highly active, and very interesting coming into the, coming into next year in the middle part of the decade here. So before I start torturing you on, on details, let's, let's open with just a, a couple of minutes. Where do you stand coming into 2024, and, and what are the key, the key readouts, key milestones, both for you and across the pneumococcal space, that you think people should be focused on?
Yeah, John, thank you for having us. Delighted to be here in sunny Miami. For Vaxcyte, we have a really big 2024 ahead of us. We have already obtained clinical proof of concept for VAX-24. We've met with the FDA. We've had our end of meeting for us to define the phase III clinical program. So we've already guided to an expectation to have the results of that phase III non-inferiority study for VAX-24 in 2025. When we have the final sets of conversations with the FDA, we'll get more specific about when we expect to start the phase III study. As it relates to incremental milestones for us, VAX-24 is in an ongoing phase II pediatric study, and we've been guiding to an expectation for the readout of that study by 2025.
So we've been saying could be as early as late 2024 or early 2025. We expect to be able to get a bit more specific about that as the enrollment concludes. That's about a 1,000-person infant study. And then, very excited about having gotten VAX-31 into the clinic, which is our follow-on pneumococcal conjugate vaccine. That phase I/II study is underway, and we expect to get the outcome from that study, at least from a top-line immunogenicity perspective, second half of next year. So next year is gonna be a big step for us.
Well, I wanna start with that 31-valent data. I think obviously in this indication, in this setting, the valency has been the main driver of utilization, has been the main driver in the entire space, and we've been hearing 20, 21, you're 24-valent, but 31 is a big step. So let's focus there if we can. What should we be expecting from your data next year, and what's giving you confidence that you're going to maintain efficacy at such high valencies where other folks have not?
Yeah, so you, you've hit on it. So the spectrum of coverage that you can provide in a singular vaccine is the key adoption criteria in this space. So obviously, you want to protect individuals from the broadest number of pneumococcal strains as possible the moment you have an opportunity to vaccinate them. So, as you say, the current state of play in this space is a 15-valent vaccine from Merck and a 20-valent vaccine from Pfizer. And even if you look at some of the potential new entrants, they're all hovering around this 20 or 21 valent sort of vaccine design. And what we have at Vaxcyte is an opportunity to leverage what we call carrier-sparing conjugates, and it's the amount of the carrier that are in these vaccines that is keeping the pressure on the spectrum of coverage from these other developers.
We have developed a new method of chemistry that allows us to get as good or better immunogenicity with less of that carrier. That's what gives us the confidence that we can stretch all the way from a 24-valent, for which we've already generated positive data, to a 31-valent vaccine. And when you push all the way to 31, you're talking about covering 95% of the circulating disease and maintaining the pressure on some of the strains that have historically circulated, but we have under control. So yes, pushing to 31 is a big step. The reason we're confident is this space has been remarkable in its consistency of having the benefit of a really high-quality preclinical model, for which our 24-valent and 31-valent vaccines have looked terrific in the animal models.
We've seen that translate to unprecedented immune responses with our 24-valent program and gives us great confidence that the 31-valent is likely to work. We did one bit more, which was looking at a mixed-dose cohort in our 24-valent clinical studies that mimicked the cumulative amount of the carrier protein that's in VAX-31. We already have a sneak peek of what we ought to anticipate coming out of that VAX-31 study. That's what gives us the confidence.
Well, we know some serotypes are a little bit tougher than others, and the mixed-dose data that you just referred to suggests that there are a couple that look maybe a little bit borderline versus PCV20, even up at 31. So what are the levers on those most challenging serotypes that you have in the 31-valent setting?
Yeah, so the good news is, the standard for approval from the FDA is extremely clear. You only have to show non-inferior immune responses relative to the standard of care vaccine. And when we looked at the results for VAX-24, the standard 2.2 microgram dose looked clean across the board. All of the comparator strains, all 20 of the common strains PREVNAR 20, we showed what would be necessary for a full approval. Now, with that mixed-dose cohort, which I referred to earlier, where we doubled the dose on seven of the conjugates, which mimicked the cumulative amount of protein that will be in VAX-31, we did see this characteristic impact on some of the serotypes. Fortunately, it was quite modest, but there were a few strains that did show some impact from what is called carrier suppression.
It's the phenomenon that holds the other competitors at around 20 or 21 strains. But for us, even when we saw that impact, it wasn't enough to suggest that we still wouldn't have good enough responses to meet that strict non-inferiority comparison. We don't need to go into all the gory details, but even as you say, there was some impact, it wasn't enough to give us pause about the sort of construct we're taking into the clinic because of the responses we could explicitly match and model as it relates to a phase III study. So, that would be if we took the precise approach that we took before, but we've also shown that if we modify the dose, we can see very clear improvement in immune responses. So we do have that lever at our disposal.
We haven't gotten explicit with regard to the doses we've taken into the clinic for competitive reasons, but we could certainly push dose a bit on those few that were lagging in order to bump their immunogenicity up a bit. So that's at our disposal.
Mm-hmm. Makes sense. You also mentioned that the FDA's bar is non-inferiority versus standard of care. So obviously, for the 24-valent program, PCV20 is the sensible standard of care at this point, but will that still be the right comp when we start talking about later-stage trials for the 31-valent vaccine? Will you expect to be running those late-stage trials against PCV20?
I think that is the expectation. Now, so the current standard of care is PREVNAR 20. The FDA has been insistent on comparing against the singular broadest spectrum competitive vaccine that's on the market. So yes, it's our expectation that the positive control for that program will be PREVNAR 20, but I think you're hinting at the possibility of the V116 program.
Could it be that?
I think it's unlikely that that would be the request to think about comparing against two separate vaccines. I mean, we haven't seen the data yet from Merck on that program. It's coming soon, as in, like, later this afternoon. So, we'll know at the end of the day today. But the expectation is that foundational vaccine, which today is PREVNAR 20, we think in the future could be VAX-24, will be the, the key comparator for which we'd be expected to look at relative to VAX-31.
But there is the possibility that it could be VAX-24. You could be, you could be... Assuming you get that approved.
It's a possibility. I mean, the pace we're on, that would be unlikely.
It's borderline.
Uh, yeah.
Yeah.
I think, you know, VAX-31 is probably 18-24 months behind VAX-24, so-
You'd have to get those studies started before VAX-24 was truly standard of care.
That's right. I think that's the expectation.
Makes sense. So let's talk about the competitive landscape. You know, obviously, as we've been talking about PCV20, the current standard of care, but both Pfizer and Merck continue to talk a lot about how they're going to expand to higher valencies and their approach to getting at the residual market here. Pfizer, in particular, has started talking broad terms about a variety of different approaches they might take. How do you view your position developing high valency vaccines right now versus those legacy players who presumably have their own approaches?
Yeah. So as you say, we're certainly not alone in this space. Both, Pfizer, who has owned the space for the last couple of decades, and now having been joined by Merck with their 15-valent vaccine that's on the market, obviously, they're acutely interested in protecting, and expanding, depending on the company, their presence in this space. But there is a long history of others trying to compete with this conventional approach that they're both taking. And every major vaccine company tried a whole array of different chemistries, different carrier proteins, in order to try to compete with that Pfizer monopoly. I mean, Prevnar was a monopoly, up until just a few years ago.
The reality is that all of those competitors were unsuccessful because these other carriers that are available have an even greater immunogenicity profile that further distracts the immune system from what you really want, which are protective antibodies against the pneumococcal strains. So there's no quick fix here. And these other competitors worked for over a decade to come up with alternatives, and frankly, Merck went back and just replicated what Pfizer did. So the idea that there's going to be a quick fix here is not practical.
Mm-hmm.
They are attempting the employment of adjuvants to try to spruce up the immune responses. Even Pfizer has said that wouldn't be applicable in the pediatric space, for which is about 3/4 of this overall market. But in the adult space, that's an area where you could accommodate an adjuvant if it drove the right immune responses. The problem, in having run an adjuvant company in the past, is that these adjuvants are not selective about how they, spruce up the immune response, and in fact, the whole-
So if you've got carrier-directed immune responses already-
Yeah, the whole problem is the carrier protein is more immunogenic than the antigens that you want to drive the responses against, which are the pneumococcal antigens. So the idea of adding an adjuvant doesn't make any sense that it would do anything but further exacerbate the carrier responses. So that's probably not a likely solution, but I don't blame them for trying.
Fair enough. The one other program I wanted to touch on explicitly is GSK's, the Affinivax program, which has their own approach in a carrier-sparing high-valency technology. That program, after GSK's acquisition of Affinivax, took a little bit of time to get up and running, but they are running in adults now and are still guiding two launches this decade. So how do you feel about your position relative to the other carrier-sparing approach that's currently in late-stage?
Yeah. So that technology that GSK got through an acquisition, I think the first headline is where you went, which is they're behind us. So they have a 24-valent vaccine that they're developing. It's a very different approach than what the convention has been. So we haven't spent a lot of time talking about what we're doing explicitly at Vaxcyte, but we're honoring these key conventions that have been established, which are using a diphtheria toxin carrier protein to drive these T-cell-dependent immune responses. We're just able to use less of that diphtheria toxin because of our site-specific conjugation technology and our non-copper click chemistry. So we're using the same immunogens that the others are using, but we're just able to dial in the amounts and precisely what the immune system sees. So we're not inviting incremental risk.
The GSK approach is, terrifically novel, in that these are novel carrier proteins. This is a novel form of chemistry that's not a covalent bond. So there are real question marks about whether or not the characteristic boost that drives the durable immune responses, particularly for infants, will be evident. And so that was even acknowledged when GSK made this acquisition. They said, "We're gonna have to figure out if this is boostable." So until they get that answer, we won't really know if this is a viable approach, because even the adult market is gravitating toward a prime boost sort of phenomena. So they're behind us with their 24-valent vaccine. They're also behind us in, relation to the questions around the boostability.
And then they've also had some issues with regard to formulation, problems that have derailed their pediatric program. So they've yet to say when they'll be able to get that back online, but we know they've lost a couple of years there, too. So I think it's a technological risk, and then timing risk as it relates to us having an opportunity to get to the market first.
Makes sense. And that leads me into my next set of questions. I would love to talk about manufacturing. From a CMC perspective, these vaccines are enormously complicated. You've got your manufacturing partnership historically with Lonza. You recently announced an expansion of the cell-free manufacturing partnership with Sutro. So where do these relationships position you for a full trial program and eventual commercial launch? What are the capacity needs that you have for those programs and for eventual commercialization?
Yeah. Andrew, Andrew, you want to take that one?
Yeah, I'm happy to take that. I mean, yeah, certainly, you're right, manufacturing is critical here. As you say, we recognized that early on, made an early investment partnering with Lonza 7 or so years ago, and so we are well positioned in our existing relationship with Lonza, in the existing facilities in which we operate, not only to satisfy the supply requirements for the clinical programs, but importantly, for the initial launch. The way this market typically works is you launch in adults first. That's today, a one-dose market, a U.S. market, and then, as you've seen with Pfizer and Merck, typically a couple of years later, your infant indication comes online. That's a multi-dose market, and that's a global market.
So our plan is to launch out of existing Lonza facilities in which we operate today, that we believe can satisfy the demand expected in the first couple of years. As you said, we just announced about a month ago a new agreement with Lonza for the long-term manufacturing solution, which would give us the ability to satisfy the expected requirements, not only for the adult market, but also for the infant global market as well. So we think we're well positioned. We'll be working over the next few years to get that facility GMP qualified and then ultimately begin to produce product for long-term supply.
Makes sense. Now, some of the wording that you used there, you begin to the initial phases, what are the... When we think about the peds, eventual peds commercial market, how far will your existing collaborations, including that most recent one with Lonza, take you into commercialization there? And is your expectation that you will eventually need to source additional supply even beyond your existing collaborations?
We think with the existing Lonza relationship and this new one into which we've recently entered, we have the capacity to address the needs for the majority of the global market opportunity in both the adult, infant populations in the U.S. and ex-US markets as well.
Perfect. Now, obviously, Lonza is a very capable partner and has a long track record as a CMC partner to a number of different biotechs. Is there any risk of delayed commercialization because of CMC issues? Obviously, we were discussing the challenging nature of CMC for these products, but is there any risk in your mind to a manufacturing-related delay as opposed to a clinical one?
Well, I think there's certainly execution ahead of us to bring on what we've described as a dedicated facility at Lonza in order to, as Andrew said, be able to rise to the occasion to supplying the global demand for these vaccines. But I think our track record speaks for itself. We've had a really good go of it, having established manufacturing at Lonza for vaccines of this complexity, which was no small undertaking. So I'm confident that our team, along with the Lonza folks, will rise to the occasion.
Anything different to expect from 31-valent versus 24 in terms of that?
No, it's, you know, this is the space we're in now is we're building off the 24-valent foundation. All 24 of those conjugates that are in VAX-24 are also in VAX-31, so it's just making those seven incremental conjugates, same protein carrier, same chemistry, so it's just making seven more, so you do get to draft off your firstborn.
Makes sense. All right, well, we are out of time, but I really appreciate the time this morning, and thanks so much, everybody, for joining us from Vaxcyte.
Thank you, John.