Invivyd, Inc. (IVVD) Earnings Call Transcript & Summary

Good day and thank you for standing by. Welcome to the Invivyd REVOLUTION Pivotal Program Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Katie Falzone, Senior Vice President of Finance. Please go ahead.

Thank you, operator, and thank you for joining today's webcast. The slides that are being used on today's webcast will be made available within the Investors section of the Invivyd website under the Events and Presentations section shortly after today's call. Today's discussion will be led by Marc Elia, Chairman of Invivyd's Board of Directors; he is joined by Dr. Robert Allen, Chief Scientific Officer; Dr. Mark Wingertzahn, Senior Vice President of Clinical Development; and Tim Lee, Chief Commercial Officer. As noted by the operator, there will be a question-and-answer session at the conclusion of today's call. During today's discussion, we will be making forward-looking statements concerning, among other things, our research and development activities, our regulatory plans, our corporate and commercial strategy, our future prospects and other statements that are not historical facts. These forward-looking statements are covered within the meaning of the Private Securities Litigation Reform Act and are subject to various risks, assumptions and uncertainties that may change over time and cause our actual results to differ materially from those expressed or implied today. These forward-looking statements speak only as of the date of this call, and Invivyd assumes no duty to update such statements. Additional information on the risk factors could affect Invivyd's business and can be found in our filings made with the U.S. Securities and Exchange Commission, including our most recent Form 10-K and 10-Q, which are also available on our website. I will now turn the call over to Marc.

Thank you very much, Katie. Good morning and thank you all for joining our REVOLUTION clinical program update call this morning. We understand that this morning is busy with earnings calls, and so a replay of our call will, of course, be available shortly after we conclude. Today's discussion will focus on the key design elements of our upcoming pivotal program for VYD2311, our antibody we are developing as an alternative to COVID vaccination among other potential uses. In order to understand how we see antibodies and VYD2311 fitting into protection from COVID, I will begin by providing some context to our current situation with COVID before my colleagues walk through various technical aspects of our work. Throughout this call and more generally, it is important for everyone in the audience to remember that discussing the strength of antibody technology for protection from COVID must not be interpreted as any form of anti-vax sentiment or second-guessing past decisions in the public health or medical arenas. While our development pipeline is designed to complement or improve upon vaccination, such innovation is definitively different than opposing vaccination in any way. We hope all listeners can appreciate that distinction as well as appreciating the importance of our technological mission at Invivyd. We hope today you will all consider together with us, a different future that involves the possibility of a choice for better, safer protection from infectious diseases such as COVID and beyond. Moving to the next slide. Invivyd focuses on making antibodies to protect people from viral disease. We make antibodies against infectious diseases because we see an obvious and attractive inspiration in nature and normal human immune function. Antibodies are the principal mechanism by which the human immune response protects people from infection. And so Invivyd's pharmaceutical innovation is simply devoted to providing better antibodies than the human immune system itself can summon. In this way, if we are successful in our work, our medicines will, in a natural way, replicate and expand on basic human immune biology. As such, we see antiviral antibodies as an attractive medical option for preventing and treating disease that presents a potentially best-in-class safety and efficacy profile that is rooted in fundamental but strongly enhanced normal human immune function. You will note that some of our early work is poised to expand Invivyd beyond prevention of COVID to perhaps treatment of acute COVID, treatment of long COVID and indeed to pathogens beyond COVID, including RSV and measles. These are all areas in which we believe humankind may benefit from accessing additional high-quality immune power against viruses that exceeds what is possible from human immune suites. We will look forward to updating you further over the coming months on these additional programs. Next slide. Our agenda today provides for a quick update on our overall situation with COVID and then a discussion of our antibodies by Dr. Robert Allen. Dr. Allen's presentation should convey the technical underpinnings of our confidence in and appreciation for the power of our antibody medicines. Dr. Mark Wingertzahn will walk us through some design elements of the DECLARATION and LIBERTY clinical studies, which should communicate the basis for our high confidence in clinical probability of success. Finally, Tim Lee will talk briefly about the commercial landscape and enormous opportunity we anticipate as we engage in commercial preparation for a potential near-term VYD2311 launch. With that, on this next slide, let's quickly move through the current situation with COVID. To start, let's remember we are in the very early years of understanding SARS-CoV-2 and COVID. We all remember the extraordinary circumstances of the pandemic, but the current and future endemic COVID landscape is still unfolding. Importantly, while we have all been tempted to analogize SARS-CoV-2 to influenza or other respiratory diseases, SARS-CoV-2 presents a very different spectrum of systemic medical insult, perhaps owing to its engagement with the ACE2 receptor itself broadly distributed and highly influential in vascular function. As a result, while, of course, COVID can present with respiratory symptoms and is transmitted via respiratory aerosols, we see market systemic cardiovascular and end organ damage in COVID, especially detectable in organs that are highly dependent on blood flow like the heart, kidneys and brain. These are critical considerations as we innovate to protect people from a lifetime of repeat infections that may cause very real organ damage and cardiovascular risk as well as still presenting a serious acute infection that can potentially drive hospitalization or even death. Next slide. Several years ago, the world was thrilled when the first COVID vaccines were successful at blocking symptomatic disease. Most people did not take special notice at the time that the vaccine efficacy evaluation period was relatively short or that SARS-CoV-2 at the time was highly immunogenic and responsive to vaccine-induced antibodies rather than the immune evasive virus we see today. However, researchers who followed coronaviruses carefully did caution at the time that because of simple limitations in the human immune response to coronaviruses, asking for any COVID vaccine to confer strong, durable long-term protection may have been unlikely. Again, it is critical to remember that any vaccine can only be as effective as the limits of the human immune system it attempts to educate, which is why we focus on adding more immune power via monoclonal antibody. Next slide. As people around the world got infected and then vaccinated in a short time, the human immune system changed quickly. At first, almost no one had antibodies to SARS-CoV-2, but soon, nearly everyone had some level of immune experience, what scientists call seropositivity. This new immune pressure forced the virus to evolve. The result was Omicron, a version of the virus that lost many of the spots antibodies usually target. That made Omicron much better at escaping immunity in people who had already been vaccinated or infected. Now almost 4 years later, we've reached a new balance. Humans can't go back to being immune naive and the virus won't return to its old forms. Because of this evasiveness in human immune imprinting, booster vaccines now add less incremental benefit than the first doses did. Boosters mostly strengthen old antibody responses rather than giving new stronger protection against the latest version of virus. Again, this new balance is why we built Invivyd to give people immune protection beyond what our systems can now summon in response to vaccination. Next slide. For a host of reasons that extend well beyond what we can cover in this webinar, Americans have learned a real measure of fear and mistrust regarding COVID vaccination. CDC survey data demonstrate that unique among comparable vaccines, the top reason that Americans avoid COVID vaccination is fear of side effects and overall safety. More and totally unique to COVID, mistrust that stems from our government actions and our recent complex medical societal arc also informs American behavior. As a result, and Tim will comment further on this later, COVID vaccine utilization, while still supporting a very big commercial business, sees much lower uptake compared to influenza vaccination. We see a major opportunity to restore trust in high-quality tools to prevent COVID with associated major medical benefit for Americans. Next slide. Because our work intersects with the public health and large populations, we are hopeful that our innovation can, as we scale, help break what appears to be a toxic stalemate for Americans and many societies around the world, a choice between an infection people don't want to get and a vaccine most people don't want to use. Our hope is that our innovation can help change the narrative and behavior regarding protection from infectious diseases generally. With that, I will turn the call over to Dr. Robert Allen.

Next slide. Thanks, Marc. At Invivyd, we are exploring SARS-CoV-2 spike protein structure and antibodies intensely because thanks to our discovery platform, we do not operate within limitations imposed by human immune systems. To our minds, while SARS-CoV-2 can evade human immune pressure, if we are doing our work correctly, the virus should not be able to evade Invivyd. To do our work, we must target our antibodies to exploit highly conserved stable epitopes on the spike protein RBD that are relatively free from immune pressure. This is the purpose of much of our structural analysis. Conceptually, it is about attacking a well-validated but moving drug target, the SARS-CoV-2-RBD in areas that represent attractive stable space. Next slide. SARS-CoV-2 mutant [indiscernible] as most everyone is aware. On this chart, we show the variants present in clinical sampling for just a short period of time, late 2023 through today. Just in this period depicted, there have been likely hundreds of millions of human infections globally and owing to the vast quantities of virus per infection and the fidelity or lack thereof of the SARS-CoV-2 polymerase, quadrillions of mutated variants. Numbers all far too big for the human mind to grasp. This is the challenge we have set forth for ourselves to tackle in our antibody design. Now much of the variation in SARS-CoV-2 does not relate to our drug target site, but it is worth noting that the virus is, of course, always in some degree of motion. Next slide. We can visualize this genetic motion in terms of individual amino acid mutations on the spike protein receptor-binding domain, or RBD, over an even longer period, in this case, from Omicron through to today. What you're looking at is the RBD presented in genetic motion with the pemivibart epitope highlighted in blue, the darker and more intense, the orange to red color at a particular spot on the RBD, the more mutation has occurred at that site. Despite all the genetic change, however, and very much critically and by design, the epitopes for our antibodies are unchanged. They are stable, and hence, we at Invivyd see a virus that appears highly druggable from our unique perspective. Next slide. Why do we innovate if we are targeting such stable territory on spike? Well, so far, our serial innovation has been devoted to antibody performance improvement and product scalability. We observed that by engineering pemivibart against more modern viruses and by selecting for improved biophysical properties, we could move from pemivibart to VYD2311 with a minimum of amino acid changes, a small handful of altered residues depicted in red that leave the antibodies about 99.5% or more identical one to the next. Just these small changes have the large effect of allowing for far greater product potency and far greater in vivo half-life for VYD2311 compared to pemivibart, both highly attractive properties that predict better, more durable clinical benefit. More by improving antibody performance while engineering such minimal structural change, we believe we can have a high degree of confidence in the likely overall safety and efficacy profile we can expect from a new Invivyd molecule. We are, after all, building nearly identical molecules against a nearly identical molecular target and with VYD2311 are doing so for the third time in 4 years. Even more, while we aim to create durable antibodies that may be active for decades or beyond, we are also highly respectful of the power of viral evolution and so we want to innovate via our platform if we must accommodate an unanticipated virus shift. Next slide. The net result of our work is a remarkable durable pharmaceutical activity of our antibodies against SARS-CoV-2 variants. This chart depicts the percentage of product potency retained over time for several antibodies, 2 of them are ours and 2 of them from other companies presented for contrast on a time line that embraces the totality of post-Omicron COVID variants. You will see one antibody, bebtelovimab and cocktail of 2 antibodies, Evusheld charted in orange and red that show, for example, a potency downward blip for Evusheld followed by total loss of activity similar to the total loss of activity for bebtelovimab. For the Invivyd antibodies at the top of the chart, you will note pemivibart in green-blue that tends to wobble around more at about 90% to 95% of original potency, better, VYD2311 represents a perfectly flat line at the top of the chart for now, an extraordinary quantum of time and virus variation. Remember, our hypothesis is that our platform allows us to make antibodies with stable, highly active and high activity to prevent COVID disease even when vaccination cannot. Based on the extraordinary ongoing activity span of pemivibart and the even more encouraging activity of VYD2311, we are optimistic that our platform can generate meaningful scalable medicines for humans in need long term. With that, I will turn the call over to Dr. Mark Wingertzahn to discuss the REVOLUTION program in more detail.

Thanks, Robby. Next slide. The REVOLUTION program is designed to assess VYD2311 protection from COVID in order to support product approval and to scale strong safe protection millions of Americans in need. Next slide. There are 3 major components to REVOLUTION we would like to discuss today. First, I will quickly review our Phase I/II study that tested super pharmacologic doses of VYD2311, far above our go-to-market dose. Then I will review our DECLARATION study, which is our Phase III randomized, placebo-controlled study of VYD2311 for the prevention of COVID. DECLARATION will be the third RCT that Invivyd has executed with highly concordant design features, testing nearly identical antibodies at the molecular level, but with some potentially unique benefits that I will discuss shortly. Finally, we will discuss our draft LIBERTY study outline, which depends on final regulatory alignment owing to the inclusion of mRNA vaccine as a comparator and combination partner, which requires coordination between CDER, where our molecules are reviewed and CBER, which, of course, regulates vaccine. Next slide. Slide 20 lays out a very simple schematic for our Phase I/II study design. You will see that Invivyd assessed 4 different dose regimens across 3 different routes of administration, all in service of stress testing safety and feasibility of a range of potential doses, including very high levels. The study was completed in the summer. And of course, the data has been reviewed by FDA as part of our IND review and in part supported the study may proceed letter for the pivotal DECLARATION study. To come back, by super pharmacologic, I simply mean that even at the lowest dose we assessed, the 1,000-milligram intramuscular dose, we dosed more drug in administration than any subject in DECLARATION will receive even in the repeat dosing arm. The highest dose we assessed, 4,500 milligrams or 4.5 grams of antibody via single infusion equated to 18 years of annual intramuscular antibody and extreme stress test of VYD2311 safety and tolerability. Next slide. As we have previously disclosed, VYD2311, even at extremely high doses was generally safe and well tolerated. Reassuringly, we have never observed any histopathological findings of note from our antibodies in preclinical testing nor have we identified any interaction between our RBD-directed antibodies in human tissue panels. As with any injectable infused medicine, there are expected AEs related to administration route. Nevertheless, we have routinely observed and have come to expect a very attractive long-term safety from our antibodies, especially when dosed at rational low dosages via intramuscular injection. Next slide. The DECLARATION study will assess the ability of VYD2311 to reduce risk of subjects getting sick from COVID versus placebo, and this is designed as the principal efficacy study that will support our product BLA. Next slide. It is critical to note that we believe the endpoint we are evaluating, the reduction in risk of symptomatic COVID is uniquely well suited to addressing the current unmet need in COVID medicines. During the pandemic, of course, we were all horrified to be forced to measure extraordinary levels of death and hospitalization and ICU utilization. Today, the scientific and clinical community embrace different but nevertheless relevant endpoints, the most important of which remains lowering the probability of an indexed infection. After any acute COVID infection, we see a series of adverse medical outcomes that affect cardiovascular system and many major organ systems such as the brain, the heart and the kidneys. But to our thinking, if we are able to demonstrate a substantial reduction in one's ability to get sick from acute COVID, it is commensurately less likely and not particularly controversial that all manner of follow-on damage would be majorly blunted. While we certainly cannot demonstrate all of those follow-on benefits in a single compact pivotal study, we believe we can demonstrate a major change in the upstream initiating infection, the risk of getting sick from COVID at all. Next slide. We intend to study VYD2311 in a very broad swath of the American population, specifically those persons over 12 years who are at risk of progression to severe COVID. Such a population is essentially identical to the population eligible for COVID vaccination. Further, dialogue with the agency suggests that a modestly sized expansion of our initial safety database in a post-approval setting could well expand the population for VYD2311 to all Americans over 12. As noted, the DECLARATION study is interrogating one simple question. Fundamentally, what is the risk reduction in symptomatic COVID with VYD2311 versus placebo? It is important to note that the precise symptomatic endpoint, so-called CLI for COVID-like illness is a standard set of clinical criteria that have been consistent in all Invivyd previous clinical studies, including our prior successful randomized controlled trials, EVADE and CANOPY. Hence, we are quite familiar and comfortable with robustly assessing this endpoint. Next slide. This schematic depicts the design of the DECLARATION study, which will be posted on ClinicalTrials.gov in the coming weeks. The study is randomized into 2 active and 1 placebo arm, randomized 1:1:1 with approximately 600 patients per arm. In order to maintain multi-dose arm blinding, the single-dose VYD2311 arm will involve 2 additional injections of placebo. And similarly, the placebo arm will have monthly injections. Given the dose of VYD2311 we have selected, which we will describe momentarily, our expectation is that the single-dose VYD2311 arm will result in a roughly 70% to 90% reduction in symptomatic COVID compared to placebo over the 90-day measurement period. We have designed DECLARATION to provide 90% power to detect a 70% reduction in risk of symptomatic COVID for VYD2311. We believe our design is quite conservative. For example, if in DECLARATION, we observed the high COVID attack rate we observed in our CANOPY study and/or if VYD2311 performs at the higher efficacy levels we expect, the DECLARATION study would be even more highly powered, well above 90%. In the instance of inadequate events, we may elect on a blinded basis to resize the study solely to preserve powering. It is important to note and underscore that if resizing were to occur, there would be no insight into or read through to product efficacy. The sole variable would be blinded event rates. The multi-dose VYD2311 arm exists to demonstrate the safety and feasibility of multiple doses. Given our analysis of VYD2311 antiviral titers, we expect a numerical improvement of 5 to 10 percentage points over what protection level comes from a single dose. DECLARATION is not designed nor powered to demonstrate a statistically significant difference between the 2 dosing arms. However, we do believe that demonstrating the safety and feasibility of repeat dosing may be important for people who may want to choose periodic additional protection to accommodate an event or a period of higher risk. Next slide. In terms of dose, in DECLARATION, we are assessing 250 milligrams of VYD2311 administered intramuscularly 1x or 3x in the case of the multiple dose arm. The chart here depicts relationship between sVNA titer and clinical protection that we impute from our analysis of our CANOPY study with pemivibart. In order to select our single dose level, we used VYD2311 product potency that reflects recent variants, coupled with the pharmacokinetic data from the Phase I/II study and then computed the dose required to achieve adequate antiviral titers at the end of the 90-day DECLARATION observation period that would correspond to 70% protection. Because the 70% protection target reflects drug levels at the end of the period, of course, the protection would be stronger at the beginning of the dosing period. You can therefore see that the 70% to 90% efficacy estimate reflects the range of titers we would expect across the 90-day treatment period. Of course, with multiple doses, the drug levels, antiviral titers and consequent clinical protection would be even higher depicted in blue. Interestingly, as you can see from the chart, the X-axis is logarithmic and hence, much flatter than portrayed on the slide. As a result, as drug half-life pass and drug levels drop, we will expect to see continued strong protection. Next slide. As a result of the long product half-life and the relatively flat correlate curve, we would still expect to see VYD2311 confer a robust protection of greater than 50% out to 1 year, a remarkable increase in protection compared to best estimates of COVID vaccines. Going forward, post approval, we may choose to formally demonstrate longer-term protection, for example, an extension study or in a head-to-head efficacy clinical trial versus vaccines. Next slide. Finally, DECLARATION represents an important milestone for Invivyd as we approach our third sequential randomized controlled trial with a near identical antibody. We would like to use data from DECLARATION to formalize the so-called correlate of protection for Invivyd antibodies for regulatory and public health bodies to consider. Specifically, every randomized controlled trial we have done has allowed Invivyd to analyze different doses or potencies of antibodies in terms of clinical protection. The EVADE study using adintrevimab assessed protection by adintrevimab at high potency doses versus Delta COVID versus the lower protection adintrevimab confirmed at lower potency versus Omicron BA.1. More recently, our CANOPY study of pemivibart demonstrated clinical protection from the active dosing, high titer phase of pemivibart as well as the long-term post-dosing phase in which much lower residual levels of pemivibart continue to exert strong protection. Because DECLARATION involves 2 active arms, we may add updated data to what is rapidly becoming a clinical meta-analysis of Invivyd antibody clinical effectiveness. Using titer and clinical data from 3 near identical Invivyd antibodies, all exerting activity across virus variants in time may allow us to formalize a so-called correlative protection curve. In our view, establishing this formal correlative protection curve could substantially accelerate new antibody development by rendering efficacy studies effectively obsolete or only confirmatory, another potential competitive advantage for Invivyd. Next slide. Moving now to our LIBERTY study, I will describe our goals. As stated, LIBERTY requires an extra step of coordination between CDER and CBER and so may further modify going forward, but bears review, nonetheless. The purpose of LIBERTY is to assess the safety and tolerability of mRNA vaccines versus VYD2311 and to assess the safety and immunologic consequence of combining vaccine and antibody. While we do not expect meaningful concomitant use of vaccine in VYD2311, demonstration of feasibility and immunologic interaction, if any, may substantially in label language and guidance to HCPs in vulnerable populations about co-administration of vaccine and antibody. Next slide. This study presents the well-understood and substantial tolerability issues associated with COVID vaccines drawn directly from product labels. Many vaccines involve called reactogenicity or the noticeable immune response that vaccines require to elicit the subject's immune system and generate fresh antibodies. However, such immune activation may carry a safety consequence and further may stand in marked contrast to the safety and tolerability profile we expect from a monoclonal antibody. Next slide. So what might we expect from a low-dose intramuscular monoclonal antibody from Invivyd. Our most informative comparable data comes from the EVADE study of adintrevimab, our first monoclonal antibody. Overall, there is very little to note here with every observation at low level and markedly different from the COVID vaccine data contained on the vaccine labels. Every injectable medicine will involve some injection site pain, as you can see here. But overall, and reassuringly, the safety and tolerability profile we expect from a low-dose intramuscular antibody is otherwise questionably distinguishable from placebo. Next slide. We have planned LIBERTY with 3 arms of approximately 70 subjects each, VYD2311 alone, mRNA vaccine alone and the combination of the 2. Our principal interest is comparing the safety and tolerability of antibody versus mRNA vaccine, but a useful output will also be the safety and any immunologic consequence of combining antibody and vaccine. We do not carry a particular expectation for safety or immunologic interaction, but we will be interested to see the results and share them with FDA to assist the agency with possible labeling language or specific guidance for HCPs in vulnerable populations on concomitant use, if approved. Next slide. Going forward, we can imagine a number of possible additional studies for VYD2311, if approved or future Invivyd antibodies that could demonstrate additional high-value benefits associated with antibody prevention of COVID or to expand our label patient populations. With that, I will turn it over to our Chief Commercial Officer, Tim Lee.

Thank you very much, Mark. Turning to Slide 35. We see an enormous near-term commercial opportunity for Invivyd. Last year, U.S. COVID vaccine sales totaled $3.8 billion. And yet as we have reviewed, the vaccines appear far from an ideal solution. We believe we may substantially improve on the safety, efficacy and durability of efficacy of protection from COVID and are looking forward to getting started. Next slide. As we consider the size of the potential commercial opportunity and remembering the CDC data that Mark presented earlier, at this point in 2025, COVID vaccine uptake is substantially below that of influenza vaccine uptake despite people being more concerned about getting COVID than they are about getting the flu. We see extraordinary medical value to create as we scale our business. Next slide. As a reminder, Invivyd currently commercializes PEMGARDA. In so doing, we have already made major headway with medical societies and key opinion leaders in establishing monoclonal antibodies as a recommended strategy for preventive COVID. Of course, we expect that if approved, VYD2311 could be a much more scalable patient and system-friendly option. We're pleased that our anticipated commercial efforts with VYD2311, if approved, will build on and benefit from the work that has already been done with PEMGARDA. Next slide. Given our anticipated rapid enrollment and the conduction of the DECLARATION and LIBERTY studies, we are already beginning our commercial planning for VYD2311. We anticipate that our work will become more visible to many of you as we try to drive awareness of COVID antibodies and alternatives to vaccination among a far greater number of Americans than could ever access PEMGARDA. We will look forward to you all seeing our work, providing feedback and ideas on what we see as an incredible opportunity to revolutionize protection from COVID in the coming years. With that, we'll take your questions.

[Operator Instructions] And our first question will be coming from Josh Schimmer of Cantor.

I guess on the design of the DECLARATION study, why have you chosen a multi-dose approach as opposed to a dose escalation approach? What were the restrictions of being able to dose higher at day 0 as opposed to breaking up the higher dose over 3 administrations?

Josh, it's Marc. And if other people want to chime in, I'll hope they will. There's really a logic that relates to the upper end of what our early formulation work allows in terms of a single needle jab. So you're quite right that, of course, we could pick an alternative pathway in which we allow people or describe clinically the effect of multiple simultaneous IM injections. And in fact, that was what drove the 1 gram dose in our first in-human. But I think what we perceive is that by dosing monthly, one could, of course, acquire effectively almost the same titer over time. And in general, for most people, we see a single dose as more than adequate, if not frankly attractive. And so going above that out of the gates is something we could also explore down the road. But I think for now, we like striking a balance with our dosing so that experientially for vulnerable people, there's really no appreciable distinction between VYD2311 and a vaccine as in, you go, you have an appointment with a caregiver, and you receive one injection. If you want more, you can go get more. So it's not so much that we don't like your concept. It's just that with finite resources, we feel as though we're essentially demonstrating similar outcomes just by an alternative pathway. But again, I wouldn't take off the table the idea that either we could do what you're suggesting in the future or with a next-generation antibody well down the road, we could be operating with formulations or molecules that would obviate the need for any of it. Does that make sense?

It does. I guess to clarify with this program, 250 milligrams is the maximum you'd expect to be able to deliver in a single IM injection, you don't expect you'd be able to go higher.

So at this point, given the formulation development work we've done, that's where we're comfortable. And I think, again, those of you who are very educated in the area of the biophysical limits of these sorts of things might appreciate that, yes, there are mechanisms by which we could go higher. But I would just say, in our interest to move quickly and get people a very high-quality option, 250 milligrams provides extraordinary potential protective benefit. And so we could actually keep tweaking and improving sort of indefinitely, but I think we are so compelled by what we see as the current safety and efficacy profile we would anticipate from 2311, it sorts of renders further improvement a nice to have.

On that point then, can you just kind of review the incremental benefit you think you're going to be able to deliver with a 3-dose regimen as opposed to 1?

Sure. So I think you can appreciate that by adding additional dose, we help subjects walk upward the antiviral titer that they would have in their serum. But the quantitative effect of it over the course of the DECLARATION study should be single-digit percentage points of improvement over the baseline. What it really is meant to describe is the feasibility of more dense dosing subject to anybody's choice out there in the world post approval. So we could, of course, use such data to imagine a world where at the very extreme end, a highly vulnerable person would seek monthly dosing. That person would be in receipt of extraordinary antiviral titers, and we don't see that as a particularly likely profile for anybody. Instead, the multi-dose arm is there to indicate the safety and the feasibility of adding more titer should one choose. Because as you'll notice, any drug with a pharmacokinetic profile that would decline somewhat over time could, on average, as we anticipate for 2311, drive very real benefit for a very long time. But given that COVID is periodic in nature, given that individual subject risk changes over time, whether that's to do with concomitant medicine or other periods of heightened vulnerability or, frankly, behaviors that represent risk, right, such as gathering or traveling and so forth. What we want to be very clear on with the DECLARATION study is that if one seeks more protection, one can get safely more protection. And so we don't look at DECLARATION as a definitive prescription for future behavior. We look at it as a demonstration of the boundaries of the possible. Do one injection per year. And we would expect you would have a superior option to your current vaccination schedule. But periodically, if you feel as though you may be at additional risk, I could say I personally contemplate how I might consider interacting with 2311 in the future. And I do see opportunity periodically in my life to wish additional incremental protection. So I think when we look at the DECLARATION study, what we're trying to do is to provide people and frankly, policy and regulators with maximum choice.

If I may, just a couple of follow-up questions on this then. Are immune-compromised patients going to be included in the DECLARATION study?

Yes, of course. There are not only immune-compromised people, but we will slightly bias our recruitment toward elderly and also toward adolescent populations to the extent that we can. So we...

Presumably then you'll be able to evaluate the protective efficacy of one versus multiple doses in those immune-compromised patients. I assume you are working with the assumption that you would see more robust protection in them with more doses.

Well, I think that's possibly true, but not something we're specifically aiming to demonstrate here because I think what we see is actually a desire to demonstrate protection across all humans. So there will be people that are more elderly or less elderly. There will be subjects that are more immune-compromised or less immune-compromised. But from the point of view of interrupting actual pathogenesis, meaning stopping symptomatic COVID, we see them essentially as questionably distinguishable risk buckets, some of whom may benefit from additional protection. But once you start to subdivide Americans into who might periodically wish additional protection, it gets very difficult to formally demonstrate a delta in protection in each of those populations, right? So to take it to an extreme, could you imagine that someone over 89 years of age might wish for more protection compared to someone under 89 years of age? Sure. But we are not going to design and power a study specifically to demonstrate that. I think it really comes down to moving the opportunity for exerting that choice to the level of the individual and their care team.

And our next question will be coming from Patrick Trucchio of H.C. Wainwright.

I think in the presentation, it noted a target reduction of 70%, 90% in symptomatic COVID compared to placebo over 3 months. I'm wondering the assumptions that underpin that efficacy range and what neutralizing titer levels are required to achieve it.

Sure. So hopefully, that was laid out in a chart that appears on a slide whose number I can't recall quite off the top of my head. But when you see our analysis of the CANOPY study, which, by the way, comports very well with prior analyses of both ours and others' antibodies, you will note the exact titers, and the exact clinical protections expected from that relationship. So it's really -- when we're using these assumptions, it's important to note we are drawing them from lived empiric controlled study experience just over the last few years. So Those, I think, charts are drawn directly from a paper you can currently find at least in medRxiv [indiscernible], which is to do with the correlate of protection analysis for the immunobridging of monoclonal antibodies. These are all increasingly well-defined relationships of continuous biological phenomena that predict the clinical benefits that we expect. So 70 to 90 embraces the range, subject to some error, of course, that would be predicted by the titers we expect to deploy.

Right. That's helpful. And then just actually on the commercial side, I'm wondering if you can talk a little bit about learnings from the PEMGARDA launch? And as well, I'm wondering how you're preparing for potential pharmacy-centered intramuscular delivery. Should we expect VYD2311 to be reimbursed by Part D or Part B?

So this, I will ask Tim Lee to chime in.

Thank you, Marc. Yes, great question. I think starting off, we ended the presentation sharing the foundation and the work that's been done with pemivibart, PEMGARDA, the broad recognition from societies and caregivers and KOLs and how that has been laid. We do see a better form factor, to your point, allowing for far greater access and availability for a broader set of patients. And so with that, we are looking deeply into all of those things that you mentioned, right? Because with that form factor not being an infusion, being injection, we see potential for it to be delivered in medical settings like a potentially MinuteClinic type of place as well as others. And so we're rapidly looking into that. And yes, it will have the ability to be reimbursed via both B and D, but we're certainly going to be ensuring that access is widely available, and reimbursement correlates with that.

And then just on the sizing of the market, there's a slide, I think, that highlights $3.8 billion in 2024 vaccine revenue. And this underscores potentially the opportunity for more durable alternatives. So I'm wondering how are you quantifying the commercial potential for VYD2311 in this endemic COVID environment? And to that end, how does the LIBERTY vaccine comparison study, how will that help, if at all, in terms of gaining more of that core COVID vaccine market?

Sure. Let me start, and then I'll ask Tim to chip in. Look, I think it's a little premature to start to try to pin down exact portions of what we see as, frankly, very, very large numbers. So for us, I guess, stay tuned as we move through the next year, and we will try to refine our thinking on where this goes and exactly how it goes there. I think what we're trying to point out is this. We see a landscape today that is substantiated largely by vaccines that confer relatively more modest, relatively short duration protection and which carry a reasonably noticeable inflammatory penalty. And so when we ask ourselves how much medical value does that create, it gives us a sense of let's say, level X, and that level X has correlated with multiple billions of revenue. Now when we look at our monoclonal antibodies, we see a potential for, of course, better protection over a longer term with far less, if any, of express inflammatory potential and associated safety and tolerability issues. And so when we consider that, we see an opportunity to create much more medical value as we scale. So again, I think we're in the rare position of moving into a marketplace that is dominated by an incumbent that is not particularly well liked among people who might benefit from its use, and we intend to build on that as aggressively as we can. Obviously, today, we're a relatively smaller company, and we are looking to change that fast. So I think as we go through the next year, we will be scaling our work to try to match some fraction of the scale of that opportunity. And then over the long term, I think what we see is potentially profound. We see an opportunity to protect many, many millions of Americans from a virus they manifestly don't want in a way that is, I think, otherwise going to be very difficult, if not impossible. But I'll pause there and see if Tim has anything to add to that.

No, I think that's a great summary, Marc. As we look at the data that Marc shared earlier, really well-done survey data from the CDC around people who did not choose to be vaccinated with either COVID, flu or RSV. You see the primary differences among those 3 as being distinct among those categories. And when you look at COVID, the reason why people did not get the vaccine, it wasn't that they weren't afraid of the virus. It was actually they were more hesitant around the treatment or more hesitant around vaccine. And that's a place where we really have an opportunity to build in that category and excited about the work that medical societies, as I said earlier, recognize the need for monoclonal antibodies. And fortunately, monoclonal antibodies are widely used in medicine today. And so we have a real opportunity to build the category here, and we'll continue to do so.

And our next question will be coming from Tom Shrader of BTIG.

Nice for holding the event. Nice to hear some of the stuff calmly discussed. A couple of remedial questions really for me. Do you understand why the other antibodies fell off in efficacy so poorly? And do you expect any IP or protection around the type of epitopes you use? Or is it all going to be on the antibody itself? And then I have a remedial manufacturing question. You have a 250 mg dose and you kind of know if this got popular, what you could charge. Is that an easy match from the manufacturing point of view? Or is that a barrier to get 250 mg dose at a price that's reasonable?

Okay. Great. A couple of things in there, and I'll go in some degree of order. I think regarding proprietary intellectual property related to the epitope, I assume people listening are now scribbling down notes and considering fascinating options, but I don't know that that's a big part of our intellectual property plan. It is related to your other question, which is why these other antibodies have fallen off as opposed to ours. And I think if you zoom out and try to think through some of what we presented on these slides, it relates to something that is hardwired into our very discovery process itself, which is a desire to innovate antibodies that don't behave particularly like human or mammalian antibodies in terms of the site on the target that they bind. So when we saw the Omicron shift in SARS-CoV-2, we saw many early antibodies beginning to struggle. And that is because very typically in the pharmaceutical industry, such pharmaceutical antibodies are sourced from mammalian discovery systems. They are either from human convalescent serum or they are from mouse-based systems that recapitulate a human immune system. And so what you're essentially doing when you discover antibodies in that fashion is you are picking your candidate medicine straight from the very evolutionary pressure pool that is moving the virus around. So it sounds maybe like a minor distinction, but I assure you, it's not particularly easy and I think has been the center of why empirically our antibodies have so far lasted, which is, well, we endeavor to work on molecules that sit away from typical immune and other mammalian pressure sets. And so typically, if you look back in time and consider some of those antibodies, I think you will find them binding classically antigenic sites on the virus. And it's just sort of a problem that is hardwired into most discovery technologies other than ours. And if that's not clear, I'll ask Robby Allen to chime in down the road. But let me come back to that and see if you have a clarifier because I want to answer your manufacturing question. We're pretty gratified to have what we think are very attractive manufacturing yields, 250 milligrams of antibody is not a particularly onerous quantum of drug to consider administering to millions of Americans at a go. So it is another area in which we at Invivyd would imagine scaling, of course, and we would be thrilled to scale our output to match what we hope would be substantial demand. Of course, in all of these new endeavors, it's possible we will have periodic mismatches along the way, but we'll be doing our best. I think what I'm trying to say is under scenarios in which we run into substantial manufacturing output issues, I think we'll all be very happy.

And I'm not showing any further questions. I would now like to turn the call back to Marc Elia for closing remarks.

Okay. Well, thank you all so much. And please do know that we, as a management team, are available throughout the day to take any more questions. And meanwhile, really appreciate your time and attention this morning. Thanks, and goodbye.

And this concludes today's program. Thank you for participating. You may now disconnect.