Good morning, I'm Eric Joseph, Senior Biotech Analyst with JP Morgan, and our next presenting company is IGM Biosciences. Presenting on behalf of the company is CEO Fred Schwarzer. There's a Q&A after the presentation. Just wait for a microphone if you have a question, and we'll get it over to you. And for folks tuning in via webcast, feel free to submit questions clicking the icon. Okay, with that, Fred, thanks for joining us. Thanks, Eric, and, thanks very much to JP Morgan for the opportunity to present. We greatly appreciate it. So this is our forward-looking statement, disclosure. We will be making some forward-looking statements in this, presentation, and, you know, there are a whole bunch of risks out there, and things don't always work out exactly the way we hope, and so we'd like to direct you to all of the risk factors that are in our filings with the SEC to, describe some of those risks. As a big-picture overview, we believe that we are the global leaders in the development of IgM antibodies. As far as we know, we represent the only significant commercial effort anywhere in biotech or pharma that's focused on IgM antibodies, and we have a nice, we believe, nice, wholly owned pipeline of medicines in oncology and autoimmune disease, and we're gonna talk about those in a moment. And we also have a very nice worldwide collaboration with Sanofi to develop three IgM agonist antibodies in autoimmune disease and three IgM agonist antibodies in oncology. So let me start by talking a little bit. Oops! There we go. I hit the mouse, and that gotta be careful not to hit the mouse there. Let me start by talking a little bit about IgM antibodies for those of you who may be a little ways away from your immunology. There are five natural classes of antibodies, of which IgM was evolutionarily the first class of antibodies to be developed, and it's your natural line of defense against invaders, bacteria, and viruses, and so forth. And it's different from IgG antibodies, which all of the drugs that are antibody drugs approved on the market today are all IgG-based. It's different in, you see, it has 10 of those red binding domains as compared to two for an IgG, and we like to talk about it as the difference between trying to hold on to a slippery target with 10 fingers, with two hands, and trying to hold on with two fingers. We think that the 10 binding domains gives us much better binding power against targets, whether they're difficult targets, low expression targets, and we'll talk a little bit about that going forward. Also, of the five natural classes of antibodies, only two of them have that little yellow J-shaped curve there. It's called a J chain or a Joining chain. In the case of an IgM antibody, it makes it into a pentamer, and in the case of an IgA antibody, it makes it into a dimer. We also work extensively in IgA, but we're not gonna talk about that today. Our pipeline, we have three major areas of focus. The first is the Death Receptor 5 target, and our lead candidate there is aplitabart, and we're gonna talk about that in a little bit. The second major area of focus is using our T-cell engager platform in autoimmune diseases, and the first product candidate there is imvotamab, which is a CD20 x CD3 T-cell engager, and we are currently exploring that in lupus, rheumatoid arthritis, and soon to be myositis. We have a cleared IND there and just getting that study up and running now. We also are going to be exploring our CD38 x CD3 T-cell engager in autoimmune diseases, and we plan to file an IND on that later this year. And then the third major area of focus is our Sanofi collaboration. As I mentioned, it's three immunology and inflammation targets that are all agonists, similar to the death receptor five agonism program, and three oncology targets, which are also agonists. And I'll just take a moment to talk about what an agonist is. Most all of the antibodies that are approved today are antagonists, and what we mean by that is they block something else binding to the target. Agonism, more complicated. What you're trying to do with an agonist is you're trying to bind to a cell surface target and reproduce the signal that would normally be produced by the normal natural ligand to that target. In a number of targets, such as Death Receptor 5, that are members of the TNF receptor superfamily, you need to bind three of those receptors at the same time. The natural ligand will bind three of them and cross-link them. It doesn't necessarily do a great job to bind three with an IgG, where we think that with an IgM, it does. It's naturally suited to bind multiple of those cell surface targets. We'll talk about that in a moment here. So, oop, again, I bumped the mouse. Let's see if we can. There we go. So Death R eceptor 5. This, as I mentioned, is a member of the TNF receptor superfamily, and what it does is it drives the extrinsic apoptotic pathway. What that means is it tells the cell to commit suicide, and it's overexpressed on multiple tumor types. So what an incredible tumor target. You just bind this target, you initiate this pathway, and the tumor cell dies. What could be better than that? Pharma figured that out, been working on it for 20 years. And, with, as you know, not a single approved antibody to date. If you look at the left-hand side of this slide, you see what was going on for the first 10 years or so, where people were trying to do this with an IgG antibody. If you remember what I mentioned to you earlier, you need to bind three of these together and cross-link them in order to send a strong signal. That IgG doesn't necessarily do that. The second generation approach here has been multivalent approaches, and those have provided efficacy, but they've had some safety issues, and the safety issues have been around hepatotoxicity. So there is some amount of DR5 that's expressed on normal human liver cells, hepatocytes. And so some of those programs have been killed due to liver toxicity. What we've seen with an IgM antibody, as you see on the left-hand side here, a little bit of the difference between the graphic of this weak apoptotic signal and the strong apoptotic signal. More importantly is the data on the right-hand side. What we did here was we took those red binding domains from the IgG antibody that you see there, and we put those onto the IgM antibody. Just with exactly the same binding domains, we increased the potency in terms of killing by 5,000, roughly, times. Huge increase in potency with the same epitope, the same binding domain, just changing the format from an IgG to an IgM. So we wanted to try to design an IgM antibody that could do a great job of killing tumor cells, but spare those liver cells, which has been historically, as I mentioned, the problem with the multivalent approaches. We're very pleased. You can see here in the blue line that our lead candidate, aplitabart, seems to spare those human hepatocytes, where we do seem to do a really good job of killing this tumor cell line. And fortunately, in our phase I studies to date, we've seen good indications of efficacy in terms of killing tumor cells, and we've also, perhaps even more importantly, seen really very, very minimal indications of any safety issues to date, including very, very little hepatotoxic liver, liver toxicity. We're feeling very good about this, and as a result, we have taken it into a randomized clinical study to test aplitabart at 3 mg per kg, plus FOLFIRI, plus bevacizumab, most of you know it as Avastin, compared to the control arm of FOLFIRI plus bevacizumab. This is a 110-patient study. Our goal is to have it fully enrolled by the end of this quarter, and we hope to have a progression-free survival readout, which is the primary endpoint in our mind for this study, by the end of this year. Interestingly, we have a crossover component to this, so that those patients who do progress on the control arm, FOLFIRI plus bevacizumab, can receive aplitabart plus FOLFIRI plus bevacizumab. That was driven in some large extent by the fact that in our single-arm studies, we saw patients who had previously received FOLFIRI and previously progressed on FOLFIRI. When they were redosed with FOLFIRI plus aplitabart, some of those patients responded, and some had very long extended stable disease. So very excited about this study. Look forward to sharing data hopefully by the end of this year. If this works in colorectal cancer, second-line colorectal cancer, we think it has broad application. Our preclinical data indicates that Death Receptor 5 is expressed on many tumor types, both patient samples and all sorts of different types of cancer, as well as cancer cell lines. We've seen preclinically that it does well with other chemotherapies, showing synergy with other chemotherapies in addition to irinotecan. We also think it'll combine well with antibody drug conjugates. So it opens a really broad development path for us, assuming that we can establish in the randomized study the potency and efficacy of this drug candidate. So our second primary area of focus is the use of our T-cell engager platform in autoimmune disease. So we believe, and many of you have seen the interesting CAR T data around B-cell depletion using CD19 CAR Ts. And you've seen some very small numbers of patients, but you've seen some startling responses there, which we see as a really interesting proof of concept, that by depleting B-cell reservoirs deeply, that you can have a substantial impact on autoimmune disease and potentially start to actually reset the immune system. So clearly, B-cells play a very important role in many autoimmune diseases, both as producers of inflammatory cytokines in their antigen presentation role and in their role as producing autoantibodies. So the goal here is to deplete those B-cells, not just in the circulation. That's relatively easy to do, but to deplete them in the tissues, the reservoirs of those pathogenic B-cells that are present in the tissue, in the spleen, in the bone marrow, in the lymph nodes, and so forth. You've seen success of CD20 antibodies in autoimmune disease, particularly Rituxan, but it hasn't been overwhelming success. It hasn't been broadly across all autoimmune B-cell mediated autoimmune diseases. We think some of that is because the ADCC antibodies, whether it's Rituxan or the next generation, Fc-enhanced ADCC antibodies, don't seem to do a really good job of depleting in those tissue reservoirs. We know that T-cell-directed cytotoxicity is much more potent than NK cell cytotoxicity. We've seen, as I said, with the CAR Ts, that if you can deplete these B-cells in the reservoirs, that you can have a very profound impact. And so what we are doing is taking our T-cell engager into these autoimmune diseases to see if we can deplete the reservoirs deep in the tissues. We think that, you know, we stand a very good chance of being able to do that, and here's some preclinical data that would help support that. You see, on the left-hand side, you see a cartoon of the T-cell engager, in this case, killing the target cell, killing the B-cell. The CD20 is on the B-cell. On the right-hand side, more important, you see some of our preclinical data about our ability to deplete B-cells in the spleen in a cynomolgus monkey study. So we think this is a quite good indication that we may be able to be effective here. And then, in addition to being able to deplete in the reservoir, we think it's really important to be able to deplete relatively low expressing low CD20-expressing B-cells. So here you see some data indicating the impact of Rituxan on a relatively low CD20-expressing cell line. You see Rituxan loses activity, that's the ADCC activity, loses activity as that CD20 level goes down. You see an IgG bispecific does better, but you see the imvotamab, the IGM-based IgM T-cell engager, really does is much more potent against those low CD20 cells. So here are the studies that are underway or about to get underway, both in SLE, lupus, and RA. You see we have a three-cohort dose exploration model. We're using the same type of step-up dosing that we used in the non-Hodgkin's lymphoma setting, where we dosed more than 100 patients, had a very, good, relatively good safety profile compared to other CD20 x CD3s. But we know that step-up dosing can significantly reduce cytokine release syndrome. So we're, we're going to explore, doses that we think will be safe as well as effective. We're going all the way up to 600 mg just to see the level of B-cell depletion that we can see with these different doses. Then, we're also about to start a study in myositis that will be exploring one dose cohort. But obviously, the learnings that we get from SLE and RA can be transferred back into myositis if we decide that one dose seems much more impactful than another. The other thing that gives us some real encouragement with respect to the potential efficacy and safety of this product candidate in T-cell engagers in autoimmune diseases is what we saw in terms of efficacy in the non-Hodgkin's lymphoma setting. So we saw complete responses in all four major non-Hodgkin's lymphoma subtypes. So clearly, this drug is clinically active. It can kill B-cells, it can deplete B-cells, even in the lymph nodes, and even rapidly growing lymphoma cells. We also really important for autoimmune disease is the safety. I think it would be very challenging to take some of the other CD20 x CD3s into autoimmune disease with, you know, 60% CRS levels and ICANS and so forth. I think that could be quite challenging. We think in this patient population, particularly the more moderate patient population that we hope to get to with these, with these T-cell engagers, we think safety is absolutely critical, and we think we have a perhaps a best-in-class safety signal here from in our CD20. But we're not planning to stop with just a CD20 x CD3. We see this as a huge opportunity for our IGM-based T-cell engager platform. We recently announced that we will also be taking our CD38 x CD3 into autoimmune diseases later this year. We're filing an IND on that, and hopefully getting those clinical studies started this year. We're looking at other potential B-cell targets that we including CD19. On the right-hand side, you see the classic B-cell lineage chart, and you see where those targets play a role in terms of which portion of the B-cell lineage they're best suited to. You see that CD20 and CD38 provide a nice coverage of pretty much all the way across that B-cell lineage. There is truly a broad range of autoimmune diseases that we can potentially address with these T-cell engagers, depending on which mechanism of action, whether it's antigen presentation, it's autoantibodies, whether it's inflammatory cytokines, which is most important in that disease, and maybe there can be sequential uses of some of these different T-cell engagers that we have. So huge unmet need and huge opportunity in terms of scope and patient numbers. And then finally, a third area of very important focus for us is our Sanofi collaboration, and that was a very attractive collaboration that we did with Sanofi. Their hypothesis was that an IgM antibody can do a much better job of agonizing targets than an IgG antibody can. And so we are exploring that with three autoimmune targets and three oncology targets, and hope to have... We do not have control over the disclosure of those targets or the disclosure of progress, but we certainly feel very good about the way the collaboration is going, and we hope at some point in the not-too-distant future, we'll have some things that we will be able to discuss. And that's about it. All right. Well, great. Thanks, Fred. And again, if you have questions, just we'll get a mic over to you. But maybe just to start out, picking up on aplitabart, the DR5 agonist. Yeah. I think I'll stick with that. It's a little easier for me. In second line, plus CRC, can you talk a little bit about what benefit in PFS you powered the study to detect, and ultimately, sort of what level of benefit would be compelling to patients and physicians? I think those are probably the same level. So, True. So what we would expect in the control arm here is that we would see a PFS, on the basis of historical controls, we'd see a PFS of about six months, and we would certainly hope that we would see an increase in that PFS of more than 20% in order to be something significant here. As you saw in our single-arm data, without bevacizumab, the historical control is about two months of PFS, and we showed in our non-bev arm that we had 5.6 months of median PFS. So I think that's supportive that we hope we'll see a significant increase PFS. I don't think we're necessarily expecting that we're gonna double PFS, but we hope that it's enough, that it is clinically meaningful, and we have powered the study to show something that... You're anticipating full accrual later this quarter. Can you just talk about sort of the line of sight you have to that, and how confident you are and, kind of, in that timeline? I guess, if we're fast-forwarding with sort of the expected PFS, I guess, with standard of care, your comparator, is it fair to think about a top-line readout here in the first half of next year? It certainly yes to the latter question. You know, finishing up by the end of the quarter is certainly our goal. We've got a lot of sites, international sites. I think we've publicly disclosed in clinicaltrials.gov that we're already at 47 sites, something like that. We certainly can't guarantee we'll hit that goal, but I feel pretty confident that if we don't hit it, we won't miss it by that much. That's gonna make a difference in whether we can have a PFS readout towards the end of this year. In the current phase II trial, you are excluding patients that have seen prior FOLFIRI, if— That's correct. I got that correctly. At the— But also kind of offering in the crossover arm, right, upon progression, you essentially will be looking at activity in a FOLFIRI experienced population, right? So again, you're kind of generating data in that field. And so, can you just talk a little bit about sort of ultimately what treatment setting I think you'd want to tackle as part of the next step phases of development, provided the phase II data warrant it? Yeah. I think that we would go straight... Well, first of all, there's potential for this study to provide the basis for accelerated approval in this patient cohort, the FOLFIRI-naïve second-line CRC. The study does provide for. Even though it's an open label study, it does provide for blinded reads of the radiographic scans, if that's what's appropriate. I would think that we would probably, assuming that we've got the signal we're hoping for here, we would probably go forward first in this second-line FOLFIRI-naïve patient population. I think there's a lot of opportunity to move into earlier lines of treatment, perhaps, and certainly, we've shown in our single-arm study that we can have impact in third and fourth-line patients who have received FOLFIRI previously. But in terms of the straightforward regulatory path, I think it would be sort of completing what we started here, just going down the same path. Just thinking about the requirements for full approval in this indication and the extent to which overall survival is a pivotal endpoint. I guess that factor might be somewhat confounded by the crossover element, or is that— Yes. —the case? Yeah? case? Yeah? It might be... You know, it's challenging to calculate overall survival with a crossover. I don't think even if we have an accelerated approval here, there would still be a, probably a confirmatory study that we would be running, and that study would look more like your classic, randomized phase III sort of study. So I think, yes, we will have to get overall survival. We don't necessarily expect that this is the last study we're ever gonna run in second-line colorectal cancer. Makes a lot of sense. Okay. All right. Maybe any questions? All right. Maybe just shifting to imvotamab in autoimmune. Feels like there's another, you know, CAR-T autoimmune program announced every week or every month or something like that. You guys are different with the T-cell engager approach. That being said, there's a fair number of programs in that realm as well. Maybe I could just sort of have you make the contrast and what you see as the clinical advantages with the T-cell engager approach over CAR-T in autoimmune. Sure. I'm happy to talk about that, and I think that as I mentioned, we think CAR-T is a great proof of concept, that what you can do with really deep B-cell depletion. We're not sure that's gonna be commercially viable for anyone other than the most severe patients. You're talking about, you know, complete lymphodepletion, a couple weeks of hospitalization, you know, all the time to make the CAR-T. It's just gonna be hard, I think, to move that very far down into the patient population in autoimmune disease, where we... And, of course, the retreatment, if you know, the disease starts to come back, it's, you know... I think it's gonna be challenging to go get insurance approval for a second CAR-T to come along, leave aside the challenge to get the first approval. So we think that a drug that's in a bottle, that can be dosed quickly and easily, and in an outpatient setting. I should emphasize that our clinical trial is all outpatient here with this T-cell engager because of the safety profile we've established in NHL. So we think that has great advantages in terms of cost, patient convenience, the ability to redose. Just commercially, it should be just much more successful in going further into the patient populations. In terms of T-cell engagers, the only other T-cell engager that we're aware of now that's actually in the clinic for autoimmune disease is the mosunetuzumab, the Roche molecule, the safer of their two molecules, and that's in SLE. But we're not aware of anyone else. Now, that doesn't mean that everyone else isn't talking about going there, but we're not aware of it right now. Okay. All right. Maybe just kind of talk us through the selection process behind the three indications that you've chosen to pursue under IND. Sure. Do we have IND clearance? Yeah. So, very multifactorial decision process. I think the first one that's probably relatively easy to explain is lupus. I mean, you've got the success of the CD19 and the other CAR-Ts in lupus, so it's pretty easy to say, "Well, let's benchmark against that and see how does a T cell engager look in that place where we know you can have efficacy?" Rheumatoid arthritis, different disease. It's a disease where we know Rituxan is approved, where you know a CD20 can have impact. Let's see if a more potent CD20 can have more impact. Also, you know, very well-studied disease with a lot of biomarkers that we can look at to see whether we're having impact. Whether we would, you know, go into a broad development program in RA, that's probably another not the decision we're making today. Today, we're making the decision, where can we find a signal that will indicate where we can, where we can go further, and help us decide where to go further? Myositis, place where antigen presentation plays a real role, and also you've got a very nice skin readout there. You can do some biopsies to see what you you know, what impact you're really having. So, they were chosen primarily with the sense of, where can we get a signal, more than what's our ultimate development path gonna be. Okay. Okay. And just in terms of the therapeutic window of imvotamab in autoimmune compared to oncology indications, where you have previously explored the molecule. Can you talk a little bit about sort of, yeah, I guess, the what an acceptable tolerability profile, or, y eah, would be, and then also sort of what experience either, you know, non-clinical or clinical informs the step-up dosing scheme that you are undertaking in the lupus and the RA trial? So I think that what we've seen. So a huge amount of what we've learned in non-Hodgkin's lymphoma, we're taking into autoimmune diseases in terms of step-up dosing. Obviously, different disease, different tumor burden. One of the first things we wanted to try to make sure was that we would not have a more challenging safety profile in autoimmune disease because of the you know, immunologic profile of these patients. And so we did quite a bit of preclinical work with patient samples and so forth, and we got quite comfortable that probably not gonna have a worse result from a safety standpoint in these autoimmune patients than you do in non-Hodgkin's lymphoma patients. A lot of folks would say, "Well, that's obvious. The tumor burden is low, you know, the cell burden is lower," and so forth. But we wanted to be safe and check, and so we did, and it looks pretty good in terms. We did not see anything that caused us to believe this was going to be more challenging from a safety standpoint than non-Hodgkin's lymphoma. I think all of the industry has learned over the oncology experiences that step-up dosing is pretty important for cytokine release syndrome and the safety of these T-cell engagers. Now, there's a little bit of empirical study that we're doing here. You can see. You've seen the dosing. We're starting with different doses, both different starting doses, different top doses. Our primary goal here is to make sure that we don't see a safety signal at all, and that we go slow and make sure that this, the safety profile we're hoping for, is here. We'll have to empirically learn, you know, is there any safety issue here, and what is the right dose for this tissue depletion? What's the optimal level of B-cell depletion you want to achieve in these? And is it the same in these different indications? Yeah. I think the answer is we don't know on both of those. I think probably there's a pretty good indication that more is better than less in terms of impacting these diseases, but you probably don't need to get to 100%. I mean, you've certainly seen with FcRNs and so forth, that if you make a meaningful impact, you can make a meaningful... On the levels, you can make a meaningful impact on the disease. I have every reason to believe that's probably gonna be the same case here, that you can have an impact on the disease even without 100% depletion, and you can go back and redose. We see this as that's one of the huge advantages of the in-the-vial drug, is you can go back and redose. If this patient needs a little more, you can give them a little more. Right. Okay, okay. I guess, I guess part of my reason for asking the question whether there's a risk of overshooting, you know, going too low in terms of depletion? Oh, too low? I don't know. If that's, if that's something you'd want to comment on. Well, I think that's a hypothetical concern that people have been—have raised. We think that our half-life here actually is an advantage because we think we will get reconstitution of the B-cell, the B-cells relatively quickly. This is not gonna have a six-month half-life that's gonna, you know, a pre-B, a CD19 pre-B comes along, it's not gonna knock it out when it, as soon as it converts to a CD20 expressing cell. We think we can get a reconstitution pretty quickly. Great point. Yeah. Great point. And maybe just talk a little bit lastly about sort of enrollment progress in these trials, the level of physician enthusiasm since the trials have gotten underway. What we found, you know, is a lot of enthusiasm. These are now global studies, both the US and elsewhere, Europe and Asia, and we found a lot of interest in joining these studies. And interestingly enough, in some of the sites that we have that have both the CAR T and the T-cell engager, we're hearing back from the investigators that, wow, it's a whole lot easier to dose a T-cell engager than it is to hospitalize somebody and lymphodeplete them, and so forth. Who knew? I think the market is feeding back to us through, as you often learn in clinical trials, what investigators think is a, you know, easier drug to use. Okay. All right. Any questions from the audience? Okay, great. I think we're gonna leave it there for time then. Thanks very much, Fred. Thank you. Thanks, everybody, for tuning into the session. Thanks, Eric.