Okay, great. Well, as participants are continuing to join, I just want to welcome everyone and thank everyone for being with us. I'm Steve Seedhouse, biotech analyst at Raymond James, it really is a pleasure to be hosting this presentation and fireside chat with VBI Vaccines. I'll be joined by Jeff Baxter, President and CEO, and David Anderson, Chief Scientific Officer. This is potentially, you know, a really exciting inflection point for the company. I think they've recently presented some intriguing phase II data for a therapeutic hepatitis B vaccine candidate and now of course are also marketing prophylactic HBV vaccine PreHevbrio in the U.S. following approval towards the end of 2021. VBI is also developing, of course, a pipeline of therapeutic and prophylactic vaccines, including a CMV vaccine for glioblastoma or GBM, a pan-coronavirus vaccine. We'll discuss all these programs. At the outset, I think what I wanna do is turn it over to the VBI team who have prepared some slides, really just to review the recent data and outlook across the portfolio of programs. Jeff and David have been kind enough to allow me to interject with questions as warranted throughout. We'll do that. This will be interactive as we get to discussing the data. I think with that, Jeff and David, thanks for doing this, and I'll turn it over to you at this time. Great. Well, firstly, good afternoon, Steve, thank you to you and to Raymond James for hosting us this afternoon. Also, to thank everyone for your interest who has joined the call this afternoon, to hear this latest data. Just before we get into that, I would just refer you to our customary forward-looking and safe harbor statements. This presentation will be available on our website, this afternoon. In fact, coincidental with this presentation. Dave and I are really excited to run through this data with you this afternoon. This is the interim phase II data from a study that was run in partnership with our partner in Greater China, Brii Bio. The trial was actually run in centers throughout Southeast Asia, and looked at a combination which Dave will expand upon later. Just at the outset, what I wanna say is that we really do believe this data is a very, very solid proof of concept, a mechanistic proof of concept, that VBI-2601 or BRII-179 can elicit robust B cell and T cell responses in chronically infected individuals. David will certainly elaborate on that, the mechanism and the data as we go through. Before we get into this, there may be some people on the call that are unfamiliar with VBI. We are a vaccine company, a biotech company. We have a commercially launched product, which is prophylactic hepatitis B vaccine. I'll be saying more about that later, but that was approved by the FDA in November 2021. Our pipeline focuses on hep B, GBM, COVID-19, and CMV in terms of therapeutic and prophylactic target pathogens. We operate out of here, our head office in Cambridge, Massachusetts. Our R&D facilities are based in Ottawa, Canada, and our wholly owned manufacturing facility is based in Rehovot in Israel. The topic for today is hepatitis B. As you can see from this schematic, Jeff, just to interrupt. We're still stuck on the introduction slide. I don't know if you have to switch to presentation mode or focus the window, but I'm seeing just the title slide currently. There we go. Perfect. Thank you. Okay, cool. Thanks, Steve. I'm glad you pointed that out. It would have got very difficult when we got to the data slides otherwise. A little technical. I'll take good note. As you can now see from this slide four, we have both the prophylactic and a therapeutic candidate in hep B space. As we've mentioned, PreHevbrio was approved in late 2021 and launched in the end of the first quarter, early second quarter of 2022. The topic of today, though, will be VBI-2601 or BRII-179, which is this HBV immunotherapeutic, specific immunotherapeutic. PreHevbrio, just before we go on, is the only prophylactic HBV vaccine that contains all three surface antigens of the hepatitis B virion, significantly differentiated from other pre- vaccines which are monovalent, only containing S and derived from yeast. PreHevbrio is derived from mammalian cells. VBI-2601 is a candidate which has been specifically developed from PreHevbrio in that it builds upon and contains Pre-S1, Pre-S2, and the S antigen, and again, is derived from mammalian cells. We also, in reformulating PreHevbrio to derive VBI-2601, changed the adjuvant. Again, Dave will say more about that, but that was to enhance both the B-cell and T-cell responses in chronically infected individuals. Just a brief word about hepatitis B. Hep B, as the slide says, remains a persistent public health problem. In fact, it is the most common blood-borne infection of the common variants. Up until coronavirus or COVID-19 was in fact the fastest growing and the most prevalent of the common variant pathogens in society. The issue with hepatitis B is it's known as the silent killer. People do not realize in younger life when they get infected or in fact get infected as pediatrics, that they will be HBV positive and have the risk of passing that infection on to others. As it says in the left-hand column, the problem is that suboptimal surveillance results really do not lead us to understand the true nature of the infection in terms of number of individuals. The U.S. estimates range anywhere from 1 million to 2.2 million individuals and up to 5 million in Europe, somewhere between 240 and 350 chronically infected HBV individuals around the world. We've seen those infection rates increase dramatically, up to 11% per annum between 2014 and 2018. In Europe, again, a very significant increase in infection rates, largely driven by the lack of universal pediatric vaccination, the lack of adult vaccination, and both the voluntary and involuntary mobility of society that's spreading that infection. As I mentioned earlier, known as the silent killer, 68% of chronically infected are unaware of their infection status. As I've also mentioned, adult vaccination levels remain very low. Recognizing this, as the bottom bullet point says, the WHO has adopted the goal of eliminating HBV globally by 2030, which is obviously a hugely ambitious and lofty goal. Having said that, many nations around the world have adopted their local national plans to tackle this significant growth in HBV breakthrough infection. The CDC and ACIP in the U.S. earlier last year actually changed the recommendation for adult vaccination to a universal adult recommendation based upon an age range of 19 to 59, rather than being on a risk-based recommendation. This is really important because it shifts the onus from the individual essentially sitting in front of their HCP to admit, if you will, that they are in a high-risk population to the clinician now actually saying that regular checkups, wellness checkups, annual checkups, et cetera, "Have you had a hep B vaccination? If not, it's now recommended that you should get one." This is a really important development, a really important tailwind for vaccination in the U.S. With that, I'll hand over to Dave, who will talk about the recent data from this phase II interim readout from the study that's running in Southeast Asia with our partner group. Great. Thanks, Jeff. You know, Steve, I think it's safe to think about the chronic HBV field much where the hepatitis C field was about 15 years ago. By that I mean, I think there is a general view and consensus that a functional cure is achievable. It's just a question of which modalities are gonna be necessary to get that kind of benefit, that cure to, you know, a significant number of patients. Exactly as to what happened with hepatitis C. Now, in terms of functional cure, just so everyone's clear on the definition. That's essentially undetectable HBs antigen levels, and the ability to remove standard of care, NUC therapy, and have controlled, you know, controlled virus, so no further replication. That's again, a consensus view. Here you can see some of the additional modalities I just referenced. Everyone appreciates that you're not gonna displace standard of care, which, you know, is a NUC inhibitor. It's very effective at suppressing virus replication. The real challenge, and this has been a challenge for decades, is the S antigen that's being pumped literally into the bloodstream. If you think generally speaking, there are two different parts. There's the infectious virion, which again is very well controlled at very low levels in patients that are on NUC therapy. Then you have at ratios ranging from 1,000 to 10,000 times higher, these subviral particles that are really comprised of just the S antigen. It's this constant barrage of immune system with this S antigen presented in a very non-inflammatory, non-immunogenic way, which literally shuts down your HBV S- specific B cell antibody and T cell response, and renders the immune system powerless to control this virus. That's really the reason there's been so much effort over the past five, six years to come up with modalities that could really drive down these S antigen levels. Now, if you go back three or four years ago, I think there were many that believed and certainly hoped that if you simply knock down those S antigen levels a couple orders of magnitude, that you might spontaneously get restoration of immunity. The reality is that, you know, what's happening, it's a term we call tolerance. It's been known and studied in models for decades, literally. A traditional definition of tolerance is you can take away the tolerogen, and yet you don't still have spontaneous restoration immune system. You know, unfortunately for the patients in the field, that's now what's come to pass. We have clinical data on, you know, four or five different siRNA compounds that have all approximately knocked down S antigen levels 1.5 to 2 logs, but it's not sustained, and it's the rare individual that has spontaneous restoration of HBs- specific B cell or T cell immunity. That's what we predicted would happen. Coming back to Jeff's point about the unique features of 2601, it's not comprised just of the S antigens, but of these Pre-S1 and Pre-S2 surface antigens. There are a lot of studies, it's not here in the slide deck, we don't have time to go through it all, but a lot of preclinical and human clinical studies demonstrating that in animals or individuals non-responsive to S, if you simply vaccinate with S plus Pre-S1 or plus Pre-S2, you could break tolerance because those antigens were still sufficiently immunogenic. Dave, just if I could interrupt. Yes. What do we know about people, just people's susceptibility to that tolerogenicity or just getting chronically infected? Are there learnings from their immune systems or things like this that inform, you know, that either the design of 2601, the design of a combination regimen that would work, the direction the field has gone in general here? Any comment on that? Definitely. I think from the time of infection, you go through different phases and, you know, one classification are individuals chronically infected that are HBe antigen positive or negative. If they're E antigen positive, it's earlier in the disease course, and the state of tolerance is probably not as profound. If you have someone that's E antigen negative that's been infected for a decade or more, it's very easy to conceptualize that they may have a more profound state of tolerance because they've been bombarded, as I said, for so long. As you start to look at data coming out, ours and other data sets that we'll undoubtedly read out in the coming year or two, the benefit that different patients get may be related to, you know, the duration of the prior infection. That's something that we're eager to investigate. We haven't had a chance to do that yet with our colleagues at Brii, but I think it's definitely something that we'll wanna look at. Having said that, you know, we need to drive down those S antigens, as I said, we felt strongly that there was a need to try to break tolerance with non-tolerized antigens, and hence the use of 2601. Go to the next slide. You know, tremendous credit to our colleagues at Brii for really driving and conceptualizing two very interesting studies that put these kind of triple combination modalities together. You can see in the top portion, this is the data that we'll be discussing this afternoon. The idea was standard of care, which is new therapy to suppress viral replication, use an siRNA modality to drive down those circulating S antigen levels, and then come in with 2601 and see if it could rekindle or restore HBsAg specific- immune responses and help further drive down to undetectable levels. That's one approach, using a genetic means, siRNA, to knock down S antigen levels. Another approach is to use not a genetic approach, but to use the immune system, the innate immune system, by virtue of treatment with pegylated interferon, which is still standard of care in China and Southeast Asia. S antigen levels. That data, we're told we can expect probably around Q3 of this year. Go to the next slide. Before going into the data from this combination trial, I think it's worth highlighting some of the data that came out of our first study with Brii, where we looked at four doses of vaccination with 2601 in chronically infected patients. The reason I'm highlighting this is because there's some very recent data from additional therapeutic vaccines being developed by GSK and Vaccitech that put this in a little bit better context. This particular cohort's patients, as I said, were dosed four times, zero, four, eight, and 12 weeks. There were 10 patients in this cohort. You can see here six out of the 10 patients had specific boosting and/or restoration of responses against S, which are highlighted in blue. If you look across the top row, that's looking at the T-cell responses using a traditional ELISpot assay. We didn't run that assay. It was run by a third party, a very experienced. Then on the bottom row, you have a antibody assay measuring specifically the response to S. Consistent with the hypothesized mechanism of how you might break tolerance against S, you can see in each one of those patients, there was a boosting in the response to either Pre-S1 or Pre-S2 in the black or open circles that was then associated with a boosting or restoration response in blue to get against S specifically. Clearly, the magnitudes differ and as you just implied, Steve, that could be dependent on, you know, how long they've been infected. If they've been tolerized for a much longer period of time, it may take more doses and more time to really reawaken that response. Gratifyingly, in every one of those cases where we boosted or restored responses to S, you could see there was a restoration of the antibody response again along the bottom, specifically to S. The reason I'm highlighting this is that if you look at data presented by Vaccitech and GSK at AASLD in November of last year, they presented similar data sets. Vaccinating into chronically infected patients. What Vaccitech saw was an ability, like others have seen in the past, to boost responses to polymerase or core, but no evidence that it could restore or boost responses to S specifically. In other words, they were unable to break tolerance. If you looked at the GSK data set, it was a little bit more encouraging. They broke it up to responses CD4 versus CD8. Among the CD8 responses, about 20% of the patients you could see clearly restoration or boosting responses to S, but at the CD4 level, it was only around 5%. Here you have the majority, you know, 60% there, certainly the minority. You'll see in just a few moments that we've essentially replicated this data set in this combination study. Dave, can I just ask you to unpack that a little bit just with respect to the compare and contrast to those other immunomodulators? I mean, what do you think it's like three antigen presentation here? What are the differences in the constructs that might manifest those different, you know, potencies on at least HBs anti-antibody response? Yeah. I think it's already implied. I think having non-tolerized antigens to help kind of break that tolerance, we think is clearly very important. That's based on a lot of past mechanistic data in animal studies. I think too, you'll see that it's not just like vaccinate and you turn on the light switch and the immune system is just roaring. It looks like it takes time to kind of reawaken it. You know, I think that's one of the benefits of 2601. It's a recombinant VLP. We can give it repeatedly. You'll see in a few moments that it's very well tolerated. In our case, we were able to give it nine times on a monthly schedule. When you use those other vector-based approaches by Vaccitech or GSK, because they're vector-based, there's a limit in the number of times you can dose because you start to develop anti-vector immunity. It could have been choice of antigen as well as the inability to dose as many times as you needed to really restore that response specifically against S. Okay, thanks. Yeah. just and then obviously we want to get into the new data, but on this slide real quick before we advance. You mentioned 2601, the adjuvant change being one distinction with PreHevbrio, and then here these data are unadjuvanted. Can you just comment on that detail with this cohort and what the relevance is there? Yeah. Yeah, absolutely. In both this study, as well as the combo study that we'll get to in just a moment, we evaluated 2601 alone, what we call kinda unadjuvanted here, which is a different formulation from what we use in the prophylactic vaccine, PreHevbrio. As Jeff said, you know, our preclinical studies demonstrated that this reformulated 2601 did drive substantially stronger T-cell responses as well as antibody responses. Our colleagues at Brii felt that formulation with a very low dose of non-pegylated interferon may further help provide adjuvant-like effect. You know, I think you'll see in just a few moments from the combo study, it certainly didn't hurt. I think given the limited numbers, I'm not sure that it added much, but you'll see for yourself. That's the difference, whether or not 2601 is co-formulated with interferon alfa. Yeah, let's get into it. Here is the trial design. Pretty straightforward. All patients again on potent new therapy to suppress viral re-replication. You can see in cohort A, the kind of control cohort, they received nine monthly doses of an siRNA compound to drive down those S antigen levels. Based on a lot of prior clinical data from, you know, this modality as well as others, you know, we expected you would see about a 1.5-2 log reduction, but not really get down to undetectable S antigen levels. You can see in cohorts B and C, starting at week eight, we co-administered, added in the 2601 immunotherapeutic. The only difference, as we just discussed, is in cohort B. It was formulated with a little bit of low dose interferon alfa in cohort B, you know, no interferon alfa in cohort C. I think for the sake of time, I'm probably going to just strike contrast between cohort A and cohort C. There being not really any significant differences between B and C at this point in time. If you look at the patient demographics, really fairly well matched across the cohorts with the caveat that if you look at the baseline HBs antigen level, you know, a little bit of an imbalance. You had, you know, about double the levels present in cohort C relative to cohort A. The reason I bring that up is, again, I think there's a consensus view that the lower the baseline starting levels of the HBs antigen, the easier it is to get down to nearly undetectable levels. It may be easier to break that tolerance with a vaccine immunotherapeutic. That's just something to keep in mind. In terms of tolerability, whether you look at it systemically or at the local injection site, as I said, this was incredibly well-tolerated. No one dropped out of study, even though they were getting nine monthly doses of vaccine. It was typically just mild injection site reaction we're seeing. Long story short, if we decide in the future to give more than nine doses, you know, I don't think that would be an issue at all. Here you can see what happened to the HBsAg levels. You can see it start, and then at the end of treatment at week 40. Long story short, no real differences in terms of the median changes from baseline across those cohorts, with the obvious caveat that there were a couple of patients, one in each of cohorts B and C, that did get down to undetectable levels, both of those notably in the combination cohort. I'll elaborate on those two patients with some of the mechanistic data that we think helps explain those outcomes in just a few moments. You know, this is really about as stark a contrast as you can. You know, hope to see. You know, if you look at. Here we're looking at restoration of S specific antibody responses. You can see in cohort A, if you look at the y-axis, that's going from 1 to 10. If you look in the combination cohorts, it's going from 1 to 10,000. You can see absolutely no evidence for restoration of antibody responses in cohort A. That's, you know, this is a limited end size. This is 10 patients, but they're now over 1,000 patients that have been dosed with SRNA compounds targeting S, and it's the rare individual that has evidence of spontaneous restoration of HBs specific antibody, and T cell responses. You can see there in cohorts B and C, you know, close to 60% of the patients have restored antibody responses greater than 10, which is the kind of protective threshold used for licensure with prophylactic vaccines. In terms of antibody response now, a 60% response rate, almost identical to what we saw in the first trial. If you go to the next slide. Yeah, Dave, can I just ask you on that slide before we a nswer two things, just on the absolute titers there, call it like the 10 to 100 to 1,000 or greater than 1,000 IU per liter levels. Can you just put it, just speaking in absolute terms, maybe put that in context, how meaningful is that? I'm also interested in the kinetics here and just sort of like the timing of the response around week 20. As you compare that to what you showed on the previous slide with, you know, the S response, what is this telling you? I mean, is this a bona fide immunologic, you know, response that you would expect to lead to functional cure at a higher rate? Maybe you can just sort of opine at the higher level conclusion from these two data points. I think candidly, no one knows what the magic antibody titer is in chronically infected patients that's gonna lead to a functional cure. I think there's been a very strong focus over the past decade or two on the importance of the CD8 killer T cell to get rid of the virally infected cells, and the cells are pumping out the S antigen. There's a growing body of literature showing that don't underestimate the importance of your antibody and B cell response. You know, you can see patients, you know, chronically infected that get B cell depleting therapies for other reasons, and they do not do well. I mean, the virus really goes unchecked. I think an antibody response is gonna prove to be very important going forward. You don't want just the T cells, you want the antibodies as well. In terms of the overall magnitude, what I can tell you is that, you know, Jeff will talk about PreHevbrio. We just ran a global phase III trial. The licensure endpoint titer is 10 in the U.S. In Europe, they like to see 100 or more 'cause they think, you know, responses are more durable. For licensure, it was greater than 10. When you're seeing titers of 100 and 1,000, those are real titers. That's, that's a very meaningful titer. That's like what you would see in completely healthy individuals that have been vaccinated with a three-dose course of vaccine. Given that, I mean, is it possible that this type of antibody response, like should you achieve functional cure in these patients, maybe it's plausible to expect they'd be more likely to essentially retain that response indefinitely or for some extended period of time? That's certainly the hope. Vaccine. Yeah. That's certainly the hope. Obviously, we need to track these patients. This is an interim readout. Let's see what happens and see if maybe some more patients get to those undetectable levels. I think what's clear is, as I implied earlier, you've given a couple of doses of vaccine at age 12, 16, it takes time to get that immune system going 'cause you're still fighting a large amount of circulating antigen. I think that's one of the interesting learnings from this, that it may take longer than we may have expected early on to really restore that immune function. Okay, thanks. As far as I say, when you look at the T-cell response, it's the same thing. Very little response rates in cohort A treated with just the si RNA modality. Very consistent with what we saw in the prior trial. The majority of patients, with boosting in T-cell responses. If we put it all together in this last slide, for the sake of time, let's just focus on patient two in cohort C. If you focus on the red line, this is looking at the circulating S antigen level. You can see that start off at 776 units per mil. A couple doses of the siRNA compound at zero and four weeks, you can see there's a very nice rapid decline, about 2 log reduction at week eight, which is entirely in line with what we expected. We start concurrent immunization with 2601. You can see the rate of decay was a little bit slower, still very steady until week 32, where we hit undetectable levels of S antigen that was sustained out to week 40. Coming back mechanistically to what we thought was gonna be the key, if you look at the T-cell response against Pre-S1, something non-tolerized, you can see the purple column at time zero, week zero. You can look at weeks 24, 36, a dramatic boost in that Pre-S1 response. That's associated with significant boosting in the T cell response against S, shown in blue. You've restored, boosted, the T cell responses against, specifically against S. If you look in the green line, you can see the increase, the steady increase over time of your antibody responses against S. This is really unprecedented. As I said, I've drawn comparisons to some of the clinical data others have reported, and this is something people have seen again and again. You can see responses to non-tolerized antigens, but seeing antibody and T-cell responses specifically against S, I think it's really unprecedented. This is why, you know, Jeff and I and the team are so excited about the outcome of this study. David, what will happen then with these patients going forward? Are they coming off siRNA and NUC? Yeah. And seeing how they do and seeing if we achieve functional cure here? Exactly right, Steve. This was the end of treatment at week 40 per protocol. Anyone who achieved, you know, lower limit of quantification or below, was allowed to discontinue all treatment, including NUC therapy. They'll be followed for at least six months to see if S antigen levels can be maintained at this level, to see if DNA levels can be maintained, and if so, then they would be considered to be functionally cured. By the same token, if there are any more patients that occur over time, that get to these levels, they too would be taken off all treatment to see if they really are functionally cured. Just for housekeeping, so the ALT sort of being stable here over the course of this treatment, can you comment on the significance of that or what the importance of that marker would be in these patients? Yeah, I mean, I think there's still some debate in the field. There are some that have argued, and I think reasonably so, that a little bit of an ALT flare may signify some restoration of HBV-specific T cell responses that are, you know, killing infected hepatocytes leading to that ALT flare. It's clearly not necessary because here we've gone down to undetectable levels. We didn't have the ALT flare. If you talk to a lot of clinicians, they are often very wary about having too much of an ALT flare because it could really lead to, you know, life-threatening conditions. Right. I think this is again, a bit of a surprise, and we'll see what happens going forward as the data set matures. Okay, great. Are you comfortable you have an optimal dosing strategy that you'd like to look at or Brii you expect would look at, just in terms of the staggering doses if needed or number of doses or interval of dosing? Yeah. I mean, I think as you can appreciate, this is really data hot off the press. We need the opportunity to speak with Brii, you know, others in the field. I think what's exciting is, as Jeff said at the beginning, we've demonstrated now in consistent studies the NUC ability to break tolerance against S at both the antibody and T cell levels. If you think that's gonna be important, I think the preponderance of clinical data suggests it is, this is a really valuable component in the regimen. I think there are a lot of different things that we could explore, and as I said, we need more time. You could potentially stratify the patients, so maybe you lower it and you limit it to, you know, say 500 and below. Maybe you give more doses. Instead of nine, you give 12. You dose monthly until you see that they get to those undetectable levels, which is the strategy that we've employed in our GBM therapeutic because, again, it's so well-tolerated. There are other modalities you could potentially add, whether it's a TLR that helps make the liver microenvironment more amenable to the peripheral T cell response that we can induce. It could be that you use something like a monoclonal to drive down those baseline levels, not just 2 logs, but 3 or 4 logs. Again, making it easier to rest control back of the immune system with a vaccine immunotherapeutic. I think short story is we don't have any concrete thoughts right now on what the optimal combination or vaccination schedule is, but I think there's a lot of flexibility, and that's something that we're, as you would expect, actively discussing. Yeah. Yeah. I mean, I think the immunogenicity data in particular here seems to warrant, you know, some exploration of novel combination regimens. Sounds like you agree. What about, I mean, I think you alluded to sort of maybe patient selection and the baseline HBs antigen levels. I mean, here you've achieved below lower limit of detection in patients with 723 and 776, which is not so low. So what... I mean, maybe you can comment on the significance of that and whether that's an interesting insight that emerged from this combo study? Yeah, no, I mean, I think, you know, if you look at some data that Vaccitech published, you know, at ASCO last year, they were able to see undetectable levels when they put their vaccine in combination with anti-PD-1, which is another modality that we could potentially layer in. Their starting level was 50 units or less, so 10 times lower. If you look at GSK, they've just announced a phase III trial with their antisense compound going after HBs antigen, and their own data led them to the conclusion that, yeah, there are certain thresholds where we think a much greater proportion of patients are gonna get a benefit. Whether it's, you know, below, you know, 100 or 250 or 500, you know, I think we still need to assess the data. I can tell you, just to give you an approximation of, you know, what portion of the patient population, we're aware of two very large chronically infected cohorts in Germany, where about 30% are at levels of 500 or lower, you know, it's not a trivial number that are down at lower levels that might lead to much better proportion of patients responding. What do you think is a realistic sort of next, you know, leap for. Like, if we're talking about designing an ideal study here, given what you learned from this, with a regimen that involves 2901, I mean, what is achievable from a seroclearance or proportion of patients achieving seroclearance perspective, given the tools available to you now? Yeah. I mean, I think as I said, with the Vaccitech data, they clearly saw an impact when they added PD-1 that would be readily available to us. I think dosing for longer periods of time, having a lower entry criteria, I think all those things could realistically increase the proportion of patients getting the benefit. Do I think that we're gonna suddenly get 70% or 80% functional cure rates? No, I don't think so. I think the way we think about it, and I think this is a view shared by many, you know, if you could hit, say, a 30% functional cure rate, that would be a good starting point. It's very similar to what we saw with the checkpoint inhibitors in immuno-oncology. When Yervoy was approved, you know, you had about a 30% response rate. What happens? You start to add in more and more modalities and figure out which combinations provide greater benefits to a greater proportion of patients. I think we wanna get to at least 30%, you know, moving forward. Okay. Yeah, maybe next steps for this program. Then I'm curious, you know, as you sort of digest this data and now sort of have it in-house and have analyzed it, I mean, strategically, how do you leverage this as a company? How do you get these combination regimens into clinical trials going forward? How are you thinking about collaboration opportunities, you know, in the U.S. or ex-China would be. Would love to hear your comments there. Yeah. Yeah. Let me take this, Steve. I think, you know, as noted on this slide, there's a couple of, very important further data points to come. First of all, from this study, in terms of the combination study in Q3 and then from the adult study, as Dave said. Again, I wanna echo what Dave said earlier. Brii have been fantastic partners to work with in terms of their, you know, understanding of the hep B market, their understanding of the space, and their understanding of the potential combinations that could get us to the target 30%-50% or whatever functional cure. I think it's fair it's just too early, to be honest, for us to really disclose, you know, what those next steps may be. I think if we can move on to the next slide, please. You know, in terms of, you know, where we go next. I mean, we've exclusively licensed BRII-179 or 2601 to Brii for greater China, as it says on the third line here. We retain rights in the rest of the world. Again, this data is early in terms of being in our hands. We've only had the data for 10 or 12 days. We need to work with Brii to further understand this data and then further socialize this data with other people that have parts of this functional cure. I think one of Dave's earlier slides had three steps to a functional cure, reducing DNA, reducing HBs. We need to talk to potential partners that have one or two, or maybe other options in those steps one and two, where we can then add in the third step. Again, I just wanna emphasize, you know, what Dave said in terms of the data and really what is stark is, you know, the ability of 2601 to restimulate the immune system such that you can see this massive uptick in B cell and T-cell response and hopefully touch wood as your question implied earlier, Steve, restore long-term immunity and stop the rebound, which we saw with other monovalent or combination therapies. Really I can't obviously go into specifics. This data gives us a strong agenda for discussion with those in the hepatitis B space that have X reducers or other kind of novel adjuvants, be it TLR9 or whatever, but they don't have a hepatitis B specific immune modulator to restimulate the immune response and hopefully basically institute long-term control. That was a lot of words, Steve, and I know it's probably not as specific as you would want, but people that understand this space will understand that there's only a couple of HBV specific immune modulators out there. As Dave has emphasized, we believe this is absolutely the best-in-class data in terms of stimulation of B cell and T cell response. Yeah. I mean, I thought it was a good enough answer to the question, Jeff, so I appreciate it. Okay. If we may, Steve, I know we were looking at both sides of the fight against hepatitis B. Moving on to PreHevbrio, please. Yeah, of course. Okay, great. As people know, who've followed the company for a while, we basically have been working with Syneos Health since 2019 on this end-to-end commercialization partnership. We are absolutely delighted with this partnership. You know, Syneos' previous experience in launching vaccines and supporting vaccines in the market has really, really helped us in terms of, you know, the quality of the people that we've been able to work with and the way in which we've been able to launch the product in the U.S. Also, following this sort of innovative trend of launching with a partner rather than trying to do it ourselves, we announced, you know, collaborations with Valneva. Valneva, you know, are a fantastically experienced vaccine company. They have six commercial products in Europe. They have a couple in the U.S. People may have seen that, you know, they also have a very exciting prospect potentially with their tick-borne product being approved in the U.S. later this year. In fact, a really interesting Lyme prophylactic vaccine, also partnered with Pfizer in the U.S. Tremendously experienced company, a lot of commercial experience in Europe, and we're looking to launch with them in the U.K. and the other markets listed on this slide. We will be launching also in Germany, and we anticipate launching in Canada. I can't provide specifics as at this point in time, about the partners that we may or may not launch with, in those markets. Again, our tactics will be to avoid the kind of distraction of, you know, progressing our pipeline, progressing other candidates, but actually launching with people that have done it before, have the experience, have great people, and probably better people than the one product bag company you can actually attract. Steve, you would expect me obviously to comment on PreHevbrio success in the U.S. market. Well, PreHevbrio has now been on the market for nine months in the U.S. We launched at the very end of the first quarter of last year. The value proposition and competitive pricing of PreHevbrio alongside Engerix-B, which is still the market leader by volume, has been extremely well received. We should bear in mind, though, that PreHevbrio was the first vaccine launched post-pandemic other than the emergency use COVID-19 vaccines, which have now obviously received their full approval. Other than COVID-19 vaccines, we were the first sort of more routine approved product to be launched. The adult hepatitis B market is still recovering from pre-pandemic levels, but it is still about 15% below the volume of the market in 2019, even with this tailwind of the universal adult recommendation. We now have nine months of our own data and have learnt a lot with respect to how we target our resources. We're now in a position where we can redefine our commercial resource deployment to capitalize upon those learnings. As I'm sure you know, Steve, you know, pre-launch, you know, you're working with data, IMS, IQVIA data, whatever, that's a couple of years out of date. You're working in a kind of vacuum of actually a theoretical approach to a launch. Now, we actually have data about where we're seeing people switch from Engerix-B in particular to PreHevbrio, and we're now getting onto the formularies. We now have the infrastructure in place. Steve, you know, if I can give you some examples of value proposition and competitive pricing of Engerix-B, it's been tremendously successful in the public health. It's been extremely well received. We've kind of broken, you know, sort of informal, unofficial records for getting onto the formularies of the VA, the Veterans Association, and the VAVS. We were on their formulary very quickly within a few months of launch. Going back to earlier, the mention of the CDC ACIP universal adult recommendation. We were actually included in the recommendations for universal adult vaccination from the ACIP, the very month actually, April of last year, when our product was launched. Also now in the private sector, in the private payer retail channel, we've been making significant breakthroughs over recent weeks. We're now on formulary with six retail chains, three national and three regional. Just to summarize where we are with the PreHevbrio launch. The value position in competitive has been extremely well. Our market access infrastructure admittedly took us longer to get in place than we wanted to. That is just the reality and the consequence of the post-pandemic world. We were trying to launch this product at the same time that Pfizer and Moderna were releasing 100 million doses of COVID booster into the supply chain. We obviously had to compete with that in terms of the attention and bandwidth of the supply chain, wholesalers, et cetera, to make sure that our product was, you know, including their systems, EDI systems at the right price and everything else. Now that market access infrastructure is in place. Then finally, based on the learnings of nine-month sales, we're redefining how we think about commercialization of this product, not in terms of the value proposition, but in terms of how we actually target and shape our resources on the ground to essentially pick the low-hanging fruit, really focus on those HCPs that have significant usage of Hep B vaccine in the adult space, particularly existing Engerix-B, and convert them to PreHevbrio. Being a very competitive product, actually now at a slightly cheaper price. Jeff, that's all sounding constructive. Would you say that 2023, you're confident this can be a year of inflection for U.S. sales? Then as you think about Europe and the partnership with Valneva, can you leverage the experience you've had in the U.S. and is t he, you know, better entrenched or well-entrenched in the markets you'll launch there to sort of hit the ground running once launched? Yeah. Great question. Firstly, in the U.S., for people that have access to IQVIA data, be it on a weekly or a monthly basis, you will have seen the first couple of data points in 2023 are very encouraging for us in terms of the sort of inflection point from the end of last year. We're very encouraged by, you know, where we're seeing the success trajectory taking us in the U.S. in 2023. Absolutely, in Europe, our tactics are exactly as you summarized, to work with people that have done this before, experienced it doing this before, and had success and very experienced multiple people on the ground that we can use to commercialize PreHevbrio. Again, I make no apologies to investors, but we are going to be competitively pricing this with Engerix-B in all of those markets because we want to capture market share. In Europe in particular, and Canada, obviously we'll launch this plan this year. They're extremely price sensitive. In terms of our value proposition, perhaps, you know, versus say, Dynavax, in Europe, we're as yet to see what their pricing strategy will be. We want to be competitive with the current standard of care. In Europe, you know, clearly, Engerix-B from GSK and Amgen own 99.9% of the market. Big opportunity for us. Okay. I think with that, Steven, cognizant of your time, and people listening in, we have about eight or nine minutes left. Perhaps, Dave, you can just very quickly introduce why we are so excited about 1901, our GBM candidate in both primary and recurrent GBM. 2023 and, you know, the first half of 2024 could be a real breakthrough for this candidate and in fact, the poor patients who suffer from this awful most fatal form of cancer. Great. Sounds good. Yeah, thanks, Jeff. You know, I think many are familiar with GBM. For a rare disease, it's surprising how just about anyone knows someone who has unfortunately, died from GBM. There are many different small and large biotechs, pharma companies that have tried to go after with, you know, to be candid, a lot of phase III failures. I think, when we launched this program, you know, the real challenge into us, to ourselves, to our investors was what do we think is gonna be different? I think it comes down to the antigen. We're targeting CMV, a viral antigen, which happens to be present in these tumor cells. You're asking the immune system to do what it likes to do. Go after a virus, only in this case, in doing so, you're essentially gonna be getting rid of tumor. Now, traditionally, for a lot of those failed efforts in GBM, what's been done are single-arm trials comparing the historical controls, looking at the clinical responses with very little evidence of actual tumor responses. If you walk around the halls of ASCO or the SNO Annual Meeting each year, you don't see spider plots like what's shown on the left-hand side because you just typically don't see tumors shrinking. I think, again, when we started this program, it was if this is gonna be real, we should be able to see an effect on the tumor. What's shown on the left-hand side are data from the high-dose part A and part B of this trial. There's 16 patients in total. You can see they're colored in orange. You know, seven out of the 16 that either had stable disease or in two cases are the solid symbols, partial response, meaning greater than 50% reduction. Those open black symbols, I mean, you can see that's tumor growth. They're doubling, tripling, quadrupling in size in six to eight weeks. That's why it's universally fatal. That's why the median overall survival is eight months, even with standard of care. So we saw these tumor responses, which is the most objective parameter we can look at. The question from the clinicians and candidly the question from the FDA is, "Yeah, but so what? What does that mean clinically?" Does stable disease for three to four months really translate into something? If you go from the left-hand panel looking at the tumor response to the right-hand panel, what you can see, and it's again color-coded in orange there, they're overwhelmingly at the bottom. The tumor responses have translated to a survival benefit. If you look at median overall survival, which is what FDA expects these days, you know, we've improved it about five months relative to standard of care, whether it be anti-VEGF in bevacizumab or a chemotherapy in lomustine. We're seeing tumor responses translating in clinical benefit. I think it's the strength of this data which prompted us to go to FDA and propose an amendment to this trial, where we're adding a true contemporaneous control arm. Patients will be randomized, and we will initially look at tumor response rate. We don't expect any significant tumor response rates with the standard of care. If we see more of the same, coming out of this randomized trial, I think we certainly have the opportunity to sit down with the FDA with the benefit of Fast Track designation and start talking about an Accelerated Approval. What I haven't mentioned is, while there are standard of care treatments, nothing has been shown to improve survival for these patients. Nothing. There's a dire need literally for something to provide benefit to these patients. We'll look at tumor response rate first. We've already documented in this trial so far that those tumor responses correlate with clinical benefit. You know, let's see. You know, depending on enrollment rates, we've been guiding that we will start enrolling, Q2, so imminently this year. We to date have been working with four s ites. That's gonna increase to about 12 sites. We can really try to, you know, speed up enrollment. You know, depending on enrollment rate, we may be able to start looking at the tumor response rates between those two arms end of end of this year. Obviously, depending on strength of that data, we would have to commit to follow those patients for OS benefit and probably run a confirmatory trial. Certainly the potential with this to really definitively demonstrate the activity for this great unmet medical need. Now, this is in a recurrent setting. If you go to the next slide, it'll summarize another exciting trial that's gonna start. This is in the front line setting. These are recurrent patients. They're highly immunosuppressed. You're trying to treat and stop the growth of a very aggressively growing tumor. In the front line setting, we're gonna be vaccinating patients that have gross tumor resection. They get it the benefit of radiotherapy. Then you come in with monthly dosing with 1901. We're gonna be adding anti-PD-1 to help sustain the activity of that T-cell response that we elicited. We know that PD-1 monotherapy doesn't work. You know, we think this sets us up for a good opportunity going forward. Hand it back to Jeff. Thanks. Just one other point I wanna emphasize that, in terms of the recurrent setting, as Dave said, in terms of we're really excited to see this data from this, the upcoming planned, randomized controlled study. If we can replicate what we saw in our phase I and phase II data in terms of, you know, three to five month extension in median overall survival rate as control group, as this bullet point, the second bullet point here says, we could have data to support an agenda for discussion with the FDA around Accelerated Approval under the Fast Track designation. This would be phenomenal for patients in this area of recurrent GBM because they can actually, for the first time, have something new, you know, which would, at a very low cost of intervention, a very simple intervention, offer them something very immediately. We could be talking about this product being available to patients in mid-2024. A very, very exciting year for us, Steve, in terms of GBM in both the recurrent and the front-line setting. Steve, I think I have one summary slide. I don't know if you have a burning question before I take 30 seconds on this one final slide. I was actually waiting for you to close up here, Jeff. Since you offered, I'll invite you to do it. Appreciate you working through those programs. Yeah, we'll just throw it to you for closing remarks. You know, the next 18 months for us, you know, are really, really exciting. I must say this year started off in a very positive way for us with this interim phase II data from VBI-2601. We talked about the two upcoming data readouts this year, which are very, very important. Because, you know, as I said, we have an agenda now today for discussion with potential partners and looking at other combinations for in the rest of the world. That's a really exciting start for the year for us, a very positive step. GBM, we talked about, again, really, really exciting opportunity and a couple of very important clinical readouts. We haven't mentioned coronavirus, VBI-2901. That's not 'cause it's not important to us. It's really important to us. It's a much earlier phase program, but we do have this clinical readout in mid-year of this year of this trivalent pan-coronavirus candidate, where we'll be testing against all the variants of concern historically, that have occurred, but also against novel strains of Betacoronavirus that haven't yet made the human-to-human leap from the animal kingdom. You know, last but not least, as I say, for people who have access to IQVIA data, we're really excited about PreHevbrio's sales trajectory and the way in which it started this year. It's gonna be and of course, the European and Canadian launches. We really believe that's gonna give us a platform for some significant revenue growth there. Great. Well, lots lying ahead, looking forward to tracking all that progress. We're up on the hour, I would say unless you guys have any last remarks, we can close it up. Anything we didn't cover that you wanted to throw in here? Only thank you to you and everyone else who's dialed in today. Yeah. Well, I can certainly echo that. Appreciate everyone joining. Thanks everyone for the time. Jeff and Dave and the VBI team, thanks so much for doing this and being available. Yeah, look forward to tracking you on all this progress and circling back and doing this again once you've accomplished all these objectives for 2023. Appreciate everyone's time. Have a great day and great week. Great. Thank you.