Okay, excellent. Well, thank you guys for joining us. Pleasure to have Vaxcyte management. I think folks are still trickling back in after lunch hour. I'll let you guys kick things off, and we'll just jump right in.
Great.
Great. Yeah, thank you for having us. Delighted to be back at the Evercore Conference and talk a bit about Vaxcyte today.
Excellent. John, you want to kick it off?
Fabulous. Well, maybe we'll start with the 31-valent infant study that we just saw drop today. So very exciting that that's getting started on time. What are your plans for 31-valent infant relative to 24-valent infant? When we discussed this a few months ago, there's really only a year to 15 months delta between the two. What's the opportunity for 24 in the context of 31 already getting started?
Yeah, John, happy to take that. And again, great to be here today. Yeah, so you're right. The 24-valent program, I think as folks know, we have guided to the top-line data from the primary series by the end of the first quarter of next year. So we're on the cusp of that key data readout, our first clinical readout in the infant population with the booster data to follow by the end of next year.
And then we reaffirmed this morning with our announcement of having started the VAX-31 infant study guidance for the primary data in mid-2026 with the booster data to follow about nine months later. So yes, about 12-15, plus or minus, months. The VAX-24 profile in the infant population is still a best-in-class profile. So our intent is to complete the phase 2 programs for each.
As to our strategy thereafter, there's significant value in reaching the infant market earlier given the size, and we think given the profile for VAX-24, but we'll monitor several things: the competitive landscape and the relative timing of the programs. We're trying to move VAX-31 as quickly as possible to determine ultimately what the strategy is for commercialization.
So when we think forward to that 24 valent data coming first quarter next year or by the end of that first quarter next year, what should we be expecting? I know typically we see adult data degrade a little bit going into infant populations. How predictive is the 24 adult data looking forward to infant? How much degradation do you expect? What's the setup going into potential pivotal studies there?
Yeah, so I think you've got it exactly right. So when we look at adult immune responses for these pneumococcal conjugate vaccines, and then you compare them to the infant results, you do see a drop in the magnitude of the immune responses. So when you're comparing the averages of one vaccine to the other, that's more manageable.
But when you're assessing the seroconversion rates for infants, it puts more pressure on the vaccine to see that sort of degradation. So that's where we've seen a significant falloff in the number of strains for which the new more broad spectrum vaccine ends up being notably inferior on some of those specific serotypes.
You're talking about Prevnar 20s versus 13 [?]
Yeah, you got it exactly right, John. So the broadest spectrum vaccine that's available today is a 20-valent vaccine. And when that vaccine was compared to what was previously the standard of care, which was the 13-valent vaccine, they missed on six of those non-inferiority comparisons in the U.S. schedule. So it does put more pressure.
But what we've seen with our pneumococcal conjugate vaccines is that we have an opportunity to not only expand coverage, but we're showing higher immune responses, certainly in the three phase two adult studies that we've conducted to date. So if we can see a preservation of those improved immune responses, it could create an opportunity for us to distinguish ourselves relative to today's standard of care vaccine as early as the first quarter of next year when we're expected to put that data out.
Are there any other key differences we should be aware of when we look at that 24-valent infant data, whether versus the adult data that we've seen or versus the regulatory bars that we expect? What should we be looking for top of mind when we see that infant data?
Yeah, I mean, we've had remarkable consistency in this category. The vaccines that have worked in adults have worked in infants, but for that caveat that I mentioned there that you do see some degradation in the immune responses.
So if we can see that preservation of the higher average immune responses that we've seen already in the infant setting, it will create an opportunity for us to start to have visibility not only on how VAX-24 might perform in this class, but also start to signal what we could expect for VAX-31 coming out of the study we started just recently.
Maybe let's talk then about VAX-31.
Sorry, John. Just on the 24-valent, can we just focus in on the trial design just a little bit on the infant trial? Can you remind? You guys haven't specified the doses.
We have. So for VAX-24, it's the same three doses that we had tested in adults, the 1.1, 2.2, and then the mixed dose.
Oh, there was no. So I remember on VAX-31, you guys used some of the takeaways from 24 over to the 31. That was not applied to the VAX-24 infant study?
No.
I see. So whatever we do see is technically not the optimized efficacy in the infants.
The VAX 31 study that we just started today incorporates those same VAX 31 doses that we had used in the adult setting. A 1.1, a 2.2, and a 3.3, but for a few strains for which we spruced the dose up a bit, which we've already disclosed. We did have those learnings, but they're applied in the context of VAX- 31.
So okay, so the dose optimization has not been applied to the VAX-24 data coming up right now. So as a base case, isn't it reasonable to assume that tracking meaningfully ahead of Prevnar 20 is probably not a base case to keep?
No, I think the 2.2 microgram dose for VAX-24 clearly showed that it was looking wonderful across all 24 conjugates. So I think that's preserved. But to your point, when we had pushed dose to equate to the kind of cumulative protein carrier load that you'd have in a 31-valent vaccine eCRM, that's where it put some pressure on those few serotypes. But when it was at the 2.2 across the board, they all look good.
Got it. Okay. Excellent. And remind us again, when is the trial complete? I know the readout's not till the end of one Q. When is the trial complete?
Oh, when did it complete?
Yeah.
I think we announced completion of enrollment, was it the first quarter of 2024 that we completed enrollment? No, no, it was late last year. Do you remember, Andrew?
It was sometime last year. I'm trying to recall exactly when it was, but it was sometime last year.
But as in the last patient on their last dose with the follow-up, when was that exactly?
I don't recall off the top of my head.
But it's already passed, right?
Oh, for VAX-24?
Yeah, for the infant, for the infant study.
Yes.
Last patient, last dose. And they're taking four shots?
Inclusive of the boost.
It's four shots, right? Not three?
Yeah, four shots. So three doses, two, four, and six months.
Immunogenicity is 30 days after the fourth shot.
After the third shot.
Correct.
So third shot, we must have been complete in order to report data by the end of 1Q. Third shot for the last patient probably is complete already or close to.
The third shot for the last patient, yes. Most of that 24-valent, yes.
Oh, yeah, for sure. Fourth shot.
That's the data. Okay, so let me just back up again. Primary endpoint is after the third shot that's coming out in one Q, correct?
They're technically co-primary endpoints after the third shot and then after the fourth shot.
Co-primary endpoint. At the end of one Q, we'll have third and fourth shot data.
We'll have the third shot data at the end of the first quarter. The fourth shot, the booster dose, we'll have by the end of next year.
Okay. So I'll tell you why I'm focusing on this. I know it took a fair amount of time to go through and evaluate all the immunogenicity across all the assays, et cetera, per serotype. And that was in adults with only one endpoint. Here you have different reads, right? You have, oh no, it's three doses, but only one read. So it's still technically only one read.
Correct.
Okay, got it. The 12-month one will come much later.
Yeah.
Okay, got it. And the timelines in going from the last patient's read on the assay to the actual readout, how has that evolved now over the last couple of years? Because it has ramifications for your phase 3 timelines as well.
Yeah, I mean, I think it's been pretty consistent with our expectations. As we're graduating from phase two to phase three, we are increasing the capacity of our immunogenicity readouts. So we do expect to be able to manage the larger sample size going from phase two to phase three and if not potentially even make up time on a relative basis. But it's been pretty consistent. I know I'm letting you down by not recalling exactly when we completed enrollment on the.
Yeah, but the throughput, as you said, the throughput will be greater for our phase three programs than we saw in phase two. We now have the data to give us the confidence. We've stepped up our efforts with the vendor we use to do both the OPA, which is the key for adults, IgG key for infants, so that the, again, the throughput will be faster, potentially substantially faster in the later trials.
Got it. And then Serotype 3 in particular, I know on Prevnar 13, that was already a problem and it amplified into Prevnar 20. Is there a realistic possibility that you guys just look really, really, really good on that one in particular? Because Pfizer's really leaning into that serotype for their next gen construct as well. So that data might come under more of a scrutiny.
I mean, the serotype three conjugate in VAX-24 that's already read out in adults is the same that we'll be reading out in infants. So we felt like our immune responses looked good. We would expect a continuation of that. But I would keep in mind that for serotype three, it's an outlier, right?
This is a very unique serotype relative to the rest in that that particular serotype sloughs off its polysaccharide sugar coat. So even when you get neutralizing antibodies that will bind to the sugar coat, which usually clears the bacteria, for this particular serotype, it may be binding to polysaccharide that's no longer part of the bacterium. So that's one of the things that's working against all of the developers in this class with serotype three.
But for that matter, the magnitude of the antibodies that are generated by these vaccines to serotype three is a fraction of what it is for the other serotypes. So you get about probably 10% of the antibodies. And even then, those antibodies aren't able to be as effective as they are for the other serotypes. So for other sponsors, they've been very focused on trying to improve the antibody responses to serotype three.
Merck showed improved, in fact, statistically significantly higher serotype three responses with the VAXNEUVANCE 15 valent that they brought to market. But even improving by two or threefold is still such a de minimis amount of antibodies. It's really not thought to be able to translate to improved effect against serotype three, unfortunately. So I think we know that Pfizer's focused on that.
But I think you'd need to see a really massive improvement to translate to true improvement in terms of stemming disease. So that is something that we're all watching very carefully. But we haven't seen anything that suggested we have a real material impact there.
Got it. I'd love to return to dosing for a moment if we can. The 31-valent adult data that you showed was really strong across all of the doses that you looked at. How do we think about dosing in the upcoming phase 3s? Any reason to change that dose array that we saw from the adult phase 2 going forward? And likewise in peds dosing, are there any learnings from the phase 2 data that you've already seen that could lead to further optimizations?
Yeah, so we'll be starting that phase 3 adult program for VAX-31 next year. We haven't specifically guided to which dose we'll be advancing. As you said, thank you, John. All three doses look good. Certainly, we saw improved immune responses as we moved up the dose threshold. We didn't see a commensurate AE increase. So for us, we've said it would either be the middle or the high dose that we'd advance. We haven't said publicly which one we'd advance, but.
So it would be one of those, not further optimized.
Yeah, I think we felt good about what we saw in that study that would suggest that it would be one of those two that we'd advance versus tweaking explicitly.
It does seem like you've got room to push, right? Obviously, that mid dose looked fine. High dose looks fine. If you gave the same aggregate amount of carrier protein on a mid dose per serotype schedule, that would push you quite high in terms of the number of serotypes you could cover. How aggressively do you think you can push the platform overall?
Yeah, I mean.
You're talking about the VAX-31?
Yeah, I'm talking about next to the 10.
45?
No.
Yeah.
I mean, that was the biggest surprise coming out of that data: in this class, it's been entirely consistent that as you add more conjugates, you pay a price. The immune system can only react so much, so historically to these immunogens. But we did not see that kind of fall off as we went from VAX-24 to VAX-31. So that was a really pleasant surprise and would suggest, to your point, that we could go beyond a 31-valent conjugate vaccine and be able to bring that to market. The issue is there just isn't enough circulating disease over and above those 31 to warrant a really strong effort.
Not today.
Not today, but over time, imagine we start vaccinating with the 31 valent, those strains will begin to be taken out of circulation and it will create a void for these strains over and above the 31 to begin to circulate, which could prompt the need, so for us, it's hard to put a point on the number. I feel like we went from 24 to 31 quite easily.
It's certainly imaginable that we could go from 31 to the high 30s and feel very good about being able to compare ourselves to the 31 results. Now, when you're at 95% circulating disease in adults with the 31 valent conjugate vaccine that we're developing here in the U.S., and it's even 98% in Europe, there's really not enough headroom, but in the future, we think that headroom will probably be driven by that shift, and we would push.
When you say you see that there's this shift, and I understand the logic to that, right? It makes sense. But when I look at the CDC data from the past 10, 15 years through the introduction of these other conjugate vaccines, it feels like that shift happens relatively slowly. It feels like it's not, it certainly doesn't happen overnight, but it also doesn't seem to expand dramatically. So I wonder how big do you expect that effect to be and how rapid do you expect that to become a meaningful amount of headroom to go after?
You got it exactly right. Serotype replacement is gradual. This is not a mutagenicity issue that we have with viruses. So it's much more gradual. It's that void being created and then the bacteria taking advantage of that. So it will be. That's why these vaccines have come out in kind of the 10-year, 10-year range because of serotype replacement driving it. So we would have expected something similar to that, but competitive challenges might suggest that we want to consider pushing that. But for the time being, we're very comfortable with our 31-valent. We know we can go past that if warranted.
John, just if I may, while we're on the record, to go back to an earlier question, just so everybody has the clarity, we completed enrollment for the VAX-24 infant study in March of this year.
In March of this year, okay. My last one on this, I know we have 40 seconds. Prevnar 20, if I remember correctly, missed eight out of 13 serotypes versus Prevnar 13 in infants. In infants is where they had a lot of misses, and then they went to secondary analyses to make up for them. I guess how should we think about characterizing your initial data when it comes out?
Yeah.
Sorry. Eight were not inferior. Five is where the miss, I think that's what John was pointing out. Five is where the miss was. So how should we think about sort of characterizing the data when you show the comparisons versus Prevnar 20, which is already kind of weaker?
Yeah. Yeah. So heading into this VAX-24 infant data next year, the first endpoint we'll read out in the first quarter, you got it exactly right. They missed on five of the 13 head-to-head comparisons between Prevnar 20 and Prevnar 13, and one of the new ones they also missed on the standard. So for us, we know we don't need to be perfect.
We know we can miss on some number of them. Heading into this data set, our thoughts are, you know, the worst-case scenario would be we could imagine missing on a few. But we think, you know, based on the clarity of the data we've generated across three different phase 2 studies, we're showing on average 20%-30% higher immune responses.
If we were to miss on a few, it would probably be more in the context of being significantly better on at least that many in contrast. But also there's the possibility we see something closer to what we've seen already, which is those higher immune responses.
So last question, because we are out of time, but I want to make sure we get a chance to ask you about the regulatory environment. Noted vaccine skeptics incoming at HHS, CDC. The regulatory environment for vaccine programs and universal recommendations seems set to change potentially pretty drastically. What range of scenarios have you guys been contemplating for the environment going forward for recommendations?
Yeah, I guess I'd start by saying, you know, vaccine policy in the U.S. is highly complex. There are multiple stakeholders involved both at the federal and state level, and these policies, practices have been in place for decades. So to affect significant change to those would require a coordinated effort, and frankly, we think it would take time to do that. It's difficult to predict, John, what is going to happen, and as a result, we're not speculating what could happen.
I can tell you that we do plan, under any scenario, to work constructively with the new administration and the various stakeholders, federal and state, to ensure that these important immunization programs, which have been so vital to protect our society and our communities, remain in place.
But we're not going to speculate, but we are, as you can imagine, on top of the situation, monitoring the developments, and I think we'll be in a position to respond accordingly, kind of whatever the outcome is here.
Excellent. Well, thank you guys for making time.