Good morning, ladies and gentlemen. Thank you for standing by, and welcome to the Corvus Pharmaceuticals R and 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. It is now my pleasure to turn the call over to Zach Couveau of W2O Group.
Please go ahead, sir.
Thank you, operator, and good morning, everyone. Thank you for joining us for the Corvus Pharmaceuticals COVID-nineteen R and 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 the link to join the webcast on the Investor Relations homepage of the Corbus website.
Joining me on the call from the company are Doctor. Richard Miller, Chief Executive Officer Doctor. Mehrdad Mobasher, Chief Medical Officer and Doctor. Stephen Willingham, Director of Translational Biology, who leads our COVID-nineteen research program. In addition to the Corvus team, we are also joined by 2 guest speakers: Doctor.
Tulia Bruno, Assistant Professor, Department of Immunology, Hillman Cancer Center at the University of Pittsburgh and Doctor. Gerard Kreiner, Chair and Professor of Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple University. Today's program will include presentations from our speakers with several question and answer sessions throughout. Turning to Slide 2, I would like to remind everyone that comments made by management today and answers to questions will include forward looking statements. Forward looking statements are based on estimates and assumptions as of today and are subject to risks and uncertainties that may cause actual results to differ materially from those expressed or implied by those statements, including the risks and uncertainties described in Corvus' most recent quarterly report on Form 10 Q and other filings the company makes with the SEC from time to time.
The company undertakes no obligation to publicly update or revise any forward looking statements, except as required by law. With that, I'd like to turn the call over to Richard Miller. Richard?
Thank you, Zach. 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-six, our unique B cell activating antibody to be a novel immunotherapy for COVID-nineteen and other infectious diseases.
During our symposium, you will hear about the basic immunology as it pertains to COVID-nineteen 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-six and the latest clinical data from our Phase 1 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-six in COVID-nineteen before the end of the year and share an update on our other pipeline programs. So to start things off, I will make some brief remarks, followed by Doctor. Tulio Bruno from the Department of Immunology at the University of Pittsburgh, who will provide an overview of the basic Several months ago, she published an article in Nature on the importance of B cells in Several months ago, she published an article in Nature on the importance of B cells and understanding response to immunotherapy of cancer and she is also chairing the SITC session dedicated to B cells tomorrow.
Recently her attention has focused on the role of B cells in COVID-nineteen. She will be followed by Doctor. 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-six research program for COVID-nineteen and was the first author of our recently published paper in medRxiv on the unique properties of CPI-six, our Phase 1 study rationale and design and a description of the broad potential for 6 for the treatment and prevention of COVID-nineteen.
Stephen will review the basic properties of 6 and its preclinical biology, including some new data that supports our findings in the Phase 1 clinical study. We can take time for Q and A after each main topic. We are delighted to have Doctor. Gerard Kreiner, Chairman and Professor of Thoracic Medicine and Surgery at Temple University Hospital in Philadelphia. Doctor.
Kreiner is an authority in pulmonary and critical care medicine and deeply involved in the care of COVID-nineteen patients at a very busy urban medical center. Doctor. Kreiner is the lead investigator on our Phase 1 trial. I've asked him to speak on the management of COVID-nineteen with particular attention to the new emerging therapies. He will be followed by Doctor.
Mehrdad Mobasher, the Chief Medical Officer of Corvus. Doctor. Mobasher will report on the clinical results from our Phase 1 trial, providing a bit more detail than the SITC presentations, as well as our plans for an upcoming pivotal randomized Phase 3 trial. Let's look at the clinical course of COVID-nineteen. I'll start by framing the clinical challenges of treating this disease.
As you can see from this figure in a publication by Zhao et al. In Lancet recently, there is a period of 2 to 3 weeks when patients go from asymptomatic or early symptoms to potentially requiring ICU hospitalization with death occurring in some patients. The question is what interventions can be done to prevent patients from moving further along the disease axis to avoid more serious complications. Our initial strategy with CPI-six 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-six has the potential to treat patients further to the left, including as a preventative therapy potentially in combination with vaccines.
Our efforts in COVID-nineteen with 6 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-six may address these opportunities, which would be a unique and valuable contribution to the treatment of patients with COVID-nineteen. 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 remains several issues that remain to be addressed over the coming months years such as how effective is the vaccine in various subgroups of people? For example, the elderly, those with comorbidities, the immunocompromised? Disease severity, does it reduce just mild disease or severe disease or both? What about the duration of immunity?
Does it last 1 month, 6 months, 1 year, 10 years? We don't know. What about viral mutation and resistance? There's a lot of virus out there and it is mutating and changing and it is unknown how long the immunity that we will have from a single vaccination would prevent infection with mutated forms of the virus as is the case with influenza. What about safety?
What about cost, distribution and uptake? So these are all questions that will people will be looking at over the coming couple of years. Now I would like to turn to our first speaker, Doctor. Bruno. Doctor.
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-nineteen patients in the Pittsburgh area. So if we go to my first slide, which is an intro slide just about myself. As was mentioned, I'm an immunologist here at the Hillman Cancer Center.
I've been in tumor immunology since I was a graduate student and through my post doc. And in my lab, I currently focus on B cells and tertiary lymphoid structures within cancer patients. So my tagline in my initial slide is T cells enthusiast, these help convert for that reason because I was trained in T cell immunology and know quite a bit about that. But I pivoted in my post doc to B cells and am currently working on that in my research program. I've provided here my email address in case there are questions that come up that are not answered today.
And also I have a very beautiful picture here that's provided by a technician in our laboratory showing basically a very key structure within our immune response known as a germinal center, which we'll learn about later on today. And so you can see this germinal center with the yellow tag here, and you can see a very circle like organ here within this tissue. And so this is from a human tonsil. This is a normal tonsil. And we'll talk more about what these look like in COVID patients as well today.
Next slide. So just to give an introduction to why we care about the immune response when it comes to viruses. We think about the immune response given this initial graph that you're seeing. So over time, there is an immune response that is generated when you first have an insult, which is a viral antigen or even now we think about this in the context of cancer as well. So that's in that initial red arrow on the left hand side.
So basically your primary immune response kicks in or your adaptive immunity kicks in. And I'll talk about that more here in a minute, after that initial exposure to antigen. And then if you then meet that antigen again and that's the second red arrow that you see here, you get a secondary exposure to antigen and you have a secondary immune response, which is quite fast in comparison to your initial response and it's much larger. And you can see the output here is antibody Next. So if we think about adaptive immunity and we think about what happens in order for this primary and secondary immune response to occur, we first think about the primary immune response.
So what you can see here is that virus is going to infect normal cells. In this case, it's going to be the epithelium and those infected cells will then initially be picked up when they are either dying and or if there are viral particles present, by dendritic cells, which then process those viral antigens and then it activates the dendritic cell. And so here we go from basically what we would call from step 1 to 2, a resting tissue to more inflamed tissue. And that more inflamed tissue then as a signal for those dendritic cells to then traffic to the lymph node. And the lymph node is you can think of it as a hub for education for the immune response to a virus.
So when you get into that lymph node, there's other players involved. So the dendritic cell comes in and it's going to activate a T cell, which there's different flavors of T cells that are going to respond both helper and killer T cells. And those killer T cells are very important because as you can see they go and attack the virally infected cells in step 4. But I want what I don't want to discount and what I want to highlight is that there is B cells here that, can also be educated within these centers that can become quite expanded and these are called clones, which I'll refer to later. And those will then differentiate into plasma cells, which are large antibody factories that then make these viral specific antibodies.
So this adaptive immune response is quite important, both next slide, this is really why we need a COVID-nineteen vaccine. And as Doctor. 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-nineteen virus. Next slide. So how do we generate what are called memory B cells?
So how do we generate those B cells that are going to recall and remember when they see virus again? This is a very simple schematic that was published in an article in 2,004 showing that at the heart of making memory B cells are these dermal that I mentioned earlier. And so when activated B cell gets into a terminal center, it will toggle back and forth between 2 zones, which I'll show you here in a minute, and it will then get educated, enough to expand and become specific to a virus or a cancer antigen or whatever it might be to then have memory. And then also you can see these large cells that have antibody production are plasma cells. This education as I mentioned occurs in what are called secondary lymphoid organ such as a lymph node, a tonsil and a spleen.
Next. So if we visualize this in a human tonsil, taking some images that were created from my lab group, you can see on the top panel that Ki67 in yellow marks one area of that very round germinal center and you can see it's very, very concentrated. That's also marking B cells that are actively proliferating or reproducing themselves within that germinal center so that they are enough that are going through somatic hypermutation or mutation to become specific. And then what you can see below in that same center, you can see a blue area or it's more of a, I guess, it's a like kind of a yellowblue area that is going to mark another zone where once those B cells are educated, they then start to interact with T cells to become highly specific. Next slide.
So, a very simple schematic on the left hand side of this B cell education is a naive B cell or a B cell 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. So during the dark zone, they'll be proliferating and that's what that yellow Ki67 marker that I showed you was indicating. And 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 by as a memory B cell or a plasma cell. So this becomes important because the agent that we're discussing today is going to amplify these memory B cell responses and so that's going to be very important as we go through.
There's also another schematic on the top that shows basically, antigen presentation or education of these B cells as it goes along in the lymph nodes. So you can see again that dendritic cell picking up in this case, it's showing bacteria, but it can be virus processing, presenting it to a helper T cell that then becomes activated, which then in turn helps to, highly select the B cell so it becomes a clone and makes a lot of, antibodies as a plasma cell. Below this schematic, there is a, infrastructure of an antibody showing light and heavy chains and more specifically where the antigen binding site is, which is basically where the viral protein is going to be recognized. So this will be this is important to also note. Next.
So if we think about as these antibodies are being generated, if we go back to this number this time graph and we look at antibody generation, it's not as simple as just one type of antibody being generated. And in particular, you'll see, in the next presentation that there's readouts of IgM antibodies and IgG. So an IgM antibody is going to be the 1st antibody that's produced when you have antigen invasion. And so you can see that happens early. And so you can see where the antigen comes in.
So in this case, antigen is going to be this viral protein and, IgM is produced. And then after that IgG will then come up after several days. And this occurs through what we call class switching, which I won't have time to go through today, but basically there's a transition that occurs and then IgG response takes over. And so what you can see on the right hand side, which is basically a summary of the different types of antibodies, which we call isotypes, You can see IgG and IgM, the structure for those 2 antibodies as well as what their function is and where you find them in this picture on the far right in the body. And then there's 3 other subtypes IgA, IgD and IgE, which we won't talk about today, mainly because IgA is found in mucosal tissues and while it might be important in local B cells, that are present, it's not necessarily in the systemic portion as you can see.
And then IgE, which is involved in allergy and won't be discussed today. Next slide. So the other thing I want to mention before I talk a little bit about what happens in COVID patients now that I've given you background on basic immunology that's occurring when there's a virus that is cleared, quickly, I want to talk about the advantages of a monoclonal versus a polyclonal antibody. So there's 2 antibody types that can be generated. A polyclonal antibody can, as you can see, has many targets that it can bind.
So you can see that there's 5 here that it could basically recognize, whereas the monoclonal antibody is very specific and is going to bind a specific target. So while a polyclonal antibody is cheaper to produce and it might be tolerant of small changes to protein structure and is often higher affinity, they're not as specific as we would like. So we tend to gravitate toward monoclonal antibodies because this is going to bind that specific target. And even though it takes more time and is more expensive to produce, it ends up being a better specific antibody for the target that we're going after. Next slide.
So now pivoting briefly to what happens in COVID-nineteen patients, our group, and it's actually myself and Doctor. Darya Lignali that are leading this charge at PIC, we are looking at patients via what is called single cell RNA Seq. So what you're seeing here are projections of immune cells, specifically B cells and plasmablasts in either patients that have ARDS, which is another airway disease that's often a comorbidity for COVID patients, given that it affects the airways, COVID patients in the middle, which are patients that are actively infected with COVID, and then healthy donors. And these 3, blood samples were processed and looked at from a transcriptome level. So basically, we have a bunch of reads where we can look at all of the different transcripts that occur within B cells and plasmablasts.
And this projection is showing you how abundant those cells are and how and then we can drill down and figure out how similar or different they are at a transcriptional level. So what you can see right away is that COVID patients have expansion of plasmablasts. And while you can see it here, you can see certain subsets of B cells that are also at higher presence than in healthy donors or in ARDS patients. So what we're currently doing is we're mining these data to understand why B cells and plasma blasts are similar or different. One thing that I will note that's not annotated on this slide is that COVID patients have an increase of CD73 on the B cell cluster that you're seeing here.
So everything that's in, like a salmon in the middle, those are going to have CD73 expression whereas the plasmoblast do not. So truly when we are thinking about the monoclonal antibody for CD73, we're thinking about basically targeting and agonizing those B cells that are within those COVID patients that then might help an increased memory of the B cell response. Next slide. So, others have shown also that COVID-nineteen patients that have very severe disease have loss of germinal centers that I mentioned earlier. So if you look from this paper in Cell this year, on the right hand side, you again see in the non COVID-nineteen lymph node, very nice bright germinal centers.
And you can see this marked by either CD3 and CD19 on the right hand side, red and green, and you can see these very nice circular structures that I showed you in some of the images earlier. This is also confirmed by a marker known as BCL-six, which is a canonical marker of teratrade of, dermal centers and we often use this even in our cancer studies when we're looking at these structures. And then the bottom right hand side is the overlay. So you can see very nicely this organization and in 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.
So you can see that the CD3 and nineteen are there, but there's not these nice structures that you're seeing and that's conferred by the lack of BCL-six staining as well. And you can see that also in the overlay. So what we're concerned about here is that that hub or that center that I was discussing earlier is really dysregulated in these COVID-nineteen patients. So their ability to make really robust antibody responses is going to be hindered as a result. And so this is why we think about long term immunity and being able to, think about a vaccine that will help or a treatment that will help generate that.
Next slide. So this is another schematic from that same manuscript, summarizing what they showed. So basically the top portion in blue is what happens when there's other immunogens or other viruses that come in and go through this, education hub. So I showed you before that it's really important for B and T cells for that virus to be shuttled to the lymph node for education so there's proper, education within the germinal centers. What's happened in COVID patients is that that is not occurring.
And so basically what's happening is these COVID patients do not have these nice germinal centers which don't allow for this education of B cells and then won't allow for B cell specific antibodies to be generated. So CD73 is a great agonistic antibody consideration for multiple reasons. First of all, it promotes adhesion of those dendritic cells or these particular dendritic cells in a dermal center reaction or a GC reaction. It helps to regulate a dermal center and it's also expressed on memory B cells. So it makes sense to think about it as a target.
If you hit the next button, please. Further, there's a lot of anti CD73 antibodies that are being evaluated as monotherapies in tumors and that's really where this started and where our interest began with CD73. And if you bring all 4 of these agents up from the different companies, you can see that CPI-six from Corbus is unbolded not only because it's the focus of this symposium, but also because it directly is going to compete with AMP for the CD73 active site. It's an agonist and it's been shown to generate robust memory B cell responses which will be demonstrated in the next presentation. So different from the others, it's quite important in that it helps to amplify that B cell response and increase antibody production.
Next slide. I also want to mention in the last couple of minutes here that basically CD73 distribution and non inflamed versus inflamed tonsils is quite different. So what you're seeing here are single plex images from a multispectral imaging platform So you can see CD20 positive B cells in these nice dermal centers that I showed you before and you can see the CD73 distribution in those tonsils. However, in patients that have inflamed tonsils or tonsillitis, which would be similar to what is happening when you have a viral infection of some sort, you see an increase of CD73 intensity within these centers and on the B cells in particular. So even if those patients don't have the germinal centers 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 this is 13 patients in total, we can look at different clusters of B cells in these patients.
And really this is quite busy. So what I want you to focus in is on cluster 2. Cluster 2 here, if you look at some of the other visualizations that I have here, if you 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 pregerminal center B cell. And we believe that pregerminal center B cells are obviously those activated B cells that are going to then form these bona fide germinal centers.
So by basically agonizing or stimulating CD73 pathway, you're going to generate more memory cells and better antibody responses, when germinal centers are being basically obliterated in these more severe patients. So that that will 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 Doctor.
Willingham's presentation and then we'll take questions on both of your presentations.
So Stephen? Perfect. Yes.
Thank you, Julie, again. That was perfect.
No problem. Thank you.
Thank you, Doctor. Miller. During this session, I'd like to introduce CD73 and review some of the reasons we are excited about CPI-six, our anti CD73 antibody that has some unique and very interesting immunomodulatory properties. CD73 is an echo enzyme present on the majority of B cells in a subset of CD4 positive and CD8 positive T cells. One function of CD73 is to convert AMP, adenosine monophosphate into immunosuppressive adenosine.
And many companies are actively developing CD73 antagonists that aim to lower the concentration of extracellular adenosine in the tumor microenvironment and 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 cell. But the results we will present here demonstrate that CD73 also has a major role in B cell activation and maturation. CPI-six is our unique dual function anti-seventy three 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-six is the only CD73 antagonist that has these dual immunomodulatory properties. CPI-six is a humanized anti-seventy three 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-six induces markers of activation and antigen presentation.
We also observed increases in markers associated with B cell differentiation and a corresponding morphologic transformation into antibody producing plasma blasts and increased immunoglobulin secretion. In addition to COVID-nineteen, CPI-six 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-six activates human B cells, resulting in the up regulation of activation markers like CD69 and CD83 and antigen presentation machinery like CD86 and MHC class 2. On the top right, you can see that B cell activation with CPI-six 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-six undergo morphological changes consistent with differentiation into plasmablasts, a cell type that is very effective at antigen presentation and antibody production. Collectively, these data show that CPI-six can cause a direct activation and maturation of human B cells.
Next slide please. On the left panel here, we again show that CPI-six induces the expression of CE69. 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. T cell activation has not previously been described in relation to CD73 signaling and is seemingly unique to CPI-six as all other anti CD73 antibodies we've tested such as CPX-sixteen 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-six suggesting that 6 binds CD73 in a unique way that enables this potential to activate B cell. 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-six. This again shows that B cell activation is independent of the adenosine modulatory activity of 6, not something all CD73 antagonists are going to be capable of.
Next slide. To assess the functional consequences of B cell activation with CTI-six, We measured the concentration of IgG and IgM secreted by healthy donor PBMCs into culture superheat. Addition of CPI-six resulted in a 3 fold increase in the concentration of IgM and IgG relative to an isotype control, demonstrating that CPI-six stimulates antibody secretion and possibly isotype class switching. On the right, we see that CPI-six induction of CD69 can be blocked with Ibrutinib, a covalent BTK inhibitor. This demonstrates that CPI-six directly activates B lymphocytes by invoking canonical B cell signaling pathways downstream of the B cell receptor.
Next slide. CTI-six 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 to 24 mgs per kg. For simplicity sake, I'll focus on the doses at or below 6 mgs per kg as these are the doses similar to those evaluated in the COVID-nineteen trial that Doctor. Mobasher will discuss later in the program.
On the far left, we show the PK of CPI-six at 1, 3 and 6 mg per kg. Along with a horizontal dash line indicating concentrations at 1 microgram per ml. This is the dosing threshold we were aiming for in the COVID-nineteen trial. But you can see in the middle graph that CPI-six activation is dose dependent with concentrations of 1 microgram per ml achieving near maximal induction of CD69. Returning to the PK graph on the left, you can see that doses atoraboveone mg per kg result in sustained concentrations above 1 microgram per ml for several days.
So we are confident that doses in this range will be sufficient to enable the B cell activation we aim to achieve. Further support for dosing at this level is shown on the far right, which illustrates a dramatic decrease in circulating CD73 positive B cells at the 1, 3 and 6 mg per kg dose levels 30 minutes after antibody infusion. Recall CPI-six is a mutant IgG1 antibody that does not induce B cell death or initiate ADCC. So this result is most likely due to the induction of CD69 and the temporary retention of activated B cells in lymphoid tissues. Taken together, this data suggests that B cells can be effectively activated with a single dose of 1 to 5 mg per kg CPI006, exactly the dose range we focused on in the COVID-nineteen 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 the lymph nodes and lymphoid tissues. We observed that B cells returned to circulation at similar levels of baseline by day 21 and 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-six. The figure on the right shows the same increase is observed in the majority of patients treated with CPI-six.
This is a very important observation as it relates to COVID-nineteen. As it has become clear that temporary protection against SARS CoV-two can be imparted by circulating neutralizing antibodies, But the key to long term immunity in preventing future outbreaks lies in the production of these antigen specific memory B and T cells that are capable of recognizing and eliminating any potential reinfection. You'll hear more about this from Doctor. Kreiner and Doctor. Mobasher later today.
Next slide. We thought we could leverage the immunomodulatory properties of CPI-six to improve clinical outcomes of patients with COVID-nineteen by significantly boosting the magnitude, diversity and duration of humoral and cellular immune responses to SARS CoV-two. Really simply, we expect CPI-six to activate B cells, generating plasma blasts 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-nineteen. PPI-six is not like the passive monoclonal Rather, our approach of activating B cells, Rather, our approach of activating B cells to enhance immunity represents a potential universal therapy, one that is immediately deployable for COVID-nineteen, but also for the treatment or prevention of the next viral pandemic for other infectious diseases or as adjuvant to enhance the efficacy of vaccines.
Next slide. We were not able to do a randomized controlled trial in our Phase I COVID-nineteen study. So instead, we utilize an animal model to determine if CPI-six could elicit antigen specific immune responses to SARS CoV-two. CPI-six does not bind to mouse CD73. So for this experiment, we use 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-six. Instead of the live virus, we immunize these mice with purified SARS CoV-two spike protein along with CPI-six 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-six. Moreover, on the right, you can see that this is an antigen specific response. Mice treated with CPI-six make antibodies to the spike protein that they were immunized with, but not to the nucleocapsid, another unrelated SARS CoV-two viral protein. These results demonstrate that CPI-six does augment humoral immunity and is expected to induce robust and durable antibody responses to SARS CoV-two in patients with COVID-nineteen. Next slide.
So to review, the results shown here demonstrate that CPI-six activates B lymphocytes, resulting in morphological and immunological changes consistent with B cell differentiation and antibody production. This property is unique to CPI-six and is independent of the adenosine modulatory activity. Treatment with CPI-six 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-six and SARS CoV-two spike protein produce antigen specific antibodies.
Mice receiving spike protein plus a control antibody do not mount a response. Therefore, we believe CPI-six may enhance immune responses to infectious agents such as SARS CoV-two. 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, Doctor.
Miller.
Thanks a lot, Stephen. That was perfect. Thank you. I think we have some time now for questions for Doctor. Bruno and Doctor.
Willingham. Operator, we can take questions from listeners.
Thank you. We will now be conducting a question and answer Our first questions come from the line of Tony Butler with Roth Capital. Please proceed with your questions.
Yes. Thanks very much. One question for Doctor. Willingham, please. Stephen, you may have said this and this may be part of the data that you had previously presented, but if you were to generate an anti CD3 antibody that was not 6, would it behave the same or differently in the NGS mice when co vaccinated with the spike protein?
Is that a fair question or?
Yes. If I understand the question, it is would other anti-seventy 3 antibodies be able to induce these antigen specific immune responses? Absolutely. And my answer to that would be almost certainly no. We know 6 is rather unique in its ability to activate B cells.
And so without these other antibodies being able to activate B cells, I don't think they would produce these same immune responses in that model.
Tulia, Tulia, you talked about the memory B cells. Is it known why some memory B cells last 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 that like measles that have longer lasting immunity versus something like a flu infection, for example, where we vaccinate every year because of the different antigens. It has a lot to do with how the virus or that protein changes, right? And so part of the reason why, as a lot of people know, you get your flu vaccine every year, you can have a lot of mutations and the virus can change and so you need to have the right proteins that it's being educated against. So it probably, that amount of immunity that's generated and the memory that's generated has a lot to do with how, viruses or other agents
that cause disease change over time, is
the kind of that cause disease change over time, is the kind of the general answer. But I think that related to COVID-nineteen, 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 what we call an acute infection and a longer term infection. So with the flu, we think about virus coming in and being cleared and there's not any disruption of lymph nodes or anything like that. Whereas with something like HIV, that's more chronic, that virus is going to be around longer and it's going to cause destruction for a longer period of time. So we're seeing something in the middle.
So I think, while we know that for some of these key agents that you mentioned, I think for the challenge for COVID-nineteen 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. Just another question. I think you showed in your data that CD73 is on the in the COVID patients is on the plasma blast. It's not on plasma cells. And of course the COVID patients have disrupted or absent germinal centers.
So do you think that B cells are being activated but can't mature, can't differentiate all the way to an antibody producing cell because the germinal center is disrupted? Yes.
I think that's exactly what's happening. And so what I mentioned when I showed some of those images of CD73 in a normal tonsil or in a normal lymphoid organ, when you have more of an inflamed area, you're seeing the distribution of that go up. So if you have basically what we would have in COVID-nineteen, 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. So I think you're exactly right.
I think that's where that disconnect is. And 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 plasma blasts that I showed you, they do not look like they're normal like they're not producing antibodies the way that they should. So that gets back to your point that they may be getting, basically becoming more regulatory in that regard and like a little bit more suppressive in some of those patients and we're still trying to tease that out a bit.
Thank you, Tullia. I believe that there's a couple of other questions from the listeners. Maybe we can take another one question or so.
Absolutely, Doctor. 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. But I guess my question then is one of a general one around B cell maturation and the ability to either qualitatively or quantitatively look at the effect, let's say that CPI-six is having on that process and whether or not you achieve a particular threshold that is necessary from the standpoint of keeping of making of having those memory B cells be active. And so, if there's anything additional you could add to that? And then secondarily, has there been any evidence of T cell activation or proliferation or even differentiation with CPI-six 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 Steven now doing some B cell receptor sequencing, which is also going to teach us a lot about sort of the evolution of those cells. But basically, if you put the story together, it looks like COVID patients and perhaps other viral infections as well, disruptions of germinal centers is not unique to COVID.
And we believe, and it's very difficult to study this in humans because you have to do biopsies of lymph nodes and spleen, That our antibody being agonistic activates B cells and chases them into the germinal centers of the lymph nodes where they can complete their maturation and differentiation. Very hard to study that in humans. We've been looking at things like PET scanning and so forth to get a handle on that. Steven's got another mouse model that he's looking out for that. But basically, an antibody that would chase B cells into lymph nodes where they could undergo differentiation, affinity, maturation, etcetera, 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 Doctor. Kreiner's presentation and it's on our poster tomorrow, some of the early evidence for that. But we do see antigen specific CD4 and CD8 effector T cells memory cells, effector memory T cells.
And as I think Tulia mentioned earlier, CD73 is on the T cells. So again, big just to emphasize something that Stephen said, there are many other CD73s, but they react with a different epitope. They do not have to my knowledge, they do not have many of them we've looked at in the lab. They do not have this agonistic activity, which is what we primarily were interested in when we made this antibody. We were going after that, because we were interested in the B cell biology and the trafficking of lymphocytes.
So with that, but that's a great question, Mara. Thank you for that. I think we probably need to move on. And I hope Doctor. Kreiner is on the line because I know he's been busy in the hospital.
So now I would like to introduce Doctor. Kreiner from Temple University Hospital. As I mentioned earlier, Gerry runs a large department at a busy urban center, which has had a relatively high incidence of COVID-nineteen. He has been working on the front lines of the pandemic and has been involved in clinical trials with a large number of existing and new potential therapies. I thought it would be most important for him to talk to us about the clinical management of these patients and what we have learned from treating these patients over the past 8 or 9 months.
Doctor. Kreiner?
Thanks, Richard. And you can move to next slide to my disclosure side. So thanks for your opportunity to give you some glimpse into the clinical perspectives of COVID-nineteen. These are my disclosures, none of them which really compete with what I'm going to say except that I was a principal investigator for the Corvus trial that we had here at Temple. And my most important disclosure is I'm not an immunologist or cancer physician.
I'm basically a pulmonary and critical care physician. Next slide. So this overall, last night, the night before last shows the picture in the world of COVID infection from the Hopkins website. Over 51,000,000 infections, about 20% of them in the United States, over 10,000,000 patients have been infected with COVID-nineteen and about 1,300,000 deaths. Again, about 25% of those are in the United States with over 240,000 deaths from the United States.
That star represents where I am. I'm in Philadelphia for which we have seen about 50% of all the COVID infections in Philadelphia County, which is the highest in the state of Pennsylvania at our center at Temple University. Next slide. So why is it so rampant? And this is just some, I think, background that some may know, but some may not, that if someone is infected with a COVID virus, they're likely to infect 2 to 3 other individuals.
And people remain infectious. The meantime, the median duration is about 4 to 5 days, but people can be infectious overall for almost 2 weeks up to about 12.5 days, 95% of patients would be infectious up to that time. The most important thing to realize is that COVID-nineteen patients are most infectious when they're asymptomatic. In the beginning of the infection, in the 1st 5 days, when there's high nasal tropism and also viral virgins in the nasopharynx overall. And it's not only just a respiratory secretions, some data has suggested that feces in 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 overall simply the natural history of COVID infection. And there's really 2 phases.
1 is the viral replication phase that happens initially like I just said. That tapers off in about 10 days, 14 days. But at that time, a host inflammatory response starts to occur. And that could be a hyper inflammatory 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-nineteen lungs. And you can see to the left a response pattern to injury with hyaline membrane formations that thickens the lung tissue 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. And hypercoagulable state has been indicated. You can see the thrombus in the 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-nineteen.
But other organs also can be infected such as the heart, the kidney, both of them in about 10% to 15% of the time. And this is an example of the spleen where lymphocyte numbers are decreased, their cell degeneration and necrosis can be seen. So this is a systemic manifestation of a viral infection in COVID-nineteen. Next slide. When you look at patients that have COVID-nineteen, this looks at lung lavage and serum fluid in healthy people, people in the ICU in the middle of these bar graphs to the left and also looks at people in the ICU but not as critically ill.
And you can see an expression in lung lavage fluid of higher inflammatory mediators that are seen. And there's also a decrease in the amount of peripheral blood T cells and B cells that occur. Severe lymphopenia is a hallmark of this disease. It's part of the diagnostic set of features that we use. And when patients respond to treatment or recover, the T cell count, the lymphocytopenia resolves.
So host directed therapies, if you has been discussed in the last period of time, hour or so, maybe an option for some patients. Next slide. And the coagulation, which is abnormalities is driven by the severe inflammation, can even be a marker of death. And as you can see in this manuscript from Lancet, the patients that had measures of hypercoagulation significantly increased D dimers and fiber degradation products were much more likely to succumb from the disease than others. And this is because of the high receptor affinity for ACE2, which is what the COVID virus binds to.
Is also expressed by vascular endothelial cells. Next slide. So this 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-nineteen infection. Next slide. So let me talk a little bit about what happened to us at Temple because this could give you a clue of the importance of coming up with therapies to help not only the patients but systems like ours to be able to deal with surges of patients who come in.
Next slide. This slide overall shows the number of patients that we've treated for COVID suspected or COVID diagnosed patients since March of this year. We've admitted almost 27,000 patients to Temple. We're in the epicenter here in North Philadelphia of the infection in Philadelphia. 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 because and important because 94% of our patients are at high risk because of their ethnicity as well as their socio demographic 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.
So we never got up beyond our cap. Right now, we have had another spike where we were at 20 to 18 patients. We've tripled and now we have today, 88 patients in our hospital with COVID infection. Next slide. So it's important to realize that we have to treat the surges of the disease.
This shows overall a snapshot of the infection in Philadelphia County, Pennsylvania and what we're all experienced across the country and in major urban cities to the left. You can see to the bottom left that the by zip codes Temple sits at 19,140 in the middle of this. We're in a highly endemic area for a high prevalence of COVID and positive cases that are in our surrounding community, our feeding area overall. And 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 6 weeks overall. Hopefully, this is going to peak sometime, but, we're not optimistic that it's not going to peak sometime in mid December to early next year.
Next slide. One of the most important things to think about the development of therapy is what patient population is experiencing the most complications. We know that infection leads to hospitalization, which leads to death. So trying to prevent hospitalizations or treat people or prevent them from being hospitalized or treat them once they're there safely is key. And if you look at the bottom right of the slide for hospitalization, who gets hospitalized?
Well, 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. So we really have to have a therapy that's going to treat patients effectively to prevent hospitalizations and once they're hospitalized, something that could be tolerated and used in people that are of older age. Next slide. We've recently written a document that's published in the Blue Journal about the care of patients with COPD and COVID infection.
And this snapshot gives you an idea of the clinical features, what we do to investigate patients based on the stage of the disease and then the possible interventions that we do overall. And you can see that it's tiered based on lung and non lung treatment, pharmacologic treatments coupled with 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-nineteen. And if you look at the categories of treatments overall, they are things that are either monoclonal antibodies or antivirals that limit the ability of the COVID virus to bind to the receptor sites on the cell wall, the ACE2 receptor site.
Then there are other agents that in the cell itself trying to prevent the translocation for RNA transcription. And then finally looking at things that can decrease the cytokine inflammatory chemokine storm that occurs in some patients. So a variety of anti inflammatory, anti infective and monoclonal antibody directed towards targets of affecting the binding of COVID virus to the receptors for the cells as well as the inflammatory mediators. Next slide. So what works and what doesn't work?
Well, what doesn't work is hydroxychloroquine or chloroquine. In fact, all the prospective randomized controlled trials have shown that that agent is not effective and has a trend towards a higher mortality, especially from a cardiovascular standpoint. So that's one therapy that does not work. Next slide. This also shows 2 recent therapies that from high levels have been reported also not to work.
Temple, we've done 35 prospective randomized controlled trials. We've done the first one. We've done these with canakinumab and sarilumab and neither of these agents are effective. Next slide. Tislelizumab and other interleukin-six antagonists has had much study.
There's been as you can see to the right, there's been 5 studies that have been reported both observational and randomized controlled trials that showed mixed success with effectiveness. There's 4 other randomized controlled trials. 1 I know of right now that's in IMPRESS and the story is not out on this, but hopefully we'll have from these other studies that are pending better elucidation of whether this can be an effective agent or not. Next slide. This is one thing that has been just received emergency approval from the FDA.
This is the Lilly product, a SARS COVID-two neutralizing antibody that was done in an outpatient setting that showed that with a targeted binding receptor site, a decrease in viral load was demonstrated in the bottom left of the slide. And next to that, you can see that the viral load on day 7 in each trial group was favorably affected by the investigational agent. And you can see on the top right of the slide that patients had an improvement in their symptoms overall, not a dramatic improvement, but an improvement nonetheless in the 1st 5 or 6 days from baseline after patients were imported in this study. So this is now going to be started as an outpatient study in patients at higher outpatient therapy in patients at higher risk. Those greater than 65 years of age or those younger who have a comorbid condition or some feature that puts them at risk.
Trying to do this, however, is going to be somewhat of a challenge to start to set up COVID positive infusion units by hospitals that's separate from their regular patient population. We're struggling with that at our institution now trying to develop that. Next slide. Some of the therapies 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. And it doesn't matter if it's decadron or dexamethasone, but if it's hydrocortisone or SoluMedrol. In patients that have COVID pneumonia and are symptomatic from it, steroids have been shown to decrease the mortality risk by 30% similar to what our Chinese colleagues told us 8 months ago. And as you can see in the right side, in the top right, those who received invasive mechanical ventilation given dexamethasone in the red, they had a survival advantage that was 25% to 30% better. If you look at the bottom right, those who did not receive oxygen therapy, however, there was no mortality benefit.
Actually patients trended to do worse when given dexamethasone compared to usual care. So steroids are effective overall. Next slide. Another agent that has first emergency FDA approval and now is got full approval is the use of remdesivir. And this is one of the pivotal studies that demonstrated this in JAMA.
Next slide. And what this shows to the right, as you can see, the patients that were given either 5 or 10 days of remdesivir tended to have 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. And these patients tended to be in the hospital for a shorter duration of time. What was thought to be is that patients that got 10 days would do better than people patients that got 5 days, but that was not the case. As you can see, only 5 days was statistically significant compared to placebo.
So now this agent is in most patients use only 5 days, not 10 days unless patients aren't responding to therapy to decrease their hospital duration and try to help to improve their outcome. However, in patients that are very ill with COVID, remdesivir has less impact rather than using it in patients with mild to moderate disease. Next slide. This is the Mayo Clinic Consortium using convalescent plasma, which we're part of overall. And I think it has some important information for what's been presented so far about CPI-six.
Next slide. And what that is, is that basically if you have higher antibody levels, you tend to have an improvement in mortality or survival. And if you give it earlier in the course within the 1st 4 days, that improvement in survival is seen not only at 7 days, but in 30 days after patients are given that therapy. Next slide. And this is shown on the following slide, the 7 day 30 day mortality, giving it to patients when they're less heal, earlier on in stage of their disease and giving it quicker, sooner after the patients present is key to their outcome.
So something like CPI-six that gives a higher level of effective neutralizing antibody sooner in the patient's course with higher more robust levels may potentially have important benefits to patients. Next slide. Another thing not to forget as I brought in the beginning that the vascular space is important. A lot of the agents that we've looked at except outside of anticoagulant therapy in terms of antiviral or anti cytokine storm has not been looked at on their impact on hypercoagulable state. But as you can see here, people that are anticoagulated fully have an improvement in survival, especially as shown to the right, patients that are sicker who receive mechanical ventilation.
So 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, But we've learned a lot in the last 8 months. We know a little bit of what helps and what does not help. But I think overall my gestalt of doing this and seen every patient remotely that came in with Temple, the 21,000 over the last 8 months, it's not going to be one magic bullet. It's going to be a composite treatment, I believe, with antiviral, anti inflammatory and antithrombotic treatments coupled with aggressive non invasive forms of non pharmacologic care.
And prevention is the key. Vaccines may be helpful, but again, we don't know how they're going to be in the real world once they're available. So thanks very much. Be happy to answer any questions someone may have.
Thank you, Jerry. That was a fantastic overview. And first of all, I want to thank you and your wonderful team at Temple for everything you're doing on this disease. I know you guys have been working amazingly hard over the past several months. So thanks to you and your staff for all the work you're doing.
I think
people are going to
be very 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 Doctor. Kreiner.
Thank you. We will now be conducting a question and answer
I have a question, operator.
Sure. Go ahead, Doctor. Lim.
Doctor. Kreiner, you mentioned in your talk that outpatient infusions in COVID positive patients is going to be problematic. How do you think how are you trying to tackle that problem at Temple?
Yes. So that's a good question. So what we are developing is a negative pressure area where we could treat 6 patients in an infusion center at the same time. That will be one part of it and then be able to staff that because you have to have emergency equipment in case someone would have an anaphylactic response and a mechanism that from this outpatient infusion center that if a patient has an emergency, where are they going to go to receive urgent care? Then the other thing is to make and this isn't going to be the only therapy that we're going to be offering to our patients who want to take something preventative from having progression of disease and not requiring hospitalization.
So we're going
to have to increase patient awareness and decrease the time from when patients are found to be positive and have access for them to get an outpatient therapy like this?
Yes. Just to follow-up on that. So a negative pressure outpatient clinic that seems pretty dramatic, but I understand the need. And with 6 patients per share of time. So time of treatment is going to be a big issue.
And I'm just wondering for like the since the monoclonals are several grams of antibody and 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. So it's really to people that check-in and all it's going to be by start of line, it'll be 45 minutes. And then the infusion overall is 90 minutes. And then the post infusion observation period is an hour. So we're really talking about 3 to 4 hours that the patients are going to be under treatment.
Yes, that's what I was thinking about as you were going through that. And that of course assumes nobody's going to have a fever infusion reaction. 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, Jerry. 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 front line 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. So maybe you could kind of walk us through that a little bit?
Yes. So I think what you're asking is what happens when things get approved and a patient is in a clinical trial. So that's happened throughout COVID that now all real COVID trials that we're doing and 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. So new therapies are going to be an additive therapy to those therapies for the foreseeable future. And most every study that 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. So 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. And this morning out of the 88 patients that we have, we've referred 26 of them for evaluation for a clinical trial overall.
And 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. Jerry, thank you very much again for a wonderful presentation. That was a great overview. And again, thanks for all you're doing. Jerry, Doctor.
Kreiner is going to be giving a paper at tomorrow's hot topic session on the results of the CPI-six clinical trial. So if you can listen in on that, that would be great. He's shifting from primary care pulmonology to immunology. So I know you can make that transition, Jerry. We'll give you an honorary membership in Immunology Society.
Sounds good. All right. Thanks, guys. Have a good one. Bye bye.
Thank you. I would now like to introduce Doctor. Mehrdad Mobasher, who is our Chief Medical Officer. Murdad will make a presentation on the trial results with CPI-six and COVID as well as the plans for upcoming registration trial. Mehrdad?
Yes. Thank you for the introduction, Doctor. Miller. And many thanks to Doctors Bruno and Willingham for providing the preclinical rationale for studying CPI-six in COVID-nineteen and of course Doctor. Kreiner for walking us through the current treatment landscape of this disease.
With the background that you have, I'll now present our CPI-six overall clinical development plan in COVID-nineteen. And on behalf of my colleagues, I'll present some of the data from the EASE-one study and our next steps. So we have initiated this Phase 1 study of CPI-six in hospitalized mild to moderately symptomatic COVID-nineteen patients. With a dose escalation design that you see in this slide, this study tested a single dose of CPI-six in addition to the standard of care. In cohorts of about 5 patients, we test doses of 0.3, 1, 3, and 5 milligrams per kg or per kilogram as you can see in the graph.
The objective of this study is to determine if treatment with CPI-six will increase the antiviral antibody response and therefore clinical improvement and of course assess the safety of this treatment in COVID-nineteen. The key endpoints of this study include anti SARS coronavirus 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 have added additional patients to the 1 milligram per kilogram cohort to capture more data in that dose. In this table here, you see summary of important patient characteristics in different cohorts. And overall, you see the overall data in the 1st row.
But in summary, we enrolled patients in a wide range of age. Our oldest patient was 76 year old. All our patients had risk factors of developing severe COVID-nineteen, including significant comorbidities that are known, like diabetes, asthma, COPD, chronic kidney disease and cancer. And as Doctor. Kreiner just mentioned, in terms of raceethnicity and high BMI, you see that the median BMI in this study was 32, which is in the obese range.
As known in COVID-nineteen patients, and just mentioned by Doctor. Kreiner, majority of our patients were lymphopenic, meaning they started the study with low lymphocyte counts. Our patients all received the current standard of care and supportive treatment for COVID-nineteen, namely all of our patients except 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. And 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 fusion 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. So overall, treatment has been convenient, pretty short infusion of about 10 minutes with no interruptions that gives us the potential for future administration and even subcutaneous 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.
So the data that I'm presenting is an update compared to when we took the clinical cut off for the poster and the presentation that Doctor. Kreiner will have tomorrow, actually, like I said, 3.5 days. And then 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 caveat around comparing data between the two studies, but I thought this would be a good point of reference. We monitor resolution of COVID-nineteen 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-nineteen related labs. We just talked about coagulation, we are monitoring D dimer and inflammatory markers like CRP and ferritin. And now I want to talk about our anti SARS CoV-two responses. In order to test the magnitude and importantly the duration of anti SARS CoV-two responses, we assess the antibody levels serially in all these cohorts.
In the 4 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 milligram per kg in green, 1 milligram per kg in blue and 3 milligram per kg in purple. There was antibody responses were measured by ELISA using purified spike and RBD And it's with a method that was described by Doctor. Kramer and his colleagues at Mount Sinai.
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 control. As you can see in this panel, antibody responses increase up to date 28 to a very high titer And these high titer are sustained for 84 plus days, including IGM. So just an example, you see titers above the 100,000. And in 1 milligram per kg, day 68, you see an IgG2 spike more than 200,000 and even IgM higher than 100,000, but these are unique numbers.
Importantly, a dose response was observed from our lowest dose of 0.3 milligram per kg to higher doses. You just heard from Doctor. Stephen Willingham's presentation that we need to reach to a certain amount of antibody in the preferred blood to see the pharmacological effect of the drug and expected outcome with T cell activation. But we chose 0.3 milligram per kg as the lowest dose because this was the first study done from in COVID-nineteen studies. And now with this dose response that we see, we believe that the 0.3 milligram per kilogram data kind of serves as an internal control when we compare our data with our higher doses.
Chatter 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 lentivirus expressing spike protein. And as we expected, we're showing here that our patients are making antibody 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 IV50 value of up to 9,000. And these high levels of neutralizing antibodies also persist beyond the points that we have tested so far beyond 50 6 days following the start of the antibody, are you actually compares favorably with recent data that you see into the literature that you see in the bottom? And 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 CK, so just more dots there. You also see longer duration of symptoms in the decays category. Vast majority of these patients have symptoms more than 10 days, and it goes as high as 50 days.
But 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-six treatment. Charges 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 2, 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.
And 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 Doctor. Iyer et al. They tested 343 patients, 93% of them are hospitalized with moderate action severe disease. And then 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 sub domains of spike protein including N terminus, RBD, S1 and S2. The Xs that you see in this graph are when we actually didn't have a sample tested for each of those patients and 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 patients treated with CPI-six appear to be preferentially directed to RBD.
Earlier, we talked about polyclonal responses versus monoclonal responses. We heard that from both Doctor. Bruno and Doctor. Willingham. And I believe that the polyclonal responses we observed after CPI-six 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 virus escaping the immune response. And so less likely to escape by mutation of a single site, which are targeted by their therapeutic antibodies. And this report here, they actually showed that very recently, Thompson and his colleagues, to the Regeneron antibodies. So overall, we believe that polyclonal and polyspecific responses will be more effective at eradicating the virus than passive monoclonal antibody therapy. So 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 see enrolled 600 patients with COVID-nineteen 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 to 1 fashion to the treatment arm of a single dose of CPI-six plus standard of care versus a single matching placebo dose plus standard of care.
Primary endpoint of this Phase 3 will be time to recovery during the 1st 28 days after dosing using a standard 8 point ordinal scale. I'll talk about the scale a little bit more to make sure everybody is 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 and we'll test serially to IgG targeting the RBD and we'll look again into the time to resolution of symptoms of COVID-nineteen. Key endpoints in this study will be tested hierarchically from the statistical standpoint and 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, and we expect to fully enroll the study by mid year next year. And 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-nineteen. And it's the same scale that remdesivir studies use for their registration and the 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. So patients in Category 4, 56 who are in the hospital with mild and moderate COVID-nineteen.
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 This is considered when the patient is recovered. I thought it would be good to just talk about our data again from the Phase 1. Our Phase 1 data shows that median time to those categories of 1 to 3 is 3.5 days. Again, acknowledging caveats with cross study comparison, 3.5 days compares favorably with the data that's just published from remdesivir that their patients had 10 days for recovery and their placebo arm was actually 15 days. So in conclusion, single dose of 6 at the doses tested in combination with standard of care has been well tolerated in hospitalized patients with COVID-nineteen.
We saw dose dependent increase in titers of our IGM and IGG. High titers to SARS CoV-two are sustained beyond 100 days beyond onset of symptoms in our patients. Our drug potentiates polyclonal antibody responses in COVID-nineteen patients targeting multiple epitopes within the N terminus RBD S1 and S2. We believe that B cell activation with CPI-six may be foundation for therapy of other infectious diseases beyond COVID-nineteen. But now focusing on COVID-nineteen, a randomized controlled Phase 3 study is planned.
Thank you very much. I'll turn it back to Doctor. 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 Doctor. Mobasher now.
Thank you. We will now be conducting a question and answer Our first question has come from the line of Tony Butler with ROTH Capital. Please proceed with your questions.
Thank you very much, Doctor. Moschwager. We appreciate the presentation. I wanted to ask as it relates to the Phase 1 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 6? Thank you.
Yes. When we think about and Doctor. Connor 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. So pretty much everybody came with pneumonia, hypoxemia hypoxemia and all that. And while the Phase 1 is not the best setting for capturing every little detail about oxygenation and the support that they got.
We heard from Doctor. Kreiner that these patients are having a good improvement in terms of their oxygenation reflected in the early discharge from the hospital. So 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 glass capacities and needed oxygen. And very soon after receiving 6, the patient became oxygen independent and was released. So some hint of that, what 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 Hee of H. C. Wainwright. Please proceed with your questions.
Hi, everyone. Thanks for taking my question. This is Arthur for R. K. So I have two questions.
One is regarding the plan, the Phase III study. When you expect the interim analysis? And what kind of milestone you can you kind of implement for those interim analysis? And second is regarding the cash you guys have in hand, is this Phase 3 study has been budgeted through with the current cash in your hand? Thank you.
Thank you, Arthur. So 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.
So we'll look at the recovery ratio and we're looking at a competitive recovery ratio to make sure what we'll see is not just a statistically significant, it's clinically meaningful addition to current standard of care? And for your second question, maybe I'll give it back to Richard and Leif.
Yes, we can Leif, you want to handle that question? Sure, Arthur. So as you know, we went out of Q3 with $51,000,000 in cash. The Phase III trial is relatively short in duration and 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, then 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. So let me just return to some of the questions that I posed at the beginning of this symposium.
And 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? And can we prevent immune evasion? We're very, very optimistic that the data that we've generated so far both preclinically and clinically with CPI-six 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 will be shown in the presentation tomorrow. Patients have been discharged the meeting of 3.5 days. So it appears, although not a randomized controlled trial, that patients are recovering quickly.
They also have rapid resolution of symptoms. And 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. And 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 2 antibodies that improve recovery. And of course, the vaccines hinted that as well. And then finally, the polyclonality really should reduce the risk of reinfection.
And we talk about spike protein and we showed nice data showing that there's polyclonal response to the spike protein. But don't forget these viruses are wily little creatures and they can change their spike a lot. And 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. So we've looked at nucleocapsid protein and we do see increases in antibodies to that. So it's not just spike protein, it's the entire viral proteins.
And who knows, maybe there'll be a day where this virus learns how to infect a cell without spike protein, be completely antigen negative. That's not inconceivable. And there, if you just immunized with the spike protein, you would be out of luck. Okay. So we believe that 6 could address many of these questions and could result in a very important therapy for COVID-nineteen both outpatient both inpatient and outpatient as well.
Doctor. Kreiner told us that giving these infusion CCP monoclonal is going to take 4 hours of the 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. So that'll be much more practical for the outpatient setting. So we're very interested in the outpatient setting.
We're doing our as Doctor. Mobasher mentioned, the next trials 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. So we look at this almost as a franchise or a technology platform that will have many opportunities.
But clearly given the nature of the COVID pandemic and the importance in the world, we are squarely focused on that right now. So I would like to now briefly update people on our other programs at Corvus. And if we go to the Corvus Pharmaceuticals overview slide, we expect to have 2 programs in pivotal registration trials in 2021. You just heard about CPI-six 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 to very quickly and this is old data, I want to just briefly remind you about CIFOR ADMINENT and renal cell cancer. On the next slide, in January 2020, we published data in cancer discovery, probably the biggest collection of clinical data with adenosine blockade available, where we showed a response rate of 17% by resist 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. And 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. And this data was updated in June at the ASCO meeting 2020. The overall response rate of 17% holds up and we begin to detect a tail on the progression free survival curve of around 25%.
So on the next slide, our clinical team now has prepared a registration strategy, which involves both a single arm Phase 2 trial in biomarker selected patients and a randomized controlled Phase 3 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 which will be in the signature positive patients will be overall response rate and PFS will be used as the endpoint in the Phase 3 randomized trial. We'll do a hierarchical analysis where we'll look at biomarker positive patients first.
So moving on to the next topic, which is our CPI-eight eighteen ITK inhibitor. At the ASH meeting coming up in early December, we have 2 papers on this product. One of these papers is an update on our Phase 1 trial in T cell lymphoma using CPI-eight eighteen 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 7 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 1 year and we have a PR in another patient.
That's both of these responses are ongoing. They're under follow-up. The second abstract at ASH is an oral presentation on the use of 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.
So let me just close with a review again of the pipeline. You've heard about our B cell activator CPI-six and about ciforadenant moving into Phase 3 trials, the ITK inhibitor data coming out. So we have really made great progress in the clinic. I believe now that we have probably over 500 patients treated on our various clinical trials, including 6 in cancer. We also recently have reported in the press release this week an update on our 6 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 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. So with that, operator, I will open it up for any other questions.
Thank you. We'll now be conducting a question and answer 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 ciforadenantin 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 the 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, schedule the briefing package has been submitted and the meeting has been scheduled. We are planning to initiate the trial in the first half of twenty twenty one.
Okay. And 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 5, 600 patient trial roughly.
Okay.
Okay. Is there no other questions?
I want to thank you.
We do have one more question. Okay.
One late question coming in.
We have Arthur Gies back into the queue. Please proceed with your questions.
Hi. Thank you for taking my question. So I just want to ask about the CPI-six, the cancer program. So what kind of venue and what time we can expect the data update from the detailed data from that program? Thank you.
Arthur, thanks for the question. Probably for sometime in 2021, maybe AACR or ASCO or something like that. I really haven't thought about that yet. The company is really, really busy now preparing for a couple of Phase 3 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 4 or 5 months.
So we've really been moving very quickly on that and we're very excited about it because it will produce data for us quickly. It's 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. So we're very, very busy now and we're very focused on COVID and getting our renal cell cancer trial up and running.
So anyway, any other questions? So 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 very, 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.