Adagio Therapeutics Inc Aktie

Good day, and thank you for standing by. Welcome to the Invivyd First Quarter 2026 Earnings Conference Call. [Operator Instructions] Please note that today's conference is being recorded.

I will now hand the conference over to your speaker host for today, Katie Falzone, Senior Vice President of Finance. Please go ahead.

Thank you, Olivia. A short while ago, we issued a press release announcing our Q1 2026 financial results and recent business highlights. That press release and the slides that are being used on today's webcast can be found in the Investors section of the Invivyd website under the Press Release and Events and Presentations sections, respectively. Today's discussion will be led by Marc Eiia, Chairman of Invivyd's Board of Directors. He is joined by Dr. Michael Mina, Chief Medical Officer; Dr. Robert Allen, Chief Scientific Officer; Tim Lee, Chief Commercial Officer; and Bill Duke, Chief Financial Officer.

During today's discussion, we will be making forward-looking statements concerning, among other things, our corporate and commercial strategy, our research and development activities, our regulatory plans, certain financial expectations, 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 that could affect Invivyd's business can be found in our filings made with the U.S. Securities and Exchange Commission, including our most recent Form 10-K, which are also available on our website.

I will now turn the call over to Marc.

Thanks, Katie. Good morning, and thank you all for joining us. It's an exciting time for Invivyd and an exciting time for the future of infectious disease medicine. The first quarter of 2026 and the current quarter have been very busy here, and we'll use this time today to remind you of our news and put it into the broader context of our mission. I'll start by recapping some recent events.

First, our pivotal program continues at high speed. As you may remember, we triggered our DECLARATION study upsizing in early April, and the recruitment speed into this additional upsized cohort occurred well faster than our internal expectations. Given the lull in COVID-19 and overall respiratory disease burden in April, we actually slowed recruitment to stretch our upsized patient exposures into what we would expect to be a normal summer COVID wave. We've resumed full speed recruitment and believe we will finish up imminently, keeping the program on time with our previous estimates.

Next, we have substantially increased our government affairs activity of late, and I'll share some general observations about what we are seeing and hearing in Washington, D.C. The overall landscape from the Invivyd point of view is highly positive, but we are very focused on making sure policymakers are aware of the potential of our medicines and so have no intention of slowing down our work. We recently published a manuscript, a preprint we call safety first that we think is perhaps more profound than it may seem at first glance.

Our colleague, Dr. Michael Mina, will walk through some of the implications of our work in more detail in a moment and describe how the analysis we are performing bear on potential overall American wellness. Finally, we're happy to announce that as we expected, we formally confirmed virus neutralization of our medicines against Omicron BA.3.2, a COVID virus variant that may reveal more about overall evolutionary trends than posing any particular and clinical challenge. Dr. Robert Allen, our CSO, will describe those findings in a bit more detail. So where does all this leave us in the big picture?

We are seeing continued growth in our monoclonal antibody revenues, while COVID vaccine utilization and revenue declined. We see overwhelming demand for our antibody study at the recruitment level, while recently, we read another company in the field abandoned a major vaccine study for lack of demand. We think this means we're on to something good. Beyond the centerpiece of our company in COVID-19 prevention and treatment, we recently disclosed our early discovery pipeline in the presentation given by Dr. Allen at the World Vaccine Congress. You can find the link on our website, and you will note that beyond the measles antibody program we've already described, there are several vaccine preventable pathogens on the slide, including mumps and rubella, the other components of the MMR pediatric vaccine, as well as Lyme disease and several other burdensome pathogens that may benefit from immune supplementation or treatment via monoclonal antibodies that can operate beyond the limits of vaccinology.

We believe that in Invivyd, we've created the premier industrial platform for the discovery, development and commercialization of monoclonal antibodies for burdensome viruses with major associated public health benefit and potential shareholder value creation. Going forward, we think investors and the broader medical community will be pleased with the scope of our technical capability and the unique role our molecules can play in improving health outcomes by adding to or synergizing with vaccination.

On government affairs, we've taken the opportunity to introduce Invivyd in our work to portions of the new administration and key advisers and influencers in that space. Without going into too much detail, we're happy to share some impressions that may surprise investors. First, our observation has been that a great many people within and the leadership of the MAHA movement often demonstrate a superior technical understanding of basic and translational immunology than we commonly encounter.

Second and perhaps less surprising, these same people often have a much more clear and detailed understanding of both the randomized and observational data around COVID-19 vaccinology than much of the medical establishment. It actually appears that the data on COVID-19 vaccines presented by the CDC over the last 5 years has been taken up and understood more clearly by elements of the MAHA movement than even the traditional infectious disease medicine establishment. That was unexpected and welcome news to us.

More and consistent with the wide range of various sources on this slide, we have observed consistent, direct and clear support for the concept of monoclonal antibody immune supplementation, not just from the medical establishment, but also from this new segment in modern medicine. Whether you are President Trump opining on the value of monoclonals or Tony Fauci or even Joe Rogan, it doesn't appear to matter what political or scientific perspective one holds. The concept of supplementing human immunity by adding the power of monoclonal antibodies appears to be regarded as a universal positive.

Some investors of ours have raised concern that "vaccine skeptical" or hesitant communities may not appreciate monoclonal antibodies. I'll take this opportunity again to disagree. Our clear experience is that to the contrary, people who describe themselves as vaccine skeptical are telling a precise truth. They're not medicine skeptical and they're not confused to assume they are as to risk missing the point and inflaming the overall debate.

Finally, and consistent with now years of experience, we have actually shared these impressions with multiple media outlets have authored multiple op eds about the shared common ground across this polarized modern infectious disease medicine complex, but have enjoyed almost no traction or uptake. The apparent fighting about vaccines and health playing out in the media will continue so long as the public continues to click on ads and find conflict more interesting than resolution.

Meanwhile, we're excited to continue to work for a better way forward, and we're thrilled with the level of understanding of and appreciation for our work we've encountered. By working in COVID and infectious disease generally, we have a duty to the public, and that begins with educating our leadership on the scientific and medical landscape to the best of our abilities. We expect that to continue. We're also beginning to educate the public at scale on the role antibodies play in basic human immunology.

The last few years have, of course, created all manner of misunderstanding and misapprehension in the public, thanks to the strange circuitous relationship the public has enjoyed with vaccinology. We think a better future starts with simple, basic immunology education that can be found on Pages 1 through 3 of any immunology textbook. But who better to inform the public on these issues than Lindsay Vonn, who is, we can assure all of you, the real deal genuine article and perhaps the single most inspiring human being many of us are likely to encounter. It is clear from our personal experiences at Invivyd that you don't want to race against her, you don't want to tell her that she cannot or should not do something.

On the flip side, you actually might want to dare her that she can't possibly do scientific education for the American public. She appears to be undertaking this challenge with real vigor. We've partnered with Lindsay on our antibodies for anybody campaign and are very pleased with the attention garnered in our initial rollout. As we move forward as a company, it's essential that we keep our eye on the basics that investors may take for granted, but on which most consumers and many health care providers are not actually all that clear. Accurately identifying the role of antibodies in human immune physiology for the general public will be an important contributor to the value of our work long term.

I'll now turn the call over to Dr. Michael Mina, our Chief Medical Officer.

Thanks, Marc. As most of you know, the pivotal program for VYD2311 is well underway. A quick update on our ongoing DECLARATION study. We're pleased that the Independent Data Monitoring Committee, or IDMC, recently recommended that post-dose subject monitoring be reduced from 2 hours to 30 minutes after review of unblinded 2311 safety data. We've modified the DECLARATION study accordingly and believe this update may reflect an encouraging indicator of product safety and tolerability post administration.

In addition to DECLARATION, we aim to have the LIBERTY study open and recruiting shortly to assess the safety and immunology of COVID-19 vaccine combined with monoclonal antibody and to assess in a direct prospective fashion, the safety and tolerability of monoclonal antibody approaches to immunization against COVID-19 mRNA vaccination. This comparison should go a long way to providing a direct view on what we believe is the first advantage of an antibody approaches infectious disease prevention, high safety and tolerability. Our view is that symptomatic vaccine reactogenicity is a major driver of people's willingness to get vaccinated and agree with data from CDC and recent statements from Sanofi indicating the same.

On that point, I was pleased to recently work with other Invivyd authors and Dr. David Putrino of the Icahn School of Medicine on a recent manuscript that evaluated adintrevimab, an old investigational antibody from Invivyd that completed a placebo-controlled pivotal study for the prevention of symptomatic COVID-19 similar to the DECLARATION study. More adintrevimab is highly similar to 2311, different by only a handful of amino acids in the variable region and was administered intramuscularly at a similar dose to 2311.

Upon seeing results from Sanofi's COMPARE Phase IV study comparing protein-based COVID vaccine against mRNA-based COVID vaccine, which demonstrated a statistically significant difference on early systemic reactogenicity symptoms such as headache, fever, chills and fatigue over the first 7 days post vaccination. We undertook an analysis of the same symptoms from the adintrevimab EVADE study over the same duration. The results of our analysis are presented on the slide as they can be found in our manuscript. There are real methodological differences in how these symptom data were collected in the COMPARE study versus the EVADE study, and so we will have to wait for liberty for an apple-to-apples direct evaluation.

Nonetheless, the comparative results are striking. We see as we'd expect that while COVID-19 vaccination relies on immune education and reeducation with its associated inflammatory response, monoclonal antibodies do not. As an epidemiologist and physician, there are implications to these data that go beyond a competitive or comparative profile and get the issues we must grapple with at the level of public health. If it's true that people's experiences with immunization directly influences their willingness to get immunized in the future, then systemic reactogenicity is itself an important consideration in public health. A vaccine that generates an 80% to 90% probability of 3 to 3.5 symptom days actually represents a meaningful portion of the symptom burden of an actual breakthrough COVID-19 infection. And so it's not surprising that we see declining vaccine utilization and therefore, declining protection from a virus and SARS-CoV-2 that is still inflicting a substantial medical burden on humanity.

We can calculate the cost to society and symptom days per million immunizations given. Logically, if a person starts with a high probability of a few days of real burdensome systemic symptoms from the vaccine itself, then the vaccine will have to be very protective against symptomatic disease for quite a while to generate a net benefit in overall symptomatic patient days. Recent COVID vaccine efficacy data does not make a particularly compelling case on that dimension with estimated protection from symptomatic disease peaking at approximately 50% for a relatively short duration.

By contrast, 2311 data look like adintrevimab safety data and do not start patients with a meaningful symptomatic burden. A monoclonal can be essentially minimally protective on the order of 10% to 15% protected with symptomatic disease while still generating a net benefit in symptoms. We'd expect any monoclonal antibody we generate to have much more meaningful protection, but the point remains the more reactogenic the vaccine, the higher the public expectation will be for consequent strong and durable protection.

The results of our modeling are presented here on Slide 11, and we expect to make this point with more refined modeling and present it to relevant policymakers and regulators as much as we can in the coming months. The big picture is clear, and I want to be clear that this is not some form of anti-vax statement, but rather the reality of the data. Our major concern at Invivyd is protecting people and doing so in a way that allows vulnerable populations to stay safe and well because low-dose intramuscular COVID antibodies appear to confer very low levels of systemic reactogenicity.

We believe that intramuscular monoclonal antibodies can address these experiential problems and can exert meaningful population level benefits at scale. Obviously, we'll look to our DECLARATION of LIBERTY studies to provide high-quality prospective and controlled data on these safety and tolerability issues near term.

I'll now turn the call over to Dr. Robert Allen, our Chief Scientific Officer.

Thanks, Michael. And we can turn to Slide 15 very quickly. And as we expected, we continue to see attractive neutralization data for our medicines against relevant SARS-CoV-2 variants. This is consistent with our hypothesis and the industrial process for druggable targets like the SARS-CoV-2 spike protein. More, we continue to believe that our medicines engage important territory on the RBD. And as usual, we have no expectation of future activity concern based on the virus variant landscape we see today.

On Slide 16, beyond COVID, in our early pipeline, we have disclosed what we view as potential best-in-class antibodies to treat and prevent critical virus threats in measles and RSV. As Marc noted, we are expanding our early discovery across a host of viruses, including vaccine preventable viruses such as mumps and rubella and key threats to chronic health in America such as Lyme disease or Borrelia burgdorferi. We see monoclonal antibody technology as underutilized across infectious disease medicine, both for prevention and treatment in many diseases and are looking forward to using our technology to open up new cases, new use cases that meaningfully improve our ability to keep people well in the face of both established and emerging viral threats.

Now, I'll turn the call over to Tim Lee, our Chief Commercial Officer, to discuss our commercial progress.

Thanks, Robbie. We were pleased that PEMGARDA once again grew year-over-year, now at 22% over 1Q in 2025. Traditionally, the first quarter is a bit weaker in the pharmaceutical industry and indeed in infectious diseases and preventive medicine, one traditionally sees a major seasonal drop-off from the third and fourth quarters to the first and second. Interestingly, we are not seeing nearly so much of that same seasonal change as you would expect from a seasonal respiratory vaccine.

We attribute our relatively more stable P&L to the fact that SARS-CoV-2 has periodic waves, including the anticipated coming summer surge. And even at low levels is a ubiquitous and ever-present threat. Vulnerable populations and their care teams appear to be making more rational decisions that reflect the nature of this viral threat. Elsewhere, our leading indicators are showing good ongoing growth, and we are preparing for and looking forward to transitioning forward into an entirely new kind of COVID antibody. And we believe that can be game changing in the form of VYD2311, if approved. Although the distribution model will be entirely different, we are pleased that much of what we have built for PEMGARDA already is going to be leveraged and expanded for VYD2311.

Turning to Slide 19. We're also increasing our exposure to new mechanisms by which health care providers access information about medicine, including the leading AI platforms. These tools promise to dramatically increase the efficiency by which companies like Invivyd as well as much bigger companies can disseminate appropriate information about our medicines to health care providers. Our expectation is to continue to think differently about how we design and deploy our resources. Our expectation is that these tools will help us to differentiate from more traditional pharmaceutical companies who historically have relied solely on feet on the street, and we'll be focused and nimble with our sales force as well as the resources we bring to market. So far, our early efforts with AI tools appear to be encouraging, and we will meter our investments in these tools appropriately over the coming quarters with our PEMGARDA business.

Turning to Slide 20. Finally, we have increased our direct-to-consumer efforts, which although still in its infancy, are beginning to generate greater disease and brand awareness. This is another efficient channel that we'll expect to ramp up if VYD2311 is approved.

And with that, I'll ask Bill to cover the financials.

Thanks, Tim. Turning to Slide 22. The first quarter of 2026 included meaningful clinical spend to support our DECLARATION clinical trial. This is a very substantial investment compared to our ordinary clinical and SG&A spending, but one we feel has extraordinary commercial potential. Our cash position remains very strong, especially considering the additional cash raised in April from long-term investors who wish to increase their position through our at-the-market offering facility. We are looking forward to continued PEMGARDA growth and as the pivotal trial for VYD2311 winds up over the coming quarters, a return to more normalized R&D spending.

Turning to Slide 23. You can see the effects of VYD2311 spend on our overall burn via this chart that provides a bridge from Q4 '25 to Q1 2026. You will note that we have also made targeted investments to prepare for VYD2311 commercialization, if approved, although it is reasonable to expect that some of these investments in personnel and commercial infrastructure could benefit our current PEMGARDA business as well.

With that, we are happy to take your questions. Operator?

And our first question coming from the line of Josh Schimmer with Cantor Fitzgerald.

First, for the 30-minute post-administration monitoring time for 2311, do you anticipate that would be ultimately included in the label? And if so, how might that impact adoption? And then second, the last I checked in terms of the wastewater monitoring for COVID, it's still at a mid-year. But do you, from your vantage point, see any indications of the new summer wave starting to emerge yet?

So I think just to go in order, hey, good morning, Josh, by the way. So on the 30-minute monitoring, I think it's a little premature. Now when we go out into the field, and you will all, I'm sure, remember from the pandemic, different medical interventions administered in different settings will carry with them some obligation typically, right? And particularly, if I recall back in 2021, I wondered the hallways of Walgreens for about 12 to 15 minutes before a pharmacist told me I could leave. So I think to us, what you're really looking at is the evolution of a clinical program only at this point. And it's -- I think as we go through FDA and then out into the field, we would hope that something that has a profile that we would expect to be relatively modestly burdensome barring the administrative out, I think let's see. I certainly don't think of it as something a variable that we are concerned about in terms of adoption and uptake bigger picture. But I'll just invite anyone else from Invivyd to have a view or?

Yes. Josh, it's Michael Mina. Certainly, what the wave ones are saying that's going to be based on the studies and our discussions. But we have -- we anticipate from what we know, in particular from a base that we're going to see high tolerability, low reactogenicity. And overall, we would anticipate that as we move into the future with an IM monoclonal that practice is going to start to look more like the way that people currently wait following a vaccine, which will probably -- as people get more comfortable, physicians get more comfortable, we would expect that concerns that would lead somebody to stick around for 2 hours would certainly fall by the wayside.

As I reflect, I would also just add, remember, early on in the -- people would often wonder what would be the biophysical relationships between, say, adintrevimab, pemivibart and then 2311. And we would have always reminded folks that when we deal in part, we are dealing in extraordinarily high doses of monoclonal antibody delivered via IV infusion. And so as we moved into the DECLARATION program, I think people were perhaps justifiably wondering, would there be meaningful per-administrative issue like, for example, hypersensitivity and allergic reaction that is common at some low rate with protein-based therapeutics and monoclonal antibodies. And again, going back to my remark about the evolution of a study, I think, again, we don't know what the IDMC is looking at, but it is to a large degree to us make sure and we would expect that there will be very little to talk about on this front as we get through the final data. But of course, there's one way to find out, and so shall we all in time.

On the wastewater I think, again, I'll ask Robbie in a minute if he has anything to add. But I think what we essentially know boils down not in terms of variant perception from what most people can see, although different wastewater services and sites have different levels of latency, okay? So all of us depending on what source we're looking at, are looking some number of days in arrears. I think there is something reassuring to the simple arithmetic of exponential growth. COVID and is a little unique among the more classically seasonal respiratory diseases. COVID, it appears to us since now 6 years to either be declining or to be rising. And it certainly appears to have radically slowed its level of decline, albeit now down to low levels. Typically, that would portend a relatively predictable rise. And the critical thing from an Invivyd standpoint is to make sure that we have the maximum number of patient exposures out there when that rise occurs.

And so again, maybe a little bit of inside baseball from a practitioner standpoint, I think it's, in some ways, unfortunate the DECLARATION started up about 2 weeks, 2 weeks only later than in hindsight, could have been ideal relative to a December, January wave. And is that a big problem or a big issue? No, certainly not. But it does go to how finally we try to map these things and tune these things to the benefit of event rate accumulation. So look, all I think I'm saying is at a certain point, we start to get conviction that a turn is either upon us and not yet detected or imminent to a point where a forward 3-month lens feels like a very attractive place to place our patient exposures. And it can't be a guarantee. It's just the experience of 6 or so years of watching this stuff. We're all going to, like we say, find out together, unfortunately, on this point, but I think we feel pretty good about our setup going into this summer and then the ramp-up of the study.

And our next question coming from the line of Patrick Trucchio with H.C. Wainwright.

Congrats on the progress. Just a couple of follow-ups on DECLARATION. The first is, I think you mentioned that even low efficacy antibody, monoclonal antibody could generate symptomatic benefit, but we're expecting much stronger protection. So I'm wondering, though, what point estimate or lower confidence down would you consider clinically meaningful, commercially viable and supportive of a BLA? And then separately, how should we think about the single dose versus multi-dose arms? How is the, I guess, the statistical hierarchy structured and commercial read-through that we should see between the single dose and monthly dose arms?

Okay. Thanks for that. Let me start, and then I know some others are going to weigh in. Okay. So on your first question, in some ways, you posed the considerations in what I think are a really interesting and important order, okay? And I'm going to go backwards in effect. In terms of what would be required for BLA, recognize that, that's a determination made by a small group of people who work for the federal government, and they make the rules and we all follow them. So we will all end up being in receipt of whatever it is, the U.S. FDA deems a positive risk benefit for the American public. We certainly, of course, expect a much better VE. We're certainly, of course, providing antiviral titers that we would imagine would carry much higher VE.

But then I'll get to your other points. What is commercially viable? Well, today, there's $3 billion or so in U.S. revenue of something that would appear to not have a particularly impressive nor particularly durable VE. So your mileage may vary on that point. And in terms of what is clinically meaningful, I think actually, whether or not you mean it, of course, you are getting at the heart of the analysis we're providing here, which is the goal of clinical medicine and infectious practice is to keep people ground. And so I think the point we're trying to demonstrate here is just that it's -- we're all operating against a very high proposed bar of overall profile when we deploy these maps. We're looking for very, very high protection at a very, very low symptomatic penalty or tolerability penalty. That's our goal.

But if you asked us what was clinically meaningful and you were talking to, let's say, a vulnerable person, and here, I'll just use myself as a fun example because I happen to be here and I'm speaking. I would be thrilled if I could routinely access something that is very low penalty modulated my risk of symptomatic disease. The reason I say that is because symptomatic disease is going to define, yes, my day-to-day experience. But typically, one would imagine that it is also a predicate for derivative follow-on benefits, right, such that if I don't get sick, it's probably unlikely I'm going to go to the hospital. If I don't get sick or go to the hospital, it's probably unlikely I'm going to die.

So again, I would just point out, you actually did [Technical Difficulty] like all of these waterfalls of consideration that suggest to us, and we're very comfortable doing this, we are operating with the aim of delivering a very, very exciting new medicine that proposes to ask very little of patients or subjects in terms of tolerability and return something really, really meaningful, which would be relatively very high protection over a very long term. We think that is awesome. All we mean to point out is that indeed, let's say we were in a dialogue over time or in some point in the future with a group of people who have been designated in our social contract to decide whether or not these are useful objects.

Remember what DECLARATION is first designed to do, I think we would argue, establish safety and tolerability relative to placebo. I say that because we all know the calculation of protection in VE is going to be dependent to some extent on infectious disease attack rate in the study, so on and so forth. That is a probabilistic thing. Again, as we've disclosed previously, we feel like we're in great shape and looking forward to completing the study. But it's critical people not lose sight of the fact that if we are able to generate a highly active anti-SARS-CoV-2 antibody that is scalable and highly safe, it's a really good thing for society through viewed through any one of those lenses you proposed.

Now in terms of the single and multi-dose, I'll just remind everybody, we first embarked on a multi-dose cohort principally because the FDA asked us to demonstrate multi-dose safety, which is a perfectly reasonable request we're happy to provide. The reason we picked the increment of 1 month was to afford future subjects of these medicines the maximum reasonable flexibility in their dosing regimen, right, such that if somebody wished to take a medicine like this monthly, I suppose if we're so fortunate as to demonstrate safety and efficacy, and we're so fortunate to earn a BLA, they could do that on the basis of that multi-dose arm and DECLARATION.

Now the only reason we didn't pick, for example, an increment of 1 day is because if one were to take VYD2311 monthly, given the antiviral potency we see now, that human being would be carrying around a fairly extraordinary quantity of antiviral power, not to suggest more couldn't be a tiny bit better. But there's a limit, I think, to how much somebody is going to end up wanting to sort of gigamap themselves on the way to maximum potential protection. It's not to say we couldn't have done a day. It's just that we picked a month because that felt like a reasonable quantum that affords some flexibility. In terms of expectation, what you're asking is really about the probabilities of study conduct in this regard, right?

Meaning if we could run DECLARATION 10,000 times like a Monte Carlo simulation of outcomes, you would, of course, imagine you'd see some level of potentially low breakthrough infection in the single-dose arm and then some much lower level of breakthrough infection in the multi-dose arm, consistent with the modeling we provided in our correlative protection analysis that was -- that went into the literature just a couple of months ago.

So the math ought to math as it were, as you go through these things. But of course, this is a clinical trial. It has its own contours, and we're all going to find out what the answer is together. I only lit we can't run it 10,000 times because I think we would all feel very, very comforted about by the mean outcome and then the tails. Nonetheless, as we're doing it in sort of real time and operational space, we still feel great about our progress and what we think we're going to demonstrate.

Anyone else want to add to that or refine?

I'd just say getting to one of your first questions, it really comes down to risk versus benefit. And certainly, we know that COVID causes significant symptoms, and we expect the tolerability and the symptom profile of our mAb to be very, very low. And similarly, what Sanofi's COMPARE study recently showed, and I discussed it, but to be very clear, it showed effects of upwards of 90% of individuals or more with an mRNA vaccine or over 80% with a protein-based vaccine, directly getting 3 or so days of symptoms as a result of that vaccine. So that's a real effect on the benefit versus detriment scale of getting a biologic that's currently on the market. And we expect our overall safety and tolerability profile to be substantially better is our expectation. And so as we look at risk benefit, the point of what I said earlier is that we anticipate it will be significantly better than 15% efficacy. But even if something as extraordinarily low as a 15% efficacy, we still expect our medicine to provide a positive benefit/risk ratio.

And I think that that's really where we're going to be focusing a lot of our discussions as we move into the future.

And I can't help myself just because I've worked on the buy side for sufficiently long to know that I want to remind everyone the dose justification we selected for VYD2311 and the corresponding antiviral titers would conceptually generate a 70% to 90% protected benefit on symptomatic disease. So just because we're spending time contemplating it what happens at much lower levels, don't mistake that for a second as something we expect. We don't. We expect something much higher, and that's how we've dosed the medicine. I just think -- I think we think this is a really, really important concept for a whole lot of people, not just our investing partners, our capital partners, but also our counterparties across both infectious disease medicine, general medicine and policymakers to really think through.

This is a really important moment, not just for our company, but hopefully, for the future of this and potentially other diseases as we start to really understand the unique merits of an emerging modality that hasn't been deployed at particular scale. So we aim to do that, and we think it's really, really important to double underline and educate what we see as a really substantial benefit set that's available here to the public if we're so lucky to have the good luck we hope and earn a BLA.

Does that all make sense? I know that was a lot.

And our next question coming from the line of Tom Shrader with BTIG.

Congratulations on a nice quarter. A couple of quickies on safety, and then I have a monitoring question. But the surveillance time, what is that for a vaccine now? Has that gone away? My memory is you're supposed to -- you were supposed to sit for a while in that case, too, so maybe 30 minutes isn't differentiating. And then I apologize if you said this, but the AEs you see, do you describe them blinded? Have you seen anaphylaxis? And again, you mentioned it, I apologize. And then I have a monitoring follow-up.

Okay. So on post-vaccine dose monitoring, I will say, I don't believe any of us in the room understand the current labeling off the top of our heads. I remember -- the practice of medicine, of course, out there runs very different depending upon which provider someone runs into, in what context and what that subject is or is not, right? So I'm going to defer because, frankly, I suspect that what was very clear, very clear in 2021, you will take this vaccine and then you will wander around or sit quietly for 15 minutes. I don't know the extent to which that is actually cued to out in clinical practice today anymore.

So stay tuned. But again, I think we would imagine that if we're successful in our work, we would be given equivalent consideration, if not superior, right? Let's just see how the profile of the medicine plays out.

In terms of monitoring our blinded pooled safety data, I'm just going to decline to answer that question mainly because while it's a fun thing to contemplate, we are, of course, running a ongoing pivotal study. And I think doing exercises such as you're suggesting raises the potential for type 1 error that we really don't need in our lives at this point. So I think all we see is that going back to adintrevimab, which is, again, a highly structurally related antibody delivered at an approximately equivalent dose, there was not much to write home about. And you'll see that in our analysis of the AVADE study. And as we have DECLARATION unfold in real time, we can only make the loose inference that a change in monitoring time may well reflect some measure of comfort that the IDMC would also have. But we don't know that. It's just a supposition we can make on the basis of the representation. So I apologize. I just don't want to get too into sort of fun but dangerous looks at ongoing studies that we're not doing.

That's a fair point and a good reminder to keep the trial clean. On the monitoring front, where is that these days? Is it as robust as it was years ago? Do you have good surveillance? And I'm curious, given you have essentially instant protection, you could, in fact, be used to respond to outbreaks. And the question is, does the infrastructure exist that you should -- maybe the antibody is appropriate for highly at-risk people all the time, but maybe the bar drops if you realize that suddenly there's an outbreak in an area. So where is the surveillance now relative to where it was? And what kind of data do you get?

So Tom, thank you for that. And I'm going to apologize in advance because you've asked a question I love so much, you're going to have to sit a little longer than usual because I'm just too excited to answer it. The monitoring is more than sufficient for the purposes you're describing. So just to answer the question plainly, of course, there's less sequencing going on out there in the world than there was in 2021. But if you ever sit with us at Invivyd and you look through some of the analytics that Robbie and his team routinely study, back in 2021, you could identify clinical and wastewater variants at such comically low frequency. I'm not sure that the sample and the sequencer wasn't the only variant that existed like that on earth at the time, meaning it was an extraordinary resolution, wildly unnecessary, right?

Akin to counting the individual fleeves on one dog, it was stunning. We don't have that today, but what you still have very clearly is you can roughly know when and where COVID is and is not. And by the way, you can do it with flu, you can do it with RSV. There are now a whole host of services, again, mainly the focus on the fecal shedding and the wastewater, which is a perfectly wonderful way to measure the overall sort of location and timing of the burden. And the reason I love your question so much is, of course, we named our program REVOLUTION. We named our studies, DECLARATION and LIBERTY because I think the kind of data you're describing is the kind of data that can actually rationalize prophylaxis, meaning, why would I go get a COVID vaccine, let's say, that may only confer short-term protection if I don't reasonably anticipate a meaningful burden of COVID anytime soon.

Say if I'm on the down slope of a recent wave and appear to be approaching in nature, well, it wouldn't be particularly rational for me as a consumer to take on the side effect and tolerability burden at that time if what I'm exchanging it for is a pretty low probability of earning a benefit back in protecting me from disease, right? And look, some of those habits are well worn. Some of them are sort of cemented by typical public health guidance of, hey, it's fall, go get your vaccine suite. Well, it turns out that might not be the best way to skin the cat, so to speak, in 2026 when we do have access to all these data. And if you look at that chart, which I will concede is not the most intuitive concept in the world in our earnings slides, you will notice that part of the point of that is to note, if you want to go through a tolerability event, you really want to protect your way back out of future sickness. So in a future that a monoclonal antibody at scale can unlock, it would be our vision and hope that it's used rationally, meaning that individuals in concert with their care teams, in concert, we hope with the federal complex and using big data can actually start to allocate prophylactic medicine across space and time in a way that resembles the underlying community attack rate, right?

So that is a really substantial shift in infectious disease medicine prophylaxis thinking, but I think it would be welcome. And again, I apologize that was too long. And I'm saying all this in front of an epidemiologist physician who specializes in infectious disease prophylaxis. So once again, Dr. Mina, surely, you can clean that up.

Well, I just wanted to mention there was a question about the duration that somebody might be anticipated to have to sit around. Currently, on the vaccine labels, there's no longer any suggestion or specificity given to the clinicians around waiting time after administration of the vaccines, and we are expecting that will fall in a similar category on in our labels.

Regarding [indiscernible], I don't have too much more to offer than what Marc already mentioned.

Well, anyway, spread the word, Robbie. I think you're thinking in the right way. And I think what you're talking about could be a meaningful step change for the overall burden of disease in our society if we can pull this off.

And there are no further questions in the queue at this time. I'll now turn the call back over to Mr. Marc Elia for any closing comments.

Thanks, operator. Thank you all for joining us this morning. I hope it's clear that we believe we are on to some pretty important and big things, and these event sets are coming your way within months. So stay tuned, and thanks so much for joining us today. We're going to look forward to your questions throughout the rest of the day. Bye-bye.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.

Good day, and welcome to the Invivyd REVOLUTION Program and Measles Update Conference Call. [Operator Instructions] Please note, this call is being recorded. I would now like to turn the call over to Katie Falzone, Senior Vice President of Finance. Please go ahead.

Thank you, Michelle. A short while ago, we issued a press release announcing an update on our REVOLUTION program progress and advancement of our novel potential first- and best-in-class measles monoclonal antibody candidate for the treatment and prevention of measles. That press release and the slides that are being used on today's webcast can be found in the Investors section of the Invivyd website under the Press Release and Events and Presentations section, respectively.

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; and Dr. Michael Mina, Chief Medical Officer.

During today's discussion, we will be making forward-looking statements concerning, among other things, our research and development activities, our regulatory plans, 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 that could affect Invivyd's business can be found in our filings made with the U.S. Securities and Exchange Commission, including our most recent Form 10-K, which is also available on our website.

I will now turn the call over to Marc.

Thanks, Katie. Good morning, everyone, and thank you for joining us. We're very pleased to update you on our recent progress and how we think it sets up the coming quarters for our business. Our agenda today here on Slide 3 comprises 2 items we announced this morning, exciting progress in our REVOLUTION clinical program for VYD2311 in COVID-19 and then the discovery of our potential first- and best-in-class measles antibody, VMS063, which further broadens our antiviral portfolio and underlines our intended future business, treating and preventing multiple viral illnesses for vulnerable Americans.

Slide 4. It's worth reminding without going through all of the scientific data that underpins these observations that SARS-CoV-2 is transmitting essentially unchecked between Americans at all times, marked by major periodic waves of disease that exert real lifespan-shortening vascular, immunologic and end-organ damage. More, the COVID vaccines, now understood to confer relatively short-term protection in modern seropositive Americans against contemporary virus, continue to be a blockbuster pharmaceutical category even in the face of substantial controversy and declining utilization.

Our aim is to make those vaccines essentially a second-line option. We believe that most people underestimate how much COVID transmits at all times and especially during waves. Of course, our American understanding of this disease has been highly influenced by years of political messaging. But Invivyd, we consistently see that even in small sample size trials, we can reliably detect COVID disease burden, a stark contrast to the messages of "It's over," or "COVID is no big deal." Until there's an appealing way to prevent COVID disease for vulnerable Americans, our belief is that as a society, we will remain at real risk of unintentionally looking away from the ongoing disease burden problem. We aim to provide that solution as soon as we can to stop the mounting damage from unconstrained COVID infections.

Moving to the next slide, Slide 5. In contrast to vaccination via spike protein rendered in mRNA form, we see monoclonal antibody technology as the next step in our protection from the 2 common medical burden of repeat COVID infections. Unlike a vaccine, which in the case of an annual COVID vaccine boost is typically a step behind the virus evolution, Invivyd engineers antibodies to last across large quantities of virus variation. Our plan is to innovate and iterate our medicines to be higher quality and higher performance as variants emerge, not to chase the virus from behind. Further, we see antibodies as an attractive solution to the problems active vaccination faces.

By contrast to vaccines, we believe our antibodies will offer subjects access to protection that is immediate, equitable, noninflammatory or reactogenic and critically free of spike protein, itself an important inflammatory and fundamentally toxic antigen. If we achieve clinical success going forward, we believe we can scale production and drive access for millions of Americans who require or desire incremental protection, and we are eagerly looking forward to further progress with VYD2311.

Invivyd itself has worked to evolve to this moment. Our current medicine, PEMGARDA, has established proof of concept that we can durably drug an evolving target. VYD2311 represents our candidate aimed at broad population use with what we anticipate to be dramatically lower access barriers compared to PEMGARDA. Beyond VYD2311, over the long term, we will continue to innovate to more patient- and system-friendly medicines so that more people can live with fewer consequences from COVID.

On to Slide 7. Let's turn to our -- to today's update on the DECLARATION pivotal study of 2311. As a quick reminder, VYD2311 is minimally evolved from our currently authorized antibody pemivibart or PEMGARDA, but 2311 has substantially improved performance parameters, such as in vitro potency and in vivo half-life stemming from just a few but critical modifications to the antibody that we engineered with our proprietary discovery technology platform.

In collaboration with the U.S. FDA, we designed the DECLARATION pivotal study to assess the safety and efficacy of 2311 versus placebo. The study has 2 active arms, 1 single dose and 1 multi-dose, and our primary endpoint is the reduction in the rate of PCR-confirmed symptomatic COVID-19 sickness compared to placebo. This endpoint is consistent with our prior COVID RCTs, including the EVADE study with adintrevimab and the more contemporary CANOPY study with pemivibart.

The DECLARATION study has been designed to capture a range of potential efficacy levels embraced by prior monoclonal antibody work, including ours and competitors. Of course, the statistical powering of any infectious disease prevention trial, including DECLARATION, relies on the target infectious disease being present in the community where the study is conducted in order to get what a trialist would call attack rate or the clinical COVID case events, which distribute across study and control arms and which are required to appear in the study in order to demonstrate drug effect. Obviously, the attack rates of infectious disease can be unpredictable and somewhat random, both in community and in the trial population, but we do our best to plan for success. We believe that the U.S. FDA has productively engaged with us on the program on an ongoing basis with a similar goal in mind.

We are pleased for the DECLARATION study, but not surprised for America to note that, once again, at approximately the midpoint of base trial conduct, our DECLARATION study is indeed capturing blinded, pooled confirmed COVID clinical event rates at a level that gives us confidence in the ultimate statistical powering of our study as events are approaching our target level and indeed can already support statistical power to the higher end of our anticipated efficacy range. We also have announced this morning that even with our exciting and encouraging progress, we've conducted our prespecified interim sample size re-estimation analysis and have duly upsized our study to a modest extent as we designed prospectively.

Why? Well, we set this algorithm to be conservative in effect to dictate upsizing unless we were highly confident in overpowering our target VE rates. We are, to the extent feasible, planning to win and do not wish to cut it close, so to speak. We will touch on what we see as the next steps for this program shortly. But to generate the most compelling data we can in our study, we wanted to reach for additional assurance if it could come at minimal cost. The future is unknown so we cannot make promises about ultimate events and powering, but we are pleased with today's update to begin to turn our attention from event accumulation to now preparing to see the clinical profile of our medicine later this year and to begin commercial preparation in earnest toward anticipated BLA filing and potential approval.

We'd like to remind everyone listening to please revisit the data generated by COVID monoclonal antibodies in the pre-exposure prophylaxis setting. There are many compelling demonstrations, including the more recent studies in modern seropositive populations in which monoclonal antibodies are now deployed on top of population immunity. We believe the best guide to our thinking is data from our recent CANOPY study and the various publications describing the results achieved in CANOPY and the statistical correlates of protection derived there from.

In general, the efficacy levels conferred by monoclonal antibodies sit above current expectations from COVID vaccines, including upcoming potential data from studies that the vaccine companies are now conducting or at least attempting to conduct against contemporary virus variants in a modern American population. More, as we know, vaccine boost can involve meaningful and burdensome acute inflammatory penalty or so-called reactogenicity. We are looking forward to seeing updated data and making our plans to compete with these vaccines going forward.

To Slide 8. This brings us to 2 additional quick updates in the REVOLUTION program. We're on track to initiate the LIBERTY study shortly, which will assess comparative and combination safety and immunology between monoclonal antibody and mRNA vaccine. This companion study, we believe, may be very useful to regulators who may wish to offer guidance to vulnerable subjects who may wish both vaccination and monoclonal antibody. And it may be useful to us in building an overall portrait of the differences between monoclonal antibodies and vaccines in a single study that can be comprehensible and unambiguous to HCPs in vulnerable populations.

We are also pleased today to note that we have achieved alignment with the U.S. FDA on a pediatric study plan that can enable us to seek BLA for VYD2311 for use in pediatric populations ages 0 to 11. Encouragingly, while we proposed an age cohort de-escalation approach to the agency, they have been -- they have responded by recommending a parallel group design, including infants and babies aged 0 to 2 to start at the same time as other cohorts. This perspective, combined with recent feedback from our DECLARATION IDMC on broadened subject eligibility for DECLARATION to include pregnant women and the dropping of certain safety check-ins, certainly speaks to the increasing appreciation of the potential safety profile of low-dose monoclonal antibodies by key counterparties.

We have named our pediatric study plan DRUMMER to honor the contribution of the youngest revolutionaries to the American revolution in keeping with our overall program theme. The DRUMMER trial will only be actioned with success in the DECLARATION study and the broader REVOLUTION program.

Overall, we're pleased with our progress in our ongoing pivotal program. It's clear that COVID disease continues to exert an alarming toll on the health and lifespan of Americans, and it's further clear that the COVID vaccines used as the backbone of our protective strategy have reached important scientific, clinical and social limits. More broadly, we believe all humans can benefit from less exposure to COVID infection and associated inflammation and fewer overall exposures to the spike protein. This is especially true for immunocompromised persons and Americans with pre-existing cardiovascular and renal diseases or who are otherwise susceptible to the burden of excess infection.

With that, I'm pleased to turn the call over to Dr. Robert Allen, our Chief Scientific Officer, to quickly discuss the recent COVID virus variant before turning to our measles program update together with Dr. Michael Mina, our new Chief Medical Officer. Robert?

Thanks, Marc. On Slide 9, I know many of you have questions about the current COVID variant landscape, including the recent sensationalized BA.3.2.2 or so-called Cicada variant. I hope a few observations answer most of your questions. First, we have been watching this variant for well over a year now. It is not in any way new and in virologic terms could even be described as ancient. Parent spike protein on this lineage arose from the combination of Omicron B.1 and B.2, which, as you may remember, began circulating in late 2021 and early 2022, respectively. And in the case of Omicron B.1 generated an overwhelmingly global burden of infections. BA.3.2.2 and related subvariants have periodically arisen in certain geographies. When there are a few fitter viruses competing for transmission, akin to a sandbar, you can only see at low tide. It is a virus that is not particularly fit and some people see the structural configuration of its RBD as disadvantaged for ACE2 receptor access. We would tend to agree with that.

We do not see this virus as driving a particular wave of COVID. We see it as unlikely to achieve dominance for any particularly meaningful quantum of time and would anticipate it becomes outcompeted by fitter viruses that have easier access to the ACE2 receptor.

There are some interesting hypotheses for whether this virus preferentially infects children and why. But those, in our view, are speculative at this time and sit beyond the scope of this call. Otherwise, this virus is only distinguished by what it may be teaching us about virus evolution and structural diversity.

Specifically, as a very old set of spike protein mutations that are able to have some limited success currently as recycled rather than brand-new structural space, it is tempting to wonder if we are beginning to see some boundary to the seemingly endless variation SARS-CoV-2 has demonstrated thus far. We do not have our own proprietary neutralization data against BA.3.2 yet, but we recently noticed an independent laboratory published VYD2311 data that looked attractive and which removes some of the suspense. Generally, because of the fundamental nature of cellular virology assays, when we see a positive result anywhere, it tends to portend attractive neutralization most everywhere as positive results are generally harder to earn than negative.

Zooming out, we, at Invivyd, have been contemplating this virus and its evolutionary backdrop and meaning for our innovative medicines for more than a year. After all, our medicines are designed to target the spike protein RBD because it is, to us, the most efficient and reliable way to interrupt virus pathogenesis. We have built our platform to address a theoretically infinite quantity of virus variation, but we were provoked by the presence of this recycled variant early. Consequently, one of our next-generation antibodies for COVID was selected last year in part for attractive potency versus a panel of contemporary viruses that included BA.3.2.2. If we are beginning to see an equilibrium develop or an exhaustion of available combinatorial space, we believe we can consider making a single antibody that never requires updating. Indeed, it is possible we have already done so. We evaluate these opportunities constantly, and we look forward to updating you all if any news emerges on that front.

On Slide 10, turning to our measles update, for which we are privileged to be working with a bona fide clinical and scientific expert in Dr. Mina, I will talk briefly about the genesis of this program, and then we will turn it over to Dr. Mina.

First, let me remind you all that last spring, various physicians responding to measles outbreaks in the U.S. asked Invivyd, given our expertise with monoclonal antibody technology, if we could make a measles antibody for their use in clinical practice. We undertook a typical Invivyd discovery campaign, which involves studying the native human antibody repertoire against measles, which is predominantly directed against the measles hemagglutinin (H) and fusion (F) proteins and then conducted extensive sequence analysis and structural biology to do hit-to-lead optimization of our candidate biologics lineages. This involves the creation and assessment of tens of millions of candidate heavy and light chain combinations, which can be combined to create what we see as an optimal lead candidate medicine with impressive biophysical properties, the VMS063.

In Slide 11, we believe that we have achieved performance on key biophysical criteria such as potency, breadth and developability that may represent best-in-class properties even over the long term. Further, if another group can improve on these characteristics, the benefits of doing so may not be clinically perceptible.

VMS063 has demonstrated highly potent neutralization of key circulating and ancestral measles variants in both authentic and pseudovirus systems and is an overall highly attractive biologic candidate medicine. We have actioned preclinical development of VMS063 and are looking forward to greater engagement with public health and regulatory authorities on development pathways near term.

With that, I'm pleased to turn to Dr. Michael Mina to walk through an overview of the disease and antibody use cases.

Well, thanks, Robbie, and hello, everyone. It's a pleasure to join an investor call for my first time here at Invivyd. Measles is a topic on which I've spent a substantial portion of my academic career, and I'm thrilled to be working with Invivyd on what we see as the first potentially important development in measles clinical practice since 1963, the year the vaccine was introduced in the U.S. and coincidentally 63 years ago, and that's the inspiration for VMS063.

Slide 12. Quickly, I'll remind you that measles is one of, if not, the most infectious viruses known to humankind with an R0 of approximately 17. Today, in the U.S., we're undergoing outbreaks of measles at a scale we've not seen for over 30 years. Many of you may be aware that vaccine hesitancy is [indiscernible] as accelerating these trends, but there's more to the story than simply populations unwilling or unable to vaccinate.

As a general matter, survivors of measles infections carry higher antiviral titers for life and vaccine recipients, which is normal and well understood. Because the -- because the first recipients of vaccine-induced immunity are now approximately 63 years old, the portion of the population carrying higher titers from natural infections has been dropping steadily and now is facing their own elderly immune senescence.

The measles vaccine is obviously highly effective, but of course, it is dependent on overall immunity in the population, which has been steadily dropping over decades as the infection experienced American population becomes replaced demographically by a vaccinated population. That drop in overall herd immune protection can be measured directly, for example, in pooled blood donor sera or pooled immunoglobulin, also called IVIG, in which anti-measles antibody titers have been steadily dropping for decades. Now as fewer Americans vaccinate, particularly in the wake of the COVID pandemic, the overall immune status of the population is dropping even faster. Thus far, the U.S. has not officially lost WHO elimination status for measles, which means we have not measured sustained transmission over 12 months. However, if current trends hold, it's reasonable to expect a significant burden of measles in the U.S. that will grow increasingly more difficult to control vaccination, especially among people choosing to delay or forego measles vaccines.

Slide 13. Many people carry the mistake and belief that measles is a benign infection. However, the historical and current trends in the U.S. are not reassuring. There's a significant burden associated with infection, including hospitalization, death and complications, including encephalitis that can damage neurologic function, follow-on issues after acute infection, such as immune amnesia and the risk of opportunistic bacterial infections, which is an area of my own prior research, along with low-frequency catastrophic late complications, all suggest that treating to disrupt these potential longer-term complications could have significant medical value.

Slide 14. Even with the vaccine as highly effective as a measles vaccine, unmet needs remain. Just as herd immunity drops with vaccine-induced titers, so for example, does the quantity of maternal-fetal antibody drop from the vaccinated versus previously infected mothers. This creates enhanced risk for neonates and babies prior to scheduled vaccination. More certain populations cannot receive a vaccine or do not wish to, including immune-compromised persons and vaccine-hesitant persons. Those populations may benefit from targeted incremental passive prophylaxis via long-acting monoclonal antibody. These populations appear to be growing.

Today, there are no approved or authorized treatments for measles. Options that are in some clinical use today beyond supportive care include immunoglobulin or IVIG, which is burdensome, poorly potent and is a complex and nonspecific mixture of donor antibodies. Vitamin A has limited data favoring its use and may have some therapeutic value in vitamin A-deficient subjects. And that's the state of the art as we consider measles prevention and therapy today.

Slide 15. Fortunately, we believe measles may be highly responsive to monoclonal antibody prophylaxis and therapy based on its responsiveness to IVIG and its demonstrated correlative protection thresholds from vaccination. We see these data, albeit drawn from imperfect and generally older data sets, as highly encouraging for the potential value of our medicines.

Slide 16. There are multiple high-value use cases for measles monoclonal antibody consistent with other viruses, whether considering treatment, post-exposure prophylaxis, pre-exposure prophylaxis in adults or pediatric bridge to first vaccination. We see a host of use cases that clinicians and public health authorities may be able to rely on to cut off the clinical consequences of measles spreading in the U.S. More, a non-vaccine, long-acting preventative could be deployed by public health authorities to attempt to respond to outbreaks and keep measles in the U.S. either from becoming endemic or if that is the situation that emerges over the coming years, using a tool like this to drive measles back to elimination, both in the U.S. and abroad.

Slide 17. Our next steps are straightforward. We've reached out to the agency and are looking forward to productive collaboration on progressing VMS063, and we look forward to updating you all on our progress. And with that, I'd like to turn it back over to Marc.

Thanks so much, Michael and Robbie. We're really excited about the future of Invivyd in COVID-19 and beyond. As you can tell from our early discovery pipeline here on Slide 18, there are great many viruses, including viruses that are vaccine preventable that may be very attractive targets for our technology as we work to lower the burden of disease in America and provide a complement to active vaccination. There have been too few new technologies brought to bear for the most vulnerable Americans over the last 10 years, and we're excited to change the trend.

With that, we'll be happy to take your questions. Operator?

[Operator Instructions] Our first question comes from Josh Schimmer with Cantor.

First, how long do you expect it will take to enroll the incremental 500 subjects? The press release suggests some uncertainty around that, but maybe you can give a bit of a range. That's number one.

Number two, are your powering and timing projections now dependent on there being another COVID wave? And if so, when?

And then the third question is, given the challenges in predicting the timing of that next wave, will there be any additional looks at powering considering this is kind of an event and a timing game, and if it's difficult to anticipate when the next COVID wave is going to occur, it might be worth one more look before closing the trial.

Okay. Well, let me first thank you for those comprehensive and thoughtful questions. I'm going to go in rough order, I think. On how long will it take to enroll? Well, we will, of course, give the Street an update when we've achieved our target enrollment. We did that for the first part of the base study. And I would just observe, I think we were pleased, and I hope some of our investors were pleased with the speed of that enrollment. So hopefully, we're starting with a running start and that our enrollment would be credibly measured in weeks, right? So stay tuned. It's very difficult to promise those sorts of things at the level of resolution that you're probably looking for, but we have, I think, done pretty well on this front so far. And if you'll bear with us, we will hope to do well by you again if we can.

Now your comment about a wave and powering and timing is a great one. One of the things that occurs mechanically by virtue of placing an upsizing event where we have placed it in the calendar is that actually one of the other things we're doing that I think is embedded in the premise of your question is we're stretching time, right? So it's not simply that we're adding an end of subjects. We are adding an end of subjects looking at -- and again, this was all prespecified. So when I say looking at, I'm simply referring to today's date and time -- the exit from a prior wave and that has commonly typically, reliably and predictably portended the arrival of the next wave. So COVID never remains flat. It is either declining or rising. It has been declining. There will be some point and it may not be in the distant future at which it starts to rise. And then we will all go through the sort of exponential growth lesson we've been learning and relearning and relearning and relearning wave on wave on wave since 2020.

So the assumption set doesn't rely on that, right, meaning this was all designed in the fall. What it reflects is, I think, and I hope we've done this before, and we're trying to leverage the totality of our experience in building these studies. You're quite right to point out that there will be some level of residual uncertainty about the ultimate powering because, of course, not only do we face an uncertain attack rate over time, we face an unknown VE, right? Hence, we have [indiscernible] and we're running the study.

But what we feel great about today is that to us, the game with an upsize is, I don't believe, even halfway over, and we really like the score. So we will keep accumulating power to the best of our ability because when you have a maybe somewhat wide range of anticipated VEs, the only thing you know is that you're not going to power the study perfectly. You simply have a choice to make, right? Would you rather make the mistake of upsizing a study and facing overpowering that you didn't require or make the mistake of not upsizing a study and underpowering your results by accident.

When we designed this prospectively, we did it with the first mistake in mind. So none of this work relies on any of the dynamics you're pointing to. But I think we are either fortunate or good. And if it works, it's, of course, because we're good. We'll see that this all aligns on the calendar with exactly the dynamics you're describing. There has typically been a summer wave. We would expect one to show up. We have no special deep intricate knowledge that you all do not possess from looking at the same trends, but I think we feel pretty good about how we set this up.

Your last question, will there be any additional looks? Well, sure, at the end of the study, right? And this brings up something that I just want to double underline very quickly, which is the following. We, of course, designed the study in collaboration with the U.S. FDA, and we did it to try to accomplish all of the various goals we share with them about generating compelling data. But I just want to remind, we, today, commercialize a medicine under EUA, which was approved using immunobridging and which is at the level of amino acid -- sorry, Josh, I -- Sorry. So we have this medicine in market today that is at the level of amino acids, I believe, 99.7% identical to 2311. So we are pleased to take 2311 for a spin in the clinic and find out what kind of numbers it generates.

But I would say any statistical exercise has to have, as it's underpinning, biological plausibility. And it is hard for us to look at iterative monoclonal antibody technology as carrying anything other than the highest presumptive biological plausibility. I will just remind, we are about to potentially be in receipt of the -- I haven't counted them as vaccine antigen update, maybe fifth, fourth, somewhere fifth, I think it's fifth, vaccine antigen update that carries about the same quantum of molecular change, one antigen strain to the next, for which there is absolutely 0 data favoring its use. I have no information on contemporary VE.

I have no information on contemporary safety. So we're pleased to do these demonstrations. We would, of course, be thrilled to power up DECLARATION even more. And we're, I think, relative to the competition, only short about $80 billion taxpayer dollars over the last 5 or 6 years, but we're doing our best, and we will take the final numbers. And I think we'll be very pleased [indiscernible] agency and have what we hope is either a very exciting and -- well, I don't even think there's [indiscernible] there. I think we're really looking forward to seeing the final score and taking it to the agency and actioning the medicine as soon as possible. Does that help?

Appreciate it.

Our next question comes from Patrick Trucchio with H.C. Wainwright.

This is Luis Santos in for Patrick. Looking at VMS063, this is a very exciting development, and we are looking forward to the next update here. But can you tell us how should we think about the framing of 63 into the target population? Are you going to be targeting infants, immunocompromised population? Or is this going to impact population beyond the vaccine ineligible? And how should we think about competition with vaccines here?

Sure. Well, let me start and then if Michael wants to add something, I'm sure -- I would welcome it. I would just say the wonderful thing about a monoclonal antibody is, of course, one can deploy it productively in all kinds of context, therapeutic and prophylactic in all kinds of populations. So we're obviously weighing and evaluating all of those things. The only reason we cannot be more definitive at this point is that particularly with measles, our work begins to intersect with, I think, broader public health interests in which the federal government may have some particularly prescriptive views.

So I think we have stated here that we see a potential for establishing proof of concept in that sort of liminal space of pre -- sorry, post-exposure prophylaxis into treatment, right, which is an area in which IVIG is useful. We would suspect from other viral diseases that a monoclonal might be very useful, but you're absolutely spot on to highlight the potential utility elsewhere. I guess it's -- when Michael was referring to future updates, this is one of the topics on which we'd like to opine further. But I guess I would just ask, do you -- can you speak broadly as an expert in the field on where you would intuitively think to go long term?

Yes. I think the world has not had a good prophylactic drug or therapeutic drug for measles ever. We currently rely on pretty poor performing and very poorly characterized IVIG and things along those lines as our mainstay, both for post-exposure prophylaxis as well as therapeutics. And so this -- having a precision-targeted medicine like a monoclonal antibody to come into market, I think there's going to be a huge array of different use cases that are going to be formulated. And they're going to work in concert with the vaccines.

A particularly interesting use case is going to be bridging to vaccination in the youngest among us. So when babies are born, we generally are waiting until about the first year of life before we want to vaccinate with the measles vaccine. And that's to optimize the response that a child is going to have that's going to sort of last them a lifetime ideally from that vaccine. However, we know that the later you can delay or the earlier you give the vaccine, it actually reduces the potential efficacy of that vaccine. And so if we can delay the vaccine safely based on new tools, I think it's going to be one of the most interesting and useful opportunities for new therapeutics that can -- or prophylaxis that can actually do that safely.

So as an example, a baby is born. We want to extend out a measles vaccine for a certain amount of time. But we don't want to keep them at increased risk during that period of time, so we give a vaccine and we can optimize their safety during that period of time as much or more as the vaccine is currently doing and put off the vaccine so that they can get the most optimal benefit. Those would be some of the things that we are thinking about and how this monoclonal could be used.

Certainly, the number of individuals who either cannot get vaccinated, which would include pregnant women, it would include many people with autoimmune disease and other immunocompromising conditions and then other individuals who are just immune suppress are going to be a major area of interest in terms of where these therapeutics can be placed, including patients on hemodialysis who are known not to respond well to vaccines or carry as strong protective antibody titers, being able to provide a monoclonal into these very large populations is going to be pretty critical. So all things are on the table in terms of really thinking through what does a new generation of therapeutics and prophylaxis look like for measles.

[Operator Instructions] Our next question comes from Tom Shrader with BTIG.

This is [ Jenny ] on for Tom. I wanted to ask about the measles asset and -- that you're targeting. You mentioned that you're targeting IND readiness in late 2026. Could you walk us through what the regulatory strategy is? Would it be like a standard IND? Or are you pursuing any accelerated pathway given the declared public health urgency? And when you were describing the measles asset, you outlined the use cases of treatment and vaccine alternative of prophylaxis. Which indication are you prioritizing first for the IND and why?

Sure. So I think the unfortunate that required answer to your question is just bear with us a little ways, right? So the particular routes and the particular gating, there's logistical aspects at our end, right, CMC and certain standard IND-enabling activities we would undertake. But I think embedded into your question is what we were trying to drive that before, which is the posture of our regulator and the federal government more broadly may play a meaningful role in how this unfolds. And what we're very pleased with today is, I think, we get to have those conversations with what we see is a really lovely asset, biologically speaking, right?

So understanding that this won't be a helpful answer sort of from like a modeling standpoint, but I think it's just really important that we bide our time to have those initial conversations so that we, Invivyd, can make specific plans and then turn around and let you know. But again, I think in the -- after of this call, just sort of thinking through exactly the cases we laid out and which Michael was kind enough to sort of expound upon, I think you'd see a lot of opportunity and a lot of alternatives. And it's -- you're quite rightly asking which first, let's see. All are possible. We see a lot of medical value to be created here, but it's just a bit too soon to get to that yet. But definitely keep coming back at us. We will look forward to adding resolution.

Thank you. And that concludes our question-and-answer session. You may now disconnect. Everyone, have a great day.

Good day, and thank you for standing by. Welcome to the Invivyd Fourth Quarter 2025 Earnings 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 speaker today, Katie Falzone, Senior Vice President of Finance. Please go ahead.

Thank you, operator. A short while ago, we issued a press release announcing our Q4 2025 financial results and recent business highlights. That press release and the slides that we are being used today on today's webcast can be found in the Investors section of the Invivyd website under the Press Release and Events and Presentations section, respectively.

Today's discussion will be led by Marc Elia, Chairman of Invivyd's Board of Directors. He is joined by Tim Lee, Chief Commercial Officer; Bill Duke, Chief Financial Officer; and Dr. Robbie Allen, Chief Scientific Officer. During today's discussion, we will be making forward-looking statements concerning, among other things, our corporate and commercial strategy, our research and development activities, our regulatory plans, certain financial expectations, 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 that could affect Invivyd's business can be found in our filings made with the U.S. Securities and Exchange Commission, including our most recent Form 10-K, which are also available on our website. I will now turn the call over to Marc.

Thank you, Katie, and good morning, everyone. I'll make a few quick remarks by way of executive summary, and then we'll discuss our clinical progress. Of note, this morning, you may have seen that we have brought an esteemed physician scientist, Dr. [indiscernible] to the Invivyd fold to serve as our Chief Medical Officer.

While Michael is unable to join our call this morning, I'm sure many of you will enjoy hearing from him going forward. After the clinical discussion, Tim Lee, our Chief Commercial Officer, will review our work with PEMGARDA and some of our pre-commercial preparation for VYD2311.

Bill Duke, our Chief Financial Officer, will touch on our financial results for 4Q, and then we will be happy to take your questions. Now on to the highlights. Our Revolution clinical program is well underway with the aim of providing Americans with an option for what we believe is needed protection from symptomatic COVID disease. We know investors have many questions about our progress, and we will provide as much detail today as we can.

Our commercial work with PEMGARDA continues, and we were pleased to demonstrate growth in the fourth quarter. Our commercial activities are establishing an attractive basis for broader commercialization of VYD2311, if approved, by demonstrating the power and durability potential of Invivyd monoclonal antibodies.

We are continuing to build awareness and understanding of our work with monoclonal antibodies among HCPs, professional societies, vulnerable populations and government public health entities. We believe that the ongoing American experience with COVID vaccination has left an extraordinary high medical and economic value opportunity to advance standard of care via monoclonal antibody prophylaxis.

In the pipeline, we are excited to begin clinical exploration of our antibodies in long COVID and post-vaccination syndrome as disclosed earlier this quarter. We are very interested that the Advisory Committee on Immunization Practices, or ACIP, a group which advises the U.S. Centers for Disease Control, have recently announced that they are having a full discussion on both topics.

The ACIP meeting is currently scheduled for March 18th and 19th, and we will be watching with interest. Our collaboration with key academic thought leaders in this space, the SPEAR study group, has yielded a clinical trial design we are moving with all haste to action in light of the substantial unmet need for millions of Americans suffering from long COVID and vaccine injury.

In the fourth quarter, we were pleased to share our identification of a highly potent, potentially best-in-class RSV antibody. As you may know, there are today 2 RSV antibodies approved and recommended for the prevention of RSV in certain neonatal and pediatric populations, and we believe the properties of our antibody are highly competitive with standard of care.

As we advance our work across multiple infectious diseases, you may notice a special interest in pediatrics. RSV, COVID and indeed other viruses exert substantial medical burden on both the elderly and the very young as well as immunocompromised persons.

Finally, as previously guided, we expect to update the Street on our measles program in the first half of this year. In light of the substantial and rapidly growing burden of disease, we are excited to share our progress with you as well as describing what we see as the potential medical value of such an antibody, which we hope can be both first and best-in-class.

Slide 5, moving on to our clinical update. On Slide 6, we know that there are investors who are new to the Invivyd story, and so we'd like to review quickly the medical and scientific background for our work with VYD2311, which hopefully will add context to the updates we provided on the declaration study in our press release this morning.

First, it's important to remember that SARS-CoV-2 has been an extraordinary unwelcome and ongoing medical burden on the human species. As an ACE 2 receptor accessing beta coronavirus adapted for high human virulence and transmissibility, it has exerted medical toll in 2 distinct phases.

In the initial pandemic phase, the virus swiftly moved through the human population, exerting substantial morbidity and mortality, especially among vulnerable populations such as the elderly and people with relevant comorbidities, such as pre-existing cardiovascular and renal disease.

After vaccination and mounting seropositivity, we see a predictably less violent mortality, but still extraordinary medical burden from this virus generally in the same population. As a vascular pro-thrombotic immunomodulatory virus that circulates pervasively, we now see accelerated human aging and broad health effects in Americans from acute infection with attendant risks through the substantial growth in long COVID prevalence.

Even American economic data collected by the Fed appears to show an unwelcome impressive growth in American disability since COVID entered our population. We must be less tolerant of this burden.

Second, given all of the relevant sociopolitical and medical aspects of this controversial field, we must touch on the evidentiary and regulatory history we have in COVID prophylaxis. The mRNA-based COVID vaccines were each formally studied in a single placebo-controlled clinical trial in the second half of 2020.

These studies assessed vaccine safety and efficacy versus placebo in a seronegative American population against highly immunologically responsive Wuhan derivative virus variants for about 7 to 8 weeks before unblinding.

These studies demonstrated high short-term protection and short-term safety. However, these original data sets also reflect the last opportunity we had as a species to assess absolute safety in randomized placebo-controlled trials. Given the broad vaccine mandates and rapid virus spread, we as a human species are now all routinely exposed to SARS-CoV-2 and its spike protein, which we see as a type of toxin. And absent a new medical option, we as a species have no real opportunity to avoid exposure to spike protein chronically going forward.

Shortly after those original vaccine studies and vaccine rollout, our entire species became immunologically educated or seropositive, either through the original campaign or circulating virus, all while undergoing excess morbidity and mortality.

Omicron phylogeny virus arose quickly following and as an evolutionary acquisition of population immunity. Omicron viruses are defined by immune evasiveness or the functional avoidance of human immunologic pressure, whether vaccine-induced or natural. One major consequence of Omicron virus was a natural, predictable apparent reduction in COVID vaccine efficacy, which has been reliably estimated by epidemiologists at CDC over the past year. And was directly measurable in diminished vaccine titers when vaccine manufacturers updated COVID vaccine compositions from Wuhan variant virus to Omicron BA.4/5 virus. These analyses can be seen in the relevant vaccine labels, and we see them as predictive of diminished efficacy.

COVID vaccine boost have undergone 5 structural updates since Wuhan virus vaccines just on the basis of immunologic comparison. Ongoing new placebo-controlled vaccine studies should provide us all with more insight into these issues in the coming quarters.

By contrast, Invivyd is now conducting its third randomized placebo-controlled trial for a COVID monoclonal antibody in 5 years. Our antibodies change one to the next, rather like the vaccines to make allowance for virus evolution, although we hope to stay ahead of virus variation rather than chasing it from behind.

On a percentage basis, our antibodies change by about the same tiny amount as vaccine antigens. But in contrast to COVID vaccines, we see our antibodies as a much more natural welcome approach to prophylaxis than serial exposure to spike protein in vaccine form.

To us, given the apparent short duration of vaccine-induced protection and the potential risks of administering spike protein in either mRNA or protein form, it is natural to now move to supplemental immune support via monoclonal antibody to exert protection. From an evidentiary and regulatory point of view, our Invivyd antibodies have undergone more extensive placebo-controlled characterization than the COVID vaccines, including now multiple placebo-controlled clinical trials and in our recent CANOPY study, long-term characterization of pemivibart in a modern seropositive population and against Omicron virus variants.

That brings us to our latest antibody, VYD2311 designed as an alternative to COVID vaccination. VYD2311 is much more potent than pemivibart in vitro and has a longer measured half-life, properties which we believe may combine to deliver equivalent protection to PEMGARDA, but in a much more scalable and convenient intramuscular form. You can see on Slide 8, a reminder of the initial pieces of the Revolution clinical program. The DECLARATION study is a triple-blind randomized clinical trial, once again evaluating the safety of VYD2311 and its ability to reduce the risk of symptomatic disease versus placebo.

Our target enrollment for DECLARATION is approximately 1,770 human subjects randomized [ 1:1:1 ] in active arms and 1 placebo arm. We were recently notified that the DECLARATION clinical trial has reached target enrollment and indeed, as is normal in these situations, may modestly over enroll as sites are permission to complete any ongoing screening and enrollment before closing.

Of note, recently, the DECLARATION Independent Data Monitoring Committee, or IDMC, conducted a prespecified review of unblinded safety and tolerability data associated with initial experience of DECLARATION subjects. While the IDMC is completely separate from Invivyd, we are pleased to relay their written communication to us following that review, which included 3 recommendations: first, that pregnant and breast-feeding women may now enroll in the study; second, that women of child-bearing age enrolled in the study are no longer required to use contraception; and third, that prespecified safety visits at days 8, 38 and 68 post dosing are no longer required.

Finally, DECLARATION is a study designed to assess the performance of VYD2311 in lowering the risk of symptomatic PCR-positive COVID-19 versus placebo. In every infectious disease prophylaxis study, a sponsor like us faces an unknown so-called attack rate or the rate of infection observed in the study to power our efficacy assessments.

Because monoclonal antibody technology in COVID has typically involved a very high efficacy Hazard Ratio or VE, traditionally, it has not taken more than a high single-digit or low double-digit number of events in a study to generate statistical significance. As you may recall, alignment with the FDA on the VYD2311 clinical development pathway included recognition that in our CANOPY clinical trial, pemivibart, the placebo-controlled arm demonstrated robust exploratory efficacy with strong statistical support on the basis of 9 total COVID events at 3 months. America is in the middle of a COVID wave, and we are pleased with the speed of our study recruitment.

The majority of our recruitment has occurred only in the past few weeks and COVID events have begun to appear in our study. We see declaration event accumulation as on track to date and on a projected basis, we anticipate suitable for robust assessment of VYD2311 effectiveness if the clinical performance of VYD2311 matches our modeling and prior experience with COVID antibodies.

Of course, attack rate in the community and in our study is outside of our control and could change going forward. As a result, declaration includes a prespecified upsizing algorithm to allow for additional patients in the trial should our event rate projections indicate that declaration would benefit from more statistical power.

This resizing feature is dependent on overall progress. And at this point, our best estimate is that such an analysis would take place in approximately April. We will make an announcement to the Street about our next steps one way or the other at that time. However, depending on overall recruitment rates, with which we have been very pleased so far, a modest upsizing to add statistical power may not meaningfully delay our achievement of "mid-year" timing guidance for declaration, which we consider as 2Q or 3Q 2026.

Of course, any upsizing would have some level of timing impact, but we would endeavor to stay within our original guidance boundaries. When we get to that point, we will be happy to provide any updated timing estimates. Irrespective of the overall number of COVID events, we are looking forward to data and believe that it may be a profound next step for our company and for infectious disease medicine if declaration can demonstrate attractive VYD2311 safety, high antiviral titers and a demonstration for the third sequential time of the vaccine-free protection that an Invivyd monoclonal antibody can provide.

With that, I'd like to turn the call over to Tim Lee to discuss our commercial update. Tim?

Thanks, Marc. It's a pleasure to update you all on our work. As we see it, more and more clinicians are turning to monoclonal antibodies. And frankly, it's common sense. Thomas Paine once wrote that common sense is often the most powerful kind of reasoning.

In health care, when evidence accumulates and risk is clear, the logical course becomes difficult to ignore. Our goal is straightforward. It's not simple. We want to give people a choice as they seek protection against COVID. We believe that choice has significant potential because there are still millions of individuals who remain vulnerable and underserved.

The medical community increasingly recognizes the importance of antibody therapy and the long-term consequences of COVID continue to be serious from in utero exposure, risk to children, neurological effects, cardiovascular complications, and voiding infection matters. That perspective is reflected in clinical guidelines. Leading organizations, including the Infectious Disease Society of America and the National Comprehensive Cancer Network recommend monoclonal antibodies for prevention of SARS-CoV-2 infection in appropriate high-risk patients.

This inclusion of PEMGARDA in the NCCN guidelines for B-cell lymphomas underscores that recognition. We are encouraged to see growing interest and utilization across hematology, oncology, rheumatology, infectious disease, transplant, neurology and other appropriate specialties.

The adoption curve is expanding, and that momentum reinforces our belief in the long-term value of this platform. There's a great deal reflected here on this slide. In many of these data points we've discussed on prior calls. I'm pleased that we continue to grow PEMGARDA to serve certain adults and adolescents who are moderately to severely immunocompromised, thus leaving them vulnerable to infection from SARS-CoV-2. What you're seeing is Invivyd is building a category. This category served to expand upon the foundation that is PEMGARDA. Nationally, we see continued growth of accounts who have utilized PEMGARDA, clearly understanding the benefits of protection offered by antibody therapy.

We've created this durable foundation with a high degree of accounts reordering PEMGARDA at 77%. We continue to increase available sites of care nationally and across multiple specialties showing a high confidence for repeat utilization. Our GPO sites of care continue to grow, and the team has been busy providing education at conferences across the nation in hematology, oncology, rheumatology, neurology, pulmonology, transplant and more.

As a team that is defining a treatment paradigm, we are in the right places, talking to the right audiences and our position is strengthening after each engagement. We've secured more than 15,000 contracted GPO sites, significantly expanding our commercial footprint.

Taken together, these milestones position us to evolve beyond serving a more limited patient population that we have today with PEMGARDA. With our next-generation monoclonal antibody, we see the potential to redefine COVID prevention, moving toward a vaccine alternative strategy designed to protect broader populations against viral infection.

Invivyd is proud to partner with Lindsey Vonn because she exemplifies the power of disciplined preparation as the foundation of enduring strength. In her memoir Rise: My Story, Lindsey writes, "Preparation is the one thing I can control, so I've always controlled it to a T".

Lindsey prepared an elite level to always perform at her best, and that requires foresight to minimize anything that can get in her way. That mindset really mirrors our approach. Invivyd's monoclonal antibody platform is built on the belief that proactive immune protection, preparing the body before viral exposure is the most effective way to preserve performance, continuity and long-term health.

Viruses should be kept in check to allow everyone to give their best performance. Staying well helps you continue showing up for the moments that matter and antibodies can help a person stay well. For this reason, Lindsey is an amazing partner to help educate on the importance of antibodies in all of our well-being.

With that, I'll turn the call over to Bill Duke to discuss our financials. Bill?

Thanks, Tim. I will quickly review our financials, and then we will open the line for your questions. Our PEMGARDA net revenues continued to grow in the fourth quarter, up 31% over third quarter 2025 and up 25% over fourth quarter '24.

Full net revenues in 2025 totaled $53.4 million, reflecting our continued efforts on driving awareness in the market. After raising over $200 million in the second half of 2025, we ended the year with $226.7 million of cash and cash equivalents.

This leaves Invivyd well capitalized through anticipated pivotal data for VYD2311 in mid-'26 and depending upon continued PEMGARDA growth and continued operational discipline, potentially well beyond. With that, operator, please open the line for questions.

[Operator Instructions] Our first question comes from the line of Patrick Trucchio with H.C. Wainwright.

Congrats on all the progress. Just a couple of follow-up questions from us. Just curious, just -- I think it was mentioned that the potential trial resizing decision in the declaration program could occur around April, depending on event rates. Can you talk a little bit more about that, what the specific statistical criteria that would sort of trigger that decision and what magnitude of enrollment expansion may be needed? And then just separately, I think beyond symptomatic PCR-controlled COVID, I'm wondering if you're collecting secondary endpoints such as viral load, [ symptom ] duration or health care utilization and how that could help characterize the clinical benefit profile that's emerging.

Sure. Thanks for the questions, Patrick. Happy to do my best to enlighten. So on your first question on the resizing, everything we do related to powering is, of course, effectively a 2x2 matrix, right? You have to understand both the expected VE for which you are powering and then the number of events that accumulate that would allow you to project a final study power.

And so right now, as we sit here, we feel pretty good about our progress in the study. All of these algorithms are essentially prespecified, of course, to avoid the potential for bias. And so I think the way I would look at it is like this.

And again, I'm speaking in concepts because, of course, we're not at that resizing yet, and we don't know what the next few weeks will hold. I think if we were to not retrigger the upsizing trigger, it would be because we are highly confident in our ability to statistically assess even a lower-than-anticipated VE or hazard ratio.

And if we do, it really couldn't even be read as a concern about underpowering as such. It would be simply because the way the trigger is designed, it would serve to potentially add power in case the target efficacy is lower than we might otherwise anticipate. So we think of it as really a safety mechanism to try to ensure to the best of our ability, which again, is unfortunately subject to that, the best of our ability to support the power of the study in case VE pencils out as lower than our modeling would suggest.

Now the good news in all of that is actually related to the speed of our recruitment. The upsizing target is not particularly onerous, okay? So you can imagine in your mind's eye, approximately another 30% of the study or so as an upsized target. And importantly, of course, that cohort would be time shifted, right, a little deeper into the spring and then into the summer, which you might imagine collectively would add to the probability that you accumulate more cases, for example, in a future COVID wave.

So while perfect is unavailable here, and we are not endowed with Godly insight into the future weeks, what we can confidently say is we are very pleased with what we are seeing, and we truly don't know whether such a resizing would be triggered. I think what is nice to consider is that if it is, we would simply be in a position to feel better about ultimate study powering.

And I think stepping back, way back to reflect on this endeavor, our goal is to have a successful study if that is what the clinical profile of 2311 allows. And so to the extent that such an upsizing might incur a relatively modest timing and overall financial penalty, I think we'd rather "make the mistake" of having upsized and then only later find out we didn't need you, then do it the other way around. So I hope that adds some level of color around the design and thinking. I think it will be very difficult for us to elaborate much more because we speak to the Street only periodically. And of course, these things occur [ semi-stochastically ] right? We have just recruited up the bulk of the study.

We just have the most of the exposure out there. And so far, things are looking great. So we'll make sure to update you as we go forward. In terms of secondaries, of course, you can imagine in a study like this, we will be recording all manner of interactions between participants and, for example, the health care complex is sort of is behind one of the questions you asked.

And I'm sure a great deal more will always come from this study as it did from CANOPY. I think I would caution on expecting meaningful powering of low-frequency clinical events, e.g., hospitalization or death. I think that would be well beyond the intended power of this exercise. But I think that's also for a reason, meaning at this stage in the game, I think we see pretty clear linear biophysical truth, if not -- that's sort of a level beyond plausibility, but let's just say it like that. That if you do not get sick from SARS-CoV-2, it is pretty unlikely for you to be hospitalized with SARS-CoV-2 or die from SARS-CoV-2. And so our progress as a species, I think, over these last 6 years has demonstrated that one of the best ways to stay well is to not get sick, and that is really what we are fixated on trying to demonstrate here.

I think that's an evergreen principle. I think it has been well elaborated in all manner of these studies. I think those relationships are pretty clear in all of the data even from the vaccines. And so our primary focus is really on a, I guess, a revisit of what was an earlier in the pandemic message, don't get sick.

Most good things we would think would follow linearly. And logically from that, I think that is the regulatory paradigm in which we're pleased to operate. And I would suspect that if we are successful going forward, there will be many, many opportunities as our antibodies move into bigger and bigger populations to demonstrate these kinds of things in classically post-approval registry and other type situations in which we'll all look eagerly to make sure that we're right in effect that not getting a symptomatic infection following exposure to a virus is just a globally good thing.

So again, not trying to be [ coier ] or not answer. I think we will collect a lot of stuff. I don't know how meaningful many of those endpoints will be from a quantitative and powering standpoint, but they will certainly be collected.

Yes. That's really helpful. If I could, I'd just like to ask about the measles antibody program. I think there's an update expected in the first half of this year. Can you give us a little bit more detail what the envision use case is? Is it outbreak prophylaxis? Is it sort of a pediatric bridge therapy before, I suppose, before newborns could get the vaccine? Or are we looking at more of a broader prevention strategy?

Great. So thanks for asking, and I hope it doesn't diminish your interest in more when we're in a position to more formally update. So I'll just stay in concept land for a little while. Look, you've hit upon the use cases, I think, quite nicely in large part, right? One of the things we very much like about this modality is that there is not a pharmaceutical premise that we -- or use case we prosecute separate from what native human immunobiology prosecutes.

So why do we all have antibody suites? It is to prevent the presentation of symptomatic disease to treat and knock down viremia once an infection is established. And yes, as you know, that means we could use such an antibody theoretically for treating active disease. It means we could use -- and by the way, that is, as we've noted in the past, I think something that sometimes clinicians will use intravenous immunoglobulin or IVIG to do.

You could imagine, of course, responding to outbreaks with essentially ring immunization via monoclonal antibody, which might be an enhanced way to look at the kinetics and potency of what we're able to put on board relative to vaccination. And then more generally, you highlighted something there that I think we have been putting a lot of thought into, which is, I think you used the concept of bridge to vaccine. We think about it almost more in the sense of vaccine enhancement, meaning I would just observe, and I think this is noncontroversial, children, babies are born without a fully developed adaptive immune system, especially the B-suite.

And so there are data demonstrating that delaying vaccination actually has the ability to improve the profile of vaccination, meaning higher, more durable titers from vaccinating older and older kids and potentially lower possibility of seronegativity or failure to seroconvert after vaccination, not to mention the potential benefits associated with allowing for early childhood neurocognitive motor development, all these other things.

So look, we are going to be in a position, we hope, to contemplate a lot of things that really, I think the medical complex hasn't been in a position to contemplate before, and that is because justifiably, absent other tools, I think that pediatric schedule is thoughtfully assembled in order to try to have the least vulnerability possible. Beginning with vaccination at an early age. Well, certain antibodies, especially nirsevimab, Beyfortus and others have demonstrated the benefits associated with passive prophylaxis in the very young.

There may be other benefits we can explore going forward. But look, it's premature to say more, although Robbie Allen is leaning in, and that usually tells me he wants to add something. So I'm going to stop in a second. But I guess I would just say, stay tuned because I think we are really intrigued by the potential for some use cases, as you put it, that just have never been contemplated before. And I think our view is there's a potential substantial quantum of medical and potentially economic value to create.

Yes. I would agree with that answer. And I think that the main thrust of this has come from inbound requests from HCPs for something to provide them with a solution in cases where they have a need for treatments or for post-exposure prophylaxis for measles. And this antibody has been designed with those use cases in mind as well as some of the potential future use cases that Marc mentioned. So that's really where we're headed with this antibody at this point.

[Operator Instructions] Our next question comes from the line of Tom Shrader with BTIG.

Congratulations on the progress. I think you're making positive event comments and certainly, the safety news is fantastic. We talked a little bit, Marc, about your ability to sculpt the trial a little bit to try to hit hotspot areas. I wonder if you can talk in broad brush about how well that has gone? And is that, in fact, self-inforcing that the people who enroll are, in fact, they know they're in areas where there's a big deal. And then a more specific question on the myocarditis monitoring, is that going to be clinical myocarditis? Yes, no? Or is that a more detailed study where you're looking at, I don't know, muscle proteins, things like that? Is that a deeper study? Or is that just the rare clinical myocarditis event?

Tom, thanks for the questions. Happy to give you some view here. So okay, listen, with respect to DECLARATION study, yes, what we've been discussing is on the margin, our ability to have sites that are in areas that are, we believe, undergoing some level of community COVID attack rate, right?

Now you can see some of that in the ways that we see it, whether it's clinical sequencing, whether it's wastewater sequencing or sometimes whether it is, for example, emergency department or sort of one of those things called the sort of like low acuity, walk-in clinic kind of census data on where people are reporting symptomatic positive COVID.

So look, we operate a U.S. study with a relatively broad catchment area because a lot of this was designed in October, November, December time frame, and we were not in possession of such a map. But we have some ability on the margin to try to place exposures where we see COVID. I think it's also a risk to overinterpret the math because these things move and they move fast.

And so for example, over the next few weeks or months, to the extent that air conditioning goes on across the U.S. South, the map can move. But we feel pretty well prepared and pretty well configured to hopefully keep seeing event accrual. Now is it self-reinforcing? I couldn't even begin to answer because I've never even contemplated such a thing.

But -- so I guess I'll leave it as I don't know. But -- so we'll see in hindsight, whether or not there is any discernible behavioral aspect to it. On myocarditis, I think at first pass, this is going to be a yes, no exercise, mainly because the LIBERTY study where we are looking for that is small. And I think the risk of overt myocarditis or pericarditis following vaccination is relatively low. Now like all clinical studies, we gather samples. We will look at data. There can always be room for more detailed exploration or follow-up. And again, if we were to see such an event following vaccination, I think we would become very interested. I wouldn't speak on behalf of the broader scientific or academic community or regulators, but I imagine a lot of people might be interested in that.

I just want to double underline myocarditis, pericarditis is not something we see with antibodies, right? This is a function of studying mRNA-based COVID vaccination in our comparative and combination LIBERTY study. So look, I wouldn't -- we'll see, right? I don't know that LIBERTY is certainly not powered or even close to powered to detect events that we would imagine are at that lower frequency, but let's all find out together.

And if I can ask a quick follow-up. You apparently have an RSV antibody you like. That would seem to be a high bar. That's been a very active area for a long time. Can you give us any detail on maybe what you're improving? Or how hard do you think it would be to have an antibody that was good enough to take on what's a pretty entrenched competition?

Sure. And now I really saw Dr. Robert Allen's body language change. So I know he's going to have thoughts. But I would just say this, the RSV antibody field goes back, I believe, to 1998 with palivizumab or Synagis and was really only updated at the molecular level. I want to say, and forgive me if I'm wrong, in 2023 with the arrival of nirsevimab Beyfortus.

Now nirsevimab is a lovely antibody. I think ours is a lovely antibody, and I think it has some properties that we see as quite compelling. And so typically, in the pharmaceutical industry, when we look at a blockbuster high-growth antibody space, it's hard to sit back and conceive of the fact that, that will be the one thing forever and only and always. And indeed, at the molecular level, we really like what we're seeing and expect to have the ability to compete. I'll let [ Robbie ] elaborate in a minute, but I would also just note, we look at RSV as a really attractive component of an emerging strategy you might well notice now as we go from COVID to RSV, perhaps to measles, perhaps onward to other viruses in which having a commercial portfolio and a real presence in pediatrics has the potential to open or expand on a field that is, I would argue, by contrast [ assertion ] in its infancy, no pun intended.

Nirsevimab in year 3 now is early. I think it's dramatic commercial success is a function of the quality of the medicine. And so to the extent that we feel great about the quality of our medicine, I can say we are very much looking forward to competing. And now that's a long way off, but we have opportunity in front of us to be clever in clinical trial design, to be clever in some other aspects that might define our overall profile. And now that Robbie is good and warmed up, why don't you add color if you think fit.

I think what you can know is that we learned a lot in the era of generating COVID antibodies about trying to be upfront about addressing evolutionary drift and recognizing that while there may not be liabilities to our epitope, drift represents a change in context that deserves to be addressed periodically. When we look at RSV, in the time since the screening was done for the 2 known actives that are in the market now, there's been a considerable amount of drift and really the design of our program was meant to address that.

And with that drift also address some of the known liabilities for the 2 known actives and overcome those liabilities by design. And so this is where we find ourselves with a very high-quality antibody that's contextualized by the recent evolutionary past of that virus. And I think that as we see with RSV, we can depend on it to drift not as much as COVID, but as SARS-CoV-2 rather, but will drift.

And so we will continue to address that as it comes up. It's really the overall strategy that we have with our antibodies is to be very upfront about updating antibodies periodically to match the environment that we find ourselves in. I hope that helps.

And I'm currently showing no further questions at this time. I'd like to hand the call back over to Marc Elia for closing remarks.

All right. Well, thank you very much all of you for joining us this morning. We will look forward to having, I'm sure, some follow-up calls throughout the day. Have a great day. Thank you.

This concludes today's conference. Thank you for your participation. You may now disconnect.

Good morning, everyone, and welcome to the Q3 2025 Invivyd Earnings Conference Call. [Operator Instructions] Please also note today's event is being recorded.

At this time, I'd like to turn the floor over to Katie Falzone, Senior Vice President of Finance. Please go ahead.

Thank you, operator. A short while ago, we issued a press release announcing our Q3 2025 financial results and recent business highlights. That press release and the slides that are being used on today's webcast can be found in the Investors section of the Invivyd website under the Press Release and Events and Presentations section.

Today's discussion will be led by Marc Elia, Chairman of Invivyd's Board of Directors. He is joined by Tim Lee, Chief Commercial Officer; and Bill Duke, Chief Financial Officer.

During today's discussion, we will be making forward-looking statements concerning, among other things, our corporate and commercial strategy, our research and development activities, our regulatory plans, certain financial expectations, 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 that could affect Invivyd's business 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, Katie, and good morning, everyone. The third quarter for Invivyd marked a turning point in our company's history, and we hope also mark the beginning of substantial change in how we may prevent COVID for vulnerable Americans in the near future. In the third quarter, in addition to growing our PEMGARDA commercial franchise, we received feedback from the U.S. FDA to develop our vaccine alternative antibody, VYD2311, for broad populations that continue to suffer from COVID and who are not adequately served by current COVID vaccines. This feedback and our next steps with Invivyd are the results of years of Invivyd innovation and dialogue on that innovation with the FDA.

By focusing on molecular evolution and by demonstrating the clinical benefits of our medicines in prospective randomized placebo-controlled clinical trials, we believe we and the FDA are working within the same highly robust intellectual framework for evaluating new medicines, all for the benefit of vulnerable populations and the American public. Following receipt of FDA feedback, we immediately moved in late summer to raise capital to power our intended studies, and in total, raised approximately $87 million in capital in the quarter and shortly thereafter.

This infusion of capital leaves Invivyd well funded to execute our pivotal clinical program as well as to expand our current commercial organization in anticipation of VYD2311 launch, all while staying highly disciplined on our operating expenditures. As a reminder, we have anticipated launch quantities of VYD2311 and a route to scaling manufacturing and supply further as we approach launch. The next 12 to 18 months promises to be an extraordinary time for Invivyd.

On today's call, I'll briefly review some aspects of our upcoming pivotal program for VYD2311, which is on track to initiate around year-end and deliver top-line data in mid-2026. And then Tim Lee will walk through recent progress with PEMGARDA and comment on the future commercial landscape for VYD2311. Finally, Bill Duke will review our financials, and then we will be happy to take your questions.

We recently conducted a webinar that contains substantial detail on our work with monoclonal antibodies and our plans for moving forward with our pivotal declaration and LIBERTY clinical studies. I will briefly touch on some design elements and background logic for those studies today, but recommended for more detail, listeners revisit our investor event webcast from last week.

To start, it's important to remember that the category of COVID prevention was born with mRNA vaccines during the first year of the COVID pandemic. At that time, speed to market was priced over the collection of long-term placebo-controlled clinical data. As a result, the placebo-controlled efficacy data we have from COVID vaccination is principally from the 2 original major studies of mRNA vaccines, each with a relatively short efficacy follow-up of 7 to 8 weeks, at which point the efficacy data was unblinded and the vaccines were authorized.

These studies were, of course, conducted then in immunologically naive humans rather than in today's seropositive human population and were conducted at a time of immunologically responsive original SARS-CoV-2 virus rather than against the immunologically evasive viruses we face today. So other than measuring modern antibody titers that may not relate particularly to past observed protection in RCTs, there is very little controlled data on the efficacy of COVID vaccines beyond this original 2-month look to inform current clinical protection and overall risk-benefit. The FDA has used those original data and various real-world data sets and immunologic data to construct labeling language for the vaccines in our current environment. Both mRNA vaccines are indicated for use at least 2 months after the last dose of COVID-19 vaccine.

But that statement does not provide any information on likely protection in a modern context if used maximally, for example, every 2 months, or used as most people use it once a year.

Finally, CDC and ACIP recommendations have generally been consistent with FDA language recommending vaccine utilization once or twice per year or no more than every 2 months for certain vulnerable populations. The point is that while COVID vaccines remain a blockbuster medical category despite widespread skepticism, as a society, we do not have any modern randomized data describing current or long-term vaccine efficacy. We do not have any placebo-controlled prospective clinical trials demonstrating the safety and efficacy profile of repeat vaccine dosing. And we do not have any prospectively designed placebo-controlled information on the relationship between vaccine-induced antibody titers and clinical protection over either the short or long term.

We designed the declaration study to address several of these issues in a compact fashion in order to advance our knowledge around COVID protection while rapidly moving VYD2311 to BLA submission if the study is successful. By using a single dose of VYD2311 with a 3-month measurement and by evaluating in parallel the safety and efficacy of monthly repeat dosing, we believe Invivyd can, in one single study, provide more information on the extent, durability, and quantitative predictability of protection from COVID than we have had from COVID vaccines over the past 5 years. We are also evaluating currently our options for evaluating longer-term protection with VYD2311 as our modeling suggests that meaningful protection following a single dose would last for a year. More in the LIBERTY study, we plan to assess in a head-to-head study the safety and tolerability profile of VYD2311 versus active comparator mRNA vaccines. Why?

The single most important reason Americans avoid COVID vaccination for is safety, and we see a critical opportunity to avoid the weaknesses of cross-trial comparison and by contrast, simply demonstrate what we expect to be the major safety advantage of antibody-based prophylaxis. Based on our prior studies of low-dose intramuscular antibodies, we expect a highly favorable side effect profile that reflects the absence of inflammation and immune engagement that can be uniquely offered by antibodies. Antibodies and VYD draw directly from normal human immune biology and do not require inflammation like a vaccine boost, and so a clear demonstration of safety and tolerability advantage may be a critical piece for educating HCPs, vulnerable populations, and policymakers on the merits of our approach.

Net, we believe that declaration of LIBERTY provides an incredible opportunity to demonstrate the power of our antibodies in protecting people from COVID. And we anticipate that our data expected mid-2026 will add to our growing body of information that can provide major confidence in a potentially superior medical approach to protection compared to COVID vaccines. Our clinical and regulatory groups have been moving quickly to stand up these studies, and we will look forward to updating you on our progress in the coming weeks and months.

I will now turn the call over to Tim Lee, our Chief Commercial Officer, to talk about our progress with PEMGARDA and our expectations for the VYD2311 commercial journey. Tim?

Thank you, Marc. Last week in our investor webcast, I said that we believe there is an enormous near-term opportunity for Invivyd. Now I'll get into the future that we see. We said that Thomas Jefferson quoted, I'm a great believer in luck. The harder I work, the more I have of it. We are able to help certain immunocompromised people avoid COVID today, while planning a broad swath of Americans avoid COVID in the future with our next-generation antibody. There's a lot to digest here from this slide because we are taking the actions that I told you that we take during our Q1 earnings call, and they are working.

I told you we're beginning to make progress on contracting. Today, we have more than 15,000 contracted GPO sites. I told you that we are refining messaging. And today, we have more than 1,200 sites offering infusion, and 76% of those accounts are reordering. I told you that we're beginning to be seen as a leader in COVID, and we're acting as leaders, and that means that we've been to more than 125 conferences. And all of this is enabling us to move from helping a smaller patient population today via infusion to a potential vaccine replacement with our next-generation antibody, if approved.

At our Q1 call, I shared that the IDSA guidelines and the NCCN guidelines for B-cell lymphomas included HMGRDA. As you can see here on this slide, today, numerous medical societies and guidelines make that recommendation. And it's important that the medical community is recognizing the importance of antibodies in preventing COVID because the long-term impact of the disease continues to be dire. The impact on children exposed to COVID-19 in uterine to our brains, to our cardiovascular systems, we should all want to avoid getting sick with COVID. We see a future that needs a widely available and accessible option to prevent COVID for most Americans. Current options simply are not enough, and we need to provide patient choice.

Now for HCPs and immunocompromised people can scale to a much bigger market share should VYD2311 be approved. We have found that people do not want to miss out on life because of COVID. They are on social media, and they are receptive to learning more. I talked about the number of conferences we've been at, and I wanted to share where we are from a commercial perspective. We're meeting HCPs who are most interested in keeping their immunocompromised patients protected against COVID and understand the damage that COVID continues to cause for immunocompromised people who are in their care.

As we consider the size of the potential commercial opportunity 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 flip. As we've seen in the CDC data, the reason why people do not get the COVID mRNA vaccine is a concern about side effects. We see extraordinary medical value to create a business to scale. So our goal is simple, not easy, but simple. We want to provide people with a choice as they seek protection against COVID. And we believe that this has blockbuster potential because there are so many people that we can help.

We see an enormous near-term commercial opportunity for Invivyd. Last year in the U.S., COVID vaccine sales totaled $3.8 billion. And yet, as we reviewed, the vaccine appears to be less than an ideal solution. We believe we make substantial safety, efficacy, and durability of efficacy of protection from COVID, and we're looking forward to getting started should VYD2311 be approved.

With that, I'll turn it over to Bill.

Thanks, Tim. I will quickly review our financials, and then we will be opening the line for questions. Our revenues continue to grow in the third quarter, up 11% quarter-on-quarter and 41% year-over-year, reflecting our continued efforts on driving awareness in the market. We also substantially improved our cash position, not just from our underwritten public offering in August, but also by a reverse increase through our initial ATM facility, now effectively exhausted and at much better prices than our August 2025 financing.

Invivyd is now well capitalized through anticipated pivotal data of VYD2311 in mid-2026, on continued growth and continued operational discipline, potentially well beyond.

With that, we will take your questions.

[Operator Instructions] Our first question today comes from Josh Schimmer from Cantor Fitzgerald.

This is Alex on for Josh Schimmer, and congrats on a great and exciting quarter. So my first question is, do you plan on winding down PEMGARDA once the next-gen product is approved? And if so, over how much time? And then I have another question.

Alex, thanks for the question. I think the easiest answer right now is simply no. PEMGARDA is, as you know, perhaps a medicine that has some slightly less attractive properties in terms of scalability and accessibility, but it does remain a differentiated medicine at the molecular level. And while the market may someday pass it by, we would have no plans to actively sunset.

And then my second question is, can you please clarify the coordination between CBER and CDER that is required for the LIBERTY study?

Well, I can certainly tell you what we know, but I think that sort of insight is best left as a question to the FDA. I think what you are simply observing in our work is that by virtue of a law that I think dates back all the way to 2002, there are different responsibilities between CBER and CDER, and therapeutic monoclonal antibodies have traditionally been handled by law by CDER. And so when we, in effect, comingle these sorts of prophylactic medicines in a study, I would imagine that there would be some level of dialogue between those 2 centers on the nature and boundary sets of our study.

So of course, I can't tell you what they're going to talk about with one another. But I think from our perspective, it's all about essentially getting confidence and alignment on what to us looks like a relatively straightforward in, right? So there are mechanistic and fundamental questions that so far have only been answered in animal systems. For example, what does happen if you concomitantly administer both a vaccine and a monoclonal antibody? It wouldn't be crazy to imagine they might interact.

Now the meaning of such an interaction, I don't know that we see a particular issue one way or the other, right? Animal work suggests that applying a monoclonal is almost like putting a little piece of masking on an antigen. And so you redirect some of the immune response to vaccine. But it's not clear to us that it will change in one way or the other. I think our suspicion would be that in seeking to advance a broadly labeled, broadly indicated monoclonal, we would want to do this sort of experiment, and the FDA would wish to reflect on such an experiment to support labeling language and a description that is useful to HCPs and vulnerable populations about what is the nature of such a combination.

So again, I think it's really just from our standpoint, a logistical step that will involve a slightly unusual coordination at their end because, to my knowledge, nobody of late has actually sought to combine such assets in one single clinical study. But that's a very different statement than us thinking it involves any particular risk one way or the other in any particular extraordinary process. I think we just wanted to flag it because I think it's an unusual study in a really, really good and interesting way, and we're very much looking forward to conducting it.

And our next question comes from Patrick Turchio from H.C. Wainwright.

This is Abella on for Patrick Turchio. Congrats on all the progress. Could you please discuss the commercial team's current reach and any plans to expand beyond infusion centers as you transition towards intramuscular delivery for VYD2311? And then I have one more.

Yes, great question. I think as you know, right, it is certainly a foundation that we've been building out around an infused specialty medication. What we're starting to do is build upon that broad foundation to meet the specialists who currently care for immunocompromised patients, as well as those who will be the right target audience for 2311 should it be approved. And so the foundation we've built is scalable. I think you'll see more from us around some air cover around digital assets and reach into the community, and then an increase in field presence as we go forward through the next year.

And then also, you mentioned early-stage discovery efforts in RSV and LIBERTY. How do you intend to differentiate those programs? And what's the realistic timeline for development candidate nomination?

Great. Well, these are programs that are in the discovery space right now. And in fact, they have very different contours. Differentiation for nasals antibody is, at this point, relatively easy to claim because there aren't any. And so we are approaching that virus with the same philosophical construct we would use for most of our discovery work in COVID and beyond. So -- by that, I mean, we want to look at virus variation. We want to look at druggable targets that are on that virus, and we want to use the platform we have to try to create the highest potency, broadest coverage, most attractive biophysical medicine we can.

Now the same is true in the RSV space with one distinction, of course, which is there are already relatively, if not very high-quality, antibodies that are blockbuster commercial medicines. And so in all of these opportunities, I think we look at potential differentiation through a couple of different lenses. The first one we would think of is a differential resistance profile because when we get out of the discovery space and into the commercial market, viral resistance, just like an antibiotics, is a principal concern. And so it is advantageous if we can bring something to the world that can be a backstop or an important addition to an existing armamentarium, just different in terms of the risk profile of the medicine presents to vulnerable populations in HCP. So resistance can be thought of as one of the first key things.

Now after that, there are any number of biophysical properties from overall potency to cost of goods and expression yields, advantages in dose and delivery that get to sort of more fine-tuning at the molecular level. And so I think we are interested in providing an update on both of those programs before the end of the year. And after we have sort of polished up something and found something we're happy with, our suspicion would be that they would both be candidates for relatively rapid advancement into the clinical space. After which, for example, RSV and measles will diverge. RSV is relatively well-understood clinical development territory. Measles, as you might imagine, is not. And so they could end up being pretty different-looking development campaigns with pretty different-looking use cases in effect. But we are just excited about the progress we're making in the discovery space, and we'll look forward to giving you all an update as soon as we can.

And ladies and gentlemen, with that, we'll conclude today's question-and-answer session. I'd like to turn the floor back over to Marc Elia for any closing remarks.

All right. Thank you all for joining us this morning and for helping us keep it nice and tight. We and the team will be around for the rest of the day to follow up with any questions you might have. Thanks very much.

And with that, everyone, we'll conclude--

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.