Good morning, everybody, and welcome to the second day of Guggenheim's SMID Cap Biotech Conference. We host this every February, and for several years running, we've had the pleasure of Vaxcyte joining us. To my immediate left is Grant Pickering, the CEO, Director, and Co-Founder of Vaxcyte. To his immediate left is Jim Wassil, EVP and Chief Operating Officer. And then to Jim's left is Andrew Guggenhime, President and CFO. Just wanted to basically ask the team to kind of set the stage. First off, Grant and Jim, if you could just kind of kick us off with a bit of a reminder of the value and safety of vaccines, particularly pneumococcal vaccines, given that this is this sort of driving force of the first programs that you have underway, what's been accomplished, disease reduction, et cetera.
Yeah, first of all, thank you for having us back, Seamus. Appreciate it. Wonderful to be here. And yeah, pneumococcal disease has been one of the plagues for both infants and adults historically. We're celebrating our 25th year of pneumococcal conjugate vaccines and their availability initially for infants. And prior to their introduction, we had no vaccines whatsoever for the infant population. And the rates of disease, and certainly the mortality rates due to pneumococcus, were amongst the highest of any pathogens. So their introduction heralded a massive change in the disease rates for infants. And more recently, 15 years ago, we were able to bring this class of vaccines to adults and also see a substantial reduction in invasive disease and pneumonia caused by pneumococcus.
So this class of vaccines has absolutely become a bedrock of the vaccine schedule and has amongst the cleanest safety profile of any class of vaccines. And we have seen at least a billion doses to date from pneumococcal conjugate vaccines. And so we're really honored to be hopefully bringing a new chapter to the pneumococcal conjugate vaccine space in order to further increase the magnitude of protection from this really critical class of vaccines.
Great. Jim, anything that you would add?
I'd say that the PCVs are probably have the greatest evidence of antibiotic or AMR reductions of any category. When you look at it, there's been like 60%-70% reduction in antibiotic- resistant strains post-vaccination. It's the only vaccine that has demonstrated actual reduction in antibiotic use post-introduction as well. And so in addition to all of the safety, all of the effectiveness, you also see a huge impact on addressing antimicrobial resistance too.
Great. And Andrew, before we get into kind of program updates across the team, obviously there's a bit of an elephant in the room to address to some degree. Maybe just give us your thoughts on the Senate committee's vote on RFK, and then also just the prospect, assuming that he is nominated, the prospect of him in HHS, but also the sort of broader landscape of experts that are being brought in by the current administration into all of the different organizations that he'll be running.
Yeah, thanks for the question, Seamus. Yeah, I'll start by saying that we have been incredibly active and engaged over the last several months at really all levels of the administration, members of Congress, staffers, and that's an effort we'll continue to undertake. But we've been fortunate to have stood up a pretty substantial government public affairs effort. Got a couple of great folks on our team and working with several DC-based firms to make sure we are both aware of the dynamic and what is happening, and more importantly, have the ability to engage with policymakers in those administrations. So we feel very fortunate to have had a level of engagement, I think I would say punching above our weight as an organization.
Of course, we've been watching with great interest the hearings last week and the discussion at the Finance Committee earlier this week at which the vote was taken. We've been very encouraged by the commitments that have been made over the course of the confirmation process. As recently as the Finance Committee vote on Tuesday, listen to Senator Cassidy and the remarks he made, as well as those by Senator Tillis, the commitments that the Finance Committee and Cassidy have obtained with respect to RFK in his role as head of HHS. There are several-fold, but including kind of a commitment to maintaining the ACIP without any changes, a commitment to ensure the existing approval and safety monitoring processes remain without separate oversight. I think in a level of engagement and transparency between the committees, particularly the Health Committee, Cassidy, and Kennedy and his team.
Cassidy referred to an unprecedented level of engagement between himself and Kennedy, a process by which if any changes will be recommended, 30-day notice needs to be provided to the Health Committee, and then the HELP in congressional oversight. I think all of these things give us and others comfort that kind of the existing systems will remain intact and a recognition, I think pretty strong bipartisan support for maintenance of the status quo, and this is rooted in evidence and science, really all in an effort to ensure we continue to protect our communities and maintain public confidence in the role that vaccines have. We'll continue to undertake more effort, but have been encouraged by what we've seen of late. My colleagues and I will be in Washington again tomorrow to meet with a number of members, staffers of the Senate, the Health Committee as well.
A level of engagement we'll continue to have to ensure that our message is delivered, but also the importance of continuing to make decisions based on science evidence for the benefit of public health.
Great. So with that as prologue, and obviously, even though there may be concerns around this, I think the reality is that the benefits of vaccines are more than obvious, I think, to the global community with comments being made on multiple other large pharma conference calls and around the world as well. So I think it sort of speaks for itself to a great degree. There's also a whole world out there of pneumococcal vaccinations that are likely to happen as well. So with that as prologue, maybe we can revisit your pneumococcal vaccine candidates and catalysts. And we got some exciting updates maybe just yesterday about your 31 pediatric programs. So maybe we can start there and proceed or proceed however you like, Grant.
Yeah, thank you, Seamus. And by the way, nice note that you put out with regard to some of the topics that Andrew talked about with regard to the reassurances that we've gotten with the new administration. Indeed, if you didn't see it yesterday, we put out news that we have completed the stage one enrollment for the VAX-31 pediatric study, which we're delighted about. We started that study just over two months ago. We were able to complete that first safety stage considerably faster than we were able to for our preceding VAX-24 pediatric study. And so we're delighted to now be into the larger stage two enrollment portion of the VAX-31 infant study. We've guided to expecting the results of that study, at least for the first of the two co-primary endpoints, by the middle of next year.
So we're not that far away from having a view of VAX-31 in infants. Obviously, the results in adults that we got earlier, or I should say in September of last year, were incredibly exciting. So certainly a lot to look forward to, but we're just on the brink of getting the results for our VAX-24 pediatric study, which will read out by the end of this first quarter of 2025. So that's probably the next biggest readout for us. And we're here talking about our thoughts about that study and our expectations for the readout. Do you want to talk about that?
Yeah, that would be great. If we could just sort of set a little bit of the sort of groundwork, because there are clear differences in the endpoints and how folks should kind of think about the different adult versus pediatric study. What you're going to see at three doses versus four. Maybe just kind of walk us through that.
Yeah, I'll start. Maybe you jump in. So I would say there are definitely differences with regard to the way we conduct these infant studies for pneumococcal conjugate vaccines. But I would say in the end, they're more similar than different. So for the adult studies, I think most of the people in the room have become accustomed to these tighter comparisons. You have to show non-inferior antibody responses compared to the standard of care vaccine. Obviously, we were able to sail through those three Phase 2 studies that we've run for VAX-24 and VAX-31 in adults with what I would say are flying colors. We were able to show substantially higher average immune responses for VAX-24 and VAX-31 relative to Prevnar 20 on those antibody responses. Now, the distinctions from the adult responses that we look at versus the infant responses are the following.
In adults, we look at the functional antibody responses, but we also measure the IgG antibody responses. And on both of those measures for both VAX-24 and VAX-31, we showed substantially higher titers across both of those measures. And in the infant setting, we focus on the IgG antibody titers. And we look at those in terms of the titer comparisons after the fourth dose that the infants look at. And we look at the very same sort of non-inferior comparisons where you need to show higher than one half of the responses relative to the standard of care vaccine. So when we get to that fourth dose, which will be by the end of this year, that will be something that you guys are very accustomed to. The only difference is IgG instead of OPA.
Now, after the third dose, which is the data point that will read out for us by the end of this quarter, there are some differences. Now, we will look at the IgG antibody titers in comparison to Prevnar 20, but the actual endpoint for which serves as the co-primary endpoint. You look at the seroconversion rates for these infants, and that's defined by exceeding a certain threshold of circulating IgG for each of the serotypes, and that has correlated with protection that was evidenced in the initial efficacy studies that were ran back 25 years ago, so we will be looking at the absolute difference between our seroconversion rates versus those of PCV20, and these comparisons have served as the full approval basis for both Prevnar 13, Vaxneuvance, and Prevnar 20, so these are very tried and true endpoints.
When you run the Phase 2 study, you're looking at a smaller sample size than you'll be looking at in Phase 3. It's about a quarter of the sample size that historically have been run by the other sponsors. This will allow us to power the Phase 3 study. In the Phase 2 experiment, it's become precedent to look more like a 15-point absolute difference as the definition of a success for which you then model the Phase 3 study. That's what we'll be looking forward to. As far as expectations go, we've seen consistently a 25%-30% average improvement relative to Prevnar 20. That's converse to what's seen with Prevnar 20 and Vaxneuvance in adults, where you see about a 25% drop on a relative basis to what their comparator was, which was Prevnar 13.
So you see a very similar drop in titers with infants. In fact, it's even more pronounced with Prevnar 20 and Vaxneuvance. So if we can see anything close to what we saw in adults, which is a substantial improvement versus a decrement, we'll be in very good shape. But that's what we'll be looking to read out. We know that you don't have to be perfect in this class. For each of the subsequent versions of Prevnar that came out after the original, they saw multiple misses on their non-inferiority comparisons. And yet that expanded coverage was enough for the agency to get comfortable that that was a trade worth making. So even if we were to miss potentially on a few of the non-inferiority comparisons across our 24-valent vaccine, we would still be decidedly excited about a best-in-class profile.
That's kind of how we're thinking about things. If we did miss on a few, we could imagine a scenario where we might be substantially better on a number of strains. That's what we've seen historically in the three adult studies. That's how we're thinking about the readout, which we'll see by the end of this first quarter. Why don't I pause there? Did I miss anything, Jim?
You covered it really well.
Oh, wow, thank you.
So in terms of a, you know, as we kind of think about a press release, it was sort of very simple with the adult. You just had the comparison on OPA. We looked at the point estimates and in all of the cases, inclusive of 24 and 31, we really didn't see any what would be characterized as misses, except maybe with the mixed dose that you studied with 24. 31 was a surprise to everyone, apparently including yourselves, going 100 for 100, so batting 1,000 on that. How does that sort of translate into 24 for peds, and then is there any reason to think that there could be a different result in the pediatric setting relative to the adult just because of the endpoints itself?
Yeah, I'm blushing a little bit. It's true. Yeah, for VAX-24, for both of the adult studies that read out, and then again for VAX-31, we didn't miss on any of the non-inferiority comparisons for the dose that we have decided to advance in adults. We haven't said publicly which dose we'll advance for VAX-31, but we had multiple choices for which we didn't miss on any of the non-inferiority comparisons, which was especially stunning given the size of the study. One would have expected you to have some misses that you might be able to make up for with a larger sample size. But we were able to hit that on a much smaller sample than others would have been able to hit. So indeed, that informs on the confidence that we're taking into the infant setting.
I would say, you know, having started the company 12 years ago, for many years and up until the fall of 2022, we were relying on the immunogenicity that we had generated in the animal models. That animal model, which we had said and turned out to be highly predictive of the human responses, perhaps best emulates the responses in infants because those animal models are in a naive animal population. The infants are naive as well, whereas the adults have become exposed to both the pathogen and the protein carrier in ways that the adult dose is as much of a boost as anything else. Whereas in the animal models, we've been able to show a really robust prime and boost with VAX-24. So this infant readout is akin to those animal models that were always decidedly convincing.
And then the last point I would make is to also remind people, and you mentioned it, that for this VAX- 24 experiment in infants, we will be looking at the mixed dose, which we had looked at in adults, which was a really wonderful predictor of what we could expect for VAX- 31. And so we'll have an early look at least a measure of the magnitude of protein carrier that we already have in the clinic in infants in the form of VAX- 31. So we think it will not only certainly indicate the probability of success in infants for VAX- 24, but we'll also tip our hand toward how confident we'll be heading into that VAX- 31 readout next year.
Great. And in terms of how much of a catalyst the sort of three-dose data is versus the fourth dose, the booster dose, in your mind, which is sort of more important, or are they both equally important, or could you see something unique or different from that third dose to the fourth booster dose? Yeah.
If you look at historically the other vaccine manufacturers, Pfizer hit on the fourth dose. They met the non-inferiority criteria post-dose four. Where they missed was post-dose three. They missed on six endpoints on their U.S. schedule, and they missed on 11 in their European schedule. So we have been saying that this initial read of the co-primary is going to be more crucial for predictability as to how we're going to do and move forward in Phase 3. So we're going to be looking very closely at this. But I also think, piling on with what Grant said, the translatability from adult to infant, the animal models are statistical analysis of the co-primary endpoints. We decided to move forward with 31 in infants before we had a 24 readout.
So if nothing else, you can see the confidence that we have deciding to go with saving time to get to a 31 infant readout versus seeing a 24 readout. So I do think that overall, we are going into this infant data readout with more confidence based on the translatability of the adult data and, as Grant said, the animal models as well.
Great. And so let's talk about 31 and the pace at which you're actually advancing it. There was a decision that was made that was extremely logical in adults to basically accelerate your 31 in adults and just sort of pass right over 24. Is there a chance that that could occur here given the pace at which you're advancing 24, or does it make sense to have both programs available in the pediatric setting?
Thanks for the question, Seamus. The plan at the moment, we're going to conduct the Phase 2 studies for both VAX-24 and VAX-31 in infants. But as we talked about, from the VAX-24 study, expect the primary series data by the end of this quarter, the booster data by the end of this year, after which we would need to pull together the full data set, including the full safety database, and engage with the regulators about a potential Phase 3 program. So we'd likely be in a position to start a potential Phase 3 program, call it sometime mid-year-ish. For the VAX-31 study, we've now moved into stage two, and we've guided, as Grant said, to having the primary data from that study in the middle of next year.
The timing of receipt of the primary data from the VAX-31 study will be on top of or close to the decision to start a Phase 3 for VAX-24. So I think that's the point at which we would make a decision as to whether to continue with VAX-24 into Phase 3, followed by VAX-31, or instead make a potential pivot to VAX-31 as we did in the adult market. And there'll be several factors that go into that, including how quickly are we able to move VAX-31 and what would be the gap between a VAX-24 launch and the infant population and a VAX-31 launch. So that'll be among several factors we'll consider as we make the decision in terms of the strategy for the program.
And it would seem to me like there could be sort of CMC-related benefits to actually and the consistency of the data set, lot-to-lot consistency studies that are conducted in adults, that could actually benefit your filing and accelerate it because there might be some differences that would need to be evaluated for 24 that could be separate. So I could see actually accelerating characteristics to your pediatric setting that could actually be value-added. Am I thinking about that the right way?
Yeah, I think that's fair. There are definitely efficiencies that come from launching a singular vaccine, but the beauty is the manufacturing line for which we're making the conjugates that go into VAX-31 is the same that we're making the VAX-24 conjugates, and of course, all 24 are in both vaccines, so there is some efficiency, but I would pause to make sure we emphasize the best-in-class profile for VAX-24 before we start talking about moving on to our next-gen vaccine, which, yes, we've done that in adults, but in infants, Jim mentioned the really key thing, which is while in the United States, Prevnar 20 is the primary competition, in Europe, that's not the case, so Prevnar 20 was unable to gain an approval on the European schedule, where they give one less vaccination than we give here in the U.S.
Therefore, the competition in Europe is really the 15-valent vaccine for Merck. Outside of the United States, over 90% plus of the pneumococcal conjugate vaccine market is driven by the pediatric segment. For us, VAX-24 has a substantial advantage over the 15-valent in Europe. Of course, in the United States, we also have a scenario where neither vaccine has a preferred recommendation. That was because in the view of the ACIP, they were concerned about that drop in antibody responses with Prevnar 20. If we're able to replicate the higher antibody responses that we've seen in adults, in infants with VAX-24, we'd have a very clear advantage in the U.S. from a titer-based perspective. Outside of the United States, perhaps not only in titers, but also substantially greater coverage than the market leader.
So I mean, I don't want to undercut the enthusiasm for VAX-24, which is reading out later this quarter. But certainly, VAX-31 would widen our advantage. But I don't want people to not be excited about the prospects for VAX-24, which would be our first-to-market opportunity in infants.
And if we just sort of scale the competitive landscape, there's a lot of noise there. And I think we only have very limited time right now. But where would you kind of characterize your timeline with VAX-24, VAX-31 in the adult setting, and also in the pediatric setting relative to what you understand of potential competitors? And we had two competitors actually announce their plans for their own programs, Glaxo and Pfizer, earlier this week.
Yeah. So I mean, we're in the lead from a timing perspective and from a certainty perspective as both GSK, in particular, have fallen back to preclinical programs for which they're certainly at a very different risk quotient than us having generated extremely positive and robust, best-in-class sort of immune responses with our 31- valent program. And then with regard to infants, again, we're on track with not only our 24, but our 31. So I think we feel extremely good about our timing and our profile relative to what the other competitors are working with.
Just as a reminder, I think this market is forecasted to be anywhere from $10-$13 billion, depending on how the adult market evolves and overseas, and even in the U.S. as well. The sort of winner-take-all dynamic that has evolved in this market over the years seems like it's a pretty good position for Vaxcyte to be in.
Yes, and I know we're in overtime, but not only is it a massive market that's growing substantially, but it's also one of the best returns on investment that society can make. Every dollar we spend on vaccines results in $7.50 in savings, so we not only have a massive revenue opportunity, but also a massive societal benefit to spin off that.
Great. Well, thank you so much. We could have had two sessions easily to go through all of this. We'll have to work on that next time. But thank you, guys, for a great session.
Thank you.