred on nucleosides, as well as on ALG-000184. We're also going to quantitate ccc DNA . We'll be able to show reductions, we hope, in ccc DNA . Overall, this is a much superior profile for HBV because compared to NUCs, we're arresting all of the components in the lifecycle of HBV that can lead to end-stage liver disease and liver cancer.
Yeah, so it's really looking like an unprecedented result here, both in terms of efficacy as well as safety. I'm wondering your vision for ALG-000184 and how it can displace the nucleoside analogs, the generics as standard of care. I think really importantly, as the backbone for functional cure regimens, how are you seeing, if we look ahead, the sort of the clinical development path and also the commercial path?
Yeah, so first, let's go to the flowchart of how we see the flow of patients through therapies. Your audience is probably aware that GSK and Osprey Bio are developing antisense oligonucleotides that are aimed at functional cure. Again, that is defined as a loss of surface antigen, in some cases production of anti-S antibodies, loss of HBV DNA, and normalization of ALT off therapy. This is a finite therapy. In the GSK studies, they're showing that patients that start at a baseline of 3,000 IU of S antigen are really the only patients that will benefit from therapy. In their phase III studies, they're selecting patients at this threshold. That accounts for about 30% of HBV patients. 70% of HBV patients right off the bat don't qualify for ASO therapy and are in need of better chronic suppressive therapies.
In this group of patients that are at 3,000 IU , about 20% of those patients get a functional cure, meaning 80% do not. That means only 6% of patients have a functional cure to antisense oligonucleotide therapies, meaning that greater than 90% of patients still need this chronic suppressive therapy. We know that people are aware of this threshold of 10 IU . If we go to the next slide, we believe that will, with the data that we're generating now, cause this drug to become standard of care for chronic suppression. In the case of these functional curative therapies, they're done in the background of NUCs, which aren't affecting stages in the lifecycle involving ccc DNA establishment and replenishment. Imagine what might happen if you added ALG-000184 to an antisense oligonucleotide. You're reducing the pool of ccc DNA .
That may cause a greater number of patients to move into that functional cure status. Likewise, with drugs like siRNA, lowering ccc DNA is very important. Even more important, some of the newer drugs that are targeting directly ccc DNA , either through methylation and quiescence or cleaving ccc DNA , would benefit from patients with lower pools of ccc DNA . Our positioning is that we're the standard of care for chronic suppression because of the superiority over NUCs. We're also the backbone of therapy because of these activities for anything aimed at cure of HBV. Along those lines, in our pipeline now, we announced recently that we have our own antisense oligonucleotide program, which you'll be hearing more about at this coming AASLD. We believe we have superior drugs to those being developed by either GSK or Osprey. We'll be in a unique position to put our ASO plus ALG-000184 together.
That's terrific. This is just an enormous unmet need in the global market.
Yeah.
You know, just with the few minutes that we have left, I did want to make sure that we touched on ALG-055009, beta agonists for MASH. In maybe a few minutes, if you could, give us some background on this program and kind of.
Yeah, so when we started Aligos, we looked at the MASH landscape. We were a company that wanted to work in liver disease and viral disease. Of course, HBV is both a viral and liver disease. It turns out that the suppression of MASH looks a lot like suppression of HBV in that the metabolic defect causes inflammation of the liver, which leads to that wound healing response and cirrhosis, fibrosis, and hepatocellular carcinoma. It turns out that in the liver of MASH patients, the normal thyroid hormone is converted from T3 to what's called reverse T3, and it makes the liver hypothyroid. That causes metabolism to become dysfunctional and form what are called lipotoxic species. What Madrigal has shown with their first generation resmetirom beta thyroid agonist is that reversal of that hypothyroidism in the liver can lead to benefits in MASH patients.
Now, when we started the company, we noted the Madrigal phase II data. We thought it was interesting, but the compound had poor PK. It has nonlinear PK, it has hypervariable PK, so individuals can have vastly different exposures, and it has some liabilities with drug-drug interactions. Now you see there's some warnings about drugs that can't be given or have to be reduced when given with the resmetirom. Lastly, it has GI toxicity. It can cause moderate diarrhea, which can overlap with some of the drugs that patients with metabolic disease are on. We invented this drug in-house. We fixed the CYP liabilities, we fixed the PK liability, and we improved the potency dramatically. In our phase II-A study, we were able to demonstrate significant reductions in fat in the liver as measured by MRI PDFF.
We eliminated the GI toxicity, and we had other very interesting effects that would benefit cardiovascular disease in general. We had marked reductions in atherogenic lipids, including lipoprotein A, which is not affected by statins. The other important finding is that in our study, we had enrolled a number of patients that had been on GLP-1 for more than a year. What we were able to show was increased reduction of fat in the liver in combination with GLP-1 compared to our GLP-1 patients with placebo, who actually increased their fat over the course of the study, showing nice compatibility with GLP-1 or other integrins. You may be aware that Madrigal has recently in-licensed an oral [integrin]. The combination of beta thyroid agonist plus GLP-1 is a very interesting combination, not only for fat reduction but also for weight loss.
There is some preclinical data that has been published that demonstrates that co-administration of a beta thyroid a gonist with an integrin can reduce the fat muscle loss and increase the period of time where fat is being reduced. There is a lot of data suggesting GLP-1 plus beta thyroid agonist is a good combination. We're currently in discussions with multiple partners on licensing ALG-055009 for metabolic disease, and we hope to have further updates on that throughout the year.
Right. Terrific. We really have, I think, two highly differentiated compounds in two very large unmet need areas of development, both with multibillion dollar potential. We also now have potentially another compound with this ASO that we'll look forward to the details emerging. I'm wondering, as we look ahead over the next 12 months - 18 months, what are the milestones, the key milestones that investors need to be aware of as we're looking ahead at, as this pipeline unfolds and as folks want to get involved ahead of some of the catalysts?
Yeah, so this was our 2025, 2026, and 2027. We had said that we would initiate the phase II study, which has already occurred. This fall, we're going to have some very important data on ALG-000184, the final data from that 96-week study that I talked about, including what happens after you stop ALG-000184 treatment. That will be presented at AASLD. In 2026, we'll have the first interim readout data from the phase II study, the B - SUPREME study that we talked about. That will really inform how we're doing, and we can adjust the sample size of the study. We could also look at moving rapidly towards phase III strategies based on that interim look. In 2027, we'll have the top line readout of the primary endpoint for that study, which will be week 48 HBV DNA data. For the ALG-055009 program, the milestone will be a partnership.
We'll be hoping to announce that sometime early next year. That will be an important milestone for the company because it will bring non-dilutive cash in the company, as well as progress the MASH asset towards approval.
Terrific. It does bring us to the end of our discussion. I'd like to thank Lawrence Blatt and Aligos for attending the conference. Thanks to all of our attendees for being with us. Have a great rest of your day and a great rest of your conference.
Thank you.