Thanks so much for joining us at the Bank of America Annual Healthcare Conference. My name is Jason Gerberry. I'm one of the biotech analysts here and pleased to be introducing our next company presenter, Vaxcyte. We've got Grant Pickering, CEO, Andrew Guggenhime, CFO, Jim Wassil, COO. Gentlemen, thanks for joining us.
Our pleasure.
Good to be here.
Thank you for having us.
Maybe, I don't know if you have any kind of brief kind of pre-prepared remarks that you may want to offer up at all, or you just want to jump straight into Q&A?
I'd say we just jump right into Q&A. We'll let you drive.
All right, sounds good. Maybe if you can just like briefly talk about just your thought process as a biotech company going into a space that is historically been dominated by large cap pharma? It's not a space we typically see a lot of biotechs going into. A lot of the barriers to entry that you see there and, you know, how you felt like the company was uniquely positioned to take on those challenges?
Yeah. It's not an accident that vaccines have almost exclusively been the purview of major pharma. There are very good reasons for that, which largely center-.
Mm-hmm
around the certainty for vaccines, which aren't usually delivered until the phase III data reads out. That's usually because certainly for a novel vaccine, we all saw this with the COVID vaccines, we had to wait for the outcome of those tens of thousands strong clinical study results that told us whether or not we actually prevented the disease. That back-loaded answer works very much against certainly venture-backed entities, where the time from formation to the receipt of that data can be so long, the capital intensity and risk profile makes it very difficult for smaller companies to address novel vaccines.
What we saw with this opportunity, despite the magnitude of a pneumococcal conjugate vaccine having historically been the largest revenue-generating vaccine in the space, is a very different dynamic, which now that we know that efficacy is derived by the early antibody responses that you get right after vaccination, those validated surrogate immune endpoints are received in phase II clinical development. You get that answer where you're de-risking the asset years before you would ordinarily, and that allows you to get that answer earlier and make that major investment to supply a vaccine which could have global demand. You get started on that supply much earlier than having to wait until the end of phase III.
Those things were all working for us as we set out on this mission to create best-in-class pneumococcal conjugate vaccines, and that's what set us up to get the answer, you know, that we got in October, which was a very clear signal that we have what it takes to deliver a best-in-class pneumococcal conjugate vaccine that was further exemplified by our phase II data set of a few weeks ago. It allows us to get ahead of that supply, which is what the proceeds of that last financing that we raised will help us do. Those were the big drivers that gave us the confidence that, unlike tradition, a small emerging company could rise to the occasion of a product of this potential magnitude.
Sure. Sure. You kind of alluded to it, but you have once you start an adult phase II trial, you can get a pretty quick answer. You know, you may be in a position to advance a 31-valent into the clinic in the second half of this year and get a pretty quick answer on that, you could have two programs in parallel. The investments that you're making in VAX-24, can you just talk about if you have this embarrassment of riches and you've got VAX-31 going for you, can those investments kind of aid you along in sort of the ramp up and scale up for VAX-31?
Yeah. I think you're really onto something there, Jason Gerberry. You know, we always felt that the technology that underpins our pneumococcal conjugate vaccines would lend itself to delivering broader spectrum pneumococcal conjugate vaccines that could exceed the spectrum of coverage that's possible with the first generation chemistry that the current vaccines are based upon. We felt like a 24-valent vaccine was what the market needed, but we felt like a 31-valent would be the best long-term solution for this market. That 31-valent started out as basically the dream that we had that we'd wanna get to eventually as we were showcasing this technology and thinking about how to manage our pipeline.
The realities and the synergies between the two made it manageable to keep VAX-31, as you say, right behind VAX-24, with an expectation to be putting an IND for that program in later this year and be in receipt of the clinical data next year. That comes from the mere fact that 24 of the conjugates that are in VAX-24 are also in VAX-31. We've been able to make adequate supply of those 24 conjugates to have us three-quarters of the way to VAX-31 already. It's just been that incremental investment on top of the 24 conjugates we already had.
That's a fairly modest increment and something we've been able to manage to keep that optionality and, as you say, what could turn out to be an embarrassment of riches with a best-in-class 24-valent and then a one better, well, seven better vaccine in VAX-31.
Got it. Sorry, were you gonna say something, Jim?
No.
Okay. You mentioned coming off the phase II, elderly data that you had recently. Maybe can you just talk about your preparations going in for phase III, what that study could look like and any clarity, you know, on when second half the FDA interaction could happen for the phase III trial design?
Yeah. Jim, do you want to take that one?
Sure. In terms of our phase III approach, obviously we gotta do three prerequisites. One is the pivotal non-inferiority study. Second is a lot-to-lot consistency study, and the third is to hit 3,000 subjects. We're developing our protocols to meet all three of those requirements. For the pivotal non-inferiority, Merck did their phase III study for Vaxneuvance in 50 years of age and above, and Pfizer did theirs in 60 and above, of which roughly two-thirds were 60- 64, one-third was 65 and above. We've got a lot of precedent to look at. We're looking at our data, but we're actually not looking at what we need to do in terms of a population to meet non-inferiority.
What we're gonna try and do is actually see if we can get some superiority claims for a few of the serotypes in our label. Merck has set a precedent where they were able to get serotype three in their label with statistical superiority. When we do our study design, we're gonna take a look at the 50 and 60 population and see if we can maximize our opportunity to have more than one, probably at least four, maybe even more serotypes in the label that allow us to say that we're statistically superior.
Who do you think is gonna read that label claim? Do you think it's the doctor, the payer, the CDC? The CDC tends to focus, I feel like, a lot more on sort of post-market, outcome events if I think about them, but maybe correct me if I'm wrong. Did you think about ultimately who that will sway in the downstream process?
I'm hoping it sways everyone. It's pretty much well established that having higher levels of immunogenicity are not going to necessarily be negative.
Mm-hmm.
It's just they might not be leading to additional outcomes. You know, the general sense is that you'll have better outcomes and longer protection with higher immunogenicity. If you look at the ACIP right now, when they were debating the Pfizer infant vaccine back in February, they were debating about immunogenicity as well as broad breadth of coverage.
Mm-hmm.
I think if nothing else, if we are able to show higher levels of immunogenicity and broader coverage, both the ACIP will acknowledge that and potentially give us a preferential recommendation. Yeah, the individual physicians, when they see higher levels of immunogenicity, statistical superiority, I think it will have a marketing advantage too.
It sounds like, I mean, from listening to more recent calls that you guys have done, that this FDA interaction's somewhat procedural. I don't want to put words in your mouth, but mainly maybe some small tweaks on composition of age subgroups and perhaps what your active comparator is. I would imagine that PCV20 might be an easier comp than Vaxneuvance, but for practical purposes, maybe you might go with the PCV20.
No, I think you're exactly right. It's, for me, you normally you go into an End of Phase II meeting, and you're really nervous. In this case, there's two precedents of programs that are on ClinicalTrials.gov that have been, you know, approved products by the FDA, and the FDA likes to stick with precedent and not treat any one company any differently. I think we've got a playbook, and we don't need to get fancy here. We just need to show the non-inferiority immunogenicity. We have to hit the lot to lot. We gotta get concomitant use with flu. We gotta do a few studies in at-risk groups, and we're ready to go.
Maybe an Andrew question. I think you exited about a billion and a half in cash. You talked about on your, I think your fourth quarter call about being in a position to supply the U.S. adult market from a supply perspective. You've added some capital, right? To sort of step that up. You've also said that to be global and supply the infant market, you know, that could be a several fold, you know, increase, perhaps I assume in sort of the cost to get there. I know CMC tends to be the big cost outlay item.
Maybe if you can just sort of frame sort of, you know, what we're up against in terms of dreaming the dream and, you know, getting to maybe a monopoly position, in both of those segments. What that might cost and how you'd sort of scale up those investments, with success-based milestones along the way.
Yeah. To your question, yes, on the balance sheet as of the March 31 pro forma from financing that was done in April, about a billion and a half on the balance sheet, certainly in a fortunate position. The proceeds of that last financing are principally directed to the long game from a manufacturing perspective. You know, we believe, Grant talked about this earlier, having two very strong and consistent data sets leads us to believe we've got it from a clinical standpoint, and now putting ourselves in the position to deliver and execute on it from a manufacturing standpoint. When we think about R&D spend, yes, the majority is directed to CMC manufacturing supply chain vis-à-vis clinical and the manufacturing really in three components. The first two we have been investing at risk even prior to the clinical data.
One, putting ourselves in a position to start the phase III trial timely after the End of Phase II meeting, making sure we've got the product to enroll patients in that trial. That's work that is already underway and will continue apace up to the start of that trial. The second category, also an investment we've been making prior to the data, we'll make at greater pace now, which is ensuring we're in a position to submit the BLA and deliver the initial supply requirements to the market. The way this typically works is we would expect to launch first in the adult
Population, which is principally a U.S. market. We are already operating with Lonza today at facilities out of which we can meet the supply requirements for that adult market. Then the third step, an investment we have not been making, but now intend to make with the proceeds from the financing, is to meet the long-term supply requirements. As we expand from the U.S. adult market, you then go into the infant population, which is a larger market, given it's a multi-dose regimen, and it's a global market, unlike the U.S. market. These proceeds, putting us in a position to complete our evaluation of and ultimately execute on a facility that can meet those long-term supply requirements.
Yep. Okay. Maybe I wanted to come back to VAX-31, just while we're in the theme of adult vaccination and, you know, the IND work, the submission. I think you guys have said basically it just encompasses some formulation work, so maybe if you can just elaborate in terms of what additional steps need to occur. If I recall, your preclinical rabbit model data with 31 looked pretty similar to 24 in terms of consistency of data. I guess I wonder, you know, what sort of confidence that animal model, you know, gives you going into 31.
Yeah. Having guided to submitting an IND for VAX-31 in the second half of this year means we're pretty close to having it all together. You know, basically, we've made all of the drug substances, all 31 of the conjugates have been made. Now we're in the final stages of doing the drug product, the final formulations. Prior to that, we had made tox batches of the drug product that went into the toxicology study. The last items that go into the IND are the readout of the tox study in animals, the final stability of that drug product, and then we'll be in a position to file that IND. We're into that, you know, one yard line kind of deliverables for that program.
As it relates to VAX-31, so wait, so you were asking the coverage, or what was the second part?
The animal model data that you've seen so far.
Yeah. Yeah. Yeah. Yeah, the animal data was very consistent with what we'd see with VAX-24, which certainly translated in a very clean way to the clinical data. As you say, the VAX-31 animal data that we've had in hand has been extremely encouraging. The last piece, of course, was the work that we did in the dose ranging with VAX-24, where we had this mixed dose cohort, which is also informing on the amount of confidence we have with the VAX-31 program. As a reminder, in that mixed dose cohort, in both of the phase two studies that we ran with VAX-24, we doubled the dose for seven of the conjugates, which is very similar to the amount of material that will go into the VAX-31 clinical studies.
those results, and as strong as those were, give us even more confidence on top of the animal data.
As a proof of safety.
Well, it's partly safety, but it's more the fact that what we've seen in this space historically is that what inhibits people from pushing coverage is the cumulative amount of the protein carrier-
Mm-hmm.
that's in the vaccine. We've already mimicked effectively that cumulative amount of protein carrier that will be in VAX-31 in the form of this mixed dose VAX-24 cohort. We know that those 24 immune responses looked good enough to have a profile for approvability and advancement. It's that combination of animal data and this mixed dose data that's giving us the confidence that VAX-31 is a probable winner.
Mm-hmm. I think you've said before the amount of protein carrier in 31 is something directionally below PCV20, but greater than 24, but nothing more specific than that in terms of sort of thinking about the, the protein carrier suppression, you know, hypothesis here.
Yeah. That's about right. I mean, we're just preserving some secrecy about the precise amount of carrier. We certainly advertise very aggressively that we have carrier-sparing conjugates, what you just described is pretty consistent with how we've said it, which is in our 31-valent vaccine, you know, we'll have something similar to what's in Prevnar's 20-valent vaccine.
Yep. Okay. Yeah, I mean, it seems pretty central to the question of, you know, other companies say they have 30, 31 valent in their preclinical pipeline. That could be a disclosure that stays static for years, right? The ability of you guys to execute on this versus competitors, as you think about that, I imagine that what you'd say is, "Hey, we think they're gonna run into carrier suppression issues with conventional conjugation chemistry techniques." I don't know if you'd add anything beyond that. I mean, I think it's Affinivax and maybe Pfizer have commented about having something in the 30-ish ballpark, or maybe it's Merck.
I hadn't heard anyone advertise anything with a three handle other than the GSK program...
Okay.
The Affinivax. I don't think they've updated their guidance on that program after they closed the acquisition. Not clear where they are with that program. Yeah, as you say, history has been very consistent with the amount of the carrier protein limiting the immune responses. I mean, we'll see what happens with that program. You know, even the data they've generated, you know, they have substantial... They've had to go to substantially higher doses of the polysaccharide to get an immune profile that looked like it'd be advanceable. Along with those, you know, much higher polysaccharide doses comes even higher doses of protein carrier and alum, which is a feature in all of these pneumococcal vaccines that we're talking about.
They're going to be in a bit of a pinch with those kind of doses when you're thinking about pushing up to the kind of spectrum.
Mm-hmm.
of 30+ . We'll have to see how that plays out.
Okay. Maybe shifting to the infant opportunity and if you can talk about from your perspective, what do you think is the strongest evidence for translatability of this adult finding as it carries over to infants? Is it mainly kind of just looking at how other vaccines have performed one population to the next and Or are there any specific metrics you flag?
I think it's the former. I mean, the consistency and the patterns that have been formed as pneumococcal conjugate vaccines have been studied in infants and then studied in adults and then vice versa, adults and then infants with these different programs that have been brought to market, there's been remarkable consistency. You know, the mere fact that there is no change to the formulation between those populations in dose or anything else, you know, means that there's quite a bit of translatability. You know, I think, you know, we've seen tremendous data in the adult population, and I think we're equally as confident that the infant data should be in the same vein.
Okay. Just thinking about what a successful phase II looks like, these aren't, to my understanding, at least others are not running statistical non-inferiority trials. I think there's a looser statistical threshold. Are these trials really it's about just generating good point estimates and something that you'll use to really inform sort of your phase III, you know, trial design and powering assumptions?
Yeah.
I think you've got it exactly right. The main goal of our phase II in infants will be to demonstrate point estimates and the statistical powering that's needed to carry it into phase III and meet those endpoints. You know, that said, you know, historically, like you said, others have used looser, you know, requirements in phase II. We're gonna keep it the same. I mean, you know, we're optimistic that what we've seen in adults, as Grant had just said, the translation of adults to infants has been pretty faithful over the course of other products. We've seen a higher level of immunogenicity in the adults. I think we should see the same in infants. We're gonna go in with the same-
Mm-hmm.
criteria for non-inferior that we need for phase III as well, though.
I would think that the margin for showing improvement over standard of care, or perhaps it's easier in infants in a way 'cause you're getting a third or fourth dose, the idea that protein carrier suppression is going to be even more problematic in that setting. You know, as we think about, you know, your study, I assume it's against PCV20, is that a dynamic that gives you maybe added comfort going into that study versus what you've learned in adults?
No, I think you've got it exactly right. The hypothesis being that the more times you see that carrier, the more likely you'll see an exacerbation of the carrier suppression. Having a less total quantity overall while maintaining, you know, better immunogenicity, I think will be a translatable property that we've already seen in adults, and we should see that in infants as well.
I know you guys get this question a lot. Just your latest thoughts on what you'd want to compare against in infants.
Yes.
Recent approval of PCV20.
Obviously, you know, we knew because the ACIP announced that PCV20's PDUFA date was in April. When we wrote our protocols, we made sure that we had a contingency that we could switch. We have a Stage I and a Stage II portion of our study. The Stage I is a dose escalation where we show safety at a low dose, go to DSMB, move to a middle dose, and then to the mixed dose. We knew that we would have time between if the PDUFA date actually did happen when it was said, which it did, that we would be able to make that transition. We have everything set up where we could move quickly to PCV20 now as the comparator in the-
Mm-hmm.
in the second stage of the infant trial.
What do you think is the key risk then in going to infants? You know, it's an immune system that's not developed and, you know, now you're exposing them to more serotypes. You know, are there any specific risk factors that you'd flag just like that keep you up at night?
I'm not worried about it, the serotypes. You know, infants get exposed to a lot of antigens in their first year of life. Having a few extra antigens shouldn't be a problem. You've seen already that we think that the carrier suppression issue is mitigated based on our platform. I'm pretty optimistic that the infants will be consistent with the adults. For me, it's just a matter of execution and making sure that we get the right quality of assays and results reported on time. It's more of an executional risk for me that keeps me up at night, if anything.
Okay. We have about five minutes left here. You know, we've talked so much about preferential recommendation and how markets, you know, can evolve, and it'll be three or four years before you're able to go commercial, at least in the adult segment. Maybe both within infant and adults, do you see this as being a Pfizer monopoly carried through until you're ready to be in a state of go to market?
Well, I think we're gonna learn a lot on June 21st and 22nd when the ACIP makes a decision about how to handle the recommendation for Prevnar 20 in infants. You know, we got a sneak peek at their thinking at the last ACIP meeting, where the working group appeared to be split between a recommendation for Prevnar 20 as a preferred recommendation. There was another group who seemed supportive of a preferred recommendation, but not initially. They would wanna see some follow-up to ensure that the lower immune responses that we're seeing with Prevnar 20 wouldn't result in breakthrough disease. We'll find out in late June if they get that preferred recommendation. If they do, it'll be a continued monopoly for them.
Mm-hmm.
If they leave the door open for physicians to choose, you know, the rationale from that group that wasn't ready for the preferential recommendation was honing in on the higher immune responses for some of the serotypes in Vaxneuvance for Merck. While not all of the 15 are higher, some of them were. We know that they're facing a conundrum between the need for broader coverage and yet the concern of lower immune responses and what that might mean for long-term protection. That's why we have a lot of confidence with what we think we can deliver ultimately, if everything stays on track, which would be the broader coverage that they're seeking and higher immune responses.
I think we are working very hard to deliver what these key decision makers are seeking in one vaccine versus what they're trying to get across a couple different choices right now.
Mm-hmm. Yeah, I wonder as you, as you were answering there, like the extent to which there's a read across to VAX-24 in the sense that, you know, PCV20 is + 5 versus closest competitor, you'd be + 4 versus the next highest competitor, you know, when you're, when you're available to come to market and, and how investors should look at that as, you know, an indication, right, of that ability to give a preferential recommendation, which isn't always a given, right, in a, in a lot of these categories.
Yeah. I mean at some level, they might seem like small differences, right? All of these serotypes have their own epidemiological profile, and they're, you know, circulating and causing disease. This is real morbidity and ultimately mortality we're trying to head off with these prophylactic vaccines. Yeah, the precedent, you know, goes back to the second generation of pneumococcal conjugate vaccines where Prevnar 13 had a +3 advantage-
Mm-hmm
... over their competitor, and that turned into a monopoly. Yeah, these, you know, +3 , +4 , +5 , they're big differences.
Yep. Yeah, I mean, I think when we've looked at, other vaccine markets, I mean, the only ones that are really competitive is where there's just no added coverage, right? Is it kind of an internal operating assumption that, you know, these differences are probably gonna tilt market share ultimately?
Absolutely. Yeah.
Yeah.
Yeah. Yeah, we've seen it time and time again. I mean, Gardasil is now the dominant player.
Mm-hmm
... there was another vaccine that was out there, and it's, you know, the competitor had inferior coverage and was eventually withdrawn from the market voluntarily. Yeah, expanded coverage has dictated the winner time and time again in vaccines.
Yep. Do you anticipate any feedback from OUS regulators that sort of shapes ongoing clinical efforts, or is it, you know, mainly the focus has been with FDA so far?
For the adult, we've been focused mostly on FDA. As we move further along in our program, we do plan on getting scientific advice from EMA and other agencies outside of Europe as well. We will incorporate some of the advice from them as well.
Mm-hmm
... again, they've approved the same, you know, 15 and 20 valent that the FDA has as well, and there's a nice pathway there. It's not like another vaccine where you're going there for the first time and trying to prove efficacy and safety for... There is a well-established pathway ex-U.S. as well.
Yep. Okay. We're out of time, but gentlemen, thanks so much for joining us at the conference.
Thank you.
Thank you for having us.
Thank you.
All right. That we can conclude the session.