Okay, we'll continue with the next session. Hi, everyone. I'm Paul Choi, and I cover this mid-cap biotech sector here at Goldman Sachs. It's my pleasure to welcome Vir Biotechnology to this session. Joining us on stage is CEO Marianne De Backer. I think we have a lot to talk about here. You obviously had some recent news and update at EASL, so we'll kick it off with Q&A here. And maybe before we get into the data and your recent EASL update, we can start with, you know, for people who may not be familiar with Vir, just broad strokes, you know, sort of where—what you focus on and what your core competencies are in terms of the areas and markets you target.
Sure. Yes, and thank you, Paul, for hosting us here at Vir Biotechnology at the Goldman Sachs conference. Much appreciated. Yeah, so for people who may not be familiar with Vir Biotechnology, we are an immunology company, and we're really aiming to power the immune system and really use sort of the immense potential of modulating the immune system to transform outcomes in disease. For the first seven years of our history, we have focused on mainly infectious diseases, and we have been very successful in doing that. There's two drugs that are on the market, one antibody against Ebola and one antibody against COVID, that came out of the drug discovery at Vir. We mainly have two platforms, two big technology platforms. One is based on antibody therapeutics and engineering of antibodies, more and more these days, using AI and machine learning.
As I mentioned, there are several proof points that that platform has been really productive. Then our second platform is a viral vector-based platform based on CMV, where we are again trying to stimulate very specific T cell responses in human participants to protect people from disease. So these are our two major platforms, and we recently, as you pointed out, last week, added an additional proof point with data that we have shown in hepatitis delta, where we have, again, an antibody that was discovered in our labs called Tobevibart. And we have shown data at EASL, where, you know, treating patients with tobevibart alone or with a combination with an RNA that showed very promising antiviral responses, very promising liver outcomes, and very promising safety and tolerability.
We will for sure be talking more about that.
Yeah. Let's go into that and talk about the hepatitis delta data that you presented at EASL. Maybe if you could summarize for us what you showed, both from a monotherapy and from a combination perspective, both on in terms of the surface antigen changes and as well as liver ALT and so forth changes, and maybe help us contextualize what that actually means in terms of the current treatment landscape, given that there's only one approved real therapy out there.
Okay, sure. So maybe to start, for people who may not be familiar with Hepatitis Delta so much, it's the most severe form of viral hepatitis. And what you see is that people that are co-infected with both Hepatitis B and Hepatitis Delta progress much faster to liver cancer and to mortality. What you see actually is that, you know, patients that are diagnosed with liver cancer and might need a liver transplant, with Hepatitis Delta tend to be rather young, in their thirties and forties, compared to people that are only infected with Hepatitis B, who also progress to that outcome of, liver cancer eventually, but are then in their fifties or in their sixties. So it's, it's a really, you know, very, very severe disease. There's nothing on the market in the United States, as you rightly pointed out.
There's only one treatment available in Europe. So the data that we have shown at EASL, I will talk about it very briefly. So I will be sharing a little bit of slides just to make it more clear, and I will be making potentially as part of that, some forward-looking statements. So we have basically shown three different data sets at EASL. The first data set really demonstrated that we could get durable on-treatment responses for almost over a year when we were treating participants with a combination of our antibody, Tobevibart and Elebsiran. So this is shown here on the slides. We call it our rollover cohort. So what we did is we treated a number of participants with either Elebsiran alone or Tobevibart alone.
And then for those patients who didn't achieve the desired endpoint, after three doses of the therapy, we rolled them over in a combination cohort where they were getting both Tobevibart and Elebsiran. And we have been following these patients now, 5 out of 6, for over 48 weeks and one patient for more than 40 weeks. And what you can see here is very strikingly, very, very quickly after putting these patients on combination therapy, we saw a very drastic reduction in the delta RNA levels to, you know, below lower limit of quantification or lower limit of detection. And that has been sustained now, as I mentioned, almost over a year. Six out of 6, 6 participants in the end achieved a level of delta RNA below the limit of detection.
Very importantly and strikingly as well, is that five out of six participants reached what we call target not detected. So the delta RNA virus could no longer be detected. Also, three out of six of these participants had normalized ALT. So again, this is... This was so our initial data that showed promise of the combination of Tobevibart and Elebsiran as a treatment for delta patients.... So this was the first set of data that we presented, and again, focused on really showing the durability of response. Then the second data set that we shared at EASL was taking Tobevibart and Elebsiran, our two therapeutic agents, and rather than having a lead-in phase, immediately de novo put patients on both therapeutics at the same time. And what you see here is our original, our initial data.
We enrolled 32, 32 patients in this cohort, and we have for 11 patients, 24-week on-treatment data. And again, this is a once-a-month therapy, so it's a once-a-month injection of both the antibody and the siRNA. And what you can see here is that very quickly, very deep virological responses were seen here on the left-hand side. You see the HDV RNA response, which was very rapid, very steep declines in delta RNA. And from these participants, 100% achieved below, below the lower limit of quantification. 91% of those 11 participants received below the lower, lower limit of detection, and more than half of the patients, after this brief period of 24-week treatment, already achieved below target not detected. So the delta RNA virus could no longer be detected in those patients.
So that was a very impressive virological response and again, a limited set of data, a limited number of patients. What you see on the right-hand side is the ALT normalization. And again, there you can see that there is a significant normalization of ALT happening and that you are moving from, you know, over time, the levels that we achieved were 64% for the 11 participants at week 24. So that combination leads us to a combined endpoint that is being used by regulators of 64%. And again, one of the best data that has been shown to date. And then very quickly, the third set of data that we showed at EASL is Tobevibart monotherapy, given every 2 weeks.
And again, what you can see here on the left-hand side is again, the delta RNA response. Again, a steep response, maybe a little bit more variability, but again, getting to lower limit of quantification and lower limit of detection. Also, 18% of those participants achieved target not detected. And then on the right-hand side, you see the ALT normalization. Again, very steep reduction of ALT to normalized levels. And also here, we achieved 64% ALT normalization only after 24 weeks. So that's sort of the three data sets, Paul, that we shared at EASL. And again, both for the combination therapy and for the monotherapy cohort, both on the virological side and on the ALT normalization side, impressive results.
Okay, great. A few questions there, maybe just starting with the ALT changes, you know, which were not quite as common as the virological changes. Can you maybe just help us understand, is that something that, at least based on the literature, moves in concordance with the virologic response? Or is that something you just need more time to suggest evidence of normalization?
Yeah. So as you can see, the kinetics of the virological response are certainly faster than ALT normalization. However, what you can see is that there is certainly a trend over time from going to increase ALT normalization. For example, in the combination cohort, we go, I think, from something like 44% to 64% between 12 and 24 weeks. So there's a clear trend in the right direction. And what you also see from both of the ALT curves is that the trend is still going down. So the expectation is that, you know, as we get more patients to, you know, the 24-week time frame, that we would see also more ALT normalization. We've actually had at EASL, an ad board with eight top hepatologists, KOLs in the world, and we've had...
We had exactly that conversation with them, and they were really not as much focused on it.
Okay.
They really believed very strongly that, you know, again, delta is a, it's an orphan disease, but it has a virological origin, and for any virological disease, they're really looking at how do you get rid of the virus first and foremost. And they, you know, they were very pleased to see the ALT normalization rates and sort of, again, it was less of a focus, and they really appreciated that, of course, the trend was going in the right direction.
Great. Maybe dig into some of the subpopulations there. You included some cirrhotic patients there as well. Maybe can you help us contextualize, you know, what was the result in the cirrhotic versus the non-cirrhotic population? Does this, you know, think of how does this potentially affect your future clinical development plans?
Yes. So one of the hallmarks of delta, unfortunately, is that patients progress to cirrhosis very quickly. So what we decided to do is in our cohorts for the de novo combination and also for the antibody monotherapy, include approximately 50% CPT A, so compensated cirrhotic participants. So we were successful in doing that. And for the combination, we have initial data. We have from the 11 patients that reached 24 weeks, there were 6 patients that were non-cirrhotic and 5 patients who were cirrhotic. And we saw absolutely no difference, not in the efficacy, the speed of virological response, ALT normalization, or safety and tolerability. So that's good news. Again, it's small data set, but, you know, certainly good news to see that.
In our antibody monotherapy arm, we only had from the 11 patients that reached week 24, one cirrhotic participant. So it's a little bit premature, but again, we will have our full data set towards the fourth quarter, and that will then also give us more insight.
Maybe just as a reminder, by CPT, you mean Child-Pugh classification, right?
Correct.
Just to clarify for the audience who may not be familiar with this. I want to maybe ask a couple things on additional on SOLSTICE, which is just in terms of your thinking about, you know, what the next data point update will be. I think it'll be later this year, presumably at the next major liver medical meeting. Just kinda remind us what the follow-up period will be there in terms of and also how many patients you might potentially be able to include in your next analysis. And then my second question is, you know, pending this longer-term data, just how do you think about and approaching regulators for a potential pivotal trial design, and just sort of what the potential timing for that might be?
Right. Yes. So as I mentioned, we have enrolled these two cohorts, the combination and the monotherapy. In total, it was about 65 patients, and thus far, we only have 22 that have reached week.
Twenty-four
... 24. So the fourth quarter, you're absolutely right. At the obvious next medical congress, we will be sharing the full data set, so for all the participants going up to week 24. So that will be very instrumental and very insightful for us to see whether the trends we have seen, you know, continue. And then the idea is to engage with regulators in the third quarter, you know, starting to share this data with them and start to have discussions on what the regulatory path could look like. And again, given the strength of this data and the high medical need, the fact there is nothing available here in the United States, we also really want to make sure that we explore all paths to acceleration.
Be it, you know, breakthrough designation, fast track, orphan designation, PRIME. So we're really looking at the full set of, you know, how do we potentially make this available to patients as quickly as possible.
Okay, great. In terms of longer-term data, I guess, you know, what... Is there a need to maybe show 48 or, or 52 week or longer, longer, longer follow-up in this population? I think Gilead has tracked, you know, their, their product for, for, for quite a long period as well, in terms of phase II and phase III studies. Just what are your thoughts on, on the need for that, that kind of data in terms of showing, you know, even longer-term data versus just the full cohort at, at 24 weeks?
And then second, in terms of durability or response, you know, in a perhaps in a washout period scenario, is that something necessary you need to see in terms of seeing what the response looks like some set of time after patients get off therapy here in the delta population?
Yeah. So, I mean, similarly, we of course follow these patients up for a very long time. I think in the case of Gilead Bulevirtide in Europe, it was the first regimen that went to market. And so, Gilead achieved conditional approval based on 24-week data, but then eventually had to show 48-week data. So, you know, we will have those conversations with the regulators. There's no precedent in the United States.
Yeah.
There's nothing available. So, you know, we will have the conversation to see, you know, what, what is the duration of the, of the trial that the regulators would look at. And then, sorry, your other question was related to potentially a finite treatment?
Yeah, a finite treatment-
Yeah.
and just understanding what patients look like once they get off therapy. Is that something you're gonna examine after 24 or 48 weeks? And just sort of what—how sticky the response rates are, in terms of patients who wash out of therapy, and just whether it, the responses are sustained.
Yeah. So for the time being, again, the whole idea here of our therapy is to come up with a chronic treatment. So it's very different from what we will be discussing potentially for Hepatitis B, where we are looking for a functional cure. So our first, you know, goal here is to select a regimen, either our combination or our monotherapy, and, you know, come up with a chronic treatment that is hopefully going to drive a lot of change for patients. Whether we will be able to move to finite treatment over time is something that, you know, is maybe a little bit premature, but that, of course, you know, we will continue to think about.
Okay, great.
Yeah.
I want to actually dig a little bit more into the monotherapy arm, which, you know, I think surprised a lot of people in terms of how well it did, and so maybe not you, but maybe some people. But, I guess, you know, the monotherapy cohort clearly did quite well. And so maybe I guess the question here is, you know, what other factors beyond the data being sustained here would impact, you know, you're thinking about whether to include a monotherapy cohort in your Phase III or pivotal trial designs?
Yes. So, as I mentioned in the beginning, one of the hallmarks, and the real expertise that we have at Vir is how to engineer antibodies for optimal function. And Tobevibart has been engineered not to just be an antibody that can bind HBsAg and neutralize, you know, the and prevent the entry of, of virions to go into the cell, but has also been optimized for, you know, half-life extension, so it has a longer durability in the patient, and also for immune engagement. So there's a lot of things that are in here that, you know, again, to your point, we are not as surprised. We're really happy to see this kind of activity, and it sort of reinforces, you know, the ingenuity with which this was engineered.
That being said, you know, our intention is to only go forward with one regimen into registrational trials, and so we will be making a decision on whether best to go with Tobevibart plus Elebsiran versus Tobevibart alone. And there's a lot of things that go into that. You know, we'll be looking at, of course, the virological response, ALT normalization, safety, efficacy, tolerability. So the whole holistic, you know, assessment of, which regimen to go for. We have shared actually at EASL on Saturday, some additional data on S-antigen response of the combination versus, the, the monotherapy. So there's some more data that we have and that we will all take into account as we make our choice.
Okay, great. I want to talk a little bit about the differences in Europe versus the US, where you know, as we've been mentioning, Hepcludex is approved in Europe, but not available here in the US, where it received a CRL a while back. Not so much for clinical issues, but more for manufacturing and quality, you know, quality issues. So you have two different paths, you know, where in Europe, you have an approved product that's already being commercialized there. And just maybe, can you highlight, you know, how you think about the treatment paradigm or commercial strategy as well, potentially evolving down the road, in Europe versus the US?
Yes. So given that situation, which is a little bit, you know, unique, I would say-
Yeah.
It is the case that we will take the bulevirtide as one of the comparator arms in our studies. Again, our studies will be global studies, and we wanna make sure that we have the optimal setup for pricing and reimbursement and comparison with the standard of care in Europe. So that's the way we think about it. You know, given the... And again, this is preliminary data, but given the very strong virological response and the ALT normalization that we have shown here, we do believe we have a potential best-in-class regimen that could displace the current standard of care. It's also for patients very convenient because it's a treatment once a month or every two weeks, depending on the combo or the monotherapy.
So, you know, we think that if we can demonstrate this kind of data in a larger data set of patients, that this could really be transformational for patients.
Okay.
Yeah.
Great. I want to take maybe a step back and think about, you know, what the SOLSTICE data means potentially for your ongoing hepatitis B program, and just sort of how, you know, we should think about the translatability or interpretability of your SOLSTICE data in what is typically a more severe and sick population, where you can see, you know, sort of treatment effect a little more clearly, versus a hepatitis B population that you're evaluating in MARCH, part B, with the same combination. And, can you maybe talk about, you know, has your clinical thinking evolved in the context of having this early set of SOLSTICE data for MARCH B and I'll have some follow-ups after that?
Mm-hmm. Yeah, of course, we are, you know, very happy to see these kind of data in the hepatitis delta population. However, hepatitis B and hepatitis delta are fundamentally very different viruses, right? One is a DNA virus, one is an RNA virus. Of course, the S-antigen is sort of the common theme there because delta sort of hijacks the S-antigen from B to be able to conduct its life cycle. I would say that, again, it's encouraging to see the deep S-antigen declines that we can drive, especially with the combination. And that was also exactly what we have seen in hepatitis B early data. Again, maybe to frame things, hepatitis B is, of course, a very different type of opportunity. It's not an orphan disease.
There is an estimated one in two out of 50 million people in the world living with hepatitis B, and an estimated, you know, 1.6 million in the United States alone. So the data that we have shown before, Paul, were encouraging in the sense that we combined Elebsiran, so the siRNA, initially with interferon, and we treated patients for 48 weeks, B patients, 48 weeks, and we saw around 26% that had S antigen loss. And so 24 weeks later, we saw, you know, about 16%, functional cure. And that's still one of the best outcomes that has been seen thus far in all comers of hepatitis B patients.
So what we then did is we added Tobevibart, our antibody, either to Elebsiran alone or to Elebsiran plus Interferon, and we saw that again, it was early days, it was at 24 weeks, that we could triple the S antigen loss at that moment in time. So what's gonna be now really important is to see our end of 48-week, end of treatment data in the fourth quarter of this year. And if that looks interesting in the sense that if those antigen loss numbers would look substantially higher than 25%-30%, then I think, you know, we could have something that is promising. Because what KOLs are telling us is, you know, there's really nothing available for patients right now. You have interferon alone, but that gives you only sort of between 3%-7% functional cure.
But if you can get to a level of 25% or 30% functional cure, then physicians would really think hard to, you know, treat their patients. And so that's what we're aiming for. And at the end of this year, we won't have the functional cure data yet, but we will have the 48-week end of treatment data, which can be, you know, a good indication whether we're going to be able to get there. So that's gonna be really important for us to see.
Okay.
Yeah.
So just to maybe remind the audience, you'll have both the triple-like combination data update, plus a double-like combination update for both Tobevibart and Elebsiran in the fourth quarter?
End of fourth quarter.
Okay, that's correct.
Yeah.
And then will it be something, not that you have to necessarily, obviously, or can control the coordination of the timing, but we'll also make that, that medical meeting in, in the fourth quarter as well, or is that just maybe a little bit too hard to predict at this point?
It is likely.
Okay.
Yes.
Okay, great. In our remaining time, you know, I want to maybe shift gears and talk a little bit about your other programs outside of hepatitis delta and hepatitis B. Maybe, you know, what would you highlight as sort of the next program to update? You know, I think, you know, since I followed the company for a while, I've always found the concept of the HIV program interesting-
Mm-hmm.
Based on the preclinical data, but can you maybe, whatever is you think is most interesting to investors or potentially that you would highlight?
Yes. And again, all our programs are really based upon our two platforms, our antibody therapeutics platform on one hand, and our CMV viral vector-based platform, on the other hand. So the platform that you are referring to, Paul, is based on our CMV platform. So we have a phase 1 program, HIV prophylaxis program, that is based on a CMV vector. And the idea is there that you would use actually the CMV vector a little bit as a carrier or a Trojan horse, so to speak, bring it into patients, but have it equipped with HIV insert, so that the participant would develop a very specific CD8 T cell responses against the HIV insert. And what is very specific about the CMV vector is that it generates immune responses that are very long lasting.
Now, this has been shown to work very well in animal models, but it hasn't been proven in human participants yet. So the second half of this year is gonna be important for us to demonstrate proof of principle, potentially, of the platform and see if we can really generate those specific T cell responses. So that is a clinical stage program, phase 1, and then we have several programs preclinically, that are, you know, sort of within 12- 24 months from the clinic. We have based on our antibody platform, a collaboration with GSK, where we're trying to come up with a unique cocktail of RSV antibodies.
We also have a next generation flu antibody that's for flu prophylaxis that we're gonna have animal data on second half of the year, and that we would aim to partner because this is a very capital intensive program, potentially.
Mm-hmm.
And then we have funding from BARDA, that helps us develop a next generation COVID antibody as well. And then on the CMV platform side, we have a next generation program that is focused on papillomavirus. And again, that's preclinical, but that is sort of, you know, based on the very same principle as I described for HIV.
Great. Since there is obviously no approved, you know, full on HIV prophylaxis therapy out there, can you maybe help us with a framework to understand in terms of like, whether it's CD8 responses or animal challenge data and things like that? And I think you have done animal challenge data in terms of the simian SIV model and just kind of maybe what you've seen there, and then maybe what the, you know, HIV expert or KOL community thinks about it as sort of potentially reasonable benchmarks or just, you know, how to approach even how to think about that initial data?
Yes. So animal models with the PIB virus and using CMV vector showed, you know, very strong protection against with HIV. So but again, in human participants, that same level of immune response has not been shown. If that would be the case and we can demonstrate that again in the second half of the year, then, you know, this would really be a, you know, a springboard to to many more potential indications that would open up. And, you know, everyone, you know, KOLs with us are sort of waiting to see that data, to see what the potential could be.
But again, what is really differentiating potentially is that once you would generate that, it would be a very long-lived response and a very long-lived response against a certain insert, in this case, HIV, that you would not typically be able to achieve with any other, you know, vaccine or anything else that has been tried out to date.
Great. In our minute or two that we have left here, I want to talk a little bit about strategy, particularly with regard to to your capital position. And just... You obviously developed a very nice war chest based on your COVID revenues. But can you maybe just remind us how you're thinking about the durability of your funding and potential inflection points in terms of, you know, clinical catalysts? We spoke a little bit earlier about your hep B and hep D updates coming up later this year, but just maybe first remind us, you know, what does your cash runway look like? And then sort of what's the longer term strategy for the capital structure?
Sure. So at the end of the first quarter, we had $1.51 billion in cash. And of course, that allows us to really fund our critical programs to the next value inflection points. As we discussed, we will have 24-week data on both cohorts, more than 60 participants, fourth quarter for hepatitis delta. We will have the 48-week end of treatment data for hepatitis B, again in the fourth quarter. And so again, with this level of, of cash, we are very well placed, to generate, you know, the next level of data that would be very, transformative potentially for the company. At the same time, we are looking externally at potentially bringing in early clinical, assets.
We have always said that we want to broaden our aperture beyond infectious disease, so we are looking, you know, where our deep expertise in immunology could potentially really drive difference.
Okay.
Yeah.
Great. We're almost out of time, so we'll have to end it on that note. My thanks to Marianne and Vir for joining us today. Thank you very much.
Thank you, Paul. Appreciate it.