All right. Good afternoon, everyone. Welcome to Jefferies 2024 Global Healthcare Conference. My name is Roger Song, one of the senior analysts covers mid-cap biotech in the US. It's my pleasure to have the fireside chat with IGM Biosciences CEO Fred. So let's. I know we have a lot to cover in terms of your IgM platform, in terms of 8444, in CRC, and then most exciting thing is the autoimmune CD20/CD3. But before that, maybe Fred, if you can highlight what are the recent updates, and then as a kind of intro remark, that would be appreciated. Sure. Well, and thanks very much for having me, Roger. Really appreciate the opportunity. I think probably the two most significant recent updates, we have just announced that we completed enrollment in May in our randomized study of aplitabart, and we over-enrolled. Our target was 110 patients, and we enrolled 127 patients, which we think is a sign of the investigator excitement about what we're doing here and the potential of this drug. And I think the other interesting update is that we've completed enrollment in the first dose cohort of our rheumatoid arthritis study using imvotamab there. So we feel like we're making really good clinical progress on both of our lead programs, and looking forward to data being generated towards the end of this year or early next year on both of those programs. Excellent, excellent. Now, maybe we stay on the aplitabart for a moment because that's your lead program, and then you have more clinical data, and then update is upcoming as well. So you say you closed the enrollment for the second line mCRC randomized trial, understanding it's an open-label study. I believe you are predicting the PFS data readout, interim data readout, gonna be 1Q next year. So tell us a little bit how you make that prediction, and then what, what it, what you wanna see in the interim. Yeah. Obviously, we don't know for sure. At this point, it's just a question of when do the events take place, and that's, that's out of our control. It's our expectation that it would be no later than the end of the first quarter next year. But, it's gonna depend on what is the median PFS on the, both the control arm and the median PFS on the drug arm. So. Yeah W e don't know, is the short answer, I guess. Yeah. But at least from the historical, because you are randomized to FOLFIRI combo versus FOLFIRI, so that's the, you know, expectation for the control arm is this, and then, you know. Right C onsidering the combo. The expectation for the control arm, based on historical standards, is about six months median PFS. Obviously, we hope we're gonna do better than that on the, on the drug arm. Yeah. Awesome. And then my understanding is this is interim PFS, but it's a PFS at the randomized trial. It's a potential if the data is robust, that you can, you know, file for accelerated approval based on the study. Tell us how you know what you have been aligned with the FDA, what makes you feel this may be sufficient to file for accelerated approval to registration? Sure. A couple things. One, we believe that PFS will be the standard for final approval, even on a pivotal study, and so we'd be talking about PFS here on this initial randomized study, hopefully signaling what PFS on the final study is going to look like for the final approval. Now, if we see a significant signal there, then it's our hope that the FDA would consider that for accelerated approval. Of course, under the current set of, particularly since the data are randomized, under the current, FDA positions, we'd also have to have the pivotal study, if not fully enrolled, substantially enrolled, I believe is the way they phrased that. So we're expecting that we will do a pivotal study here under any circumstances. The question will be, when we get that pivotal study mostly enrolled, will we be able to get accelerated approval there or not? I think in terms of big picture, it probably doesn't make that much difference in the sense that the PFS here is gonna be reasonably short. So once you've got that, pivotal study fully enrolled, you're probably looking at a readout in, you know. N ine months. Yeah, just not that much further than the accelerated approval. I see. I see. Yeah. So and then, in terms of the accelerated approval pathway, what kind of PFS signal potentially can support that? And then, how confident you are the PFS will be the registrational endpoint or primary endpoint for the approval, both for the accelerated and the full, versus the overall survival? We're feeling pretty confident, and obviously, we need to have a full discussion with the FDA, but we're feeling pretty confident that PFS will be acceptable for final approval. I think that our goal here is to see something that's clinically meaningful, and so, you know, we'd wanna see at least a 20% improvement in PFS over what you see in the control arm. Hopefully we'll do better than that, but hopefully it is at least 20%. We think that that's probably a, you know, an approvable endpoint somewhere in that range. Got it. Got it. So do you think this 20% is supporting the accelerated approval, or that's something for the final approval, kind of threshold? Well, I think the standard for accelerated approval is probably a little bit higher than the standard for final approval, so I don't know exactly what accelerated approval standard would be. I think it will depend on, you know, hazard ratio and a variety of other things. As you know, we've also got a crossover arm in the current study that we're running. You know, it's possible that we'll see some really intriguing data there in that crossover arm, which could help support the overall story that the drug is really making a difference for folks. So maybe that, in combination with the PFS data, would be helpful for accelerated approval. But again, that'll be a sort of facts and circumstances at the time, and from a strategic perspective, we're really not that focused on accelerated approval as opposed to the final solid approval, particularly in light of the IRA and the number of years and so forth. I think the, you know, the final approval is what we really are concerned about here. Yeah. Yeah, and particularly as you mentioned, you need a substantial enrollment anyway for the approval. Exactly. Even for the accelerated approval, it not gonna change much. It's not gonna change that much. T he timeline. Exactly. Got it. Okay, and then also, this current regimen is 3 mg per kg for the 8444 in the potential registrational study. You're also running a single-arm third-plus line for the 10 mg per kg. So where, where is that regimen? And then, if at all, you will incorporate into the pivotal kind of analysis. Right. We recently announced that we're fully enrolled with that arm of 10 mgs per kg with FOLFIRI plus Bev with 22 patients. We expect that we would see the. That's primarily a third line set of patients. Yep. So we expect that we would see a readout on that towards the end of this year, again, the beginning of next year, very much in line with when we expect to see the readout on the randomized study. So we think that those two pieces of data come together at exactly the right time. Mm-hmm. And how, if at all, you will incorporate that into just, you know, if, well, FDA were looking at those both kind of regimen to say you have to, you know, incorporate that, you know, in the randomized setting for 10 or this 10 is really satisfy this kind of Project Optimus in terms of dose ranging? We hope that the 10 data that we generate here will satisfy Project Optimus. You know, I think the underlying motivation or much of the underlying motivation for Project Optimus is focused on safety as opposed to efficacy, and so our current expectation is we're taking the lower dose forward, not the higher dose, and so I would think that the FDA will be receptive to us taking the lower dose forward into the pivotal study without running the higher dose, unless. Right O ur data indicates that the higher dose is gonna be just substantially more efficacious, and I think that that's not our current expectation. I think when you go with higher doses, you've got longer infusion times, you have time, you know, possibility of more infusion reactions. So I think on balance, I'm hopeful that we'll be able to convince the FDA. Well, assuming that the 10 mg data are not substantially better than the 3 mg data, I'm hopeful we'll be able to convince the FDA that we don't need to test the 10 mgs in the pivotal study. Got it. Particularly if your 3 mg per kg is efficacious. Exactly A nd then how you gonna, you know, 10 mg not gonna be beat that 3 mg too much, right? By too much margin. Right. Exactly, and it, yes, that's our expectation, that it just isn't gonna be enough to make it convincing that we, well, and to be clear, if it was that much better, then we would probably want to do something. Yeah W ith the 10 mg. We wanna, yeah. You don't wanna leave the efficacy on the table. You don't wanna leave significant efficacy on the table. Right. Exactly. Right. Got it. Got it. Okay, I really wanna move into the CD20, CD3, because that's literally dominant the conversation I have with the investors about the IgMs, so make sure we spend enough time on this. To set this up, how imvotamab CD20, CD3 IgM therapeutics bispecific designed to be maybe more suitable or suited for the autoimmune disease, compared to IgG4, maybe CD19 IgG form or some other, you know, kind of therapeutics in development for autoimmune disease? Sure. Well, let me address the CD20 aspect of it first. Yeah A nd then maybe we'll go to the CD19, because. Yep 19 versus 20 seems to be a top-of-mind question for a lot of investors. Yep. So relative to IgG forms of CD20 x CD3, and I would remind everyone that when almost all companies looked at this question of how are you going to create a T-cell engager in non-Hodgkin's lymphoma? And they thought about the question of, do you do CD20 or do you do CD19? virtually everybody, even though Blincyto at that point was the only T-cell engager approved for leukemia, everyone made the decision that 20 is a better target than 19 for. That's right. Mm-hmm. Mm-hmm. And I think they made that decision for a few reasons. One, certainly the safety profile of Blincyto was not particularly attractive, and there was some significant neurotoxicity there, and there have been questions about, is that CD19 related as opposed to CD20 related? Leaving that aside, the other issue for CD19 as a T-cell engager, as opposed to CD20, is CD19 is much more quickly internalized than CD20. CD20 is a four-pass membrane receptor, so it hangs around on the surface significantly longer, and also you are seeing antigenic loss, much more downregulation of CD19 than. Tend to see with respect to CD20. So we think it's a. CD20's a really good target. If we compare that to the other CD20s that are out there, the IgG CD20 T cell engagers. A number of those, if you think about glofitamab, and epcoritamab, and you think about the Regeneron molecule, those have had pretty high CRS rates that are somewhere in that 60% range, and they've had some ICANS and so forth. So we think those are probably not well suited to autoimmune applications. With respect to mosunetuzumab, which is the one that the CD20 that's the closest to us, we believe in safety. Roche has taken that into a study in SLE. Not clear exactly how committed they are to that approach. But in terms of why do we think an IgM can do better, with the avidity of the IgM, the 10 binding domains, we think we can do a better job, and we've shown this preclinically, we can do a better job of binding and killing and depleting low CD20 cells as compared to a 1-by-1 bispecific. And that's gonna be important as you transition from those memory B cells into the plasmablast. It isn't like 20 is an on/off switch. It gradually, you know, modulates down, and we think that with our extra avidity, we're gonna get a better chunk of those late memory and plasmablast cells that you're gonna get than you're gonna get with a 1-on-1 CD20. But probably most important is the safety advantage that we think we get with the IgM platform. So we've talked a lot in the past about how we think we create a more physiologic synapse with the T cell T cell receptor. And so we instead of getting close binding of the CD3s, the size of the IgM keeps the binding of CD3s separated at what we think is a safe distance, and we think that's why we get that much better safety profile in terms of CRS and potentially that relates to ICANS as well. Got it. Yeah, the CRS, ICANS, and also the CD20 expression versus CD19 expression, that's all the dynamic why CD20, CD3 IgM T-cell engager may be, you know, well suited for the. Right Autoimmune. The only piece you left out there was the low CD20 cells as well. Expression. Where we think the IgM is gonna be better against those low CD20 cells than the IgG. Because of the avidity. The avidity, the 10 binding domains. We've shown over many different targets that the IgM does a better job of binding to low cell surface expression just because of the Velcro effect of, you know. Once one of the binding arms manages to bind, the IgM flops down on the top of the cell, and you get the Velcro effect. And it's why we have essentially a 0 off rate. Once the IgM binds to the cell surface, it just never leaves. The other thing we haven't talked about much in the last few months is that that stable position on the top of a cell allows us to be more efficacious when T cells are rare, because that IgM just stays there and is able to wait for the passing T cell when there aren't that many of them around. So we've shown some preclinical data where we do much better than an IgG bispecific, where the T cell counts are low. Is that tied to the tissue penetration because you are going to the peripheral, you know, from the peripheral to the tissue, and then you can stay there and waiting for the T cell to. Yes P erforate and penetrate? Right. In those places, we think that T cells can be relatively rare. Yeah. Mm-hmm. And so we get into that, that tissue compartment. Once we bind to the surface of the cell, we just don't leave, and so we can wait for that rare T cell to come along. Yeah. Got it. And another key topics I've been talking with the investor is the dosing, right? So obviously, you have developed it in the BCL lymphoma. You see some kind of dose kind of response there. How should we think about the difference between the autoimmune dose response versus the BCL dose response, and why you think it's maybe different? Like, you know, you tell us a little bit about dosing selection you for the autoimmune as well. We don't know the answer to whether it's going to be different or not. We know that the target is a little bit different in terms of the location, so what we know that in autoimmune disease, we need to drive the IgM antibody into distal inflamed tissues, and we don't know whether a higher serum concentration is gonna be helpful in driving that IgM further out into the tissues. We know that it kills, depletes B cells very effectively at any dose. Yeah. It's really not a question of are we gonna get, you know, depletion of B cells in the bloodstream. That's gonna happen. The question is Where are we gonna get it, particularly in those distal tissues that are really important, distal inflamed tissues that are really important in autoimmune disease? Mm-hmm. Yeah, got it. Now it's not—we are not just hypothetically talk about the autoimmune disease. You are enrolling the clinical trial phase I, and the reasons, as you mentioned earlier, you already closed the first dose cohort for the RA trial. I think, you know, obviously right now, CAR T cell therapy very active in this. I think one of the key issue they are facing is how to enroll, because it's a very complicated regimen, and it require a lot of the multidisciplinary kind of collaboration. Tell us about the enrollment you have been seeing so far. What's the patient experience outside of it, just to inject your drug? Well, we think that that's one of our huge advantages, both in terms of clinical development, but probably more important, we think that's gonna be one of our huge commercial advantages relative to CAR T. So to be clear, this imvotamab is dosed on an outpatient basis. It just can be your basic rheumatologist can just dose this on an outpatient basis, just like they would do with Rituxan or something else. So we have seen a huge amount of screening, both on lupus and RA. We're currently limited by the FDA as to the severity, the requirement for significantly severe disease in these patients. That's been the primary limitation in terms of taking those screening patients on the SLE side and turning them into dose patients. But, you know, we're making good progress there. Mm-hmm. On the RA side, there are just, you know, more of those patients out there, and we feel like that study should enroll pretty quickly going forward. Yeah. It makes sense. You know, it's a new modality, and the only validation so far, we only have the CAR T, which is in a later line, kind of the last line of the therapy. You know, start from there, but to your point, if it's outpatient, if it's efficacious and proven to be safe, you know, why not move into the earlier line? No, no reason to believe that. Absolutely, and once we've got some initial safety data, we're planning to try to get some of these restrictions loosened so that, you know, we can go into less serious patients. Although, as I said, particularly in RA, we're not having any trouble finding patients to enroll even with the current severity standards. Yeah. And then what we're gonna see in the next data? I understand you don't wanna dribbling kind of the incremental data. You wanna give us the totality, at least the initial kind of data package. How much we can expect from there? And then what decision you're gonna make out of this initial data package? Well, our hope, and we've been consistent throughout this, our hope is that we can show you a couple of dose cohorts. We wouldn't necessarily separate RA from SLE, so in the sense that we wouldn't wait for two dose cohorts of SLE to come along before we showed two dose cohorts of RA. Now, just focusing on RA, for example, what we'd hope to see is not just the initial data and the initial B cell depletion, but and all of the biomarkers that go along with that and the initial safety. What we really wanna see is, does it look like the B cells that come back look different than the B cells at the time of initial dosing. Have we changed the ratio of pathogenic B cells to non-pathogenic B cells? Mm-hmm. That, to us, is the most important signal to indicate that we're on the right track. We're doing something that's gonna be positive and that is hopefully gonna be different than something you can do with Rituxan. And if we know we're on the right track, then we know we can. Even if we're not there all the way there at that point, we know we can dose more, we know we can dose higher, we can dose sequentially for a longer period of time. And importantly, we can come back three months later, six months later, nine months later, whatever the appropriate timeframe is. When an individual patient seems to be their situation seems to be changing, we can redose at that point. So I think, you know, in summary, the most important thing in our minds is how do those B cells look when they come back? Yeah. You know, you wanna reset the immune system, and then given this, you know, T-cell engager regimen, you can redose them. You have the flexibility to redose, you know, for the different. Right R egimen. Yeah. We wanna see that we're doing something there. Yeah. But to be clear, we think that the standard here, at least initially, and hope even commercially is. Just are we doing something that looks better than what you can do with Rituxan and with the ADCC molecules? Because we think we're hopeful that the safety profile is gonna be very acceptable. And so, if we're doing something, even if we don't get all the way to CAR T efficacy initially, that's just fine. Yeah. We think that's commercially very, very attractive. Yeah. You know, it's a balance, a totality. You don't need to get there in order to be a very viable kind of option there. Okay? Yeah. Last minute, we haven't talked about CD38. Absolutely, a lot of the discussion around that as well. So tell us what else you wanna highlight for the last minute. Well, I think we are extremely excited about CD38, and we think the combination of CD38, which will take out the plasma cells and the plasmablasts, you know, if that combination. Not talking about dosing them at the same time, but in terms of getting coverage of all the pathogenic B cells, the combination of 38 and 20, we think covers everything. In the B-cell lineage that is going to be pathogenic from an autoimmune standpoint. And, you know, we've seen some recent success with the HI-Bio and their CD38. We think we can—we should be able to do that at least. And we think we can be maybe effective in things like myasthenia gravis and, you know, some of the kidney diseases and so forth. So we think there's a huge opportunity for a CD38 therapeutic in diseases that are primarily autoantibody-driven. We also think that in conjunction with CD20, it can be very helpful in diseases that are much more multifactorial. Excellent! Thank you, Fred. I really appreciate the attendance, and thank you, everyone, for listening. Thank you.