All right. Good afternoon, everyone. I'm Stephen Willey, one of the senior biotech analysts here at Stifel. Very glad to have with us presenting from IGM Biosciences, CEO Fred Schwarzer. Fred, thanks for doing this today. This is just gonna be a Q&A format for everyone who's listening. There is a chat function if you have questions, that you can populate those questions into. We'll try to get them asked and answered. Before we get into Q&A here, Fred, I'm not sure if you wanna make any kind of opening statements. First, thanks for inviting me to participate, and it's been a good conference, so really appreciate the opportunity to talk about IGM. I think I would say that we're very excited about our DR5 program moving into the randomized clinical trial here to test 3 mgs per kg and 10 mgs per kg against control FOLFIRI plus bev in both cases. We're also really excited about taking imvotamab into autoimmune diseases. Those are our two primary areas of focus for this year. All right. Very good. Maybe we can start with DR5. You know, you showed us some preliminary data back in January. Again, this is IGM-8444. Really interesting just in terms of directionality, but also fairly limited just in terms of patient numbers. I know that you've talked about having another, you know, 20-25 patients worth of data to share at some point. How are you just thinking now about the timing of a follow-up disclosure? I guess, are there any rate-limiting steps to be able in terms of being able to provide that next update? No real rate-limiting steps. It's just a question of when do we have enough patients who've been through a couple of scans, the same way we presented at JP Morgan, those patients who've been through a couple of scans. When do we have a big enough bolus of those patients to make it meaningful to present? We're, we're looking at all of that now. We haven't decided on a particular time, but we'll have some additional patients in the FOLFIRI alone combination, as well as some patients in the FOLFIRI plus bevacizumab combination. We'll have some additional progression-free survival data. Just trying to decide when it makes the most sense to present those data. Okay. You talked about the phase II trial, which I know that you just recently dosed. Mm-hmm. Patient in. Not sure that study's actually been posted to ClinicalTrials.gov just yet, but you did mention you brought the 10 mg per kg into the, into the mix. Maybe you can just expand upon, you know, that decision-making process a little bit? You know, it seemed like this decision was predicated on biomarker data and, you know, do you have clinical data that correlates, you know, kind of the full change in this, in this biomarker, to improve clinical outcomes? I think it was, it was based on two factors. One, regulatory, and our regulatory combined with our excitement about DR5 and what we're seeing at 3 mg per kg, and biomarkers, as you said. We do not have any additional 10 mg per kg CRC patients or any 10 mg per kg patients. In combination with FOLFIRI, it's still just the same three or one patient, one CRC patient that we presented at JP Morgan. When we thought further about this study and we talked to the FDA, we thought about it from our, you know, our level of excitement about what we hope to see here, seemed to us that it really made sense that in conjunction with those very positive biomarker indications that we discussed in March, where it looks like we're hitting the target harder at 10 mgs than we are at three. We decided that it made the most sense from a regulatory approval clinical trial standpoint to get this dose selection out of the way as quickly as possible in light of the FDA's Project Optimus advice that they want to see two doses, or they want to make sure that you've adequately explored dose selection. We decided, let's do it right now. Let's make this study even more robust than we had previously planned. Let's make this a study that we can get more data, and we can quickly, early in the process, answer the question, does 10 look better than three? So it's, it really, more than anything, it's an acceleration of our clinical development process and acceleration of our clinical development thinking. Let's, let's go all in. Let's get the answer as fast as we can. Yeah. As we go, as we go further downstream, we don't have to go back and do this 10 mgs versus three, or we don't have to do dose selection, with a much larger cohort. We hope that this initial set of patients is gonna allow us to put the 10 versus three question to bed and move forward with the best dose and only one dose that we move forward with. Okay. I know you've talked about this trial potentially having registrational capacity. I guess, does the addition of a second dose, the 10 mg per kg, does that complicate those plans at all? I guess I ask the question because, you know, presumably you have a formal statistical plan that is in place. I'm guessing that's now been designed- Right. -to accommodate both doses. You know, to your point whereby you end up potentially selecting a single dose to move forward, how does that decision get made within the confines of a blinded trial, if one dose appears to be outperforming the other? Is that a decision that a trial DMC could make while you still preserve the blind of the study itself? Well, first, let me clarify. This is not a blinded study. Okay. This is an open label study. We may, at some point, have the scans read in a blinded fashion. It's all open label to the company. We'll be watching each and every patient as it goes, as they go along, as they get their scans, et cetera. To your question, we are not saying that this would necessarily be a study that could be expanded to be an approval study. There is the possibility that that could happen. That will depend on FDA interactions, the data, et cetera. To the point of your question, we think adding the 10 mgs per kg to this study significantly increases the chance that this could become or expand into an approval study, because you will be answering that question about 10 versus three. As you put both of those, though, from a statistical standpoint, as you increase the size to have both the 3 mgs and the 10 mgs versus control, you should have a better sense of your signal here. You know, you're gonna have twice as many patients dosed with IGM-8444 as you would've had otherwise conceivably. We think it's all good from that perspective, and that's a significant part of our decision to add this 10 mgs per kg to the study now rather than wait till later. Okay. Okay, that makes sense. Maybe just a couple of questions on DR5 biology, which I know that you showcased, I liked the Stifel water bottle, by the way. There you go. Which I know, you guys showcased at AACR. You showed, and you've, and I think you've shown this before in other venues, but, you know, that only really kind of a fraction of cell lines across a broad spectrum of different tumor types are sensitive to single agent IGM-8444. Do we know if this sensitivity that you're seeing to single agent therapy is that directly correlated to DR5 expression? We believe it is not directly correlated to DR5 expression. We believe it's very multifactorial, things that inhibit the apoptosis pathway. It's a very complicated mix of factors that determine sensitivity. Some amount of DR5 sensitivity is critical for effect, but that's a relatively slow, small amount and almost, you know, a high% of tumors are going to have that. Having more doesn't necessarily indicate more sensitivity across different cell lines. What I would say is we believe that if you take a specific cell and you upregulate the amount of DR5 through something like chemotherapy or some other senescence drug or whatever, that in itself, in and of itself will make that cell more sensitive to DR5 apoptosis. Okay. I know at AACR you showed that, you know, if you pretreated a cell line that was sensitive. Right. -to single agent DR5 agonism, that you would see this upregulation of DR5 expression that if that cell line was pretreated with chemotherapy. I guess I kinda came away with a question of, would you see that same level of receptor upregulation in a cell line that was insensitive to single agent 8444? Yeah. We think probably that adding chemotherapy to a given set of cell lines will increase the number of those cell lines that will in fact be responsive and probably through, in some form or another, creating senescence, upregulating DR5, downregulating the inhibitory pathways. Mm-hmm. A variety of things like that. Okay. -that will create, can create sensitivity in cell lines that might previously not have been monotherapy sensitive. Okay. Net, net, it's not just the DR5 receptor expression story and chemotherapy, I guess, could be taking the brakes off of some of these intrinsic pathway modulators that can block extrinsic signal. Yeah. They can be increasing that, absolutely. They can be increasing DR5 expression on a given cell, and that can help, you know, on any particular cell, more is probably better is our view, to a certain point. At which point it probably doesn't matter. I guess this concept of synergy with chemotherapy was also kind of a focus point or the focal point. Mm-hmm. Of the presentation that you made last week as well. You've talked about, you know, moving IGM-8444 forward with another chemo-based combo at some point. Right. Right. I know that docetaxel and gemcitabine appears. Mm-hmm. Yeah. They were added to the phase I protocol, I think, at some point last year. I guess my question is, you know, have you dosed any patients with either of those agents? Not at this point. We've not dosed any patients with any chemotherapy other than FOLFIRI at this point. Okay. We are very excited about the opportunities to use some of those chemos that you saw on the ACR page, poster, to start another arm of the phase I study and see what we see what kind of signal we see in combination with those chemos. I think what we'd look for there is a situation similar to CRC. We'd look for a situation where the response rate is not high, you know, there's a really big unmet medical need so that if you've got a signal, you're gonna see something. You're not talking about 80% response rates and, you know. You're talking about low response rates, big markets, hopefully, and places where chemo, this particular chemo that we wanna combine with, is standard of care. We think from a development standpoint, that is by far the easiest development path to take standard of care, add something to it that has almost no seemingly, I need to watch my words, very good safety profile, and then, that's, you know, that's the development path that's probably the easiest. Okay. Interesting. I guess you can kinda look through the matrix of some of those synergy scores. Absolutely. -see which of those chemos are generating the highest amount of synergy, think about where those chemos are currently standard of care and kind of back into- Exactly. What a couple of those opportunities might look like. What's the level of success with those chemos? You know, what's the signal? Is it, you know, is it 20% response rate? You know, or what's the PFS? Those are the factors that we would look at. Those are the factors we are looking at to decide where do we go next. Okay. Interesting. In addition to chemo, you're looking at combos of 8444 with birinapant, and also with venetoclax. Right. I guess what are the next steps here, right? I know you're gonna be completing dose escalation with birinapant here at some point shortly. Mm-hmm. Do you think that you have enough data to select a solid tumor type or types for further dose expansion? I think we have some indications of where we have some ideas as to where we might go in expansion, but we're still in escalation, and so we don't have enough data to be able to say, "This is where we want to expand." I think we'll have to decide, you know, what does it look like? Where do we see the opportunities? You know, and expand there to get more, a broader signal. venetoclax is an interesting opportunity because there you know where you're gonna use venetoclax. It's an already approved drug, and if you can show, you know, same sort of signal of adding efficacy to venetoclax in some patients who have otherwise very bad prognosis, we think that could be very interesting. Mm-hmm. That's been moving a little bit slower. I think you're still in dose level 1. Is there any explanation for- Sure. I guess why that's lagged or? Yeah. It's primarily because we've been focusing on FOLFIRI. Our investigators in FOLFIRI are all solid tumor investigators. We had to open a new you know, get new investigators who see AML patients and get that started. We are started now. We're hopeful that that will see some signal there that's interesting. Okay. I know you also kinda recently announced, I guess, the formal deprioritization of imvotamab in, as a single agent in oncology. Right. Mm-hmm. Again, I don't think that was or perhaps shouldn't have been surprising for anyone who's heard me speak for most of the last 36 months. Right. I think the AI opportunity is really interesting, but I think I would probably need a whole separate 30-minute session to hash that out with you, and I'm gonna stick to the oncology theme here. Curious how you think about your ability to leverage, you know, what you learned about imvotamab in the clinic. Yeah. To kind of the next generation of bispecifics that are now coming out of the pipeline, specifically 2644, the CD38 x CD3, and how you think those learnings might be able to accelerate dose optimization. Well, we think that what we've learned, we hope, imvotamab looked like it had a, we think, a best-in-class safety profile from the standpoint of CRS in lymphoma. We're really hopeful that we will see similar improvements over IgG bispecifics in terms of CRS, both in terms of, well, CD38, where there really isn't a competitor, and also 123, frankly, where there isn't much of a competitor. In multiple myeloma, you've got other bispecific IgGs that have very significant CRS. You've got a lot of infections, a lot of infection risks. We think there's a huge safety window that's available in 38 by three, where we hope we can become a safe and more potent next generation daratumumab. Similarly, with CD123, a lot of companies have tried and failed there, and that's been a safety issue primarily. We're hopeful that, as you saw in our AACR posters, that we have selected binders that are gonna be both effective and safe, that are gonna spare, and, you know, immune effector cells in the case of CD38 and are gonna be safe in the CD123. That's, we think if we can solve the safety issue with both of those, that, those are both gonna be very attractive opportunities. You mentioned CRS, and obviously we've seen a lot of the IgG data that's been generated in myeloma. Again, I know it's a different disease relative to DLBCL and lymphoma, a different target antigen. I guess, is there any reason to believe that the kind of sub 10% incidence rate of all grade CRS that was seen within imvotamab wouldn't translate to 2644 in the setting of myeloma? I think there is reason to believe that we will have a significantly better CRS rate relative to the IgG bispecifics. Whether we're gonna hit that 10% or below number, can't predict at this point. It's a different disease. It's a different target. It's leukemia. You got a lot of circulating cells. We're very hopeful that our IgM-based platform where we reduce the amount of CRS by having only one binder per IgM and keeping the CD3s segregated, we're very hopeful that that's gonna lead to a significantly better CRS profile than the IgG bispecifics. I can't say, is it gonna be 10% or 5%? I just can't say at this point. Yeah. We gotta do the experiment. Okay. I will say the final thing is just we do hope that it's gonna be significantly differentiated from a CRS profile relative to the IgG bispecifics. Yes. So. Yeah. Understood. How are you just thinking about the longer term development strategy of 2644 in myeloma, right? This is obviously a disease where, you know, treatment is very combination focused. Yeah. We've seen a lot of other companies kind of pursue single agent development in kind of this penta-refractory patient population. Is that interesting to you, or? No. Do we kinda think about this development program as, you know, maybe being DR5-like in the sense that you go straight into combinations and just kinda rip right through single agent dose escalation? That's what we wanna do. We're not interested in being a fifth line, fighting it out with the CAR-Ts and all the rest of those folks. We wanna find out as soon as we can we do better than dara in these combinations presumably, you know, starting with the second or third time that a patient has seen dara? Can we show a difference relative to dara in those, in that setting? It's just like DR5. We wanna get it into randomized studies as fast as we can. As soon as we've got safety, we wanna get into those randomized studies. Okay. Maybe just a couple more questions while we finish up. I know that you're currently dose escalating IGM-7354. This is the PD-L1 that's conjugated to IL-15. This was also shown at AACR last week, and just curious how you're thinking about the longer term development opportunities for this, for this asset specifically. That asset has an incredible range of development opportunities. It starts all the way from the relatively narrow, so you can imagine using this as a preconditioning for CAR-T harvesting, for example. Or, you know, that you're gonna boost up these T-cells that are gonna be harvested as a very narrow indication. You can imagine using it post CAR-T or CAR NK after those cells start to wane, and if you need to boost them, can you get some boost there? All the way to the other end of the spectrum where you imagine using it in combination with PD-1s or using it in combination with ADCC drugs. It's a really broad range of potential applications. Anywhere you might wanna use an immune stimulant, that's like a lot of places. Okay. We have not made any decision about where we would go there. I think we would probably start with the easy ones first. Yeah. We'd start with maybe the boosting the T cells where, you know, or where you get a real, you know, you get a clear signal pretty quickly. Okay. Maybe just last question here. Maybe you can just talk a little bit about how the Sanofi collaboration's progressing, when we might hear about the targets that you're pursuing on both the oncology and AI fronts, and also, you know, how you think about potential business opportunities, BD opportunities over the? Yeah. more near term. Well, Sanofi seems to be going really well. We're pushing along. Our relationship has been great. Lots of mutual respect and sharing of information and data. Couldn't be better from that standpoint. When the targets will actually be announced, that's. Initially, that's within Sanofi's control. It might be until you see something on ClinicalTrials.gov before you know what the target is, I'm afraid. It's not our decision, it's their decision. I think, you know, you previously kinda guessed around what the likely. They're all agonist targets. There are three in oncology, three in autoimmune, so, you know, you can guess probably. Other business development, we've got a lot of stuff in the pipeline, we'll need to think about what things might make sense for us to bring in a partner, you know. I think at this point it's a full menu of things that we might discuss partnering. All right. And are you- Not to mention one more thing, the, our Signal 1, Signal 2 new T cell engager platform, which we think should be quite interesting and very differentiated. We think that will be quite interesting to partners for solid tumor T cell engagers where there hasn't been much success so far. Yeah. No, agreed. I think there was a lot of that on display at AACR last week, definitely some industry interest there. Fred, thank you as always. As always. Appreciate the discussion. Thanks everyone for listening. Take care. Thanks.