For joining this session with Vir Biotechnology. My name is Alec Stranahan. I cover mid-cap biotech at Bank of America, and I'm the covering analyst for Vir. It's my pleasure to introduce Marianne De Backer, Chief Executive Officer of Vir. Marianne, thanks for being here. Yeah, my pleasure. Thank you. Yeah. Looking forward to the discussion. I guess just jumping right into it, you've effectively built a two-engine value story for Vir. You've got the near-term potential from HDV, which we can talk about, and the longer-term oncology platform, using the PRO-XTEN technology. I guess, when you look at how the market is valuing the company today, where do you see the biggest opportunity for re-rating? Is it on HDV approval and launch? Is it on the VIR-5500, you know, progress to registrational studies, or is it maybe the broader platform as the TC data matures? Sure. Yes. Thank you. Thank you, Alec, for hosting us and Bank of America for hosting Vir Biotechnology. We are very fortunate that at Vir Biotechnology we have multiple pathways to value creation, as you point out. Obviously, our most advanced program is our Delta Program, already in registrational trial. Initial data gonna read out starting fourth quarter of this year. Obviously that's, you know, an important route to value creation near term. Then, as you mentioned, we have a portfolio of three clinical assets, three clinical masked T-cell engagers, and just in February we read out quite promising data for our Prostate Cancer Program. Again, you know, huge opportunity potentially. T-cell engagers have, in the solid tumor space, been very challenging, you know, faced with a lot of toxicity, and we believe that with our PRO-XTEN platform we can really address that and come up with T-cell engagers that have a unique therapeutic index. Thirdly, to your point, we have the platform, and we really think that the PRO-XTEN platform is like an IND machine, we have started seven preclinical programs. Of course, we will not keep them all wholly owned. We are going to partner some of them. Again, that's going to be another important path to the future and more mid and long-term value creation for the company. Great. Obviously we can get into the partnerships that you've already struck for VIR-5500. Maybe just before we get there, in terms of capital allocation and prioritization within the pipeline, your cash runway is pretty extensive after the recent raise. I guess, how are you balancing the phase III ECLIPSE trials of which you've got three ongoing, and the commercial build-out in HDV with maybe the dose expansion and the combination studies across the oncology TC portfolio? Sure. At the end of the first quarter, we had $809 million, and because we entered into a partnership with Astellas, we will have about $350 million coming in. One important aspect of the funding for the VIR-5500 program is that due to the partnership with Astellas, Astellas will be taking on 60% of the clinical development costs going forward. That is very important because we really want to fully explore the potential of that asset, and we are doing a number of trials in parallel, and obviously that's going to be quite funding intensive. On the other hand, again, our delta trial is in registrational phase, so that is really taking up the bulk of our investment at this moment in time. You can sort of expect that, over time there will be a shift from, you know, investment into our delta program to, you know, floating more of that investment into our oncology portfolio. Okay. Great. Well, maybe we can start with VIR-5500. You recently had an update at ASCO GU, which showed very good efficacy, I think 82% PSA50, 53% PSA90, 45% ORR at the go-forward dose. As you move into the expansion cohorts, I guess which of these metrics, either the depth of the PSA response, the ORR by RECIST or durability, or maybe a combination of these sort of stand out and give you the most confidence in moving these to phase III study? Yeah. As mentioned, the real crux of being able to come up with the best-in-class T-cell engager for solid tumors is to get to a very favorable therapeutic index. If you look at a lot of T-cell engagers, again, in that space, you can get to reasonable efficacy, but you know, it's combined with pretty problematic toxicity. It's really not just looking at efficacy, but it's the combination of efficacy and safety. The data that we showed in February were, of course, quite compelling, to your point, very promising PSA data, and it was perfectly concordant with RECIST data, with PSMA PET evaluations, with RECIST evaluations. Our efficacy, you know, very nice dose response, you know, nice concordant data, but more importantly, it was combined with a very nice safety profile. Predominantly only grade one CRS. That is really what we would want to see. The expansion cohort has actually already started for late-line mCRPC. We have selected our dose, and the idea there will be at one dose level to explore, obviously, a broader set of patients, and then also explore a little bit more than we have done up to now what it looks like in pre-radioligand therapy and post-radioligand therapy patients. I see. I guess when you think about the durability of response, I think we have, you know, a few case studies that could speak to the long sort of deep response that's possible with VIR-5500. You know, what do these responses and the durability sort of suggest about the mechanism? Any initial thoughts on sort of PFS and what you would want to see there? Yes. On the durability side, we had a number of case studies. As you pointed out, we had a patient that had been eight months on study, we had a patient that had been a year on study, we had a number of patients where we had RECIST responses that confirmed post 27 weeks. Those were sort of the initial signs of durability. The dataset was still pretty much immature at the time of sharing it back in February. We will, in our expansion cohort and, of course, in our existing cohort, continue to look at durability. From our perspective, there's no reason why you wouldn't see durability. There's a number of other T-cell engagers in the prostate cancer space, you know, STEAP1, KLK2, that have shown durability, there's really no reason why a PSMA-targeted T-cell engager would not show durability. Again, we have these early, very promising signs. The other thing I would say is that, you know, given our technology, our masking technology, which is the same across all our clinical assets, in our HER2 program, where we use the same masking technology, we had a patient that we showed data on last year that also had been 18 months on treatment. We also see that the masking technology across different targets actually allows us to get results and also allows us to show durability. Again, this is still sort of case-specific, but as the data matures, we hope to show more. As to your question on rPFS, you know, again, our datasets in February was a bit early, but in our expansion cohort, it's of course absolutely the intent to look at rPFS and share that data when available. Okay. Great. I guess when we think about the patients that respond well or respond less well, I think you had two early progressors with PSA, PSMA-negative lesions. I guess as you plan combinations with enzalutamide and explore earlier lines of therapy where PSMA expression is maybe more variable or could maybe be suppressed after PLUVICTO, although I'm not sure that that's well-studied. How are you thinking about, you know, prospectively monitoring antigen loss in your pivotal programs, just to make sure that patients are expressing the target? Yes, you're absolutely right. I mean, you have obviously heterogeneity on PSA levels between patients. Then you have actually, you know, different levels of PSMA expression depending on, you know, which tumor within the patient. You have intratumor variability. It is something that we pay a lot of attention to. Our translational biomarker study, you know, using PSMA PET is really looking to look at, you know, pre-treatment, post-treatment. Then again across patients and intra-patient at potential variations in PSMA levels. I wanted to say, though, that in our earlier dataset from February, we had about seven patients that had been having PSMA radioligand therapy. Unfortunately, there was only one patient that was already at efficacious dose for which we had the data. That patient showed incredible responses, PSA 99s, you know, very clear T-cell infiltration in the lymph nodes. You could see on PSMA PET complete, you know, completely the lesions clearing up after nine weeks. It's not the case that if you have a PSMA directed therapy that, you know, it isn't possible anymore to use our T-cell engager after that. Again, this is something that in our expansion cohort, the late-line monotherapy, we're gonna explore a bit further. Right. You're obviously testing post-PLUVICTO and also pre-PLUVICTO. Correct. Yes. Yes. Not just PLUVICTO, also other actinium, et cetera. Mm-hmm. Mm-hmm. Radioligand therapies. Okay. You alluded to this, but the CRS profiles looked very good. 50% of patients were entirely, you know, grade 1-2, largely early cycle with no need for prophylaxis really. How much of this differentiated CRS profile would you attribute to the dual mask versus, you know, maybe patient population or dosing schedule? Yes. We really believe that it is our masking technology that makes all of the difference. Our masking technology is basically, you know, this hydrophilic, you know, protein structure that we form around the T-cell engager, and we mask both the CD3 binding domain and also the tumor-associated binding domain, so the PSMA binding domain. The dual masking obviously is important, but the masking technology is really crucial because what the masking allows us to do is really, again, the whole idea is that through creating this mask around the T-cell engager, you can dose the patient. The masked T-cell engager gets a longer half-life. In the case of VIR-5500, it's eight to 10 days. It can safely sort of transport into the bloodstream of the patient. It can get to healthy tissues and nothing happens. When it enters the tumor microenvironment, the protease cleavable linkers are going to be cleaving, being cleaved by the proteases in the tumor that, you know, where they are dysregulated. The masks fall off, the T-cell engager can exert its effect. When the masks are removed, the half-life is really reduced to only a couple of hours. That mechanism, you know, is really allowing us to dose up quite high, so you get good efficacy, and that you can combine with, you know, again, a really differentiated safety profile. Because it's really protected outside of the tumor. I guess when you think about moving to earlier line patients, is there any reason to think that the CRS profile might be better or worse? Just thinking about, you know, tumor debulking, sort of the cytokine release itself, how much pent-up cytokine is it within the tumors? Any sort of biologic rationale for why, you know, a frontline or an earlier line patient might have better or worse CRS? Yeah. We see in a very refractory patient population already really good results. I just want to remind you the patients set for VIR-5500, almost half of the patients had visceral metastasis. You know, one in five had liver metastasis, so really patients with very big very bad prognosis. In that data set, we showed really good efficacy. What KOLs believe is that if you go to earlier lines, you even might have the possibility to see better efficacy because obviously there is a possibility that you have a healthier T-cell repository there. Of course, for T-cell engagers to be effective, you need good CD8+ T-cells. You know, we don't have that data yet, but it could be that it actually is going to be looking, more, even more promising. Okay. Maybe one more question circling back on a point that you mentioned about the dual mask and, you know, the cleavage in the tumor. I think you showed 93% of patients had unmasked drug concentrations that were essentially undetectable in circulation. When you look at patients that have distant metastases, does the cleavage profile change at all across different tumor microenvironments? I guess, how does that data sort of shape your confidence on expanding to broader, more heterogeneous population? Yeah. First of all, we have designed our protease cleavable linker such that there is a level of promiscuity, there's different protease families that can cleave the linker and, you know, it is based on, you know, of course, decades of understanding what proteases are upregulated in tumors. What we know now, and of course, we are learning as we go, but what we know now is that obviously we get effective cleavage in, you know, the prostate. We see that we get effective cleavage in the metastatic sites. You have seen, you know, evidence of that in the lung, in the lymph nodes, in the liver. We have, you know, a lot of examples now. Also with our HER2 program, we have shown that, you know, we saw some effects in metastatic colorectal cancer, in a breast cancer patient. I think this shows you that it's actually a very versatile platform. That the unmasking actually really does happen across a broad tumor set of tumor types. Okay, great. I guess in terms of the dose optimization and sort of your strategy going into the pivotal, you know, what does the expansion cohort data set really need to show to justify a particular go-forward dose? I guess given that the eight-10 day half-life of the masked molecule, are you exploring, you know, maybe step-up dosing or other approaches to further flatten the CRS curve? Yes. We have selected a go-forward dose for our late line monotherapy cohort. We have selected indeed a step-up dosing of 800, 2,000, 3,500. The way it works is that patients get dosed at 800 mcg per kg, a week later at 2,000, then a week later at 3,500, and then actually the therapy starts with every three weeks, 3,500 mcg per kg. That is the go-forward dose we have selected for monotherapy. We haven't shared yet the data around the go-forward dose for the combination cohorts. Those cohorts haven't been started up yet, but, you know, we will share that data as it becomes available. We will also be doing some further optimization to satisfy Project Optimus. Okay. Okay, great. Maybe looking beyond VIR-5500, obviously having the Astellas collaboration kind of in your pocket for when you were re-releasing the data was a stroke of confidence, obviously, for the program. Does the Astellas collaboration kind of represent the ideal partnership archetype, for other TCs such as 5818 or 5525? Or will the partnership maybe vary depending on the tumor type or the stage of de-risking in the clinic? Yeah. Whether we keep a program wholly owned or whether we partner and how we partner really depends on the program. It depends on, okay, what is the unmet need? You know, what other competitive regimens are there already there? How can we really come up with a differentiated offering? What would it take, you know, development-wise, and what would it cost to get there? There's a lot of considerations, I would say. We will really be looking, and we are strategically looking at each program, what might be optimal for the program. For VIR-5500, we think that the deal with Astellas is really, you know, optimal because it's a co-development, co-commercialization deal. We retain 50% of the profit in the U.S. They share, as I mentioned, 60% of the development cost going forward, and it allows us to really go faster, and grow the pie bigger, faster. We can now do, you know, late line, early line mCRPC and HSPC in parallel, you know, much faster than we would have been able to do on our own. Okay. I guess when you think about advancing new TC assets forward in preclinical development and into the clinic, how do you sort of navigate the potential target space? Obviously, it's a very flexible platform. There's a lot of ways you could take it. Do you have a preference to going after well-known targets or well-studied indications, or are you looking for something a little bit more novel? I mean, what we really want is to find an application for our technology that offers something that is really differentiating. What we can really differentiate on is getting to T-cell engagers with a broad therapeutic index, so much safer than any T-cell engager that is unmasked or single masked or masked with a different technology. What we have been looking at is largely targets where there is a clear biological rationale, so they're not novel, they're not unproven. There's some gradation in biological validation, but there is generally biological validation. Where, you know, just given the targets, it has been difficult to come up with safe molecules. Again, that's where we really can make a difference. Okay. Maybe on that last point, EGFR has been a difficult space to develop any sort of TC against, masked or unmasked. I guess, does your view on partnering or portfolio prioritization change at all following the discontinuation of a competitor's EGFR TC program? Not really. EGFR is certainly a more difficult target. If you compare it to PSMA, for example, PSMA is of course expressed in the prostate. It's also expressed in some other tissues, but it's relatively limited. If you look at an EGFR, of course, it's expressed in a lot of tumors, but it's also expressed in a lot of healthy tissues. The bar for any masking technology is very, very high. We do believe that we have a very unique masking technology, and we are now putting it to the test in our clinical trials. But yeah, we will be continuing our monotherapy and combination therapy, and then as soon as we have some meaningful data set, we will be sharing it with the public. Okay. Okay, great. I wanna shift gears now to HDV. This is kind of the other arm of the pipeline, and, you know, the focus from investors from my conversations tends to shift back and forth between this and your TC portfolio, so I do wanna give it the time that it deserves. Maybe we can just start on the competitive landscape here. I guess, how do you view the broader competitive landscape? How did, you know, bulevirtide or, you know, I guess the recent data from Mirum, from the AZURE-1 data, particularly on, I guess, target not detected. You know, how does this sort of shift your thinking around your approach to [cross talk] program and execution, or market expectations? Yeah. Obviously, because Hepatitis Delta is a viral disease, what you really want to get at is to get to undetectable. Get some music. We're shifting gears now. We're really shifting gears, yeah. You're really trying to get to undetectable and undetectable virus, and the way that undetectable virus is measured is through target not detected, TND. What we know now is Gilead is one of our competitors in the space. They're going to launch with a daily administration regimen probably very soon, and they get to target not detected rates of around 12%-20% after 48 weeks. Mirum recently shared their data with their monthly regimen. They had a target not detected rate of 5%. Just give you a comparison, we also have a monthly regimen, and our target not detected rate at the same time point is 41%, and it goes to 66% at 48 weeks and actually to 88% at 96 weeks. I think from a monthly regimen perspective, we're by far, you know, viral efficacy. Mirum has a weekly regimen that has shown about 30% TND at 24 weeks, and again, that compares to 41% for us. Also on, you know, ALT normalization, which is a very a specific marker, but nevertheless, we see now that, you know, competitors are getting normalizations between 40%-45%. We had last week probably 56%. I think that we really are seeing the potential for our regimen to be first-in-class for this disease. That's great. Maybe the next question sort of around positioning. That was nice. That was a lovely backdrop for that last response. I guess just as we think about bulevirtide in the real world, obviously this is approved in different geographies. We're thinking maybe it will expand. I guess as the efficacy and convenience contrast becomes clearer for your asset, versus bulevirtide, I guess how do you expect prescribing to evolve? You know, will switching under responders be common, or is your primary launch opportunity sort of the bulevirtide value patients? Yes. The way that we have designed our trials is we can show actually how our regimen is doing in bulevirtide naive patients. We have our ECLIPSE 1 trial, which is comparing to a deferred treatment. It's basically an almost placebo-controlled trial. We have ECLIPSE 2, where we look at patients that have been on bulevirtide but have not been adequately virologically controlled and that are switched to our regimen. We have a third trial where we compare head-to-head our regimen with bulevirtide. We will really be equipped by the time that we get to market, to, you know, obviously be prescribed for, you know, naive patients, treatment-naive patients, but also to really capture those patients that come off, bulevirtide. Again bulevirtide is a daily injection. Patients need to inject themselves daily, and as I mentioned, they get to about 12-20% undetectable after 48 weeks. With our regimen, it's monthly two injections, and we get to 66% undetectable after 48 weeks. It also allows us with a monthly administration to have both at home administration patients can dose themselves every month at home. For those patients who prefer or are unable to inject themselves, they can also have in-office or in the hospital administration on a monthly basis. It's really a very conveniently, very convenient regimen in that regard that leaves open the option for at home or in-office. Okay, I guess for those maybe less familiar with HDV, it is a fairly underserved patient group and maybe even underdiagnosed to a certain extent. I guess with Gilead likely to launch bulevirtide in the U.S., how does this, you know, we've talked about the competitive differentiation. I think that'll be proven out with ECLIPSE. How does Gilead sort of building out the initial market kind of benefit you guys once ECLIPSE does read out and you're thinking about the launch next year? Yeah. First of all, this is great for patients. The disease awareness is going to significantly increase is our estimation. We believe that diagnosis rates will go up once you know, at this moment in time, even though it's very easy to diagnose Hepatitis Delta, it's not happening. There's only 10%-15% of the patients that are getting diagnosed, the reason why it's not happening is because there's really nothing available in the U.S. to treat patients. We believe that once a treatment is on the market, there will be an impetus to test patients. Again, testing is not difficult. There will be a possibility to do reflex testing. I think the patient journey and treatment pathways will become much clearer. We think that Gilead launching ahead of us is actually very beneficial, again, for patients and also for us who are then coming, you know, with a regimen that is much more convenient and with a much more efficacious profile. Okay. obviously you'll have ECLIPSE 3, which is the head-to-head versus bulevirtide. I think the top line from that is expected in 1 Q of next year. Correct. You've said in the past that this is probably not required for an NDA, I guess how critical do you expect this data set will be in your payer conversations, and is there a risk that a strong head-to-head data becomes table stakes rather than upside? Yeah, I mean, it's something that you just need to have, right? You need to be able to show what your value proposition is compared to, you know, what might be standard of care at that time. We will have that, and again, given phase II data that we have and what we know about bulevirtide, it will not be very difficult to show that added value. We think it's a very important study to do, and it will be even more important we believe in Europe, for example, a s a region for pricing and reimbursement negotiations. Okay. you know, you mentioned the cash position. It sounds like it's scaling even up to $1 billion currently. How do you see investments in the commercial build-out in HDV? What does that process look like? When do you start that process? What does it leave for investing in TC and other parts of the company? Yeah. We have guided to a cash runway until the second half of 2028. We have now a small commercial group. We have a number of medical science liaisons that have already been out for quite some time since last year that have been involved in the studies and are involved in insights generation. We are really building this up very gradually. What is important is that delta is a rare disease. It's an orphan disease. It's the patients are geographically quite concentrated in certain metropolitan areas. It's not like you need this, you know, broad swath of sales or MSL people to put. You have to take a very surgical approach, and that's exactly what we are preparing for. Okay. A lot of exciting things happening at the company, especially over the next 12 months. Really wanna thank you, Marianne, for the great conversation. Looking forward to the updates, thanks for bearing it with us through the technical difficulties. Yes. It wasn't that disruptive, hopefully. Thanks everyone, for your attention. Thank you. Okay. Thank you, Alec.