Good day. My name is Margo, and I'll be your conference operator today. At this time, I'd like to welcome everyone to the Vaxcyte VAX-24 phase II infant study results conference call. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question-and-answer period. If you would like to ask a question during this time, simply press star, followed by the number one on your telephone keypad. If you would like to withdraw your questions, please press star two. Today's call is being recorded. I would now like to turn the call over to Andrew Guggenhime, President and Chief Financial Officer of Vaxcyte. Please go ahead.
Great. Thank you, Margo, and good morning, everyone. I'd like to welcome you to Vaxcyte's conference call to discuss the top-line results of our VAX-24 infant phase II dose-finding study evaluating the safety, tolerability, and immunogenicity of VAX-24, our investigational 24-valent pneumococcal conjugate vaccine, or PCV, designed to address invasive pneumococcal disease, or IPD, in healthy infants. I'm joined today by our Chief Executive Officer, Grant Pickering, and our Chief Operating Officer, Jim Wassil. Earlier this morning, we issued a press release announcing these data results. Copies of this and our other press releases, latest corporate presentation, and SEC filings can be found in the Investors in Media section of our website.
Before we begin, I'd like to remind you that during this call, we'll be making certain forward-looking statements about Vaxcyte, which are subject to various risks, uncertainties, and other factors that could cause actual results to differ materially from those referred to in any forward-looking statements. For discussion of the risks and uncertainties associated with these statements, please see our press release issued today, as well as in our most recent filings with the SEC, including the risk factors set forth in our Form 10-K for the year ended December 31st, 2024, and any subsequent reports filed with the SEC. With that, I'll turn the call over to Grant.
Thanks, Andrew. We appreciate all of you joining us today. Our agenda for today's call will begin with me describing the highlights of today's results. I'll then reflect on the potential opportunity these data present before handing it over to Jim to take you through the study results in detail. Finally, I'll pick back up with concluding remarks on our strategy and next steps for our PCV franchise. At the outset, I'd like to make one important note. We've all been eagerly awaiting these results. Prior to announcing this data, we made a concerted effort to accumulate as much data as possible, and we're pleased to share that today's results include not only the post-dose three IgG data, but also the OPA data, post-dose three, and an interim look at the post-dose four IgG data.
Having set the stage, let's now delve into the main findings we're here to discuss. On behalf of the entire Vaxcyte team, I'm pleased to share that the data from our VAX-24 infant phase II dose finding study is positive. VAX-24 hit the mark on safety with a profile similar to the standard of care. VAX-24 demonstrated the potential to achieve the broadest coverage of any pediatric PCV available today in a coveted category. Post-dose three, we hit the target on all of the highest circulating U.S. strains contained in VAX-24 and elicited substantial immune responses. The interim booster dose IgG data show robust memory responses across all doses. Finally, and importantly, we saw dose-dependent immune responses with little to no evidence of carrier suppression, which means we have headroom to optimize dose further, bolstering our confidence going into the VAX-31 infant data readout and phase III development.
Leading up to this readout, we have consistently recognized that while our goal is always perfection, missing the target on a few serotypes would not preclude us from delivering an approvable and highly compelling profile. In this phase II study, the VAX-24 mid-dose missed the threshold on four serotypes, which is consistent with each successively broader version of Prevnar in infants in their final formulation. Fortunately, these were not on any key circulating serotypes, and we believe we can optimize the VAX-24 dose to reduce or eliminate these misses in a phase III program. We also feel VAX-24 is well-positioned in light of the totality of the data approach applied by regulators in multiple instances. Based on this data, we're announcing that pending review of the results of the top-line VAX-31 infant phase II study readout, we plan to advance either VAX-24 or VAX-31 to a phase III infant program.
What's perhaps most exciting is the continued validation of our carrier-sparing platform, with little to no carrier suppression evidenced in infants, even less than seen in our adult PCV studies. This is a remarkable achievement that instills even greater conviction in our PCVs as we head into the VAX-31 readout next year and set us up to unveil our third-generation PCV candidate today, VAXXL. While we won't be sharing many details just yet, VAXXL is intended to offer even broader coverage than VAX-31. If VAX-31 is designed to be the category killer, VAXXL is intended to be the category keeper in our PCV franchise. I do want to take a moment to reiterate why developing a broader spectrum PCV matters. Despite widespread use of effective vaccines, the global impact of the disease remains significant and is associated with high case fatality rates and antibiotic resistance.
As a result, the public health community continues to affirm the need for broader spectrum vaccines to prevent invasive pneumococcal disease. We're committed to ensuring that people stay aware of the relevance of the various serotypes, as they are not all created equal. Their importance depends largely on how actively they're circulated. As we walk through the data, you'll see that we consistently highlight and assign relevance to each serotype accordingly. You can also see that VAX-24 and VAX-31 have the potential to become the broadest spectrum PCVs to prevent the most disease in infants. With that, I'll hand it over to Jim to go through these positive results in detail.
Thanks, Grant. Over the next few slides, I'll review the study design, disposition and demographics, safety and tolerability profile, and top-line immunogenicity data.
Before I get into the details of the results, however, I'll reiterate the overall design of this VAX-24 infant phase II dose-finding study. This was a randomized, observer-blind, active-controlled dose-finding study designed to evaluate safety, tolerability, and immunogenicity of VAX-24 at three dose levels: low, middle, and mixed, compared to PCV20, the current standard of care in 802 healthy infants. Phase I of this study evaluated the safety and tolerability of a single injection of VAX-24 at three dose levels compared to PCV15, the standard of care at the time, with an initial safety evaluation for seven days after each dose. VAX-24 subjects from stage one were included in the stage two safety and immunogenicity analysis.
Subjects received a dose of VAX-24 or PCV20 at two, four, and six months of age and a booster at 12 to 15 months, and were monitored for safety and tolerability throughout this study. Serology was taken at both one month post-dose three and one month post-dose four, and immunogenicity was assessed. All subjects continued to be monitored for safety through month six following the booster dose. The dose levels evaluated in this infant proof of concept dose-finding study were identical to those used in the VAX-24 adult clinical studies. The low dose contained 1.1 micrograms of polysaccharide per serotype. The mid-dose contained 2.2 micrograms, while the mixed dose contained 2.2 micrograms for 17 serotypes and 4.4 micrograms for seven serotypes. These serotypes at 4.4 micrograms, such as 3 and 19F, were chosen based on the epidemiological relevance of those serotypes or prior evidence of dose-dependent immune responses.
As you may recall, the mixed dose was strategically chosen to simulate the VAX-31 mid-dose to assess whether there was any carrier suppression as we moved from 24 to 31 serotypes in the vaccine. PCV20 was dosed as it is per its approved label at 2.2 micrograms per serotype, with the exception of serotype 6B, which was dosed at 4.4 micrograms. Now, turning to study disposition and demographics, the study enrolled 802 subjects, which were evenly distributed across the four groups. Small imbalances in group size were expected, as the 12 comparative subjects who received PCV15 at the first dose of the study vaccine in stage one are excluded from the PCV20 group. 26% of vaccinated subjects are not included in the post-dose three immunogenicity evaluable population due primarily to unavailable or ineligible blood samples, with only 5% of subjects discontinuing the study before the post-dose three blood draw.
None of these were because of a safety event related to the study vaccine. With respect to study population demographics, subjects were generally well-balanced across cohorts based on age, sex, race, gestational age, length, birth weight, and BMI, and similar for both the safety and the post-dose three immunogenicity populations. The only small imbalance is a slightly higher percentage of female subjects in the VAX-24 low and mid-dose groups. Now, moving on to safety and tolerability, VAX-24 was well tolerated with a demonstrated safety profile similar to PCV20 at all dose levels. Tolerability data is currently available for each of the primary vaccinations, with post-booster data coming in the final analyses. Reported solicited local reactions, including redness, swelling, and tenderness, were generally mild to moderate in severity and resolved on their own within a few days, and there was no evidence of a dose-dependent response.
Subjects were also monitored for solicited systemic reactions consisting of fever, irritability, decreased appetite, decreased sleep, and increased sleep. Reported solicited systemic reactions were comparable to PCV20 and also generally mild to moderate and resolved on their own within a few days, with no evidence of a dose-dependent response. Only mild decreased appetite in the VAX-24 mixed group occurred at a higher rate than in the PCV20 group. Typical for infant vaccines, rates of solicited reactions tended downward with subsequent primary vaccinations. The overall balance between the VAX-24 low, mid, and mixed and PCV20 groups were as would be expected for this population. Safety data, including rates of unsolicited treatment emergent adverse events, or TEAEs, medically attended adverse events, or MAAEs, new onset of chronic illnesses, or NOCEs, and serious adverse events, or SAEs, were monitored.
While interim, they represent all safety events reported through one-month post-booster dose for 98% of subjects and through study completion for 261 subjects. There were no differences in the rates of TEAEs, MAAEs, NOCEs, or SAEs across the four groups, and reported events were typical of what would be expected in an infant population. There have been no reported related SAEs, and for the only related NOCE in this trial, the occurrence of mild chronic nasal congestion, vaccinate remained blinded to the treatment assigned to this subject. There has been one death reported in the study, a subject in the PCV20 group who died 49 days after administration of the first dose of the study vaccine with a cause of death reported as SIDS. This event was thoroughly investigated and deemed not related to the study vaccine.
Before I jump to immunogenicity results in detail, let's briefly revisit the criteria for the infant phase II immunogenicity measures to support advancement to phase II. For the 20 serotypes in VAX-24 common to PCV20, the criteria for success of achieving noninferiority for the primary series is deemed as a lower bound in the 95% confidence interval, with a difference between the proportion of participants achieving an IgG concentration of greater than or equal to 0.35 micrograms per mL is greater than -15% for each serotype. I note that for formal phase III noninferiority registration studies, which are much larger, we will use the traditional lower bound of greater than or equal to -10% for each serotype. For the unique serotypes, the comparison will be with the lowest response rate in PCV20, excluding serotype 3.
For the booster dose, phase III noninferiority registration studies have required the lower limit of the 95% confidence interval for IgG geometric mean ratio to be greater than 0.5 for each serotype. For the unique serotypes, it will be compared to the serotype with the lowest IgG geometric mean ratio in PCV20, excluding serotype 3. Traditionally, IgG GMRs with a point estimate of greater than 0.6 for each serotype in phase II have supported advancement to phase III, as larger phase III studies have resulted in tighter confidence intervals, improving the likelihood of the lower bound confidence interval meeting the traditional 0.5 GMR requirement. Historically, in cases where the traditional endpoints are not achieved, the FDA has assessed the totality of data that includes IgG antibody levels post-dose three, functional antibodies or OPA levels post-dose three and post-dose four, and IgG seroconversion rates post-dose four.
Percent of circulating disease for each serotype, magnitude of antibody responses, and degree of shortfall are also taken into account. We believe we're well-positioned to meet these secondary criteria. Turning now to the immunogenicity results, this slide shows the percent of infants that have achieved an antibody level of 0.35 micrograms per mL or higher by serotype, a threshold that is generally believed to correlate with protection in infants. All 24 serotypes in VAX-24 elicited high seroconversion rates at all three dose levels, with infants achieving the protective threshold at rates well above 90% for the majority of serotypes. Of note, for serotype 3, which is the most common serotype causing invasive pneumococcal disease in U.S. infants, VAX-24 had between 70% and 88% of infants meet or exceed the seroconversion threshold, compared with a little less than 40% for PCV20.
Now, beyond serotype 3, for the seven serotypes that cause the majority of invasive pneumococcal disease cases in US children less than five years old, 93.1% was the lowest seroconversion rate. This means that in this study, VAX-24 was deemed to provide a high degree of protection in the vulnerable first months of life. For all the unique serotypes, we did exceptionally well with seroconversion rates at or near 100% for all VAX-24 doses. These are the same seroconversion rates that were shown in the previous slide, but now they're shown in comparison to PCV20. To orient you, if you take a look, the zero mark in this forest plot means we would have had a seroconversion rate that's equivalent to PCV20 in terms of the number of infants who achieved a protective threshold.
If the point estimate is to the right of the line, we improved versus PCV20, and to the left, we were a little lower. The gray bar, or sorry, the gray box marks the -15% threshold we are using to assess our phase II data that I mentioned earlier. The results are ordered based on circulating disease from highest to lowest. As you can see, for the most commonly circulating serotypes, we performed similar to PCV20, with the exception of serotype 3, the most commonly circulated serotype, where we observed a significant improvement compared to PCV20. We met our criteria for 20 of 24 serotypes in the study at the mid-dose, and as mentioned, for the four serotypes that we did not meet, three of these serotypes are not circulating, and only one is circulating at a rate of less than 1%.
For the unique serotypes, our performance was very strong, substantially higher overall than PCV20 as well. Turning now to post-dose three IgG geometric mean ratios, or GMRs, this format is similar to the forest plots that you've seen before when we presented our adult data. The line at one means VAX-24 IgG GMCs were equivalent to PCV20. To the right, they were higher, and to the left, lower. The dotted line at 0.6 corresponds to the criteria that we have for advancement to phase III. Serotypes three and 19F account for almost 30% of circulating disease. These serotypes had significantly higher GMCs for all VAX-24 doses, with geometric mean ratios ranging from 1.65 to 2.60. I also wanted to note that for those strains where we had 1.1, 2.2, and 4.4 micrograms in this study, we did see a clear dose-dependent response.
For example, the gray bar highlights 19A and 7F. If you look at 7F, we were just slightly above 0.6 at the low dose, improved on the mid-dose, and we almost got it back to 1.0 for the 4.4 microgram dose. 19A was similar, and while the GMR started a little higher than 7F, there was a similar overall improvement in the 2.2 and 4.4 microgram doses, respectively. We saw a dose-dependent response, and that's important for those serotypes where we were a little bit lower because we feel that we can optimize the dose on those serotypes and be able to improve the responses to position us well for potentially achieving phase III coprimary immunogenicity endpoints for all serotypes. For the unique serotypes, again, you're seeing GMRs that are remarkably high and extremely robust.
Here we have the functional antibody or OPA responses for a subset of individuals. You'll note the dotted line at eight. Historically, a GMT of eight or above is believed to correlate with protection. What's important to note here is that both of our titers and the titers for PCV20 are substantially above what is considered to be a protective threshold, and we feel for those strains that have a little bit lower IgG geometric mean concentration, such as serotype 1 and 6A, we still had strong evidence of OPA responses well above this GMT correlate. Now moving to post-dose four, this slide shows interim post-dose four data, and we will walk through it using a similar approach as the slides that I presented for post-dose three. First, here's the post-dose 4 % of infants that achieved the seroprotective threshold of 0.35.
As you'd expect, after administering a booster dose, for the vast majority of serotypes, both VAX-24 and PCV20 were at or near 100% seroconversion rates. For serotype 3, we maintain a favorable profile compared to PCV20, and for serotype 12F, where we had a lower response after the primary series, you can note that the mid-dose is now on par with PCV20. Overall, very good seroconversion rates. When evaluating PCV vaccines, the FDA wishes to see a very robust booster dose response following dose four. This is the IgG geometric mean concentrations for the mid-dose with the post-dose three GMCs in light green and the post-dose four in darker green. As we had hoped, we observed a strong booster response across all 20 shared serotypes, as well as the four unique serotypes, well above levels considered important for long-term protection for the majority of these serotypes.
Finally, here is the post-dose four geometric mean ratios with serotypes arranged in order of decreasing incidence in U.S. infants. Similar to post-dose three results, we maintained our advantage for serotype 3 and 19F. While we did have a few serotypes hover around the 0.6 threshold, we believe, as I've shown before, that we have the tools available for optimization given our dose-dependent responses. We are already assessing if a dose-dependent response can improve immune responses with VAX-31 for serotypes one, five, and 22F. When we receive the VAX-31 infant phase II data readout, we'll be able to assess whether optimizing the dose improves responses for these serotypes in infants.
Now, based on the current data, we believe VAX-24 has the potential to make a meaningful contribution to the field, offering broad coverage for infants and reinforcing the critical role of PCVs in reducing disease burden and supporting public health. With that, I'll turn it over back to Grant.
Great. Thank you, Jim. Let's talk about our game plan heading into phase III. As we previously indicated, these results reinforce our confidence that we have an approvable infant profile, whether it's with VAX-24 or VAX-31. As demonstrated in our adult program, the 2.2 microgram dose is the optimal chassis to build on and is well-suited to deliver the basis of an optimized formulation for phase III in infants. Our carrier-sparing platform gives us exquisite control of dose, enabling us to fine-tune responses and address the laggards in the post-dose three seroconversion rate.
We were pleased with the PD3 IgG GMRs, and we would expect to see some improvement on PD4 IgG GMRs on some of these serotypes in a larger study. The optimized formulation of VAX-24 will come out of these learnings. The optimized formulation of the mid-dose will allow us to include enhanced dosing for select serotypes to bolster the potential for an increased immune response in a phase III study. Here is the bottom line. With the 2.2 microgram mid-dose, we hit on all the highest circulating strains contained in VAX-24 post-dose three, with a few missed strains that do not meaningfully contribute to the disease burden, but we will nonetheless look to improve those responses in phase III. Underpinning this confidence is our observation of consistent dose-dependent responses, indicating a clear opportunity to optimize dose where appropriate, building an enhanced formulation for phase III.
Here you can see a characteristic dose-ascending immune response for the highlighted serotypes. They went from laggards to exceeding the threshold and meeting the endpoint for the study, allowing us to gain confidence we can increase dose to get improved responses. This is what we will do for a handful of the serotypes heading into phase III in the final dose-optimized VAX-24 formulation. If you recall in adults, when we looked at the mixed dose data, it indicated that we could be confident heading into the VAX-31 data readout because the cumulative amount of protein on board enabled strong immune responses. This came at the expense of a few of the serotypes, one, five, and 22F, that looked okay at the mid-dose but had fallen back in the mixed dose.
Now, when you look at the 17 serotypes that were left at 2.2 micrograms in either the mid-dose cohort or those dosed at 2.2 in the mixed dose cohort, you can see that downward pressure seen in adults did not manifest itself at the same level in infants. This is a positive indication that we are seeing less carrier suppression in infants, which gives us confidence that as we head into the VAX-31 data, the immune responses will not be under significant pressure based on the incremental material. Further manifestation of this is clear on review of the adult data we have been able to produce in phase II as we went from VAX-24 to VAX-31. The gray bars here are the adult data for VAX-24. The green bars are for VAX-31. On the far left, you see one, five, and 22F were the ones that had lagged in VAX-24.
We increased the dose for those in the VAX-31 formulation in this same population and saw the benefit from that. As to the mixed dose data from VAX-24, we saw that on the seven that we doubled the dose, we did not need to do that. We dialed them back, optimizing the dose downward in VAX-31, and we saw that we could get the right immune responses we needed with a lower dose. This tells us we are in really good control. There is great consistency across the dose responsiveness, and that is what gives us confidence, even though we had a few off the mark, that we can build off that VAX-24 chassis to get the optimized formulation to go into phase III. We are incredibly excited and gratified to know we have a clear path forward.
These results provide further validation of our carrier-sparing platform, and as we look ahead to the VAX-31 infant data, we'll evaluate which candidate to advance. Based on the totality of the data, we know we have something differentiated in this substantial infant market and an opportunity to expand coverage via the addition of additional conjugates. As we move to wrap, obviously, we will be keeping you guys updated on the key milestones as we move ahead. We have the initiation of the VAX-31 adult phase III clinical program at mid-year this year. We'll be able to obtain the balance of this study's results before the end of the year for VAX-24, and that leads us up to the VAX-31 pediatric data for which we will obtain the phase II dose findings by mid-next year.
With all that data in hand, we'll then be able to lock down the formulation and vaccine that we will advance to phase III in infants. Just as a reminder, this is a really massive market opportunity for us. We think we've got the best-in-class profile. We've got unique carrier-sparing conjugate technology that we will leverage across not only VAX-24 and VAX-31 and now VAXXL as well as we invest in our PCV franchise. With that, I think we can move into the Q&A section, Margo.
Thank you very much. Ladies and gentlemen, if you would like to ask a question, please press the star one on your telephone keypads. You may remove yourself from the queue at any time by pressing star two. Once again, that is star one for a question. We'll take our first question from Roger Song with Jefferies. Please go ahead.
Great, Jim.
Thanks for that and taking our question. I think maybe instead of focusing on each individual serotype, can you tell us what is the overall immunogenicity you have observed in this infant readout from the post-dose three and the post-dose four compared to Prevnar 20? Thank you.
Yeah, it's a little hard to boil it down to a single number, but when you look at the outcomes after post-dose three, that's where we have the final results. Obviously, for PD4, we have an interim. We'll get the full balance of that at the end of the study. It's really it comes down to what extent can you assure protection for these infants in their first year of life when they're most vulnerable? That's as simple as taking the seroconversion rates multiplied by the circulating disease rates.
If you do that, we are significantly in excess of what Prevnar 20 is providing today as the standard of care. I think if you multiply their seroprotection rates times their coverage, they're in the mid to high 50s. If you look at our data, Jim, I know you did this calculation.
They're closer to 70 with the 9N and 20C being 3% of circulating disease.
That has been a means with which other vaccines have represented their coverage. We're talking about stretching from mid-50s with today's current standard of care to more like 70% coverage. That is quite meaningful.
Got it. That makes sense. Understanding you will do some dose optimization for VAX-24 as you lay out the dose dependence, how should we think about the assay variability translation from phase II to phase III?
If you can remind us your post-dose four, how many subjects you already see the data, and then how do you think about the rest of the subjects who will see the full data by the end of the year? Thank you.
Y eah, this interim look represents about two-thirds of the data that we expect to have by year-end. Yeah, we have effectively 50% more of the data that will roll into that PD4 final look. Just keep in mind that for a phase II study where the primary objective technically is safety, the immunogenicity endpoints are secondary, and the stats are actually descriptive. You do have the latitude as long as you assure appropriate blinding to supplement the data by the end for which we then roll into the end of phase II data that we take formally to the FDA.
Yeah, we do have a meaningful balance for the PD4 data. As it relates to variability, there is one outlier in the data that we have, which is 12F. You can see that the error bars for that one on the IgG data are substantially wider than the others. We will note that we did have similar experience to what Pfizer experienced with the 12F IgG assay for which there appears to be more limited affinity binding, which results in lower IgG antibody responses, which is the exact same thing that they saw. When they looked at the totality of the evidence and they saw OPA responses, which are the functional antibody responses that assure killing, they were able to lobby the agency for inclusion of 12F despite having substantially lower responses. We're seeing something similar there, Roger.
That's unique variability that we don't think will apply to the others. Of course, our OPA data for 12F looked really wonderful as well, well above what would be considered to be correlated with recognized protection. That one, if you're referring to that one, is an outlier. As we think about going from phase II to phase III, where the error bars are really the name of the game, for the formal criteria, you need to have the lower limit of that confidence interval over a particular level. The bigger the study you run, the tighter those error bars get. If you look back at the registration studies for today's standard of care, they had about 1,000 subjects per cohort.
Obviously, in this study, we're looking at 200 subjects per cohort at the enrollment and then something less than that for the immunogenicity evaluable population. Heading into phase III, if we were to run the same size study, we're looking at something five times larger. Of course, with a much larger sample size like that, you'll see error bars tighten up significantly. Certainly, as we look at that PD4 GMR data, quite a number of the serotypes are right on the borderline of the 0.5 standard for which the lower limit needs to exceed. Even in this sample, we could see some movement there to exceed the threshold. Certainly, heading into phase III with similar treatment effect, we could meet the endpoint. The key thing is we're not coming out of phase III with missed threshold sort of outcomes.
We're heading into phase III with the lever of dose still fully at our disposal. We'll have an opportunity to optimize the dose on those strains for which we believe we'd see benefit and take that strategy into phase III.
Y ep, all makes sense. Congrats if I did not say that earlier. Congrats for the polygenic data for those findings study. Thank you.
Thank you, Roger.
Thank you. Next, we'll take our next question from David Reisinger with Leerink Partners. Please go ahead.
Hey, good morning, guys. This is Brian on for Dave. I heard you guys say that it was two-thirds of patients in the interim PD4 data that you had. Real quick, would you expect the point estimates to change meaningfully with the full sample size? I guess it is more of a statistical question.
Yeah, thanks, Brian.
I think the point estimate is less likely to move relative to the confidence intervals as I was just referencing. Yeah, we took into this study in terms of expectations for success in phase II the same sort of approach we took in adults, which was focusing on the point estimate but realizing that the confidence intervals are what ultimately matter at the end of the day. There were some that were right on the line at the point estimate, but somewhat to our surprise, the confidence intervals were pretty tight. Although the point estimate was right on the margin, we actually are very close to exceeding the technical threshold, which we'll ultimately need to hit in phase III. Yeah, to your point, with only two-thirds of the data, those confidence intervals will tighten up.
You can't predict precisely how much, but it would be more in that respect than in the former.
Okay. Yeah, that's super helpful. And then just one more on the VAXXL vaccine that you unveiled today. Does it use the same technology as your prior vaccines? I guess, what are you hoping to achieve with this program?
To be sure, our carrier-sparing technology is what makes this engine run. To be sure, we'll be leveraging that. This is how we've been able to generate the sort of data that we have, which is frankly unprecedented. When I say that, the most shining example of that has been the VAX-31 data in adults, where we were able to produce data that was so well in excess of what others had seen without degradation in immune responses despite having 31 conjugates.
Yeah, we will be building off that chassis with regard to VAXXL. It will have broader coverage and more conjugates than VAX-31. Beyond that, we're not going to get into further detail just given the competitive nature of this space. The key for us is to recognize that at the moment, VAX-31 is in the mid-90s in terms of coverage in adults. We saw that data earlier today, 92% in infants. That is really going to sweep the board in our view from a coverage perspective. We know with broad vaccination with this class of vaccines, other strains emerge and begin to circulate at higher rates. We want to have readiness in order to be able to provide the most protection possible and also be able to ensure that we can not only build but maintain this franchise.
Okay, excellent. Thanks so much, guys.
Thank you. Next, we'll go to Salim Syed with Mizuho. Please go ahead.
Great. Thanks for the questions, guys. This is a couple from us. On the PD4 data, could you guys clarify, I guess, was this in line with your expectations or a scenario that you thought the PD4 data, even on an interim basis with two-thirds of the patients, could look worse than the PD3 on the IgG GMR? What would be the basis for that, you think, now that we have the data? On the 31 infants data that we're getting mid-2026, just could you clarify for us? I do not know if you mentioned during the call, which serotypes so far have been tweaked? Do you feel like you're tweaking the right ones? Are there additional ones you think you need to tweak or can tweak?
Is there any room for protocol change if you need to do that sort of thing? Thank you.
Yeah. Yeah, yeah. Thanks for the question, Salim. Let me answer the second one first, and maybe my colleagues will remind me if I forget what the first one was. Right now, I have them both in mind. Let's talk about the doses first. Looking at today's data in this key population of infants, we are seeing a repeat that one, five, and 22F even could benefit from a higher dose, certainly one and five more so. Those were the same ones that we had identified in the adult data that could benefit from a higher dose. We have already generated that data going from VAX-24 to VAX-31 with a higher relative dose of those three to all the others.
We have already shown that that is possible. Of course, as it relates to the upcoming VAX-31 data, we had pushed dose altogether there. In this VAX-24 formulation and all the VAX-24 formulations to date, for seventeen of the serotypes, we had not gone above 2.2. Seven of them we had pushed all the way to 4.4. As a reminder, the formulation for VAX-31 that has already read out positively in adults is the same formulation that we have taken into the ongoing infant study that will read out next year. In that study, not only did we increase the dose of one, five and 22F across the board on a relative basis, but we also increased the dose of all of the serotypes at the high dose. All thirty-one are at 3.3 or higher.
There are 28 that are at 3.3, and then three of them that are at 4.4. Yes, the VAX-31 data will contribute meaningful additional dose response data. Collectively, between this VAX-24 phase II study and the VAX-31 phase II study, we're extremely confident that we'll lock down an optimized formulation of either VAX-24 or ideally VAX-31 to advance to phase III. That's the dosing question. To your question about PD4, recognizing we don't have the whole story, I would acknowledge that the magnitude of the immune response going from PD3 to 4 did not exceed as much as we might have expected. The good news is, and we showed this data, we're seeing really clear evidence of memory responses, which is shown in terms of the magnitude of increases on the IgG responses between post-dose three and post-dose four.
That is precisely how the FDA measures and gives you credit for the generation of that memory response. That is good. That memory response is directly correlated with the impact of the protein carrier that it contributes in the primary series and onto the boost. We know our eCRM protein carrier is delivering the goods that are producing a meaningful boost, and that represents the memory response. That said, it is not as big a response on the GMRs that we saw in adults, right? We were so much higher than the relative immune responses for the standard of care vaccine that that was such a phenomenal outcome that exceeded our expectations at that time. I would say that we came back to earth a bit with these responses here.
The difference is, of course, adults are already effectively primed because over the course of their lives, they've been exposed to not only the protein carrier in the form of the natural diphtheria toxin, but also the pneumococcal polysaccharides. The boost or the immune responses that are evidenced in adults are partially a boost response. Whereas in these infants, they are wholly naive. You're building the response in the primary series. Remember, even when we're comparing what sound like comparative doses to standard of care, which the current standard of care vaccine is mostly dosed at 2.2 micrograms, when we talk about our 2.2 microgram dose, that is the same amount of the polysaccharide, but we have about half as much of the carrier protein, which is why we call them carrier-sparing.
Now, we're still getting immune responses that rival theirs, but we haven't outpaced them dramatically the way we had across the board in adults. We are outpacing them materially on quite a number of strains, and fortunately, on the two most prominently circulating strains, but we don't see it across the board the way we have. This is one of the reasons why pushing dose in this infant population has merit. Because the more we push dose, the more carrier protein we'll administer, and that will help us build the boost as we go from PD3 to PD4. This is kind of the inside baseball reason why pushing dose for us in this population is especially reassuring as we think about a phase III formulation.
Okay, got it. Thanks so much, Grant.
Thanks, William. Thank you. Next, we'll go to Umer Raffat with Evercore. Please go ahead.
Hi guys. Thanks for taking my question. I have three here if I may. First, I want to focus on the three out of the four misses that are narrow. Second, I want to focus on the bigger miss, and then there's a third question. On the narrow misses, my sense is obviously the confidence intervals are you can power up the phase III, and that should improve. On the flip side, the threshold for non-inferiority is also going to shrink from minus 15 to minus 10 into phase III. As I process those two, my read is that you don't just need about 800 patients per arm like Prevnar. You may need perhaps up to 1,200 patients per arm to be able to meet those non-inferiority margins. Am I on the right path there, number one?
Second, on the bigger miss, which is 12F, it seems like the threshold you're using for seroconversion is meaningfully different than Prevnar. Prevnar used a 0.69. You guys used a 0.35. As a result, Prevnar itself dropped from 48% up to 80%. How confident are you that your threshold was appropriate and whether you could change that? That, to me, is like the biggest lever for fixing 12F, if I may. Finally, I realized the comparator arm today is Prevnar 20. When I look at the post-dose four data, 9N, which is not covered by Prevnar 20, gets to like 80% seroconversion, meaning it almost reads like a Prevnar 21.
My question is, when we see VAX-31 data for the additional serotypes that are tracked, what are your expectations on how many additional serotypes from the comparator arm end up looking like they're active? Thank you very much.
Thank you, Umer. Yes. Your first question was about effectively near misses versus those that might be wider. I think if you look at the PD3 and PD4 coprimary endpoints, we have the same approach that other sponsors have had, which is in smaller initial phase II dose-finding studies, you apply a different hurdle relative to what you would apply with more information and more sample heading into phase III. I mean, for us, 12F, we'll get to that in a second. That was clearly the one with the widest error bars and the biggest miss on PD3.
That one, there are some extenuating circumstances. It is quite interesting. I mean, if you look at the PD3 data for us in the mid-dose, we had said going into this we would always be looking at a 15-point delta in phase II , as other sponsors had had. If you look at the 10-point delta, which is the formal licensure criteria, we only have one more miss relative to using the more appropriate and relaxed criteria in phase II. I think if you look at this data in that regard, we are pretty close. Certainly, as you suggest, running a larger sample will help manage that and tighten these confidence intervals. I think it is a bit early to say precisely what the numbers will look like. We will do some projections with regard to the anticipated immune responses.
I mean, if you're right and we need to run 1,200 per cohort versus 1,000 per cohort, in light of the fact that this is a multi-billion dollar market opportunity, that would not be intimidating in the slightest. As it relates to PD4, it's kind of a similar story. I think I did mention this earlier. Yes, we have taken the same consistent look at point estimates for a projection of what to anticipate in phase III. We had a number of strains that were right on the line there. Applying the more rigorous ultimate licensure criteria, we have quite a number that are right on the borderline exceeding the 0.5 formal criteria. We're not far off. As we've said, we could see improvement in these, even in this study as we go from interim to final.
Certainly, heading into phase III, we'll have some confidence that we're right there. Of course, we'll be pushing dose on those ones that are close for all the right reasons. You asked about 12F. Yes, it's true. They used a higher threshold of 0.69 in their phase III study. These are all about the assays themselves. Jim, do you want to unpack that for a moment?
Yeah. It was noted previously with the PCV20, which is the only other study or study vaccine that had 12F, that there were some analytical assay issues with assessing 12F. What we note is that the OPA responses that we had were extremely robust and very, very high. From that perspective, it may be that the 12F for IgG is detecting a lot more high affinity antibodies and not detecting low affinity antibodies.
If that is the case and we can demonstrate that, then we can make a justification for altering the 0.35 threshold, as Pfizer had done with their vaccine.
Jim, if I may just push back on that just a little bit. Pfizer used a higher threshold. You guys used a lower threshold on 12F. When you go at your own threshold of 0.35, when you go from dose three to dose four, the responder rate goes up meaningfully. I am almost wondering, maybe your real threshold is 0.25. If that was used, you may not have that large discrepancy versus Prevnar 20. I am almost wondering, even your 0.35 could be too high, judging by how much it rose on 12F into post-dose four.
Sorry if I confused you a little bit on my answer. I am agreeing with you on that.
I think that once we do the assessment and do a little bit more digging with our assay, we may be able to justify exactly what you're suggesting.
Thank you. Yeah. It's a good catch, Umer. We did recover in the post-dose four. The seroconversion rates were right up there. Yeah, the bottom line is the precise threshold for seroconversion, it is generally 0.35. That's been the historical. You're right. When you lock down your phase III assays, you actually qualify them, and there can be some shift, but that's based on the sensitivity of your assay. It's not technically a higher hurdle necessarily. It's just akin to the assay sensitivity.
Thank you guys so much for taking all our questions.
Thank you. Next we'll go to Seamus Fernandez with Guggenheim. Please go ahead.
Hey, thanks for the question.
Just a few quick ones here. In terms of the sort of 0.6 threshold and the number of serotypes that sort of fell below that 0.6 TMR, can you guys help us understand where your expectations were for that in particular as you translate from your adult to PEED data? Again, you made tweaks to the 31 formulation that seemed to work incredibly well and I think is underappreciated. Just wanted to get a better sense of historically that translation has been from PEEDs to adults and has actually worked extremely well. It just looks like there's a little bit more sort of dose ranging opportunity here that may be underappreciated and in fact is already being explored in the pediatric 31 data set. Just wanted to get a better sense of the dialogue there, and I have a couple other questions.
Yeah.
I mean, I think that's fair. I mean, we've shown as we graduated from VAX-24 to VAX-31 that we could take the dose response data and flex on dose to our benefit, right? And so we elected to take the same formulation of VAX-24 into infants knowing we'd have that same opportunity, except we got ahead of it in this case because we'd seen the VAX-31 data in adults showing that based on the 24 data, 15 and 22F could be laggards. We've shown that we can improve that in adults, and now we've already rolled that into the infant program for VAX-31. Yes, what we're basically saying today is we're going to optimize a handful of doses, but we feel like we're likely halfway there with the upcoming VAX-31 data that we'll read out.
We may be all the way there in light of the fact that all the serotypes will go up to the 3.3 microgram dose that we'll read out in infants. We've tried to point this out. The fact that we're seeing less impact on serotypes when we push dose in the context of the mixed dose formulation gives us a lot of confidence that we can push on dose in infants in ways that could even exceed the magnitude of the push that would be warranted in adults. We've got such high immune responses in adults. We'll manage that to optimize. I think we feel good about the levers that are at our disposal.
Just a final question.
Can you guys give us a sense of how you're feeling about the 2-1 dose regimen and maybe the sort of vaccine advance point of discussion relative to Prevnar 20 in Europe in particular, where they sort of seem to prefer a 2-1 regimen? How do you feel either VAX-24 or VAX-31 could potentially shape up against that 2-1 regimen? Thanks.
Yeah. I mean, to your point, the European markets have really adopted the 15-valent vaccine because of the two plus one schedule for which that vaccine was able to pass, whereas the 20-valent vaccine wasn't able to deliver with the two plus one. Yeah, when we looked closely at those responses, the responses after two doses weren't much different than after three doses.
We will be planning to run a two plus one study with either, I mean, either VAX-24 or VAX-31 at the appropriate time. All the more reason why this data in hand for which we will be optimizing dose to deliver the highest immune responses warranted on a serotype-by-serotype basis would set us up to give us the most confidence heading into a two plus one regimen. That is a bit further down the road, Seamus.
Great. Thanks, everybody. Congrats on the processing of all this, a huge amount of data for sure.
Thank you, Seamus.
Thank you. Next we will go to Chris Shibutani with Goldman Sachs. Please go ahead.
Great. Thank you very much. Maybe I could turn to some strategic and bigger picture questions.
Just to confirm, is this the first time that you are disclosing that for phase III plans in infants, you will advance either 24 or 31 as opposed to both? Secondly, talk us through a little bit about the decision to announce XL and how has that been incorporated into your previously provided commentary about financial guidance? And then with the decision to go to XL, again, aiming for the pneumococcal market, how did you weigh advancing another generation of improvement in PCV versus potentially maybe making more advancements or investments for other indications, i.e., advancing further diversification of your pipeline overall?
Yep. Thank you for the questions, Chris. Yeah. To be sure, this is a big moment for the company. We've very much demonstrated that we've got the best-in-class pneumococcal conjugate vaccines in adults. For the first time, we're able to unveil infant data with VAX-24.
We very firmly believe that we are on track to deliver the broadest spectrum vaccine relative to today's standard of care in the form of VAX-24 for all the reasons we've emphasized on this call, our ability to manage dose to put the best profile forward heading into phase III. That is a big moment. We do not have the complete picture. We will have it by the end of this year. By the time we have readiness to advance VAX-24 into phase III, we will be obtaining the VAX-31 infant data. We have talked about balancing the ability to potentially start a bit earlier with phase III with VAX-24.
In light of the additional information that VAX-31's infant study is going to provide, it just becomes obvious to us that we know we have a product, but we want to make sure we advance the product that's going to have the most impact into phase III. We know that could be VAX-24, which is a really luxurious position to be in. Ideally, it will be VAX-31 because we've seen the immune responses not falling off when we add additional conjugates. If we can deliver a vaccine that has 92% coverage relative to today's standard of care, it would be such a huge advance forward, and we would eliminate so much more disease. That would make so much more sense. Knowing we've got a highly competitive vaccine in the form of VAX-24 is decidedly reassuring. It is a big moment for the company.
We're super excited about it. The decision on XL, this is something that you might imagine we've had in the works for some time. For us, we really believe that we have something unique in the form of our carrier-sparing conjugates. We're able to push on not only dose, but the number of conjugates to provide the broadest coverage in ways that others have not been able to follow. For us, we know with a widely utilized 31-valent vaccine like VAX-31, it's going to put additional pressure on circulating strains that haven't circulated because they've been crowded out by these other strains. Once those start being eliminated from circulation with VAX-31, it will create incremental disease that we'll all want to address. We think we've got the technology that can uniquely scale to address that challenge.
I think we feel like it's our obligation to do that. For us, keep in mind, the reason we were able to keep VAX-31 right on the heels of VAX-24 is they share the same 24 conjugates across those two vaccines. Going back in the old days, as soon as we finished perfecting the 24 in VAX-24, we rolled right into the next seven for VAX-31 in order to have that vaccine right on the heels of VAX-24, which was our lead. We're just applying that same logic here as we go from VAX-31 to what we're not going to disclose precisely is the delta between 31 and XL. What's key for us, Chris, is to make sure we have a level of readiness that, as the epidemiology warrants, we'll have an ability to deliver a vaccine that can provide the maximal protection.
Of course, this is a highly competitive space, so we want to stay ahead of the competition, and we think we're uniquely equipped to do that with our technology. As it relates to guidance, let me hand it to Andrew.
Yeah, Chris, with respect to our guidance, our balance sheet reminder just over $3.1 billion at the end of 2024. Yes, the cash runway guidance incorporates the inclusion of XL into our plan. It does not alter the period over which we believe we can fund several milestones, not only across our PCV franchise, but other programs as well over the next few years.
Thank you.
Great. Thanks for the questions.
We'll next go to Jason Gerberry with Bank of America. Please go ahead.
Hey, guys. Thanks for taking my question. A couple for me.
Just when you think about potential dose tweaks for 24 or even potentially 31 in the infant setting, I just wanted to get clarity. Do you think you can, as you flex up, flex down certain doses, you can keep your aggregate protein carrier levels sort of in the ballpark of Prevnar 20 with the 31, VAX-31? My second question, just with VAXXL, just conceptually, I would have thought you would have waited until new serotypes become more problematic of invasive disease and then develop a new vaccine to address that. Is the idea conceptually to just get in front of that with something that maybe has broader coverage even against strains that are epidemiologically irrelevant today? Last question, if I could just squeeze it in. I realize this is outside the scope of today's call, but just it's been weighing on the stock.
Just curious, anything you guys are hearing on the policy front as it pertains to development pathway that may differ from that of recently approved PCVs? Thanks.
Yeah. Thank you, Jason. Yeah. As it relates to protein carrier load, we have substantially less protein on a relative basis with the competition. Given that today's standard of care is dosed at 2.2, they do have one serotype that's dosed at 4.4. We chose not to push dose on that particular serotype and have been rewarded for that choice. So that's 6B. When you look at our data, we've got half as much polysaccharide and perhaps as little as a quarter of the protein carrier, and yet we're still able to generate responses that are right in league with theirs.
Yeah, if you look across the cumulative vaccine, we're still being guarded about disclosing precisely how much of the protein carrier is in each of our conjugates, but we generalize it by saying we have about half as much. Yeah, it means we could double the dose across all the equivalent serotypes and still have a similar amount of protein carrier. The bottom line is I think we've kind of broken that link at some level. I mean, we thought we would see carrier suppression with the VAX-31 formulation in adults going from VAX-24 to VAX-31 precisely because of the incremental protein carrier. We had always said heading into that data, we thought we had plenty of room to maneuver given how much higher the immune responses had been with VAX-24, but we didn't see that fall off.
We not only were able to demonstrate something unprecedented with equating a protein carrier load to the immune responses cumulatively across the vaccine, but we then followed that up here with this dataset today where in the commensurate mixed-dose cohorts across adults and infants, we saw even less degradation in immune responses with incremental protein carrier load. Jason, to us, this is further representation that we really do have something highly unique relative to the tools that the other developers are using. Those tools are the ones that have resulted in the kind of effects that we've seen today, which is a highly protective and efficacious vaccine class. We seem to be preserving that with the same immunogens, but the way we're able to put them together is allowing us to stretch coverage in ways that defy what one might have expected given the historical data.
As it relates to VAXXL, I think conceptually you've got it right. I mean, there are some smoldering serotypes that are out there that together don't accumulate to the point where they create a meaningful impact in incremental coverage over VAX-31. Just a reminder, we're at 95+% in adults, 92+% in infants with VAX-31. There is modest headroom there, but nonetheless, there is some there. Our view is the way we've seen serotype replacement occur historically in this space is in response to strains being effectively taken out of circulation through widespread vaccination. We know there are some that are circulating at modest rates today, and yet those are the ones that will be most likely to begin to circulate more in the future.
Basically, at this stage in the game for us, it's a very modest investment to obtain those serotypes and have conjugates at the ready that we would fold into the final composition of VAXXL. We are staying ahead of the curve effectively, Jason.
Jason, to your question, this is Andrew with respect to kind of the external environment. Look, we fully appreciate kind of the impact on the sector of the noise and the news flow, but I do think it's just important for us all to continue to distinguish between kind of noise and news flow and the political maneuvering that is common in transitions, particularly in this one. That political maneuvering includes personnel changes. I think it's important to separate that from substantive policy change, which I know is your question.
To that specific comment, we have not seen substantive policy change or impact as a result of this kind of noise, news flow, maneuvering. Obviously, we'll continue to watch for that. We'll continue to monitor it. We're highly engaged with folks to be attuned to that, but have not seen that, generally speaking, and particularly as it relates to the vaccines field.
Got it. Thanks, guys.
Our next question comes from Tara Bancroft with TD Cowen. Please go ahead.
Hi. Good morning, and thanks for taking the question. I have kind of a two-part, more forward-looking question. The first is you have good coverage of the higher circulating serotypes, particularly serotype three and four, which I know matters a great deal to ACIP.
Do you think that changes the bar at all on how many you'll be able to miss on in phase III for approval if you were to miss on more than these four, potentially even greater than six? I know this is hypothetical, but Pfizer did have more misses in phase III than in phase II. Just trying to think about it in that context. I guess, in a related way, as it pertains to VAX-31, would you say, based on these data, at this point in time, are you more or less likely to choose going forward with VAX-31 as opposed to 24? What would be the minimum result that you need to see to decide to go with that one over 24? Thanks.
Yeah. Yeah. Thanks, Tara.
I would suggest that it's not clear that in the case of Prevnar 20, they have more misses in phase III than they did on phase II. I don't think that we really know that because we've combed that data. I don't think that's an expectation that people. I mean, the way this class works is the totality of your vaccines offering is what is taken into key consideration. In the historical realm of pneumococcal conjugate vaccines, there have been as many as six misses in a vaccine, four misses in a vaccine, singular misses. In every case, the corroborating supportive evidence has warranted the inclusion of that serotype. There's plenty of evidence to suggest if there were some that fell short of the threshold, as long as there's the same sort of corroborating evidence that would support it, they would be included.
To be sure, to your point, one of the lenses is to the extent that strain is relevant based on what disease it's actually causing and how long, perhaps, ago has it not been causing disease. Yes, to have knocked it out of the park on three and 19F, we couldn't have handpicked two better to do so much better on. For those that we have seen lag, we probably couldn't have handpicked ones better than we see in this data. The object heading into phase III, like I said earlier in my prepared remarks, will be perfection. We're going to try to deliver on all of the included serotypes. Based on the dose data, we think we have an opportunity to do that.
Of course, at the end of the day, we will prioritize to make sure all the strains that are circulating will be addressed because they're more important. Yeah, heading into it, we're going to do everything we can to have as broadly a protective and as convincing a package coming out of phase III to create a vaccine that will be most impactful to people and obviously most impactful for our business.
Great. Thanks.
Thank you. There are no further questions at this time. I will turn the floor back over to Grant Pickering for any additional or closing remarks.
Thank you, Margo. Thank you, guys, very much for dialing in quite early. We're really excited about these results, looking forward to getting the balance of this data as we head into the end of the year.
Very excited, obviously, as we continue to refine the game plan moving forward into phase III for not only VAX-31 in adults, but either VAX-24 or VAX-31 in infants. Big day for the company. Thank you, guys, for your interest and your support, and have a great week.
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