Vaxcyte, Inc. (PCVX) Earnings Call Transcript & Summary

Good morning. My name is Ashley, and I'll be your conference operator today. At this time, I would like to welcome everyone to the Vaxcyte conference call to discuss the VAX-24 Phase II adult program, including the Phase II study results in adults aged 65 and older. [Operator Instructions] I would now like to turn the call over to Andrew Guggenhime, Chief Financial Officer of Vaxcyte. Please go ahead, sir.

Thank you, Ashley, and good morning, everyone. I'd like to welcome you to Vaxcyte conference call to discuss data from our Phase II study evaluating the safety, tolerability and immunogenicity of VAX-24, the company's investigational 24-valent pneumococcal conjugate vaccine in healthy adults aged 65 and older. Additionally, we will be discussing full 6-month safety data from the adult Phase I/II and Phase II study as well as the prespecified pooled immunogenicity analyses of data from both adult Phase II studies. I'm joined today by our Chief Executive Officer, Grant Pickering; and our Chief Operating Officer, Jim Wassil. Earlier this morning, we issued a news release announcing these results. Copies of this and our other news releases, latest corporate presentation and SEC filings can be found in the Investors & 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 a discussion of the risks and uncertainties associated with these statements, please see our press release issued today as well as the most recent filings with the SEC, including the risk factors set forth in our Form 10-K for the year ended December 31, 2022 and any subsequent reports filed with the SEC. With that, I'll turn the call over to Grant Pickering. Grant?

Thank you, Andrew. On behalf of the entire Vaxcyte team, it gives me great satisfaction to announce that VAX-24, our breakthrough designated vaccine, has delivered another outstanding Phase II result in adults. We believe the positive results from the Phase II study in adults aged 65 and older confirmed the clinical potential of VAX-24 in the adult population delivering broader coverage and better average immune responses relative to today's standard of care. On Slide 3, we've laid out the agenda for today's call, which will begin with me describing the highlights of VAX-24's exciting results, along with the ensuing milestones for our PCV franchise, including the initiation of Phase III development in adults for VAX-24. I will then briefly reflect on the opportunity at hand before Jim takes you through the detailed results from the 65 and up study. The results of the prespecified pooled immunogenicity data analyses from both Phase II adult studies that we believe puts us in a great position to move into Phase III. And finally, the full 6-month safety data from our adult program. I'll then pick back up with some concluding remarks and anticipated next steps. Moving on to Slide 5, where we highlight today's data results beginning with the 65 and older study. VAX-24 has confirmed in this older population the robust responses evidenced in the prior study in 50- to 64-year-olds, further substantiating its potential to become a best-in-class PCV. From a safety perspective, we're releasing the results of the full 6-month safety data from both adult studies that demonstrate safety and tolerability results for VAX-24 similar to Prevnar 20 at all doses studied. When it comes to immunogenicity from the 65 and up study, VAX-24 hit the target responses for all 24 serotypes at the 2.2 mcg dose, once again demonstrating the potential to expand coverage and improve immunogenicity over PCV20. Despite the small sample size, VAX-24 met the non-inferiority criteria for 18 of 20 serotypes in common with PCV20 and met the superiority criteria for all 4 additional serotypes in VAX-24. In this older age group, at the 2.2 mcg dose, VAX-24 showed overall improvement in immune responses versus PCV20 relative to already strong results from last fall's Phase II results in adults 50 to 64 years of age. At this VAX-24 dose, we also saw higher GMRs for 16 of the 20 serotypes in common with PCV20. These Phase II results have VAX-24 extremely well positioned for an upcoming Phase III pivotal study in adults, having confirmed the 2.2 mcg dose is optimal for advancement. We have also generated the prespecified pooled immunogenicity data from both Phase II adult studies, looking at the same 50 and up or 60 and up age ranges from precedent Phase III PCV programs. Either approach yields OPA responses for VAX-24 that not only exceed the non-inferiority criteria for all 24 serotypes in VAX-24, but also demonstrate the potential to show superiority across a number of serotypes. Armed with this data, we plan to meet with regulators and anticipate a Phase III pivotal study, enrolling approximately 750 subjects per arm. Our PCV franchise is poised to deliver on an array of milestones in the near term. Beginning with the VAX-24 end of Phase II meeting with the FDA in the second half of this year leading to the Phase III pivotal immunogenicity data that we expect to read out in 2025. Having initiated the Phase II study in infants last quarter, we are marching toward receipt of the top line immunogenicity data from the primary 3-dose series by 2025. Thus, we believe this potential best-in-class 24-valent PCV is on track to deliver best-in-class coverage to protect our most vulnerable adult and infant populations. Last but not least, we continue to track to the VAX-31 IND filing for adults in the second half of this year that we anticipate will deliver top line immunogenicity data next year. Moving on to Slide 6. We remind you that invasive pneumococcal disease continues to be a major cause of global morbidity and mortality despite widespread vaccination and expenditures of over $7 billion per year to protect our populous from the threat of pneumococcal bacteria. On Slide 7, we emphasize the rationale for VAX-24's design and justification for which received the breakthrough designation from the FDA, which revolves around its potential to address an additional 10% to 28% of circulating invasive pneumococcal disease. This magnitude of incremental protection has historically resulted in a dominant position for the more broadly protected PCVs, which bodes well for the potential of VAX-24. In addition, VAX-24 promises to deliver a PCV that fully eclipses the spectrum of coverage of the first-generation polysaccharide sugar-only vaccine, Pneumovax 23, that has occupied a recommended slot for adult vaccination for nearly 15 years. Given Pneumovax's incremental coverage over and above 8 PCV to date, its continued usage negates the opportunity to prime and boost adults with the PCV, which inhibits the ability to begin vaccinating adults routinely at younger ages such as age 50. The opportunity to fully eclipse the coverage of Pneumovax 23 was a central reason why we pushed the 24 serotypes with VAX-24, which we believe affords us a significant [indiscernible]. On Slide 8, we remind you all what makes our PCV franchise unique relative to conventional PCVs. Our proprietary cell-free protein synthesis platform allows us to effectively purpose conventional immunogens but do so in a manner that avoids the off-target responses that diminish the protective immune responses and produce carrier -- and it allows us to produce carrier-sparing conjugates that have demonstrated in the clinic the ability to allow for broader coverage without sacrificing immunogenicity. On Slide 9, we reflect on the magnitude of this opportunity, which is anticipated to grow from today's already massive $7 billion market to upwards of $13 billion per year, driven primarily by growth in the adult market as the opportunity to prime boost adults is expected to catalyze universal vaccination in younger adults. With that summary and backdrop, let me hand it to Jim to walk you through the details of today's tremendous results for VAX-24, beginning with the 65-plus data. Jim?

Thanks, Grant. I'm excited to review with you the results of the VAX-24 Phase II clinical study in older -- adults 65 years of age and older. In the next few slides, I plan to review the disposition and demographics of the study, safety and tolerability data, immunogenicity data, including the prespecified pooled immunogenicity analyses from both Phase II adult studies. And finally, I'll also cover the full 6 months safety data from both adult Phase II studies. But first, I'd like to reorient you as to the overall study design for this VAX-24 study in adults 65 years of age and older. This study is a randomized, observer-blind, dose-finding, controlled study to evaluate safety, tolerability and immunogenicity of VAX-24 versus the standard of care in adults aged 65 years of age and older. Like the previous study in the 50- to 64-year-olds, all participants were screened and randomized into 4 separate arms. On day 1, all subjects received the dose of either the comparative vaccine, which in the study was PCV20, which is currently considered as a standard-of-care in adults in the U.S. or 1 of 3 different doses of our VAX-24 investigational products. These included a low, middle and mixed dose, which I'll define shortly. So local and systemic AEs were monitored for 7 days and on day 29, serology was taken and immunogenicity was performed on the samples. Subjects were also assessed for safety for 6 months. That said, this study includes a low, middle and mixed dose with the same dose strength as the previous study in the 50- to 64-year-olds. The middle dose is similar to PCV20 containing 2.2 mcg of polysaccharide for each serotype, while the low dose had half or 1.1 micrograms of polysaccharide for serotypes. The mixed dose had 2.2 mcg of polysaccharide serotype, except for 7 serotypes that had 4.4 mcg. This was done for 2 reasons. First, these incremental serotypes were chosen as we wanted to ensure we met the non-inferiority margin for the serotypes that were more prevalent and therefore, more epidemiologically significant. But second, we chose 7 incremental serotypes deliberately to double the amount of polysaccharide so that the mixed dose could approximate the VAX-31 vaccine formulation as it contains the same amount of polysaccharide and a similar amount of carrier protein as VAX-31 and we could get an early read on how our VAX-31 clinical studies may play out. In terms of the safety statement -- in terms of safety studies outcomes for this study, we measured solicited local and systemic reactions through day 7, unsolicited adverse events and serious adverse events or SAE through day 29 as well as SAE's new onset of chronic illnesses or NOC's and medically extended adverse events for MAEs through the 6-month safety follow-up period. In terms of immunogenicity, the key measure for this study is the OPA or opsonophagocytic activity assay geometric mean titers. OPA measures neutralizing the antibody titers and the geometric mean ratios are important in determining whether we are able to meet the historical non-inferiority criteria. In addition to ensure consistency in the outcome measures, we collected other important immunological outcomes like IgG geometric mean concentrations, percent achieving a fourfold rise to reverse cumulative distribution curves. I'll now review the disposition and demographics of the study. There were a total of 207 subjects enrolled in the study. They were distributed across 4 study arms with a minimum number of subjects of about 3.4% and discontinued. We also added a similar percentage of subjects who were included in the immunogenicity study, as in the previous VAX-24 Phase II study in the 50- to 64-year-olds, with 91% of those enrolled ultimately included in the immunogenicity evaluable population. Turning to demographics. The median age in the study was between 66 and 67 years of age across cohorts, which is typically a study running this age and population. And as with other vaccine studies in the age group, there was a higher proportion of females who enrolled in the study. Importantly, though, this proportion was maintained across all study arms. Same is true for the other parameters, including age, race, height, weight and BMI. And now I'll review the safety and tolerability results from the VAX-24 Phase II study. Local solicited adverse events of VAX-24 confirmed the prior adult study results in the VAX-24 clinical study that was done in the 18- to 64-year-olds. The incidence of redness, swelling and pain were similar to the comparator, which was PCV20 and which has a well-established safety profile. Further, as you can see, there was no evidence of any dose-dependent increase of adverse events. And in terms of severity, the majority were mild and moderate resolving within the first 24 to 48 hours post vaccination. The profile of solicited systemic events was similar to the solicited local events. There was no fever reported in this age in any of the subjects and like the local solicited adverse events -- the solicited systemic adverse events for VAX-24 confirmed the prior study results were similarly to PCV20 and no evidence of any dose dependent increase of adverse events and the majority of being mild and moderate resolving in the first 24 to 48 hours. And so now I'd like to share with you the immunogenicity data from the study. The first included here are the precedent regulatory criterias that have been used to evaluate other PCV and pivotal Phase III clinical studies. The 2 that are important to note as they are apparent on the upcoming immunogenicity evaluation slides are: one, the non-inferiority criteria for the 20 serotypes common between VAX-24 and VAX-31 PCV20 is that the lower bound of the 2-sided 95% confidence interval of the OPA geometric mean titer ratio is greater than 0.5. Or said another way, the lower bound of the CI or confidence interval has to be greater than 50% or half of the GMR comparing VAX-24 and PCV20. The second is for the 4 incremental serotypes in VAX-24. The lower bound of the difference in the percent of subjects who achieved a fourfold rise needs to be greater than 10%. So here is the data from the 2.2 mcg dose, which is our lead candidate we plan to move in advance of the Phase III. And this shows on the left side, the results of the common 20 serotypes in PCV20. And then on the right is the percent difference from those achieving a fourfold rise in OPA antibody titers for the 4 incremental serotypes. So on the left, the forced plot shows the OPA geometric mean ratios for the 20 common serotypes with PCV20. And now just before I go into the data, I just want to inform you what this means in that one, the gray area of the plot represents the area where the non-inferiority criteria is not met when the lower bound of the 95% confidence interval process the 0.5% threshold. The other important point on this slide is the line that's drawn at the GMR of 1.0. This line represents when the OPA response to VAX-24 is identical to PCV20. So any point estimates to the right of this line would mean that VAX-24 response is higher than PCV20. And you'll notice now that 16 of the 20 common serotypes had higher immune responses for VAX-24 than PCV20. And of the remaining 4, the lowest point estimate is above our targeted response of 0.71. What's also worthy to highlight here is that with the smaller sample size as expected, the 95% confidence interval significantly increased. And even with these large confidence intervals, we were able to meet the non-inferiority criteria for 18 of the 20 serotypes. This was because, overall, there was about a 30% higher OPA of the GMR for VAX-24 on average compared with PCV20. And as Grant highlighted, this means the vaccinate work showed overall improvement in immune responses versus PCV20 relative to our previous results from the Phase II in adult age 50 to 64. Now in terms of the 4 incremental serotypes, as you can see, all had robust fourfold rise in OPA titers with all well above the historical regulatory thresholds for superiority. And like the data in the other serotypes, the overall comparative results for the incremental core were improved in the 65-plus population compared with those in the 50- to 64-year-olds. Data is now shown for each of the 3 doses, and this was consistent also with the previous study in adults 50 to 64 years of age. And like before, there was a dose response that was evident within the range of the doses tested. Results from the low dose indicated a profile that we felt we could advance into Phase III. However, as before, immunogenicity results improved between the 1.1 and 2.2 mcg formulation. As a result, the 2.2 mcg dose has become the leading candidate for advancement into Phase III. The mixed dose had a similar profile in the study as it did in the previous adult study. And like the 2.2 mcg dose, GMR is generally improved compared to those from the previous 50- to 64-year-old study. And for the few serotypes that were a bit more susceptible to carrier suppression, the priority taken meds to improve the immunogenicity as we move forward with our VAX-31 program. Here, as shown, the absolute OPA geometric mean titers for the 3 VAX-24 investigational doses as well as PCV20. Now I won't spend a lot of time on this slide as we've already reviewed the OPA geometric mean ratios. But I do want to highlight that as expected, compared to the previous Phase II study results, the absolute OPA GMTs did actually decrease slightly, which is typical as we immunosenescent in older population. However, as noted in the relative OPA GMRs in the previous slide, the OPA GMT is more acutely declined in the PCV20 arm than for VAX-24 resulting in improved geometric mean ratios overall in this population. And now I'll show you the IgG geometric mean concentrations. The IgG geometric mean concentration for the investigational VAX-24 dose compared to PCV20 did reinforce the previous OPA geometric mean titer results. In terms of the VAX-24 IgG geometric mean concentrations, they generally mirrored the OPA GMTs in terms of relative response compared to PCV20, but I think it is worthy to note that 18 of the IgG GMC's for the 2.2 mcg dose were numerically higher out of the 20 when compared to PCV20. Now I'd like to go into and review the prespecified pooled immunogenicity analyses for both VAX-24 Phase II adult studies. So before showing the prespecified pooled immunogenicity analyses, I just want to reorient you to the plots for the 2 Phase II adult studies shown here separately. On the left, you can see the results from the adult study age 50 to 64. And due to the large sample size, confidence intervals were tighter. Also, as you may recall, we met the non-inferiority criteria for all 20 common serotypes with 16 over responses being numerically higher than PCV20. So the right is the data that we just reviewed in those aged 65 and above, and similar to the 50- to 64-year-old age group, 16 OPA responses were numerically higher and even with much wider conference intervals, as I highlighted before, we achieved noninferiority of 18 of the 20 serotypes. And finally, as previously noted, GMR's overall generally improved even further compared with PCV20 in the age group of the 65 and above compared with the 50- to 64-year olds. And now for the prespecified pooled analyses. Shown here are the prespecified pool analyses for the GMRs comparing VAX-24's 2.2 mcg dose to PCV20 in both adults 50 and above as well as 60 and above. In both groups of large sample sizes -- with larger sample sizes, I might add, all met the non-inferiority criteria with the majority of immune responses higher for VAX-24 than PCV20 in both data sets. As we noted in our press release, 4 serotypes in the 50-plus pooled population and 3 in the 60-plus group reached statistical significance. Only 3-point estimates in both data sets were less than 1.0, with the lowest point estimates being 0.87 and 0.81 in the 50-plus and 60-plus data sets respectively. Overall, these results give us confidence to move forward in either age group in a Phase III pivotal study with the 2.2 mcg dose, which we were expecting to have even higher sample sizes in our Phase III. And now finally, before concluding, I'd like to review the full 6-month safety and tolerability data from both VAX-24 Phase II adult studies. Here the 6-month safety data is shown from VAX-24 Phase II study in adults aged 65 years of age and older. And as you can see, they were consistent across cohorts for each category including treatment emergent ever, the MAEs, NOCs and SAE as well as similar to PCV20. No safety signals were evident including the clustering events in any of the arms that could be of concern. There was 1 death in the study in a 66-year-old white male with preexisting cardiac risk factors, including severe obesity and hypertension. The participant suffered a sudden cardiac death 6 months post vaccination and was determined by the principal investigator to be not related to the study due to the history of the hypertensive cardiovascular risk disease. There were no NOCs, SAEs or death that were deemed by the study investigator to be related in this study to be -- sorry, there is no NOCs, SAEs investigating to be related by study investigators in the study, including in the PCV20 arms. Now included here is the updated 6-month safety data from VAX-24 Phase I/II study in adults 18 to 64 years old. Similar to the previous study, results were consistent across cohorts for the TDAEs, MAEs, NOCs and SAEs that were similar to PCV20. There were no safety signals as evidenced, including no clustering of events. And there were no NOCs, SAEs, MAEs or deaths that were deemed by the study investigator to be related to a study, including those in the PCV20 arms. And finally, you can see on this last slide here are the full 6-month safety data for both adult studies, which overall show a similar number of events across cohorts, including PCV20 and indicate a safety profile that is sufficient to move forward into Phase III clinical studies. With that now, I'd like to turn it back over to Grant to cover program conclusions and [indiscernible].

Thanks, Jim. As we move to summarize and conclude today's prepared remarks on Slide 35, VAX-24 met all the key objectives in its 1,000 subject Phase II adult program, supporting its best-in-class potential and further demonstrating the promise of our carrier-sparing conjugates and cell-free platform. The full 6-month data shows safety and tolerability similar to PCV20 with no meaningful differences observed across the cohorts. The 2.2 mcg dose distinguished itself having achieved its target immune responses for all 24 serotypes in each of its Phase II studies and met the non-inferiority criteria for all 24 serotypes, in the prespecified pooled analyses. This data set positions VAX-24 to advance to a Phase III pivotal study that is expected to utilize the same basic design as the already completed Phase II studies and to enroll approximately 750 subjects per arm. Subject to FDA review and approval of our program, this potential tripling of the number of subjects relative to our 2.2 mcg Phase II sample should substantially increase the chances of delivering noninferior immune responses and may, in some cases, produce statistically superior immune responses relative to PCV20. In Phase III, we expect to employ similar validated surged immune endpoints that have served as the basis for multiple precedent PCV programs that have advanced from Phase II to Phase III. In our case, we have the benefit of choice with strong data using either precedent age range of 50-plus or 60-plus and the benefit of materially higher average immune responses relative to PCV20. This puts Vaxcyte in a position to potentially set the new bar with VAX-24 that if achieved, would put VAX-24 in a strong competitive position in this coveted market. Looking ahead on Slide 36, I want to highlight the anticipated milestones for our PCV franchise through 2025, beginning with the adult indication for VAX-24. We expect to conduct the end of Phase II meeting with the FDA to finalize the Phase III program in the second half of this year. That will tee us up to deliver the top line safety, tolerability and immunogenicity data from the Phase III pivotal study expected in 2025. For the infant indication, we expect to announce the top line safety and immunogenicity data from the first co-primary endpoint from the ongoing Phase II study by 2025. Lastly, VAX-31 is on track for a second half 2023 IND filing as our strategy to deliver a singular PCV that should not only cover upwards of 95% of today's circulating strains in adults, but should also maintain coverage of the historically circulating strains that we believe will rebound if coverage is discontinued. We expect to see the top line immunogenicity results of the VAX-31 Phase I/II study in adults next year in 2024. Thank you all for your attention. And with that, let's move on to Q&A. Ashley?

[Operator Instructions] And our first question is coming from Jonathan Miller with Evercore ISI.

Congrats on the data, it looks very strong. I wanted to ask about the Phase III design. Obviously, you say you can move forward need a 50-plus or 60-plus patients with the study anticipated to start relatively soon. Can you talk about what the pushes and pulls are on the study design at this point? And when would you communicate that to us?

Yes, Jon, thank you for the comments and the question. As you can see from the data, we've got options. The movement of the ACIP to show receptivity to vaccination universally for adults starting at age 50 certainly skews our interest toward proposing the 50-plus population to regulators. So that is something that we'll discuss with them at that meeting. I think that's the key topic. But Jim, any other pushes and pulls that come to your mind?

No. I mean we just got the data and myself and Jakub Simon, our CMO, will sit down with that as addition to do an analysis to try and optimize to make sure that we have an optimal chance of meeting the non-inferiority criteria first and foremost. But as you can see, some of the serotypes were actually much higher than 1.0 and there is expressing that Merck was able to get statistical superior in the label. So we'll actually be evaluating whether or not we can also make that plain for several serotypes as well. And so we'll look at the study design, and I think we're in a good position where we're looking at the trying to power study superiority versus noninferiority.

Yes, I think you nailed it. It's really for us, uncharted territory relative to the norm, the conventional size of these Phase III studies, Jon, have really been driven by trying to hit that non-inferiority hurdle, which has driven the numbers up to the 750 to 1,000 plus per cohort. You can see from our data, we're hitting those sort of outcomes with much smaller sample size. So when we talk about 750 per arm, that's really to drive the statistical significant outcomes that we think are possible. But again, as Jim said, that's something we'll be reviewing with our statisticians and discussing with the regulators.

Great. One follow-up. When I look at the earlier data from the younger adults. One thing that popped out of me is that serotypes 15B and 22F, which are the 2 that you missed in the older adults aren't necessarily the worst at the younger adults cutoff. So what sort of variability should we expect between serotypes as we translate between age groups? And do you have any expectation for -- do you think you have a good sense of what serotypes are going to be the challenging ones in the Phase III trial?

Yes. I think looking at this, the first I'd say is the small sample size in the 65-plus created a bit of noise with some of the serotypes. So I don't know how much the 22F and 15B are truly low performance that's just variability of the data. When we look at things like pre-existing titers in that population, things like that can affect the GMR significantly. So I think that based on the data, and you can see the 50-plus pooled data and that we're going to be going into both the younger adult population being relative 50 to 64 and 65 plus. When you look at that pooled data, we're in really good shape to make sure that we meet the non-inferiority criteria for all of the serotypes.

And we'll take our next question from Seamus Fernandez with Guggenheim.

So congrats on the data, looks really great. In terms of the -- I guess, some of the follow-up opportunities, I think everybody is very interested in the opportunity for 31. Jim, I was just hoping you could comment on your thoughts on the opportunity for 31 to show a similar type profile to this as we move forward. And if there are serotypes that you're focused on as you mentioned that the team is working on improving the immunogenicity. [indiscernible].

Yes. No, great question. I think the intent of that mixed dose is to see where we have a bit more susceptibility to carry suppression and I was pleased with the fact that there was consistent responses between the 50 to 64 and 65-plus and that the same serotypes showed a bit more sensitivity. So that consistency allows us to focus on a few serotypes. We won't share which ones they are, but I think everyone can really look at the data set and can pretty much guess. But we do have a number of mechanisms to help improve immunogenicity. You can see we do have a dose-dependent response, whereas we increased the polysaccharide content, we actually improved the immunogenicity for those given serotypes. So that is one option, but we have other options as well, and the team is hard at work making sure that when we go in the VAX-31 that we try and optimize the success. That said, I think the profile as it is and historically, the fact that you don't have to hit noninferiority on every single serotype being able to expand coverage to 31 strains and go about 90-plus percent coverage, even if we did end up missing on 1, 2 or 3, I think it's an approvable product profile.

Great. And then just as a follow-up question. From a manufacturing perspective and timing of being able to start the full Phase III with commercial-ready product and then also with the execution of the clinical study, timing of a launch, just hoping Andrew or Grant, if you guys could give us a sense of how far along we are in that process. And in terms of commercial scale-up to then drive to a potential pediatric opportunity. I just love to get an update there.

Yes. Thanks, Seamus. We've been very confident with this program. And so we've been manufacturing at risk pretty much every step along the way. And so we've been hard at work producing the material to allow us to initiate the Phase III study, Seamus. So for us, we'll find out the timing associated with the meeting with the FDA. And I think at that time, we'll be able to guide more specifically to when we'd anticipate initiating the Phase III study.

Okay. Great. And then just as a final question, maybe back to Jim. As you look at this data, your enthusiasm to kind of deliver a 3 dose -- a potential 3-dose regimen in the pediatric setting. And then I'll jump back in the queue.

Yes. I think when you look at it so far, our theory all along was that this site-specific conjugation would allow for a potentiation of the carrier protein as well as obviously using less carrier protein leading to an enhancement or at least a lack of carrier suppression. I think these results continue to confirm that our premise, I think, has weight and bearing. And I think it will be translatable to the infant population as well.

We will take our next question from Louise Chen with Cantor.

This is Cari on for Louise from Cantor. Congrats on the data. First question is, what gives you the confidence that you can still get preferential recommendation for VAX-24? And our second question is, how does the data percentage today impact your commercialization strategy for VAX-24?

Yes. Thanks for that question. Well, it's really looking at precedent and the most recent ACIP determination effectively granted a preferred recommendation to Prevnar 20 over VAX in advance with regard to the catch-up population. They're now suggesting that adults receive a subsequent vaccination if they were previously vaccinated with a lesser valent PCV. And so that was specifically granted for Prevnar 20 over that in advance. So that sort of increment of coverage for -- between those 2 products is similar to the sort of advantage that we believe we'll have with VAX-24 relative to Prevnar 20. So I think that's part of the argument for us but then we have this incremental contribution, which is the ability to eclipse that first-generation polysaccharide sugar-only vaccine Pneumovax, which has truly been applying the ointment since pneumococcal conjugate vaccines have been recommended in adults. And so removing that vaccine from the regimen will open up an opportunity to prime and boost adults, which is really what's preventing the age de-escalation down to 50 and above. So we think that argument will be solved with the 24-valent pneumococcal conjugate vaccine that removes any incremental benefit of continued use of Pneumovax 23. So it's really a combination of the incremental coverage and that ability to simplify the regimen that we believe puts VAX-24 in a position to justify a potential preferred recommendation. And maybe just to add, the market has spoken historically that even without a preferred recommendation, the broader spectrum vaccine is what becomes the dominant vaccine in the marketplace. So obviously, with the preferred recommendation, that would be the strongest position we could find ourselves in. But with a broader spectrum vaccine and those arguments I just went through, I think we'll be extremely well positioned one way or the other.

Got it. And on our second question about the commercialization. Are you -- would you be thinking about partnering? Or would you be thinking about launching the drug on your own after today's data?

Yes. So we've been working at this for quite some time to ensure that the company has a go-to-market strategy so as to control and maximize the value of VAX-24 and our PCV franchise. So this data only strengthens our resolve and better positions the company to believe in its best-in-class potential for VAX-24. So given the commercial lift in this market for adults with the appropriate backing from the ACIP, I think we can definitely rise to the challenge of delivering this vaccine in ways that will maximize its potential initially in the U.S. and then as we expand to other regions and other indications, we'll continue to scale that operational machinery. But yes, that is the path that we are on, and we believe that we can deliver on that.

And we will take our next question from Roger Song with Jefferies.

Great. Congrats for this impressive data -- another standard data set for VAX-24. A few quick ones from us. The first one is understanding the focus is on estimates for the GMRs and then you see a pretty wide confidence seems well. Just curious, is that wide confidence in term mostly driven by the standardization in terms of the variability from younger to older? Or it's mostly driven by smaller end?

Thanks, Roger. I appreciate the congratulations. And yes, I mean, what's been observed in similar studies going from the 50 to 64 to 65 plus studies is that there is greater variability in the older population because immunosenescence doesn't arrive at exactly the same rate in older adults. So definitely, there's been historically greater variability in that older population. So I think it's a little hard to tease out precisely, which of those we attribute to. Jim, do you have a perspective?

No, I think it's hard to tease out. But what we did see in the data, even though you do have wider confidence intervals, overall, the GMRs were higher in the older population such that this teases in, even though there's variability in the rates that adult immunosenescence it appears on the totality in this older population, the OPAs declined a bit more rapidly than ours. And so as a result, we improved our overall GMRs. So I would take that away from the study as well. But yes, I don't think we could exactly calculate how much of that was the smaller end versus how much of that was inherent variability in an older population.

But certainly, we're now armed, Roger, with our own data to be able to project the sort of treatment effect, if you will, that we can expect to see in Phase III. And you hit -- it's really those GMRs that we are focused on, and we wanted to see GMRs that were at or above 0.65 at the minimum. And we saw that now in both of the Phase II studies that we run. And as we think about a considerably larger Phase III study, as we said, that could triple the total exposed population to the 2.2 mcg dose that we've seen today will have a substantial tightening of those confidence intervals, which is what gives us the confidence that even at the lowest end of the performers, we think we're in a position to demonstrate data that would exceed the non-inferiority threshold.

Excellent. A quick follow-up. I remember the younger adult data, you see overall like a 20% greater GMR or GMT compared to Prevnar 20. Do you have a rough number? If I missed -- maybe I missed that earlier, do you have a rough number for the GMT increase in this older population compared to Prevnar 20?

Yes. Thanks, Roger. I think Jim did let it slip in the presentation, but we definitely don't want you people to miss that. And we did include a table this time that shows the explicit GMRs and the confidence intervals to complement the forced plots. So yes, what we've said is, if you look back historically at other PCV studies comparing broader spectrum versus lesser broad-spectrum vaccines, generally, you see about a 20% reduction in common serotype responses for the broader-spectrum vaccine. Whereas last fall, the 50- to 64-year-old data we showed on average a 20% improvement for the common serotypes relative to Prevnar 20. In this 65 and older study that exceeded the data from last fall. So whereas we saw a 20% improvement in the prior Phase II study in this 65 and up study, the average improvement was over 30%. So yes, sorry, we missed that, but it was 31% to be precise.

Excellent. Okay. So one last question, understanding with this pretty robust data, you potentially will power your Phase III to maybe kind of reaching the superiority. And then you mentioned you anticipate a Phase III sample size 750. Just curious that 750 is powered for how many and which serotype for the superiority? Is that possible you have the flexibility increase to power more?

Yes. To some extent, and I say this in a good way, we're in uncharted territory with regard to the possibility of being able to show across an array of serotypes statistically superior immune responses. There's 1 precedent, as Jim had referred to with a prior program that had superior immune responses, I think, on 1 serotype. But we have this singular precedent where a 1.2x GMR was the hurdle for superiority. So we won't be able to comment with precision on this one until we actually work that out with regulators. But we've kind of been targeting something around that sort of magnitude as we have guided to the 750 subject per arm. But it will actually be an outcome associated with this conversation that's upcoming with the regulators.

And we'll take our next question from David Risinger with SVB Securities.

Yes. And let me add my congrats to you, Grant, and your team on the phenomenal data. So a number of my questions have been asked. I guess I was just hoping for some additional perspective on VAX-31. So obviously, that will include 7 additional serotypes of coverage. And it would just be great to have you talk a little bit about how this data informs your confidence in VAX-31 and some of the key considerations look ahead to those initial results in [indiscernible].

David, you kind of broke up at the end. You said the initial results and then we lost you.

Sorry. And [indiscernible].

We're losing you, David. Why don't we -- why don't I respond to the first part. First of all, thank you for the congratulations. And your question about VAX-31, I think the first thing to point out is that VAX-24 has a best-in-class profile and is the fastest path to delivering a broader spectrum pneumococcal conjugate vaccine that we think can create a really substantial presence for Vaxcyte. And that VAX-24 data, you can look at this pooled analyses to give us, I think, the best leading indicator of what we could expect to come out of a potential pivotal Phase III study, has this opportunity to set a new bar relative to the competition. And that new bar, we think, will serve as substantial defense relative to other potential competitors. Then VAX-31 has an opportunity to do better yet. And so it's those incremental 7 strains, while preserving coverage over historically circulating strains, that we think has an opportunity to create an optimal vaccine to provide the broadest coverage, the fastest to this adult and exposed population. So if that incremental coverage that we see somewhat modeled from the mixed dose cohort that we've run across 2 successive Phase II studies. And as we pointed out, we're effectively showing a similar amount of immunogen and protein carrier to the immune system and the responses we continue to see across the mixed dose cohort are decidedly reassuring to give us an indication of what we could expect across an incremental amount of material that we'd expect with the 2.2 mcg dose across the board for VAX-31. So yes, this is further indication that we're on track with what we've affectionately referred to as a category killer vaccine with VAX-31. Hopefully, that answered your first question. We still didn't get the second part of your question. So David, if you're still there, please repeat that.

Yes. [indiscernible].

Okay. It sounds like we covered it. Sorry, we keep losing you.

Yes. Ashley, we'll take out of the next question, if we can. Thank you. David, if you can get a better line and want to come back, let us know.

[Operator Instructions] We'll take our next question from Jason Gerberry with Bank of America.

And also my congrats on the data update as well. So first off, just a commentary about pushing and expanding to 50-plus, how you think population in a Phase III might skew versus traditional adult studies? Is the aim going into this phase in the Phase II meeting just to get an FDA clearance on a greater mix of younger adults that I think in the past, you've talked about maybe 1/3 of patients in the Phase III falling in this greater than 65 age subgroup. So maybe you can go lower. Just sort of curious about some of those dynamics. And then my follow-up, I'm curious, do you look at the pooled analysis for the mixed dose, I think what 5 serotypes shared strains fell outside the NI criteria. I think 2 fell outside of that criteria in the other Phase II that you reported last year. So I believe you said that this has the same amount of protein carrier. It's mixed dose as the VAX-24. So just trying to think through that, the relevance of that analysis ultimately. And maybe just a question of where you apply the 4.4 mcg dose on which serotypes strain the 31.

Yes. Thank you, Jason. Appreciate that. Yes, as it relates to 50 and up for pneumococcal conjugate vaccines in adults for -- as far as precedent. This is not something new [indiscernible] their most persuasive data with their original package seeking approval in adults. The most persuasive clinical data came out of their 50 to 64 Phase II study. Their Phase III was 65 and up, but the most persuasive data that was leaned on came out of that 50 to 64-year-old study. And then more recently, the PCV15 Phase III program had 50 and up as its age range. So there is quite a bit of precedent looking at that population. And as we've had more uptake in 65 and up adults over the last decade, the greatest value will come from extending [indiscernible]. So I think there will be -- we're expecting receptivity given the precedence and the need. And of course, the data for us looks quite compelling in either the 50 or 60 plus pooled analysis. But yes, I think there will be a leaning toward pushing for [indiscernible]. And then your second question was related to VAX-31 and how we think about infant dose. We went into this Phase II program identifying those serotypes for which we certainly didn't want to miss noninferiority not having had any clinical data to date. And what we've seen is, and we see here again, pushing to the 4.4 mcg dose for those 7 selected serotypes actually don't -- aren't required in order to show the sort of data we'd want to see to move into Phase III. So I think what you're hinting at is whether or not we want -- we might want to reassign some incremental material to some of the other strains where we haven't seen as robust responses as we have for most of the strains. And that's something that. I think Jim may have ticked his hand a bit toward. I think we'll think about a few strains, definitely higher material. But we'll do that quite carefully because as you guys know, many strains are under control. We don't want to lose that control. But there's [indiscernible] circulating more aggressively, and those will take priority as we think about how to apply the appropriate amount of material. I think that covered it. Jim, did I miss anything?

No. I mean, while we didn't show the prespecified pooled analysis of the 50-plus and the mixed does, and I've got it in front of me on my own computer, it's decidedly reassuring that when we go into -- they were up 2 of these serotypes. And I'm just saying just 2. We can meet the noninferiority for all 20. So it's clear that based on the pooled analysis and the 50-plus, 18 should meet noninferiority. And if we do some adjustments to the other 2, we have a good chance of meeting it all 20.

We'll take our next question from Joseph Stringer with Needham & Company.

Now that you have the 2 sets of data, Phase II data in adults in hand, what is the read-through to the program in terms of -- should we expect to see similar results from both an efficacy and safety tolerability perspective? And would you expect there would be more or less variability from the Phase II trial in that particular patient population?

Yes. Thanks, Joey. I appreciate that question. Yes, as we think about the potential read-through from these Phase II results to infants, there's been remarkable consistency historically between adult and infant population. After all, the exact same formulations and doses are administered to adults and infants, but for the fact that infants receive more vaccinations with the same dose. So I think that is decidedly to our advantage because we believe our carrier-sparing approach while showing substantial differentiation in the adult population could be even further enhanced in infants given that these children are receiving substantially more protein carrier across multiple doses. So it's natural to anticipate that less material at each of those vaccinations could sway in our favor immunogenicity results. So I think we're decidedly reassured heading into infants and the fact that the last couple of vaccines tested initially in adults and taken to infants, one has already been approved. And the other, at least from the sponsor is anticipated to be approved, we'll see soon enough. But yes, I think it's decidedly reassuring to see us our ability to go from the middle age population to the older adults, and I think it sets us up well for infants. But let me ask Jim, if he has any comments to complement that.

No, I think that was well said.

We'll take our next question from Tom Shrader with BTIG.

Congratulations on the data. I understand we're trying to extract a huge number of data points from a small data set. But do you have a sense of whether your conjugation is your relative immunogenicity relative to Prevnar kind of the same? And I'm kind of asking about how much the FDA has to think about the differences and whether this greater than 30% increase might make it into the label as kind of an expected general trend.

Yes. Thanks for the question, Tom. Yes, I mean, Prevnar has been an incredible breakthrough. This vaccine has prevented untold cases of [indiscernible] to that vaccine is obviously very encouraging and the fact that these immunogenicity [indiscernible] this ability to make a slight modification to the same immunogens and show improved immune responses is a real luxury. And so as I said earlier, robust immune responses that exceed this precedent with so many of the serotypes included in our vaccine. So yes, we have to hang our hat on where another [indiscernible] sponsor showed significantly and they got it in their label. So again, we'll have to discuss it. [indiscernible] We're going to have an opportunity to show across substantially more serotypes than statistically superior data, which should give us an opportunity to have similar consideration to have included in the label. So yes, it's very encouraging.

If I can ask a quick follow-up. You made an intriguing comment about fall-off with age maybe being more shallow. How much data are you going to have in patients over 70 and over to chase that signal in Phase III?

Yes. I think in studies that are in this population because you have to enroll naive subjects who have not previously received a pneumococcal vaccine and there's a recommendation in the U.S. to receive a vaccine at 65, about 60% to 70% of adults get those. While we do have subjects as old as 88 years of age in the study, I think the numbers in the older subset will be too few for us to make any inclusive analysis. But in the Phase III, we'll have higher numbers, and we'll be able to look at that.

And we'll take our final question from David Risinger for SVB Securities.

Yes. Sorry about my connectivity issue earlier. So just to follow up on VAX-31. If you could just comment a little bit more on reassigning material, just how easy that is to do and when do you expect to finalize the vaccine. And also comment on demonstrating noninferiority when you deliver those results in 2024 in the context of Prevnar 20s challenges when it was trying to demonstrate noninferiority relative to Prevnar 13.

Thank you, Dave. You came in loud and clear that time. Yes, maybe I'll take the first part and ask Jim to pick up on the second part. But with regard to, as you put it, reassigning material, that comes into play with regard to the final drug product. And we've been able to demonstrate exquisite control over the amount of material that's included in each of the drug product formulations across the 3 doses that we tested. And you see that manifest in the clinical results as well. So having that sort of control gives us the confidence that we can make those tweaks and what we were able to do was to begin that process upon receipt of the Phase II data that we obtained in the fall. So we've said publicly that we're going to be in a position to file the IND for VAX-31 in the second half of this year. And with further follow-up questions, we said we've made the -- sink the individual drug substances for all 31 conjugates and that we are approaching the final drug product phase. So yes, we've been armed with good data. And I think this data that we've read out today is consistent with that similar findings. So yes, we're in well position to make the sort of tweaks we want, which are minimal. But some tweaks we think are appropriate for VAX-31 going forward as we lock down the DP to permit the IND filing. And then as it relates to prior examples, Jim, do you want to take that second part of the question?

I wasn't exactly sure.

Okay. Yes. David, can you repeat the second part, you're talking about the Prevnar comparisons across different formulations?

Well, I guess just maybe you could comment more broadly. So clearly, Prevnar 20 struggled -- I guess it was certainly [indiscernible] but struggled to demonstrate noninferiority versus Prevnar 13. And so I guess I'm just hoping for you kind of contextualize looking ahead to VAX-31 as you add those additional 7 serotypes, just how you're thinking about and how you'd be setting expectations for VAX-31's ability to demonstrate noninferiority on the 20 serotypes that are common. And how -- to what degree you have to power the study to show that?

Yes. I mean, this is not news that it's difficult [indiscernible] technology and add incremental serotype conjugates and face a challenge to show noninferiority against the lesser valent comparator. And this has been going on since the beginning of pneumococcal conjugate vaccine development. And that has what inspired us to make a subtle but critically important change that you see manifest with our carriers bearing conjugates. But going back to the very beginning, I believe there was a quadrivalent form of pneumococcal conjugate vaccine that was ultimately compared to a 7 valent form, which was then compared to a 9 valent, then compared to an 11 valent, 13 valent, and then finally, the one you're referring to, which is the 20 versus 13. And in every instance, you see a characteristic drop in immune responses with the broader spectrum vaccine versus the less broad-spectrum vaccine. So this is nothing new. And this is what we believe we can do that is different than the others, which is generate these carrier-sparing conjugates to improve the probability of increasing coverage without facing that same sacrifice. And now having the second readout in Phase II only further encourages us that we have arrived at an outcome that we think is going to be very important in order to expand coverage to address the circulating strains of the day. So yes, I think the history has been very kind to us in terms of the predictability of this, and we're seeing the same characteristic responses that we think will allow us to power a Phase III with high confidence in the anticipated outcome.

There are no further questions at this time. I will turn the floor back over to Grant Pickering for any additional or closing remarks.

Yes. Thanks, Ashley. I'd just like to thank everybody for joining today. And on behalf of all of our Vaxcyte colleagues, the medical professionals that helped us execute this study, the volunteers who acted as subjects in the study, we want to thank everyone for their support. A very exciting day for the company, and we look forward to advancing these programs further. Thank you very much.

Thank you. And this concludes today's conference call. Please disconnect your lines at this time, and have a wonderful day.