Good morning, ladies and gentlemen. Thank you for standing by, and welcome to the Corvus Pharmaceuticals R&D Symposium Webcast and conference call. At this time, all participants are in a listen-only mode. There will be several question- and- answer sessions throughout the presentation, and instructions will follow at that time. If you would like to ask a question, please be sure to dial in to the conference call line. It is now my pleasure to turn the call over to Zack Kubow of W2O Group. Please go ahead, sir.
Thank you, operator. 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 two 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 two, 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 Pharmaceuticals's 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. 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 in 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 CPI-006 for the treatment and prevention of COVID-19. Stephen will review the basic properties of CPI-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 The Lancet recently, there is a period of two to three 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 withCPI- 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 immune evasion? So far, all of the preclinical and clinical evidence suggests 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 one month, six months, one 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? These are all questions that 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 this 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. 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. In my lab, I currently focus on B cells and tertiary lymphoid structures within cancer patients. My tagline in my initial slide is T 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 am currently working on that in my research program. I provided here my email address in case there are questions that come up that are not answered today. 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. You can see this germinal center with the yellow tag here. You can see a very circle-like organ here within this tissue. 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.
Just to give an introduction to why we care about the immune response when it comes to viruses. We think about the immune response given this initial graph that you're seeing. 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. That's in that initial red arrow on the left-hand side. 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.
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. You can see the output here is antibody concentration. This is going to be antibodies that are produced by B cells, which I'll introduce more here in a few minutes. Next. 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. What you can see here is that virus is going to infect normal cells. In this case, it's going to be the epithelium.
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. Here we go from basically what we would call from step 1 to 2, a resting tissue to more inflamed tissue. That more inflamed tissue then is a signal for those dendritic cells to then traffic to the lymph node. The lymph node is, you can think of it as a hub for education for the immune response to a virus. When you get into that lymph node, there's other players involved. 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.
Those killer T cells are very important because, as you can see, they go and attack the virally infected cells in step 4. What I don't want to discount and what I want to highlight is that there are 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. Those will then differentiate into plasma cells, which are large antibody factories that then make these viral-specific antibodies. 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. If we hit the next slide, this is really why we need a COVID-19 vaccine.
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. How do we generate what are called memory B cells? 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.
When an activated B cell gets into a germinal center, it will toggle back and forth between two 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. 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. 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 Ki-67 in yellow marks one area of that very round germinal center. 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. What you can see below in that same center, you can see a blue area, or it's more 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. 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 two zones, the dark zone on the top and the light zone on the bottom.
During the dark zone, they'll be proliferating, and that's what that yellow Ki-67 marker that I showed you was indicating. They go through this selection in 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, as a memory B cell or a plasma cell. This becomes important because the agent that we're discussing today is going to amplify these memory B cell responses. 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 node.
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 the B cell so it becomes a clone and makes a lot of antibodies as a plasma cell. Below this 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. This is important to also note. Next. If we think about as these antibodies are being generated, if we go back to this time graph and we look at antibody generation, it's not as simple as just one type of antibody being generated.
In particular, you'll see in the next presentation that there's readouts of IgM antibodies and IgG. An IgM antibody is going to be the first antibody that's produced when you have antigen invasion. You can see that happens early. You can see where the antigen comes in. In this case, antigen is going to be this viral protein. IgM is produced, and then after that, IgG will then come up after several days. This occurs through what we call class switching, which I won't have time to go through today. Basically, there's a transition that occurs, and then the IgG response takes over. 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 structure for those two antibodies, as well as what their function is and where you find them in this picture on the far right in the body. There's three 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. IgE, which is involved in allergy and won't be discussed today. Next slide. The other thing I want to mention before I talk a little bit about what happens in COVID-19 patients, now that I've given you background on basic immunology that's occurring when there's a virus that is cleared quickly, I want to talk about the advantages of a monoclonal versus a polyclonal antibody.
There's two antibody types that can be generated. A polyclonal antibody, as you can see, has many targets that it can bind. You can see that there's five here that it could basically recognize, whereas a monoclonal antibody is very specific and is going to bind a specific target. 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. 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.
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, we are looking at patients via what is called single-cell RNA-seq. 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. These three blood samples were processed and looked at from a transcriptome level. Basically, we have a bunch of reads where we can look at all of the different transcripts that occur within B cells and plasmablasts.
This projection is showing you how abundant those cells are, and then we can drill down and figure out how similar or different they are at a transcriptional level. What you can see right away is that COVID patients have an expansion of plasmablasts. While you can see it here, you can also see certain subsets of B cells that are also in higher presence than in healthy donors or in ARDS patients. 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. Everything that's in a salmon in the middle, those are going to have CD73 expression, whereas the plasmablasts do not.
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-19 patients that then might help and increase memory of the B cell response. Next slide. Others have shown also that COVID-19 patients that have very severe disease have loss of germinal centers that I mentioned earlier. 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. 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. The bottom right-hand side is the overlay. You can see very nicely this organization and in the normal lymph node, a 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. You can see that the CD3 and CD19 are there, but there's not these nice structures that you're seeing, and that's conferred by the lack of BCL6 staining as well, and you can see that also in the overlay.
What we're concerned about here is that that hub or that center that I was discussing earlier is really dysregulated in these COVID-19 patients. Their ability to make really robust antibody responses is going to be hindered as a result. 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. This is another schematic from that same manuscript summarizing what they showed. 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. 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 centers.
What's happened in COVID patients is that that is not occurring. 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.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 germinal center reaction or a GC reaction. It helps to regulate a germinal center, and it's also expressed on memory B cells. 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.
If you bring all four 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, it's been shown to generate robust memory B cell responses, which will be demonstrated in the next presentation. 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 minutes here that basically CD73 distribution in non-inflamed versus inflamed tonsils is quite different.
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. 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. Even if those patients don't have the germinal centers and those germinal centers are dysregulated, they have the appropriate marker that could help bring those responses back and help with memory B cell generation. Next slide.
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. Really, this is quite busy, 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 scan 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 bona fide germinal centers.
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. That'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.
Stephen.
Perfect. Yeah.
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 and very interesting immunomodulatory properties. CD73 is an ectoenzyme 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. Many companies are actively developing CD73 antagonists that aim to lower the concentration of extracellular adenosine in the tumor microenvironment and restore immune responses by blocking this enzyme function. We note that Resta and Thompson originally characterized CD73 as a co-stimulatory molecule and an adhesion molecule on T cells. 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-CD73 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-CD73 IgG1 antibody engineered in a manner that abolishes Fc 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 observe increases in markers 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 return 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 upregulation of activation markers like CD69 and CD83, and 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, 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 plasmablast, a cell type that is very effective at antigen presentation and antibody production. Collectively, these data show that CPI-006 can cause the 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 CPI-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 CPI-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 culture supernatants. Addition of CPI-006 resulted in a three-fold 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 study, we are evaluating doses from 1 mg/kg to 24 mg/kg .
For simplicity's sake, I'll focus on the doses at or below 6 mg/kg , as these are the 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/kg , along with a horizontal dashed line indicating concentrations at 1 microgram per milliliter. 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 milliliter achieving near maximal induction of CD69. Returning to the PK graph on the left, you can see that doses at or above 1 mg/ kg result in sustained concentrations above 1 microgram per milliliter for several days.
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/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. 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 mg/kg to 5 mg/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 return to circulation at similar levels to baseline by day 21, and that these circulating B cells were enriched in CD27- positive, IgD- negative, class-switched 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 has become clear that temporary protection against SARS-CoV-2 can be imparted by circulating neutralizing antibodies.
The key to long-term immunity and 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.
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 an adjuvant 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. 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, for this experiment, we used special mice called NSG-SGM3 mice that have no mouse 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 immunize 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. On the right, you can see that this is an antigen-specific response. Mice treated with CPI- 006 make antibodies to the spike protein that they were immunized with, but not to the nucleocapsid, 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. 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 is independent of the adenosine modulatory activity. 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 and SARS-CoV-2 spike protein produce antigen-specific antibodies. Mice receiving spike protein plus a control antibody do not mount 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.
Our first question comes from the line of Tony Butler with ROTH Capital. Please proceed with your questions.
Yes, thanks very much. 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-CD73 antibody that was not CPI-006, would it behave the same or differently in the NSG mice when co-vaccinated with the spike protein? Is that a fair question?
Yes, if I understand the question, it is would other anti-CD73 antibodies be able to induce these antigen-specific immune responses?
Correct. Absolutely.
in the mouse model? My answer to that would be almost certainly no. We know CPI-006 is rather unique in its ability to activate B cells. Without these other antibodies being able to activate B cells, I don't think they would produce these same immune responses in that model.
Thank you.
As a reminder, if you would like to ask a question during this session, please press star one on your telephone keypads. There are no further questions at this time. I'll now hand the. Oh, 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, last 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 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? 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. 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.
I think that, related to COVID-19, I think the challenge has become that 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. 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. We're seeing something in the middle. 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, these secondary lymphoid organs.
Okay, thanks for that. Just another question. I think you showed in your data that CD73 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. 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. What I mentioned when I showed some of those images of CD73 in a normal tonsil or in a normal lymphoid organ, when you have more of an inflamed area, you're seeing the distribution of that go up. 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 cells still, it would basically be able to reinvigorate that memory response that's not occurring because those germinal centers are not present. I think you're exactly right. I think that's where that disconnect is.
In fact, in 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. They're not producing antibodies the way that they should. That gets back to your point that they may be basically becoming more regulatory in that regard and a little bit more suppressive in some of those patients. 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.
Absolutely, Dr. Miller. Let me bring the first person through. First questions come from the line of Mara Goldstein with Mizuho. Please proceed with your questions.
Thanks so much for taking the question. I think you answered, I think in part, our question as you responded to Richard. 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 CPI-006 is having on that process and whether or not you achieve a particular threshold that is necessary from the standpoint of having those memory B cells be active. If there's anything additional you could add to that. 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. Basically, if you put the story together, it looks like COVID patients, and perhaps other viral infections as well, disruptions of germinal centers is not unique to COVID. 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 at for that. 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. We do see antigen-specific CD4 and CD8 effector T cells, memory cells, effector memory T cells. As I think Tullia mentioned earlier, CD73 is on the T cells.
Again, 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, 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. With that, but that's a great question, Mara. Thank you for that. I think we probably need to move on. I hope Dr. Criner is online because I know he's been busy in the hospital. Now I would like to introduce Dr. Criner from Temple University Hospital.
As I mentioned earlier, Gerard 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 eight or nine months. Dr. Criner?
Thanks, Richard. You can move the next slide to my disclosure slide. 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. Next slide. 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. Why is it so rampant? This is just some background that some may know but some may not, that if someone is infected with the COVID virus, they're likely to infect two to three other individuals. People remain infectious, the median duration is about four to five days, but people can be infectious overall for almost two weeks, up to about 12.5 Days, 95% 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 five days, when there's high nasal tropism and also virions in the nasopharynx overall. It's not only just the respiratory secretions. Some data has suggested that feces and urine also can be a source if it's aerosolized or contact transmission. Like many other viral infections, you don't have to be an immune-compromised host or very old or very young. Everyone is susceptible to suffer from this infection. Next slide. This is a cartoon that goes over simply the natural history of COVID infection. There's really two phases. One is the viral replication phase that happens initially, like I just said. That tapers off in about 10 days, 14 days. At that time, a host inflammatory response starts to occur. That can be a hyperinflammatory response in some individuals.
This is the body responding to this infectious agent with inflammatory mediators, chemokines, and cytokines that try to protect the host, which is us, but can be dysregulated 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.
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, the air sac, the interstitium, but also the vascular bed in the lung as well as the other veins of the body. A hypercoagulable state has been indicated. 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.
Other organs also can be infected, such as the heart, the kidney, both of them in about 10%-15% of the time. This is an example of the spleen, where lymphocyte numbers are decreased. There's cell degeneration and necrosis can be seen. 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 and serum fluid in healthy people in the ICU in the middle of these bar graphs to the left. It also looks at people in the ICU but not as critically ill. You can see an expression in lung lavage fluid of higher inflammatory mediators that are seen. 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 and it's part of the diagnostic set of features that we use. When patients respond to treatment or recover, the T cell count, the lymphopenia resolves. Host-directed therapies, as been discussed in the last period of time, hour or so, may be an option for some patients. Next slide. The coagulation, which is abnormalities, it is driven by the severe inflammation and can even be a marker of death. As you can see in this manuscript from The Lancet, the patients that had measures of hypercoagulation, significantly increased D-dimers and fibrin degradation products, were much more likely to succumb from the disease than others. This is because of the high receptor affinity for ACE2, which is what the COVID virus binds to. It's also expressed by vascular endothelial cells. Next slide.
Just 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. 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. We're in the epicenter here in North Philadelphia of the infection in Philadelphia, and we've had close to 2,800 patients that have been swab positive.
Our mortality overall is about 4.6%, which to us is relevant and important because 94% of our patients are at high risk because of their ethnicity as well as their sociodemographic status. We have more of a safety net hospital here at Temple. Next slide. What we did at the beginning of 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. 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. Now we have today 88 patients in our hospital with COVID infection. Next slide.
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 experiencing across the country and in major urban cities to the left. You can see to the bottom left that 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. At 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 till early October, and then is on this upward linear trajectory really over the last six 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. Trying to prevent hospitalizations or treat people or prevent them from being hospitalized or treat them once they're there safely is key. If you look at the bottom right of the slide for hospitalization, who gets hospitalized? Well, at our 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.
We really have to have a therapy that's going to treat patients effectively to prevent hospitalizations, and once they're hospitalized, something that can 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, this snapshot gives you an idea of the clinical features, what we do to investigate patients based on the stage of the disease, the possible interventions that we do overall. You can see that it's tiered based on lung and non-lung treatment, pharmacologic treatments coupled with non-invasive 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, and 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. 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. There are other agents that in the cell itself trying to prevent the translocation for RNA transcription. Finally looking at things that can decrease the cytokine inflammatory chemokine storm that occurs in some patients. 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.
What works and what doesn't work? Well, what doesn't work is hydroxychloroquine or chloroquine . In fact, all the prospective randomized control trials have shown that that agent is not effective and has a trend towards a higher mortality, especially from a cardiovascular standpoint. That's one therapy that does not work. Next slide. This also shows two 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 are effective. Next slide. Tocilizumab, another interleukin-6 antagonist, has had much study. As you can see to the right, there's been five studies that have been reported, both observational and randomized control trials that showed mixed success with effectiveness.
There's four other randomized controlled trials, one I know of right now that's in press. 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, the SARS-CoV-2 neutralizing antibody that was done in an outpatient setting that showed that with a targeted binding to the receptor site, a decrease in viral load was demonstrated in the bottom left of the slide. Next to that, you can see that the viral load on day 7 in each trial group was favorably affected by the investigational agent. 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 five or six days from baseline after patients were imported in this study. This is now going to be started as an outpatient study in patients or 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 I’ve demonstrated to you have been a mixed bag. People trying to prevent, people that are sick.
This is one therapy that works in sicker people, and that's the use of steroids. It doesn't matter if it's Decadron or dexamethasone , but if it's hydrocortisone or SOLU-MEDROL. 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 eight months ago. 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%-30% better. If you look at the bottom right, those who did not receive oxygen therapy, however, there was no mortality benefit. Actually, patients tended to do worse when given dexamethasone compared to usual care. 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, this is one of the pivotal studies that demonstrated this in JAMA. Next slide. 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 less need to go on to more invasive forms of respiratory support in terms of higher levels of oxygen or high flow or being intubated. 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 patients that got 5 days, that was not the case. As you can see, only five days was statistically significant compared to placebo.
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-19, 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 about CPI-006. Next slide. What that is that basically if you have higher antibody levels, you tend to have an improvement in mortality or survival. If you give it earlier in the course within the first four days, that improvement in survival is seen not only at 7 days but in 30 days after patients are given that therapy.
Next slide. 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 in the stage of their disease and giving it quicker, sooner after the patients present is key to their outcome. Something like CPI-006 that gives a higher level of effective neutralizing antibodies 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 anti-cytokine storm has not been looked at on their impact on hypercoagulable state.
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 receive mechanical ventilation. Next slide. In summary, this is the most important pandemic of 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. We've learned a lot in the last eight months. We know a little bit at what helps and what does not help. I think overall my gestalt of doing this, and I've seen every patient remotely that came in with Temple University, the 21,000 over the last eight 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 non-invasive forms of non-pharmacologic care. 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. Thanks very much. Be happy to answer any questions someone may have.
Thank you, Gerry. That was a fantastic overview. 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 working amazingly hard over the past several months. Thanks to you and your staff for all the work you're doing. 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.
Thank you. We will now be conducting a question- and- answer session. If you would like to ask a question, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment, please, while we poll for your questions.
As a reminder, that is star one to ask a question.
I have a question, operator.
Sure. Go ahead, Dr. Miller.
Dr. Criner, you mentioned in your talk that outpatient infusions in COVID-positive patients is going to be problematic. How are you trying to tackle that problem at Temple?
Yeah. That's a good question. What we are developing is a negative- pressure area where we could treat six patients in an infusion center at the same time. That'll 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? The other thing is, 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.
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.
Yeah, just to follow up on that. A negative- pressure outpatient clinic, that seems pretty dramatic but I understand the need. With six patients per shift.
Area
per time. Time of treatment is going to be a big issue. I'm just wondering, since the monoclonals are several grams of antibody and CCP, how long are those infusions and how long do you have to monitor the patients before and after you give the product?
That's a good question. It's really the people that check in and all, start a line will be 45 minutes, and then the infusion overall is 90 minutes, and then the post-infusion observation period is an hour. We're really talking about three to four hours that the patients are going to be under treatment.
Yeah, that's what I was thinking about as you were going through that. That, of course, assumes nobody's going to have a fever or infusion reaction.
Right.
Have you seen infusion reactions with monoclonals or the CCP?
They've been fairly well tolerated. No, we haven't seen any serious anaphylactoid responses to anyone so far.
Okay. Let me turn it back over. I think there's a question from a listener. Thank you, Gerry.
You're welcome.
Another question, operator, I believe.
Sure. Thank you. Our next questions come from the line of Mara Goldstein with Mizuho. Please proceed with your questions.
Great. Thanks for taking the question. I have a question as a practitioner and somebody who is really obviously right in the frontline, as they say here a bit. You mentioned just the sheer number of trials listed in ClinicalTrials.gov, and I'm just curious as to, you are at a place which has a large population of patients who are in the hospital, but the decision tree around what you refer for clinical trial, whether it be supportive care or not, relative to what you might refer out now that there is an antibody available, now that you have remdesivir. Maybe you could kind of walk us through that a little bit.
I think what you're asking is what happens when things get approved and a patient's in a clinical trial. That's happened throughout COVID, that now all real COVID trials that we're doing, other therapies since its inception have been found to be effective, such as steroids, remdesivir, have allowed to be added on as part of the standard of care overall. New therapies are going to be an additive therapy to those therapies for the foreseeable future. Most every study we've been involved with has allowed that to occur. They realize that patients are sick and it's clinical research, but it's also clinical care. That has not been an issue overall. What we do is we examine every patient that we see every day for their eligibility for a clinical trial. All the criteria are different for them.
This morning, out of the 88 patients that we have, we've referred 26 of them for evaluation for a clinical trial overall, then talk to the patient about which, if they're eligible for more than one, which one would they be more likely to be one to be involved with.
Okay. Thank you.
Okay.
All right. Gerry, thank you very much again for a wonderful presentation. That was a great overview. Again, thanks for all you're doing. Gerry, Dr. Criner is going to be giving a paper at tomorrow's hot topic session on the results of the CPI-006 clinical trial. If you can listen in on that would be great. He's shifting from primary care pulmonology to immunology.
Sure.
I know you can make that transition, Gerard.
Yeah, thanks for the confidence.
We'll give you an honorary membership in The Immunology Society.
Sounds good. All right. Thanks, guys. Have a good one.
All right.
Bye-bye.
Thank you. I would now like to introduce Dr. Mehrdad Mobasher , who's our Chief Medical Officer. Mehrdad will make a presentation on the trial results with CPI-006 in COVID-19, as well as the plans for upcoming registration trial. Mehrdad?
Yes. Thank you for the introduction, Dr. Miller. Many thanks to Doctors Bruno and Willingham for providing the preclinical rationale for studying CPI-006 in COVID-19. Of course, Dr. Criner for walking us through the current treatment landscape of this disease. With the background that you have, I'll now present our CPI-006 overall clinical development plan in COVID-19. On behalf of my colleagues, I'll present some of the data from phase I study and our next steps. We have initiated this phase I study of CPI-006 in hospitalized mild to moderately symptomatic COVID-19 patients. With a dose escalation design that you see in the slide, the study assesses a single dose of CPI-006 in addition to standard of care.
In cohorts of about five patients, we test doses of 0.3, 1, 3, and 5 mg/kg , or per kilogram, as you can see in the graph. The objective of this study is to determine if treatment with CPI-006 will increase the antiviral antibody response, and therefore clinical improvement, and of course, assess the safety of this treatment in COVID-19. The key endpoints of this study include anti-SARS-CoV-2 antibody level on day 28, as well as safety and clinical outcome. We have now enrolled this study fully for the study design that I showed and we've added additional patients to the 1 mg/kg cohort to capture more data in that dose. In this table here, you see summary of important patient characteristics in different cohorts. Overall, you see the overall data in the first row.
In summary, we enrolled patients in a wide range of age. Our oldest patient was 76 years old. All our patients had risk factors of developing severe COVID-19, including significant comorbidities that are known, like diabetes, asthma, COPD, chronic kidney disease and cancer. As Dr. Criner just mentioned, in terms of race, ethnicity, and high BMI. You see that the median BMI in this study was 32, which is in the obese range. As known in COVID-19 patients, and just mentioned by Dr. Criner, majority of our patients were lymphopenic, meaning they started the study with low lymphocyte counts. Our patients all received the current standard care and supportive treatment for COVID-19. Namely, all of our patients, except one, received remdesivir. We just heard about steroids. All of our patients received a form of steroids.
There was no patient who actually received convalescent plasma or any of the novel monoclonal antibodies. I'll next present the interim data from the study as we are following all these patients who have been enrolled over time. An independent data monitoring committee, or an IDMC, was formed that monitors safety of the study, including evaluation of dose limiting toxicities before any dose escalation. There has been no treatment related adverse events. Specifically, we just talked about infusion related reactions that commonly happen with monoclonal antibodies. We did not have any infusion related reactions. No dose limiting toxicities at any of the cohorts has been determined per the assessment of the IDMC. There has been no treatment related lab abnormalities. Overall treatment has been convenient. A pretty short infusion of about 10 minutes with no interruptions.
That gives us the potential for future administration and even subcutaneous administration in the future. In terms of the clinical benefits we have been assessing in this study, all our patients are now released from the hospital. Median time to discharge was 3.5 Days, with 82% of our patients discharged from the hospital by day 7. The data that I'm presenting is an update, compared to when we took the clinical cutoff for the poster and the presentation that Dr. Criner will have tomorrow. Actually, like I said, 3.5 days . When you compare that with remdesivir study that was just recently published in New England Journal of Medicine , only half of the patients were recovered by day 7, and median time to discharge was 8 days.
I, of course, acknowledge the caveats around comparing data between the two studies, but I thought this would be a good point of reference. We monitor resolution of COVID-19 related symptoms. Median time to resolution of symptoms like cough, fever, shortness of breath, and headache has been 7 days. We also saw improvements of COVID-19 related labs. We just talked about coagulation. We are monitoring D-dimer and inflammatory markers like CRP and ferritin. Now I want to talk about our anti-SARS-CoV-2 responses. In order to test the magnitude, and importantly, the duration of anti-SARS-CoV-2 responses, we assessed the antibody levels serially in all these cohorts. In the four panels in this slide, you see the titers over time from the pretreatment baseline assessment to day 28, day 66, and day 84.
For IgG to trimeric spike and RBD that you see on the top, and also IgM to trimeric spike and RBD that you see in the bottom panel. Cohorts are color-coded, as you can see, with 0.3 mg/kg in green, 1 mg/kg in blue, and 3 mg/kg in purple. The antibody responses were measured by ELISA using a purified spike and RBD, and with a method that was described by Dr. Krammer and his colleagues at MathFinite. It's a sensitive and standard method. We also used the same method in our lab and tested some serum convalescent plasma samples that we obtained, just to serve as a control. As we can see in this panel, antibody responses increase up to day 28 to a very high titer. These high titers are sustained for 84+ days, including IgM.
Just an example, you see titers above 100,000. In 1 mg/ kg, day 68, you see an IgG to spike more than 200,000, and even IgM higher than 100,000, that these are unique numbers. Importantly, a dose response was observed from our lowest dose of 0.3 mg/ kg to higher doses. You just heard from Dr. Stephen Willingham 's presentation that we need to reach to a certain amount of antibody in the peripheral blood to see the pharmacological effect of the drug and expected outcome with B cell activation. We chose 0.3 mg/ kg as the lowest dose because this was the first study done in COVID-19 studies. Now with this dose response that we see, we believe that the 0.3 mg/kg data serves as an internal control when we compare our data with our higher doses.
Titer in our patients are higher than those in the convalescent plasma samples that we tested. You're all aware of importance of neutralizing antibodies, and of course, we studied that in our patient samples. We used a lentivirus expressing spike protein. As we expected, we're showing here that our patients are making neutralizing antibodies, actually with the same pattern as what I showed in the slide before. We see high levels. You see that there is an ID50 value of up to 9,000. These high levels of neutralizing antibodies also persist beyond the points that we have tested so far, beyond 56 days following the start of the antibody. It actually compares favorably with recent data that we see in the literature that you see in the bottom.
Before I present more data from our clinical trial, I wanted to show you this slide that I used based on an article recently published in Cell, which actually reminded us of the importance of sustained production of antibodies, in this case, IgG. Importantly, because it is associated with short disease duration, which is what we ultimately want. In this graph, each dot is a patient that they tested, and they have grouped them in 2 groups. You see in the X-axis, sustainers of antibody level and decayers, those who actually lose their antibodies. In the Y-axis is the duration of symptoms in days. First, you see that majority of patients in this report fall in the category of decayers. They're just more dots there. You also see longer duration of symptoms in the decayers category.
A vast majority of these patients had symptoms more than 10 days, and it goes as high as 50 days. When you look at the sustainers in red, only one patient had a long duration of symptoms, and most of them had much lower duration of symptoms. This supports the importance of boosting antibody response and the duration that antibodies remain at a high level. With that background in mind, here we looked at the antibody responses also relative to the period of onset of symptoms. As I showed in my patient characteristics slide, onset of symptoms had a wide range from 1 up to 21 days before the start of CPI-006 treatment. Titers of almost all patients was very low, regardless of onset of symptoms. This has been actually reported by others, and the reason that I'm showing the data in this fashion now.
Again, note each line in this graph is one patient. You see IgG levels on the top, and you see IgM in the bottom. Note that patients make antibody response very rapidly, because now we are showing day 7 antibody response too, which is very important in patients' recovery because we want to accelerate immune response. These titers that I'm showing, again, you can see in this fashion that are sustained. As mentioned in the last slide, you appreciate better when you even look at the green line that is indicating the overall trend. Here I want to compare the data that you see on the left from our study, to a recent paper that came in, Science Immunology, by Dr. Iyer et al. They tested 343 patients. 93% of them are hospitalized with moderate to actually severe disease.
When you compare, you see that our data shows both IgG and IgM appear to be sustained much longer than this report. If you look at the red vertical line, that's the point that indicates time point of negative seroconversion. We tested serum samples from several patients for reactivity to various subdomains of spike protein, including N-terminus, RBD, S1, and S2 . The X's that you see in this graph are when we actually didn't have a sample tested for each of those patients. Different shades of blue shows the different titers of the antibody. We saw that IgG responses to all domains are observed at various time points. Interestingly, and we don't know the importance of the observation, but IgM responses in that patient treated with CPI-006 appear to be preferentially directed to RBD. Earlier we talked about polyclonal responses versus monoclonal responses.
We heard that from both Dr. Bruno and Dr. Willingham. I believe that the polyclonal responses we observed after CPI-006 administration shows a diverse set of antibodies recognizing binding sites along the entire length of the spike protein. Recognition of these multiple sites minimizes any risk of a virus escaping the immune response, less likely to escape by mutation of a single site, which are targeted by the therapeutic antibodies. This support here, they actually showed that very recently, Thompson and his colleagues, to the Regeneron antibodies. Overall, we believe that polyclonal and polyspecific responses will be more effective at eradicating the virus than passive monoclonal antibody therapy. Based on the rationale and the data that we have so far, our very next step is proceeding to a placebo-controlled randomized phase III study.
The study design we have now finalized in collaboration with our lead investigators is shown in this graph. You see the patient population in the left of your slide. We will enroll 600 patients with COVID-19 who are hospitalized with mild to moderate symptoms. This study will be stratified by region of the world, age of patients, and existence of series of comorbidities. Patients will be randomized in a 1:1 fashion to the treatment arm of a single dose of CPI-006 plus standard care, versus a single matching placebo dose plus standard care. Primary endpoint of this phase III will be time to recovery during the first 28 days after dosing using a standard 8-point ordinal scale. I'll talk about this scale a little bit more to make sure everybody's familiar with that. We have key secondary endpoints that include clinical improvement, again, using the same scale.
We'll look at the change from baseline, we'll test serially to IgG targeting the RBD, we'll look again into the time to resolution of symptoms of COVID-19. Key endpoints in this study will be tested hierarchically from the statistical standpoint, this study will have an interim analysis for efficacy. This study will be a global study, based on the current epidemiology of the disease. We are planning North America, Europe, and Latin America. We expect the first patient to be enrolled in this study next month, we expect to fully enroll the study by mid-year next year. Now about the 8-point scale. I want to go back and talk about that a little bit. This is what we are using to assess our primary endpoint of this study. This is a standard scale.
Some of you are probably familiar with it because it's widely used now in registrational studies for development for treatment of COVID-19. It's the same scale that remdesivir studies used for their registration and their recent approval. What it means for the study that I just talked about, we will enroll patients that you see in the middle in orange. Patients in category 4, 5, and 6 who are in the hospital with mild and moderate COVID-19. The first day that they meet categories of 1, 2, 3 in the green, which means they're discharged with no limitations, they're discharged with some limitations and some oxygen, or they're still in the hospital, but they don't require any oxygen therapy or medical care, which actually happens a lot because some of these patients can't go back home or to the nursing home that they were before.
This is considered when the patient is recovered. I thought it would be good to just talk about our data again from the phase I. Our phase I data shows that median time to those categories of 1 to 3 is 3.5 days. Again, acknowledging caveats with cross-study comparisons. 3.5 days compares favorably with the data just published from remdesivir, that their patients had 10 days for recovery, and their placebo arm was actually 16 days. In conclusion, single dose of CPI-006 at the doses tested, in combination with standard care, has been well-tolerated in hospitalized patients with COVID-19. We saw a dose-dependent increase in titers of our IgM and IgG. High titers to SARS-CoV-2 are sustained beyond 100 days beyond onset of symptoms in our patients.
Our drug potentiates polyclonal antibody responses in COVID-19 patients, targeting multiple epitopes within the N-terminus, RBD, S1, and S2 . We believe that B-cell activation with CPI-006 may be foundation for therapy of other infectious diseases beyond COVID-19. Now focusing on COVID-19, a randomized controlled phase III study is planned. Thank you very much. Back to Dr. Miller.
Thank you very much, Mehrdad, for that very clear presentation. That was wonderful. I think we can, operator, open it up for some questions for Dr. Mobasher now.
Thank you. We will now be conducting a question- and- answer session. If you would like to ask a question, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you would like to remove yourself from the queue. One moment, please, while we poll for your questions. Our first question has come from the line of Tony Butler with ROTH Capital. Please proceed with your questions.
Thank you very much, Dr. Mobasher. I appreciate the presentation. I wanted to ask, as it relates to the phase I study, can you correlate or were you able to get hints of what's happening with patients who present and are hypoxic, and what's happening over time with respect to their oxygen in those patients that got CPI-006? Thank you.
Yes. When we think about, and Dr. Criner briefly mentioned about that, patients who actually get hospitalized, most of them are in the moderate category, which has been the case in all of our patients. Pretty much everybody came with pneumonia, hypoxemia, and all that. While the phase I is not the best setting for capturing every little detail about oxygenation and the support that they got, we heard from Dr. Criner that these patients are having a good improvement in terms of their oxygenation, reflected in their early discharge from the hospital. The one patient that I mentioned that didn't get remdesivir, for example, it was a young patient, 28 years old with comorbidities, came to the hospital with obvious ground-glass opacities and needed oxygen. Very soon after receiving CPI-006, the patient became oxygen independent and was released.
Some hint of that, but it will show us the definite answer will be our next study.
Thanks very much.
Sure, Tony.
Thank you. Our next questions come from the line of Arthur He of H.C. Wainwright. Please proceed with your questions.
Hi, everyone. Thanks for taking my question. This is Arthur He for RK. I have two questions. One is regarding the plan, the phase III study. When you expect the interim analysis, what kind of milestone you can implement for those interim analysis? Second is regarding the cash you guys have in hand. Is this phase III study has been budgeted through with the current cash in your hand? Thank you.
Thank you, Arthur. Regarding your first question, like I mentioned, the study will start soon. We expect all 600 to be enrolled before mid-year next year. The interim analysis will be on some of our patients, not all of them. We expect that to happen around April, will be based on the primary endpoints. We'll look at the recovery ratio, and we're looking at a competitive recovery ratio to make sure what we will see is not just a statistically significant, it's clinically meaningful addition to current standard of care. For your second question, maybe I'll give it back to Richard and Leiv.
Yes, we can. Leiv do you want to handle that question?
Sure, Arthur. As you know, we went out of Q3 with $51 million in cash. The phase III trial is relatively short in duration. We have sufficient cash to get the answer for that phase III trial.
Great. Thank you. Thank you very much.
Okay. If there are no other questions, I'll proceed. First of all, I want to thank every one of the speakers for really excellent presentations. I have the now difficult task to summarize this and talk about our next steps and the rest of our pipeline. Let me just return to some of the questions that I posed at the beginning of this symposium. If you recall, those questions were: Can we accelerate the immune response? Can we make the immune response more effective? Can we accelerate recovery? Can we reduce transmission? How long will immunity last? Can we eliminate or reduce reinfection? Can we prevent immune evasion?
We're very optimistic that the data that we've generated so far, both pre-clinically and clinically with CPI-006, shows that it has the potential to address these challenges, such as we see very rapid onset of production of high titers of IgG and IgM antibodies that are polyclonal and polyspecific and high affinity, along with increases in memory B cells that'll be shown in the presentation tomorrow. Patients have been discharged in a median of 3.5 days. It appears, although not a randomized control trial, that patients are recovering quickly. They also have rapid resolution of symptoms. We see sustained antibody levels now out to over 100 days in these patients. Very high titer antibodies, better than we see in the literature in any study we've seen so far. I think it's now pretty firmly established that sustained antibody response is a good thing.
It correlates with disease recovery. It correlates with memory B- cell production. What it basically means is you're recruiting a lot of B cells and a lot of different antibodies, and that's a good thing. I think we clearly know that antibodies are important in eradicating virus, both the monoclonal antibody studies show that we have a single antibody or two antibodies that improve recovery, and of course, the vaccines hint at that as well. Then finally, the polyclonal really should reduce the risk of reinfection. We talk about spike protein, and we showed nice data showing that there's polyclonal response to the spike protein. Don't forget, these viruses are wily little creatures, and they can change their spike a lot.
Since the immunogen in our patients is the virus, there are also antibodies made to other viral proteins, like the nucleocapsid protein, membrane protein, envelope protein, and other proteins. We've looked at nucleocapsid protein, and we do see increases in antibodies to that. It's not just spike protein, it's the entire viral proteins. Who knows? Maybe there'll be a day where this virus learns how to infect a cell without spike protein. It'd be completely antigen negative. That's not inconceivable. There, if you just immunized with the spike protein, you would be out of luck. Okay. We believe that CPI-006 could address many of these questions and could result in a very important therapy for COVID-19, both inpatient and outpatient as well.
Dr. Criner told us that giving these infusion CCP monoclonals is going to take 4 hours of a nurse in an outpatient clinic that's going to have very limited capacities because of air handling systems and PPE and all other kinds of things. We believe that our dose, which is 100 milligrams or less, as opposed to thousands of milligrams, can be given, well, already is given in a 5- to 10-minute IV injection, and we're moving towards being able to give that subcutaneously. That'll be much more practical for the outpatient setting. We're very interested in the outpatient setting. We're doing our, as Dr. Mobasher mentioned, the next trial is mild to moderate inpatients, but very quickly we want to follow up with an outpatient study. We also are very interested in other infectious diseases now.
We have conversations going on with experts in the fields of virology, dealing with things like influenza. Also in bacteriology, dealing with things like Pseudomonas bacterial infection. We look at this almost as a franchise or a technology platform that will have many opportunities. Clearly, given the nature of the COVID pandemic and the importance in the world, we are squarely focused on that right now. I would like to now briefly update people on our other programs at Corvus. If we go to the Corvus Pharmaceuticals overview slide, we expect to have two programs in pivotal registration trials in 2021. You just heard about CPI-006 trial beginning by the end of this year, 2020. We will be meeting with FDA in December to discuss our plans for registration trials with ciforadenant in late-line renal cell cancer, which is our lead oncology program.
Just very quickly, this is old data, I want to just briefly remind you about ciforadenant and renal cell cancer. On the next slide, in January 2020, we published data in Cancer Discovery. The biggest collection of clinical data with adenosine blockade available, where we showed a response rate of 17% by RECIST criteria in a subset of renal cell cancer that is identified by a novel biomarker called the adenosine gene signature. The adenosine gene signature is present in about 50% of renal cell cancer. It's also present in other cancers as well. In the adenosine signature-positive group in patients who have failed PD-1s and TKIs and many other therapies, so this is 3rd-, 4th-, 5th-line therapy, we see 17% ORR. Other patients who don't meet the criteria for ORR but had tumor regression are also shown on the waterfalls on this slide.
This data was updated in June at the ASCO meeting 2020. The overall response rate of 17% holds up, we begin to detect a tail on the progression-free survival curve of around 25%. On the next slide, our clinical team now has prepared a registration strategy, which involves both a single-arm phase II trial in biomarker-selected patients and a randomized controlled phase III trial in all comers, biomarker positive and negative. Ciforadenant will be combined with atezolizumab in late-line patients with renal cancer who have failed PD-1s and TKIs in both these arms. The gene signature biomarker will be utilized in both trials. The endpoints in the phase II, which will be in the signature-positive patients, will be overall response rate, PFS will be used as the endpoint in the phase III randomized trial. We'll do a hierarchical analysis where we'll look at biomarker-positive patients first.
Moving on to the next topic, which is our CPI-818 ITK inhibitor . At the ASH meeting coming up in early December, we have two papers on this product. One of these papers is an update on our phase I trial in T-cell lymphoma using CPI-818 as a single agent. As mentioned earlier this year, we have seen objective responses in patients with peripheral T-cell lymphoma , PTCL, who have failed multiple prior therapies, and these responses have been durable. This swimmer plot shows the data for seven PTCL patients. There is one complete response. This is a patient who had failed CHOP and then failed an autologous bone marrow transplant, so highly refractory disease. That patient has been now a CR for more than one year, and we have a PR in another patient. Both of these responses are ongoing. They're under follow-up.
The second abstract at ASH is an oral presentation on the use of CPI-818 in autoimmune diseases. This is something that we haven't really talked much about, but it's quite clear that inhibiting T-cell proliferation or T-cell activation could have an important role in autoimmune disease, and we're going to be talking about that at the ASH Meeting this December. Let me just close with a review again of the pipeline. You've heard about our B-cell activator, CPI-006, and about ciforadenant moving into phase III trials, the ITK inhibitor data coming out. I believe now that we have probably over 500 patients treated on our various clinical trials, including CPI-006 in cancer.
We also recently have reported in the press release this week an update on our CPI-006 cancer trial, where we've now completed enrollment of all the cohorts, including the triplet, where we've seen some very nice activity, and we're also confirming the use of the adenosine gene signature. Finally, I do want to mention our recent deal with Angel Pharmaceuticals in China. I'm pleased to report that Angel is off to a very rapid start. We believe Angel brings Corvus investors an opportunity to participate in the rapidly growing healthcare and biotech markets in China, and it has the potential to facilitate, accelerate our global development of our products. With that, operator, I will open it up for any other questions.
Thank you. We'll now be conducting a question-and-answer session. If you would like to ask a question, please press star one on your telephone keypad. The confirmation tone will indicate your line is in the question queue. One moment, please, while we poll for your questions. Our first question has come from the line of Mara Goldstein. Please proceed with your questions.
Sorry, I was on mute. Thanks for taking the question again. I know obviously you've spoken to moving forward with a pivotal trial with ciforadenant in 2021 . Can you just maybe confirm whether or not you have a meeting with FDA, and then how quickly you can get up and running with a trial based on the work that you've already done with earlier programs with sites up and running and the like?
Okay. Mara, I can confirm that we have a meeting with FDA in December scheduled. The briefing package has been submitted, and the meeting has been scheduled.
Great.
We are planning to initiate the trial in the first half of 2021.
Okay, do you have a sense of how many sites you'll be initiating with?
I don't know if I can answer sites yet, but this is around a 500- to 600-patient trial roughly.
Okay.
Okay. If there are no other questions, I want to thank everyone.
We do have one more question.
Oh, okay.
for Dr. Miller.
One late question coming in.
We have Arthur He back into the queue. Please proceed with your questions.
Thank you for taking my question. I just want to ask about the CPI-006, the cancer program. What kind of venue and what time we can expect the data update from that program? Thank you.
Arthur, thanks for the question. Probably sometime in 2021, maybe AACR or ASCO, something like that. I really haven't thought about that yet. The company is really busy now preparing for a couple of phase III trials, including our COVID trial, which is going to be done internationally, I might add. This program went from start to where we are now in what? Four or five months. We've really been moving very quickly on that, and we're very excited about it because it'll produce data for us quickly. It's a very innovative product. I don't really see any competitors, although I know people are working on it right now. They're going to try to make an antibody that has the same properties. We're very busy now. We're very focused on COVID and getting our renal cell cancer trial up and running. Anyway, any other questions?
I want to thank everyone for participating in our symposium. It was a great meeting. I want to thank all the speakers again for wonderful presentations. We look forward to updating all of you on our progress as we move forward, and we believe that the next few months and early part of 2021 are going to be a very important time for the company. Thank you very much.
Thank you. This does conclude today's conference. You may disconnect your lines at this time. Thank you for your participation, and have a great day.