Corvus Pharmaceuticals, Inc. (CRVS) Earnings Call Transcript & Summary

Good morning, ladies and gentlemen. Thank you for standing by, and welcome to the Corvus Pharmaceuticals R&D Symposium webcast and conference call. [Operator Instructions] It is now my pleasure to turn the call over to Zack Kubow of W2O Group. Please go ahead, sir.

Thank you, operator, and good morning, everyone. Thank you for joining us for the Corvus Pharmaceuticals COVID-19 R&D symposium and pipeline update. This symposium is being webcast with presentation slides. We encourage participants to join the webcast in order to view the slides. You can find a link to join the webcast on the Investor Relations homepage of the Corvus website. Joining me on the call from the company are Dr. Richard Miller, Chief Executive Officer; Dr. Mehrdad Mobasher, Chief Medical Officer; and Dr. Stephen Willingham, Director of Translational Biology, who leads our COVID-19 research program. In addition to the Corvus team, we are also joined by 2 guest speakers: Dr. Tullia Bruno, Assistant Professor, Department of Immunology Hillman Cancer Center at the University of Pittsburgh and Dr. Gerard Criner, Chair and Professor of Thoracic Medicine and surgery, Lewis Katz School of Medicine at Temple University. Today's program will include presentations from our speakers with several question-and-answer sessions throughout. Turning to Slide 2. I would like to remind everyone that comments made by management today and answers to questions will include forward-looking statements. Forward-looking statements are based on estimates and assumptions as of today and are subject to risks and uncertainties that may cause actual results to differ materially from those expressed or implied by those statements, including the risks and uncertainties described in Corvus' most recent quarterly report on Form 10-Q and other filings the company makes with the SEC from time to time. The company undertakes no obligation to publicly update or revise any forward-looking statements, except as required by law. With that, I'd like to turn the call over to Richard Miller. Richard?

Thank you, Zack. Good morning, everyone. We are ready to start this morning's program. I'll try to be brief because we have a lot of exciting things to cover. This symposium is intended to provide a thorough review of the biology preclinical evidence and clinical results that support the potential of CPI-006, our unique B-cell activating antibody to be a novel immunotherapy for COVID-19 and other infectious diseases. During our symposium, you will hear about the basic immunology as it pertains to COVID-19 as well as the current patient management and emerging novel therapies for this disease. We will also share new research and preclinical data on CPI-006 and the latest clinical data from our Phase I clinical trial which was reported at SITC this week, and in fact, another oral paper tomorrow on that. We will also discuss our plans to initiate a pivotal registration study for CPI-006 in COVID-19 before the end of the year and share an update on our other pipeline programs. So to start things off, I will make some brief remarks, followed by Dr. Tullia Bruno from the Department of Immunology at the University of Pittsburgh, who will provide an overview of the basic immunology and the role of B cells and antibodies in COVID-19. We are very fortunate to have Dr. Bruno for this overview. She is an expert in this area. Several months ago, she published an article in Nature on the importance of B cells and understanding response to immunotherapy of cancer, and she is also chairing the SITC session dedicated to B cells tomorrow. Recently, her attention has focused on the role of B cells in COVID-19. She will be followed by Dr. Stephen Willingham, Director of Translational Biology at Corvus. Stephen is well accomplished in immunology and antibodies, being one of the key developers of the anti-CD47 antibody now in Phase III trials for leukemia. He is the leader of our CPI-006 research program for COVID-19 and was the first author of our recently published paper in medRxiv on the unique properties of CPI-006, our Phase I study rationale and design and a description of the broad potential for 006 for the treatment and prevention of COVID-19. Stephen will review the basic properties of 006 and its preclinical biology, including some new data that supports our findings in the Phase I clinical study. We can take time for Q&A after each main topic. We are delighted to have Dr. Gerard Criner, Chairman and Professor of Thoracic Medicine and Surgery at Temple University Hospital in Philadelphia. Dr. Criner is an authority in pulmonary and critical care medicine and deeply involved in the care of COVID-19 patients at a very busy urban medical center. Dr. Criner is the lead investigator on our Phase I trial. I've asked him to speak on the management of COVID-19 with particular attention to the new emerging therapies. He will be followed by Dr. Mehrdad Mobasher, the Chief Medical Officer of Corvus. Dr. Mobasher will report on the clinical results from our Phase I trial, providing a bit more detail than the SITC presentations as well as our plans for an upcoming pivotal randomized Phase III trial. Let's look at the clinical course of COVID-19. I'll start by framing the clinical challenges of treating this disease. As you can see from this figure, in a publication by Zhou, et al in Lancet recently, there is a period of 2 to 3 weeks when patients go from asymptomatic or early symptoms to potentially requiring ICU hospitalization with death occurring in some patients. The question is what interventions can be done to prevent patients from moving further along the disease axis to avoid more serious complications. Our initial strategy with CPI-006 is to target patients during the time period outlined in red. When their symptoms and/or risk factors are serious enough that they require hospitalization but before the outlook worsens. However, we also believe CPI-006 has the potential to treat patients further to the left, including as a preventative therapy, potentially in combination with vaccines. Our efforts in COVID-19 with 006 are focused on the following challenges. To help patients battle the progression of the disease and to prevent reinfection. Can we accelerate the immune response? Can we make the immune response more effective at eradicating the virus? Can we accelerate recovery? Can we reduce transmission? How long will immunity last? Can we eliminate or reduce reinfection? Can we prevent antigen-negative escape, otherwise known as [immunnovation]. So far, all of the preclinical and clinical evidence suggest that CPI-006 may address these opportunities, which would be a unique and valuable contribution to the treatment of patients with COVID 19. Before turning to our first guest speaker, let me make a few comments on the preliminary results of the Pfizer vaccine announced this week. We're all very pleased to hear about these results and that vaccination against this virus appears possible and may lead to prevention of disease. However, there remain several issues that remain to be addressed over the coming months and years, such as how effective is the vaccine in various subgroups of people, for example, the elderly, those with comorbidities, the immunocompromised, disease severity. Does it reduce just mild disease or severe disease or both? What about the duration of immunity? Does it last 1 month, 6 months, 1 year, 10 years? We don't know. What about viral mutation and resistance? There's a lot of virus out there and it is mutating and changing, and it is unknown how long the immunity that we will have from a single vaccination would prevent infection with mutated forms of the virus, as is the case with influenza. What about safety? What about cost, distribution and uptake? So these are all questions that will -- people will be looking at over the coming couple of years. Now I would like to turn to our first speaker, Dr. Bruno. Dr. Bruno?

Yes, I'm here. Thank you so much for the invitation to join in on the symposium today. I'm quite excited, given my work in cancer on B cells as well as given the work that we're currently doing in COVID-19 patients in the Pittsburgh area. So if we go to my first slide, which is an intro slide just about myself. As was mentioned, I'm an immunologist here at the Hillman Cancer Center. I've been in tumor immunology since I was a graduate student and through my postdoc. And in my lab, I currently focus on B cells and tertiary lymphoid structures within cancer patients. So my tagline in my initial slide is B cell -- "Enthusiast B cell Convert" for that reason because I was trained in T-cell immunology and know quite a bit about that. I pivoted in my postdoc to B cells, and I'm currently working on that in my research program. I've provided here my e-mail address in case there are questions that come up that are not answered today. And also, I have a very beautiful picture here that's provided by a technician in our laboratory, showing basically a very key structure within our immune response known as a germinal center, which we'll learn about later on today. And so you can see this germinal center with the yellow tag here. And you can see a very circle-like organ here within this tissue. And so this is from a human tonsil. This is a normal tonsil, and we'll talk more about what these look like in COVID patients as well today. Next slide. So just to give an introduction to why we care about the immune response when it comes to viruses. We link about the immune response, given this initial graph that you're seeing. So over time, there is an immune response that is generated when you first have an insult which is a viral antigen or even now we think about this in the context of cancer as well. So that's in that initial red arrow on the left-hand side. So basically, your primary immune response kicks in or your adaptive immunity kicks in, and I'll talk about that more here in a minute after that initial exposure to antigen. And then if you then meet that antigen, again, and that's the second red arrow that you see here, you get a secondary exposure to antigen and you have a secondary immune response which is quite fast in comparison to your initial response and is much larger. And you can see the output here is antibody concentration. So this is going to be antibodies that are produced by B cells, which I'll introduce more here in a few minutes. Next. So if we think about adaptive immunity and we think about what happens in order for this primary and secondary immune response to occur, we first think about the primary immune response. So what you can see here is that virus is going to infect normal cells, in this case, it's going to be the epithelium, and those infected cells will then initially be picked up when they are either dying and/or if there are viral particles present by dendritic cells, which then process those viral antigens and then it activates the dendritic cell. And so here we go from, basically, what we would call from step 1 to 2, a resting tissue to more inflamed tissue. And that more inflamed tissue then, as a signal for those dendritic cells to then traffic to the lymph node. And the lymph node is, you can think of it as a hub for education for the immune response to a virus. So when you get into that lymph node, there's other players involved. So the dendritic cell comes in and it's going to activate a T-cell, which there's different flavors of T-cells that are going to respond, both helper and killer T-cells. And those killer T-cells are very important because, as you can see, they go and attack the virally infected cells in step 4. But I want -- what I don't want to discount and what I want to highlight is that there is B cells here that can also be educated within these centers that can become quite expanded, and these are called "clones", which I'll refer to later. And those will then differentiate into plasma cells, which are large antibody factories that then make these viral-specific antibodies. So this adaptive immune response is quite important, both in the primary stage and then in the secondary stage, and B cells are in the center of that education. So if we hit the next slide, this is really why we need a COVID-19 vaccine. And as Dr. Miller mentioned, while we have some promising agents, there's still a lot of considerations for the vaccine to make sure that this immune response that the vaccine will stimulate works optimally against the COVID-19 virus. Next slide. So how do we generate what are called memory B cells. So how do we generate those B cells that are going to recall and remember when they see virus again. This is a very simple schematic that was published in an article in 2004, showing that at the heart of making memory B cells are these germinal centers that I mentioned earlier. And so when a B-cell gets activated -- B-cell gets into a germinal center, it will toggle back and forth between 2 zones, which I'll show you here in a minute. And it will then get educated enough to expand and become specific to a virus or a cancer antigen or whatever it might be to then have memory. And then also, you can see these large cells that have antibody production are plasma cells. This education, as I mentioned, occurs in what are called secondary lymphoid organs, such as a lymph node, a tonsil and a spleen. Next. So if we visualize this in a human tonsil, taking some images that were created from my lab group, you can see on the top panel that KF67 in yellow marks one area of that very round germinal center. And you can see it's very concentrated. That's also marking B cells that are actively proliferating or reproducing themselves within that germinal center, so that they are enough that are going through somatic hypermutation or mutation to become specific. And then what you can see below in that same center, you can see a blue area or it's more of a, I guess, it's like kind of a yellow/blue area that is going to mark another zone where once those B cells are educated, they then start to interact with T-cells to become highly specific. Next slide. So a very simple schematic on the left-hand side of this B cell education is a naive B cell, or a B cell that's never seen anything, will come into this germinal center reaction and will basically toggle within that germinal center, as I mentioned, between these 2 zones: the dark zone on the top and the light zone on the bottom. So during the dark zone, they'll be proliferating, and that's what that yellow [indiscernible] 67 marker that I showed you was indicating and they go through this selection. And the light zone where they interact with T-cells, specifically what we call "follicular helper" T-cells to make a high-affinity BCR, which means it becomes very specific for a viral protein or an antigen. After this occurs, the cell then can be kicked out, as I mentioned, by -- as a memory B cell or a plasma cell. So this becomes important because the agent that we're discussing today is going to amplify these memory B cell responses. And so that's going to be very important as we go through. There's also another schematic on the top that shows basically antigen presentation or education of these B cells as it goes along in the lymph nodes. So you can see again that dendritic cell picking up -- in this case, it's showing bacteria, but it can be virus processing, presenting it to a helper T-cell that then becomes activated, which then, in turn, helps to highly select a B cell, so it becomes a clone and makes a lot of antibodies as a plasma cell. Below the schematic, there is an infrastructure of an antibody, showing light and heavy chains and more specifically, where the antigen binding site is, which is basically where the viral protein is going to be recognized. So this will be -- this is important to also note. Next. So if we think about as these antibodies are being generated, if we go back to this number -- this time graph and we look at antibody generation, it's not as simple as just one type of antibody bean generated. And in particular, you'll see in the next presentation that there's readouts of IgM antibodies and IgG. So an IgM antibody is going to be the first antibody that's produced when you have antigen invasion. And so you can see that happens early. And you can see where the antigen comes in. So in this case, antigen is going to be this viral protein, and IgM is produced, and then after that, IgG will then come up after several days. And this occurs through what we call class switching, which I won't have time to go through today, but basically, there's a transition that occurs and then IgG response takes over. And so what you can see on the right-hand side, which is basically a summary of the different types of antibodies, which we call isotypes, you can see IgG and IGM, the structures of those 2 antibodies as well as what their function is and where you find them in this picture on the far-right in the body. And then there's 3 other subtypes: IgA, IgD and IgE, which we won't talk about today, mainly because IgA is found in mucosal tissues. And while it might be important in local B cells that are present, it's not necessarily in the systemic portion, as you can see. And then IgE, which is involved in allergy and won't be discussed today. Next slide. So the other thing I want to mention before I talk a little bit about what happens in COVID patients now that I've given you background on basic immunology that's occurring there when there's a virus that is cleared quickly, I want to talk about the advantages of a monoclonal versus a polyclonal antibody. So there's 2 antibody types that can be generated. A polyclonal antibody can, as you can see, has many targets that it combines. You can see that there's 5 here that it could basically recognize. Whereas a monoclonal antibody is very specific and it's going to bind a specific target. So while a polyclonal antibody is cheaper to produce, and it might be tolerant of small changes to protein structure and is often higher affinity, they're not as specific as we would like. So we tend to gravitate toward monoclonal antibodies because this is going to bind that specific target. And even though it takes more time and is more expensive to produce, it ends up being a better specific antibody for the target that we're going after. Next slide. So now pivoting briefly to what happens in COVID-19 patients. Our group, and it's actually myself and Dr. Dario Vignali that are leading this charge at Pitt (sic) [University of Pittsburgh], we are looking at patients via what is called single cell RNAC. So what you're seeing here are projections of immune cells, specifically B cells and plasmablasts, in either patients that have ARDS, which is another airway disease, that's often a comorbidity for COVID patients given that it affects the airways; COVID patients in the middle, which are patients that are actively infected with COVID; and then healthy donors. And these 3 blood samples were processed and looked at from a transcriptome level. So basically, we have a bunch of reads where we can look at all of the different transcripts that occur within B cells and plasmablasts. And this projection is showing you how abundant those cells are and how -- and then we can drill down and figure out how similar or different they are at a transcriptional level. So what you can see right away is that COVID patients have expansion of plasmablasts. And while you can see it here, you can also see certain subsets of B cells that are also at higher presence than in healthy donors or in ARDs patients. So what we're currently doing is we're mining these data to understand why B cells and plasmablasts are similar or different. One thing that I will note that's not annotated on this slide is that COVID patients have an increase of CD73 on the B cell cluster that you're seeing here. So everything that's in like a salmon in the middle, those are going to have CD73 expression, whereas the plasmablasts do not. So truly, when we are thinking about the monoclonal antibody for CD73, we're thinking about basically targeting and agonizing those B cells that are within those COVID patients that then might help an increased memory of the B-cell response. Next slide. So others have shown also that COVID-19 patients that have very severe disease have loss of germinal centers that I mentioned earlier. So if you look from this paper [in cell] this year, on the right-hand side, you again see in the non COVID-19 lymph node, very nice, bright germinal centers. And you can see this marked by either CD3 and CD19 on the right-hand side, red and green, and you can see these very nice circular structures that I showed you in some of the images earlier. This is also confirmed by a marker known as BCL6, which is a canonical marker of germinal centers, and we often use this even in our cancer studies when we're looking at these structures. And then the bottom right-hand side is the overlay. So you can see very nicely this organization and in a normal lymph node of really nice set of structures. What's problematic with COVID patients, on the left-hand side, is that these patients' lymph nodes are in quite disarray when they are analyzed. So you can see that the CD3 and 19 are there, but there's not these nice structures that you're seeing, and that's conferred by the lack of BCL16 as well, and you can see that also in the overlay. So what we're concerned about here is that, that hub or that center that I was discussing earlier is really disregulated in these COVID-19 patients. So their ability to make really robust antibody responses is going to be hindered as a result. And so this is why we think about long-term immunity and being able to think about a vaccine that will help or a treatment that will help generate that. Next slide. So this is another schematic from that same manuscript, summarizing what they showed. So basically, the top portion in blue is what happens when there's other immunogens or other viruses that come in and go through this education hub. So I showed you before that it's really important for B- and T-cells for that virus to be shuttled to the lymph node for education, so there's proper education within the germinal center. What's happened in COVID patients is that, that is not occurring. And so basically, what's happening is these COVID patients do not have these nice germinal centers, which don't allow for this education of B cells and then won't allow for B-cell-specific antibodies to be generated. So CD73 is a great agonistic antibody consideration for multiple reasons. First of all, it promotes adhesion of those dendritic cells or these particular dendritic cells in a dermal center reaction or a DC reaction. It helps to regulate a germinal center and is also expressed on memory B cells. So it makes sense to think about it as a target. If you hit the next button, please. Further, there's a lot of anti-CD73 antibodies that are being evaluated as monotherapies in tumors, and that's really where this started and where our interest began with CD73. And if you bring all 4 of these agents up from the different companies, you can see that CPI-006 from Corvus is bolded, not only because it's the focus of this symposium, but also because it directly is going to compete with AMP for the CD73 active site. It's an agonist and it's been shown to generate robust memory B cell responses which will be demonstrated in the next presentation. So different from the others, it's quite important in that it helps to amplify that B cell response and increase antibody production. Next slide. I also want to mention in the last couple of minutes here that basically, CD73 distribution and non-inflamed versus inflamed tonsils is quite different. So what you're seeing here are single plex images from a multispectral imaging platform that I reduced down, so you could really see the signal of both CD20 which marks B cells and CD73 which marks CD73 positive B cells. So you can see CD20 positive B cells in these nice germinal centers that I showed you before, and you can see the CD73 distribution in those tonsils. However, in patients that have inflamed tonsils or tonsillitis, which would be similar to what is happening when you have a viral infection of some sort, you see an increase of CD73 intensity within these centers and on the B cells in particular. So even if those patients don't have the germinal centers and those germinal centers are disregulated, they have the appropriate marker that could help bring those responses back and help with memory B cell generation. Next slide. So to end, the other thing that I will mention from some of our data in cancer is that if we look at melanoma patients, and this is 13 patients in total, we can look at different clusters of B cells in these patients. And really, this is quite busy. So what I want you to focus in is on cluster 2. Cluster 2 here, if you look at some of the other visualizations that I have here, if you stand and you go to CD73 on the bottom row, you can see that it's very, very red or high expression of CD73 in cluster 2. That cluster is conferred here that it is a pre-germinal center B cell. And we believe that pre-germinal center B cells are obviously those activated B cells that are going to then form these bonafide germinal centers. So by basically agonizing or stimulating CD73 pathway, you're going to generate more memory B cells and better antibody responses when germinal centers are being basically obliterated in these more severe patients. So with that, I'll stop because I'm a little over time. And I'll stop to take any questions related to this presentation. Thank you for your attention.

Tullia, this is Richard. That was a great presentation, very clear, and I think sets the stage for subsequent talks. Why don't we do this since we want to catch up a little bit on time: let's move to Dr. Willingham's presentation, and then we'll take questions on both of your presentations.

Perfect. Yes, thank you.

Thank you, Tullia, again. That was perfect.

No problem. Thank you.

Thank you, Dr. Miller. During this session, I'd like to introduce CD73 and review some of the reasons we are excited about CPI-006, our anti-CD73 antibody that has some unique, very interesting immunomodulatory properties. CD73 is an ecto-enzyme present on the majority of B cells in a subset of CD4-positive and CD8-positive T cells. One function of CD73 is to convert AMP, adenosine monophosphate, into immunosuppressive adenosine. And many companies are actively developing CD73 antagonists that aim to lower the concentration of extracellular adenosine in the tumor microenvironment and restoring immune responses by blocking this enzyme function. We note that Resta and Thompson originally characterized CD73 as a costimulatory molecule and an adhesion molecule on T-cells. But the results we will present here demonstrate that CD73 also has a major role in B cell activation and maturation. CPI-006 is our unique dual function, anti-73 antibody. It not only blocks CD73 enzymatic activity, but it also has the additional ability to directly activate B cells. This B-cell activation is independent of the adenosine modulatory activity. And as far as we know, CPI-006 is the only CD73 antagonist that has these dual immunomodulatory properties. CPI-006 is a humanized, anti-73 IgG1 antibody, engineered in a manner that abolishes [SD] effector functions, such as the ability to fix [complement] and initiate ADCC. It is also not directly cytotoxic to any immune or epithelial cell we've tested. In the following slides, we'll show that stimulating B cells with CPI-006 induces markers of activation and antigen presentation. We also observed increases in markets associated with B cell differentiation and a corresponding morphologic transformation into antibody-producing plasmablasts and increased immunoglobulin secretion. In addition to COVID-19, CPI-006 is also being evaluated in a Phase I clinical trial in advanced cancer patients. Biomarker studies in these patients show a rapid, but transient redistribution of B cells out of the peripheral blood and into lymphoid tissues. An increased frequency of memory B cells is observed when the cells returned to circulation by day 21. Next slide, please. Let's look at some of the data to support these claims. In the results shown on the top-left, you can see that CPI-006 activates human B cells, resulting in the up-regulation of activation markers like CD69 and CD83. An antigen presentation machinery like CD86 and MHC Class II. On the top-right, you can see that B cell activation with CPI-006 also results in the increased expression of CD27 and IgG, CD38 and CD138, all markers associated with B-cell maturation. On the bottom-right, we show that naive B cells stimulated with CPI-006, undergo morphological changes consistent with differentiation into plasmablasts, a cell type that is very effective at antigen presentation and antibody production. Collectively, these data show that CPI-006 can cause a direct activation and maturation of human B cells. Next slide, please. On the left panel here, we again show that CPI-006 induces the expression of CD69. This is an activation marker of particular interest as a result in the prolonged retention of activated B cells in lymphoid organs and the thymus. This increased residence time provides the B cells with an opportunity to complete activation and interact longer with T follicular helper cells to shape downstream immune responses. B cell activation has not previously been described in relation to CD73 signaling and is seemingly unique to CPI-006 as all other anti-CD73 antibodies we've tested, such as CPX-016 shown here, do not have this ability. These other antibodies all block CD73 enzymatic activities, but we know they bind to other regions or epitopes on CD73. They also do not cross block CPI-006, suggesting that 006 binds CD73 in a unique way that enables this potential to activate B cells. On the right, we show B cell activation is not a consequence of the concentration of extracellular adenosine. Addition of NECA, a potent and stable adenosine analog, does not blunt the induction of B cell activation markers by CPI-006. This again shows that B cell activation is independent of the adenosine modulatory activity of 006 and not something all CD73 antagonists are going to be capable of. Next slide. To assess the functional consequences of B-cell activation with CPI-006, we measured the concentration of IgG and IgM secreted by healthy donor PBMCs into cultures ]. Addition of CPI-006 resulted in a threefold increase in the concentration of IgM and IgG relative to an isotype control demonstrating that CPI-006 stimulates antibody secretion and possibly isotype class switching. On the right, we see that CPI-006 induction of CD69 can be blocked with ibrutinib, a covalent BTK inhibitor. This demonstrates that CPI-006 directly activates B lymphocytes by invoking canonical B cell signaling pathways downstream of the B cell receptor. Next slide. CPI-006 is currently being evaluated as an immunotherapy for cancer in a Phase I trial. In this dose escalation, repeat dose studies, we are evaluating doses from 1 to 24 mg per kg. For simplicity sake, I'll focus on the doses at or below 6 mg per kg, as these other doses similar to those evaluated in the COVID-19 trial that Dr. Mobasher will discuss later in the program. On the far left, we show the PK of CPI-006 at 1, 3 and 6 mg per kg. Along with a horizontal dash line indicating concentration at 1 microgram per mill. This is the dosing threshold we were aiming for in the COVID-19 trial, where you can see in the middle graph that CPI-006 activation is dose-dependent with concentrations of 1 microgram per [milligram] achieving near maximal induction of CD69. Returning to the PK draft on the left, you can see that doses at or above 1 mg per kg results in sustained concentrations above 1 microgram per [milligram] for several days. So we are confident that doses in this range will be sufficient to enable the B cell activation we aim to achieve. Further support for the dosing at this level is shown on the far-right, which illustrates a dramatic decrease in circulating CD73 positive B cells at the 1, 3 and 6 mg per kg dose levels, 30 minutes after antibody infusion. Recall CPI-006 is a mutant IgG1 antibody that does not induce B cell death or initiate ADCC. So this result is most likely due to the induction of CD69 and the temporary retention of activated B cells in lymphoid tissues. Taken together, this data suggests that B cells can be effectively activated with a single dose of 1 to 5 mg per kg CPI-006, exactly the dose range we focused on in the COVID-19 trial you will hear about later. Next slide. We next looked at what happens to these B cells when they return to the circulation after having been sequestered in the lymph nodes and lymphoid tissues. We observed that B cells returned to circulation at similar levels of baseline by day 21, and that these circulating B cells were enriched in CD27 positive, IgG negative class switch memory B cells. An example from a single patient is shown on the left, where memory B cells increased from 11% to 29% after treatment with CPI-006. The figure on the right shows the same increase is observed in the majority of patients treated with CPI-006. This is a very important observation as it relates to COVID-19. As it becomes clear that temporary protection against SARS-CoV-2 can be imparted by circulating neutralizing antibodies, but to keep the long-term immunity in preventing future outbreaks lies in the production of these antigen-specific memory B and T-cells that are capable of recognizing and eliminating any potential reinfection. You'll hear more about this from Dr. Criner and Dr. Mobasher later today. Next slide. We thought we could leverage the immunomodulatory properties of CPI-006 to improve clinical outcomes of patients with COVID-19 by significantly boosting the magnitude, diversity and duration of humoral and cellular immune responses to SARS-CoV-2. Really simply, we expect CPI-006 to activate B cells. Generating plasmablasts that will produce durable, high titer, polyclonal, IgG and IgM neutralizing antibodies as well as memory B cells that will provide long-term immunity and protection from reinfection. Notably, this strategy is not restricted to COVID-19. CPI-006 is not like the passive monoclonal antibodies developed by Regeneron, Lilly and others, that specifically bind and neutralize SARS-CoV-2. Rather our approach of activating B cells to enhance immunity represents a potential universal therapy, one that is immediately deployable for COVID-19, but also for the treatment or prevention of the next viral pandemic, for other infectious diseases or as adjuvants to enhance the efficacy of vaccines. Next slide. We were not able to do a randomized controlled trial in our Phase I COVID-19 study. So instead, we utilized an animal model to determine if CPI-006 could elicit antigen-specific immune responses to SARS-CoV-2. CPI-006 does not bind to mouse CD73. So for this experiment, we used special mice called NSG-SGM3 mice, that have no B-, T- or NK cells, but they have been reconstituted with a human immune system. These mice have human B cells that can be activated with CPI-006. Instead of the live virus, we immunized these mice with purified SARS-CoV-2 spike protein, along with CPI-006 or an isotype control antibody. On the left, you can see that anti spike antibodies were only produced when the B cells were activated with CPI-006. Moreover, on the right, you can see that this is an antigen-specific response. Mice treated with CPI-006 makes antibodies to the spike protein that they were immunized with, but not to the nuclear capsid, another unrelated SARS-CoV-2 viral protein. These results demonstrate that CPI-006 does augment humoral immunity and is expected to induce robust and durable antibody responses to SARS-CoV-2 in patients with COVID-19. Next slide. So to review, the results shown here demonstrate that CPI-006 activates B lymphocytes, resulting in morphological and immunological changes consistent with B-cell differentiation and antibody production. This property is unique to CPI-006, and it's independent of the adenosine migratory activities. Treatment with CPI-006 induces the redistribution of B cells with an increase in returning memory B cells and expansion of new B-cell clones. Changes in lymphocytes are consistent with an induction of adaptive humoral immunity. Humanized mice vaccinated with CPI-006 in SARS-CoV-2 spike protein produced antigen-specific antibodies. Mice receiving spike protein plus a control antibody do not [manage a] response. Therefore, we believe CPI-006 may enhance immune responses to infectious agents such as SARS-CoV-2. Next slide. Finally, I encourage you to check out our paper available on medRxiv for additional details related to the preclinical, translational and early clinical results presented today. Back to you, Dr. Miller.

Thanks a lot, Stephen. That was perfect. Thank you. I think we have some time now for questions for Dr. Bruno and Dr. Willingham. Operator, we can take questions from the listeners.

[Operator Instructions] Our first questions come from the line of Tony Butler with ROTH Capital.

One question for Dr. Willingham, please. Stephen, you may have said this and this may be part of the data that you had previously presented. But if you were to generate an anti-CD3 antibody that was not 006, would it behave the same or differently in the NGS mice when co-vaccinated with the spike protein. Is that a fair question? Or...

Yes. If I understand the question, it is would other anti 73 antibodies be able to induce these antigen-specific immune responses. And my answer to that would be almost certainly no. We know 006 is rather unique in its ability to activate B cells. And so without these other antibodies being able to activate B cells, I don't think they would produce these same immune responses in that model.

[Operator Instructions] There are no further questions at this time. I'll now hand the call -- sorry.

Actually, this is Dr. Miller. I have a question for Dr. Bruno. Tullia, you talked about memory B cells. Is it known why some memory B cells last a longer time than others, for example, memory B cells to measles virus, for example, lasts for decades as opposed to memory B cells to other antigens which are shorter. Is there anything known about the mechanism of that?

I think that's a great question. I actually would have to probably go and look and see what the comparison is for some of these diseases that, like measles, that have longer lasting immunity versus something like a flu infection, for example, where we vaccinate every year because of the different antigens. It has a lot to do with how the virus or that protein changes, right? And so part of the reason why, as a lot of people know, you get your flu vaccine every year. You can have a lot of mutations and the virus can change and so you need to have the right proteins that it's being educated against. So it probably -- that amount of immunity that's generated and the memory that's generated has a lot to do with how viruses or other agents that cause disease change over time is the kind of the general answer. But I think that related to COVID-19, I think the challenge has become that's there's a lot of things that we're seeing in this virus that is not -- it's kind of a mixture of seeing both a -- what we call an "acute" infection and a "longer-term" infection. So with the flu, we think about virus coming in and being cleared, and there's not any disruption of lymph nodes or anything like that; whereas with something like HIV, that's more chronic, that virus is going to be around longer and it's going to cause destruction for a longer period of time. So we're seeing something in the middle. So I think while we know that for some of these key agents that you mentioned, I think the challenge for COVID-19 is we're not really sure what's happening with the long-term memory. We believe that there's memory cells there, but it's possible that they're just being sequestered or they're not being energized properly because of this lack of structures and this lack of education that occurs in these normal organs, the secondary lymphoid organs.

Okay. Just -- okay. Just another question. I think you showed in your data that CD73 is on the -- in the COVID patients is on the plasmablast. It's not on plasma cells. And of course, the COVID patients have disrupted or absent germinal centers. So do you think that B cells are being activated, but can't mature, can't differentiate all the way to an antibody-producing cell because the germinal center is disrupted?

Yes. I think that's exactly what's happening. And so what I mentioned when I showed some of those images of CD73 in a normal tonsil or a normal lymphoid organ, when you have more of an inflamed area, you're seeing the distribution of that go up. So if you have, basically, what we would have in COVID-19, which is you have a lot of inflammation, but then you also have, in addition, this viral infection that's kind of disrupting those centers, if the CD73 is present on the B-cell still, it would basically be able to reinvigorate that memory response that's not occurring because those germinal centers are not present. So I think you're exactly right. I think that's where that disconnect is. And in fact, some of our data, what I can tell you is I didn't show all of it just due to confidentiality reasons. But basically, if we interrogate those plasma cells or those plasmablasts that I showed you, they do not look like they're normal, like they're not producing antibodies the way that they should. So that gets back to your point that they may be getting -- basically becoming more regulatory in that regard and like a little bit more suppressive in some of those patients, and we're still trying to tease that out a bit.

Thank you, Tullia. I believe that there's a couple of other questions from the listeners. Maybe we can take another one question or so.

First questions come from the line of Mara Goldstein with Mizuho.

I think you answered, I think, in part, our question as you responded to Richard. But I guess my question then is one of a general one around B-cell maturation and the ability to either qualitatively or quantitatively look at the effect, let's say, that, that CPI-006 is having on that process and whether or not you achieve a particular threshold that is necessary from the standpoint of keeping -- of making -- of having those memory B cells be active. And so if there's anything additional you could add to that? And then secondarily, has there been any evidence of T-cell activation or proliferation or even differentiation with CPI-006 in addition to what you've shown from B-cell activation perspective?

Thanks for those questions, Mara. I'll take the first question. In terms of the characterization of the memory B cells that are produced, we're not completely done with that analysis. I know Stephen now is doing some B-cell receptor sequencing, which is also going to teach us a lot about sort of the evolution of those cells. But basically, if you put the story together, it looks like COVID patients, who perhaps've other viral infections as well, disruptions of germinal centers is not unique to COVID. And we believe -- and it's very difficult to study this in humans because you have to do biopsies of lymph nodes and spleen. That our antibody being agonistic activates B cells and chases them into the germinal centers of the lymph nodes where they can complete their maturation and differentiation, very hard to study that in humans. We've been looking at things like PET scanning and so forth to get a handle on that. Stephen's got another mouse model that he's looking out for that. But basically, an antibody that would chase B cells into lymph nodes where they could undergo differentiation, affinity maturation, et cetera, would be -- I must say, a big breakthrough. Now your second question on T-cells, yes, we are seeing evidence of antigen-specific T-cells generated. We have not done as much work in that area. It's going to be in Dr. Criner's presentation and it's on our poster tomorrow, some of the early evidence for that. But we do see antigen-specific CD4 and CD8 effector T-cells, memory cells -- effector memory T-cells. And as I think Tullia mentioned earlier, CD73 is on the T-cells. So again, big -- just to emphasize something that Stephen said, there are many other CD73s, but they react with a different epitope. They do not have, to my knowledge, they do not have -- and many of them we've looked at in the lab, they do not have this agonistic activity, which is what we primarily were interested in when we made this antibody. We were going after that because we were interested in the B cell biology and the trafficking of lymphocytes. So with that, but that's a great question, Mara. Thank you for that.

I think we probably need to move on. And I hope Dr. Criner is on the line because I know he's been busy in the hospital. So now I would like to introduce Dr. Criner from Temple University Hospital. As I mentioned earlier, [Gerry] runs a large department at a busy urban center, which has had a relatively high incidence of COVID-19. He has been working on the front lines of the pandemic and has been involved in clinical trials with a large number of existing and new potential therapies. I thought it would be most important for him to talk to us about the clinical management of these patients and what we have learned from treating these patients over the past 8 or 9 months. Dr. Criner?

Thanks, Richard. And you can move to the next slide to my disclosure side. So thanks for your opportunity to give you some glimpse into the clinical perspectives of COVID-19. These are my disclosures, none of them which really compete with what I'm going to say, except that I was a principal investigator for the Corvus trial that we had here at Temple. And my most important disclosure is I'm not an immunologist or cancer physician. I'm basically a pulmonary and critical care physician. Next slide. So this overall last night, the night before last shows the picture in the world of COVID infection from the Hopkins website. Over 51 million infections, about 20% of them in the United States, over 10 million patients have been infected with COVID-19 and about 1,300,000 deaths, again, about 25% of those are in the United States, with over 240,000 deaths from the United States. That star represents where I am. I'm in Philadelphia, for which we have seen about 50% of all the COVID infections in Philadelphia County, which is the highest in the state of Pennsylvania at our center at Temple University. Next slide. So why is it so rampant? And this is just some, I think, background that some may know, but some may not, that if someone is infected with the COVID virus, they're likely to infect 2 to 3 other individuals, and people remain infectious in the meantime, the median duration is about 4 to 5 days, but people can be infectious overall for almost 2 weeks, up to about 12.5 days. Ninety-five percent of patients would be infectious up to that time. The most important thing to realize is that COVID-19 patients are most infectious when they're asymptomatic. In the beginning of the infection, in the first 5 days, when there's high nasal tropism and also viral -- virens in the nasopharynx overall, and it's not only just a respiratory secretion. Some data has suggested that feces and urine also can be a source if it's [aerial], [salives] or contact transmission. Like many other viral infections, you don't have to be an immune compromise host or very old or very young. Everyone is susceptible to suffer from this infection. Next slide. This is a cartoon that goes overall simply that natural history of COVID infection. And there's really 2 phases. One is the viral replication phase that happens initially. Like I just said, that tapers off in about 10 days, 14 days. But at that time, a host inflammatory response starts to occur. And that could be a hyperinflammatory response in some individuals. This is the body responding to this infectious agent with inflammatory mediators, chemokines and cytokines to try to protect the host, which is us, but can be disregulated that can cause severe injury to the lung and to other organs. In the lung, it's manifested by diffuse infiltrates that can be checked, but in others cannot be checked, and these patients go on to a full-blown cytokine storm that creates a syndrome of acute respiratory distress syndrome, where patients are severely ill from a respiratory standpoint with low levels of oxygen in the body. Next slide. This is a brief slide that shows about the patterns of inflammation and injury that have been documented in COVID-19 lungs. And you can see to the left, a response pattern to injury with hyaline membrane formations that thickens the lung tissue, that makes it more difficult to get oxygen into the body through the lung. The center "C" picture shows interstitial mononuclear inflammatory responses, but it's important to realize that the response to this infection not only affects the lung parenchyma of the air sac, the interstitium, but also the vascular bed, in the lung as well as the other veins of the body. An hypercoagulable state has been indicated. And you can see the thrombus in a pulmonary artery shown in the D picture to the right side of this slide. Next slide. I talked a lot about the lung. And the lung is the most important organ in the body because I'm a pulmonologist, but it's the most important organ that can cause immediate death in patients with COVID-19, but other organs also are -- can be infected, such as the heart, the kidney, both in them in about 10% to 15% of the time. And this is an example of the spleen, where lymphocyte numbers are decreased. There's cell degeneration and necrosis can be seen. So this is a systemic manifestation of a viral infection in COVID-19. Next slide. When you look at patients that have COVID-19, this looks at lung lavage in serum fluid in healthy people, people in the ICU in the middle of these bar graphs to the left and also looks at people in the ICU but not as critically ill. And you can see an expression and lung lavage fluid of higher inflammatory mediators that are seen. And there's also a decrease in the amount of peripheral blood T-cells and B cells that occur. Severe lymphopenia is a hallmark of this disease. It's part of the diagnostic set of features that we use. And when patients respond to treatment or recover, the T-cell count, the lymphocytopenia resolves. So host-directive therapies has been discussed in the last period of time -- hour or so, may be an option for some patients. Next slide. And the coagulation, which is abnormalities, that is driven by the severe inflammation, it can even be a marker of death. And as you can see in this manuscript from Lancet, the patients that had measures of hypercoagulation significantly increased D-dimers and fiber degradation products were much more likely to succumb from the disease than others and this is because of a high receptor affinity for ACE2, which is what the COVID virus binds to. It's also expressed by vascular endothelial cells. Next slide. So this to reemphasize pneumonia respiratory failure, acute respiratory distress syndrome are important, but other derangements of other organs happen. So systemic treatment is key to treatment of COVID-19 infection. Next slide. So let me talk a little bit about what happened to us at Temple because this could give you a clue of the importance of coming up with therapies to help not only the patients, but systems like ours to be able to deal with surges of patients who come in. Next slide. This slide, overall, shows the number of patients that we've treated for COVID suspected or COVID diagnosed patients since March of this year. We've admitted almost 27,000 patients to Temple, where in the epicenter here North Philadelphia of the infection in Philadelphia. And we've had close to 2,800 patients that have been swabbed positive. Our mortality overall is about 4.6%, which to us is relevant because -- and important because 94% of our patients are at high-risk because of their ethnicity as well as their social demographic status. We have more of a safety net hospital here at Temple. Next slide. What we did at the beginning at Temple of the pandemic was create one building, shown by the arrow, where our COVID patients were hospitalized and that can take care of 250 patients overall. At the height of the pandemic for us at the end of April, we had about 226 patients hospitalized. So we never got up beyond our cap. Right now, we have had another spike where we were at 20 to 18 patients, we've tripled, and now we have today 88 patients in our hospital with COVID infection. Next slide. So it's important to realize that we have to treat the surges of the disease. This shows, overall, a snapshot of the infection in Philadelphia County, Pennsylvania and what we're all experienced across the country and in major urban cities [ on left ]. You can see to the bottom left that the -- by ZIP codes, Temple sits at 19140 in the middle of this. We're in a highly endemic area for a high prevalence of COVID and positive cases that are in our surrounding community, our feeding area overall. And in bottom right, you can see the peak of the infection that happened to us in Philadelphia County in May, went down through the summer months until early October, and then is on this upward linear trajectory really over the last 6 weeks overall. Hopefully, this is going to peak sometime, but we're not optimistic that it's not going to peak sometime in mid-December to early next year. Next slide. One of the most important things to think about the development of therapy is what patient population is experiencing the most complications. We know that infection leads to hospitalization, which leads to death. So trying to prevent hospitalizations or treat people or prevent them from being hospitalized or treat them once they're there safely is key. And if you look at the bottom right of the slide for hospitalization, who gets hospitalized or are hospital, it's driven by elderly Hispanics more than 70 years of age, followed by elderly African-Americans and then Asians overall. Caucasian individuals are much less likely to be hospitalized in the Philadelphia region related to COVID infection. So we really have to have a therapy that's going to treat patients effectively, to prevent hospitalizations. And once they're hospitalized, something that could be tolerated and used in people that are of older age. Next slide. We've recently written a document that's published in the Blue Journal about the care of patients with COPD and COVID infection. And this snapshot gives you an idea of the clinical features, what we do to investigate patients based on the stage of the disease and then the possible interventions that we do overall. And you can see that it's tiered based on lung and non-lung treatment, pharmacologic treatments, coupled with noninvasive respiratory modalities, high flow oxygen, doing anything we can do to avoid intubation, to avoid the risk of death once patients become intubated for severe respiratory failure. Next slide. These are the pharmacologic targets that have been looked at so far in -- I don't have it in this deck, but there's close to 98,000 different clinical trials on clinicaltrials.gov that you can see directed towards COVID-19. And if you look at the categories of treatments overall, they are things that are either monoclonal antibodies or antivirals that limit the ability of the COVID virus to bind to the receptor sites on the cell wall, the ACE2 receptor site. Then there are other agents that in the cell itself, trying to prevent the translocation for RNA transcription. And then finally, looking at things that can decrease the cytokine inflammatory chemokine storm that occurs in some patients. So a variety of anti-inflammatory, anti-infective and monoclonal antibody directed towards targets of affecting the binding of COVID virus to the receptors for the cells as well as the inflammatory mediators. Next slide. So what works and what doesn't work? Well, what doesn't work is hydroxychloroquine or chloroquine. In fact, all the prospected randomized control trials have shown that, that agent is not effective. It has a trend towards a higher mortality, especially from our cardiovascular standpoint. So that's one therapy that does not work. Next slide. This also shows 2 recent therapies that from high levels have been reported also not to work. At Temple, we've done 35 prospective randomized control trials. We've done the first one, we've done these with canakinumab and sarilumab and neither of these agents effective. Next slide. Tocilizumab, another interleukin-6 antagonist, has had much study. There's been -- as you can see, to your right, there's been 5 studies that have been reported, both observational and randomized control trials. It showed mixed success with effectiveness. There's 4 other randomized control trials, one I know of right now that's in press. And the story is not out on this, but hopefully, we'll have, from these other studies that are pending, better elucidation of whether this can be an effective agent or not. Next slide. This is one thing that has been just received emergency approval from the FDA. This is the Lilly product, a SARS-CoV-2 neutralizing antibody that was done in an outpatient setting that showed that with a targeted binding receptor site, a decrease in viral load was demonstrated in the bottom left of the slide. And next to that, you can see that the viral load on day 7 in each trial group was favorably affected by the investigational agent. And you can see on the top right of the slide that patients had an improvement in their symptoms overall. Not a dramatic improvement. But an improvement, nonetheless, in the first 5 or 6 days from baseline after patients were reported in this study. So this is now going to be started as an outpatient study in patients with higher -- outpatient therapy in patients at higher risk, those greater than 65 years of age or those younger who have a comorbid condition or some feature that puts them at risk. Trying to do this, however, is going to be somewhat of a challenge to start to set up COVID-positive infusion units by hospitals that's separate from their regular patient population. We're struggling with that at our institution now trying to develop that. Next slide. Some of the therapies have demonstrated to you have been a mixed bag. People trying to prevent, people that are sick. This is 1 therapy that works in sicker people, and that's the use of steroids. And it doesn't matter if it's Decadron or dexamethasone, that if it's hydrocortisone or solumedrol. In patients that have COVID pneumonia and are symptomatic from it, steroids have been shown to decrease the mortality risk by 30%, similar to what our Chinese colleagues told us 8 months ago. And as you can see in the right side, in the top right, those who received invasive mechanical ventilation, given dexamethasone in the red, they had a survival advantage that was 25% to 30% better. If you look at the bottom right, those who did not receive oxygen therapy, however, there was no mortality benefit. Actually, patients trended to do worse when given dexamethasone compared to usual care. So steroids are effective overall. Next slide. Another agent that has first emergency FDA approval and now is -- got full approval is the use of remdesivir. And this is 1 of the pivotal studies that demonstrated this in JAMA. Next slide. And what this shows to the right, as you can see, the patients that were given either 5 or 10 days of remdesivir tended to have a less need to go on to more invasive forms of respiratory support in terms of higher levels of oxygen or high flow being intubated. And these patients tended to be in the hospital for a shorter duration of time. What was thought to be is that patients that got 10 days would do better than people -- patients that got 5 days, but that was not the case. As you can see, only 5 days was statistically significant compared to placebo. So now this agent is, in most patients, used only 5 days, not 10 days, unless patients aren't responding to therapy to decrease their hospital duration and try to help to improve their outcome. However, in patients that are very ill with COVID, remdesivir has less impact rather than using it in patients with mild to moderate disease. Next slide. This is the Mayo Clinic consortium using convalescent plasma, which we're part of overall. And I think it has some important information for what's been presented so far by CPI-006. Next slide. And what that is, is that basically, if you have higher antibody levels, you tend to have an improvement in mortality or survival. And if you give it earlier in the course, within the first 4 days, that improvement survival is seen not only at 7 days, but in 30 days after patients are given that therapy. Next slide. And this is shown on the following slide. The 7-day and 30-day mortality, giving it to patients when they're less ill earlier on the stage of their disease and giving it quicker, sooner after the patients present, is key outcome. So something like CPI-006 that gives a higher level of effective neutralizing antibody sooner in the patient's course with higher, more robust levels, may potentially have important benefits to patients. Next slide. Another thing not to forget as I brought in the beginning, that the vascular space is important. A lot of the agents that we've looked at, except outside of anticoagulant therapy in terms of antiviral or anticytokine storm, has not been looked at on their impact on hypercoagulable state. But as you can see here, people that are anticoagulated fully have an improvement in survival, especially as shown to the right, patients that are sicker, who received mechanical ventilation. So next slide. In summary, this is the most important pandemic over our lifetime. I've been doing medicine pulmonary critical care for 30, 35 years. There is nothing like this in terms of the sickness of the patients and the surge of patients that are sick overall. It's not over as everyone knows in the U.S. right now. But we've learned a lot in the last 8 months. We know a little bit of what helps and what does not help. But I think overall, [indiscernible] thought of doing this, and I've seen every patient remotely that came in with Temple, the 21,000 over the last 8 months, it's not going to be one magic bullet. It's going to be a composite treatment, I believe, with antiviral, anti-inflammatory and antithrombotic treatments, coupled with aggressive noninvasive forms of nonpharmacologic care. And prevention is the key. Vaccines may be helpful. But again, we don't know how effective they're going to be in the real-world once they're available. So thanks very much. Be happy to answer any questions someone may have.

Thank you, Gerry. That was a fantastic overview. And first of all, I want to thank you and your wonderful team at Temple for everything you're doing on this disease. I know you guys have been looking amazingly hard over the past several months. So thanks to you and your staff for all the work you're doing. I think let's -- I think people are going to be very interested in asking you questions. So we'll deviate a little bit from our schedule. Let's maybe open up to listeners for any questions for Dr. Criner.

[Operator Instructions]

I have a question, operator.

Sure. Go ahead, Dr. [ Lowe ].

Dr. Criner, you mentioned in your talk that outpatient infusions in COVID-positive patients is going to be problematic. How do you think -- how are you trying to tackle that problem at Temple?

Yes. So that's a good question. So what we are developing is a negative-pressure area where we could treat 6 patients in an infusion center at the same time. That will be one part of it, and then be able to staff that because you have to have emergency equipment in case someone would have an anaphylactic response and a mechanism that, from this outpatient infusion center, that if a patient has an emergency, where are they going to go to receive urgent care? Then the other thing is to make -- and this isn't going to be the only therapy that we're going to be offering to outpatients who want to take something preventative from having progression of disease and not requiring hospitalization. So we're going to have to increase patient awareness and decrease the time from when patients are found to be positive and have access for them to get an outpatient therapy like this.

Yes. Just a follow-up on that. So a negative pressure outpatient clinic, that seems pretty dramatic. But I understand the need. And with 6 patients per shift or time -- so the time of treatment is going to be a big issue. And I'm just wondering for like the -- since the monoclonals are several grams of antibody and CCT, how long are those infusions and how long do you have to monitor the patients before and after you give the product?