VAX-31 data and then the pipeline as well. Maybe Grant, if you can give us some opening remark covering the most recent updates from you, and then we can go to the conversation.
Yeah, as, as you were hinting at, we have some very important upcoming milestones. So we've fully enrolled a 1,000-subject adult study with VAX-31. That vaccine is set to read out top-line immunogenicity data in the third quarter of this year, so that will be a big moment for us. Obviously, we, we're really happy with the data that we saw coming out of the VAX-24 Phase II program in this older adult population. So, very excited to take this next step with VAX-31. And then, VAX-24 also has a fully enrolled infant study that will read out across two different co-primary endpoints next year. So the first co-primary endpoint will read out by the end of the first quarter, and then the second will read out by the end of next year.
Over the next series of quarters, we have two really, really important milestones reading out on the clinical front.
Excellent. Yeah. So I have to say, the third quarter, this VAX-31 data readout is, you know, at least one of the most anticipated data readout in the biotech world. A lot of investors very interested. Maybe just take a moment to remind us what's the design, and then particularly people interested in the dosing regimen. I know you haven't disclosed much, but how much you can tell us about the dosing? How should we think about the different dosing for your VAX-31?
Yeah. These adult studies have a very conventional design. It's a single vaccination of your experimental vaccine compared to the standard of care. So just like we saw with VAX-24 in adults 50+, we compared VAX-24 to Prevnar 20, and we're doing similarly the case with VAX-31 compared to Prevnar 20. So single dose, you get the top-line functional antibody responses, and to remind everyone, that is and has been the basis for a full approval for these pneumococcal conjugate vaccines. These functional antibodies are a validated surrogate immune endpoint, so you no longer need to run field efficacy studies for this class of vaccine given the long track record of the close correlation between the antibody responses and protection from disease. So you also hinted about the next part, so I will just go on.
So, like we did with VAX-24, we will be looking at three different doses of VAX-31 compared to the commercial dose with Prevnar 20.
Just to remind people, the dose of Prevnar 20 is 2.2 micrograms of the polysaccharide across the 20 conjugates in that vaccine, with one exception, one is dosed at 4.4. The cumulative amount of protein carrier in that vaccine exceeds 50 micrograms of the diphtheria toxin protein carrier. For VAX-31, what we've said publicly is that we're looking at a low, a middle, and a high dose of VAX-31 compared to Prevnar 20. We were a little bit more forthcoming with the VAX-24 doses. What we studied with that particular set of Phase IIs was a 1.1, a 2.2, and then a mixed-dose cohort, where 17 of the conjugates were dosed at 2.2, seven of them were dosed at 4.4.
So what we have said is that with these low, middle, and high doses, we're certainly not exceeding that dose range of 1.1-4.4, and in fact, the doses could be within that range across the low, middle, and high. And we've also acknowledged that for a few of the strains, we might have boosted the dose a bit to give us the best chance of showing the right immune responses, which are non-inferior immune responses across the common 20 strains. And then for the incremental 11 strains that are in VAX-31, you're looking to show a fourfold improvement over antibodies relative to baseline. Yeah.
And then, you mentioned the carrier protein total in Prevnar 20 is up to 50 nanogram, microgram-
Microgram
... microgram. And then how should we think about your carrier protein? Because your technology is actually carrier protein-sparing technology. Yeah.
Yeah, that's exactly right. So we call ours carrier-sparing conjugates. So, whenever you hear these numbers of a 20-valent or a 31-valent, you're talking about 20 or 31 different drug substances that are all mixed together into a final vaccination- into a final vaccine. And we haven't stated publicly precisely how much protein carrier is in either VAX-24 or VAX-31, but we have given a relative sort of approximation. What we've said is that VAX-24 had somewhere between the amount in Prevnar 20 and the amount in Prevnar 13. Prevnar 13 has 34 micrograms, so somewhere in there is the amount that we have in our 24-valent vaccine. And in VAX-31, it's something closer to the amount that's in Prevnar 20, but spread across 31 different conjugates.
Okay, got it. So 24 is close to Prevnar 13, and 31 is close to Prevnar 20.
Yeah, closer.
Close. Yeah, close. Yeah. Okay, good. So let's talk about the data readouts. It is immunogenicity data readout. Before we talk about it, maybe talk about the timeline, because the investor is, you know, key, key to the timeline. You know, you closed the enrollment in January, right?
Yep.
And then your 1-month immunogenicity and then 6 months safety profile kind of follow-up, it's adding that, you know, you're guiding 3Q, how should we think about the timeline, and how you get those data point? Because I remember when you read out the 24, you are batch by batch, kind of a real-time kind of assay kind of a readout. But I mean, the assessment, but this time is that like a, you know, totality, and then you get the all the data all together. Then tell us a little about that logistics.
Sure. Yeah, happy to take that one, Roger.
Yeah.
Just to remind, we have, and we confirmed this just a couple weeks ago in our Q1 earnings update, but we continue to reaffirm the guidance to expect the data in the third quarter. We have not narrowed it beyond that. A couple of data points, you know, for our first adult study, and our second adult study, you know, the third quarter guidance is more akin to the timing of that second adult study. I think a couple things to keep in mind in this context: one, this is a larger study than either of those two studies previously. We have 1,000 subjects here, and the largest of the two prior studies was about 800 subjects. And two, we're now looking at 31 serotypes as opposed to 24 before.
The number of assays that need to be performed is substantially-
Yeah.
higher in this study than it was in the previous two. In terms of the process, having completed enrollment, we work with a third-party vendor who performs those assays across all the serotypes, across all the subjects. Those data are then delivered to a third-party data services provider, and we would expect the sequence ultimately here to be no different than previously, where ultimately, the point at which you all will hear about the data will be days following the point at which we first learn about the data.
Got it, and, will anyone from Vaxcyte still blinded to the data along the way, or you will have a small team start to see the data along the way? Yeah.
Our team will not see any data from an immunogenicity perspective, blinded, or not, until the very end. Our team, certain members are privy to the blinded safety data-
but no, immune response data.
Got it. Okay, good. That's one of the key question I know. I know you, you haven't narrowed down to 3Q. I hope you can narrow down here, but, you know, if you don't, that's okay.
We will not.
Yeah. And then, you know, if we narrow, we will highlight that, right? But on the other side is, you know, how are you going to define the success for your Phase II VAX-31? I think that's the most debatable question, you know, kind of, topic out there because you're going to make decision to move forward your 24 versus 31, and how are you going to make that decision really based on this upcoming data readout? Just say... Yeah, give us some.
Yeah. We expect to be able to declare which of the two vaccines will advance into Phase III clinical development based on this top-line immunogenicity data. So you know, I think, it's become clear that in this class, the decision-makers have grown accustomed to trading increased coverage for lower immune responses. So much so that even those low, lower immune responses result in formally inferior immune responses for certain strains. So every single broader spectrum vaccine that has been approved has had at least one serotype for which they've missed the non-inferiority comparison. So we know that, perfection is not the price of admission for these broader-spectrum vaccines.
That said, we were fortunate enough with VAX-24 when we looked certainly across the pooled population, which is the same population we're studying, with this particular study, and the same number of subjects, that we are able to exceed the threshold for all 24 of the conjugates. We don't know-- I mean, we know that we don't have to repeat that with VAX-31 to have a program for which we would believe that we could be on track for an approval. So, you know, we'll see it when we see it, but, we've certainly seen examples of approved and recommended pneumococcal conjugate vaccines, for which as many as six-
... non-inferior immune responses across the conjugates has been acceptable. You know, so that kind of precedent is already there.
Mm-hmm. Yeah. You know, the good thing and the bad thing is you set a very high bar for yourself, for your 24. You may not see anything, some of them even superiority, but as you said, 31 does not need to as 24 to be able to move forward because it's a broader coverage, and then you have the benefit over the 24.
Yeah, that, that's exactly right. And, you know, the, the margin for error, frankly, ought to correlate with the incremental coverage that your vaccine is conferring relative to the standard of care. So for VAX-24, relative to today's standard of care, which is the 20-valent vaccine, we were improving coverage from 50%-65%, and so for VAX-31, we're exceeding that. We're pushing that all the way to 95% coverage. So yes, that, that margin of error is only increasing on a relative basis for VAX-31-
Got it
... for adults.
Another deep in the weeds question or statistical question is the GMR point. Just like you said, the definition of the non-inferiority is the lower bound of confidence interval above 0.5, but actually, from the previous Phase II study with the larger N, as long as your point estimate GMR reaching 0.6, you should be able to meeting the non-inferiority. Just tell us a little about how you interpret that data if you have a couple non-inferior to, not missing the non-inferior 0.5, but you know, most of them are getting the 0.6, how are you confident moving to the Phase II?
No, I think you've got it exactly right, Roger. Our focus in the study, as it was in the prior two study readouts, is on that GMR, kind of the, the mean ratio, and given the study readout, though it is sizable for a Phase II at 1,000 subjects, you've got 250 subjects approximately per arm. That pales in comparison to the size of a Phase II study that we would ultimately undertake, which would be 3-4 times that size. So the, the error bars, the confidence intervals in this Phase II study are inherently therefore going to be wider than one would see in a Phase II study.
So the focus is on these mean ratios, and as you say, if we see a ratio of 0.6 or higher in this study, that will give us high confidence that in a Phase III study, we would meet the statistical non-inferiority endpoint, such that in that study, the lower bound of that 95th confidence interval would be north of 0.5. And we've seen this in the previous 2 studies that, you know, we may have some confidence intervals that dip below the 0.5 in this study, but to the extent the mean ratio is 0.6 or higher, we would have a high confidence. And as Grant said, you know, even in the absence of achieving that in a Phase III study, precedent has shown that the FDA oftentimes, and has historically granted full approval.
Yeah. No, not saying you will guide us, say you will miss the non-inferiority in the phase 2 anyway, but, you know, the street right now seems a little bit too focused on the non-inferiority in the Phase II. And while, you know, I think they you know, everyone should be educated to say the Phase II, the focus should be the GMR. Of course, we're going to take a look at the non-inferiority. If that hits, just like a 24, it's a blue sky scenario. But as long as you hit the point six, the Phase II, you should feel confident, confident you can move into the Phase II . Is that fairI to say?
Yeah, I, I think you've got that exactly right. That's, that's how we'll be looking at it.
Yeah. Okay, good. All right, so a couple more topics related to the program. One is the CMC, right? Because that's something, you know, kind of a black box to many people, including myself, and what's the progress there, and then given you're moving towards the Phase II, and it seems you already aligned with the FDA and have a lot of conversation with the FDA so far?
Sure. Yeah, I mean, we continue to make good progress. Certainly, CMC is a major area of investment for us, given the scope of the opportunity here, and we've been working with Lonza for the better part of the last eight years now. We've recently stepped up that relationship with Lonza to build out a dedicated custom facility or a dedicated suite in an existing complex at Lonza. But we continue to progress well on really three fronts, which is, one, manufacturing the product necessary to support the clinical trials in both the adult and infant populations for VAX-24 and VAX-31.
2, preparing for the initial commercial launch and launching out of existing Lonza facilities at which we operate today, and that would be the adult launch, which is typically a U.S. market that is sizable, but smaller in size than the infant market. And then this new investment with Lonza, putting us in a position to support a global launch in both the adult and infant indications that would follow, of course, that initial launch, that we would hope for and expect in the adult market.
Okay, got it. All right, and then, you know, assuming the Phase II VAX-31 is good, and then you're going to make decision into the Phase III. Tell us a little bit about the timeline for the Phase II program, and when we will expect your adult kind of PCV gonna get approval onto the market?
Yeah, maybe I'll just go with the guidance that we have offered here, and as Grant and we've discussed, is, you know, once we turn over this data card for the VAX-31 study in adults, expect to make the decision whether to stay the course with VAX-24 for a Phase III program or instead pivot to VAX-31. To the extent we stay the course with VAX-24, the guidance we've issued is that we would expect to start the first of the required Phase III studies by the end of this year, and the balance of the studies in 2025 and 2026.
To the extent we make the decision to pivot to VAX-31, we would start the first of the studies in 2025, but the last of them also starting in 2026, which puts us in the position of whether it's VAX-24 or it is VAX-31, the last of the Phase III studies in either case, would start in 2026. We would expect those studies to read out in 2027, and we would expect to be in a position to file the BLA shortly thereafter.
Excellent. Okay, good. As you mentioned, the bigger kind of market for PCV is the infant. You do have an infant program in VAX-24. In contrast to the adult, you are deciding 24 versus 31, but for infant, you're probably going to push forward with the 24, regardless. So tell us where you are. I remember in the timeline , you know, you closed the enrollment by in March this year, and then this is a longer trial, right? So that's, you're guiding towards the data readout first, the primary is in 1Q next year, and the follow nine months later for the, for the, the booster.
Tell us where they are and then how, how should we think about that data, and how confident you are for the infant, because this is a bigger market?
Yeah. So, you got it exactly right. We're going to see the results of both co-primary endpoints next year, starting in the first quarter with the first of the two co-primary endpoints. The infant market has historically been the larger of the two markets on a relative basis with adults. There is an expectation the adult market is going to catch up to the infant market, but for the time being, that infant market has been the largest proportion, so that data is going to be really meaningful for us.
As far as expectations, you know, I think our carrier-sparing approach could have even a more meaningful impact in the infant space because as opposed to the adults who have historically gotten a single vaccination, the infants get 3 vaccinations in the first 6 months of life, and then they get a 4th vaccination when they turn 1. So to the extent the amount of carrier has been really the rate limiter in terms of expanding coverage, you know, each dose is conferring more and more protein carrier. So the fact that we're giving less, I think is only going to be compounded in the infant indication. So there is a chance that we could see even an improvement on a relative basis. We certainly don't need to see that.
We saw on average, 25% higher antibody responses across the common 20 strains in the adult setting. So just matching that would be a fantastic moment for us. But there is the possibility that the carrier-sparing approach could result in an even larger improvement. And I say that just because the relative immune responses going from Prevnar 13 to Prevnar 20 across the adult and the infant space showed an even bigger deterioration in immune responses when the carrier protein went from, you know, the mid-30s up into the low 50 micrograms per dose.
Yeah. Yeah, so your comparator, the immunogenicity, is going down, and I remember in your, the preclinical study with the repeat dose, you don't see too much degradation from the, primary to the booster.
Yeah, that's right. And the other interesting dynamic that's at play is, you know, in the United States and the trial design for which we'll be reading out next year, is the 3+1 schedule. So in the U.S., we give these 3 vaccinations, and within the first six months, we follow it up with a boost. Outside of the United States, it's a slightly different regimen. So in Europe, for instance, they have what's called a 2+1 schedule, so only 2 vaccinations within the first six months. It happens to conform with their well-baby visit schedule. And interestingly, when the Prevnar 20 Phase III studies ran out or read out, I should say, using that 2+1 schedule, they missed on 11 of the non-inferiority comparisons for that first co-primary endpoint.
Although Prevnar 20 was approved in Europe earlier this year, it was actually only approved for the 3 + 1 schedule. So it remains to be seen how that's going to get reconciled in Europe, but the approval doesn't match the actual usage practice, whereas the 15-valent from Merck did receive the 2 + 1 schedule. So we'll have to see how things play out in Europe, but it's clear that, you know, it was not the optimal outcome. So we'll have to see what happens in Europe, but the competition ultimately could be the 15-valent vaccine there.
Yeah.
We'll eventually run a 2 + 1 study, following this 3 + 1 readout.
Yeah. Very clear, the current vaccine, it's a suboptimal, you know, with the multiple dose, particularly for the infant, right? Okay, let's talk about staying on the commercial side, understanding this market is very kind of policy-driven market. So we're going to have, you have one competitor, which is a large pharma, and that they will have the ACIP meeting, kind of a recommendation pretty soon, assuming they get approval. So we already have some previews and discussion, so it seems, people are talking about lowering the age group to 50, maybe some catch-up dosing, the vaccination. How do you think about the outcome from the ACIP going to impact you? And then what you think of if your 24 or 31 get to the market, how this ACIP will change?
Yeah. So there's an upcoming regularly scheduled ACIP meeting at the end of the month. The schedule just came out recently, and so on June 27th, 2:00 P.M., they'll be debating what is an expected approval of Merck's V116 program. And as you say, Roger, as per the norm, at the last regularly scheduled ACIP meeting, they did debate how they would expect things to go, anticipating an approval of V116. And at least at that meeting, the direction they were headed was a joint recommendation for both Prevnar 20 and V116 in adults, so effectively allowing the clinicians to select which vaccine they think is right for their patients. So, you know, we'll find out soon enough if that holds.
And then, you know, I think the next two topics in the PCV space of great interest are, you know, how will they recommend a catch-up recommendation for V116? So that's in a context where a patient had received a lesser broad-spectrum vaccine previously, and there's an opportunity to get incremental protection with a new vaccine. So that, that's an open question. They really didn't debate that topic at all at the last meeting, so hard to forecast precisely what they'll do. And then last but not least, they have been debating the idea of lowering the universal recommendation age from what has been 65 and up for adults in the U.S., down to 50 and up, for which would increase the pool of potential vaccinees by 65 million Americans overnight. So that's an eagerly anticipated discussion point. Hard to forecast.
At the last meeting, they said it was a probably yes decision, but the question is, will they take that decision at this next meeting, or will they watch and wait to see how adoption unfolds with a new entrant in the space? So, yeah, those are the three topics we'll be watching closely.
Yeah, excellent. Maybe just one last minute. Very interesting as a small biotech, you will—I would say you're even in a stronger position for the competition because vaccine space, you know, historically is a large pharma play, but because of technology, because of you are ahead of many others in terms of the broadest coverage. So which are the ones, you know, in development for the, from the, the competitors, you are keep watching, and then you say, "Wow, maybe I should pay more attention to this, maybe more competitive?" Because a lot of company doing the, the pipeline, to me, if your 31 works, that doesn't matter, right? But, you know, which ones you think, "Okay, that program, if they succeed, maybe have some more sort of threat to the, to your program?
Yeah, yeah, I mean, the space has been extremely consistent. The broadest-spectrum vaccine has won historically. You know, Merck took a creative approach with this V116 program, where they are able to, you know, talk about significantly broader coverage relative to Prevnar 20. But the missing part of that is that they pulled out 10 of the strains that are currently under control. And so what we think is paramount is continuing to maintain that pressure on strains that are under control while stretching to pick up coverage of the currently circulating strains. And certainly with VAX-31, where you're covering 95%-98% of the circulating disease in the U.S. or in Europe, we think we have what is the broadest-spectrum approach. Certainly, the approach that's leveraging convention, which has been incredibly effective, it just isn't stretching to meet the moment.
So yeah, I mean, I think we're aware of the other folks that are out there, but I think we have a chance to be first to market with the most broadly protective vaccine that's in clinical development, and I think we're, you know, out in front.
Yeah. Excellent. I think we went through everything for PCV. Last minute, anything you want to mention your earlier pipeline, or otherwise, we can wrap it up?
Yeah, I mean, you know, we have these generational pneumococcal conjugate vaccines across 24, 31. We think we're in a position to reset the bar. We think we've done that with VAX- 24. We hope to be able to do that again with VAX- 31. We believe our technology could stretch beyond that if there were additional strains to begin circulating of importance. And so, that's really the headliner within our pipeline, but most definitely, we have other programs we're excited about. We have another glycoconjugate program to prevent Group A strep infections, which is another similarly prevalent disease that afflicts adults and infants. So that's probably the next biggest program that we have coming out of the pipeline.
We expect to be able to guide to when we'll have that program in the clinic later this year, and we've got a couple other exciting protein-based vaccines behind that, too.
Excellent! Thank you, Grant. Thank you, Ken, and Drew. Thank you, everyone.
Thank you.
Thanks, Roger.