Okay, we'll continue with the next session. I'm Paul Cox, and I cover the SMID-cap biotech sector here at the firm. It's my pleasure to welcome Dynavax to this session. Maybe what we'll do is let Ryan kick it off with some introductory comments on Dynavax, and then we'll get into Q&A if that's okay. Yeah, that's perfect. Thanks, Paul. Thanks for having us. So just a quick overview for those of you who are maybe new to the story or don't know us very well. Dynavax is a commercial-stage biopharmaceutical company focused on protecting the world against infectious disease by developing novel vaccines. Currently focused on leveraging our adjuvant platform, which has been used to develop our first commercial product, HEPLISAV-B, a two-dose adult hepatitis B vaccine approved in the U.S., as well as in Great Britain and Europe, which the company launched in 2018 in the U.S. and has been commercializing ever since. It's launched in Germany through a commercial partnership. So pretty excited to give you guys an overview of the business today. Okay, great. So maybe in terms of the platform and your core competencies, could you maybe explain a little bit about how the adjuvant platform approach works here and just kind of how is it potentially, at least initially applied here in Hep B and maybe potentially in other areas in the future? Sure. So the adjuvant CpG 1018 is the differentiating factor in our adult hepatitis B vaccine, which is the adjuvant plus the surface antigen. In that product, it enhanced the immune response to allow us to take what was traditionally a three-dose regimen over zero, one, and six months and turn it into a two-dose regimen over zero and one month while also delivering higher levels of seroprotection. So you kind of got the multiple benefits of the adjuvant. Another key element of CpG 1018 is it provides an enhanced immune response, but does so with a very favorable tolerability profile, which is not necessarily what's the normal situation with adjuvants. And so that's what's allowed it to be a very unique adjuvant for hepatitis B. We're building off of that experience and our experience with COVID as providing adjuvant for the COVID response to continue to build collaborations in the space as well as develop our own products leveraging the adjuvant. Okay. Maybe turning to the commercial side with HEPLISAV-B, I think that the shorter dosing regimen, to your point, has really resonated with patients and prescribers as well as the efficacy. And you guys have clearly had very steady market gains ever since launch. And so I guess now that you're a few years into the launch here in the U.S., could you maybe help us think through what the commercial trajectory looks like over the intermediate to longer term? I think you guys have spoken to a particular market size a few years out and just kind of how we think about the cadence or pace of that evolving over the next few years. Sure. So the product's been doing pretty well. We saw 2024 was a big year of growth for us. I'm sorry, 2023 was a big year of growth. The revenue for us grew 69% over 2022. So that's fairly meaningful growth. We expect that trend to continue. We've captured a very good share across our core areas of focus, which are the retail pharmacy channel and health systems or what we call integrated delivery networks or IDNs, where we have a 55% share as of the end of the last quarter in both of those segments. So the product is doing quite well. By our calculations, it's the market-leading vaccine at the moment. You noted our long-term projections. We do believe we'll continue to see success in the marketplace. This year, we've guided to $265-$280 million of revenue, which is a 25%-30% increase over last year. We have provided long-term guidance where we believe the market will continue to expand to be about $800 million by 2027. We expect with our profile that we're poised to take a majority market share of that large market opportunity. That market expansion is critical to the value of the program as well as the continued capturing of additional market share. Just a quick note, the market expansion is driven by a change that happened in 2022 to the recommendation in the United States where the ACIP recommended that all adults be vaccinated against hepatitis B at some point. So that creates a very large population of Americans that are eligible for vaccination. Okay. Can you maybe just remind us how that conversation goes with doctors post the ACIP change? If you want to touch on that and just kind of is this something that's coming up particularly more commonly for, let's say, an elderly or higher-risk population? Is it in younger patients' annual physicals to the degree that they do utilize their healthcare services? Just kind of what is the nature of those conversations, I guess, that you're hearing from? Yeah. I mean, it depends. Each segment's a little different. So within the hospital setting, it's going to be typically the well visits. So what we're seeing is you'll have EMR flags, for example, where that will prompt the healthcare provider to have a recommendation, have a conversation with now all patients. So it makes it very easy from an age-based recommendation versus kind of a risk-based recommendation, which that's what it was before. That's what you kind of find in the kind of hospital setting. In retail, really, there's a lot more origination opportunities as people originate to retail quite more often than they do to their physician. So that conversation is a little bit different. A lot of times it'll happen around other vaccine opportunities. So it'd be a co-admin, if you will. So when you think about adult vaccines, including Hep B, there's opportunities where it'd be a kind of a plus-one campaign or, again, a recommendation where there's prompts that are given to pharmacists to see that this patient's now originated. Once again, age-based recommendations are much easier to do than risk-based, even for pharmacists as well. So it just kind of depends based upon the segment that they're originating within. Okay, great. Maybe speaking a little bit more about each of these particular channels and areas, you mentioned your share. It's a little over half the market, both in the retail and the IDN large clinic segment. Can you maybe speak a little bit to the growth rates that you're seeing there in terms of the individual markets? And does this remain sort of in lockstep with where they are right now, or does one, I guess, represent a faster growing opportunity versus the other? Yeah, so both those segments. So we've stated that the overall market would be 10%-15% every year growing. And retail and IDN are going to be the two segments that are going to drive the vast majority of that growth. When you look at retail, retail probably has more opportunities for more significant growth due to the fact that retail is looking for ways to continue to grow their immunization business. They're aligned around strategically thinking about immunizations as a growth driver for their business. Right. This is the back of the store versus the front of the store. Correct. Exactly. The store growth. Hep B represents kind of a unique opportunity for retail in particular in the sense that with the universal recommendation, it's a massive bolus of patients now available for retailers to kind of grow each and every year relative to other adult immunizations. So again, we think about retail as providing more opportunities and infrastructure to grow and a lot of it coming out of the pandemic. So retail today versus retail four years ago is much different. So the infrastructure capabilities that retail has today are also reasons why we believe that that segment will probably continue to grow a bit more rapidly than, say, IDN. But both of those segments will be critical to maintaining our overall growth of 10%-15% a year for the whole U.S. market. Great. In terms of that retail opportunity that you just mentioned, can you maybe speak a little bit to what the strategies are? Sort of is it directed advertising, online advertising, just kind of what helps grow that segment further? And does that mean incremental spend? I guess it would be one question there. And then I guess a related question there is, and I ask this of all my infectious disease companies, in terms of the post-COVID, post-pandemic landscape, just how you and the company sort of think about potential vaccine fatigue here and just kind of what does that look like in terms of being a potential headwind to uptick? Right. So we start with our sales teams. We have a dedicated sales team within retail pharmacy. So we have a dedicated CVS team, dedicated Walgreens team. And so that allows us to engage the retailers both at the headquarters, but also the divisional, the regional, and the district level. So that allows us to really form these types of relationships that helps us think about our spend. So when we think about the spend, whether it's around advertising, engaging the consumers, working with retailers like CVS and Walgreens, we can be very precise on the types of advertising that we do through the relationships that we have. So it's our spend, but also, as I said before, for retailers, it's a strategic priority. So you'll see that retailers will also do their own infrastructure spend as well. A great example of what they've been doing is around, say, the scheduler. So when you schedule one vaccine, hepatitis B now becomes something as an opportunity or an option for you to schedule as well during that same visit. So those are all the different types of tactics that are done in the setting for retail that, again, goes back to why we're so confident around the growth within that segment. Around the question on vaccine fatigue, you see it a little bit. You see it with providers as well. One of the things we talk about is the respiratory season. It's a busy season. A lot of vaccines are given during the respiratory season. So there's, I think, a little bit of a pause that you will have around providers as well and patients. But again, that's temporary. We're starting to see that pick back up to back to non-respiratory season, which we're in right now, where we don't see that fatigue issue as much. Again, I think it's just one of those subtle things that you see kind of coming out of the holidays, respiratory season, a little bit of fatigue, but again, we don't see that now, which is good. Great. The company's track record has been really, really stellar over the years, but you did have a recent setback with the FDA in terms of getting CRL for your sBLA filing. Can you maybe just remind us what was the rationale from the FDA for rejecting the sBLA and just kind of what are next steps, I guess, for potentially addressing that there? Sure. So just a little context too. The dialysis market operates with a different dosing regimen than the healthy market. So there's a specific product. It's a 3-dose product. And then the Engerix is used as four double doses. So it's 8 doses, but over 4 visits. So we were evaluating a 4-dose regimen for that marketplace beyond the current 2-dose regimen. That market is about 7% of the dialysis is about 7% of the overall market, shrinking to probably 5% as the rest of the market expands. So just contextually, it's a relatively narrow slice of the pie. You asked about the CRL content. It was basically the FDA said in the CRL that the package did not have sufficient data for them to fully evaluate the safety and efficacy of the 4-dose regimen. And so that was the main feedback. Now, that was a result of an unfortunate handling of source documentation by the clinical trial sites where records for about half the patients in that study were destroyed. Now, from our view, that doesn't impact the data or the quality of the data or our confidence in the regimen or the safety of the product, but it does have an impact on good clinical practices and their ability to evaluate the data and do appropriate verification of the source documentation. So we're evaluating our options, and we look forward to working with the FDA to see what the next steps are. I think we recognize that there's already utilization in the space. Obviously, physicians can utilize the product as they see fit and the data and the dosing regimen and the data are published. We're evaluating the current utilization and our options with the FDA to figure out the best path forward. Okay. In terms of any other next steps that may be involved there, so you obviously lost some documentation from the clinical trials, I guess, and you did speak to the drug already being approved there. And so I guess the opportunity remains there for them to use it as they see fit. Is that? That's right. I mean, it always has been. The indications for adults over 18 years of age. There's specific in the data. There's specific wording in the label that says safety and efficacy have not been established for dialysis, which limits our ability to promote. Physicians can use products how they see fit. And again, like I said, the data is published, and the ACIP actually has a recommendation for immunocompromised of two check two. So two shots, check titers, give two more. So there's some guidelines already out there for how to manage patients like that with the product. Not our guidelines, not our efforts, but they exist in the marketplace, which has supported some uptake already in the segment. So we'll keep an eye out on how that evolves. Like I said, work with the FDA once we have all of our work done on our various options. Okay. Great. Maybe thinking about the program overall, you did mention you obviously have some OUS approvals. You're partnered in Germany and so forth. And just as you think about sort of expansion opportunities for HEPLISAV-B, where are those additional pockets of potential growth? How do you think about that, whether it's labeling, other markets where it may not be available that maybe investors just aren't thinking about in terms of that longer-term commercial potential here for your franchise? Yeah. Well, I mean, look, the reality is the U.S. market is the majority of the opportunity. Mainly, one, it's always the largest market. And then when you add on the universal recommendation, which we believe will result in an $800 million opportunity by 2027, that far surpasses the international opportunities. We are approved in Germany and in the U.K. And we look to our partner in Germany there to continue to grow the opportunity in Germany as the most valuable market in Europe. So we're excited about the ability for those sales to continue to increase over time. And we'll look for opportunities to get after the U.K. market and possibly elsewhere in Asia. But the primary value driver for the brand will continue to be the U.S. Okay. Maybe looking at a corporate level, I guess the aim is to drive HEPLISAV-B here in the U.S. to profitability. Where are you tracking on that in terms of achieving that and just kind of where sort of the longer-term profile of the company might be in your mind in terms of profitability? Yeah. Well, I mean, HEPLISAV-B as a brand is absolutely profitable and has been for some time now. We turned over $213 million of sales last year that was profitable as a brand with obviously our projections of $265-$280 for this year. We also noted that we closed the year with $742 million, and we made the clear statement that we expect to be cash flow positive for the course of 2024 already. And that has an R&D estimate of $60-$75 million in there. So we think that that's a fairly robust business, and we look forward to continuing to grow the top line. So we're excited about the long-term prospects overall from a corporate perspective, both from an overall capital, but also the ability to continue to invest. Okay. Great. I want to turn maybe to the pipeline if we could and Shingles specifically. Can you maybe provide us an overview of your Shingles program and just kind of where you think the opportunity is to differentiate versus some of the existing therapies that are out there in terms of the vaccine landscape? Sure. So I think we all know shingles is a pretty large market because the elderly vaccine market continues to expand, and there's good uptake of these important vaccines. And we believe there's opportunity to compete in that marketplace. The current market-leading product is very effective, but it does have a challenging tolerability profile. It's fairly well known. And as I mentioned, one of the benefits of 1018 that we've seen, at least historically in other products, is that it generates a fairly robust immune response with relatively low impact on reactogenicity and tolerability. And so we're looking to leverage that profile in shingles and deliver a product that can provide high level of efficacy, but do so with improved tolerability as a key element to be able to compete in the marketplace. Okay. In terms of developmental efforts, first, my first question is, given the size of the opportunity, is this something you'd want to pursue by yourselves, or is this something you're still looking to potentially partner on? And then secondly, as you think about your developmental strategy, to your point, I think you're talking about SHINGRIX here clearly. It's a well-established program. And so just kind of can you walk us through what maybe like a non-inferiority trial might look like or just kind of what the sort of general parameters of a trial design might be for your Shingles program? Yeah. So there's a couple of elements. So the next trial that we're starting imminently here in the second quarter, so in the next few weeks, is a phase I/2 study that will evaluate different adjuvant systems, so with and without alum, basically CpG 1018 with or without alum and with different levels of antigen to find that optimal dose. Longer term, we will be taking the product assuming, obviously, the data continues to hold up, take it into a phase III study that will be head-to-head against placebo for an efficacy study. And then separately, a head-to-head study with Shingrix to compare tolerability and reactogenicity so that we can have that. That's a very important comparative item to have in the label. And then obviously, with the comparison to placebo, we have to demonstrate a very high efficacy to be able to compete with Shingrix. Okay. And then in terms of partnership versus risk capital and taking this on by yourself. No, thank you for mentioning that. So the strategy here is once we have the data from the phase I/2, we would leverage that data with BD efforts globally. Dynavax's mission is to continue to develop products, but we want to leverage our commercial capabilities in the U.S. We don't want to partner assets that we can develop. We'll never develop a portfolio that way and leverage our capabilities. But globally, there could be good opportunity to be very aggressive with BD early on so we can develop the product kind of in parallel across the global need and either use that capital to offset some of the risk of the phase III efficacy study or work through some sort of combined global database. So we have to figure that out. BD will be a very high priority once we have the phase I/2 data focused on international markets. Okay. Can you maybe just remind us when that phase I/2 data might be coming out? I know you said you're just kicking it off near term there. Yeah. Assuming enrollment meets our expectations, that data should read out in the second half of 2025 on the top line. So that'll be the first immunogenicity data one month after vaccination. And then we'll continue to follow patients both for safety and immunogenicity because what we do want to see is how one of the things we're sort of acutely aware of is your initial immunogenicity response, what happens over time, and how does that compare. So we'll also look out 12 months at the T cell signatures for both ourselves and Shingrix later on. But top line data for one month post-vaccination will be available in the second half of 2025. Okay. In terms of the go, no go, I guess, decision for your phase three, just kind of maybe remind us what the data, I guess, in your mind would potentially have to look like in terms of, I guess, thinking about the competitiveness of 1018 here versus the existing products? Yeah. I mean, to simply put it, you'd want your CD4 T cells to look similar to Shingrix. I think the question is really what does similar mean and how do you evaluate? This is not a powered study, right, to have confidence intervals and show non-inferiority. So we're going to have to pick the dose and the data that hopefully will provide us good insight. Now, this is immunogenicity data, but we're trying to approximate an efficacy result. So the average or the mean is not really relevant. It's really how does each patient score above what we think would be a threshold to provide protection. So we don't have that. There's no correlate. We're going to have to see the data to help figure out how to interpret the data, but recognizing that the bar is pretty high on being able to be confident that we can deliver the same level of efficacy. Okay. Great. Maybe looking a little further down the road, assuming clinical success, given it's a fairly well-characterized disease and target, I guess, as you think about down the road in a few years, if you have approved and commercial stage product, what does the sort of, I guess, commercial infrastructure look like for launching a shingles? It's clearly a product that gets DTC advertising, I guess. Can you leverage your existing commercial footprint? And where do sort of, I guess, in your mind, guidelines figure in for developing that and commercializing that product? Yeah. Let me give my thoughts, and Don, you can clean it up. The variable will be DTC. It will be that marketing. The commercial infrastructure component, the sales team, I think we're adequately staffed to be able to manage that because of the setting in which it's mostly delivered, which is retail pharmacy, is a vast majority of the vaccine. And like Don said, we've made investments to have a very strong and highly capable team in retail, plus our IDN capabilities. So I don't think there's really a sales augmentation needed, but it would be a very different marketing program than what we do for Hep B. I think from a DTC perspective, I mean, the one thing that, as I mentioned before, with our relationships with retail, it's not just the spend, it's the targeted spend. And being able to see in segmenting out the different types of patients where this profile product would actually be very attractive. There's ways for us to think about DTC differently. And leveraging our relationships today into that point when we're ready to go and launch, I think we'll be in a very good position to be really smart about the types of DTC investments we do in partnership with retailers. But to Ryan's point, from a salesperson perspective, we are adequately prepared and can easily handle a vaccine that is really retail-focused today. Okay. I think that holds true for our Tdap program as well. These are why some of these programs are so interesting to us because they will really leverage our capability. Yep. Maybe just to close out the Shingles discussion here, just on the international side, you talked a little bit about BD and being potentially active there and just kind of what is the market and sort of where it stands in terms of adoption penetration of Shingles vaccines, I guess, in ex-U.S. and ex-maybe Western markets? Where does that stand currently? And just kind of what is the size of the TAM, I guess, potentially there? That's a good question. I mean, it continues to expand. I think that it's a pretty large TAM. I think the real question is where is it at by the time we get to market? And so that's one of the big questions because right now we are dealing with a catch-up cohort versus an annual cohort. So I think the catch-up cohort is being depleted in the meantime, but I do think that there will be a pretty reasonable TAM, especially internationally. There's a lot more people in the world beyond the 300 million in the U.S. So it should be quite large for the international population, especially if you're thinking about China and other large population centers. Okay. Great. You brought up actually my next set of questions, which is Tdap. Can you maybe provide us an update on your ongoing Canadian study, where that stands, and just sort of where that stands and just sort of when we might potentially get data updates from there? Yeah. So the recent update that we made was that we found a way to optimize the program and basically remove the previously planned challenge study from the development timeline and program. And that was due to some regulatory feedback that said the FDA wanted our challenge study to use a pertactin-deficient strain of pertussis because that's the current circulating strain in the U.S. Now, the challenge model, which had been developed over time, used a pertactin-positive strain. So that study was going to be basically a pilot study to learn the ropes on running that, but it was going to be required to be redone at a later date once the pertactin-negative strain was available. So given that the key element of this program is really durability, we decided to not do the pertactin-positive challenge study. It's not on the critical path. It was not on the critical path given that we plan on running a long-term phase two immunogenicity study that will allow us to see immunogenicity data for pertussis toxin in comparison to Boostrix or Adacel or both over time. That's the key next study to get started because obviously it's a long-term study, so we need to start it soon. We removed the planned challenge study, initiated an extension of our phase one study. We are bringing back patients from the phase one study to see what their immunogenicity, the comparative immunogenicity is compared to Boostrix, which was used in that study, at 2.5 and 3 years. With that data, we will feel more confident about embarking on a long-term phase two immunogenicity study, which would start in the beginning part of next year. We'll have data from the phase I extension in Q4. Okay. And so you should expect a program update in Q4, basically. Okay. Great. In terms of the developmental path after that and just sort of what could be potentially a pivotal/registrational data points and just sort of size of the data set as you think about that, how could this be potentially a seamless trial and just what does that sort of strategy look like? Yeah. It's really interesting, but it's pretty well defined. So we would actually be running a rather large challenge study to demonstrate that the antigens are effective. They're the same antigens that are in the competitor products. They're just manufactured in a different process. So the FDA says, "Well, that makes them not the same." So we need to demonstrate that those are effective, not just immunogenic. So that's where the challenge study comes in. And then we use that data and the immunogenicity in those subjects to bridge to a larger safety and immunogenicity study that would be a phase three safety and immunogenicity study and the phase three challenge study. Those are the core data packages that we would need. And then in addition, we will be running on top of that a long-term phase two immunogenicity study focused on that long-term result. So we have all of that. That package would be available at the time of filing. So it's relatively straightforward, although I would say the phase III challenge study is a fairly unique element. Okay. And maybe just to round out the discussion here, what is the, I guess, sort of run rate of the Tdap market currently and just kind of what is, I guess, you've sized up the U.S. Hep B market at potentially $800 million in a few years. Just is there expansion opportunity here in Tdap, or is it more of a share gain type? No. The market's pretty good. It's $700 million in the U.S. right now, probably another four-five ex-U.S., I mean, everywhere. So it's over $1 billion globally with a heavy weight in the U.S. There's about 20 million doses given a year across adolescents, maternal. There's still a decent dose used for family members around a pregnancy as well as the 10-year tetanus booster is often there to get the benefit of the boosting of the pertussis response every 10 years. And so pretty good existing market. I don't actually help the existing program. So we know there's pertussis vaccine given at adolescents, booster, and then throughout your life with this 10-year tetanus boost, but we know immunity wanes rapidly. After it starts waning at two years, three years, four years, it's down really low. So you're left with these big gaps in protection. We think with just simply a product that has a bit better durability, it just fills in the gaps of the existing program. So it doesn't have as much. In our closing minutes, I want to touch a little bit on sort of biodefense and pandemics and plague in particular. In the news, I'm sure everyone's noticed bird flu and things like that have been very topical and just people are worried about sort of the next pandemic here. But also people worry about things like plague coming back here. And so you have a program that's ongoing there. And sort of what is the status of the program? Sure. That program is in collaboration and funded importantly by the Department of Defense because plague is not necessarily a huge pandemic threat. It's more of a bioterror threat that you could weaponize plague very effectively. And so the DOD sees that threat and it wants to have an improved vaccine. So they already have an antigen that they demonstrated as a three-dose, so zero, one, six-month antigen or schedule, sorry, for that vaccine. And they want to improve it much like HEPLISAV. So we're using 1018. We conducted a phase II safety and immunogenicity study, which we'll read out in Q4. And while in parallel to that, they decided to start conducting non-human primate challenge work, so lethal challenge models with non-human primates to establish efficacy of the two-dose regimen. We'll have data from non-human primates as well as from the phase two study in Q4 of this year. That will allow us to have a better insight into what the forward-looking plan for that program is, both the development plan and then start to build out some more awareness of how the DOD would see this fitting into either a vaccination regimen for troops or a stockpile play. We'll be able to provide more updates as we progress out of the phase two study. Okay. Q4 this year. Great. I guess maybe we're coming up on time, so I wanted to maybe ask a little bit about just as you think about the company and the shape of the company here over the next 12-18 months, you'll have some data sets like you talked about in terms of plague. You're on both the phase one and two program here as well. So I guess as you think of the trajectory, is there anything you feel like that's not understood or appreciated by investors or the market, whether it's the commercial piece of it, whether it's the pipeline side of it, and just kind of like what would you highlight as maybe sort of the best opportunity that are near term for you guys? Yeah. I mean, I think obviously the commercial growth is a critical aspect of the value story. Continue to deliver. But I think we have delivered has shown up. And what I mean by that is a recommendation is a recommendation. It really doesn't mean patients don't actually respond. So when that recommendation was made in 2022, we had no idea how that was going to play out. And then through 2023, it was a big question mark. Coming out of 2023 into 2024, we know that patients respond from their healthcare providers to get a Hep B vaccine. So that provides us a lot of confidence that this market will continue to develop, will continue to grow. And we've never wavered in our confidence on our product profile, both from a safety perspective and an efficacy perspective. We believe that the only way you're really going to protect people against Hep B is to use a shorter regimen just due to adult compliance issues. So we're fairly confident about the brand. We're very excited about the opportunity to continue to show everybody what this product can do and then also how that positions Dynavax as a company to continue to grow. We talked about our pipeline assets. We generated a significant amount of money through our efforts during COVID, which we're very proud of how we ran that, both as a response to the pandemic and how we ran it as a business. So we are looking forward to being able to leverage those good fortunes into identifying other strategic assets and executing on those just as well as we've done with the ones we've had to date. So really, I think that's the story, and we're excited about getting after it. Great. Okay. Thanks, Ryan and Don, for joining us, and we'll end it on that note. Thank you. Thanks, Paul. Appreciate it. Thank you.