So, Andrew, I woke up Saturday and I had a text message from Vinay. I'm like, Vinay's texting me. What is going on? And I realized I was on some email chain. So I started reading it, and that's when I shot you an email on Saturday morning. Wow, what's going on here? So let's just start. Where are things standing on FDA? Because I feel like that's probably the most important thing the market just wants to understand and get an appropriate amount of perspective on as well.
Sure, well, first of all, Umar, John, thanks to Evercore for the invitation to be here. Great to be here. Had a great day here in Miami. No, certainly the question on folks' minds, and maybe I'll just kind of level set quickly for folks on that topic. You know, we are engaging, I would say, in kind of two parallel paths. The first is our work on the government and public affairs front, and where we're engaging with the executive branch, members of Congress, and folks in the agencies. We've got a couple of folks on our team, advisors with whom we're working, so continue to advocate for vaccines and certainly Vaxcyte in that regard, and I would say constructive conversations in those areas where we're not only gathering intel as best we can as to what's happening, but also building important relationships.
And then, in parallel to that, I would say our day-to-day interactions with FDA in normal course operation. In the context of preparing to stand up a large phase III program in adults, we have guidance out there. We expect to initiate this non-inferiority study for our phase III adult program for a 31-valent vaccine in this month, December. We have been engaging with FDA over the course of the past many months, both on the clinical front and the CMC front, and looking forward to sharing the details of the phase III program, specifically the non-inferiority study, when we start that. Those dialogues, the team with which we've been interacting, has been consistent. The tone of those conversations has been consistent. The protocol is in. We have very clear feedback and believe we'll be hitting the mark with respect to that study.
As we've said, as it relates to the non-inferiority study, the concept of placebo-controlled efficacy study and outcome study and outside safety database has not been a part of those conversations or a request from FDA. Now, Umar, to your point, yes, we all saw the kind of meaty reports and the memo that was leaked, written by Prasad, obviously at the helm of CBER. And, you know, as written, our view of that memo is entirely consistent and aligned with what has been the approach for developers for adult pneumococcal conjugate vaccines and is aligned importantly with what has long been our plan in this field. And when we submitted our application for breakthrough therapy designation, we committed to, as is normal course in this field, to conduct this post-market study with respect to pneumonia.
So the memo, as we see it, does not change importantly our development plans and expectations in either the adult or the infant population. So maybe I'll pause there just to level set and go into that.
But Andrew, do you think what he wrote was a little more politically driven and much more targeted at the MAGA base and Moderna and Pfizer COVID-19 vaccine, and you're kind of getting lumped into a broader theme? Or is it truly intended for broadly every single vaccine?
I think, Umar, that is a great question to which we don't have a good answer, and we've been, I think, as you can appreciate and investors as well, we've been hesitant to speculate just because it's difficult to do so, and, you know, so we don't know what its ultimate purpose or intent was, other than, you know, what is in there is, as I said, consistent with what our plan is.
At least on the adult side. So can we talk a little bit about the requirements on the infant side? Because it does seem like the memo does specifically say for pneumococcal pneumonia, adults post-marketing, pneumonia reduction would seem to be acceptable. But the political landscape primarily has been around infant adoption of vaccines and widespread infant vaccination schedules. Has that changed at all? Have you had conversations with anybody at the agency about the increased push towards efficacy-based studies for infant?
Yeah, maybe I'll tee that up and turn it over to Jim. You know, we have, of course, had conversations with the agency as it relates to our phase II studies, but the bigger conversations would likely occur in the context of an end of phase II discussion in advance of a phase III. And we are a couple of years from having that conversation, and it's difficult to predict what the climate will be like at that point in time. I would say it is fair, yes, the focus has been much more so on the infant vaccines than adults. But I think Jim can speak to, you know, I think one opportunity we have to potentially be forward-leaning in the current climate that, you know, our 31-valent program affords us, if that's the direction we go, much like we have in adults.
Jim, maybe perhaps you can comment on that.
Yeah, in infants, it's a little bit different. There are clinical outcomes that occur in infants that you could actually study in a pre-licensure setting in less than 5,000 subjects. Otitis media occurs; there are more cases of otitis media than there are children born every year. The vast majority of first-year infections are strep pneumonia-related. What we're seeing right now in the U.S. is about 35%-40% are covered by PCV20. More than double of that is covered by our VAX-31. So we could, you know, obviously not want to do a placebo control, but we could do a head-to-head study with outcomes, show a difference.
With a reasonable amount of confidence.
With a reasonable amount of confidence in less than 5,000 subjects. So we were looking at that already, independent of this, because there is no clear clinical correlate of protection for otitis media. So in order to get a claim in your label, you need to do an outcome study. So we saw enough cases of otitis media detected in this VAX-24 study, and we're using those rates to try and drive our study power and how many subjects we would need to do it in a phase III.
You think you could get an otitis media-related outcomes label and avoid a pneumococcal pneumonia requirement to do a pneumococcal pneumonia outcome study?
Yeah, and infants don't have as great of incidence of pneumonia as well.
Yeah, but that's a more severe.
Yeah, yeah. So we would want to get the invasive with the IgG as a surrogate of protection and do an outcomes-based study with otitis media.
Makes sense. Potentially very important and obviously, doing a placebo-controlled study would seem to be very challenging.
Yeah, yeah. But even from a health economic perspective, demonstrating significant reduction in otitis media, and I'll get a little bit scientific. My belief is that I mentioned the majority of first infections are strep pneumonia. Well, the real nasty ones come after the first. But you need that first preceding infection to create inflammation so the other nasty bugs like Moraxella catarrhalis, nontypeable Hib, come limping afterwards. So I think there's also a possibility to demonstrate reduction in all-cause otitis media regardless of which bug caused it as well. So from a public health perspective, that would be extremely compelling.
There's also the side benefit of just reducing the consumption of antibiotics and the growing rise in antimicrobial resistance. I mean, the proportion of antibiotic scripts given to school-aged children that are due to actual or suspected otitis media are significant.
Yeah. I think your number one and number two causes under 10 for antibiotic scripts are group A strep and otitis media due to primarily Strep pneumoniae.
Interesting. Excellent. Maybe just I want to go through each of the trials in a little more detail linearly, but I guess one question up top. I think, Andrew, you mentioned earlier as well that for some of the FDA conversations that are ongoing, even if you go by some of the language used in some of those emails, they're implying post-marketing commitments. How large a dollar commitment would that be? And does it necessarily have to be the size of CAPiTA trial to run a post-marketing commitment like that?
No, I don't think so. And in fact, Capvax have agreed to, and they're currently undergoing that study. The study is on the FDA's website as well. And they need about 5,000 incidents. So they're thinking no more than 15,000 subjects that need to be surveyed. It's a different type of study, though. You set up surveillance catchments in hospitals. You watch for individuals coming with pneumonia. You diagnose them as pneumococcal pneumonia. Then you see if they were vaccinated or not. And you do a comparison between a standard control and your vaccine, and you see what the overall level of effectiveness is. So it's not like a normal clinical study. It's not as expensive. There may be additional subjects, but it's by no means.
It's inspirational.
Yeah, it's not a CAPiTA-like cost or size.
It's not. So half that, something along those lines?
Oh, was that about a seventh of that?
Oh, yeah. I don't think we've necessarily gone yet to, and obviously it's not a study we would be conducting in the next couple of years to fully.
Sure. No, I'm basing it on what.
Much more efficient.
I'm basing it on what Capvax Therapeutics have put out there.
Right, right, right. Makes sense. I guess for the purpose of everyone who's been tracking the story, Andrew, but maybe not fully hasn't evaluated it in more detail lately, can you just remind everyone 31 and 24 and what indications and which ones being used where?
Yeah, so we've got two programs underway in the infant population. We reported out the data for our 24-valent program in infants in the first dataset in March of this year and then the second dataset just a couple of weeks ago. And we have an ongoing 31-valent program in infants that we actually modified to add a new arm to in light of the 24-valent data. That study is currently enrolling patients, and we expect we can walk through the timelines data from that study by the end of the first half of 2027 with the possibility that the first dataset from that study would come about six months plus or minus before. The infant population comprises about $6 billion of the total $8 billion market. The balance is represented, of course, by the adult market.
In the adult setting, we are, as I mentioned, about to embark on our phase III program in that population with the first and most important study, the non-inferiority study, starting in December of this year, reading out in 2026 next year. Then the balance of the studies that would comprise that phase III program starting next year with those studies reading out in either 2026 or 2027, which would enable us to continue to march toward the possibility of submitting a BLA in 2027 and then being on market in 2028 in that adult setting.
Meanwhile, in infants, where you've, I think the bulk of the attention now is on the 31-valent program, and you said you just modified that phase II, the modified phase II is now coming in 2027. What does it mean for timelines if you go forward with the 31-valent?
Yeah, so it would, you know, regardless of sort of the disclosure plan, we would expect to be in a position to have and announce the booster data, which is the last of the two co-primary endpoints by the end of the first half of 2027. Then we would pull together the full dataset there, be in a position to engage with the FDA in a phase II meeting, and then commence the phase III. It is customary, if you look at the timelines for either PCV15, Vaxneuvance, or PCV20 from Pfizer, the infant indications typically follow two to two and a half years behind the adults for two reasons. One is you typically cannot move into infants until you've demonstrated safety, tolerability, and immunogenicity in adults.
So they start later, and they are just longer studies to conduct because you're administering four doses, at least in the U.S., over the course of up to 15 months versus one dose in the adult market.
Makes sense. Maybe let's start to get a little more specific on the infant data, perhaps. Jim, could you remind us, has there been any changes to the dose levels being used for some of the serotypes where you want to optimize further?
In terms of the 31 study?
In the VAX-31 study, as well as how you're thinking about any further changes into phase III, because I feel like a lot of folks are looking at the data very statically as if it's never going to change from here.
No, this is a phase II study. The intent of this was to figure out what we want to bring into phase III and optimize our chance of success. When we got the first readout of VAX-24 back in the end of March, based on what we saw, we saw that there was clearly a dose-dependent response between the 1.1, 2.2, and 4.4 microgram doses for the seven, well, six out of the seven serotypes that were dosed at 4.4, and we didn't see a subsequent significant decrease or carrier suppression effect in the other ones, so based on that data and the fact that we saw some of these serotypes were a little bit lower than we would hope for in the VAX-24 study, we decided to see if we could add an additional dose to the ongoing VAX-31 study.
So in the 31 study, we have a 1.1, 2.2, and 3.3 microgram dose. And for the one that's 3.3, we already had 4.4 at 1, 5, and 22F, which turns out in the 24 study were three of the lower performers anyway. But we did decide to add what we're calling an optimized dose, which pushes the majority of serotypes all the way up to 4.4 with the remainder dose at 3.3. So we think we now have the opportunity to bracket with enough data and have an understanding of what we're going to take into a phase III. I can't tell you what it is. Obviously, we'll wait and see what the readout looks like for the 31 study.
But I am optimistic if we see the same improvement in dose response that we saw in the 24, that we will have a really, really solid vaccine to move forward.
At the very least in that optimized dose, if not in one of the lower doses.
If not,
or somewhere in between the high dose and optimized dose. It could be anything.
Even if you have to triangulate between those two, moving into phase III.
Exactly.
Jim, I guess if I may, and I realize it's not fair to just focus on one specific serotype, but looking at serotype 6A, for example, I don't know if I necessarily see that dose response, but I don't know if we can take away from that one data point alone. How do you see that?
Yeah, well, I mean, 6A was one of the doses that we did not put at 4.4 in the mixed dose. So we had 1.1, 2.2, and 2.2. So two data points, sometimes it's hard to see the difference in response. It's a small study. It's a phase II, so there could be some variability. For the seven that we did dose at 1.1, 2.2, and 4.4, we saw about a 20%-25% improvement for six of the seven. For one of them, we did not see an improvement. And yes, I'm okay with taking a six out of seven chance of going from 2.2 to 4.4 and seeing improvement because, yeah, for the most part, the ones that were lower performers were the ones that aren't circulating right now. And just aside for 6A, before you get 6A is a very high responder to begin with.
And so the FDA will look at magnitude of response as well as degree of miss. And so with 6A, we're fortunate enough to have a very robust response as well.
Yeah. But Jim, I was going to ask specifically about that for 6A, right? Because we know that some serotypes have better responses in general than others. Some serotypes, obviously, as we've just discussed, have better dose-dependent responses than others. And 6A specifically, is this one where from a, even if from a non-inferiority headline you miss, is this one where the magnitude of the immune response is sufficient to hit on secondaries the way that we've seen in the past?
I'll put it this way. The accepted surrogate of protection is 0.35 micrograms per mL. But long-term, public health wants post-boost to see you above one in terms of your IgG antibody titers of micrograms per ml. The reason being that it allows you to decay above 0.35 for the first few years of life and they maintain protection. 6A, we had a GMC of five. So from that perspective, if you're from a public health, this strain is not circulating. You're still well above what is considered the threshold for long-term protection. And you're doing double the response rates in serotypes three and 19F, which are accounting for 30% of the disease. I think on a net, the balances would favor instead.
Not worrisome.
Yeah. And I just do think that kind of speaks kind of the setup for VAX-31 as we think about it. We kind of put the serotypes into three broad categories. First, you have the serotypes that are unique to our vaccine. In the VAX-24 study, there were four of those. In the VAX-31 study, there are 11 of those, 31 in our vaccine versus 20 in PCV20. We did exceptionally well on those unique serotypes in the 24 study. We would expect to do quite well on those. So those serotypes collectively comprise about 30% of disease. Then you have the two most commonly circulating serotypes that themselves comprise about 30% of disease. We also did incredibly well in the 24 study on that. We would expect to do well in the VAX-31 study.
And then you get to these other serotypes that themselves comprise about 30% of the disease where we did well on some, but would like to see improvement on others, and where we believe these two doses that we're exploring that are higher than any explored in the 24 study will enable us to deliver better results.
I think we have seen the residual disease burden by serotype change over time as these vaccines have become more and more widespread. We can track that in the CDC data, but it's not exactly one-to-one. It's not like serotypes that get vaccinated against suddenly drop off the face of the map, nor is it necessarily the case that showing lower immune response in a vaccine that gets uptake and immediately results in those serotypes coming roaring back. So how do you interpret the CDC tracking data over the years when we think about the relative immunogenicity that we see in any new vaccine?
We have not seen with the diminution of PCV7 to PCV13 or PCV13 to PCV20, any emergence or increase.
Reemergence.
Or reemergence. There was an interesting case, though, in Belgium. In Belgium, there was a PCV10 that was approved, and then it was PCV13. Belgium was using PCV13, and they saw a significant drop-off in some of the strains that were in the 13 that weren't in the 10. And they were like, "Okay, we don't have circulating disease." So they're like, "Okay, we switched to the 10." The main reason the 10 was manufactured in Belgium. So they were trying to be accommodating to the country's industry. And within two to three years, 19A suddenly reemerged very quickly. So I think we haven't seen that, but the opportunity for that is there. And so the concern is if you start to see consistent reduction over time or immunological creep, there could be at some point a threshold that is hit, and you could see that reemergence.
And so best we can do is to try and maintain that immunogenicity as much as possible.
Excellent. Maybe one last, Jim, for me, which I was somewhat confused about heading into the recent data set you guys put out. I was expecting each arm to have 200 patients, and I think it's about 120 out of 200 is what the total was posted. But I asked that not so much about the completion, but more because I think that's driving how confidence intervals are getting evaluated. So could you just expand on that a little bit?
Yeah, and I think we should have done a bit better job of setting expectations. For adults, you get one dose, you get blood the next month, you get 90% of enrollees in your immunogenicity-evaluable population. In kids, historically, it's between 50%-75%.
Why is that?
There's a number of reasons. One is the length of time it takes for follow-up. Multiple visits, kids could move during the study. The main driver is actually getting enough blood for the serology. One of the main reasons that the FDA accepts IgG and not OPA in infants is because OPA requires so much more blood or serology. It's very difficult sometimes at seven months to get that adequate level. The main driver actually is getting a sufficient amount of blood to run all of the serological tests to be able to study that.
So, where did you end up, just to close the loop on that?
About 220, we're about 60%. Yeah, using UMRS number, it was a little higher than 60%, but that's where we ended up.
So, I guess maybe that's a good place to sort of conclude this. I know we're at time as well. Between the sample size changes and because it'll be at least 800 patients per arm in phase III, correct?
In phase III, we will power it sufficiently to try and get enough serology to hit the immunological endpoint. So I don't know what it will be.
Okay. But my point is between the end, which will clearly go up some fold, we can discuss what that is, plus some of the dosing changes you're implementing in the ongoing VAX-31 study. I guess what's the level of confidence within Vaxcyte like that? Of the five misses you had on the VAX-24, that number could be shrunk down to, let's say, half that or even less than that.
I'd answer by saying I don't think we need to shrink. You heard Andrew's answer on where we're at. Getting those incremental 11, which you're comparing to the second lowest responder of PCV20 other than serotype three, basically, plus the improvement on 19F and three, which account for 30% of the disease, if we even keep the remaining profile the same, I think that's a very strong approvable product. If we miss five, I think that's acceptable, but our goal is not to miss on. We're trying to miss on as few as possible.
We do think we should be in a position to do so given these higher doses we're exploring.
Got it.
Look forward to getting that answer.
And, sorry, one last. Andrew, I know you were the CFO of the year. When was it? Last year, I think.
Some point.
In that time frame. And I remember one of the things you were very focused on was making sure the company was well capitalized through any sort of turbulent times, markets, etc. Could you just catch us up on phase III, the scope of programs needed, and how far out can you stretch out the current cash balance?
Yeah, so we're fortunate to be in a position with a strong balance sheet, $2.7 billion at the end of September. What we've said is that's sufficient in our view to carry us through operations until the mid-2028 time frame. That puts us to the cusp of, not necessarily through, the potential launch of the VAX-31 adult program and funds the conduct and readout from all the phase III studies that would comprise the adult VAX-31 program, as well as to continue to advance the infant programs, including the readout of the VAX-31 phase II study. And importantly, obviously, invest in the manufacturing that is just as important as the clinical data to be in a position to meet the supply requirements of this market.
So a proportion of the spend over the next couple of years is to build inventory levels to satisfy the expected demand requirements.
Outstanding. Fantastic. Well, we'll leave it right there. Thank you so much for joining.
Thanks, Umar.
I'm excited for what's coming up.