Hello. I think we should get started. We have a lot to cover today. We're really excited to be back in New York, able to meet all of you and to review all the programs at Corvus. First of all, can everybody hear me? Good. I'm not gonna use that podium because I don't know, it's kinda boring, and I'm afraid I'll fall off of it. I think that this enables me to move around and make some eye contact. My name is Richard Miller. I'm the CEO of Corvus Pharmaceuticals. We have a really packed agenda today, so I would like to get started. The next slide is our forward-looking statements, which you can review at your leisure. I'm very pleased today to be joined by three other speakers. I will be presiding at the meeting, but really, that's at my pleasure to be associated with these three individuals. First, we have Dr. Neel K. Gupta, who's an oncologist from Stanford University. Neel is a clinical assistant professor and is an expert in lymphomas. We're also joined by Erik Verner. Dr. Verner is a chemist and is the inventor, named inventor on ibrutinib patent, as well as CPI-818, which we're gonna talk about today. Also Suresh Mahabhashyam. Suresh is Corvus's VP of Clinical Development, and he'll be reviewing a couple of our programs as well. Let's move to the agenda. What we plan to do today is to move through each of our programs. We'll have some time for Q&A at appropriate spots where we can ask questions to the speakers and also myself. The plan is to review what we've been doing and to also tell you about what our plans are going forward. Now, we've not had a lot of interaction with the street, so I think this is a really great opportunity for us to highlight all the achievements that we've made and where we're going. We have three really novel products that are moving nicely through the clinic and through the laboratories. Okay, let me start with sort of the overall Corvus development strategy. My team and I have been through this before. We've made immune drugs for cancer, namely Rituxan and ibrutinib. We like to think of our products as being integrated and connected together, where when we work on one, we leverage the expertise, the experience, the assays, and various other things help the other products. This allows us to make progress very efficiently. I think anybody who's familiar with Corvus knows that we're very efficient. Not only does this allow us to develop our products efficiently, it also gives us deep expertise in the science behind these products. We think about this the following way. Our products are designed to modulate tumor immunity. Okay, what does that mean? Well, we have drugs or antibodies that interact with B cells. You're gonna hear about that. They interact with T cells. You'll hear about that. They interact with something you may not have heard much about, but is very, very important in what we call the tumor-immunity axis, and those are lymph nodes. Okay, those are, like, the most important part of the whole story. Our drugs target precise molecular targets. You're gonna hear about that. We know how our drugs bind to their targets down to an atomic level. You'll see some examples of that. Mupadolimab binds to CD73. Our ITK inhibitor, we know exactly where it targets, where it goes, and our A2A receptor antagonist, ciforadenant. Broad applications. Pretty broad. You're gonna hear today about solid tumors like kidney cancer, lung cancer. You're gonna hear about lymphomas. You're gonna hear about autoimmune disorders. You're gonna hear about allergies, and you're even gonna hear a little bit about infectious diseases. I don't know what's left in medicine. Maybe cardiology, I guess, we haven't covered. Okay. Let's talk a little bit about just the very basic science underpinning, integrating, connecting these products together. We call this the tumor-immunity axis. Corvus's products are designed to interact at various precise points in this axis. Now, I'm gonna be describing this a little bit different than maybe you hear from other companies. I have to admit, I'm a well-trained oncologist and immunologist, so I always back up to the science and think about, how do we move these things through the clinic? How do we do our clinical trials? Where do we get biopsies? Where do we look at biomarkers? There's three players here, the tumor, the lymph nodes, see down in the right lower corner there, and the vascular system, which is blood vessels or lymphatics. We'll lump blood vessels and lymphatics together as one. Those are the three key players that we need to think about. The lymphatic system or the immune system is a little bit different than other organs in the body in that it's really dispersed throughout the entire body as opposed to, let's say, your liver, which is in one place. Now tumors, infections, autoimmune diseases, they can release antigens, foreign or altered proteins. These antigens can either remain localized in the tumor, in the tumor microenvironment. They can spread through the bloodstream or lymphatics and go to other lymphoid structures like lymph nodes. Or more commonly, they're picked up by macrophages, phagocytic cells, and they're carried to the regional lymph nodes. Now, in those lymph nodes, is where you have a lot of things happening, both in the lymph nodes, in the blood, and in the tumor. This is where antigens are processed. T and B cells start talking to each other, in the lymph node. They mature, they acquire higher and higher affinity and specificity for the antigen. And these cells, these T cells and B cells, then leave the lymph nodes. They go into the bloodstream or the lymphatics. And basically, two kinds of cells leave. One is called the memory cell, memory B cell, memory T cell. That's the basis of immunologic memory. So the next time you see an infection or the tumor antigen, you're immune to it. That's why you get vaccinated. Okay. You get a shot in your shoulder, a COVID vaccine, and it goes to your lymph nodes. The other thing that leaves the lymph nodes and goes to the tumor are called T effector cells. These are the cells, these are the soldiers. They're armed and ready to go to destroy the tumor or the infection or whatever. Memory B cells, memory T cells, effector T cells, effector B cells. Now, of course, B cells can differentiate and make antibodies. B cells do a lot of things. They can make antibodies, as you well know. They can present antigen. They're involved in this crosstalk and this refinement of the immune response. Okay, let's talk about where do our drugs interact. This morning you're gonna hear about CPI-818. That's an ITK inhibitor, and you'll hear from Dr. Verner and others what is ITK and what's that about. This drug does some remarkable things. It actually modulates or affects the differentiation of T cells and skews them so that they become, or biases them, so they become more like effector cells. How do we know that? You're gonna see the data for that in animals and in patients. That's CPI-818. Where does it do that? It does it in lymph nodes, it does it in the blood, and it does it in the tumor as well. You're gonna hear about mupadolimab, which is an anti-CD73 antibody, but a very unique antibody in that its primary mode, we believe its primary mode of action is stimulating B cells. You're gonna hear a lot more about B cells today. mupadolimab binds to the target in the blood, in the tumor, and in the lymph nodes. Same three guys. It activates those cells, stimulating an immune response. We're gonna talk about our A2A antagonist, ciforadenant, which blocks the immunosuppressive adenosine from binding to, the A2A receptor. That can happen in the tumor, which is where it's most likely or most people think it happens, but it also has a big role in the lymph node, and this is something that most people don't appreciate. CD73 and adenosine play very important roles in the function of lymph nodes, specifically germinal centers, which is the main player here. Okay, just a quick review of where we are with these products, our pipeline. CD73, mupadolimab, a human anti-CD73, has been examined in well over 100 patients as monotherapy and as combination therapy with standard agents and with, other IO agents. We are planning to start a randomized placebo-controlled phase II study with mupadolimab, pembrolizumab, and chemotherapy in front line stage four lung cancer, all comers with lung cancer except for the EGFR mutants and ALK mutants. This is a big opportunity, and we are gearing up to start that study in the H2 of this year. The A2A receptor antagonist, ciforadenant, also been in over 100 patients, both as monotherapy and combinations. You're gonna hear about a lot about monotherapy now because it's really important to study a drug carefully as monotherapy. I don't mean three patients, I mean 50 or 100 patients, so that you really understand its safety, its efficacy, and its biomarkers, its effect on the immune system. Once you put things together in combinations, game over, you can't figure anything out. I bring that up because a lot of companies are doing that. Ciforadenant is about to go in a first-line study in renal cell cancer based on some really interesting science that Corvus has uncovered. We're gonna go through that a little bit today. I won't be able to discuss all of the scientific basis for it, but it's very interesting new approach to an IO combination. Our ITK inhibitor. We've not talked much about this drug, deliberately so, 'cause nobody else has it. We wanna spend a significant amount of time this morning telling you why we're so excited about CPI-818, our small molecule oral ITK inhibitor. Okay. First, before we roll into ITK and its potential use in T-cell lymphomas, I've asked Dr. Neel K. Gupta to talk to us a little bit about T-cell lymphomas, the prognosis and management. Now, Neel's an expert in lymphoma. I've personally worked in the clinic with Neel, and I can tell you that he is an extraordinarily good doctor. Neel? I'm gonna spend a few minutes reviewing just the basics of T-cell lymphoma to provide a little context for the rest of this morning's discussion. T-cell lymphomas are a very diverse set of aggressive non-Hodgkin's lymphoma. The WHO in 2016 reclassified them into four distinct clinical phenotypes. Nodal, extranodal, cutaneous, and leukemic presentations. I've highlighted some of the more common T-cell lymphomas, which we'll talk about in a few minutes. In part, their biologic and clinical diversity can be explained by their cells of origin and the respective cytokines that are elaborated by these cells that contribute to the clonal proliferation of these lymphoid disorders. In the United States, there are approximately 10,000 new diagnoses of T-cell, mature T-cell lymphomas per year. In the U.S. and in the world in general, peripheral T-cell lymphoma, angioimmunoblastic lymphoma, and natural killer T-cell lymphoma make up the majority of lymphomas that we see in clinical practice, as demonstrated by the pie chart on the left. It is worth noting that the frequency of certain subtypes varies by geographic region. For example, in North America and Europe, peripheral T-cell lymphoma, not otherwise specified, and angioimmunoblastic lymphoma are seen most commonly. Whereas in Asia, natural killer T-cell lymphoma and adult T-cell leukemia lymphoma are more frequently seen. It's thought that the reason for this increase in prevalence and incidence in Asia for these two subtypes is largely due to the endemicity of certain viruses, including Epstein-Barr virus and human T-lymphotropic virus, which is thought to drive the pathogenesis of these two lymphomas. I think this is a really important slide to give us context for what our patients are facing when they're diagnosed with a T-cell lymphoma. The bottom line is T-cell lymphomas have a markedly inferior prognosis when compared to B-cell lymphomas. We are able to delineate individual prognoses based on a very simple but powerful prognostic tool called the International Prognostic Index. This index uses very simple data that can be abstracted from the electronic medical record, including a patient's age, their so-called performance status or their ability to be functional with a diagnosis of cancer, the number of extranodal sites, the stage at presentation, and whether or not a tumor marker called LDH is elevated at presentation. Using these very simple indices, we can calculate someone's five-year overall survival. As highlighted here in the red box, you can see that if someone is diagnosed with peripheral T-cell lymphoma or angioimmunoblastic lymphoma, and they don't have any of these risk factors or maybe one risk factor, their five-year survival rate is essentially a coin flip. It's about 50%, 56%, depending on the data. Now, if they have all of these risk factors or most of these risk factors, you can see their survival at five years is pretty dismal. Contrast this with the table on the right and look at this. This is a revised International Prognostic Index for diffuse large B-cell lymphoma, which is our most common type of aggressive non-Hodgkin's B-cell lymphoma that we treat in the United States. If you don't have any of these risk factors for DLBCL, your four-year survival rate is greater than 90%. If you have all of the risk factors, your four-year survival rate is about 58% or essentially approximating the good risk category for T-cell lymphoma. A marked difference between the two groups. How do we treat T-cell lymphoma? Is there a standard of care in this country and in the world? I would say probably most clinicians would argue there isn't a true standard of care. There are some common regimens that we incorporate into practice. I'll list the two most common. CHOEP is CHOP chemotherapy plus etoposide. This regimen was devised by the German High-Grade Non-Hodgkin's Lymphoma Study Group. Based on retrospective data, they found a pretty decent signal in terms of three-year overall survival for various subtypes of PTCL. I will tell you, in clinical practice, this is a difficult regimen to administer. It's very myelosuppressive. People's blood counts routinely are low, requiring blood transfusion. It's difficult to get a patient who is older than 60 years of age through this regimen. One of the main limitations of this regimen is that all of the data derived for it was retrospective. The new kid on the block is BV-CHP, brentuximab vedotin plus CHP. CHP is CHOP minus vincristine. This data was published in The Lancet in 2019, and this was on the strength of the ECHELON-2 study, which is a randomized controlled trial looking at BV-CHP versus CHOP chemotherapy. Obviously, you can see that the progression-free survival favored BV-CHP in this study, but there are some really important caveats with this study. This was a study that mandated that 70% of the patients in the trial had a very specific subtype of PTCL called anaplastic large cell lymphoma, which is known to be uniformly CD30 positive. Despite that very significant caveat, the data for this trial has been extrapolated to other T-cell lymphomas, although we don't know whether or not it's truly effective in the majority of T-cell lymphomas. Then the last thing I'll say, the comparator arm was CHOP, and nobody really gives CHOP chemotherapy for T-cell lymphomas. I would say the deck was stacked in favor of BV-CHP for this trial. A brief word about stem cell transplantation or high-dose chemotherapy with stem cell rescue. Although I wouldn't say it's considered the standard of care, most lymphoma clinicians, if they get a patient in first remission with one of two regimens that we just discussed, they will consolidate that induction for the purpose of prolonging their survival. On the basis of one very prominent study published in JCO in 2012 with a five-year survival rate of 50%, most patients go on to bone marrow transplant in CR1. However, again, important caveats. There has not been a randomized study looking at chemo versus chemo plus transplant, and one could argue that the results of bone marrow transplant are fairly middling. Certainly, there's no dispute that a bone marrow transplant is a toxic maneuver. Lastly, we really don't know which particular subtypes benefit most from a bone marrow transplant, so some significant caveats to that. This, I think, is the other really important slide. The plight of our patients who have relapsed and refractory disease. It's, we talked about how poor the prognosis of patients are at initial diagnosis. Well, it's even worse with relapsed and refractory disease. This really terrible-looking survival curve was derived from a dataset by the Vancouver Group in British Columbia, and it's the largest study of its kind, looking at 153 patients who have relapsed and refractory PTCL, NOS, AITL, or anaplastic large cell lymphoma. None of these patients received transplants. 89 of these patients went on to receive chemotherapy as their second line of treatment, so they relapsed or they never responded to their first line, and they went on to receive second-line chemotherapy. This is their median overall survival. It's absolutely abysmal. These patients are quite desperate for effective therapy. Now, for some patients who do respond, there is the option to go on to an allogeneic stem cell transplant, where another person's immune system is essentially imported into your body, and we rely on the graft versus lymphoma effect. There is some data to suggest we can have durable remissions with this maneuver. As those who practice know, an allogeneic stem cell transplant is a very toxic, very costly maneuver, and you're really reliant on the availability of a matched-related donor. I think the other main obstacle, frankly, is in order for a transplant like this to work, you have to get the disease back under control again. You need to be able to get them into a second remission if possible. As demonstrated, that's not an easy task. What are the options? How do we get someone back into remission? What's the current state of things in this space? I'm gonna focus mostly on what the FDA-approved indications are currently for relapsed T-cell lymphoma. I do wanna point out, as maybe you have heard, that one of the current options being studied, which, duvelisib, which is a PI3K inhibitor, has recently been pulled from the market due to concerns over toxicity. Frankly, it was not all that effective to begin with. I do wanna hone in on what we have. These are the available single agent therapeutics for the T-cell lymphoma space that have been FDA approved. Pralatrexate is an antimetabolite similar to methotrexate, and romidepsin and belinostat are HDAC inhibitors. I think this table sort of says it all. The overall response rates are pretty poor, and really maybe only one out of ten patients are going to derive a complete response from these available agents. We need to do better than this. What is better? What's needed in this space? I think we need a therapy with a novel mechanism of action. It has to improve patient outcomes in a clinically, not just statistically meaningful way. Preferably would be single agent, while able to be combined with other cytotoxics and other therapies. Obviously, safety is a primary consideration. These are sick patients. They've been pre-treated. They have low blood counts. We need a drug that doesn't impair that further. We got a sense of how diverse T-cell lymphomas are. The ideal therapy should be active against a range of T-cell lymphomas. Then finally, from my perspective and from the patient perspective, you know, remember, these folks have gotten multiple lines of treatment, and they're not feeling well. Something that's less burdensome, something that comes in a pill form versus something that is a weekly or even more frequent IV therapy would be ideal in this population. With that, I'd like to close out and, looking forward to taking some questions during our Q&A session. Thank you, Neel. Great. We'll have time to ask Dr. Gupta some questions when we finish the section on CPI-818. I'd like to now ask Dr. Erik Verner. As I mentioned earlier, Eric is a chemist, a medicinal chemist, and really one of the pioneers in kinase discovery and synthesis. Eric? Yeah. As Richard has mentioned, I was the VP of chemistry at Corvus Pharmaceuticals, and I'm currently the Senior VP of Angel Pharmaceuticals. I worked with Richard at Pharmacyclics, at Principia, Corvus, and now Angel Pharmaceuticals, where, you know, we're focused on developing innovative therapies for primarily oncology. I'm pretty excited to be here at Angel. I think that these programs are really exciting to me and to be a part of something like this, an ITK inhibitor, which I'm gonna describe to you later, is I think it's pretty innovative, and I'm pretty excited about it. As I mentioned, Corvus was founded by the inventors of ibrutinib, and that of course is Richard Miller, Joseph Buggy, and myself. With our success in targeting the tyrosine kinase BTK with ibrutinib, we set out to target the T cell homolog that's ITK in T cells. What we were able to do is make a novel and uniquely selective ITK inhibitor. This ITK selectivity is very important, and I will describe why we wanted that and the features of ITK or the features of CPI-818, and also its differences between ibrutinib, which are really critical. Like BTK in B cells, BTK affects, you know, activation, migration, and proliferation. ITK in T cells affects these same functions, but it's also involved in T-cell development as well as differentiation and importantly for us, immune modulation. Looking at TH1 cells, if you look at the graph on the right-hand side, in TH1 cells, they express ITK and another kinase called RLK, which stands for resting lymphocyte kinase. These two kinases play a supportive and redundant role in TH1 and TH17 effector cells. If you look at TH2 cells, they exclusively express ITK. There is no RLK expression. When you have a selective ITK inhibition, you're able to achieve TH1 cells and effector cells can function normally, and you suppress TH2 cells. Richard's gonna describe the clinical features of this later on in the presentation. This is specifically what we set out to do, was to make an ITK selective inhibitor. Now, if you compare, our eight-one-eight to other approved kinase inhibitors, for example, sunitinib. If you look at the graph on the right-hand side of the screen, that's a kinase tree, or it's called a dendrogram. That particular panel represents over 300 human kinases. If you look at sunitinib, the red circles represent kinases that it inhibits. The larger the circle, the more or the tighter the inhibition or the greater the inhibition. For something like sunitinib, which is used to treat kidney cancer, it's a very non-selective kinase inhibitor. Now if you compare that to ibrutinib, which is the middle panel kinase tree, you see that ibrutinib, much more selective than sunitinib, but on the upper part of that tree, it inhibits a family of tyrosine kinases. Some of these are in the Tec family, some of these are in the EGFR family, and some other like Src and JAK family. If you drill down even further and you look at CPI-818, you see that it exclusively inhibits ITK. Now if we look at those panel of tyrosine kinases on the left-hand side of the screen, you can see that ibrutinib is very potent on its intended target. For BTK, it has a binding inhibition of 0.42 nanomolar. It's a sub-nanomolar inhibitor, which is why we picked that compound. It is a very potent covalent BTK inhibitor. You can see it also inhibits other kinases in this panel. For example, RLK, 0.52 nanomolar, is equipotent on BTK, and it's less potent on ITK. Ibrutinib has the opposite selectivity profile of what we wanted to achieve with CPI-818. If you look at the 818 panel, 2.5 nanomolar on ITK and its thousands of nanomolar are much less potent on this other panel. You can see we have over a hundredfold of more selectivity over RLK. This was pretty challenging to achieve because within this tyrosine kinase family, you have a lot of sequence homology amongst all these kinases. It took us a while to achieve this particular selectivity, but we wanted that ITK selectivity over RLK for the reasons that I described on the previous slide. For something like CPI-818, you can see that it has good biochemical activity, and it also has good T cell receptor pathway inhibition in a cellular context. If you take primary human T cells, treat them with CPI-818, and then activate them, you can measure different functions downstream, but for this particular panel, we have the inhibition of IL-2 expression of these primary human T cells. You can see that it's about 75 nanomolar. It's a very potent inhibitor of the T cell receptor pathway in a cellular context, biochemical and also cellular. Richard's gonna describe to you why the clinical features of CPI-818. Thank you, Eric. I'm really glad I've got Eric around, and I'm glad that Angel has him now. That's a very tough act to follow Eric, so I'll try to do my best. The biology is never quite as precise as the chemistry. Okay, I want to get back to this cartoon. As Eric mentioned, getting selectivity for ITK over RLK is not easy, and we're able to do that based on our experience and talents and so forth. As shown in this diagram on the left, on the slide, CPI-818 blocks ITK, part of the T cell receptor signaling. The main pathway that sends a signal when a T cell binds to an antigen down to the nucleus telling it what to do. ITK is more complicated, and this is known from mouse and human studies over the past 20 years. ITK is involved in the differentiation of T cells into various subsets. There's all kinds of different T cell subsets, and Eric mentioned that, there's one subset called TH1, stands for T helper cell one. That's a critical cell. If you wanna kill cancer, it's the most important cell. If you wanna kill viral infected cells, it's the most important cell because that is the cell that creates both killer T cell CD8 cells and killer CD4 cells. You need TH1. Okay? Now, it's so important that nature has a redundant pathway, called RLK. It's run by RLK. If you just block ITK, the TH1 cell can still form. It's biased. You can drive the cell that way. If you block both ITK and RLK, it won't get it 'cause you've blocked both pathways. Now, the TH2 cell and TH17 cell, which are also on this diagram, those are T cells on the right-hand side of the screen. Those are T cells that'll play a role in inflammation, autoimmunity, allergy, killing parasitic infections, things like that. ITK is the only pathway to differentiate along that way. If you block ITK, you block TH2, you block TH17. Good for cancer to block those and skew towards TH1. Bad for autoimmune disease. Bad is you're gonna make autoimmune disease less severe by blocking those cells. Potentially, here's a drug that could be used to skew TH1, kill cancer, an immunotherapy play for cancer, or it can be used to block inflammation and autoimmunity. Now, there's a cell down at the bottom called a suppressor cell, T regulatory cell. That also has ITK, but it goes the opposite direction. If you block that completely, actually the T cell suppressor cell goes up. That's good if you wanted to prevent organ rejection, good if you wanted to prevent autoimmune disease. Not good if you're trying to treat cancer. Okay? Let me just review this. ITK is involved in two main functions, the T cell receptor signaling, which would block all T cells if you give enough of it, or skewing or biasing the differentiation. In some applications, you'd wanna block inflammation, allergy. That you do by blocking ITK. You don't get TH2 or TH17. If you wanna treat cancer, you want to bias towards TH1. You wanna get the killer cells. Now, let's see if we can do this. Okay, the way we start here is getting pure TH2 cells is not that easy, but mother nature had a way of doing it for us. It's called Sézary syndrome. Sézary syndrome is a kind of leukemia. It's a cutaneous T-cell lymphoma where the cells circulate primarily in the blood. Here's an experiment where we take Sézary cells and the normal T cells from three different patients, patient one, two, and three, and a healthy donor, and we look at the anti-proliferative effect of CPI-818 in a proliferation assay. You can see that the Sézary cells are way more sensitive to ITK inhibition. They're TH2 cells. We're blocking TH2. They can't proliferate. Okay? It takes much more drug to block the CD4 and CD8. In normal CD4 and CD8, you have a mixture. You have some TH1s and some TH2, so you're getting some inhibition there as well. But what this shows in a pure population of TH2, the Sézary cell, you have very potent inhibition, blocks TH2. This experiment from patients with Sézary shows you block TH2. Now, by the way, the clinical manifestations of Sézary syndrome, if you don't believe me, go talk to a patient with Sézary syndrome. When their cells move into their skin, they have horrible inflammation, redness, itchiness, pruritus, et cetera, because the TH2 cells secrete various cytokines. Okay, let me just touch very briefly on autoimmune disease because it also is instructive in the TH2, TH1, TH17 story. These are three different models. Two of them have already been presented, one in the middle hasn't. If we look on your left, that's a mouse model of a very bad autoimmune disease, where the mice, it's a genetic disease of a mutation of what's called Fas ligand. In that mouse model the animals get lymphadenopathy, autoantibodies to red cells and white cells, autoantibodies to their kidneys, autoantibodies to their skin, T cell infiltration, etc., etc. It is a bad autoimmune disease and if you treat these animals with CPI-818, they're cured. Actually, even better than cyclophosphamide, which causes profound hematologic and immunosuppression in these animals. That was presented in 2020 at ASH. Okay. It is very effective in this autoimmune disease model. As a matter of fact, people at the NIAID, National Institute of Allergy and Infectious Diseases, wanna do a trial with eight-one-eight in children with this disease, which by the way is called ALPS, A-L-P-S, autoimmune lymphoproliferative syndrome. We're working on a protocol with them now. It's a disease, you're born with it. You have it into adulthood, and these poor children are on immunosuppressants and cyclophosphamide forever. Now, in the middle is just a classic psoriasis model, an imiquimod model. An imiquimod is a chemical, causes a lot of inflammation. It's a TLR agonist. Basically, in this model, eight-one-eight is as good as Decadron. Shown on the bottom there. On the right is a recent paper at the ASH meeting just a few months ago from the Sloan Kettering group. This is an allogeneic bone marrow transplant model in animals, in mice. Basically, with very high doses, 300 milligrams per kilogram, that's a high dose of CPI-818, they basically block graft-versus-host disease. That's organ rejection. It's the grafts rejecting the host. That happens because as shown in the lower right, in the lymph nodes there, the T-regulatory cells have gone up. Remember, if you block ITK really, really hard, you get an increase in the T-reg cell. Good for treating organ rejection, good for autoimmune disease. You don't wanna do that for cancer, though. Okay, now let's return to cancer. I'd like to introduce you to my friends Chloe and Rudy. Chloe is a seven-year-old boxer, a dog, canine, who has aggressive peripheral T-cell lymphoma. Rudy is an 11-year-old golden retriever who has cutaneous T-cell lymphoma. Dogs get lymphomas just like people. They get naturally occurring lymphomas. They can get B-cell lymphomas, and they can get T-cell lymphomas. Frankly, they're treated with very, very often they're treated with the same drugs we give people, except obviously you can't treat them as aggressively. These two dogs had T-cell lymphomas, and we treated them with eight-one-eight. This was right out of the ibrutinib playbook. We did this with ibrutinib, obviously in dogs with B-cell lymphoma. We saw activity, and that was one of the motivators to go into patients with cancer. As you can see, Chloe had prompt reduction of lymphadenopathy shown in the graph on the upper panel. Rudy, with cutaneous T-cell lymphoma usually involving the snout of these dogs. I don't think it involves the snout of people. That's just more generalized. You can see that Rudy had resolution in 14 days. We showed monotherapy, single agent. Monotherapy means single agent, not combination. It was active. That's what this taught us, and it was safe. This led to a phase I/IB clinical trial in patients with advanced refractory T-cell lymphomas. The kind of lymphomas you just heard Dr. Gupta describe. This was your typical eligibility and your typical three-by-three dose escalation. We gave 100 milligrams BID, 200 BID, 400, etc., 600. It's an oral medication, of course. The objectives were safety, PK, immunologic parameters, and of course, looking for signs of efficacy as well. Based on that, we could expand into the various T-cell lymphoma subsets, as Dr. Gupta described. For us, the main ones are PTCL-NOS, that stands for peripheral T-cell lymphoma, not otherwise specified, or AITL, angioimmunoblastic T-cell lymphoma. Those diseases are very closely related. You have to be a pretty expert pathologist to tease those apart. Okay, so let's look at tumor plot. This is about 30 patients. Now, remember, of course, when you're doing a phase I trial, you start at the low dose, and then you go to the next dose, and then you go to the next dose, et cetera. You have longer follow-up on the earlier cohorts, of course. When you look at this, you see something really interesting. You don't need to be a statistician to look at this swimmer plot and see that the 200 milligram cohort, the dark blue. The light blue was 100, dark blue 200, 400, 600 BID. The dark blue looks the best. 200 milligrams BID looked the best. Pretty clear. As a matter of fact, if you go through each of those patients, the CTCL patient had a nodal CR. That means the skin didn't quite make CR, but the nodes went away. Skin is very hard to interpret in these patients. A PTCL patient had a CR, complete response, monotherapy, 19 months. All of this is monotherapy. An AITL patient. Another PTCL patient has a PR, treatment ongoing, partial response. The fourth patient is responding. There's regression of adenopathy, still on treatment. Just started on treatment recently. Nodal CR, PR ongoing, responding ongoing, and then one patient progressed. Now we see a little whiff of maybe something in the next cohort, but they were all CTCLs. Let's talk about why this is happening. Why did this happen? Think back to that cartoon that Eric showed and that I showed about the effect of ITK on the differentiation of T cells, the different impacts and the different subsets of these cells. Okay, I wanna go through now. Case reports are very important in medicine 'cause they can teach you a lot. If you study patients carefully, you can learn a lot. I'd rather study one patient carefully than a hundred not carefully. Okay. That was done a long time ago. That led to what was called Rituximab. You study one or two patients really carefully. Okay, let's look at these patients now. We're gonna talk about patient number one, two, and three. All right, this is a lady with PTCL NOS, had multiple nodes throughout her body, pathologic nodes. She was treated with CHOP chemotherapy and got a PR. Only five months. Pretty typical. These responses don't last very long. Then, in relapse, she went on to receive an autologous stem cell transplant, high-dose myeloablative chemotherapy, a bone marrow transplant. She got into remission again, but the remission lasted less than a year. Remember Dr. Gupta's curves. They don't look so good. Okay, then she came on our study, and she was treated with CPI-818 monotherapy. For you in the audience, that's not combination, that's monotherapy. She went into CR. Her lymph nodes regressed, and this is a PET scan, very sensitive test by the way, much more sensitive than a CT scan. She went into CR. The drug was discontinued at 12 months because she was in complete remission. The question was, does she need it, keep needing it? We wanted to see what would happen if we stopped it. We stopped the drug. She went another seven months with no other therapy. In CR, remained in CR, and then finally relapsed with her tumor coming back. That's where she is now. Okay, here's patient number two. Again, PTCL NOS. Now this patient's interesting 'cause it's EBV positive. Many of these tumors are EBV positive. Not all of them, but many. Of course, the question is, it's always been thought that T-cell lymphomas are caused by viruses. Many people believe we just don't know what the viruses are yet. We haven't been able to identify them. That's certainly true in mice. Mice, by the way, get more T-cell lymphomas than B-cell lymphomas, and they're all virally related. Okay, this lady has a football growing on her, on the side of her abdomen, subcutaneous large mass, in addition to lymphadenopathy, bone marrow infiltration, and circulating tumor cells. This lady has extensive disease. She received CHOEP. You heard about CHOEP from Dr. Gupta, four times, had a PR, short-lived, failed, and she went on GDP, stands for gemcitabine, Decadron, and platinum. Very aggressive regimen, oftentimes used in this kind of disease. Stable disease, then relapsed, then went on anti-PD-1, azacitidine, and an HDAC inhibitor. Didn't really respond to that. She came on our study and was treated with monotherapy and had dramatic reduction in this large subcutaneous mass on the abdomen, as well as lymphadenopathy seen on CT scan, as well as blood, and as well as bone marrow. Now, let's study this a little bit more carefully. Look at the laboratories. They're quite elucidating. Some of the laboratories are shown in the chart at the bottom, right. Let's look at the lymphocyte count first of all. I think that's really interesting. The lymphocyte count was around 6,000. That's a little high. Not terribly high, but a little high, because there's tumor cells there, circulating, malignant lymphoma cells, as well as normal lymphocytes. On day 15, that count actually went up, and then it comes down. Does anybody know what that's reminiscent of? Where you treat somebody with these lymphomas and the counts go up and then down? That's ibrutinib. That's the ibrutinib effect. First described early on with ibrutinib. In fact, it was very puzzling 'cause people started stopping the therapy because they thought maybe the tumor was growing, but then they realized that, hey, the lymph nodes are shrinking. You get this transient lymphocytosis. What causes that with ibrutinib or CPI-818? Not clear. It's almost as if the lymph nodes as they're shrinking or the tumors are squeezing out those cells, and they go into the blood where they apoptose. That's what's thought to happen with ibrutinib or BTK inhibitors. Look at the eosinophil count. 17,000 is a very high eosinophil count at baseline, pretreatment. Drops in 8 days, stabilizes at around 1,000, 4,000, back around 1,000 now I heard recently. Eosinophil count is high. That's a telltale sign of a TH2 tumor by the way. Look at the platelet count. The platelets were low. These people often have splenomegaly and bone marrow infiltration, and they have thrombocytopenia, low platelet count. The platelets were 105. That's low. Within a few weeks they come up to 150,000, which is normal. LDH. You heard from Dr. Gupta LDH is a bad sign. When you have a high LDH in a lymphoma patient, it's a sign of tumor burden. High tumor burden. The LDH dropped from 665 down to around 250. 300 is the upper limit of normal in most labs. Let's look a little bit more carefully at the immunobiology. In this patient, because of this large mass that was readily accessible, we could get some other information. Here we're looking at their very good markers and flow cytometry for TH1 cells and TH2 cells, et cetera. This is sort of standard immunobiology work. If you look at the panel on the left, we're looking at the TH1 cells in the blood, that's the blue curve, and in the tumor, baseline and on day 84. You can see marked increase in the TH1 cells in the tumor, increase in the blood as well. Remember, these cells are probably being made in lymph nodes, and they go into lymphatics in the blood, and then they home into the tumors, okay? That's how the immune system works. Look at the right. The right shows CD4 effector cell. Remember I told you before, the, you know, memory cells that come out of lymph nodes and effector cells? The effector cells are armed. They're ready to go. They're ready to pounce on the guy. Look at the blood and look at the tumor. They both increase. Okay. Let's go to the next slide. Now, this is looking at CD4 and CD8 cells for the expression of PD-1. When cells get activated, they often express PD-1. PD-1 can mean other things as well, but most likely it's a marker of activation. The cells are turned on. Look at the eights and fours, CD4 and CD8 in the blood on the left and in the tumor on the right. You see they both have increased. What can we conclude from that? We can conclude that just like that cartoon we showed you, we're skewing towards TH1. We're blocking TH2 because the eosinophil counts went away in that lady. We've increased the effector cells that have infiltrated the tumor. We've increased the TH1 set of infiltrated the tumor. They went through the blood, and that's all predictable by the blockade of ITK. Not the general blockade of everything that you would get if you really were, you know, tried to block their T cell receptor, but the selective blockade of the differentiation pathways. Okay? Here's the next patient. This is shorter follow-up. All we have is blood on this patient. If we look at CD4 and CD8, again, another patient with failed multiple chemos, on CPI-818 monotherapy, responding to treatment. This again shows activated T effector cells in the blood of CD4 and CD8. All very consistent. Now, at the same time that we're generating these T effectors, and at the same time we're seeing these TH1 cells that are infiltrating the tumor, the tumor's going away. I mean, that's the last sentence I said is the crucial one, right? Because who cares about, you know, these fancy immune tests? What we care about is that those things are actually having a clinical impact, and they are. Okay, let's get back to this, swimmer plot. It's very interesting, predictable swimmer. For immunologists, very predictable. Okay, what is the reason that we see this dose effect, this dose response effect? Well, we have to go back to our cartoon. There is a dose, probably around 200-400, and we have the PK now and the occupancy and all that stuff very well worked out. There is a dose where you block TH2 differentiation, TH17 differentiation, and bias toward TH1, and that's now been seen reproducibly. Okay. If you give too much drug, you block T cell receptor signaling or you increase the T reg, the suppressor cells, and then you block all T cell function. There are applications where you might wanna do that. In fact, we have an inflammatory bowel model where you do that and the animals get better. The explanation for the dose response swimmer plots that we see are based on the skewing or biasing towards TH1 and the inhibition of the other inflammatory cells. Okay, so let's summarize eight-one-eight. Does it modulate tumor immunity? Remember, this was from our early slide. This is our strategy. Yes, it induces TH1 skewing very selectively and potently and blocks TH2. I've never seen a drug that does that as selectively, where you can precisely control an immune response. It increases the effector cells in the tumor. Those T cells are activated. The molecular target, eight-one-eight, is an oral covalent drug. We know exactly where it hits. We know exactly what it binds to. It's been very well tolerated. I have not talked about safety, but we've had people on this for many, many months. It's active in PTCL, CTCL, AITL, in the preclinical models I showed you in various autoimmune diseases. We think that this drug can have a broad range of effects in lymphoma and in, autoimmune disease. Now, here's the interesting part, okay? We're getting tumor regression here, not because our drug is killing the cancer cell. I'm gonna repeat that. We're not killing the cancer cell with our drug. We're activating the immune system, the normal cells, to kill the T cell tumors. Maybe we can do that for a colon cancer or lung cancer or kidney cancer. Those experiments are ongoing now. In fact, there's a paper published last year by Adam Mor at Columbia University here in town, who we're now collaborating with, where he actually shows that there is synergy if you block ITK while you give PD-1. Solid tumors are on the table now. B-cell lymphoma is on the table, especially if it's EBV positive. I didn't show you this, but one of those patients who's EBV positive became EBV negative, okay? Which you would expect if you do TH1 skewing. The clinical applications are, we think, much, much broader than T-cell lymphoma, and much more broad than cancer. Next steps. Corvus is enrolling patients at the optimal dose. Angel, our Chinese partner, has been phenomenally important to us. They're talented, great scientists and clinical researchers. They have been contributing patients and really fundamental scientific discoveries that are incredibly valuable to us. The Angel relationship is really, really important to us, and it is, and it turns out to be absolutely a great idea for Corvus. Absolutely. Angel is enrolling patients, and we expect to have more data in our T-cell lymphoma open-label trial later this year, perhaps at ASH or some other meeting. We're already planning a phase two study, global phase two. We're even thinking about frontline therapy. Eight one eight is so novel mechanism of action, so well-tolerated, it's easy to envision combining it with other agents, chemotherapy agents, or other immuno-oncology agents. This is a good point to stop. I'd like to ask maybe Dr. Verner and Dr. Gupta to come up here and we can take some questions from the floor if there are any. I see one question. Of course, it's a webcast. Can you identify yourself and another microphone. Lee Watsek from Cantor Fitzgerald. Thank you very much for this comprehensive presentation. I guess first one for Dr. Neel. I mean, can you just provide your perspective on the data so far for CPI-818? And then I guess, how do you think this drug can fit in the current, I guess, the treatment landscape? You discussed there's a lot of unmet need here, but then you also said there are approved therapies. So how do you think about potential sequencing there? And I have another one for Richard Miller. Oh, do you wanna have? Yeah. Dr. Gupta? Let me just repeat the question again for the benefit of the webcast. Lee Watsek asked, I think, to Dr. Gupta, "How do you see this treatment fitting into the therapeutic armamentarium of current T-cell lymphoma therapy? And what about the other approved agents, like duvelisib, et cetera? No. Go ahead. Yeah. Thank you for that question. This is Dr. Gupta answering for the webcast crowd. Yeah, I appreciate that question. I think the first part of your question was what do I think of CPI-818 so far in terms of the preliminary data. You know, if you remember my last slide, there's some criteria that I think are necessary for the next great drug in this space. From what I've seen so far, this checks a lot of the boxes. I think, kind of leading into your second question, the current state of drugs in this space is fairly dismal. From a clinician's perspective, pralatrexate, romidepsin, belinostat, it's not like we are eagerly awaiting to put our patients on these drugs because they really are not that effective, truthfully. Also, they're fairly difficult for patients to tolerate. I view this particular drug as a very exciting opportunity to both, improve their disease state, but also make them feel better, most importantly. I think there's an opportunity here for it to really make inroads in T-cell lymphoma. Right. I have another question for Rich. I have a question about this 200 mg dose that you picked. I guess you have maybe this theory why this happened. I guess can you share some, I guess, biomarker data, maybe at higher doses? Does that support your, I guess, thesis that you actually, if you go higher dose, you actually see more like T-reg and- Uh, the- Yeah. The evidence is on- Oh. Good question. Yeah. If you look at the swimmer plot, when you go to 400, little bit of activity, 600, no activity. Very, very rapid relapses. We also know from animal models, at those doses, you block T-cell receptor signaling. On the one hand, if you induce a T effector cell, but you block the T-cell receptor, it's not gonna work. Right? You, it's one thing to get it to differentiate, but you can't block the receptor. Also on the selection of 200 mg dose, I wonder if you had any discussion with FDA on this dose already or that's your plan to do. We have not had any discussions with FDA about that. We are singing the FDA song here. I mean, think about this. We're gonna go in there not recommending the highest dose, but actually recommending a lower dose. Okay. We've carefully studied these dose levels in over 30 patients now, and we're studying more patients on study now. I think in terms of dose selection, this is the paradigm of how you do it. Okay. I think we're in great shape there. By the way, the 200 milligram dose, 'cause we used to talk about this a lot, and now we realize it's actually not as important as some of the other things you measure. It was important with ibrutinib, but not as much here, is occupancy. The occupancy of the 200 milligram dose is anywhere from 75-90%. Pretty good. Another question. Thank you. This is Mara Goldstein from Clear Street. I just wanted to expand on that a little bit, or ask you to expand on that a little bit. In the earlier work that was shown, you expressed that you got complete receptor occupancy at the 600 milligrams. So I just wanna understand the relationship between that receptor occupancy at the 200 milligram versus the 600 milligram. And if there's, you know, within the realm of drug development, where, you know, going to that lower receptor occupancy. And then the last question that I had is one on the safety. I mean, these are relatively low numbers anyway, but in the 200 milligrams from the 2020 data set, you saw higher incidence of pruritus, and I'm wondering if that's mechanistic. All right. Okay. Mara's question has to do with occupancy and dose selection, and second question about pruritus. Let me dispense with the pruritus. First of all, these people all have skin disease, so the pruritus is disease related. There's no pruritus in this room. They all have a lot of lymphoma in their skin, most of these people. That's a disease-associated ache for sure. Okay, now the dose. The occupancy assay, there's a little bit of a ceiling effect here. You can't. The way the assay's done, you can't be above 100%. When you start getting to, you know, 80, 90, 100%, it's really hard to distinguish that. Keep in mind, we're sampling mostly the blood. Almost always we're sampling the blood. The blood is only one of several compartments. You have the tumor, you have lymph nodes, you have spleen with other things. With the 200 milligram dose, we have pretty good occupancy. At the peak levels, you're up around 90% or above 90%. It's only a little bit better when you go to 400 and 600. Occupancy is not the right thing to be looking at. I mean, that's our fault. We were promoting that because that seemed to be very useful in the development of ibrutinib. BTK doesn't have the myriad of functions that ITK has. At least not. It's not known. ITK plays a more important role in the differentiation of many different kinds of T cells, and those are more finely controlled, more precisely controlled. Yeah, I think you have to have some occupancy. I mean, you can't have, you know, zero. But you know, we have trough-to-peak with 70%-90%. That's pretty good occupancy. Even now with ibrutinib, due to side effects that ibrutinib has shown, people are backing off on that dose. Now, again, it may depend on what you're going after. I think if you're gonna go after organ rejection, you're gonna wanna, like, really push the dose. I don't think I would be looking at occupancy. I'd be looking at more functional things. Okay. If I could just ask a clinical treatment landscape question and there are a handful of, you know, experimental treatments that we're looking at, T-cell lymphomas more from the cell therapy side. I'm curious from a cellular therapy perspective. I'm just curious about, you know, how this will exist with, you know, the potential for those experimental therapies. Okay. I think the question was, there's a growing interest in CAR T for T cells. Correct. Good luck on that one. I wish you well, and we can come back in 10 years, and you can tell me how that's going. You know, there's just a small amount of data. It's hard because you have the problem of suicide, right? If you make a CAR T to a T cell, it kills itself. So you have that problem. It's extremely expensive. Yeah, I mean, you know this, Mara. Even in the B-cell lymphomas, where I would admit CAR T, CD19 CAR Ts are pretty effective. I mean, that's a last resort. Okay. Now, of course, the landscape with bispecific antibodies and other things. I mean, I would not that optimistic that that's gonna be a growing area. The opportunity for CAR T is really gonna be in solid tumors if anybody can get that to work. In T-cell lymphoma, I don't view that as a threat. PD-1 has been another. Anti-PD-1, that's been mixed. I mean, we would know that we're working. It's been going on for four or five years now. Many people are concerned about anti-PD-1s in T-cell lymphomas because there are some papers that claim that it stimulates the tumor. I mean, right now, especially with the removal of duvelisib from the market, the PI3K, and that happened because people were dying in the B-cell lymphomas with longer follow-up. It was worse. That's a very toxic drug. Even though PFS looked good early on in the response rate, I think, right? You know, with longer follow-up, they actually have a worse survival. That drug is gone now. There is no PI3K on the market now. All you have is pralatrexate, belinostat. As Neel said, those drugs are just. I've actually never seen them used. Do you actually use them? It's rare. I mean, there, the difficulties that we mentioned. Yeah. toxicity and And, and- lack of efficacy. I think it's also, he has a slide on the response rate with those drugs, belinostat, pralatrexate. It was, like, 25-30%. That's very generous because if you look at those patients, they were very favorable patients to begin, to go on that study. I think that's a pretty generous number to begin with. Anyway, I think we should probably. Any other questions? I think, Mara, did that answer your question? Yes. Thanks so much. Okay. Thank you for that. All right. I think then, we can move on. We move on to the next speaker, which unfortunately is me. So, I'm actually earning my wage today. Okay, so let's move now to mupadolimab. Okay, so we were talking about T cells, how we're gonna control T cells. Now we're gonna talk about B cells because mupadolimab is a very, very unique anti-CD73 antibody. Corvus and our team of scientists have really been pioneers in this area, I would say along with AstraZeneca. So let's talk about this antibody further. A little background for those who are new to this subject. CD73 is an ectoenzyme. It's present on the outside of cells, T cells, B cells, other tissues. It's pretty highly expressed in B cells. It can be the majority of B-cells, 70, 80% in the blood, depending on who you look at. CD73 is known to catalyze the conversion of AMP to adenosine, clips off the phosphate. Less well appreciated, although we've been talking about it now for a couple of years, is that its main function for which it was originally described is it's an adhesion molecule. It has a structure of an adhesion molecule. It's involved in lymphocyte migration and activation, homing. Okay, that's really one of its main functions. Mupadolimab is a humanized IgG1 antibody that's been engineered to be Fc receptor deficient. So this antibody does not fix complement. It does not mediate cellular cytotoxicity. That's by design. It's very good at blocking the catalytic activity of CD73. It pretty much totally blocks adenosine production in vivo and in vitro in animals when we can measure. As most importantly, we believe most importantly is that mupadolimab stimulates, it's an agonist, stimulates B-cells and T-cells, but mostly B-cells, to divide and differentiate or to differentiate and mature. Okay, we see the strategy here for Mupa to be, okay, we have an IO agent that stimulates B-cells, that stimulates immunity. Wouldn't that be nice to combine with an anti-PD-1 or agents that release the brakes, release the negative signal? It's a complementary mechanism. You wanna remove the negative signal, you wanna add the positive signal. That's been our strategy. Now, there's a lot of companies and people working on CD73s. This is a very short list. It's not everyone. I think there are, like, 40 companies working on this now. We were one of the first, along with AstraZeneca. I believe we're the only company that's actually published any papers on this. AstraZeneca has as well. Our antibody fully blocks adenosine, strongly activates B cells. I'll show you the data for that. Basically in phase two now. Oleclumab blocks adenosine pretty well, very weak in terms of B-cell activation. None of the other antibodies that we've gotten our hands on, none of the other anti-CD73s have we been able to show B-cell activation. Now, some people are claiming that, but then they never show you any data to support that. I don't know if it's true or not. Why is this happening? Why is mupadolimab unique? We know exactly why it's unique, and that's shown in this very elegant study that we did. This is using cryo-EM, cryo-electron microscopy, where we took the CD73 homodimer and incubated it with mupadolimab. We know exactly, based on the cryo-EM studies, where Mupa binds in terms of CD73. It binds on the amino terminal, amino acids 205- 300. In case you're interested, we know every salt bridge, we know every pi bond, we know every other interaction. Now also shown there are oleclumab. There's a published EM structure of that. Dalutrafusp alfa, there's a published EM structure of that. Some of the others, I don't know if they've actually been, if they've done EM, but those are purported regions of the molecule. Mupadolimab binds to a very unique epitope, and we know precisely what that is. Now, this diagram, by the way, just shows an Fab, one arm of the antibody, just for clarity. Of course, there's really two arms of the antibody. What you actually have formed, interestingly, is a tetramer. You have two antibodies and two of the homodimers of CD73. So you have, like, this ring-shaped complex that forms. Very interesting. So we know it's different than the others, than everybody else's. By the way, we already knew that because I told you previously at some other meetings we had, they don't cross block. So none of this was a surprise, but now we know exactly the determinant. Now, the real question is how does it activate a B cell? How does that signal get from the outside, from that region into the B cell? We'll talk a little bit about that, but first, let's compare mupadolimab and oleclumab. Oleclumab is AstraZeneca's CD73. They have become the leader in the field, of course. Both antibodies are humanized IgG1s. Theirs is a lambda, ours is kappa. As far as I can tell, that would make no difference. Both are engineered to be deficient Fc gamma receptor binding. Both are very good antibodies. Anybody would call high-affinity antibodies. Those are antibodies with low 100 picomolar Kds. These are good antibodies, very tight-binding antibodies. What about antigen internalization? We never see internalization of the antigen. When we bind to the surface of the cell, we don't see the antigen go inside. Oleclumab does that, and it's reported in the literature. That has to do with how the complex is formed on the surface of the cell. Now, whether that's good or bad clinically, I don't think anybody knows. I don't think it really matters. Hook effect. Hook effect is something that a lot of people are talking about. That means when you get really high with the antibody concentration relative to the antigen, you lose binding, you lose affinity. We never see that. They do see it, and they've published that, and some of the other antibodies have that. Again, what is the significance of a hook effect? Does it matter clinically? I really don't think so because in order to get to that hook effect, you gotta go pretty high. So, I don't know if it's clinically relevant. And then some of these other things you can see there, T-cell restoration, dosing. We actually use a lower dose, 1200 milligrams q 3 weeks. Oleclumab is given in a loading dose, 3000 milligrams the first couple of cycles, and then 3000 milligrams every month. It's a little bit more antibody, actually, but not grossly more. Okay, let's look at some of the science behind this. Very quickly, what the panel in the upper left shows you, and I won't go through the details, is that if you take a human CD73 positive tumor and grow it in an immunodeficient mouse and give either control or mupadolimab, panel on the left shows that you don't lose the antigen. I just told you that it's not internalized. This is proof of that. In the middle panel, it shows that the mupadolimab is there. The mupadolimab got to the tumor because when I come back and stain that or try to react it with a labeled mupadolimab, it doesn't react 'cause there's a mupadolimab already sitting there. The antibody got there. The antigen is still there. The antibody's there. It's fully saturated. Then the third panel is the enzyme. If we take the tumor out of the mouse and assay it for adenosine, there is no adenosine. It's blank. It's completely block adenosine formation. This antibody is reacting with an epitope that's involved in signaling the B cell, but it also is blocking the enzymatic activity of that protein. Okay. The more interesting thing is at the bottom, and this is dramatic. If you take B cells, human B cells, and incubate that with mupadolimab, within hours you see stuff happen. Actually, within minutes. You can see over a couple of days, these cells transform into what's shown in the middle there, these large plasmablasts. Plasmablasts are the cells that become plasma cells. Plasma cells, of course, make antibodies. Plasma cells also can be memory cells. They can go to the bone marrow and be long-lived cells. They can go elsewhere, make antibody, and then do their job and go away. Now interestingly, if you look at the lower left, we look at a marker called CD69. That's been the workhorse in our labs. CD69 goes up when cells are activated, lymphocytes are activated. CD69 goes up very high with mupadolimab, goes up a little bit with oleclumab, the black bar on the lower left. So what is CD69? Why am I even talking about that? CD69 is a protein that's expressed on lymphocytes that keeps it in the lymph nodes. The B cells or T cells are circulating around the lymphatics, the bloodstream, the tissues, the lymph nodes, and when they encounter antigen, whoop, CD69 appears. They're trapped there. They're stuck in the lymph nodes 'cause they wanna process that antigen. They wanna have a tighter fit. They wanna get better. It's called affinity maturation. Then they eventually go out as memory, B or T effector cell, memory cells or effector cells. CD69 means activation and homing to the lymph nodes. Okay. Very quickly, there's a bunch of other markers that change, CD27, CD38, CD138, CD69. I mentioned CD83, HLA class II, CD86. These are markers that tell you that the B cell is differentiating into a plasma cell, and it's differentiating into an antigen-presenting cell. Okay, antigen-presenting means they pick up an antigen on the cell surface, and then they present it to T cells, and they educate the T cells. B cells do that very well, and they do it differently than macrophages because they don't do it with peptides. They do it with the whole protein. Very different. Okay, let's look at CD69 low on the right. You see mupadolimab causes the expression of CD69, the blue curve, oleclumab just a little bit. In fact, maybe that's your hook, your hook effect there, where if you go really high, you start to lose it a little bit. The other, Clone eighty-two is another CD73 antibody, which doesn't do it. CD69 goes up in vitro, and plateaus at around a microgram per ml of antibody in vitro. Okay. Now, what about adenosine? We know this blocks adenosine, but is adenosine involved in the activation of the B cell? The answer is clearly and emphatically no. It is not. And on the left, and I won't go through every detail of this experiment, but if you look at all these activation markers, 69 to 83, and you throw in tons of adenosine in the form of NECA, which is a potent analog, agonist, you don't affect it. You don't block it. It is not involved in this property. The middle panel gets to the question of, well, how is this activation occurring? So again, looking at CD69 expression, mupadolimab causes CD69 expression. Ibrutinib blocks it almost completely. Now, we've done this experiment with other agents that block the B cell receptor signaling pathway. We are sure now, we are certain that Mupa is causing activation of B cells through the B cell receptor pathway. Okay? It's almost a co-stimulatory molecule. Details I won't go into today, we know exactly the complex that's formed in the cell membrane. Those are gonna be really great druggable targets, by the way. We understand that now. The final evidence, which I won't dwell on, is you get phospho-ERK when you stimulate with Mupa, meaning, again, B cell receptor signaling pathway is involved. Okay. Let's get back to the third player because I neglected my third player that I told you was the most important. Talked about the tumors and we talked about the blood. Let's get back to our lymph nodes. A lymph node, obviously, you know, lymph nodes are all over your body, thousands of them, and they're connected, and they eventually feed into the bloodstream. These are two lymph node specimens, two individuals stained with CD20, which is a B cell marker, and CD73, which we've been talking about. These are the germinal centers. Some people refer to them as the follicles of a lymph node. Again, this is where the action takes place. You'll notice there's a clear zone and a dark zone. In fact, some people call it clear zone and dark zone. Some pathologists refer to it as that. We more recently called it the germinal center and the mantle. Mantle cell lymphoma comes from that area. That's why you've heard about mantle cell lymphoma. You can see that CD73 is pretty extensively expressed in this normal lymph node. Okay? It's in the germinal center, it's in the mantle, and it's out in the what we call parafollicular areas. Those are mostly T cell areas. Okay, what's CD73 doing there? Good question. Okay. Lymph nodes are so important. They're so important that tumors said, "You know what? I gotta make some of my own lymph nodes." Infections, tuberculosis, chronic infections. They sometimes say, "Hey, I gotta fight this infection. I better make my own lymphoid structures." Those are called tertiary lymphoid structures. What are we talking about here? On the left are the follicles in a normal lymph node. Low magnification. That's normal. In the middle there, up in the upper middle, you have a tumor. You can see, if you look carefully, there's these darker areas. There are two of them. Those are lymphoid structures, germinal centers that are forming within the tumor. Sometimes they're in the tumor, sometimes they're around the tumor. Those have been known for 100 years as being associated with a good prognosis. 100 years ago, pathologists saw those things and said, "Hey, those little dark blue things mean you're gonna do well." But of course, they didn't know what they were looking at. Now, what are those tertiary lymphoid structures? Well, very quickly on the far right, they're germinal centers. They have CD20 in the middle, B cells. They have CD4 helper cells in the mantle zone. They have CD8. So they're little lymph node structures. What are they doing? They're making immune cells. They're making T cells and B cells, trying to fight the cancer, trying to fight the infection. The cancers are smart, and they outsmart them. Okay, back to B cells. There's intense interest now in tertiary lymphoid structures. How do you control them? What induces them? What are they doing? Et cetera. What are the ligands? What is CD73's natural ligand? Not known. Okay. CD73 wasn't made for Corvus to make mupadolimab. It has some other function. B cells are now a hot topic in immuno-oncology. What are they doing? What is their role? There's already tons of papers on, well, the B cells are making antibodies to viruses. They're making it to HPV. They're making, in some study, recent study, in Immunity showed the B cells are actually crawling up the fibroblasts into the tumor, turning into plasma cells as they do that. Really interesting. Now let's turn to what we see in our patients. We've heard about ITK. We studied the immunology, and then we go on our patients and does that happen in patients when we treat patients? I'd like to ask Suresh, Dr. Mahabhashyam, to give us an update on our clinical trials. Thanks. Thank you, Richard. Richard just talked about some of the preclinical data, the mechanism of action of mupadolimab, the B cell activation, the adenosine blockade. I'm going to walk you through the mupa clinical program and how this mechanism of action could translate into clinical activity. The phase I study for mupadolimab is a comprehensive study. We evaluated mupa as monotherapy and in combination with pembrolizumab and ciforadenant. The primary objective of this study being a phase I, 1b, is safety and tolerability. Based on the PK/PD data and safety, we were also able to pick an optimal dose for mupa for expansion and for other studies. This is a classic dose escalation followed by dose expansion design. In dose escalation, we studied multiple ascending doses of mupa in monotherapy and in the combination arms. Now, currently we are enrolling squamous cell head and neck and non-small cell lung cancer patients in the mupadolimab plus pembrolizumab expansion arm. This study has enrolled over 100 patients. I think Richard mentioned that before. I talked about dose escalation, dose expansion. The dose escalation part of the study is done for both monotherapy and for combination. Now, for monotherapy, we went up to doses of 24 milligrams per kilogram of mupadolimab given every three weeks, once every three weeks. In combination, we went up to the dose of 18 milligrams per kilogram given every three weeks in the combination arms. The MTD, or the maximum tolerated dose, was not reached for either the monotherapy or combination. If you look at the table on the right, the characteristics of these patients who are enrolled in this study, these are, you know, patients with advanced cancers and have received multiple prior lines of therapy. If you look at the median number of prior therapies, it's three-four prior therapies. We also enrolled different tumor types. It's a phase I study in a colorectal, pancreatic, renal, head and neck, and of course, lung cancer. Earlier, Richard mentioned, you know, the data about B cell activation, you know, as the mechanism of action of mupadolimab. We looked at the peripheral blood of our phase I patients, and we looked to see what were the changes in the B and T cells in the peripheral blood. Now, if you look at the panel on the left that shows the B cell dynamics, and we see the B cell dynamic at a dose as low as 1 milligram per kilogram. This is data in patients who got a dose of 12 milligrams per kilogram or above. It shows the fold change in circulating B cells compared to baseline. Now, if you look at this panel on the left, within 30 minutes after mupadolimab infusion, you see this rapid decrease in the B cells. This reduction is actually correlated with CD73 expression. You see those two red dots. Those are patients who had low baseline CD73 expression, so you don't see that appreciable immediate drop in B cells for those patients, although you see some at 24 hours. This reduction is dependent on the CD73 expression on B cells. These B cells, they partially return to baseline levels and, when they return to baseline levels at day 21, they are CD73 negative B cells. We see a similar dynamic with the T cells. If you within 30 minutes of infusion, you see this reduction. You see the decrease in circulating T cells. The T cells return to baseline levels by day 21. Now, as a note, over 60% of these patients at baseline, the B cells are CD73 positive. Moving on to clinical activity. This is data that was presented at SITC. It shows a waterfall plot that you know compares the percentage change in the target lesion from baseline to the time in study. This is in 25 squamous head and neck cancer patients and non-small cell lung cancer patients who got a dose of mupadolimab of 12 milligrams per kilogram and above. If you look at the table on the top, these patients, if you look, almost all of them had prior PD-1 or PD-L1 therapy before starting on this trial. Again, the median number of prior therapies was 3. Heavily pretreated advanced cancers. When you look in these patients, we did observe some tumor regression in these patients, as noted on the right side of the waterfall plot. You see patients with tumor regression. You know, one thing we did was we saw tumor regression with mupa. How did that compare with their experience on their most recent prior therapy before starting on mupa? If you look at the table on the bottom, that shows the best response these patients had on their most recent prior therapy before mupadolimab. You look at those patients on the right that had tumor regression. Most of them had a PD-1 or a PD-L1 as an immediate prior therapy, and their best response to that therapy was progressive disease. They failed a PD-1 or a PD-L1, and then they came on the study, got mupa, either as monotherapy or with cifo in these, in some of these patients, and we saw tumor regression. The time on treatment for these patients who had tumor regression was anywhere between 4.5-12.5 months. We do see clinical activity in these, you know, advanced cancer patients with mupadolimab. CD73 as a target has been validated. AstraZeneca presented some data on oleclumab, its COAST and NeoCOAST studies in the recent months. In both these studies in earlier stage lung cancer patients, the combination of oleclumab and durvalumab, the anti-PD1, showed improvement in clinical outcomes. In the NeoCOAST study, they also showed upregulation of genes involved in B cell activation. As a result of this data, you know, the next steps, the next studies have been initiated, a phase II NeoCOAST-2 and a phase III study, in phase II frontline non-small cell lung cancer. What does all this mean for mupadolimab? What are the next steps? We have seen clinical activity in advanced cancers in non-small cell lung cancer patients. We have the validation of CD73 as a target in earlier stage lung cancer patients. We are planning on a randomized placebo-controlled phase II study. The planned start for this is in H2 of this year. This is in frontline stage four or metastatic non-small cell lung cancer patients, regardless of PD-1 expression. These patients and in patients who don't have an EGFR or ALK mutation. This is a fairly large population in the frontline metastatic setting. These patients will be randomized one to one to one of the two treatment arms, one of the arms being mupadolimab plus standard of care pembrolizumab and chemotherapy. The mupadolimab-pembrolizumab and chemotherapy is considered standard of care in this setting. You know, in one of the arms, patients get mupadolimab in addition to standard of care. In the other arm, patients get placebo in combination with standard of care pembrolizumab and chemotherapy. There is a comparator there. Primary endpoints are progression-free survival. Secondary endpoints are ORR, DOR, overall survival, and safety. This is a blinded study, so the site, the investigator, and the patient are blinded to the study treatment assignment. Corvus will remain unblinded. We have multiple interim analyses built into this study. At the time of these interim analyses, we will be monitoring the clinical data, safety and efficacy. Our goal is if we see a positive or an encouraging signal, you know, we are poised to do a phase three study. Moving on to summary of mupadolimab. You know, we talked about Corvus' development philosophy, our strategy. This fits in right, you know, right in there, modulating tumor immunity. We see evidence of B-cell activation with mupa, the B-cell redistribution to lymphoid tissues, evidence of antitumor antibodies, precision molecular targets. Earlier talked about the cryo-EM data where we know the epitope that mupa binds to. Complete adenosine blockade. The phase one study with mupa has shown favorable safety in monotherapy and in combination with pembrolizumab and ciforadenant. From a clinical applications perspective, you know, the antitumor activity in those advanced cancers is encouraging, and hence our next steps in non-small cell lung cancer. There's also the potential application in infectious diseases. From a next steps perspective, we are initiating the randomized placebo-controlled phase two trial in frontline non-small cell lung cancer in combination with pembro and chemo in the H2 of 2022. Well, I wanna thank you for your time, and I'll hand this off to the next presenter. Happy to be with you. Thank you, Suresh. We'll take questions on the mupadolimab and ciforadenant after I talk about ciforadenant, which is our adenosine A2A receptor inhibitor. I will show some new clinical data here. Just by way of background, I know you're all familiar with this, so I won't dwell on it. Extracellular adenosine is produced in the tumor microenvironment, and it can interact with the A2A receptor, which is present on T cells and certain other immune cells, and suppress an immune response. That's the dogma. Ciforadenant is an oral small molecule antagonist of the A2A receptor, which has been shown, we've published this now, to be active in animal models and in some of our early clinical results. You can see in the cartoon on the right, adenosine is made really by several different pathways, probably dozens of different pathways, and it interacts with A2A. There's another receptor called A2B that it can interact with, and we'll come back to that in one moment. Adenosine's immunosuppressive. Here are the biochemical features of ciforadenant. It's a very good A2A inhibitor, low nanomolar KI, 3.5 nanomolar. Pretty good selectivity over A1. You don't wanna hit A1 because A1 is in the heart and other places. A2B 1,500. Let's talk about A2B because I've just been hearing about this a lot recently that, "Oh, my inhibitor hits A2B" or. Here's the fact you need to know. A2B, and you can Google this and look it up, A2B has another name. It's called the low-affinity adenosine receptor. Low affinity. The Ki for adenosine binding to A2B, I should say, not blocking, binding, is over 20,000 nanomolar. Okay? Let me tell you what that means. That means that ciforadenant blocks A2B. Does everybody else's. Pretty much every A2A antagonist I've seen, if you're at 1,000, a couple of thousand nanomolar Ki, you're gonna block adenosine binding to the low-affinity A2B receptor. Moreover, what the function of A2B is sort of unknown. As a general rule, I can tell you that most pharmaceutical people like to make drugs as selective as possible. We're primarily interested in A2A, but just keep in mind that the adenosine binding to A2B is so weak that pretty much everybody blocks it. On the right side of this slide shows just a signaling pathway. Ciforadenant completely blocks the A2AR signaling pathway. This is data that was published by Stephen Willingham in Cancer Immunology Research in 2018. This paper got lots of data on the biochemistry and preclinical, et cetera. What was little noticed back in 2018, but what now is getting increasing attention, and we're working on it a lot now in the laboratory, is the information in these preclinical animal models. In MC38 and CT26 and other models, the best combination with ciforadenant is not a PD-1 but an anti-CTLA-4. In fact, in a combination of CIFO and anti-CTLA-4 in MC38, which is a very immunogenic tumor, you have 100% cures in animals who have established disease. They're all cured with the combination. CT26, they're not all cured. It's a much less immunogenic tumor, but still, most you can see in the green curve there in the lower right, there's a marked regression when you use the combination of CTLA-4 and CIFO. In fact, also in that paper, if you reduce the dose of PD-1 and CTLA-4, use a quarter of what you usually use in the mouse, you can still show really good efficacy in this model in the CT26 model, a very poorly immunogenic tumor, where most of the animals, 60% or so, are cured. It turns out that CTLA-4 is the best thing to partner with CPI, with A2A. It's not gonna be specific to CPI. It's gonna be any A2A. That's gonna be your best partner. Now, why is that? Before we get to that question, now we've published our data on CPI pretty extensively, and I'm gonna show you some more of an update on it now. We published a clinical trial in Cancer Discovery in 2020. Larry Fong was the first author. We reported on 68 patients with advanced metastatic renal cell cancer. The details are on this table. Median prior therapies is three. 92% were PD-L1 negative in the tumor. Most but not all had prior PD-1. In this study, patients were assigned to either get the combination with atezolizumab, cifo plus atezo, or monotherapy with cifo. That's the way the trial was set up. Again, this has been published, and what you see from the waterfall and spider plots here in this patient population, first thing you see, and this is the only thing I actually ever look at, is the blue. There are some blue bars there. There are some patients actually who responded to monotherapy. We like to see that, okay. Now there are also some red bars. There's more red bars. Several of those red bars are people who didn't get a prior PD-1. It's possible that that would have occurred anyway, even if you didn't give cifo. That cannot be ruled out. The monotherapy activity gives you some extra belief that the CIFO is doing something in this system. Okay, also in this paper, very careful analysis of biopsies and some very fine laboratory work showed that when you take peripheral blood immune cells and you add adenosine, you ask, well, what genes? What happens when immune cells are exposed to adenosine? What we found, the details are in the paper, are that there's eight genes that get expressed by adenosine. The immunosuppressive effect of adenosine are mediated through these eight genes, CXCL1, 2, 3, 5, 6, IL1B, IL-1 beta, PDGF2. If you express those genes in your tumor biopsy, which was expressed by 59% of the patients, 40% didn't express those genes, you are more likely to have tumor regression. That's shown by the letter, the yellow heat map on the lower left. Adenosine signature expression meant you were more likely to respond to adenosine blockade. Well, that's pretty obvious, but it wasn't obvious back then. Those are adenosine-induced things and, if you block it, of course you're more likely to respond. Right around this time, and independent of us, McDermott, the reference is down there at the bottom. McDermott et al. published in Nature Medicine, Genentech study in 400 patients with frontline renal cell cancer treated with atezo versus Sutent versus atezo Avastin. In that study, they described a myeloid signature, and if you had that myeloid signature, you did not respond to atezo. The response rate was low single digits. Terrible. Okay? Putting all that together, if you're tracking with me, it means that the adenosine signature or the presence of adenosine works against an anti-PD-1 or an anti-PD-L1, and so you wanna block the adenosine related proteins that are expressed. Now, more recently, the Sloan Kettering group, and I believe their paper's now been accepted and it's coming out in Nature Medicine also, has shown same thing, same genes. They added a couple of genes. They call it the Sloan Kettering signature now, I think. Basically the same thing. These genes are predicting resistance to PD-1s. Okay. In fact, if you looked at the clinical data, and again this is from our publication, if you were adenosine signature positive, you had a 17% ORR by RECIST confirmed versus 0%. Okay? That's pretty good, 17% versus 0 in a heavily pretreated population. Okay, now we've updated this. These are more patients. They include the patients I just described, but these are patients who have all failed PD-1s. We wanted to look at PD-1-refractory patients. On the top, you see the waterfall and the swimmers for renal cell cancer, median three priors or more failed a prior anti-PD-1 or PD-L1. Again, you can see the blue. There's some blues and there's the red. Now, these are all PD-1 refractory, so it's a little different than the waterfall I showed before. Okay. You can see the swimmer lanes. Some of those people are out there a pretty long time, two years. Metastatic renal cell cancer, that's a long time. The response rate to monotherapy, by the way, by RECIST, everybody did atezolizumab without RECIST, is 11%. Not bad in three or four prior therapies, PD-1 failures. Okay? Okay, now below, that's monotherapy. Monotherapy is great 'cause it tells you more about what you're doing. This is 80-something patients, I think. At the bottom is lung cancer. Same story, PD-L1 failures. Lung cancer, multiply recurrent lung cancer is a bad disease. I mean, renal cell cancer, you can salvage some people, but lung cancer is a different beast. I mean, second, third relapse is a really bad disease. Anyway, you can see again in the waterfall, there's some blue bars, there's some red bars. Again, these are PD-L1 failures. I think the response rate by RECIST here is for the combo 7%. You know, 11.5, 7% heavily pretreated population. You know, we think that's pretty good. It's certainly as good or better than what any other company has reported that I'm aware of. Okay, let's get back to what we're doing with CIFO. You know, we were barreling down the track of late-line renal cell cancer. That's become a very difficult space. There's several agents approved. How you do a registration trial in late-line renal cell cancer has become complicated, and frankly, I'm not sure there's a need for it. Here's what's interesting. What really changed the thinking of people in this field and why they're coming to us is the Motzer presentation, Dr. Moatsher from Sloan Kettering, presented in ASCO 2020. The updated data on CheckMate 214, which was the registration trial for frontline renal with ipi-nivo, anti-CTLA-4 and anti-PD-1. What this progression-free survival curve shows is there's a plateau. Plateaus are great in oncology because that means you have the opportunity of curing those patients. They might be cured. In fact, similar plateaus have now been seen in lung cancer. Ipi-nivo is approved for frontline lung. We've seen melanoma, of course, as well. The Kidney Cancer Research Consortium led by Eric Jonasch, who's the head of GU Oncology at MD Anderson, said, "Well, wait a second. You guys showed in 2018 that CTLA-4 is really good to combine. Why don't we add ciforadenant to ipi-nivo with the idea that we can maybe raise the PFS plateau, cure more people?" That's the idea. That's what we're doing. Now, this study has been slow to get going 'cause it's a multi-center study involving eight different academic centers, very good centers. We're now targeting July to start this. Here's the protocol design. Newly diagnosed advanced renal cell cancer, frontline therapy, a little run-in phase, ipi-nivo in the usual doses. The ipi is 1 milligram per kilogram every three weeks for four doses. That's a relatively lower dose. Plus ciforadenant continuously, around 50, 60 patients enrolled. It's an open label trial. What we're looking for, the endpoint, which we'll be able to read very quickly, is what's called deep response rate. Those are CRs and deep PRs. The MD Anderson group had shown that if you use criteria of 50% or more tumor reduction rather than the typical 30%, that correlates best with PFS, with prolonged PFS. The endpoint is deep PR/CR. That's about 30% historically. With maybe 10%-20% CR. We'll be looking for CRs in this. Really good responses. Okay? All right. Now just one more thing. Now why is CTLA-4 synergistic? We're beginning to understand that, and it makes perfect sense. When you know the biology of CTLA-4, and you think about that adenosine signature a little bit, and that's a clue, it starts to make really perfect sense. Okay, the CPI-006 admin summary. Modulate tumor immunity, enhance T-cell infiltration in tumors, that's been published. New T-cell clones in blood, that's been published. Augment efficacy to PD-1 and CTLA-4. Precise molecular target, of course, it binds the receptor selectively. It's been very well-tolerated. We've identified this very relevant and reasonable biomarker. Broad clinical applications. Obviously, we've shown you data in renal cell cancer, lung cancer, other cancers potentially. The next steps are this upfront trial in renal cell cancer with the Kidney Cancer Research Consortium. Before I open it up to questions, let me just kinda give you what we think are the three takeaways from this symposium. Number one, three clinical programs with significant anticipated near-term milestones. Second, a unique pipeline focused on the tumor immunity axis. We've been the leaders in this field. Okay, other companies are working on this. ITK, we're the only company, I think. Although I think tomorrow there'll be several others. Robust preclinical and clinical data with particularly paying attention to monotherapy and identification of the biological features. 818 data later this year. CIFO in the clinic, data will be coming on that as we enroll it. Mupa frontline, together with pembro and chemo, randomized placebo-controlled trial. Just a word about that, as you well know, in addition to dose, the front-runner program at FDA now is asking companies, "Hey, when you do all these combination trials and you have a control arm, I don't know what you're doing." We've been hearing that, and we've been saying that for years now. We're gonna be doing that in our phase two lung cancer trial, and we'll have interim data, and we'll know. We'll have a control arm that tells us whether we're having an effect. The pipeline, very well-defined targets, unique targets. Mupa's unique in its characteristics, even though there's other CD73s. ITK is certainly unique. The A2A, I think we have more data and use of our signature than anyone. I think the preclinical data and the clinical data we've generated, we have experience in a large number of patients. We've been a pioneer in this adenosine pathway. In fact, I'm giving a lecture up at adenosine meeting Thursday in Boston. I think we've been the first to show clinical activity of an ITK inhibitor in lymphomas and immune diseases. I don't know if any company's actually put an ITK inhibitor into humans. I don't think that's been done actually. If so, I think some people were interested in looking at it for autoimmunity or allergy. Finally, we've identified this marker. Okay. First of all, I wanna thank everybody for hanging in there. Your patience has been extraordinary. Maybe I can ask the other speakers to come up, and we can open it up for questions about CIFO or any other thing that's on your mind. Yes, Lee. Right here. From Cantor. I guess I have two questions on Mupa. Can you expand a little bit more on the clinical relevance of activating these cells, especially in non? You showed us B cell dynamics and T cell dynamics. Can you just put into perspective for us what does that mean? Like, why is that relevant, and how does that tie up with the tumor reduction you saw in the clinic? The question was, what is the relevance of activating B cells and expanding them in terms of, you know, clinical benefit and, you know, the-- what's gonna happen to the patient? I think that's we know that tertiary lymphoid structures are important in cancer. Pathologists will tell you that for 100 years. They predict this. We more recently know that B cell infiltration in tumors, and again, you can look up these papers, there's dozens of papers now showing that B cell infiltration in the tumor is an important prognostic factor, both for how they do the standard therapy, how patients do, and how they respond to IO therapies. And of course we know that antibodies to tumors, I think it goes without saying, have been an effective, somewhat effective way to treat cancers. I think that our part of the puzzle here is that we have a way of driving through CD69 and B-cell activation, driving these B cells into tumors and into lymph nodes, where they're gonna play a bigger role in antigen presentation and antibody formation. This is hard to do because you don't know what the antigen is in the cancer patient. We have looked for antibodies to tumor antigens in some of our patients, and we have found them. For example, anti-CEA. Okay. Or anti-PSMA, prostate membrane-specific antigen. We think we're doing that. Now, a lot of times you don't know what the antigen, so it's really hard to look for antibodies. We've not been able to do this in people because it's hard. You'd have to do really multiple biopsies to show that the B cells are getting driven in there. We have a humanized mouse model where you can cut out the lymph nodes and stuff and give mupadolimab, 'cause mupadolimab reacts with these cells in these mice, and you can see we're driving them in there. That's it. You know, direct evidence is lacking, but I would say that direct evidence is lacking that adenosine is important in cancer, in cancer response as well. I have another question on the interim analysis of the phase two. You mentioned you wanted to see a positive signal. Can you just sort of expand it on that a little bit, what that signal might look like for you? If you look at KEYNOTE-189. You want to know what a positive signal could be, right? These interim analysis are based on events, PFS. Let's look at KEYNOTE-189, the pembro pivotal trial in non-squamous. The PFS, median PFS was 8.8 months in the pembro plus chemo arm versus 5 months. There's room for improvement there. We're gonna use that as a benchmark. In addition, we have control group, the pembro. You know, as the data matures, we're gonna use those benchmarks to guide us on whether that's a positive data, encouraging data. Any other questions? Okay. This is Ted Wang, a co-founder of Angel Pharmaceuticals. First, I just want to say that it has been a great, from Angel's perspective, a great fruitful collaboration between Corvus and Angel. Those type of joint venture companies very rarely work out just because of the complications in the alignment of interest and you know the cultural differences and the personalities involved. But in this case, it can't be happier. I think the resources of the two companies pulling together and working in a very synergistic manner on clinical programs and in exploring solutions in some of the most difficult to treat patients. This is what you know Angel and Corvus is all about. It's been benefiting greatly under Richard's leadership for Angio. Thank you, Richard and the Corvus team. This really was fantastic. My question really is more about Richard and Dr. Gupta, which one of the things we're mentioning here is for T-cell lymphoma, you know, it was a very devastating chart you showed about the survival rates. The median survival rate is 5.6 months. Not only that, but also that the toxicity of those treatments is very hard to take for patients. What we have found so far is that CPI-818 has been very mild, I would say, in its side effects. The question is, from a clinician's perspective and you talking about treating a patient that is, you know, the survival is not so great. How would the quality of life for those type of patients that has, you know, refractory and relapsed T-cell lymphoma and the kind of the quality of life type of decisions coming into your treatment options and how would that guide into the key drug development and potential implications for the regulatory path in 808? Dr. Neel Gupta and Richard Miller, you can have comments. Sure. No, I really appreciate the question because this is always on our mind as clinicians. The question is what role does quality of life play into decisions about your therapeutic options for these patients? I think what's not fully captured in the slides is, I alluded to this a little bit, these are sick patients. They do not feel well. They've been heavily pre-treated, plus their disease itself is quite debilitating. This does always enter our thought process when we're thinking about romidepsin, belinostat or pralatrexate. We do it with a little bit of fear because we know they're already feeling poorly. When we give them these drugs with kind of a crossing of our fingers hoping it's gonna work, we understand that we're probably gonna make them feel even worse. To your point, these unfortunate patients don't have too much longer to live. It's actually a very challenging thing for us clinicians to put our patients through that. When you have the potential for something, you know, let's remove for just a moment the efficacy argument. If you have the potential to give something that's not going to make these patients feel worse, this is a huge deal. It's not accurately captured, you know, by any sort of paper or data that we can readily have for you. It makes all the difference in the world for a clinician and of course our patients. Thank you. Mara? Thanks. I just wanted to ask, in the CIFO study, I thought the primary endpoint there is the percent of patients who end up with a greater than 50% tumor reduction. That's in the phase two study. I'm hoping maybe we could just spend a moment on that, on that hurdle rate of greater than 50% tumor reduction, both, you know, from a trial perspective, but also clinically. You know, is there meaning in less than a 50% reduction on top of, you know, what we already see? I think the question is basically why are we picking the the so-called deep response rate criteria and what's behind that? The Sloan Kettering, sorry, the MD Anderson group had published papers that so-called deep response, which was CR plus greater than 50% shrinkage of tumor by RECIST, that was the best predictor of PFS. They like that endpoint because it's quicker. It's a lower number, and you can get a feel faster for whether your drug is doing something. In their hands, I think, I don't know, the best results are like 30%. Okay? CR and 50% greater reduction. I think in our study we're hoping to see, you know, like improvement over that. Really it's even easier than that. Really look at CRs. One of the disappointing things in immuno-oncology, frankly, with the agents we have so far, is that even though PFS curves are improved, no question, PR rates have improved, no question, CR rates have not improved that much. Okay? Now I'm a lymphoma doc, Neel's a lymphoma doc. He'll tell you that at least at Stanford, when you go in and say you got a PR, your attending throws you out. I don't want PRs, I want CRs, because CRs are potentially cures. PRs are not going to be cures. The goal is cure. From my standpoint, I'll be looking if we're making an impact on CR, I'd be very impressed. For example, if we treat the first patient, first 10 patients, and we get a couple of CRs, I'd be very excited. Now, of course, we're gonna look at overall response rate by the usual criteria, right? You're not gonna ignore the 30% criteria. That's important too. You know, 30%, 50%, you know, sometimes these measurements are not, you know, as precise as we like. In some patients, yes, it's pretty precise. Other patients, it's more difficult. As you know, you know, it drives me crazy when people get so hung up on this because, you know, it's one thing to have a 2-centimeter tumor shrink by 30%. That's really hard to even see on a CT as opposed to, you know, a 10-centimeter tumor shrinks, you know, to 6 centimeters. That's a big difference, okay? That's a lot of cell kill. The details on all this stuff are as important. That's why I did those case reports for case histories for you. Okay. When you see a big tumor like this go away in 15 days, I don't need a statistician to tell me. Okay. I need to see it. Like, gone. Patient comes in. Nothing's ever worked. I got all this chemotherapy and suddenly it's gone. That's why I've been, you know, you hear me stressing the monotherapy because I am really, really somewhat discouraged by all the R&D going on in the biotech industry where, you know, people go right to combinations. I feel they're not gonna learn anything. I feel it's actually not even fair to patients because, you know, the bargain we make when we put a patient on a study is that you're being kind enough to donate yourself for the betterment of knowledge. The burden is on us to do a study that answers a question so that even if our drug doesn't work, we can at least say, "Okay. Well, you contributed to knowledge." That's the bargain we make when we put a patient on a clinical trial, not to put them on a study that's not gonna do anything. Okay. Now, I know at Stanford, we have scientific review committee, not just a IRB. The IRB is the easy part. Scientific review committee, it has to be scientifically meritorious, right? It has to be a good question. Be a good study that's gonna give an answer to a question. That's what we're doing. You know, just doing a study and putting 20 patients like chemotherapy and PD-1 and this and that, and that's like, okay. That's not fair to the patient. It's not gonna contribute. It's not gonna get a drug approved. Frankly, I think the FDA is now reacting to that with these new initiatives. The dosing one and the, you know, Dr. Pazdur's, you know, admonishment now, "Hey, let's move this up earlier. It's ethical. It's okay." Lung cancer frontline, most of those patients still die. Okay. It's okay to give them standard treatment and add something to it. Now, you need to know a little bit about the safety of your agent before you do that. It's okay to add something to standard therapy in front line. It's even, in fact, more ethical because you're gonna get an answer that's gonna move the field, and it's gonna be better for the next group of patients. I think, you know, frankly, I think it's incumbent upon us I think that you need to be, you know, saying, "Hey, guys, what's this gonna do for us? How are you gonna know?" I know the answer you'll get is, "Oh, well, there's this paper published in 1858 that showed that standard treatment with leeches didn't work," or something like that. Obviously, I'm exaggerating, but boy, gotta be very careful if you're gonna use literature controls and stuff like that, as you all know that. Anyway, it's a very interesting time we're in now because we have a lot of cancer agents now, and a lot of agents in development. How that's all gonna be sorted out is gonna be complicated. Rest assured, it will be sorted out. One of the reasons, I mean, we're taking some bold moves. Front line lung cancer, combination with chemo, randomized trial for placebo control, okay? We'll know after 50 or 100 patients whether, you know, whether we're on the margin or whatever. BTLA for CIFO. We're looking for CRs, basically. Okay. ITK, nobody's done that. Now, rest assured, next week they'll be doing it. I have no doubt. One of the reasons that we haven't been talking much about that. So we've, you know, we're sticking to our strategy, developing novel agents, being careful on the science, being careful on what we get out of our monotherapy, putting together intelligent ways, and doing the laboratory work to justify and to give us the ideas. Also uncover new targets. All right? That's my sandbox speech today. Any other questions? Again, I wanna thank. If not, any other comments from the speakers? First of all, I wanna thank you all for your attention and hanging in there for this long two-hour session almost. Appreciate it. If you have any follow-up questions, let me or any of the speakers know or anyone else at Corvus. We do wanna, you know, keep the street more informed about what we're doing 'cause we're really excited about what we're doing. I wanna thank Dr. Wang for coming and appreciate that. If any of our angel friends are listening in at this late hour, we appreciate them as well. Thanks everyone.