I cover pharma and biotech at Bank of America, and I am pleased to be introducing our next company presenter, Vaxcyte, joined by Grant Pickering, co-founder, director, CEO, and Jim Wassil, Executive VP and Chief Operating Officer. Grant's got a few opening remarks on state of pneumococcal vaccination space, then we'll go into my questions after that.
Excellent. Thank you, Jason. Appreciate you guys having us here to Las Vegas for the Bank of America Conference. As most people know, we have fully enrolled our phase III program, all three of the phase III studies for VAX-31. We are in the business of setting expectations around the pivotal study that we'll read out in the fourth quarter of this year that we call OPUS-1. We wanna make sure people have clarity of thought as it relates to expectations around that study. The pneumococcal conjugate vaccine space has had a long history of successful reviews of broader and broader forms of these vaccines to rise to the occasion of the incremental strains that are causing disease over and above those strains in the standard of care at the time.
What we've seen from past vaccines is a recognition that in some cases, there are missed non-inferiority comparisons. In the scheme of the totality of the evidence, it warrants the approval and inclusion of all of the serotypes in order to produce the broadest protection possible. As we think about expectations for OPUS-1, we're comparing VAX-31 to not only PREVNAR 20, but also CAPVAXIVE, the 21-valent product that's out as well with equal standard of care recommendations. With VAX-31, we have the benefit of having 31 serotypes, which are 11 more than PREVNAR 20. In the context of having already done a direct head-to-head comparison against PREVNAR 20, we saw really resounding positive immune responses from VAX-31 and very robust responses across the full spectrum of those 31 conjugates.
As we think about an expected outcome heading into this phase III study, we recognize that while 18 of the 20 serotypes that are in common were better than those responses in PREVNAR 20, there were two that were lower, and one was appreciably lower. In that context, we see that as an expected serotype for which we will miss the non-inferiority comparison. It's serotype 22F. It slightly exceeds the minimum threshold in phase II, in light of certain uncertainties heading into phase III, our thesis is that we should just expect to miss on that 1. In the context of a 31 valent vaccine relative to a 20, that would be a decidedly better profile than the continued recommendation for PREVNAR 20.
In the case of serotype 22F, the magnitude of the immune responses against that particular serotype are extremely high in ways that we think there would be continued confidence that we'd see effectiveness going forward. As it relates to the comparison to the other vaccine, Capvaxive, we have again 31 relative to 21, so 10 incremental serotypes, which would confer an incremental 15%-20% coverage on top of what's offered from the 21 valent vaccine. The situation is that while both Capvaxive and VAX-31 have been compared to PREVNAR 20 in well-controlled studies, we don't have a direct comparison of VAX-31 to Capvaxive yet. We will get that data in the fourth quarter. Looking across those studies, what we see is in a number of cases, higher immune responses coming from VAX-31.
In others, in other instances, a handful of serotypes for which we think there's a reasonable expectation that we'll miss on the noninferiority comparisons of that handful. In the context of a 31-valent vaccine compared to a 21-valent vaccine, we do believe it will be a decidedly best-in-class offering in light of our expected outcomes from the study. When we look at the specific serotypes, we do see that serotypes 3 and 8 are ones that we think we can reasonably expect to miss, as well as serotypes 23B, 31, and 35B.
I would say that the magnitude of the immune responses that we have seen with VAX-31 would suggest to us that they would meet the same relative criteria that the FDA has applied to past instances where they've formally missed non-inferiority, but the magnitude of the immune responses would suggest that they would continue to offer protection, particularly in the context of a broader spectrum vaccine, one that would put VAX-31 in a position to have a best-in-class profile, heading into the BLA filing. That's how we're thinking about it. We're calling this a handful of misses. I should caveat, I'm sure Jason will ask this the very first question, I'm going to preempt him.
We do have the study set up such that the 11 serotypes that are in all three vaccines are set up such that it's an either/or. We need to just hit on one or the other. In the instances of 22F, 3, and 8, we think we'll hit on at least one of the two vaccines in ways that we wouldn't expect those to come out of the study as an official miss. That's the way we're setting expectations heading into the fourth quarter readout for OPUS-1 for VAX-31. Why don't I stop there and move on to the balance of the Q&A, Jason?
Okay. As a follow-up to the Capvaxive analysis that you guys have done. Is the right way to think about this, hey, this is a worst case analysis when you say a reasonable expectation that those five could be a miss. Not that there's still a possibility that you could, but you want to set the expectation, and that's maybe a worst case planning analysis.
Yeah. What we are trying to do is to remove the ambiguity out of the question that we tend to get from investors, which is how many can you miss on? We try to be as precise as we can with that. Our view has been that there's been too much residual ambiguity around precisely what that means. In our view, this is our best expectation. Particularly for the Capvaxive situation where you don't have a head-to-head, you have two different similar but slightly different OPA assays. We need to wait until the data emerges out of the study. What gives us the most reassurance is the magnitude of the immune responses we're seeing are decidedly encouraging around the way that these are tended to be handled with regard to the actual review by the FDA.
Would these have met at 0.5 as lower bound but not at 0.65? Is that fair to say that the heightened hurdle is impacting this?
Yeah. I do think that at 0.5 we were fairly confident that we should be able to do much better obviously than that. Serotype 3 may or may not miss it, but that's the only one that at 0.5 would be possibly a miss.
Okay. Al right. Maybe before we jump into OPUS-1 and specific trial-related questions, a couple of the high level change again afoot at the FDA. I would imagine that perhaps leadership-related headlines and overhangs on your business over the past year and a half have been more about HHS and CDC than it has been about FDA. The latest news and how you think about that impacting pre-agreements, discussions with FDA and any approach that you're taking.
Yeah. We've had an extremely constructive dialogue on a continuous basis with the FDA. We have the benefit of a breakthrough designation, fast track designation, and a real recognition that expanding coverage for pneumococcal conjugate vaccines is a critical priority. I mean, for us, we just went through the whole process of locking down the phase III clinical program for VAX-31, and we thought that was a very constructive dialogue. We don't expect any changes there in light of how similar that outcome was relative to what has been the historical set of precedents. Yeah, we're comfortable.
The other news is Pfizer's 35-valent vaccine that they disclosed. It's not in the clinic yet, obviously, but if you think about the timeline for VAX-31 on market 2028, I would presume they would if you are successful, they may have to run a head-to-head trial against VAX-31. Maybe if you can just talk about timelines, how entrenched you need to be as a standard of care to prompt a future competitor from having a higher developmental bar.
Yeah, that was big news. As you point out, last week, Pfizer announced that they are no longer advancing the 25 valent vaccine, their fourth generation vaccine that was expected to be going into phase III clinical development, and instead pivoting backward to a preclinical 35 valent vaccine for which they're not providing any detail. For us, we're already in phase III clinical development with a 31 valent vaccine. If you could imagine the optimal 35 valent composition, it wouldn't move the coverage from where we are at with our 31 valent, which is covering 95% of the circulating disease, to more than 96% or 97%.
Even if you could get on track with a 35-valent vaccine, as you say, it would come well after us, would likely require a direct comparison to VAX-31 for which on a relative basis we're showing 25% higher on average immune responses relative to Prevnar 20. The trick has always been how do you get more of them into a single formulation without the immune responses dropping further, and further. For us that was just means we have less competition behind us. We'll find out soon enough, as they tell us more about that particular program.
If things play out as you've outlined here, right, so I guess relative to PCV20, you'd have a net gain of 9 serotypes versus Capvaxive, you'd have a net gain of 5 serotypes. There's obviously discussions about preferential recommendation, things like that. Maybe if you can contextualize what that clinical benefit means and how that could move markets.
I mean, I would say that it's definitely not as simple as subtracting a number of technically inferior outcomes from your coverage. I say that because for the same reason that PREVNAR 13 and PREVNAR 20 are what they are despite having three and six misses on non-inferior comparisons, the magnitude of their immune responses were sufficiently reassuring to the authorities that they preserved that coverage even with the misses. That's the expectation that we're setting with our data. I'll give you a good example. We talked about the expectation in missing on 35B.
The magnitude of those titers are extraordinarily high. They were 11,000. That is an extremely high titer and would be extremely reassuring to anyone who's knowledgeable in the space. It certainly wouldn't be the case in our mind that it would be a matter of reducing the coverage in light of those potential misses. For us, we're talking about a 95% coverage with VAX-31, which compares to around 80% for Capvaxive and more like 62% for Prevnar 20. Those are massive upticks in coverage, which we'll be rewarded for when the time comes.
Now, I'll just add that at the same conference that Pfizer's presenting their infant data next week, the CDC actually has an abstract talking about the growing trend of serotype 4 in the western states in the U.S. Capvaxive is missing that. There's also that consideration that in certain regions, especially where we're in right now, it's very critical to have that type of serotype coverage as well. That factors into it too.
Yeah.
One thing you didn't mention, but you're optimizing certain dose levels to get greater immune responses, and you have statistical superiority testing also factored into the program. How some of those puts and takes may ultimately net out, right? It's a complicated algorithm to deduce this down to. Curious, do you think that comes into play at all?
The anxiety on the part of the regulators was with each successively broader spectrum version of the pneumococcal conjugates that have come before us have arrived with significantly lower immune responses across the board. They've been forced to make that trade-off between broader coverage and lower immune responses, and this is well chronicled in the space. In the head-to-head studies that we've done with VAX-31, we've reversed that trend.
When we're talking about having on average 25% higher on relative to Prevnar 20 immune responses, you're precisely right. Many of those are because we're showing substantially higher immune responses, seven of whom in phase II showed statistically significantly higher. We're expecting a repeat of that. While we're saying we might miss on a few, we expect to be much better on many others. That is part of the trade-off here.
Thinking about product labeling, right? 'Cause this is the test, is you can select NI on the weaker of the two on the shared strains. Is it that there's really only risk of lacking an ability to beat either or on just one strain or?
To your point, yeah, what we're saying is that in the either or, the way the study is set up, since we have two standard of care vaccines that are not given preferential, there are three serotypes for which we might miss independently. Across the two comparisons, we wouldn't expect misses on those. It would really be those few that are in Capvaxive over and above the 11 that are in common.
It is the individual comparison, but on either or, you're expecting to hit on all.
Correct.
Right. Presumably in showing a robust immune response, even against the stronger of the two, the expectation presumably would you'd get recognition of all 31 strains in the label.
That is the expectation, yes.
Yeah. The precedent is others have missed in the past. They still were able to claim that serotype in the label. We would expect based on that precedent to be similar position.
Unless, if it's a huge miss, and I don't know what a huge miss would be. Then there would be a debate. I don't think we're expecting any huge misses here. They're gonna be near misses.
I t seems like this is more of a be an investor thing to prepare people for in terms of analyzing data. As you think ahead to the infant program when you move to pivotal, do you think that the higher non-inferiority thresholds are going to be applicable in those phase III studies as well? It seems like that's kind of the main drag here.
The rationale behind the increase, the higher bar for adults was really driven out of the regulators' concern that in the adult space, you don't have a clear, bright line on what is a seroprotective threshold. If you're above a particular level, they're reassured, but as you get closer and closer to lower levels, that's anxiety-inducing. That's why they wanted to see the bar raised. In infants, it's a different set of circumstances. The three field efficacy studies that were ran back in the day when Prevnar was first approved, showed that there was a very clear, bright line for which over a certain magnitude of IgG antibody titers showed protection in the field efficacy studies.
There isn't this same question of titers that aren't correlated, how far can they go? These are correlated to protection in infants. That's one of the reasons why they regulate the infant vaccines differently than the adults. They actually require separate IND filings. That for certain means that that endpoint won't change. There is a comparison of the antibody titers as part of the pivotal study designed for infants. There is some possibility they could raise that bar for the second of the two co-primary endpoints, but it's not a given.
Okay. Assuming clinical success in the fourth quarter with OPUS-1, just remind us the sequencing of the other two registration enabling trials, when the earliest possible filing could be, and just remind us your FDA discussions. You're shooting for greater than 3,000 patients with the safety database to satisfy what the regulators need, but just confirm that.
That's a pretty standard number of subjects you need. You need 3,000 subjects exposed with your final manufacturing formulation for safety. You've seen our OPUS-1, our OPUS-2, OPUS-3. We go well beyond that minimum requirement. We've had these discussions with the FDA already. In terms of timing, we said OPUS-1 comes towards the end of this year in the 4th quarter, OPUS-2 and 3 in the 1st half of next year, and then we will have one more additional clinical study that we will do, which is a manufacturing consistency. The other requirement the FDA has is that you demonstrate with your commercial process that you can manufacture multiple batches. Do it and get consistent clinical results. That will be our final clinical study, and that will gate us to our ultimate BLA submission.
How long would that take, the manufacturing study?
Relatively speaking, it shouldn't take very long. You're talking maybe 1,500 subjects, give or take. It's about 500 per arm. It wouldn't necessarily have a comparator this time.
Same thing. You do the study, you do one month later, you're still gonna have to do the 6 months for safety. I would expect us to be able to have the serology and the safety all done within that 6-month period after the last subject.
Is that something that you can expedite or move faster, or do you need to wait for some of the OPUS studies before you can start that manufacturing study?
No, we don't need to wait for those other studies to start that. I mean, the expectation is that we'll be able to get that study started in due course and have it dovetail into the anticipated BLA filing late next year.
Okay. Al right. That's what I was trying to get at. All right. Let's see. Post-marketing commitments to FDA, I know that that was part of the rumblings about how things are changing. How are the post-marketing commitments different at all from, like, what you've seen Pfizer and Merck have to do in the past?
I'll caveat this by saying traditionally, a lot of your post-marketing commitments are one of the last things you negotiate, and the reason is the FDA wants to see the totality of your clinical package before they impose any of those additional requirements. That said, we've had some discussions already. We're comfortable that we're gonna do a post-licensure test negative design study to demonstrate efficacy against pneumonia or effectiveness since it's post-licensure, similar to what Merck had done as well. Of course, as with every vaccine, an extensive safety follow-up will be also required to ensure that when you go into a larger population that's not controlled in a clinical study, that you still have the same safety that you reported in your clinical trials.
Yep. Maybe just a commercial question, how big do you think the adult market is today? I mean, we could take the Capvaxive revenue. What we don't know is how much that's taking from the Prevnar franchise. We have the over other issue of a catch-up market too in there. How do you disentangle that? Do you have a sense of, like, what the size of the adult market will be steady state when you're ready to go to market?
I n this moment, our belief is, it's about a third, a third, and a third between the infant market, the adult market, and the international opportunity. Yeah, I mean, Capvaxive has had a really good start. It doesn't appear to have eaten into PREVNAR's revenues materially, so it seems like it's incremental growth of the adult segment, which is what we have been expecting for quite some time. The adult market is gonna be the fastest-growing part of this market. It's an $8 billion segment today. It's anticipated to grow to $12 billion. The question is, what portion ultimately will the adult market take? It's going to approach 50/50, probably won't get all the way there, but could get somewhere close to that eventually.
Okay. As we sit here a year from now, you guys are gonna be close to hopefully a BLA submission and becoming a commercial entity. Talk about the infrastructure build between now and launch. What are gonna be some of the capital commitments and big hurdles and milestones to having your manufacturing between Lonza and your U.S. facility all teed up and buttoned up and ready to go?
Yeah. We've been spending a lot of time benchmarking, building out the initial leadership team for our commercialization effort. Jim is spending a considerable amount of time. The beginnings are usually with regard to thought leader development, the Medical Science Liaisons group is growing, that will be the initial outreach, over time, we'll begin to scale the balance of the organization. Our view is that we can handle a launch of this complexity.
We've been able to look at the uptake for Capvaxive, which has been quite impressive. That's a product that has limitations. With a product like VAX-31, we see a great opportunity to bring a better product to market. We'll do everything required to deliver on that.
Okay. Maybe pivoting to the infant program and talk a little bit about the phase II trial, which will read out next year. These trials are obviously underpowered, can produce results. If you look across the history of phase II infant studies, that may be difficult for some investors to interpret 'cause there's a lot of different comparisons. There's a post-dose 3, a post-dose 4, assessment here. Just maybe level set in terms of to what extent you expect carrier suppression maybe plays an issue in a phase II study and just the noisiness and how would you kind of coach investors through that one?
Well, there's no question it's a lot more complicated to describe than the adult setting. In the adults, you give one vaccination, one month later you get the antibody responses, and there you have it. As you say, with infants, it's considerably more complicated. They get 4 vaccinations. We only take two immunological readings after the third and the fourth dose. Yeah, it is more complicated, but we've got a fair amount of time. We're not gonna read out the study until first half of next year. We haven't decided definitively if we'll take advantage of the fact that there is a chance to look at the first endpoint prior to the boost data. You don't have the whole story until you see the boost data. We've guided that we will get specific about our unblinding plan.
In any case, we'll have the full measure of that study by mid-year next year, so we have quite a bit of runway to set expectations. In this moment, we just say, our VAX-24 data that read out last year was really encouraging. We think we have a path to the market with our 24-valent vaccine. As it relates to carrier suppression, we've seen even less manifestation of carrier suppression with our vaccines in infants than we had seen in adults, and that being in the context of having shown substantially less carrier suppression than others. We're seeing the benefits of the design of our pneumococcal conjugates as we built them to avoid carrier suppression. VAX-24's data looks really encouraging in the context of that carrier suppression.
We're confident that we can add these additional 7 conjugates on top to get to VAX-31 and get them to be immunogenic across that spectrum. We did have a handful of misses in the VAX-24 data. Fortunately, they were not on key serotypes that are circulating in any relevance, so we have a really good base to work from. We are testing higher doses with VAX-31. We've seen really nice dose response to improve immunogenicity with higher doses. In this study, we're testing multiple higher doses. The hope is that increase in antibody responses could rescue some of those serotypes for which we'd missed.
But if we deliver on the incremental serotypes on top of Prevnar 20, which is today's standard of care, it would create a major opportunity to expand coverage again from around 60% to 90%, which would be a massive increase. That will be driven by the incremental serotypes. Across the common 20, we had already shown improved immune responses on the most important circulating serotypes. It was really on those ones that were not as strategically important where we missed. If we can improve any of those, it just strengthens the set of arguments as we try to deliver VAX-31, not only to adults, but to infants. That's the best I've got today, but we'll be working.
On those five that with VAX-24, where there were the misses, just for our understanding, talk about which of those you're pushing dose to potentially mitigate that?
In the context of the doses, just in order of how we've progressed we took VAX-24 into adults first. We got our first clinical data. We showed with higher doses, we saw improved immune responses. When we moved VAX-31 into adults, we kept pushing the dose upward and kept seeing more and more data associated with higher dose equals higher immune responses. When we got the first infant data with VAX-24, we did see room for improvement, we already had VAX-31 at higher doses, we added an increment over and above that.
Our view is that we already had in one of the formulations, higher doses for a few of those serotypes that did end up showing room for improvement. When we added the optimized dose, Jason, on top of that, all those that showed room for improvement, we moved up to the high end of the range. We'll have multiple shots at higher doses to produce the best profile possible, coming out of phase II.
Okay. Lastly, we have 30 seconds here, just beyond Pfizer and the stated ambition to have a 35-valent, your just general understanding of who you view as competitive, possible competitors at least with a 30 handle or a three handle on their serotype coverage.
We've got GSK with their affinity bound constructs. They are in a phase I study with a 30-plus valent vaccine. They are in early stage clinical development. You've got Pfizer in preclinical. I'd say the issue that people have found in adults is they're mixing multiple protein carriers. That's turned out to be really problematic. I know we're running out of time. There have been multiple attempts at that. No one has succeeded. We have the benefit of not needing to try to mix in something new and exotic to expand coverage to the 30s. There are people trying. We'll see.
Al right. We're out of time. Gentlemen, thank you so much for joining us.