Good morning, everyone, and welcome to the Jefferies Global Healthcare Conference. My name is Ashwin Surapaneni, and I'm with the Jefferies Healthcare Investment Banking team. It's my pleasure to introduce Michael Sofia from Arbutus Biopharma. Thank you.
Great. Thank you. It's a forward-looking statement. So Arbutus Biopharma is a company that's whose mission is to find a functional cure for hepatitis B. Our strategy is to actually use a combination therapy that includes direct-acting antivirals and immunologics to achieve that functional cure and a finite duration of therapy with at least greater than or equal to 20% functional cure rate. We are able to achieve this by combining a talented team who has incredible experience in drug discovery in the virology space, who's been there and done that, with a portfolio of internally developed assets that include Imdusiran, our siRNA lead candidate, which is in Phase II clinical trials.
which is currently moving forward in combination therapy with other agents that I'll describe today, with a strong cash position and also leveraging our LNP technology, in the sense that, we have a litigation with both Moderna and Pfizer looking at, patent infringement on that, which also adds value to the company. So our portfolio in clinic looks at imdusiran or known as AB-729, in three phase IIa clinical studies, IMPROVE I, II, and III. That includes combination with either interferon, with VTP-300, it's a therapeutic vaccine, collaboration with Barinthus, or, the third phase IIa study includes the combination with, durvalumab, which is a PD-L1 antibody.
In addition, we have a phase I study with AB-101, which is our small molecule, orally bioavailable, PD-L1 inhibitor that we hope to be able to combine with Imdusiran going forward, and I'll describe that later. So if you look at HBV, it's a huge unmet medical need, right? Diagnosis rates are low. The cure rates are very low with current standard of care, which is either interferon or nucleoside therapy. And so the rationale is to develop a combination therapy that will be able to increase functional cure rates, as I said, to greater than or equal to 20%, but also to have that short duration of therapy, so patients don't have to take lifelong therapy as they currently do with nucleoside therapy. As I mentioned, the market is very large.
It's greater than 250 million people globally, 2 million, greater than 2 million in the US, greater than 15 million in the EU, and obviously, a very large percentage of the patient population is in the Asia Pacific region. So our strategy has revolved around this paradigm, and the paradigm is that one needs to be able to do three key things. First, reduce HBV DNA to undetectable levels. Second, to reduce S antigen levels. Now, S antigen is a product of the virals, the virus that is involved in immune exhaustion, so controlling the host immune response. And then third, boost the host immune response with another agent, and ultimately, achieve functional cure with this combination of agents. So first, I'm going to talk about our RNAi therapeutic, imdusiran AB-729.
Imdusiran is a single trigger, GalNAc conjugated siRNA with a proprietary GalNAc conjugation technology. It is pan-genotypic. It demonstrates complementarity with other agents to be able to combine it in the clinic. It is a single trigger that both knocks down S antigen produced from the cccDNA, which is the viral genetic material that resides in the nucleus of a liver cell, as well as reducing S antigen coming off of transcripts that have been integrated into the host genome. AB729 in phase Ia/Ib clinical studies have demonstrated to be very safe and well tolerated. It's just shown robust S antigen declines, regardless of dose, dose interval or e antigen status.
This drug has demonstrated to be able to be dosed every 8 weeks, which is a competitive advantage, we believe, for this agent, with a very low dose of 60 milligrams or 90 milligram doses. The S antigen declines have demonstrated to be very substantial and sustained over a long period of time, even off therapy with AB-729. And the other thing that we've demonstrated is, in fact, with AB-729, one has demonstrated that we can enhance or increase the host immune response, when this agent is given. So demonstrating that, in fact, we are seeing immune reactivation, with AB-729 and nuc therapy combination. So I'm going to talk about IMPROVE I, which is our phase IIa clinical study in combination with interferon.
This data has now been released early this morning at the EASL conference in Milan. This involves an imdusiran lead-in phase of 24 weeks, followed by a combination of imdusiran plus interferon plus nucleoside therapy for either 24 or 12 weeks of therapy with interferon. That then followed by an end of treatment phase, which is just nuc therapy alone for 24 weeks, and then follow off therapy of all therapy with these agents. So what this data has demonstrated, in fact, is that at the end of treatment phase, we see 33% of patients that are below the limit of detection for HBsAg as well as HBV DNA.
These patients have demonstrated to be S antigen negative, even using a very highly sensitive now assay known as the next assay, so which, which measures down to 0.005 international units. Patients with sustained S antigen loss have had correspondingly high HBV S antibodies, which is important. These patients have demonstrated this combination to be very safe and well-tolerated across all patient populations. All six undetectable patients that have discontinued nuc therapy after 24 weeks post end of treatment continue to show undetectable S antigen levels in this population. So we're very excited about this data.
The 33% reduction in HBsAg end of treatment is a very significant number for us, and we hope to continue to move this forward with further analysis of data, of which all patients are off all treatment, and report that data in the future. This shows individual patient data for this study. As you see in the A1 cohort, this is the 24 weeks of interferon plus 48 weeks of imdusiran. And what you see here is the number of patients going undetectable out to past 72 weeks or 78 weeks of therapy. So very excited about this data, as it was reported this morning.
The other phase IIa study is a combination study with imdusiran plus VTP-300, which is in a collaboration with Barinthus Biotherapeutics. VTP-300 is a therapeutic vaccine. It's a ChAdOx MVA boost therapeutic vaccine, and the study design here looks at a lead-in phase of imdusiran for 24 weeks, followed by randomization to a VTP-300 addition versus a placebo, and then a follow-up period after that. We've also introduced a third cohort into this study, which looks at the combination of imdusiran nucleoside VTP-300 plus nivolumab. Nivolumab has been demonstrated by Barinthus to enhance the effect of the VTP-300 to reduce S antigen.
Preliminary results have presented at AASLD in 2023, shows that the combination of the VTP 300 and imdusiran has added benefit, as demonstrated here, where you see the, the red line, where is the imdusiran alone. At the end of the 24-week period, you see after a period of time, you see begin to see rebound of S antigen levels, but in combination with the VTP 300, you see sustained reduction in S antigen over a period of time. So you see this robust reduction of S antigen during the imdusiran treatment period.
Clearly, lots of a large percentage of patients retain that less than 100 international units at the time of VTP-300, and the VTP-300 seems to maintain that low S antigen level going forward. Another phase IIa study that we are looking at, which is known as IMPROVE-3. This study looks at the combination of imdusiran plus durvalumab. Durvalumab is a PD-L1 antibody. This goes back to a thesis that we have, that PD-1, PD-L1 axis is playing an important role in the immune exhaustion phase of hepatitis B.
And so we wanted to see the concept of a reducing S antigen, so reducing that, that, you know, the immune tolerizing load, and then bringing in the PD-L1 antibody to see if we can, you know, reduce in, in, reduce further S antigen levels and achieve a functional cure. I also want to comment on a strategic collaboration we have with Qilu Pharmaceutical in China. Obviously, the Asia Pacific region is a huge market in HBV, and we've been very happy to partner with Qilu, a large pharmaceutical company in China, to be able to capture that market more effectively as a strategic partner. We've had very good economics on this particular collaboration, $40 million upfront, $50 million in equity investment.
And this program is now continuing to move forward in the China sphere, in collaboration with Qilu. So now I'm gonna change to our PD-L1 small molecule program. As I mentioned, we have a very strong belief that PD-1, PD-L1 axis is playing an important role in HBV. What you see is PD-1, PD-L1 checkpoint axis in the immune tolerizing phase of HBV, PD-L1 is expression upregulation is expressed in HBV-infected patients. PD-L1 upregulations in HBV-specific T cells and B cells, I mean, PD-1 upregulation. And there's been some indication with some early clinical trials with antibodies that, in fact, you can achieve certain levels of S antigen drop with a PD-1 antibody.
Now, the concern that we in the field have always had with antibodies in this space is the immune-related adverse events associated with this. And so our strategy has been, can we develop a small molecule that will overcome those immune-related adverse events, take advantage of PK/PD relationships, in small molecule space, and therefore, achieve not only efficacy but a much improved safety profile? That led us to the development of the small molecule AB-101, which is an orally available, small molecule. It's very potent at blocking the PD-1, PD-L1 interaction. It operates by a very novel mechanism of action, and that mechanism causes dimerization of PD-L1 on the surface of the cell, internalization, and degradation. Once you wash out the drug, you get full reconstitution of PD-L1 on the surface.
We've demonstrated preclinically that, in fact, if you take PBMCs from HBV patients and treat them with the PD-L1 small molecule or antibody, that you can get reconstitution of T cell function in those cells. So very excited about this. This molecule is currently in phase Ia clinical development. This is just data showing that, in fact, you can reconstitute HBV T cell function or activation with PD-L1, with AB-101 or a PD-L1 antibody. And that, in fact, the PD-L1 antibody, this is a atezolizumab versus AB-101, equipotent in an MC38 mouse tumor model as far as reducing tumor burden. So, as I said before, you know, we're currently in phase I clinical development.
We've completed the single ascending dose portion up to 25 mg dose and have demonstrated, in fact, safe and well-tolerated regimen, and also that we've shown that you can get 50%-100% receptor occupancy. So we're getting, we're hitting the target that we want, and we're doing what we want, we believe, with this. So this program is now moving forward in a multiple ascending dose study, which we'll report in the future, as well as in the patient studies. I obviously need to mention the litigation that we have with Moderna and Pfizer. We have an extensive portfolio of LNP technology patents that we are continuing to defend in this space.
We've obviously had recent developments in our Moderna litigation with the Markman hearing or claims construction hearing that we believe has confirmed our position on the claims that we want to move forward with in this particular litigation. Continued steps going forward now is to continue sort of expert reports and depositions, moving forward, with a trial date set for April of 2025. Pfizer litigation activities continue to sort of lag behind the Moderna litigation, but continue to move forward as well. And finally, key milestones for our programs to date, you know, IMPROVE1 end of treatment data. We reported, as I mentioned, here, as well as EASL this morning.
We've completed our phase an IMPROVE-3 initiation program there in phase IIa study. And the AB-101 preliminary data for healthy subject cohorts we reported in a press release recently in May and continue to move that program forward. And we'll. I look forward to updating everyone on the rest of these objectives for the rest of the year. And thank you for your attention. Any questions? Yes.
The litigation, is it about just the lipid nanoparticles or the ones that contain messenger RNA or mRNA?
It's the lipid nanoparticle technology is where the litigation revolves around for us. That's our proprietary technology that we are, you know, defending in the courts.
It is very specific because everybody's using now, I mean, nowadays.
Right. Right. There is a lot of use of lipid nanoparticle delivery, you know, oligonucleotide technologies of various types. We believe we have, you know, foundational patents in that space, and we'll continue to defend our patent position.
That would be on the composition of the particle?
There are a whole litany of patents that revolve around composition of particles, molar ratios, et cetera, of how, you know, the particle is constructed.
Can I ask one more question?
Yeah.
Take all the time. So I, I've always been curious, the people in Asia, is there a genetic predisposition that makes it more prevalent there, or what is the reason?
I don't believe that there's a genetic predisposition, at least none has been identified.
Mm-hmm.
The prevalence there is, you know, I think, at least in mainland China, the vaccinations are. You know, so there's a preventive vaccine that's been around since the 1980s. Access to those vaccines have been limited in that region for an extended period of time. One of the major transmission rates, transmission modes for HBV is mother to child at birth. So that's where a lot of the early transmission happens.
From mother to child?
Oh, yes.
I see. Thank you.
Thanks for coming. Just a quick question. Given the positive EASL data that was released this morning, is there any update on kind of strategic actions that you might take around the HBV portfolio, maybe a partnership or licensing agreement or anything like that?
Look, I think we always talk to those out there that are interested in the HBV space. So as we did with the Qilu deal, we've done partnerships, you know, globally for this asset. So I would say we continue to talk to people as we have always had in the past. Dennis?
Hi, Mike. Thanks so much for the great presentation. I just had a couple questions around your EASL data. If you can go back a couple of slides, you show pretty interesting results on off-treatment durability, at least initially. But how do we think about, you know, functional cure at six months if you guys will have some more data towards the end of the year? And what do you think would be a clinically meaningful result?
So, functional cure, look, we hope to have some data at the end of the year. You know, we have a number of patients in that cohort, especially the A1 and A2 cohorts, that have now been, you know, out 12 weeks, you know, and still maintain undetectability off of all therapy, so we're really excited about that. What's meaningful in functional cure, you know, talking to key opinion leaders, the belief is, you know, anything above 15% looks like it could be very meaningful for the space and for patients.
We're very excited about the fact that we only have to give 24 weeks of interferon, which has been very well tolerated, and the feedback we get is that that is an acceptable regimen, rather than the 48 weeks, which is much less well tolerated for patients.
Okay, got it. And then, you know, when you guys report that data, I appreciate that it's probably gonna be in a relatively small N-
Right.
a small number of patients. You know, how do you think about moving forward into a pivotal, a phase III? And, with this sort of data in hand, and presumably, you guys would have more follow-up over time in 2025, but, you know, what are some of the gating factors, that prevent you from going into the phase III, and, you know, what kind of additional data do you have to see, maybe from the oral PD-L1 or others? Just help us think about, your path forward into phase III.
So, for the interferon combination, I think, look, we need to get the rest of the data to see if all it holds up, and if they all hold up, I think, you know, we'll look at the portfolio and see, you know, does it make sense now to move forward with an interferon combination going forward? I do believe that, you know, the sort of short duration of interferon is very positive, and that's the response we've gotten from KOLs overall, so I think everyone's excited about the data. We'll look at the results from certainly the Barinthus study, as well as, you know, the opportunities for our PD-L1 Durvalumab combination study to see, you know, what looks like the best combination to take forward from here.
But it certainly, I think the interferon study looks very interesting at this point in time. You know, one of our beliefs, as I mentioned before, is that, you know, PD-L1 plays an important role in immune exhaustion. Can we then leverage our strategy with a small molecule? It provides a better, you know, route of administration than injection, more well-tolerated, more acceptable by patients, and that could be a. You know, it's a little further behind than interferon, but it could be that sort of next wave coming forward, as we always believe. This is gonna be an iterative process. You know, you'll get new modalities out there. You'll learn from that and continue to move forward.
On the oral PD-L1, you guys are in phase I.
Right.
Have you started the phase 1b portion yet?
We've not reported on that yet.
Okay, but once you start, and assuming you get some kind of positive data, maybe in 2025, could the oral PD-L1 go directly into phase III in combination with imdusiran, or would you need a separate phase II to investigate that?
I think we would have to probably do a phase II proof of... At least prove that the combination is, that additive, gives you that additive benefit. I don't think the regulatory agencies will let us drop, you know, miss the phase II studies.
Okay, uh-