All right, good morning, everyone, and thanks for joining us on day three at the Morgan Stanley Healthcare Conference. I'm Mike Gold, one of the biotech analysts here, and it's my pleasure to introduce Fred Schwarzer, CEO of IGM Biosciences. Just a reminder, the format for today is fireside chat. But before we get started, I just need to read a quick disclosure. "For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative." And with that, Fred, thanks for joining us today, and maybe I'll just turn it over to you to give us some brief background on IGM, and then we can get into some Q&A. Great. Well, thanks, Mike. I really appreciate the opportunity to present here, and great to see you again, as always. For those who are not familiar with IGM Biosciences, I guess our name says it all. What we do is IgM antibodies, and to the best of our knowledge, we still represent the only significant commercial effort anywhere in biotech or pharma on IgM antibodies, which remains remarkable to me, 13 years later, that we're still the only people making IgMs. Which, you know, sort of raises the question, well, how come? How come you're the only people bothering— Right. To do this crazy stuff? I, I think that's a, that's a much longer question than we have time for today. Right. So maybe I'll, I'll talk a little bit about why we. That, that involves all sorts of corporate strategic planning and so forth, so we'll leave that question. But in terms of why we're doing IgM antibodies, why do we think it makes sense, let me take you back to your basic immunology. IgMs are one of the five natural classes of human antibodies. They were evolutionarily the first antibody developed, and their primary function has been to protect you against invading bacteria and viruses, which, you know, evolutionarily, that makes a lot of sense. That was what was gonna kill people, you know, real fast. A lot faster than cancer was gonna kill people. So, this antibody was evolutionarily developed to protect you against viruses and bacteria. Now, the way it does that is it has 10 binding domains, as compared to the 2 binding domains of an IgG antibody that represents the rest of the, commercial market, or all the commercial market, basically. And what those 10 binding domains allow you to do is bind to viruses and bacteria while you have relatively low affinity and relatively low specificity, because your body obviously doesn't know what virus or bacteria is going to attack it, but it has to be able to neutralize every virus and bacteria. And so you can't have an affinity-matured IgG, ready on demand when the next virus hits you. So what we've done is we've taken the natural advantages of the IgM antibody, which is those 10 binding domains, and we've swapped in the high affinity, high specificity binding domains of an affinity-matured IgG, so that we now get the benefit of the massive avidity of the 10 binding domains, together with the affinity and specificity of IgG. So we think it's, you know, a little bit the best of both worlds. And we think it's, it's really good at a number of things. First, we think it's really good at cross-linking cell surface receptors that need to be cross-linked. So our lead program now is a Death Receptor 5 program. Death Receptor 5 is a member of the TNF receptor superfamily. Those need to be trimerized. The natural ligand trimerizes them in order to send a signal. An IgG, with its two binding domains, doesn't do a particularly great job of trimerizing, where an IgM can do a really excellent job of trimerizing. So that's one inherent advantage of IgM antibodies. Another inherent advantage of IgM antibodies is you can use that affinity and avidity, the massive binding power, to bind to relatively low expression level cell surface targets, and that's really important in oncology applications, particularly where some of these tumor antigens or the antigens that you want to hit may be relatively low in expression level. And so we think we can do a much better job of binding to low expression level tumor antigens than an IgG. Now, we can also flip that on its head. So you know that in the solid tumor space, the primary issue, or an important issue, is very few of these solid tumor targets are pure tumor-only targets. There's some low level of expression on normal tissue, and the challenge is, how do you make sure you hit the tumor and not hit the normal tissue? Obviously, it's more highly expressed on the tumor, or else it wouldn't be a target at all what we can do is we can detune the affinity of those individual binding domains, but we retain the power to bind where there's a high level expression with the avidity of all of the 10 binding domains. So we believe we can do a much better job of separating tumor from normal, as well as a better job of hitting those very low expression tumor targets. And then the final thing, I think it provides us a real advantage, is the ability to create a completely different kind of bispecific antibody. So we have a bispecific antibody that's one binding domain to the T- cell CD3, 10 binding domains to the tumor target. We think that that gives you a more natural physiological kind of T- cell activation, which we think leads to, you know, our CD20 by CD3 seem to have the best-in-class safety profile in terms of cytokine release syndrome. We think that that's a function of that format, the one to ten. Now, we're taking that format to a new level now. We've now added to—w e put the CD3 on what's called the J chain or the joining chain, which is what? It's a little protein that makes the IgM into a pentamer. It like takes one—i f you think of an IgM as a six-slice pizza, the J chain is one of those slices, and the other five are the binding domains. So our first generation had one CD3 binder on the J chain. Our second generation, that we're very excited about, has two binding domains to the T- cell, one that binds to CD3 and one that binds to CD28. And we think that that gives us two real significant advantages: one, more avidity, two binding domains versus one to the T- cell, but probably more importantly, a co-stimulatory signal. So not only do you get the CD3 signaling through the TCR, but you also get the CD28 signaling. And our preclinical data there are very, very exciting to me, and in terms of T-c ell proliferation, T- cell activation and we're really looking forward to taking that forward into the clinic in solid tumors is where the biggest need is. Yep. Maybe just to follow up on that, what are the tumor targets, or have you shared those yet, I guess? We haven't shared those yet. Okay. But I think that it's probably fair to say that we don't have to go after completely unproven novel targets. Yep. We can go after targets that are clearly on tumors, and these are what our Chief Scientific Officer likes to call a dumb target. It doesn't have to be a target that is creating an activity. It just has to be present on the tumor. What it does is a little bit irrelevant ' cause you're just using it as a hitching post to bind up the T- cell together with the tumor cell. So there are so many potential targets that we won't run out of solid tumor targets anytime soon. Yeah. It'll keep you busy, that's for sure. A long time. A long time. All right, great. Maybe we can go to your lead program, aplitabart, that's your DR5. You talked about the advantage of the multi-cross linking in this situation, so—b ut maybe talk a little bit about the development strategy. You've shown some encouraging phase I data and sort of picked a development path. Maybe just walk us through some of that. Yeah. T he data and why you went that direction, et cetera. Well, we're very encouraged by the progression-free survival data that we saw in the single-arm study to date. We're very encouraged by that. That caused us to go into a randomized study, randomizing aplitabart against, Well, FOLFIRI plus bevacizumab, which is standard of care in second-line colorectal cancer, and we're randomizing 8444 you know, plus and minus. We also have an interesting crossover design here. So we were quite encouraged by what we saw in the single-arm study for those patients who had previously received FOLFIRI. So almost all of our patients had previously received FOLFIRI. Despite the fact that they had previously received FOLFIRI, you know, a number of those patients had responses and, as we've shown, majority of those patients actually wound up spending more time or having longer progression-free survival on IGM-8444 plus FOLFIRI than they did the first time around with FOLFIRI, which is completely flipped from what you would expect. Normally, if you redose with a chemo like FOLFIRI, you get nothing or very little. Yeah. So that led us to say: Are we sensitizing the FOLFIRI, are we reinvigorating FOLFIRI here with 8444? And so we wanted to test that as well in this, in this randomized study. So, a patient in the control arm who progresses on FOLFIRI plus bev can be immediately crossed over into the drug arm and receive FOLFIRI plus bev plus 8444. So that's the only real twist. Otherwise, it's a straightforward, randomized, plus and minus, against standard of care. We think the endpoint that is important is progression-free survival. We think that that endpoint could conceivably lead to accelerated approval if the, if the, data look, compelling enough. Yep. Can you maybe talk about progression-free survival in terms of the the control arm and what's sort of the expectation there? Yeah. Maybe also tell us what you saw in the phase one that kind of gave you confidence that you can, you know, do better than that? Yep, absolutely. So what we saw in the—l et me start with that. Sure. What we saw in the phase one, in the arm of our study, we started without adding Avastin bevacizumab to FOLFIRI. We started with an arm that was just FOLFIRI alone, plus 8444. Recent data at ASCO GI confirms that progression-free survival in that—I mean, it was different. It was LONSURF, so it's not exactly the same, but confirmed in third line that without bevacizumab, progression-free survival is 2 months. We had a—this was a median third-line patient group, a lot of fourth-line patients as well. What we saw was median progression-free survival of 5.6 months, so more than double what you would expect to see in that cohort. Now, obviously, not a huge. It was only 24 patients and, you know, lots of questions. That's why we're doing the randomized study, is to confirm it. But quite—we've, we felt quite encouraged by that increase in what was normally expected to see in this cohort of patients. Yep, makes sense. And then, what we would expect in the control arm in second line. Yep. Now, we're moving to second-line, and that's because standard of care in second-line is FOLFIRI plus bevacizumab. That's not third-line standard of care. Third-line is LONSURF and so forth. We would, on the basis of historical data, we would expect approximately six months in the control arm there of PFS, and obviously, we're hoping to do, you know, significantly better than six months. Yep. So the study is set up with 110 patients, randomized 1: 1 with this crossover that we talked about. We hope to have the study fully enrolled by the end of the first quarter, and we hope to have PFS read by the end of next year. So we're very excited about this. It's going to be great to see in a randomized study, you know, to confirm the signal and to see what to quantitate the signal as well. Yep. Get some sort of sense of what we see in terms of— The— Increase in PFS. So the primary endpoint is PFS. Yeah. W hat about response rates, and can we see that sooner, or will we? Yeah, I mean, response rate is not historically well correlated w ith PFS in colorectal cancer, and you've seen that over a number of studies that it doesn't. So yes, I mean, I think we'll probably see an improvement in response rate, but I'm not, I'm not sure that that's gonna matter as much. Yep. I'm gonna be focused on do we have the PFS improvement because that's what's gonna get us the approval. PFS seems to be well, reasonably well correlated with OS in this case. Yep. So, which is the ultimate final approval endpoint will be OS. Yep. So in terms of timelines, again, complete enrollment by the end of this year, PFS data by the end of next year. Is that how to think about it? Complete enrollment by the end of the first quarter of next year. Okay. Yep. And then hopefully PFS by the end of the year. Okay. Gotcha. Give or take depending on how long it takes to get median PFS. Right. Yep, makes sense. Maybe just talk about dosing a little bit, the 3 mg/kg versus 10, and your, your thinking there. Yeah. So we wanted to get a signal as fast as we could, a definitive signal on how does 3 mg/ kg look in terms of PFS in a randomized fashion? And so that's why we're pushing forward with the three. At the same time, we are also currently dosing patients with 10 milligrams in the single arm study, in expansion of the single-arm study. And so we will get data over this year and early next year as to how does 10 mg/ kg look in the same cohort of patients. It's gonna be all third-line and fourth-line patients. It's gonna look like the cohort from the single-arm study. It's not gonna be second-line patients, but we'll see how does that look relative to 3 mg/ kg. If it looks just a whole lot better, well, then it's easy for us to put a 10 mg/ kg arm into the randomized study. I think once, if we've got data that shows that 3 mg/ kg has a significant impact on PFS, we're all gonna be very happy, and then we'll figure out whether 10 looks better or 10 looks the same. But for right now, the intention is we're pleased with the signal we're seeing with 3 mg/kg. We think 3 mg/kg is, hopefully, gonna show a positive signal in this randomized study, and we're not sure that 10 mg is gonna be that much better than 3, but we'll find out. We'll know by, you know w e'll get a sense by early next year. Yep. Can you also maybe talk about safety and, in particular, liver toxicity? 'Cause this has been an issue with other DR5, but you guys don't seem to be seeing that. I guess, any thoughts on mechanistically why that could be? Yeah, we're spending a lot of time trying to figure out mechanistically. We saw this pre-clinically before we went into the clinic, and we selected 8444 specifically for that safety profile because historically, liver tox has been the issue that has killed a lot of programs here, including Genmab's program, and so it's, it's been, it's been a big issue. Yep. So we selected a molecule that we thought was gonna be safe, but we didn't know. But when we went into the clinic, it seems to be—we seem to have no liver tox signal, and it seems very—it seems to have a very safe profile from a liver tox standpoint. We think, as we've continued to do research after, through this period, we've learned that there are different epitopes on DR5, and there are actually different conformations of DR5. There's an inactive conformation and an active conformation, and it appears that, that which epitope you bind has an impact, but also we think that the structure of the IgM may have an impact in terms of creating. T he IgM creates a very structured clustering of DR5 because it's a relatively rigid you know, it has disulfide bonds around the ring, and it when it sets down on a cell, it adopts what we call a crouching or crab position. It sort of compresses in a little bit, and so this is the structure that you're gonna get of the DR5 clustering. Where if you've got some other antibodies that maybe don't have that fixed structure, you can create a little bit of a polymeric mesh across the surface of the cell, and perhaps that is related to the liver toxicity. There's also a kinetic aspect to it that what we see is 8444 creates these clusters a little more slowly because it, it, it binds to the epitope that's in the inactive, you know, the, the. It does not bind to the epitope that's in the inactive form, only in the active form of DR5, so it maybe takes a little longer to cluster, and that kinetic seems to give the normal, healthy liver cells more time to upregulate their survival pathways. But we're busy doing a lot of basic science right now, trying to figure out DR5 and all of this mechanism, and there'll be much more intelligent people talking about this at various AACR and other presentations, so I probably just messed it up. That's okay. Why don't we shift to imvotamab? You made the decision to sort of prioritize autoimmune disease earlier this year. Maybe talk a little bit about, you know, what drove that decision, kind of what data you're seeing so far, and maybe what direction you're heading in, when we might see data, et cetera. Yeah. It was a really easy decision. We looked at the DLBCL space, and boy, it feels really crowded right now. We were behind where some of the other bispecific molecules were in terms of clinical development and approval pathway. So we were, we were definitely behind, and it looked like it's gonna be very crowded. But what we saw is that we seemed to have the best safety profile of any of those molecules. We thought about B-cell depletion, and we thought about the Georg Schett data about using a CD19 CAR- T and creating some really interesting results by deep B-cell depletion in lupus. And it seemed to us that safety was gonna be critical in the autoimmune space, that it's probably, autoimmune docs are probably not gonna tolerate 60% CRS and, a lot of ICANS and so forth. But we think that we have a safety profile that could be quite tolerable in autoimmune disease, and we're quite hopeful that we can achieve a level of B-cell depletion that is sufficient to start to address the underlying pathology of some of these diseases. Maybe if we can get rid of these pathogenic B-cell clones, that we may be able to have some lasting impact on disease, these diseases. So, and the market sizes are huge there. You've seen, we've announced that we're starting with both lupus, SLE, and rheumatoid arthritis. Now, those are places that are important proofs of concept for us. But if we can show that B-cell depletion using a T-cell engager can have a significant impact on disease, then there are dozens of diseases that are mediated by pathogenic B- cells. We think that can be really broadly, broadly applicable. We think we can be leaders in the T-cell engager space for autoimmune disease, and we're not necessarily gonna stop with a CD20 by CD3. We've also got a CD38 by CD3, which can go to a different portion of the B-cell lineage. We're working on a CD19 by CD3, again, a different portion of the B-cell lineage. And we've, you know, got the two signal version of a T-cell engager as well, if we decide that we need more potency. So we see this as a real franchise opportunity broadly. Yep. You, you're starting phase I studies. Assuming you see some positive results there, how do you manage—y ou know, it'll give you your proof of concept, and you just mentioned broad opportunity. How do you, how do you manage that, or how do you think about it? Do you, do you partner specific indications? Do you partner specific molecules or, or just talk, talk to us about that. Yeah, those are really good questions. It is. I don't know. Yep. I don't know the answer to those questions. Yep. I think we see it as a broad platform, and it may be that certainly eventually, it would probably be a good idea. It's such a broad platform it'd be a good idea to have a partner on some or, or even broadly across that platform. So those are, those are discussions that we expect we'll be having over the course of the next, the next months as we, as we start to generate some initial data here. Yep. And maybe we can just keep with the theme of partnerships. You have a partnership with Sanofi, so maybe just in the last few minutes here, if you just remind us the structure of that partnership, where it's focused, and, and when can we see some updates there? Yeah. It's a preclinical partnership. It's focused on three oncology targets, three autoimmune targets. They're all the similar in that they're all agonist targets. It's all using an IgM to hopefully be a significantly better agonist than an IgG. And that's related to what I talked about with DR5. As you cross-link more cell surface receptors, certainly with the right receptors, you will get a stronger signal with more cross-linking than you will with just an IgG. And that was what Sanofi was interested in, was the ability of an IgM to be a stronger agonist. We're very pleased with the way that partnership is going. We're very encouraged. We don't have the ability to say much about anything about that partnership, other than we're pleased and we're encouraged, and t hat's about all I can say I'm afraid. Got it. No problem. We're just about out of time, so why don't we wrap it up there? Thanks so much, Fred. Appreciate your time today. Thank you. Appreciate the conversation.