All right. Welcome everyone to our Jefferies 2026 Global Healthcare Conference. My name is Roger Song, senior analyst, covers med tech, biotech here. It's my great pleasure to welcome our next company, Vaxcyte. We have President and CFO, Andrew Guggenhime, we have the Chief Operating Officer, Jim Wassil. Welcome, gentlemen. Great. Thanks, Roger. Thanks, Roger. Great to be here. Appreciate the invitation. Awesome. All righty. Maybe Andrew, you can give us some statement for Vaxcyte. You have a lot going on and a very exciting time ahead of you. We can go into the conversation. Thanks for the opportunity to make some introductory remarks. Vaxcyte is a company focused on vaccines to prevent or treat bacterial infectious diseases. We have a proprietary cell-free protein synthesis platform that we're leveraging across our pipeline. We are most known for and headlined by our programs in pneumococcal disease. We have a pneumococcal conjugate vaccine franchise. As you said, really exciting kind of 12 months ahead of us as it relates to our lead programs. We are pursuing PCVs in both the adult and infant markets. In aggregate, these markets total $8 billion today. Projections show this market growing to $12 billion, $13 billion over the next 5 to 10 years or so. Really excited about the opportunity to develop broader spectrum vaccines to prevent circulation of this disease. In our adult franchise, we have an ongoing substantial phase III program underway. We have three trials ongoing for which we've completed enrollment. The OPUS-1 study is the most important of those three studies. That's our non-inferiority study comparing ourselves to the two standards of care today. We've continued to guide to expect top-line data from that program in the fourth quarter of this year. That's a really important data set for us to define the opportunity. Then we have a couple of complementary programs, the OPUS-2 and OPUS-3 studies that we expect to read out in the first half of next year. Together, in addition to one other study enabling the submission of a BLA, which we continue to target by the end of 2027 to be in a position to be on market in 2028. Really excited, and I know we'll get into how we see the opportunity there and what constitutes success for those programs. As we conduct this phase III program, we are readying ourselves for a future commercial launch. We hired our first-ever Chief Commercial Officer in the fall of last year, Mike Mullette, who's in the audience today. Methodically preparing for, as I said, future commercialization while we conduct this clinical program, in addition to preparing to be able to meet the supply requirements for this large market opportunity via manufacturing. In the infant market, which comprises today about 70%-75% of the global opportunity, we have a phase II program underway for our 31-valent program. We showed data from our 24-valent program last year, and the 31-valent program also has completed enrollment, and we're continuing to guide to top-line data from that study by the end of the first half of next year. Over the next 12 months, we expect to have three readouts from the VAX-31 adult phase III studies, and then the readout from the VAX-31 infant phase II study. Then I would say outside of our PCV franchise, we are now resuming advancement of our pipeline programs. Just yesterday, after the close of the market, we announced we had dosed our first participant in our VAX-A1 study. This is a phase I study for the prevention of Group A Strep, a disease that continues to be problematic. Rates of invasive disease are growing. Antibiotic resistance is growing. We think this is a blockbuster opportunity. We believe we're in a lead position, even though we're first now moving into the clinic, and expect to have data from that study in the second half of next year, principally focused on safety and tolerability. We continue to pursue other programs behind those two, but certainly the next 12-18 months will be headlined by our PCV franchise programs and now the Group A Strep program. Excellent. Very glad that you are expanding the pipeline, and then because your platform can be suited for many other vaccine outside of pneumococcal. Today's conversation probably will be still focusing on the pneumococcal, but we can break down into adult and then the infant. Start from adult, because that's the pivotal data going to come in third, fourth quarter this year, OPUS-1. It is a statistically powered non-inferiority study. It's interesting. I think in recent earnings, you start to make some expectation setting type of the comment related to how many misses you think is a base case for the non-inferiority compared to PREVNAR 20 and then CAPVAXIVE. Maybe tell us the background of doing this and why you want to give us this kind of expectation, and then do some math and behind that, what's the evidence to support this base case? Yeah, maybe I'll take the lead in sort of why we did it and talk about, again, what those expectations are. Look, we think it's just really important to be crystal clear and unambiguous in our expectations for this trial. In fact, yesterday we posted a new version of our corporate presentation, which we outlined over three pages, how the FDA has consistently evaluated this category, and really the punchline for that is it's about the totality of the data. Importantly, also setting our expectations for the base case outcome for the study, which we believe would constitute a significant win and enable not only FDA approval, but also importantly, a best-in-class vaccine in this market. Also what would constitute the upside case. We've been very specific. We've gotten a lot of questions, notwithstanding what we thought were pretty clear expectations we've been communicating over the last few months. We have continued to get questions about. Well, exactly how many serotypes can you miss on? When you say miss, is that against PCV20, which is one of our comparators, or is it against PCV21? We just wanted to be very clear and on the record and in writing what our expectations are, what constitutes success, and how the FDA has really evaluated vaccines in this category. To answer the second part, how did we come up with the list and the guidance? Well, for PCV20, it was more straightforward. We did a phase II. We have a lot of data already with that, and from that, we can make an assessment for the 20 strains that are in PCV20 that are in ours. For CAPVAXIVE, we haven't done a head-to-head. We had to do a bit more work, and I'd say more orthogonal approach to determining what our probability of success is, with the caveat that they're different studies, different assays, and in potentially different populations where there could be different circulating disease. All those caveats aside, though, we had the benefit that PCV21 compared themselves to PCV20, and we compared ourselves to PCV20. For the 11 serotypes that are in our vaccine that are also in PCV20 and PCV21. We felt a bit more confidence in our assessment because there is a reference. In both studies that helps to ameliorate some of the variability, especially assay variability. For the eight serotypes that are in CAPVAXIVE, that are in our vaccine, but not in PCV20, we had to look at a few other measurements. We looked at geometric mean fold rise, we looked at reverse cumulative distribution curves, IgG, and Geometric Mean Titers. On that basis, we came up with an assessment of where we thought we may miss in our phase III study. If that makes sense. Yeah, sure. Roger, I just might add. Yeah Just to kind of set the backdrop here, right? There have been a number of vaccines approved in this space over the last 10, 15 or so years. Every single program that's come before the FDA has had at least one miss as it relates to the non-inferiority requirement. The most recent approval, which was Pfizer's PCV24 for infants, had six misses of the 20 serotypes in total on the first of the two co-primary endpoints. We would want to be crystal clear that every vaccine has had at least one misses, and as I said, in some cases more. The FDA has consistently looked at this category based on the totality of the data. If you do miss, on how many do you miss? By how much do you miss? What is the circulation of the serotype on which you miss? What are the absolute immune titers? All these data are really important in the FDA's assessment. Again, as I said, looking at the totality of the data and doing a risk/benefit analysis to see whether the incremental serotype and disease coverage that your broader spectrum vaccine confers relative to the then standard of care, and does it represent an improvement in the ability to prevent this disease. Yeah, got it. I want to just put that on the record. By the way, everything you said makes sense to me. This is very good kind of baseline guidance. Put on the record is, people asking me, has management team from Vaxcyte seen the data, that's why they put out the guidance? Just make sure this is not the case here. Yeah. We've been crystal clear. We have not seen a shred of data as it relates to immunogenicity. This is just a continuation of the guidance we've been communicating over the last several months, but wanted to put a finer point on it, be more clear about it, and now have it in writing in our slides. Yeah. Got it. Then in terms of, I think, if I remember correctly, PREVNAR 20, you have a risk to miss one, then for CAPVAXIVE, maybe five. Among those six, any of those serotypes you think in terms of the epidemiology, the disease burden, any of them are you think critical serotypes you don't want to miss at all? Well, we'll begin by saying that serotype 3 is the most prevalent circulating strain in. It's not. Mm-hmm. About 18% of disease. Yeah U.S. adult population is serotype 3. We have guided that we will likely miss against CAPVAXIVE on serotype 3. However, we believe serotype 3 is a unique serotype, different than all the others. In fact, at a recent conference at ISPPD, Merck tried to prove that their improvement of 2-fold improvement in immune responses versus PCV20 would lead to better clinical outcomes. They did a challenge study where they immunized individuals with PCV20 and PCV21, and then they gave them serotype 3 disease, and watched to see what the rates of carriage were for acquisition rates, density, and length of carriage, as well as some symptoms. They didn't see any clinical difference between their vaccine and PCV20. A lot of the experts believe that you need as much as an eightfold improvement in titers before you start to see clinical differentiation for serotype 3. That would be your most important serotype. Within the range of CAPVAXIVE and PCV20, the belief is that there is not going to be any different relative clinical outcomes that will differentiate us. Got it. Okay. That's helpful. I know the serotype 3 is critical. We will talk about the recent finding... Yeah -disclosure as well in a minute. The other thing is, am I right? Because the study design is you need to hit non-inferiority either against PREVNAR 20 or CAPVAXIVE. For example, the serotype 3, you may miss on CAPVAXIVE, but you can hit the non-inferiority against the PCV20. Technically, it not consider as a miss on the non-inferiority? According to our protocol as written that we submitted to the FDA, for the 11 serotypes that are in our vaccine, PCV20 and 21. it's an either/or situation. Right. If we meet non-inferior on either PCV20 or 21, that is considered meeting the non-inferiority criteria. That's right. Yeah. We've guided to missing on PCV21, but we believe we will make that on PCV20. For 22F, we've got it on missing for PCV20, but we feel we will make it versus PCV21. For those three, officially, according to the protocol, they will meet non-inferiority. I did the math records. You have one plus five, but you actually have a one and a two, may not technically miss by protocol, so in total maybe three. I understand that's kind of protocol, you also seems to be conservative. Maybe FDA still want to look at this. This vaccine is five, the other vaccine separate looking at it, because always my question is, you have this two group people as a comparator arm, either/or, will FDA really put them apart and then look at the individual non-inferiority. When you talk about the missed non-inferiority, you're using the sample size for each cohort. The VAX-31 against subpopulation of the PREVNAR 20 and the subpopulation of the CAPVAXIVE. Yeah. I would say just, it's also important, I think that is all correct. It's also, the discussion really shouldn't be on is it two misses, is it four misses, is it five misses? Because again, it's really this totality of the data assessment. As I said, the most recent example for PCV20 was missing on six of 20. So what we believe we will be evaluated by is, there are two standards of care today, PCV20. We have 11 more serotypes than PCV20, and we confer an incremental 31%-34% disease coverage. Right? Relative to PCV21, we have 10 more serotypes, and we confer an additional 15% ± of disease coverage as well. The question is, do the results from our program reflect an incremental benefit relative to either or both of the standards of care today? Will misses be a factor? Yes, but there's not a bright line because it really is about the totality of the data in terms of the overall immune responses, the relevance of serotypes on which we might have a technical miss, among other factors. Got it. Yeah. No, I don't want to go down the rabbit hole further, but just that, in terms of the misses on the non-inferiority, I totally hear you, Andrew, you say it's a totality, right? Right. It's the overall immunogenicity, overall disease coverage, and then, honestly, all the past approval, they all have some compromise, right? Trade-off as you broaden the disease coverage, but you're losing the immunogenicity. I think of VAX-31, maybe the first PCV don't need to have that trade-off. Right. Increase the coverage while still maintain, even increase the immunogenicity. You are focusing on potential misses. We also, in our phase II, had seven serotypes that were statistically superior to PCV20 as well. How that factors in, who knows? It's at least reassuring that there could be a lot of serotypes where we actually do much better than the standard of care as well. Which is, again, is a departure from history, right? Historically, when companies have pursued broader spectrum vaccines, they've seen an overall drop in immune responses relative to the then standard of care. If we're able to show results in our phase III study comparable to what we showed in our phase II, we would see an overall increase in immune responses. That's important in the context of potential misses, that if we can show overall improvement in immune responses, that would be a very different setup with the agency, in contrast to kind of historical programs that have preceded ours. Yeah. Got it. In terms of the FDA did give you some guidance in writing in terms of what they want to see. Didn't specify how many misses they need to have. I think the wording is a handful or a few. Yeah, the FDA, and we've had written correspondences acknowledged, and the contemplation of a few misses in the context of the totality of the data. Again, it's really the focus on totality of the data that we think is kind of the most important factor and consistent with how they've evaluated these vaccines to date, not just in the PCV space. Got it. Also for the ACIP, which is the CDC division of the recommendation body for vaccine. First of all, they don't necessarily need to give you their preferential recommendation. On the other side is that in order to be much commercially successful, on the other side is highly likely if you can increase the disease coverage and while not compromise too much of the immunogenicity, they will give you the preferential recommendation. Yeah. I don't think we're planning on getting a preferential recommendation out of the gate. If you look, PCV20 didn't have a preferential recommendation either versus PCV15, and they had over 95% market share. Historically, broader coverage in this space dominates the market, whether there is a preferential recommendation or not. With the situation as it is and with us being a new manufacturer, part of getting a preferential recommendation, they want to make sure you can supply the market, because if they give a preferential, then typically you end up with 100% market share very quickly. We feel that even without one, though, the broadest coverage commercially will end up dominating the market share. Yeah. In our view, we don't think the lack of a preferential recommendation, which again is very clearly our base case, has a material impact on the peak sales opportunity for VAX-31. It would change the slope of the curve in terms of the time to get there, but over the long term, doesn't have a meaningful impact on the opportunity. As Jim said, we don't expect it out of the gate. Is there an opportunity down the road to get that? Perhaps, but not something that we are using in our base case planning. Sure, got it. Maybe quickly on the competitive side, it's interesting, you seems to be a standalone VAX-31 or 30-plus valent for adult population, because your competitor basically sequentially drop off the race, and then because they think you are too competitive and then they want to move on to the high valency as well. How much you know about their high valency or 30+ valency technology, and then how you think about the competitiveness in the long- term? Maybe I'll start and then turn it over to Jim. Yes, you're right. Over the last few years, we've seen Sanofi not advance its 21-valent program in adults. We've seen GSK not advance its 24-valent program in adults. Most recently, just in the last couple of weeks, Pfizer announced its decision to not advance its phase III-ready 25-valent program in adults. Over the last couple of years, I think our position has only improved in terms of the lead time we would have in the market with a broader spectrum vaccine. Even in the adult market at the recent ISPPD conference, there's some new data presented on the epidemiology front that I think widens our differentiation relative to CAPVAXIVE, which is Merck's 21-valent program on the market as well. Jim, maybe you can talk about what we learned and potential implications. Sure. Well, what he's specifically referring to is the CDC presented at this conference that serotype 4 continues to increase, particularly in Western states. In Alaska, it represents 50% of circulating disease. Even California, Arizona, Washington, states are seeing increases, as well as increase of serotype 14, both of which are not in CAPVAXIVE. We think that that improves our competitive position at launch. In terms of your question on Pfizer and their 35-valent, you probably know just as much as we do. Pfizer's been very tight-lipped. They did say that they're moving towards for 35-valent. We are watching the patent, so we can speculate what they're doing, but we really aren't sure. They said that they are going to be moving out of preclinical into the clinic by the end of this year. What we do know is that they pushed off the 25-valent. They're going to a 35, and that just gives us additional runway for our 31 to launch. Yep. Got it. Okay. Maybe we spend most of the time on adult because that's more near- term. You do have the infant phase II VAX-31 upcoming early next year. Maybe just tell us what is the current expectation compared to your phase II, and then also what will be the profile you feel comfortable moving to the phase III? Yeah, I guess I would say at a high level, given the timing of the readouts, we are most focused on clearly articulating our expectations across the adult programs, those 3 readouts expected to occur in advance of the infant readout. We will soon be similarly setting very clear expectations for the infant 31-valent phase II study. I would say our view is, if we are able to show results that are comparable to what we showed with a 24-valent study in infants, we believe we have a best-in-class vaccine and an approvable vaccine because the 31-valent provides 95% of disease coverage. In the context of that level of disease coverage, a significant benefit over the current standard of care, that would be a winning hand. That said, we are exploring two dose arms in this study that are higher than any of the dose arms explored in the 24-valent study. Even though we think comparable results would represent a best-in-class profile, we are expecting improved results just by way of dosing at higher levels, which we think will deliver better immune responses. One of the key learnings that came out of the dose-finding study in the 24-valent. We will be providing more granularity, more specificity in the months ahead, once we make sure the expectations for the adult studies are very well understood and appreciated. Yeah. Well, 31-valent in infant potentially can be another leading PCV for infant. Before you show the phase II data, seems competitors continue to move forward with slightly higher but not reaching 30, including Pfizer's 25-valent. ISPPD data, it's very interesting. They only give us one serotype, which I think is a problematic serotype for them. How should we interpret that? They certainly say they were moving to phase III, and then knowing you are running the phase II and then potentially can move into phase III as well. How should we think about the strategy for Pfizer, and then why they cannot do that for the 35-valent for infant? Yeah. Sure. For those who aren't as familiar with the Pfizer data, they presented at ISPPD on their 25-valent. When they did, they primarily, well, solely showed the results for serotype 3. They only showed IgG, and they didn't show the results for the other 24. It's very hard for me to speculate with that. I think it's promising because serotype 3 is the most significant serotype, so having an improvement of IgG of 9 to 15-fold seems promising. The consensus amongst the experts for serotype 3 is a little bit different than the others. For others, IgG correlates very closely with functional antibody or OPA responses. Serotype 3, you don't have that same degree of correlation. One of the questions asked during the presentation was, how does the OPA data look? They said it will come out in a publication with the 2024 data. To me, seeing the OPA data for serotypes 3 and seeing the remainder of the serotypes, maybe we can get a better understanding of what our competitor will look like. They did move it into phase III, so obviously they feel that there's a probability of success that's significant enough to take the risk of spending the money and doing a phase III clinical study. I would say, too, that the question of what serotype 3 immune responses are clinically relevant. Merck had compelling serotype 3 data for VAXNEUVANCE, its 15-valent program. That didn't ultimately translate into a commercial advantage relative to Pfizer's PCV20. PCV20 garnered 95% of the market despite an inferior serotype 3 immune response, which is consistent with what this market has demonstrated over the years, is which broader spectrum coverage wins the day. The impact of inferior serotype 3 responses did not translate into commercial differentiation as between VAXNEUVANCE and PCV20. By the same token, as we mentioned earlier, we might very well see superior immune responses for our adult program. We also don't think that translates into meaningful commercial benefit either, because it really is about what is the spectrum of coverage of your vaccine. That is what has driven commercial adoption in this market historically. Got it. More so than individual serotype responses. Yeah. No, I think right now Pfizer. This revenue or the PREVNAR family is very critical to their commercial franchise. They're not going to give away. On the other side, it's not easy to come up with good technology to increase the valency without sacrificing the immunogenicity. We'll see the fight, and then I think we bet on you to have the better vaccine. All right. I think that's pretty much good for the PCV franchise. Since we mentioned this A1 you just recently dosed, and then also the cell-free platform. Maybe just give a minute or two related to the pipeline and then how much focus, how excited you are about this pipeline. I'm really excited that we've just started the Group A Strep study. I think Group A Strep is one of the most underappreciated diseases out there. If you look at it in terms of disease and mortality, you're talking about tuberculosis, malaria, HIV, and then Group A Strep. Group A Strep doesn't get the level of interest or research that I think it warrants. In fact, in the past decade, including in the U.S. and elsewhere, there's been significant increasing rates of invasive disease have more than doubled. Antibiotic resistance to three major categories of antibiotics have more than tripled. There is some evidence of circulating genes for penicillin susceptibility now, which would be extremely problematic. Even if antibiotics do work, they're over-prescribed because any time you have a sore throat, a kid gets a prescription because they're afraid it's Group A Strep. Almost one out of every five antibiotics written between three and nine is due to Group A Strep. Presumed Group A Strep. Presumed Group A Strep, yes. As a result of all that, the actual cost of direct medical expenses spent in the U.S. every year is $6 billion. I was talking to the person who did that study at this ISPPD conference, and he told me that the CDC is having him redo it because the rates have increased so much. $6 billion is actually a low estimate at this point, and you can expect the publication to increase that. With all that in mind, I think you've got a really significant market opportunity. For us, yes, our platform allows us to do some unique things. We are using a carrier protein now that is also immunogenic because we can avoid B and T cell epitopes. We have a universal polysaccharide, which is called a Group A carbohydrate, that is across all strains. It's linked to what's called SpyAD, Streptococcus pyogenes, which is Group A Strep, adhesion, and division. We're going after the ability of the bug to attach to the tonsils. We have an exotoxin that we're targeting, SLO, that leads to things like necrotizing fasciitis or that characteristic strawberry-colored tonsils. If you can go after the exotoxin, you can go after adhesion. Finally, Group A Strep has this protein that interferes with complement cascade. It interferes with the ability of our immune system to kill the bug, and so we're going after that as well. We've got the traditional conjugate plus adhesion, plus an exotoxin, plus this additional complement interference protein. We think that the combination of all those should have a significant impact. We're going into adults now. We will be able to go into school kids after that. Because the disease is so ubiquitous, we think we can do an efficacy study in infants in less than 1,000 subjects. We will get an early proof of concept as well. Excellent. All right. I think we are time up. I really appreciate both of you joining us, and thank you, everyone, for watching and listening. Great. Thank you. Thanks, Roger