Good morning. My name is Ashley. 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. At this time, all participants have been placed in a listen-only mode. The floor will be open for your questions following the presentation. If you would like to ask a question at that time, please press star one on your telephone keypad. If at any point your question has been answered, you may remove yourself from the queue by pressing star two. That others can hear your questions clearly, we ask that you pick up your handset for best optimal sound quality. Lastly, if you [audio distortion] press star zero.
I would now like to turn the call over to Andrew [audio distortion] of Vaxcyte. Please go ahead, sir.
Thank you, Ashley. Good morning, everyone. I'd like to welcome you to Vaxcyte's 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 over. Additionally, we will be discussing full six-month safety data from the adult phase I/II and phase II study, as well as the pre-specified 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 presentations, 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 our most recent filings with the SEC, including the risk factors set forth in our Form 10-K for the year ended December 31st, 2022, and any subsequent reports filed with the SEC. With that, I'll turn the call over to Grant Pickering. Grant?
Thanks, 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 confirm 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 three, 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 pre-specified pooled immunogenicity data analyses from both phase II adult studies that we believe puts us in a great position to move into phase III. Finally, the full six-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 five, 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 years- 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 six-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 four 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 result in adults 50 years- 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 pre-specified 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 these 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 three-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 six, 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 populace from the threat of pneumococcal bacteria. On slide seven, we emphasize the rationale for VAX-24's design and justification for its receipt of Breakthrough Designation from the FDA, which revolves around its potential to address an additional 10%-28% of circulating invasive pneumococcal disease. This magnitude of incremental protection has historically resulted in a dominant position for the more broadly protective 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 1st-gen polysaccharide sugar-only vaccine, Pneumovax 23, that has occupied a recommended slot for adult vaccination for nearly 50 years.
Given Pneumovax's incremental coverage over and above any PCV to date, its continued usage negates the opportunity to prime and boost adults with a 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 to 24 serotypes with VAX-24, which we believe affords us a significant addition. On slide eight, 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.
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 nine, we reflect on the magnitude of this opportunity, which is anticipated to grow from today's already massive seven-billion-dollar 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+ 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 pre-specified pooled immunogenicity analyses from both phase II adult studies. Finally, I'll also cover the full six-month safety data from both adult phase II studies. 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 year-64 year-olds, all participants were screened and randomized into four separate arms. On day one, all subjects received a dose of either the comparative vaccine, which in this study was PCV20 , which is currently considered as the standard of care in adults in the U.S., or one of three different doses of our VAX-24 investigational product. These included a low, middle, and mixed dose, which I'll define shortly. Solitary local and systemic AEs were monitored for seven days, and on day 29, serology was taken, and immunogenicity was performed on the samples. Subjects were also assessed for safety through six months. This study includes a low, middle, and mixed dose with the same dose strength as the previous study in the 50 year-64 year-olds.
The middle dose is similar to PCV20, containing 2.2 mcgs of polysaccharide for each serotype, while the low dose had 1/2 or 1.1 mcgs of polysaccharide per serotype. The mixed dose had 2.2 mcgs of polysaccharide per serotype, except for seven serotypes that had 4.4 mcgs. This was done for two 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.
Second, we chose seven 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 studies and its, s orry. In terms of safety studies outcomes for this study, we measured solicited local and systemic reactions through day seven, unsolicited adverse events and serious adverse events or SAEs through day 29, as well as SAEs, new onset of chronic illnesses or NOCIs, and medically attended adverse events or MAAEs through the six-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 antibody titers. 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 the four-fold rise in reverse cumulative distribution curves. I'll now review the disposition demographics for the study. There were a total of 207 subjects enrolled in the study. They were distributed across four study arms with a minimal number of subjects of about 3.4% who discontinued. We also had a similar percentage of subjects who were included in the immunogenicity study as in the previous VAX-24 phase II study in the 50 year- 64 year- olds, with 91% of those enrolled ultimately included in the immunogenicity evaluable population.
In terms of demographics, the median age in this study was between 66 years and 67 years of age across cohorts, which is typical of study run in this age and population. As with other vaccine studies in this 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. 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 year- 64 year- olds. The instance 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. In terms of severity, the majority were mild to moderate, resolving within the first 24 hours- 48 hours post-vaccination. The profile of solicited systemic events were similar to the solicited local events. There was no fever reported in this age in any of the subjects. Like the local solicited adverse events, the solicited systemic adverse events for VAX-24 confirmed the prior study results were similar to PCV20. No evidence of any dose-dependent increase of adverse events, and the majority being mild to moderate and resolving within the first 24 hours-4 8 hours. I'd like to share with you the immunogenicity data from the study.
First, included here are the present regulatory criteria that have been used to evaluate other PCVs in pivotal phase III clinical studies. The two 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 PCV20 is that the lower bound of the two-sided 95% confidence interval of the OPA geometric mean titer ratio is greater than 0.5. Said another way, the lower bound of the CI or confidence interval has to be greater than 50% for 1/2 of the GMR comparing VAX-24 and PCV20. The second is for the four incremental serotypes in VAX-24, the lower bound of the difference in the percent of subjects who achieve the four-fold rise needs to be greater than 10%.
Here is the data from the 2.2 mcg dose, which is our lead candidate we plan to move in advance into phase III. This shows on the left side the results of the common 20 serotypes in PCV20, and then on the right is the percent difference in those achieving a four-fold rise in OPA antibody titers for the four incremental serotypes. On the left, the forest plot shows the OPA geometric mean ratios for the 20 common serotypes with PCV20. Now just before I go into the data, I just want to orient 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 crosses the 0.5 threshold.
The other important point on this plot 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. Any point estimate to the right of the line would mean that VAX-24's response is higher than PCV20. You'll notice now that 16 of the 20 common serotypes had higher immune responses for VAX-24 than PCV20. Of the remaining four, the lowest point estimate is above our targeted response of 0.71. What's also worth to highlight here is that with the smaller sample size, as expected, the 95th% confidence interval significantly increased. 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 GMR for VAX-24 on average compared with PCV20. As Grant highlighted, this means the VAX-24 showed overall improvement in immune responses versus PCV20 relative to our previous results from the phase II in adults aged 50- 64. In terms of the four incremental serotypes, as you can see, all had robust four-fold rise in OPA titers with all well above the historical regulatory threshold superiority. Like the data in the other serotypes, the overall comparative results for the incremental four were improved in the 65+ population compared with those in the 50 year- 64 year-o lds. Data is now shown for each of the three doses, and this was consistent also with the previous study in adults 50 years-64 years of age.
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 mcg 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. Like the 2.2 mcg dose, GMRs generally improved compared to those from the previous 50 year-64 year-olds study. For the few serotypes that were a bit more susceptible to carrier suppression, we've already taken measures to improve the immunogenicity as we move forward with our VAX-31 program.
Here is shown the absolute OPA geometric mean titers for the three 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 in adults, the absolute OPA GMC did actually decrease slightly which is typical as we immuno assess in an older population. However, as noted in the relative OPA GMRs in the previous slide, the OPA GMCs more acutely declined in the PCV20 arm than for VAX-24, resulting in improved geometric mean ratios overall in this population. Now I'll show you the IgG geometric mean concentrations. You know, the IgG geometric mean concentrations 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 GMRs in terms of relative response compared to PCV20. I think it is worthy to note that 18 of the IgG GMCs for the 2.2 mcg dose were numerically higher out of the 20, when compared to PCV20. I'd like to go into and review the pre-specified pooled immunogenicity analyses for both the VAX-24 phase II adult studies. Before showing the pre-specified pooled immunogenicity analysis, I just want to reorient you to the four spots for the two phase II adult studies shown here separately. On the left you can see the results from the adult study aged 50-64, and due to the large sample size, confidence intervals were tighter.
As you may recall, we met the non-inferiority criteria for all 20 common serotypes, with 16 OPA GMR responses being numerically higher than PCV20. To the right is the data that we just reviewed in those aged 65 and above, and similar to the 50 year- 64 year-old age group, 16 OPA GMR responses were numerically higher and even with much wider confidence intervals as I highlighted before, we achieved non-inferiority of 18 of the 20 serotypes. Finally, as previously noted, GMRs overall generally improved even further compared with PCV20 in the age group of the 65 and above compared with the 50 year-64 year-olds. Now for the pre-specified pooled analysis. Shown here are the pre-specified 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 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, four serotypes in the 50+ pooled population and three in the 60+ group reached statistical significance. Only three 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+ and 60+ data sets respectively. Overall, these re-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.
Now finally, before concluding, I'd like to review the full six-month safety and tolerability data from both VAX-24 phase II adult studies. Here is the six-month safety data shown from VAX-24 phase II study in adults aged 65 years of age and older. As you can see, they were consistent across cohorts for each category, including treatment-emergent adverse events, the MAAEs, NOCIs, and SAEs as well as similar to the PCV20. No safety signals were evident, including no clustering events in any of the arms that could be of concern. There was one 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 six months post-vaccination and was determined by the principal investigator to be not related to the study due to the history of this hypertensive cardiovascular risk and disease. There was no NOCIs, SAEs, or death that were deemed by the study investigator to be related in this study. There is no NOCIs, SAEs, and deaths deemed to be related by study investigators in the study, including in the PCV20 arm. Included here is the updated six-month safety data from VAX-24 phase I/II study in adults 18 year- 64 year- olds. Similar to the previous study, results were consistent across cohorts for the TDAEs, MAAEs, NOCIs, and SAEs and were similar to PCV20. There were no safety signals evident, including no clustering of events.
There were no NOCIs, SAEs, MAAEs, or deaths that were deemed by the study investigator to be related to the study, including those in the PCV20 arms. Finally, you can see on this last slide here are the pooled six-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 in the next section.
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 thousand-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 six-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 pre-specified 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 non-inferior immune responses and may, in some cases, produce statistically superior immune responses relative to PCV20. In phase III, we expect to employ similar validated surrogate 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+ o r 60+ , 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 wanna 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. With that, let's move on to Q&A. Ashley?
Certainly. The floor is now open for questions. At this time, if you have a question or comment, please press star one on your telephone keypad. If at any point your question has been answered, you may remove yourself from the queue by pressing star two. Again, we ask that you pick up your handset for posing your questions to provide optimal sound quality. Thank you. Our first question is coming from Jonathan Miller with Evercore ISI. Please go ahead.
Thanks so much for taking the question and congrats on the data. It looks very strong. I wanted to ask about the phase III design. Obviously, you say you're can move forward and either 50+ or 60+ 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?
Yeah. Jon, thank you for the comments and the question. Yeah, as you can see from the data, we've got options. You know, the movement at the ACIP to show receptivity to vaccination universally for adults, starting at age 50, certainly skews our interest toward proposing the 50+ population to regulators. You know, that is something that we'll discuss with them at that meeting. I think that's, you know, the key topic. 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 statisticians, do an analysis and try and optimize, to make sure that we have an optimal chance of meeting the non-inferiority criteria first and foremost. As you can see, some of the serotypes were actually much higher than 1.0. There is precedent that Merck was able to get statistical superiority in the label. We'll actually be evaluating whether or not we can also make that claim for several serotypes as well. We'll look at the study design, and I think we're in a good position where we're looking at trying to power study superiority versus non-inferiority.
Yeah, 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, you know, the 750 to 1,000+ per cohort. You can see from our data, we're hitting those sort of outcomes with much smaller sample size. When we talk about 750 per arm, that's really to drive the statistical significant outcomes that we think are possible. Again, as Jim said, that's something we'll be reviewing with our statisticians and discussing with the regulators.
Great. Thank you. One follow-up. When I look at the earlier data from the younger adults, one thing that pops out at me is that serotypes 15B and 22F, which are the two that you missed in the older adults, aren't necessarily the worst, at the younger adults, cutoff. You know, what sort of variability should we expect between serotypes as we translate between age groups? 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 trials?
Yeah. I think looking at this, the first I'd say is, the small sample size in the 65+ created a bit of noise with some of the serotypes. I don't know how much the 22F and 15B are truly low performers. That's just variability of the data. You know, when you look at things like pre-existing titers in that population, things like that can affect the GMR significantly. I think that based on the data, and you can see the 50+ pooled data, and that we're going to be going into both the younger adult population being relative to 50, 64 and 65+ . When you look at that pooled data, you know, we're in really good shape to make sure that we meet the non-inferiority criteria for all the serotypes.
Makes sense. Thanks so much.
Thanks, Jon.
We'll take our next question from Seamus Fernandez with Guggenheim. Please go ahead.
Oh, thanks, guys. Congrats on the data. It looks really great. you know, in terms of the, I guess some of the follow-up opportunities, you know, I think everybody's 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. you know, if there are serotypes that you're focused on, I think you mentioned that, you know, the team's working on improving the immunogenicity.
Yeah. [crosstalk]
If there's anything you can help with.
No, I can. Yeah, no, great question. I think, you know, the intent of that mixed dose is to see where we have a bit more susceptibility to carrier suppression. I was pleased with the fact that there was consistent responses between the 50- 64 and 65+ in that the same serotypes showed a bit more sensitivity. That consistency allows us to focus on a few serotypes. You know, we won't share which ones they are, but I think everyone can really look at the data set and pretty much guess. We do have a number of mechanisms to help improve immunogenicity. You can see we do have a dose-dependent response, where as we increase the polysaccharide content, we actually improve the immunogenicity for those given serotypes.
That is one option, but we have other options as well. The team is hard at work making sure that when we go into VAX-31, that we try and optimize the success. That said, I think, you know, the profile as it is, and historically, the fact that you don't have to hit non-inferiority on every single serotype, being able to expand coverage to 31 strains and go above 90%+ coverage, even if we did end up missing on one, two or three, I think it's an approvable product profile.
Great. You know, just as a follow-up question, from a manufacturing perspective, and you know, timing of being able to start the full phase III with commercial-ready product and then also, you know, with the execution of the clinical study, timing of a launch. You know, hoping Andrew or Grant, if you guys could give us a sense of how far along we are in that process, and you know, in terms of commercial scale up to then drive to a potential pediatric opportunity. Love to get an update there. Thanks.
Yeah. Thanks, Seamus. you know, we've been very confident with this program, and so we've been manufacturing at risk, you know p retty much every step along the way. We've been hard at work producing the material to allow us to initiate the phase III study, Seamus. For us, you know, 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. You know, just as a final question, maybe back to Jim. As you look at these data, your enthusiasm to kind of deliver a three-dose, a potential three-dose regimen, in the pediatric setting, and then I'll jump back in the queue?
Yeah, I think when you look at so far, you know, that our theory all along was that this site-specific conjugation would allow for a potentiation of the carrier protein as well as, you know, 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'll be translatable to the infant population as well.
Great. Thanks so much. Congrats again.
Thanks, Seamus.
All right, we'll take our next question from Louise Chen with Cantor. Please go ahead.
Hi. Good morning, everyone. This is Carnegie on for Louise from Cantor. Congrats on the data, and thank you for taking our questions. Our first question is: What gives you the confidence that you can still get preferential recommendation for VAX-24? Our second question is: How does the data presented today impact your commercialization strategy for VAX-24? Thank you so much.
Thanks for that question. Well, you know, it's really looking at precedent. You know, the most recent ACIP determination effectively granted a preferred recommendation to Prevnar 20 over Vaxneuvance with regard to the catch-up population. You know, they're now suggesting that adults receive a subsequent vaccination if they were previously vaccinated with a lesser valent PCV. That was specifically granted for Prevnar 20 over Vaxneuvance. That sort of increment of coverage between those two products is similar to the sort of advantage that we believe we'll have with VAX-24 relative to Prevnar 20. I think that's part of the argument for us.
We have this incremental contribution, which is the ability to eclipse that 1st generation polysaccharide sugar- only vaccine, Pneumovax, which has truly been a fly in the ointment since pneumococcal conjugate vaccines have been recommended in adults. 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. 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. 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.
Maybe just to add, you know, the market has spoken historically that even without a preferred recommendation, the broader spectrum vaccine is what becomes the dominant vaccine in the marketplace. Obviously with a preferred recommendation, that would be the strongest position we could find ourselves in. 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. On our second question about the commercialization, would you be thinking about partnering? Would you be thinking about launching the drug on your own after today's data? Thank you.
Yeah. We've, you know, 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. This data only strengthens our resolve and better positions the company to believe in its best-in-class potential for VAX-24. 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. as we expand to other regions and other indications, you know, we'll continue to scale that operational machinery. Yes, that is the path that we are on, and we believe that we can we can deliver on that.
Great. Thank you so much. You can go out again. Thank you.
Thank you.
We will take our next question from Roger Song with Jefferies . Please go ahead.
Great. Congrats for this impressive data. Standard data set for VAX- 24. A few quick ones from us. The first one is understanding the focus is point estimate for the GMR, and then you see pretty wide confidence interval. Just curious, is that wide confidence interval mostly driven by the standard deviation in terms of the variability from younger to older, or it's mostly driven by smaller N? Thank you.
Thanks, Roger. Appreciate the congratulations. Yes, I mean, what's been observed in similar studies going from the 50- 64 to 65+ studies is that there is greater variability in the older population because immunosenescence doesn't arrive at exactly the same rate in older adults. Definitely there's been historically greater variability in that older population. I think it's a little hard to tease out precisely which of those we'd attribute to. Jim, do you have a perspective?
No, I think it's hard to tease out. 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 it seems as if even though there's variability in the rates that adults immunosenesce, it appears in totality PCV in this older population, the OPA declined a bit more rapidly than ours. As a result, we improved our overall GMRs. I would take that away from the study as well. Yeah, I don't think we could exactly calculate how much of that was the smaller N versus how much of that was inherent variability in an older population.
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. You, you've hit it. You know, 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. We, you know, we saw that now in both of the phase II studies that we've run.
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. Thanks. A quick follow-up. I remember in younger adult data you see general overall like a 20% greater GMR 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?
Thanks, Roger. I think Jim did let it slip in the presentation, but we definitely don't want people to miss that. We did include a table this time that shows the explicit GMRs and the confidence intervals to complement the forest plots. What we had 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 year-64 year-olds 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.
Whereas we saw a 20% improvement in the prior phase II study, in this 65 and up study, the average improvement was over 30%. Yeah, sorry you missed that, but it was at 31% to be precise.
Excellent. Thank you. Okay, one last question. Understanding with this pretty robust data, you potentially will power your phase III to maybe kind of reaching the superiority. You, 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 to even increase to power more? Thank you.
Yeah. You know, 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 one precedent, as Jim had referred to, with a prior program that had superior immune responses, I think, on one serotype. You know, we have this singular precedent where a 1.2x GMR was the hurdle for superiority. We won't be able to comment with precision on this one until we actually work that out with regulators. You know, we've kind of been targeting something around that sort of magnitude as we have guided to this 750 subject per arm. It'll actually be an outcome associated with this conversation that's upcoming with the regulators.
Perfect. Thanks. Thanks all the comment and responses. Congrats.
Thank you, Roger. Appreciate it.
We'll take our next question from David Risinger with SVB Securities. Please go ahead.
Yes, thank you. Let me add my congrats to you, Grant, and your team on the phenomenal data. A number of my questions have been asked. I guess I was just hoping for some additional perspective on VAX-31. Obviously, you know, that'll include seven additional serotypes of coverage. It would just be great to have you talk a little bit about, you know, how this data informs your confidence in VAX-31 and some of the key considerations, look ahead to those initial results in [audio distortion].
David, you kind of broke up at the end. You said the initial results, and then we lost you.
Oh, sorry. [audio distortion] Going into the results that [audio distortion]
We're losing you, David. Why don't we, why don't I respond to the first part? Like, first of all, thank you for the congratulations. You know, your question about VAX-31, you know, I think, you know, 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. VAX-24 data, you know, as you know, you can look at this pooled analysis 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.
That new bar, we think, will serve as a substantial defense relative to other potential competitors that VAX-31 has an opportunity to do better yet. It's those incremental seven 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. It's that incremental coverage that we see somewhat modeled from the mixed dose cohort that we've run across two successive phase II studies. As we pointed out, you know, we're effectively showing a similar amount of immunogen and protein carrier to the immune system.
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. Yes, this is further indication that we're on track with what we've, you know, 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. David, if you're still there, please repeat that.
Yes. [audio distortion] I just wanted to oh [audio distortion].
Okay. Sounds like we covered it. Sorry, we keep losing you.
Yeah. Ashley, we'll take, the next question if we can. Thank you. David, if you do get a better line and want to come back, let us know.
Sorry. As a reminder, we do ask you to ask one question and one follow-up. We'll take our next question from Jason Gerberry with Bank of America. Please go ahead.
Hey, guys. Morning, I'll send my congrats on the data update as well. First off, you know, just a commentary about, you know, pushing and expanding to 50+ . How do you think population in a phase III might skew versus traditional adult studies? You know, the aim going into this phase, in the phase II meeting, just to get FDA clearance on a greater mix of younger adults. I think in the past you've talked about maybe 1/3 of patients in the phase II falling in this greater than 65 age subgroup. Maybe, maybe you can go lower. Just sort of curious about some of those dynamics. Then, you know, my follow-up, I'm curious, do you look at the pooled analysis for the mixed dose?
I think, what, five serotypes, shared strains fell outside the NI criteria. I think two fell outside that criteria in the other phase II that you reported last year. I believe you said that this has the same amount of protein carrier, this mixed dose as the VAX-31. Just trying to think through that, the relevance of that analysis ultimately. Maybe it's just a question of where you apply the 4.4 mcg dose on which serotype strain in the 31.
Yeah. Thank you, Jason. Appreciate that. Yeah, as it relates to 50 and up for pneumococcal conjugate vaccines in adults for, as far as precedent, you know, this is not something new [audio distortion] 13, 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. The most persuasive data that was leaned on came out of that 50 year- 64 year-olds study. More recently, the [PCV-15] phase III program had 50 and up as its age range. There is quite a bit of precedent looking at that population.
As we've had more uptake in 65 and up adults over the last decade, you know, the greatest value will come from extending B+ . I think we're expecting receptivity given the precedents and the need. Of course, the data for us looks, you know, quite compelling in either the 50+ or 60+ pooled analyses. Yeah, I think there will be a leaning toward pushing forward. Your second question was related to VAX-31 and how we think about important dose. You know, we went into this phase II program, identifying those serotypes for which we certainly didn't want to miss non-inferiority, not having had any clinical data to date.
What we've seen is, and we see here again, pushing to the 4.4 mcg dose for those seven selected serotypes actually aren't required in order to show the sort of data we'd want to see to move into phase III. I think what you're hinting at is whether or not 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. That's something that I think Jim may have tipped his hand a bit toward. Yeah, I think we'll think about a few strains that we 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 some circulating more aggressively, and those will, you know, 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 pre-specified pool analysis of the 50+ in the mixed dose, I've got it in front of me on my own computer, it's decidedly reassuring that when we go into or up two of these serotypes, and I'm saying just two, we can meet the non-inferiority for all 20. It's clear that based on the pooled analysis and the 50+ 18 should meet the non-inferiority. If we do some adjustments to the other two, we have a good chance of meeting it all 20.
Got it. Great. Thanks a lot.
Yeah. Thanks, Jason.
We'll take our next question from Joseph Stringer with Needham & Company. Please go ahead.
Hi, thanks for taking our question. Now that you have the two sets of data, phase II data in adults in hand, what is the read-through to the program in infants in terms of, you know, should we expect to see similar results in both in efficacy and safety tolerability perspectives? Would you expect there would be more or less variability from the phase II trial in that particular patient population?
Yeah. Thanks, Joey. Appreciate that question. Yeah. As we think about the potential read-through from these phase II results to infants, you know, there's been remarkable consistency historically between adult and infant populations. 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. You know, I think that, you know, is decidedly to our advantage because we believe our carrier-sparing approach, you know, 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. It's natural to anticipate that less material at each of those vaccinations could sway in our favor the immunogenicity results.
I think we're, you know, decidedly reassured heading into infants and the fact that, you know, 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. Yeah, I think, it's decidedly reassuring to see our ability to go from, you know, the middle-aged population to the older adults, and I think it sets us up well for infants. Let me ask Jim if he has any comments to complement that.
No, I think that was well said.
Okay.
Great. Thanks for that.
Yeah. Thanks, Joey.
We'll take the next question from Tom Shrader with BTIG. Please go ahead.
Good morning. 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 relative immunogenicity relative to Prevnar kind of the same? 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. Thanks.
Yeah. Thanks for the question, Tom. Yeah, I mean, you know, Prevnar has been an incredible breakthrough. This vaccine has prevented untold cases of [audio distortion] that vaccine is obviously very encouraging. The fact that these immunogenicity [audio distortion], you know, the, you know, this ability to make a slight modification to the same immunogens and show improved immune responses is a real luxury. As I said earlier, robust immune responses that exceed this precedent with so many of the serotypes included in our vaccine. Yeah, we have to hang our hat on where another sponsor showed significant, and they got it in their label.
Again, we'll have to discuss [audio distortion], we're gonna have an opportunity to show across substantially more serotypes than statistically superior data, which, you know, should give us an opportunity to have similar consideration to have included in the label. Yeah, it's very encouraging. Thank you, Tom.
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 to chase that signal in phase III?
I think, you know, 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, and about 60%- 70% of adults get those. It, you know, while we do have subjects as old as 88 years of age in this study, I think the numbers in the older subset will be too few for us to make any conclusive analyses. In the phase III, we'll have higher numbers, and we'll be able to look at that.
Good. Thank you.
Thanks, Tom.
We'll take our final question from SVB Securities. Please go ahead.
Yes, thanks very much. Sorry about my connectivity issue earlier. 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. Also comment on, you know, demonstrating non-inferiority when you deliver those results in 2024 in the context of, you know, Prevnar 20's challenges when it was trying to demonstrate non-inferiority relative to Prevnar 13. Thank you very much.
Yes, thank you, David. You came in loud and clear that time. Yeah. Maybe I'll take the first part and ask Jim to pick up on the second part. With regard to, as you put it, reassigning material, you know, that comes in to play with regard to the final drug product. 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 three doses that we tested. You know, you see that manifest in the clinical results as well. Having that sort of control, you know, gives us the confidence that we can make those tweaks. You know, what we were able to do was to begin that process upon receipt of the phase II data that we obtained in the fall.
You know, we've said publicly that we're gonna be in a position to file the IND for VAX-31 in the second half of this year. You know, with further follow-up questions, we've said, you know, we've made the individual drug substances for all 31 conjugates and that we're approaching the final drug product phase. Yes, we've been armed with good data, and I think this data that we've read out today, you know, is consistent with that, similar findings. Yeah, we're in well-positioned 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.
As it relates to prior examples, Jim, do you wanna take that second part of the question?
I wasn't exactly sure.
Oh, okay. Yeah, David, can you repeat the second part? You're talking about the Prevnar comparisons across different formulations?
Well, just maybe comment more broadly. Clearly Prevnar 20, you know, struggled to demonstrate non-inferiority versus Prevnar 13. I'm just hoping for you to kinda contextualize, looking ahead to VAX-31 as you add those additional seven serotypes, just how you're thinking about, and how you'd be setting expectations for VAX-31's ability to demonstrate non-inferiority on the 20 serotypes that are common, and how to what degree you have to power the study to show that.
Yeah. I mean, you know, this is, this is not news that it's difficult-technology and add incremental serotypes, serotype conjugates, and face a challenge to show non-inferiority against the lesser valent comparator. This has been going on since the beginning of pneumococcal conjugate vaccine development, and that is what inspired us to make a subtle but critically important change that you see manifest with our carrier-sparing conjugates. You know, going back to the very beginning, you know, I believe there was a quadrivalent form of pneumococcal conjugate vaccine that was ultimately compared to a seven-valent form, which was then compared to a nine-valent, then compared to an 11-valent, a 13-valent, and then finally the one you're referring to, which is the 20 versus the 13.
In every instance you see a characteristic drop in immune responses with the broader spectrum vaccine versus the less broad spectrum vaccine. This is nothing new and, you know, this is what we believe we can do that is different than the others, which is, you know, generate these carrier-sparing conjugates to improve the probability of increasing coverage without facing that same sacrifice. Now having, you know, this second readout in phase II only further encourages us that we have, you know, 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.
Yeah, I think, you know, the history has been very kind to us in terms of the predictability of this, and we're seeing the same characteristic immune responses that we think will allow us to power phase III with high confidence in the anticipated outcome.
That's great. Thanks again.
Yep. Thanks, David.
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. 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 call. For this call, please disconnect your line at this time and have a wonderful day.