Perfect. All righty. Well, thanks everybody for joining. My name's David Risinger, and it's very much my pleasure to welcome two members of Vaxcyte senior leadership team, Grant Pickering, CEO, and Andrew Guggenhime, who's the President and CFO. I don't know how you do all that, Andrew, but hope Grant's paying you for that. It's a pleasure to host you. You got a lot of exciting news flow ahead over the next, basically 15 months through to next summer. Maybe we could just start off with you framing for everyone how to think about Vaxcyte as a company, your vision for it. Maybe actually start with, and I don't wanna go into too much detail, but start with, you know, when you founded the company, you've been at this a long time, made tremendous progress.
It's a lot of heavy lifting to bring vaccines to market. Just talk about your vision for the company, and also fit in the recent planned advancement of the Group A Strep vaccine into the clinic.
Yeah, great. Well, Dave, thank you for having us. We're delighted to be here. Yeah, this is the 13th year since we got the company started, and we had a recognition that the cell-free protein synthesis platform for which we have exclusive rights for the field of vaccines, could serve as the basis for the development of either improved or novel vaccines altogether. That's really driven on two different planes. The first of which is, you know, we're able to make proteins in a vector that is devoid of a living host. In doing so, it allows you to adjust reaction conditions to make proteins that can't be made in the conventional vectors. That does underwrite some of the applications we have. We have actually a Shigella vaccine in early stage development.
What we've really been known for is our ability to perform site-specific conjugation using proteins for which you can then cite the addition of particular antigens that can hone in on pathogens of interest and produce T-cell mediated immune responses to create durable protection. It's really those two different planes for which we've been focused, and in that site-specific conjugation technology, that's where our pneumococcal conjugate vaccine franchise was born, and that's what we've really become known for. This is a critical vaccine that, you know, allows us to congregate just like this. Pneumococci has been a bacteria that's been really difficult to avoid as humans. This has been a really critical class that has been the most important class, at least economically, and I would argue for humanity.
We've got technology that allows us to create broader spectrum forms of this class of vaccines, and it's driven by our ability to meter the amount of the protein carrier. We call these carrier-sparing conjugates. What we have done is develop initially a 24-valent form of a pneumococcal conjugate vaccine, and now more recently, we've graduated to an even more broad spectrum vaccine in the form of VAX-31. That's the primary focus of the company this moment. As you mentioned, we have a number of key clinical readouts coming over the next year.
That same ability to perform site-specific conjugation technology is also enabling this novel vaccine that we've recently announced is going into the clinic, and that's a vaccine for Group A Strep, which is another very persistent problem for humanity that we're looking to develop the first of its kind, a vaccine to prevent Group A Strep infections. That's kind of a high-level view, just to persist for a moment. Indeed, for VAX-31 in the adult indication, we are in the midst of a comprehensive phase III clinical development program for which the initial pivotal study, which we call OPUS-1, which is a large 4,000 subject study where we'll be comparing VAX-31 to the two standard of care vaccines that are out there today, the 20-valent from Pfizer and the 21-valent from Merck.
We expect the results of that study in the fourth quarter of this year, and that will be followed by two other phase III studies that will read out in the first half of next year, which altogether, along with a manufacturing consistency study, will make up the anticipated BLA filing next year.
Excellent. That's great. We'll come back to VAX-A1 later in the conversation. Could you just talk a little bit about the VAX-31 phase II results, which were exceptional, and then help us think through what you're expecting for the first phase III readout in the fourth quarter?
The VAX-31 phase II data that we obtained in the fall of 2024 was truly an unprecedented finding. The convention in this class has been to always try to pursue more broadly protective forms of these vaccines because the vaccines that this class of vaccines have been so effective that when you administer them broadly to a population, you largely take those included serotypes out of circulation, and that void ends up being filled by incremental serotypes that then fill in and begin to cause disease. It's been a situation where you can't stop vaccinating against the older strains, but you need to start to pick up the newer strains.
The exchange has always been that using the conventional technology, when you add additional conjugates, you end up with this carrier suppression that's driven by the protein carrier, and when you're adding more and more conjugates, you're adding more and more protein carrier. What's been seen and shown over and over and over again is that when you add more conjugates to get more coverage, you get lower and lower immune responses, which is not a great trade. What we have realized is that with our technology where we can use less of the carrier but dial in the key T-cell epitopes, we're able to sidestep that carrier suppression phenomena. Our VAX-31 results exceeded even our own high expectations, where we were able to show a vaccine that had 31 conjugates compared to a 20 conjugate vaccine.
We not only showed that we could get 31 to work together, but when we compared our 20 that were in common with the standard of care 20-valent vaccine, we showed better immune responses on 18 of the 20 common serotypes. You have this unprecedented pheno-phenomena of expanded coverage and improved immune responses. That phase II finding has underwritten our phase III program. In the meantime, there's been a 21-valent vaccine that's been developed where they acknowledge that they're using the same technology as Pfizer is using with the same limitations. To their credit, they actually elected to take out 10 of the serotypes that were under control and replace them with serotypes that were not in the current vaccines.
A very clever application of the technology, but it's created a situation where you have two different recommended vaccines that cover different scope of the circulating serotypes. Our vaccine has 31 and exceeds both of their coverage while continuing to address the historically circulating serotypes. This is the study that is underway. We began this study in December, and as we've guided, we'll have the top-line results in the fourth quarter of this year. We have very high expectations given that we've already run a head-to-head against the 20-valent, and we can look across the 21-valent comparison to the same comparator, and it gives us a lot of confidence that we're on track for what we think will be a compelling outcome to underwrite our BLA filing.
Excellent. In terms of the details, could you talk about the difference in the non-inferiority margin in this phase III trial? Just the fact that you know, it's gonna be tougher to match every single one of the 21 serotypes in CAPVAXIVE. How many might you miss on, or how should we think about that?
Yeah. Yeah, I guess the first thing to point out is, no pneumococcal conjugate vaccine has ever been perfect. There's always been. What's going on here is you have historically the same serotypes at the base, and then you're adding serotypes on top of that. The regulators wanna make sure that we don't strive to increase coverage at too great a cost by losing the control of the historically circulating serotypes. To confirm that, you do a non-inferiority comparison on the common serotypes, and the historical bar has been that you wanna see no less than a drop of 50% in terms of the immune responses.
This is defined by the lower limit of the confidence interval that cannot drop below 0.5 on the ratio of antibodies for your vaccine divided by the antibodies shown for the comparator vaccine on a serotype by serotype basis. Boy, that's a mouthful. There's this non-inferiority set of comparisons, and then it's relatively easy to show what's required for the incremental serotypes because they're not in the comparator vaccine. So we've got 11, you know, 10 or 11 more than either of these two comparators, which sets us up for a really great set of, you know, arguments. On the common serotypes, we did actually agree to a higher bar than has historically been applied because we acknowledged that with the other technology, we're seeing lower and lower immune responses, which is really not where we wanna go. That's the wrong direction.
In adults, there is not an absolutely crystal clear seroprotective threshold. With these lower and lower immune responses that we've seen with the comparator programs, the regulators were concerned that they weren't entirely clear on how far they could go. When they saw our data and we saw our data, we showed these improved immune responses. That's obviously the right direction. We agreed to a higher threshold for the definition of non-inferiority. Instead of being one-half, we agreed to show that we'd be better than 0.67 of what their immune responses were. In effect, we're raising the bar from a non-inferiority perspective and hopefully raising the bar in terms of the scope of coverage that a singular vaccine can provide.
In doing so, if the data delivers the way we expect, it would put us in a position to have a best-in-class vaccine in this really large and important segment. As I said at the outset, no vaccine in this class has ever been perfect. The regulators acknowledge that, we know that we can miss on a few to a handful of these non-inferiority comparisons and still be able to rely on the totality of what a 31-valent vaccine can provide in comparison to the 20 or 21-valent vaccines for which we'll compare ourselves to. We think the setup is really good, and we'll find the results out in earnest in the fourth quarter.
Excellent. Could you talk about the two additional OPUS trials?
Yeah. Do you want to take those?
Yeah, sure. In addition to this OPUS-1 study that Grant said we expect to read out in the fourth quarter of this year, we have the OPUS-2 and OPUS-3 studies, which are, along with the OPUS-1 study, continuing to enroll subjects. We expect these studies to read out, both of them, in the first half of next year. The OPUS-2 study is a study exploring VAX-31 concomitant with a high-dose flu vaccine. This is a study that's been conventionally run by other PCV developers in their phase III program. It's the OPUS-1 study that is the key study from an approvability standpoint. The OPUS-2 and OPUS- 3 studies really are, one, to ensure we have enough subjects exposed from a safety database standpoint, as well as to, you know, run studies comparable to what other developers' done.
These aren't studies necessary for regulatory approval, but they're important from a recommending body perspective. As I said, OPUS-2 is looking at subjects concomitant with flu vaccine. The OPUS-3 study is an interesting one that's looking at subjects who've been previously vaccinated with a lesser valent PCV, whether that's PCV 13, 15, 20, or even likely have some, although not a material number of subjects who've been previously vaccinated with CAPVAXIVE. This is really a study to evaluate whether we can see a boost in immune responses via VAX-31 compared to subjects who've been, again, previously vaccinated with a lesser valent vaccine. This could be an important study from a recommending body perspective.
Some of the additional PCVs on the market today essentially have what's characterized, we refer to as a polysaccharide-based preferred recommendation, where these current standard of care vaccines are recommended for adults who've been previously vaccinated with a lesser vaccine and for whom it's been five years since their previous vaccination. We see a potential opportunity. It's not the base case. The base case already reflects a large and growing adult market, but an upside case in which VAX-31 could garner the same type of polysaccharide-based preferred recommendation.
Are you enrolling patients in that category greater than five years prior, vaccination?
For us, the criteria is for whom it's been at least six months. It's not...
At least six months.
At least 6 months. 6 months or more, from their prior lesser valent pneumococcal conjugate vaccine.
Could that result in a different recommendation for VAX-31, or no? Would the recommending body still suggest using it if you've had a vaccination five or more years ago?
I think if you show an improvement six months, the view is it'll be an even greater improvement if it's been, you know, longer, you know, five years before.
Sure.
I mean, I think that's something we'll have to discuss among the team, but I think the baseline expectation would be if it is the recommendation is garnered, it'd be consistent with what has been done today, which is five years.
Okay
In terms of the recommending body perspective.
The recommending bodies do have the latitude to decide, but, you know, the benefit will be the incremental coverage over and above...
Sure
any of those inferior vaccines and the potentiation of the immunity they'd already developed.
Got it.
The overlapping serotypes.
Got it. Before we go to infants, maybe we could just talk about the manufacturing scale-up, and when you might be able to file for approval for VAX-31, assuming all the trials hit.
As we talked about the OPUS-1, OPUS-2, and OPUS-3 studies, all of them reading out by the first half of next year. Grant also mentioned this manufacturing consistency study, the design of which we're finalizing with FDA. Thus, that study is run typically in 18-49-year-olds, so it's a relatively quick study to enroll. It's those studies that will comprise the basis of the BLA submission, for which we are targeting the end, by the end of next year, 2027. With breakthrough therapy status, that would put us in line for potential approval and launch of 2028. That's the timeline on the adult program to which we have been tracking over the last few years.
Got it. Okay. Perfect. Why don't we turn to infants? With respect to the VAX-24 study results that were released close to a year ago, those results were a little bit mixed. Could you remind us about the efficacy differences between the mid-dose and the mixed-dose formulations? And we can go from there.
The VAX-24 infant data indeed read out, March of last year. What we saw relative to what we'd seen in adults was that you can have too little of the protein carrier. When we have these carrier-sparing conjugates, we have meaningfully less protein carrier than the products that are already on the market. In adults, it worked extremely well. We kind of showed perfect results across the board. In infants, this is a different setting where these, two-month-old children are just beginning to have their immune systems come online. What we found was that when we tested the higher doses of our vaccine, where we had similar amounts of the protein carrier to the marketed products today, we showed very good immune responses.
In those lower doses, where we had meaningfully less protein carrier than the comparator vaccines, we saw lower immune responses. We know that we have a dose response that we can model the formulations to derive optimal results. We tested a range of 1.1, 2.2, and 4.4 micrograms of our conjugates. When we're dosing at 4.4, that means we have the equivalent amount of protein carrier to what is in Prevnar at their 2.2 microgram dose. What we saw was that all of the conjugates that were dosed at 4.4 at the first endpoint achieved the non-inferiority comparison. Overall, the results were actually quite good. We showed for the incremental 4 serotypes, they were adequate. They looked very good and superior to what we saw from Prevnar 20.
For the overlapping 20, we saw for the serotypes that were most strategically important, which are those serotypes that continue to circulate, we actually looked really good. We looked better on a number of those and equivalent on others. It was ironically the serotypes that are circulating at the lowest rate where we saw some of the poorer responses or room for improvement. That's a nicer way to put it. We saw a good overall response across the vaccine. We just showed room for improvement on a handful of serotypes for which these higher doses that we're testing in the current, currently ongoing VAX-31 phase 2 study that gives us confidence that we can improve on some of those relative immune responses. We were just fortunate enough that it was the least relevant serotypes for which we showed room for improvement.
In the context of a 31-valent vaccine, having a handful of misses would still put VAX-31 in a best-in-class sort of scenario. Our view is that even if we didn't see the sort of improvement we're expecting with higher doses, we still have a highly competitive best-in-class product when you have 90%+ coverage compared to today's standard of care, which is in the 60 percentile range. The question is, how much improvement will we see with these higher doses? In VAX-31, we're testing two meaningfully higher doses, where we'll be matching up on the amount of protein carrier in the respective conjugates.
Could you just compare, those doses, just contextualize those versus VAX-31 for adults?
Yeah. Yeah. What we had seen, when we went from VAX-24 to VAX-31 in adults was that we were seeing higher and higher immunogenicity responses as we moved the dose upward without any trade-offs from a tolerability perspective. Where we settled was on a combination of conjugates dosed at 3.3 and 4.4. The final formulation that we've advanced to phase III has most of them at 3.3, and just a few of them are at 4.4. We have that same uptick formulation in the VAX-31 infant study. In light of this recognition of the immune system only coming online in these infants, we added a higher dose set of conjugates where most of them are dosed at 4.4, and then the minority are dosed at 3.3.
We think either of those two are the most likely to be the advanceable coming out of phase II, but obviously we need to wait to see the results of those, for which we've already completed enrollment in the study, and we're expecting the results in the first half of next year, by the end of the first half of next year.
I'll ask something very pointed, which is, let's say that those two doses, so the new high dose...
Mm-hmm
... the prior high dose in the infant trial deliver the same results by chance, and you miss on five serotypes after the fourth dose. You know, I think, I guess my perception is, you know, if you were to miss on five out of 31, right, given what we've seen with other vaccines, how regulatory bodies operate and how you know, both providers and patients want the broadest coverage vaccine, that still sweeps the market. Maybe you could comment since I'm, you know, I'm not the expert.
Yeah. I mean, I think the best example of how that plays out is CAPVAXIVE and the success that it's having today. I mean, they explicitly took out 10 of the serotypes that have historically been in the vaccines and are on their way to what would appear to be a dominant market share position. It's not exactly the same in infants as in adults. If we're in a position where we're adding 11 conjugates in the form of VAX-31 over and above the standard of care, and the only inferior immune responses we'd show were in serotypes for which there is not circulating disease, that would be a great trade. There's more to it than that.
The reason why the regulators have allowed misses in the class, and it is the case that every miss that every pneumococcal conjugate vaccine has had has resulted in that serotype still being included in the label, still getting credit for coverage. It's because there are immune responses. It's just how are they stacking up relative to the alternative vaccine? It's the case that for most of these serotypes, even if you're statistically inferior, what really matters is the magnitude of the antibody responses and whether or not they're expected to provide durable protection. Many of these conjugates instill magnitude of antibody responses in the 10,000-12,000. If you have 9,000 and your comparator's at 12,000, it could technically be inferior. When you have antibody titers of that magnitude, it still provides confidence that you're gonna have protection.
That's usually how it's gone down. That's why it's our view that even if we had a handful of misses, as long as they're these serotypes that are not as relevant, and we have the corresponding antibody titers to support, you know, confidence-inducing responses, that in the context of a much more broadly protective vaccine for which we're getting no coverage of these serotypes that are circulating in abundance, that would be a highly compelling and best-in-class offering.
Maybe just even to add to Grant's point, and we fully agree with everything he said, you know, another example is the approval of PCV20 in that same infant population, where on the first of the two co-primary endpoints, they missed on six of 20 serotypes. Missed on six of 20, and the incremental disease coverage that PCV20 was conferring over PCV13 is less than what VAX-31 would confer over PCV20. In the context of missing on five of 31 for a profile like VAX-31 has, we think that'd absolutely be a winning hand. We have said if we see results for VAX-31 that are consistent with what we saw with VAX-24 in the infant population, we believe that would represent an approvable profile, which by definition would make it a best-in-class vaccine.
We hope to see improved responses given the higher doses we're exploring in the study than those we used in the VAX-24 program. Excellent. Since the non-inferiority margin was changed for phase III for adults, do you think that would happen with respect to infants, you know, when you move to phase III in infants, or not necessarily?
Not necessarily, for sure.
Okay.
The reason is what I mentioned earlier. In adults, there is not a clear seroprotective threshold, which is what is the anxiety-inducing part of seeing diminishing immune responses. Whereas in infants, there is a clear seroprotective threshold, which traces back to the original efficacy studies, for which there were numerous conducted. It is not the same set of circumstances between adults and infants, which leads us to believe that there's not an expectation that the threshold would change. That being said, there are two different co-primary endpoints, the first of which is that seroconversion threshold. If it was to change, it would not apply there at all. It could apply in the context of the second co-primary endpoint, for which that is a GMR derivation.
If anything, the change would occur there, but we don't have any indication that that would be the case.
Okay, very good. With respect to that protein content of, you know, the VAX-31 infant dose that was added last summer or early fall, could you talk about that, just the difference in the magnitude?
We haven't said. What I can orient you to is the high-dose formulation, for which we've advanced into phase III for adults and is also the same formulation that is in the VAX-31 phase II study. What we've said is the cumulative amount of protein carrier in that formulation is in the ballpark of where Prevnar 20 is. Obviously, in the optimized dose, where we're using higher doses, it's going up, but we haven't said the magnitude of that.
Got it. Okay. All righty, thank you. We're gonna run out of time, and I wanna get to the Group A Strep vaccine.
Yeah, let's do it.
Would love for you to hit the highlights on that. Seems like just a phenomenal opportunity for the company longer term. If you could just share what we should be focused on.
Yeah, we're really thrilled to be able to reinvigorate the Group A Strep program. We had put a pause on it last year. We're now guiding to initiating the clinical development of VAX-A1, which is the Group A Strep vaccine, this year. We're super excited about this opportunity. This is a white space opportunity. There are no Group A Strep vaccines. This is a similar phenomena to other bacterial targets that have been successfully vaccinated against with conjugates. We're going after this with a conjugate vaccine approach, which has been the solution for multiple other bacterial vaccines. We have a combination of conserved antigens that give us confidence that we're going to get a protective and durable response to prevent this disease.
It starts with a carbohydrate, which is similar to the way that you target pneumococcal conjugate vaccines, but what's unique about Group A Strep is the carbohydrate is a species-defining one. It is on every single variant of Group A Strep. We have a conserved polysaccharide, if you will. And then we're site-specifically conjugating it to a conserved protein which is accessible to the immune system, which is unique to Group A Strep. For pneumococcus, you can't really get to any of those conserved protein sequences 'cause they're all underneath the polysaccharide surface. We have more access points for Group A Strep. We have those two conserved sequences and then two other conserved antigens that are intermingled as well. It's a bit of a belt and suspenders approach, one that we have unique access to.
The carbohydrate, we have exclusive rights to this particular antigen. We have belief in the construct for which we're advancing into the clinic, and there's clarity that this is a really important unmet need. This is a big problem in children and in adults. You know, it's only been a decade or so since we began to vaccinate adults to protect them against pneumococcal disease. That was a great decision. It's turned into a multi-billion dollar market. In the context of Group A strep, the amount of invasive disease is double that of what pneumococcal disease caused at the time it was recommended universally for adults. It's arguably an even bigger problem and an even bigger opportunity and one that we're very excited to get into the clinic.
Excellent. Just to wrap up, maybe you could talk about timing. I'm assuming that you'll see phase I results next year. Is that the right assumption?
Yeah. We wouldn't expect to see results this year. You know, the time consistent with our practice when we, you know, dose the first subjects in the study, we will make that announcement, you know, reveal the ultimate design of that study and guide to the timing of data. We would not expect it to be a 2026 event. The primary focus of this first study will be safety and tolerability. We will be doing an immunogenicity assessment on select subjects, so we'll get a hint of that, but principally focused on safety tolerability.
Perfect. Wonderful. Well, thanks again for being here. Really appreciate it.
Yeah. Thanks, Dave.
Thanks, Dave.