Aligos Therapeutics, Inc. Common Stock 12th Annual Cantor Fitzgerald Global Healthcare Conference

Yeah. Well, thank you, and thank you for having us at the conference. It is a very exciting time right now in HBV research. We have spent more than a decade now working on new therapeutics. There were a lot of ideas over a decade ago, and now some of those are rising to the top, and some of those are being weeded out. The first thing that we should note is that patients on nucleoside analogues, while they do have benefit, they are still at risk for progressing to end-stage liver disease and hepatocellular carcinoma. So there is an unmet medical need in that the NUCs are not completely suppressing the progression of the disease. The goal of therapy, again, is to block the progression to end-stage liver disease and liver cancer, and there is a number of approaches you can take to doing that.

I think a lot of people have talked about the idea of functional cure, and the reason we call it functional cure is because you cannot actually get rid of the virus. What you do is you are shifting the balance in that state when, prior to that, the virus is controlling the immune system, so the virus is an immunosuppressant, to where the immune system controls the virus. There were a number of approaches that people took, and they were all centered around HBV surface antigen. People believe because HBV surface antigen is immunosuppressive, if you lowered HBV surface antigen, you can get immune reconstitution, and patients would cure themselves. That largely turned out not to be true, so that is why we do not see siRNA monotherapy progressing on for FDA and worldwide regulatory approval.

But there was one therapy, and is one therapy, that is both a drug that can knock down S antigen through an antisense oligo mechanism but also is a immune activator. It's a Toll-like receptor 8 activator, and that's bepirovirsen from GSK. There's two other ASOs in development, one by AusperBio and the other by us, and maybe we'll have time to talk about that. The thing about the ASOs is that they only work in a subset of patients. So patients have to have baseline HBV surface antigen at a threshold of 3,000 international units or less, and this comprises something like 30%-40% of HBV patients. And in that population, GSK reported in the phase III study a 19% functional cure rate, meaning 81% of patients did not have a functional cure.

So if you think about 20% of 30%, that's 6% of HBV patients, or even if you say it's 40%, it's 8% of HBV patients can ultimately get a functional cure. So the question is: What can you do to help the greater than 90% of patients that are left out there? And that's where Aligos comes in. And we have really a two-pronged strategy. One is through a capsid assembly modulator mechanism that's very new, very novel, that works on components of the HBV life cycle that nucleoside analogues don't work on. And for that matter, neither do ASOs or siRNAs. And we believe that those components will lead to better disease outcomes in those patients. I'll pause there. Sure. That was a lot to cover.

Yeah. First, let's talk about what a NUC does and what a CAM-E does. NUCs are chain-terminating analogues. When HBV is replicating, it's actually a retrovirus, just like HIV, and nucleoside analogues are added to the elongating DNA chain from the RNA substrate. It stops the reaction, so you get a short genome, and the virus doesn't replicate. That doesn't really affect other components of the HBV life cycle. HBV is a very complicated virus. It deposits into the nucleus of host cells, something called the cccDNA, which is basically a chromosome. So it deposits its own chromosome into the nucleus. If that wasn't enough, it also integrates a portion of its genome into the genome of the hepatocyte. Those are very important steps that need to be reconciled.

What is interesting about pevifoscorvir is pevifoscorvir can block three of those steps. Pevifoscorvir blocks replication very efficiently. The way pevifoscorvir works is it's a capsid assembly modulator. Notice I didn't say inhibitor.

It modulates the assembly of the HBV capsid, which is the protein shell that goes around the virus. That protein shell is made up of the HBV core protein. Pevifoscorvir binds to that core protein, changes the conformation slightly, and forms empty capsids, so it doesn't have the pregenomic RNA. If you don't have pregenomic RNA, you can't make DNA, so therefore you block replication. What happens if pevifoscorvir isn't 100% efficient and some of those viruses are actually made? Pevifoscorvir actually blocks the second step, and the second step is that once the DNA is contained inside the capsid, it can recirculate, uncoat, and travel back into the nucleus to form new cccDNA or new integrants. Pevifoscorvir can actually block the transport or uncoating of that capsid so that DNA is sort of stuck in the cytoplasm.

By blocking that second step, pevifoscorvir can lower cccDNA, and that's very important because cccDNA is the reservoir of the virus. As long as you have cccDNA, you will have HBV replication. Pevifoscorvir also blocks the transport of what we call double-stranded linear DNA that's made in about 10% of virions, and that's the form of HBV DNA that integrates. Pevifoscorvir works on replication, which we know is involved in disease pathogenesis. Pevifoscorvir works on lowering the reservoir, which obviously is important for disease pathogenesis, and pevifoscorvir blocks the form of the virus that integrates, which is very important because we know that integration can cause directly HCC. Integration can transform a cell into a cancer cell.