Hey, welcome everyone to day one, first meeting of Jefferies Healthcare Conference in London. Our first company is Vaxcyte. Welcome, Andrew and Jim. Great. Thank you, Roger. Great to be here. Thanks to you for the invitation to the Jefferies team. Great to kick off the conference this year. Awesome. Happy to have you. So my name is Roger Song, one of the senior analysts cover biotech in the US. In the next 25 minutes, we're gonna have this fireside chat to talk about Vaxcyte's recent progress and future plans. Great. Okay, so maybe get this started. It seems we're in Europe, maybe not everyone kind of very familiar with Vaxcyte or someone already know you but haven't really heard about you for some time. What is your updated elevator pitch for the investors? Yeah, we are, Vaxcyte is a company dedicated to develop vaccines to prevent or treat bacterial infectious diseases. That is our expertise, that is our focus. We have a cell-free protein synthesis platform, which enables us to do things that some of the conventional technologies are unable, and we have been repurposing that technology. We're most known for our pneumococcal conjugate vaccine franchise or PCV programs. We have a 24-valent vaccine, and just recently now a 31-valent pneumococcal conjugate vaccine in development to develop what we believe can be a best-in-class program, broader valent forms of this vaccine, improving immunogenicity levels versus those we've seen historically in what is today a $7-$8 billion market, expected to grow to $12-$13 billion over the next few years. We are also repurposing that technology toward an interesting pipeline, admittedly earlier stage, for programs to prevent Group A strep, to treat periodontitis, and Shigella vaccine as well. Awesome. All right, I think you have a very good, unique, vaccine platform. I think today's conversation will likely mostly focus on the PCV, but you do have an earlier pipeline as well. We do. You know, so I've been covering Vaxcyte for a couple of years. Before that, I don't even know pneumococcal vaccine, how big the... I know pneumococcal vaccine, but I don't know how big the market category is. It's like a $5-$10 billion kind of global sales, and it, it's growing, right? Yes. So maybe we, maybe we can dive in, dive right in into your lead program, VAX-24. Understanding you just recently completed the conversation with the FDA regarding the clinical portion of the pivotal program. Maybe just let us know what are the key outcomes from that conversation and how happy you are about the results. Yeah, as you say, we just announced last week as part of our earnings release, that we completed a successful End-of-Phase II meeting with the FDA at the end of October. That, as you say, Roger, was focused on the clinical design of the upcoming Phase III program. Believe we have agreement with the FDA on really all aspects of the clinical program, total number of patients required, the primary and secondary endpoints. Importantly, that immunogenicity analyses, as expected, will suffice for regulatory approval and no field efficacy study will be required. And also importantly, that we reached agreement with FDA on the definition of superiority. As I mentioned earlier, we've seen in our prior trial results the ability to not only increase spectrum of coverage, but also improve immunogenicity versus prior vaccines. We have alignment with the FDA on the definition of superiority. In parallel now with the completion of the clinically focused end-of-Phase II meeting, we continue to have discussions with FDA on the CMC component, which we expect to occur through the first quarter, which will enable us to ultimately then commence the Phase III program. Excellent. Yeah, CMC is absolutely one of the key components for pneumococcal vaccine. Let's talk about that in a moment. Maybe just any other kind of clarity you will provide us regarding the phase III pivotal program. Maybe that's kind of when you start or when we're gonna learn more, for example, like age group or any additional program outside of immunogenicity non-inferiority based phase III study. Yeah, no, fair question. I would expect once we've completed all the discussions with FDA and ready to commence that trial, we would be providing more clarity on the size of the trial, the endpoints for the trial, the population, as you say, in which the trial will be explored. It'll be, it'll be an adult trial. This is our adult program. We have an infant program that continues to enroll patients, but more clarity to come as we commence the trial. Yeah, that's fair. That's fair. Okay, so for CMC, seems investors a little bit kind of nervous about what's the progress of the CMC, but you seem very confident it can be completed early next year, and you can commence the phase III. So just give us some flavor. What are the key components outstanding for the CMC? Any, you know, should we really concern? Yeah. So for those who aren't as familiar with vaccines, for vaccines, the product is the process for the FDA. You do have to do what's called a Lot-to-Lot Consistency Study in Phase III, where you manufacture three separate lots or manufacturing batches, and you do have to show consistency in your clinical immunogenicity to be able to get licensure. So there is an elevated level of scrutiny by the FDA for vaccines. We know this. We've known this for a while. We've been working very hard, but essentially, there's a lot of work that needs to be done for both the process validation work as well as analytical validation as well. And for us, you know, I think, you know, we've got a good handle on it. but there is a significant volume of work. When you're doing a 24- or 31-valent, we have 24 different polysaccharides, it's not just one assay that you need to validate, you have to do it multiple times. And so, we're in those discussions with the FDA. We're trying to figure out what needs to be done. There are different levels between what is required to go into phase III and what you need for BLA and commercialization. So we've staged our approach as well, and we're in those final discussions with the FDA to really confirm what it is that they're needing for us, ultimately, not as much for phase III, I think, it's more to try and see what we need to get to that BLA. Yeah. So because the whole pivotal program is really for the BLA and the future commercialization. We will talk about the recently updated longer partnership. So it seems that also, you know, set up for the future scale up for the commercial. Yeah. Okay. So we have been talking about this, you know, adult program, which is most advanced, kind of, stage in the Phase III-ready stage, but also understanding for the pneumococcal vaccine, pediatric is much bigger population at the current market, 80%-ish. So where are you for the peds program? I understand you just started the Phase I/II, and how's the enrollment look like, and what's the key features of the design? I'll be able to talk about status, and Jim can talk about- Yeah ... the features of the design. In terms of status, we are—it's a Stage I/II trial in the infant population. We've completed Stage I, which is really a safety assessment, and we are now enrolling patients in Stage II. That continues to progress. We have continued to maintain our guidance. For infants, very different from adults. Infants, it's 1 vaccination, and then 30 days later, you're—later- Adults. Adults, sorry. Adults, thank you, Jim. Yeah. 30 days after vaccination, you're measuring the immune responses. For infants, in the U.S., it's a 4-dose regimen. Infants get vaccinated at months 2, 4, and 6, and then at between months 12 and 15. So it's a longer trial, 4 vaccinations, and there are 2 co-primary endpoints. The first is after the first 3 doses, called the primary immunization series, and then you're measuring again after the booster dose, about 9 months or so later. And we've guided to having data from that primary series, which is the most important of the 2 co-primary endpoints, guided to having those data by 2025, so between late 2024 and early 2025, with then the top-line data from the booster dose to follow approximately 9 months later. Awesome. You covered the design, too. You know? Yeah, you will have some additional- Yeah, yeah, yeah ... questions as well. So, if we didn't mention before, your adult phase I/II in the younger adult, younger adult, and then later phase II, older adult, data is very impressive. And then investors, really interesting is, how this adult data will translate into the pediatric population. So what gives you the confidence this will be translatable? You know, the design is one of them. Maybe talk, talk a little bit about the preclinical and any other kind of precedents we can, kind of refer to. Yeah. Well, I mean, first I, I'll say is, you know, our adult study was really, really, really strong. And we had on average between 20% and 30% higher immunogenicity, even though we increased the number of strains in the vaccine as well, which is unprecedented, in the industry so far. So all the other manufacturers have been able to show successful results in adults. It's translated into infants, and they've had lower levels of immunogenicity than we have. So, so the first is, that gives us confidence, is that, that we've got this robust response in the adults. Second is, I think we validated our platform and our whole hypothesis that being able to do this site-specific conjugation using less of the carrier protein allows us to improve immunogenicity. When you go into populations that I would consider more stressed, infants are a little bit more stressed. They're in, their immune system has not been fully developed. When we look at the older adults, we did much better in the older adults versus PCV20 than we did in the younger adults. We, you know, were 20% higher in the younger adults, we were 30% higher in the older adults, so. Older adults are immunosuppressed. So the other reason I have confidence that as we move into the infant population, that we should do well is that we have shown that we can do better in situations where there is a little bit more of a not as robust of an immune response. Yep, got it. I think, Andrew, you mentioned this pediatric population is the prime and the booster. How significant is that? So, understand, you have done some preclinical tests, but some of the competitor had not. So tell us a little bit why you are confident about your boost, kind of, which is very important for pediatric population, your booster can be as good as your prime dose. Yeah. So I mean, historically, with PCV vaccines, what you've seen is, like for instance, Pfizer, when they did their PCV 20, they had to demonstrate non-inferiority after the primary series and after the boost. Yeah. They met all of the requirements after the boost, but they missed on six endpoints after the primary series in the U.S., and for the European schedule, they missed on 11. So actually, I'm not as worried about the boost because toddlers have a more developed immune system. They've been previously exposed. The booster seems to do okay with PCVs. However, you know, there are other technologies out there, and I think that's what you're referring to, that don't necessarily have the demonstrated capability of demonstrating a boost technology like the affinity binding approach, for instance. So I think for us, with the PCV, we're not as worried about the boost. We're gonna keep a close eye on the primary series. That's where Pfizer had most trouble. For some of the other technologies, yes, the boost, because you have to demonstrate that you're priming and that you're not developing anti-linker antibodies, and you're not decreasing the immunogenicity, which would all be seen with a boost. As Jim said, a boost is the price of admission. It's required for regulatory approval in the infant population. Today, in the adult market, it's just, as I said earlier, a single dose, but it's our, in the market expectation that over time, for reasons we can get into, that market itself will also convert to a prime boost market. So the boost, critical today in infants, we think in the future will be critical in the adult population as well. Awesome. Okay, good. We take 10 minutes to talk a little bit about your lead program. I'm really excited about your second generation or the, you know, another, VAX-31, also in the PCV franchise. So how should we-- how excited should we be for this program, and what's the overall strategy, given you already have a very impressive, VAX-24 in the franchise? Yeah. So with the 31, we're pretty comfortable as well with this program. It just started in the clinic that we announced recently. It does expand coverage to, since we're in the UK, 98% coverage here, in terms of overall coverage in adults, so that's quite substantial. We think we've got a good formulation, and the reason we think that is that when we did our 24 study or with 24 strains, we actually included an arm in that study that simulated the exact formulation of our 31. We had the exact amount of polysaccharide in there. We had the exact amount of our protein carrier, so we actually almost got an early phase 1a read on our 31, and we were able to see what we needed to do to shore up that formulation before starting the 31 study. So we used the 24 actually to help us improve the chances of success for our 31. We expect now, as Jim said, we just announced, I think a month or so ago, the clearance of the IND and a couple of weeks ago, the commencement of the phase I portion of that trial. The next announcement from us would be the commencement of the phase II portion, subject to satisfactory safety out of the phase I portion, and continue to guide to having data from that trial in the second half of next year. In contrast to the VAX-24 program, where we first ran that study in younger adults and then moved into the older adult population with two different readouts. For VAX-31, we're doing the entire adult population, 50 and over, in one larger study, so it'll be a more comprehensive readout, that again, we're expecting the second half of next year. Excellent. Yeah, let's just spend a little bit more time on this because this data readout gonna be happening second half next year. I would consider this a very big kinda catalyst for Vax, Vaxcyte and also the entire PCV space. So Jim, you mentioned something very critical, maybe not all the investors will appreciate this. Maybe you can give us a little bit more details. When you read out the—when you designed the VAX-24, you have the mixed dose with the, you know, the, as you said, the formulation mimic what the VAX-31 look like. Tell us how the design and why you think it will have some research to the VAX-31, you know, with the carrier protein versus the polysaccharide. Yeah. So what we wanted to do, and this is a unique situation. It's the first time in my career that we've been able to do this. We had obviously the 24-valent vaccine in the clinic, and we're gonna follow it up with the 31. So we're adding an additional seven strains or seven serotypes, seven polysaccharides. What we did with the mixed dose was we had 24 of the strains at 2.2, but then we took seven of those, and we doubled them in terms of polysaccharide content. So we basically simulated the exact formulation for our 31. Now, there are different polysaccharides, so we still have to prove that the incremental seven are immunogenic and can demonstrate a robust immune response. But in this category, what happens is as you add more and more strains, the protein interferes with the polysaccharide response, and it reduces the polysaccharide overall immunogenicity. And that's the antigen that you want to get protection. So by adding additional protein, adding additional polysaccharide, we were able to see if there was any interference, and where there was a little bit, we were able to tweak our formulation and actually improve it. So that's why we feel a lot more comfortable going into the 31, that we'll have a good outcome of this study. Yeah. Got it. So is that fair to say your 24 mixed dose, you already used almost the same amount of the carrier protein, but you double the seventh strain kind of polysaccharide, but your 31, you have a different, you have overall 31 kind of a valent, but those 7 additional polysaccharide will be different polysaccharide compared to 24? Yeah. So other than the different polysaccharides, the formulation is identical. Right. Yeah. Yeah, go ahead. The strategy behind VAX-31, as Jim outlined, is really to include the serotypes that are responsible for the overwhelming majority of disease today. As Jim said, it's 98% coverage here in the U.K. Yeah. It's 95% coverage in the U.S. So there's a point of diminishing returns, and we felt 31 was the right number to cover an overwhelming majority of disease, far more than any of the other vaccines in development that we're aware of today. Yeah. Yeah, got it. Okay, and then in terms of the readout, second half next year, I believe you're gonna put all the data together to read out. And what's the news flow will look like? Okay, you will let us know. Okay, we're passing the phase I safety portion and then different age group and all the way towards the final readout. Just give us some news flow. Yeah, so obviously, recently, we announced, as noted, the commencement of the phase 1 portion of that trial. The next announcement from us would be, again, subject to a DMC giving us the go ahead from a safety perspective, announcing that we've dosed the first participants in the phase II portion of that trial. Following that would be an announcement of completion of enrollment for that phase II portion of the trial, at which point we're likely to narrow our guidance from what is today, second half of the year. We'd likely sharpen our pencils to narrow the window, and then ultimately, it would be the announcement of the top-line data from the full adult population, both adults in the 50-64-year-old group and then the 65 and older age group. Okay, awesome. Very much look forward to that readout. And then, so we know PCV has been a pretty competitive kinda space. Not a lot of player, but, you know, you have those kind of heavyweight, kinda wighter kinda people, the large pharma. So you as a, you know, emerging biopharma company and, how do you think your overall franchise strategy gonna play into the future, landscape for the PCV, kind of a vaccine? Well, we really think we have a great opportunity. You know, this market, as I said earlier, is $7-$8 billion today. It's expected to grow $12-$13 billion over the next several years, principally driven by growth in the adult market for reasons we can get into. Historically, spectrum of coverage has been the primary adoption feature, and historically, Pfizer has had the broadest spectrum vaccine on the market, initially Prevnar 7, Prevnar 13, and today Prevnar 20. There have been other competitors that have, for a fleeting period, GSK developed a 10-valent vaccine, but it was inferior in spectrum of coverage to PCV 13, so PCV 13 took the, essentially the entire market. Yeah. More recently, Merck has developed a 15-valent PCV Vaxneuvance, but Pfizer has one-upped that with its 20-valent PCV, and as a result, in both the adult and infant markets, taking the overwhelming share. So with a 24-valent and ultimately a 31-valent, we believe we have the opportunity to have best-in-class programs and garner the necessary recommendations from the recommending bodies, and then ultimately commercialize around the globe to- Yeah. You know, since we're in the U.K., just to make it a bit more tangible... Yeah. The way that the process works here is there's a recommending body called JCVI, Joint Committee on Vaccines and Immunization. They look at all the data, and they make a decision and a recommendation to the Public Health England. In the case of Prevnar 13, they looked at Prevnar 13, and then GSK had a 10-valent vaccine called Synflorix. JCVI said: "You have to use the 13 because it has broader coverage." So in this space, broader coverage historically has led to a preferential recommendation. Pfizer then goes to, you know, NHS does the contracting. They drop ship the vaccine in Heathrow, and the NHS, because public health wants to get as high of a vaccine uptake as possible, pushes it through and gets over 90% immunization uptake for infants. So from a commercialization perspective, there's not a lot of effort. From a decision-making perspective at the physician, it's really made by these recommending bodies, and religiously in most countries, the physician follows it. So and historically, as Andrew said, breadth of coverage wins. So if we get a little bit more coverage, and you can hear with the 31, we're up to 98% coverage, where, you know, roughly or 95% in the U.S., where PCV 20 is roughly 50% coverage. So if we can improve our coverage and competitors can't follow us, then we expect to get those preferential recommendations and really drive the uptake. Yeah. Awesome. So I think it's pretty clear, 31's strategy is to trump everything in the market and in the future. If we talk about the 24, we know recently Merck reannounced the V116 data, and that they are talking about 85% coverage and in those kind of more prevalent kind of strain. So how should we think about that vaccine maybe compared to your 24 versus 31? Because that was have been the one of the key, most recent competitor update from the field. So what Merck has done and you'll see this, like, it looks as if through the existing technology, about 20 strains is their limit. Then interference starts to reduce the immunogenicity so much. Sanofi is looking at a 21-valent. Merck is looking at a 21-valent as well. So you're seeing them basically reach that limit. If they could go farther, I'm sure they would. What Merck tried to do or is doing actually is they decided, "Okay, the existing strains that are in the current vaccine have led to a reduction of disease to where they're essentially not currently circulating." So they're removing those from their vaccine, and they're replacing them with new strains. So they're getting to 21, and they're getting 85% coverage by putting in new strains but removing the old ones. I think, you know, that can be a good short-term strategy, but the difficulty with that is that these strains are not circulating, but they're not gone either. And there's a famous example in Belgium, where Belgium switched from Prevnar 13 to the GSK's ten-valent Synflorix, and within two years, one of the strains that was covered in Prevnar that is not in Synflorix reemerged with a vengeance, with about 30%-40% of the circulating disease. So, while Merck is getting maximum coverage today, if you let up on that selective pressure on the current strains, there could be a reemergence. So, we'll have to see how the recommending bodies react to this. I think, like I said, I think it's a good short-term strategy, but, either way, regardless, our 31-valent covers what's in their vaccine and contains the old strains as well. So we'll make sure we maintain the selective pressure and broaden coverage, so we'll have the best of both worlds. Yeah. And we know Merck have another vaccine in the market. Maybe they're thinking about some combination strategy, but we will say, "Okay, which one you want to combine?" And also, once we have the 31, assuming it's successful, we don't need to combine, right? So you just one shot covers everything. Okay, so we have a couple of minutes. Maybe, Andrew, you can—if you can give us some your high-level strategy for the commercialization in terms of U.S. versus ex-U.S., and then we can wrap up from here. Great. You know, our base plan is to commercialize on our own in the U.S. market and in most of the major markets around the world as well. As Jim said, it's a unique market, and the role of the recommending bodies, not only in the U.S., U.K., and other countries, is important. We think it's very commercializable for a company of our size in the U.S. market and in many of the major markets. There are certain markets where, you know, give China as a prime example, it very well might make sense for us to partner there, to have in-country expertise from a clinical development and manufacturing and ultimately, a commercial perspective. You need a lot of feet on the street in that market. A very different approach, as Jim said, in the U.K. and other countries where there are socialized forms of medicine. In the U.S., we believe you're looking at a 300-400 person all in sales and marketing organization, and in the context of a multi-billion-dollar market in the U.S., something we think is very feasible for a company like us to address on our own. Great. So last minute, what's your cash position? Anything else we haven't touched on and you want to discuss? I understand we haven't talked really about the early pipeline. Yeah, we have a little over $1.4 billion on the balance sheet. Been fortunate to raise a good amount of capital on the heels of the last couple of data readouts we had October last year, April of this year. We've said we believe that's sufficient to carry us at least through our expected phase III data readout for the VAX-24 program in adults, to which we've guided in 2025. As we've talked about today, we have a couple of very important readouts prior to that, the VAX-31 readout, second half of next year, and then the infant study readout either in late 2024 or early 2025. The only other comment I'd make, we continue to invest in the pipeline. As Jim talked about manufacturing, we recently signed an important agreement with Lonza. We've been working with them for the last six or seven years. Manufacturing is absolutely critical in this space, so they're one of the premier CDMOs. It gives us the confidence that we have the ability to meet the ultimate potential demands of this market if we're successful in getting there from a clinical perspective. Yeah, we, we haven't really talked about the, the manufacture. Really interested in maybe we can, do a kind of a lab tour or the, the manufacturing tour at some point- Great. All right, great. Thanks. Really, really appreciate the time, and thanks, everyone, for attending. Thank you. Yep, thank you.