Morning, everyone. Welcome to the H.C. Wainwright 26th Annual Global Investment Conference. I'm Thomas Yip from H.C. Wainwright Equity Research. For our first presentation of the day, we have Arbutus Biopharma, and presenting for us today, we have Interim President and CEO, Michael McElhaugh. Mike, great having you with us. Please go ahead.
Thanks, Thomas. I appreciate it. Thanks, everyone, for being here this morning. Good morning. I know it's early, and I appreciate you taking the time to join us this morning. These are our forward-looking statements. We'll be making some forward-looking statements today. Arbutus Biopharma is a company that is exclusively focused on developing a functional cure for hepatitis B. We intend to do that through a combination therapy that includes antivirals and immunologics, and our goal is to increase the functional cure rate to something greater than 20%. Right now, today, the rate is significantly lower than that, and we'll get into that in a little bit more detail as we work our way through the slides. Hepatitis B is a tremendous opportunity. There are greater than 250 million patients chronically infected with hepatitis B globally.
And this is not just in China, which as you can see, there are a large percentage of patients in China. There is a tremendous opportunity also in the United States, with two million patients infected, and also in Europe, where there's 11 million patients. About 820,000 patients die annually from Hepatitis B. This is a very serious disease, and one that we're looking to address. The diagnosis rate and treatment rate is extremely low, at 13% and 3%, respectively. With better treatments, those numbers will increase dramatically. Just to give a little overview on Hepatitis B, Hepatitis B is a disease of the liver. Hepatitis B virus infects hepatocytes and causes cirrhosis and liver cancer when it infects patients chronically.
As far as treatments are concerned, there are a few treatments that are available, but they are not very good. There's nucleoside analog therapy, which is lifelong daily therapy. This is an oral therapy that targets hepatitis B DNA only. It does lower the risk of cirrhosis and hepatocellular carcinoma, but patients need to take the drug for the rest of their lives. There's also pegylated interferon. This is administered weekly, but it's very poorly tolerated over 48 weeks of treatment, and that's the approved dose. We and others are looking to reduce that treatment duration if we're going to use pegylated interferon in the future. Less than 5% of patients currently achieve functional cure. I've used that word, those words a couple of times. I should probably define it.
So functional cure is undetectable HBV DNA, undetectable hepatitis B surface antigen for at least 24 weeks off of all therapy. So I mentioned that nucleoside analogs are lifelong. It's unlikely that with nucleoside analogs patients will get to functional cure. And pegylated interferon, the numbers are extremely low as well. Surface antigen loss is strongly associated with a reduced risk of long-term adverse critical outcomes. So that's why we'd like to get patients with a finite treatment duration to functional cure. Get them off their drugs and enjoying their lives. We believe we can accomplish this through a three-pronged approach. We believe we need to suppress viral DNA in the cccDNA pool. We need to reduce viral antigens, in particular, hepatitis B surface antigen, which is the one that I just mentioned.
Ultimately, we need to boost the host immune system. That hepatitis B surface antigen is responsible for exhausting the immune system, which is what leads to chronic disease. We have to give the immune system a little bit of a kick, and there are a couple of ways that we can do that going forward. We do believe that therapeutic success is gonna require a combination of agents with complementary mechanisms of action. This is the Arbutus pipeline. This is how we anticipate attacking this functional cure problem. We have an RNAi therapeutic in development called Imdusiran, previously AB-729.
This is currently in phase II development in two separate clinical trials, one called IM-PROVE I, in combination with interferon, short courses of interferon, and the second called IM-PROVE II, which is a combination trial with a therapeutic vaccine called VTP-300. That's in collaboration with our partners, Barinthus Biotherapeutics. We also have a PD-L1 inhibitor, which we believe will help with the immune-boosting component of the regimen. This is called AB-101. It's a small-molecule, liver-targeted PD-L1 inhibitor, and that's currently in phase I development. We'll get into some details about those trials as we move forward here. Let's start with Imdusiran, the RNAi therapeutic. Imdusiran is a single-trigger RNAi agent targeting all HBV transcripts. It inhibits HBV replication and lowers all HBV antigens.
And this is delivered via proprietary GalNAc conjugate delivery technology, which targets Imdusiran to hepatocytes, the location of viral infection. We started Imdusiran in a phase 1a/1b clinical trial called AB-729-001, where we found that Imdusiran was generally safe and well tolerated. We put that drug into over 40 patients with chronic hepatitis B. And what we also found was we looked at a lot of different parameters, including dose, different dose levels, dosing intervals, antigen status for patients, either HBe antigen positive or negative. We looked at naive versus nucleoside analog-suppressed patients or DNA status. And what we found was that Imdusiran showed comparable levels of surface antigen reduction, somewhere between one point eight and two logs of surface antigen reduction, regardless of the dose, dose interval, or viral status.
And what we also saw was when we stopped treating these patients, the majority of them stayed pretty low for HBV DNA and surface antigen, for a long period of time. This is in contrast to what you see with a nucleoside analog, for example. When you stop nucleoside analog in patients, you typically get a very robust reactivation of HBV DNA, and that is not the case with, with Imdusiran. So we were interested in that, and that sort of tells us that maybe there is some activation of the immune system with Imdusiran alone. And in fact, that's what we saw when we did some work. We saw T-cell immune restoration and a decrease of exhausted T-cells in some patients when we did the analysis with Imdusiran alone.
Okay?
So we selected imdusiran 60 milligrams every eight weeks for either 24 or 48 weeks, for a phase II trial. So we moved imdusiran into phase II trials. I mentioned these trials when I went through the pipeline. The first one I'm gonna talk about is the IM-PROVE I trial. That's a phase IIa clinical trial, looking at imdusiran plus a nucleoside analog in combination with pegylated interferon. Now, remember I said that 48 weeks of interferon was not well tolerated. This is short course of interferon. So if you can reduce the dose of interferon, you can actually improve the tolerability for patients, okay? So, just a quick overview of this trial. We dosed initially with imdusiran plus a nucleoside analog for 24 weeks.
We then randomized patients into one of four groups, either in continued imdusiran, or stopping imdusiran, with interferon added for either twenty-four weeks or twelve weeks, okay? I'm gonna share some data with you now. That was shared at the EASL conference earlier this year, and what we found was that we could get some patients undetectable for surface antigen, and that those patients were actually sustained, and we're very excited about that because that's the precursor to functional cure, as I mentioned. So I'll draw your attention to the table on the left-hand side of the slide here, and this is patients with undetectable surface antigen at key time points. This is cohorts A1 and A2.
These are the 24-week interferon-containing arms, with either continued Imdusiran dosing in cohort A1 or stopping the Imdusiran dosing in A2. I'm gonna focus your attention on cohort A1 on the first column there, because that's the cohort that performed the best in this particular study. What you can see is at the end of treatment or the end of the interferon dosing, 33% of the patients were undetectable for hepatitis B surface antigen. Importantly, you'll see a column there, a row there that says: "24 weeks post-end of treatment, nucleoside analog therapy only." So once we got to the end of the interferon treatment period, we continued patients on only nucleoside analogs for a period of 24 weeks.
When we got to the end of that period, all of those patients were still undetectable for surface antigen, okay? We then stopped nucleoside analog. We're continuing to evaluate those patients. Those patients are on their way to functional cure, assuming, of course, that they remain hepatitis B surface antigen undetectable. Those patients will achieve functional cure. That is a meaningful number, right? 33% is a very good number. We also looked at a couple of other parameters. You'll see a mention of a Next Assay negative here. The standard assay for hepatitis B surface antigen has an undetectable level of 0.05 international units per ml, okay? The Next Assay is a next-generation assay that's in development by Abbott.
It's not commercially available yet, but that, threshold is 0.005, right? and we still had patients undetectable even by that, that more robust assay, and that continued as well, so that's, that's exciting. I'm just gonna hit a couple of the key findings on the right-hand side of the slide. One thing that's important as you start to sort of slice and dice the data, if you look at patients with surface antigen at baseline less than 1000 international units per ml, that undetectable level goes up to 67%, which is a phenomenal number, and that is a large, a large percentage of patients that are available, globally.
We also saw anti-HBs levels in patients who were undetectable for surface antigen, ranging from 43 to over 1,000, and that's meaningful as well because we want patients to develop or to reestablish their immunity against hepatitis B. And we're seeing evidence of that as we move forward. Generally safe and well-tolerated, no related SAEs or AEs leading to discontinuation. So, this was very well tolerated, and we're excited about this data going forward. These are the spaghetti plots, the individual patient plots, same data. What you can see here, if you look, let's just focus on cohort A1, for example.
This is hepatitis B surface antigen level by visit, and you can see during the imdusiran lead-in phase, and imdusiran was given in those vertical dashed bars. That's when imdusiran was actually dosed. You can see a robust reduction in hepatitis B surface antigen during the imdusiran lead-in period. Interferon was given during that, let's say, peach peach bar in the middle there. And what you can see is after a little bit of interferon dosing, those patients that are gonna go undetectable fall off the shelf, right? And their surface antigen goes down to undetectable very rapidly, and we've been able to maintain that in a certain number of patients, which, as I mentioned, we're very excited about. Okay? Moving on to IM-PROVE II.
This is the Phase 2a clinical proof-of-concept trial with Barinthus Biotherapeutics, evaluating imdusiran in combination with their immunotherapeutic VTP-300. This is a ChAdOx-MVA construct. And as you can see, the top bars there, imdusiran plus nucleoside analog, so same sort of concept as we had in the IM-PROVE I study. We reduce hepatitis B surface antigen with imdusiran plus a nucleoside. We then randomize to either continue to receive placebo plus a nucleoside analog or VTP-300 plus a nucleoside analog, and then we follow up those patients. We subsequently amended this trial and added an arm that includes low dose Nivolumab during the boost component of the regimen, based on some data that the Barinthus folks saw in their ongoing clinical trials.
We do have some data for this trial as well that we presented at the EASL conference as well. Basically, what we saw was at week 72, which is 24 weeks post end of treatment, we did see a statistical significance in lowering hepatitis B surface antigen in Cohort A, which is the VTP-300 active cohort, and Cohort B, the placebo cohort. You can see that on the right-hand side, those are the mean values, and you can see the split at week 72 between the placebo arm in red and the active arm in blue. Now, those are. I will caveat that that's a small number of patients at this point.
We'll continue to follow those patients up, and we'll continue to report that out as the data evolves. On the left-hand side of this slide, you can see these stacked bars. And what this is really showing is that there are more patients who are lower with hepatitis B surface antigen in Cohort A, the active arm, versus Cohort B, the placebo arm, over time, as people continue to progress through the study. The darker blue equates to lower hepatitis B surface antigen. Okay? In the interest of time, I'm gonna skip that slide and that slide 'cause I wanna be able to talk about our oral PD-L1 inhibitor as well. Okay. This oral PD-L1 inhibitor is called AB-101. We're developing this to, again, boost the immune system for hepatitis B.
The idea here is that there is good rationale for why the PD, PD-1, PD-L1 checkpoint axis plays a key role in immune tolerization in chronic hepatitis B. HBV immune tolerance is a critical driver of chronic infection, as I mentioned earlier. We're taking a small molecule approach. Of course, there are some antibodies that are available for PD-1 and PD-L1, but a small molecule approach allows controlled checkpoint blockade. Patients in hepatitis B are different than oncology patients. They have a different risk profile, right? Sometimes the issue with dosing antibodies is that once you give them, they are on board, and it's difficult to turn them off.
There are issues with immune-related adverse events that are, of course, tolerable in an oncology patient, but not necessarily tolerable in a hepatitis B patient. So a small molecule approach targeting the liver allows us to control that much better. It allows oral dosing, and it's really designed to reduce systemic safety issues seen with those antibodies. And if we do happen to see those issues, we can obviously stop dosing and turn this off, right? So that's important. AB-101 blocks the PD-L1, PD-1 interaction very well, sub-nanomolar concentrations. We do see evidence of activation of HBV-specific immune responses in T cells from chronic HBV patients in vitro. We have some of that data on the next slide. We're very excited about this particular trial.
It's currently in phase 1a/1b clinical trial, and we'll get to that design in a second. I wanna show you some preclinical data first. Highly potent, activates HBV-specific immune cells from chronic HBV patients. In the graph on the left-hand side, you're looking at patient PBMCs that are activated with peptides in the presence of the PD-L1 AB-101 or not. And what you can see is when you treat those patients with the patient samples with AB-101, and then stimulate the T cells with peptides, you see increase in interferon-gamma-producing T cells for either AB-101 or PD-L1 antibody at similar levels versus inactive samples.
On the right-hand side, this is an in vivo experiment in an MC38 tumor mouse model, also showing once-daily administration of 101 with profound tumor reduction in this MC38 tumor mouse model. You can see that, compared to the Atezolizumab, which is a monoclonal antibody targeting PD-L1, versus vehicle alone, highly statistically significant. Okay. AB-101-001 is our phase 1a/1b clinical trial with 101. It's two parts. Actually, it's three parts. Parts one and two in healthy subjects, part three in chronic HBV patients. Part one is single ascending dose. We're through four cohorts in single ascending dose, as of this time.
We're currently in part two, multiple ascending dose in healthy subjects, and we've already seen evidence of receptor occupancy between 50 and 100%, in dosing as low as 25 milligrams with this particular drug. Receptor occupancy is a measure for activity. So we are