All right, good afternoon, everyone. I'm Stephen Willey, one of the senior biotech analysts here at Stifel, and glad to be joined with us for the next session. CEO of IGM, Fred Schwarzer. Fred, it's always a a pleasure to speak to you. I know this is an oncology-focused event, so I think we'll try to stick to the theme of the day for most of it, but, I'll probably try to sneak in a few autoimmune questions towards the end if that's if that's okay. Maybe we can just start with the news of the day. I know that you announced a refocusing of the Sanofi partnership to immunology targets only, which means, I guess, that the three oncology targets that were also covered under that collaboration now fall back under your control. Can you elaborate on what might have driven Sanofi's decision-making process, how much progress had been made on these three oncology targets of interest? I know this is relatively new news, but, you know, how are you thinking about the plans for these targets now that they've fallen back under the control of of the company? Yeah, great. Thanks, Stephen. I'm really glad we had a chance to talk to you about this today live, so the timing worked out really well. I have to say, if you've been following Sanofi's announcements since roughly November of last year, this didn't come as a real surprise. They're clearly refocusing their pipeline around Dupixent and immunology, where they feel that they have global leadership. And so we weren't at all surprised that the early-stage oncology, discovery level sort of collaborations that we had with them went by the wayside. That being said, we are really excited about the data that we've seen to date. It appeared to us that their team was also very excited about the data that we've generated on these targets. So I think, and just for the cynical folks in the audience, Sanofi saw absolutely nothing in terms of the DR5 data, etc., etc. This is completely independent of anything with respect to DR5. So, you know, the data were really good. The leads look really look really good, frankly. We think the targets have some real potential for an IgM, where we think that an IgG is likely to struggle with these targets. And our data indicated that the IgMs that we produced greatly outperformed the IgGs against these targets in terms of agonism. You know, they were oncology-agonist targets. You probably won't have a lot of trouble figuring out what the classic targets are there, but they're places that other people have failed. And we think we have a path forward. But in terms of what we do next, as we said in the press release, our current priorities are our clinical stage assets, the aplitabart, as well as the imvotamab in autoimmune. Those are the things that are going to drive the most value for the company in the short term. So I think we'll have to think about whether we were to take these forward, when we might take these forward, and/or if we were to take them forward with another an alternative partner. Okay. Yeah. You preempted my skeptical DR5 aplitabart question. Well done. Maybe just lastly on this, right? I know that you've talked about there being some potentially meaningful milestones emerging out of the collaboration. I think you would characterize some of those as being a bit front-end loaded in nature. Mm-hmm. Right. So, just want to make sure this doesn't have any real impact on capital allocation decisions over the course of the next 12-24 months. No, none of that was included in our modeling. So, no, it has no impact on that. I think, you know, to the extent there's an impact, we won't have to spend as much money on these programs as we otherwise would have been spending. So there's a lot of, a lot of out-of-pocket expense that will, you know, go away or allow us to redirect towards other programs. Okay. Maybe a bit of a bigger picture question. So I guess, you know, kind of similar to Sanofi, you've refocused, deprioritized a lot of your development efforts in oncology over the course of the last 12 months. How would you characterize the opportunities for value creation in oncology right now? And I guess, what are some of the key challenges that you and, I guess, other companies like yourself are facing? And how does that differ relative to what you believe the opportunity to be currently in INI? Yeah. So let me let me just—I'm really glad you asked this question, and let me, let me talk about it for a little bit. I think, you know, we were all around five years ago when there was a laundry list of all the immuno-oncology targets that we were all going to address. And I think it's fair to say that there's been limited success with those immuno-oncology targets to date, particularly with the, you know, obviously all IgG-based approaches to those targets. ADCs have clearly been hot. That's the, you know, what's really hot today. And then I think the other thing that factor people need to keep in mind or do keep in mind is Hem-onc is just really crowded right now. So where we see the opportunities, we believe that T-cell engagers for solid tumors is the, you know, could be the next generation of ADCs, if you will, could be the next really hot thing. We think in order to do that, you probably need Signal one, Signal two, you know, the CD3 and the CD28. We think our format is hopefully the safest format to address that, where we think safety is going to be really critical. And so we think that that's a huge opportunity in oncology and one that we do want to pursue as time and funds allow, and also to these agonist broadly applicable T-cell stimulation targets that you might presume were some of the targets in the Sanofi collaboration. We think that an IgM approach to that, those targets, may well—just like in DR5, where we're quite hopeful that, you know, for 20 years, people have tried IgGs against DR5 and have failed. We're hopeful that IgM is going to succeed there because of the additional cross-linking. We're hopeful, and our preclinical data would support, that in some of those agonist targets that, an IgM may succeed where IgGs have failed. So I think those are the two areas where we see for us the biggest opportunity in oncology: Signal one, Signal two T-cell engagers for solid tumors, and then these broadly applicable, T-cell agonists. On the Signal one, Signal two leveraging CD28 co-stimulation, I know that there's been a lot of effort here. I don't think there's been any success in putting these two signals on the same on the same chemical scaffold. Can you maybe just talk a little bit about the progress that you've been able to make to date on this? It obviously kind of sounds like it's still an important aspect of R&D activity at the company. And then how are you hoping to improve upon those other CD28 those other CD28 approaches that we've seen taken in the clinic to date? Yeah. So we've seen preclinical success across multiple solid tumor targets with our Signal one, Signal two, approach. So we think it's not a one-off. We think it can be broadly applied to a number of solid tumor targets. We think that, as we said, safety's going to—we all remember TeGenero and CD28 and how difficult that can be. We think that having two signals on the same antibody is going to be significantly superior to the approach that some folks are taking of the one—you know, two one, tumor antigen with two different antibodies. One has CD3 on it, and the other has CD28 on it. The advantage that we see to our format is you get first, you get avidity to the T-cell. You get two binders to the T-cell from the antibody. You get both the CD3 binder and the CD28 binder. By definition, they're right there in the same synapse. They're right next to each other. And, our preclinical data to date indicates that, we don't expect to see any safety issues, unlike what some other folks have seen with the independent, one-by-one sort of 28s. So, we're optimistic. It's just a resource question for us at this point, as to when do we, have the time and the funds to take these forward into the clinic. Okay. Obviously, we want to pick the very best target. We want—so we're still, you know, still doing some preclinical work on that, but we think it's a potentially very large opportunity. Understood. Should we assume that there's probably not going to be a whole lot of target risk taken on some of those first candidates that emerge? Yeah. I would assume that's the case. I think these solid tumor targets are pretty well understood. I think we might look at some targets that are targets that are uniquely applicable to an IGM. So one of the things you remember, Steve, is we're really good at carbohydrates, because of that avidity. So that could be a really—you know, carbohydrate-type targets, could be really interesting for us. But yeah, we don't—we're not go planning to go after some completely, novel, isolated sort of, you know, unproven, I guess, relatively unproven target. Understood. Okay. Maybe we can jump into aplitabart. I know you talked a little bit about the mechanism, some of the historical challenges with the IgGs. You did reference the preclinical data, which I think is actually fairly exquisite, right? I know that you've shown the ability to really kind of create this therapeutic index for yourself as a function of engaging a very particular epitope on the receptor. That engagement appears to dictate the kinetics of caspase induction, which kind of gives you that kind of clear TI. How are you thinking about, you know, what you've learned with this molecule in the clinic to date? I think there's a bunch of follow-up questions that I have, but maybe you can just kind of speak to your level of confidence in what the preclinical data told you, what you're seeing in the clinic, and how that kind of portends for the future of this development program. Well, I think we feel very good that the preclinical data indicated that aplitabart should be very safe in the clinic. And all clinical indications to date are that it looks like it has a really good safety profile with respect to liver toxicity, which is, of course, that's been the Achilles heel of some of the other programs here. We've learned an incredible amount about DR5 as a target over the last five years as we've worked on it. You referenced the kinetics issue in terms of how quickly the caspase comes up. I think this—we're learning that the safety is also more complicated than just kinetics. It also appears that it seems to be related to how dense a mesh you create on the surface of the cell. The denser the mesh, the more liver toxicity you seem to see. And interestingly, they're related to the density of the mesh. It seems that if you use constructs that hit two separate epitopes at the same time—so if you use one antibody that's binding one epitope and another antibody that's binding a different epitope—that seems to increase the density and seems to increase the toxicity here. So we think that the structure of the, while the kinetics is important, epitope does have a bearing on kinetics. We think that the structural integrity of the IgM seems to be providing us with some of that safety in addition to, in addition to epitope selection. So as we look at our clinical data to date, we're very encouraged, and we think it, you know, there—we may be able to approach other epitopes. We may be able to do, it looks like maybe there's room for even more potency and so forth if we were to decide to do something like that. But so it's very complicated, and we think we're learning how to address it, and we think the IgM is really important in addressing the liver tox, the IgM structure. Okay. So I know that there was some discussion last June when you provided the update around potentially, you know, disclosing more of the 3 mg/kg cohort data that was done in combination with FOLFIRI and BEV. I think the vast majority of patients there were still on therapy at the time of data cutoff. Are there any plans to provide any kind of update here ahead of the randomized trial data, which we'll get to in a minute? Yeah. Let me just start by saying we're very pleased with what we've seen in that BEV, the remainder of that BEV arm. There's nothing there that does anything other than support our hypothesis that we seem to be doing a really nice job of extending PFS beyond what you would normally expect for that group of patients. All that being said, we're really focused, one of the lessons that we've learned as a company is that randomized data is just absolutely critical, and getting to randomized data as fast as possible is critical. And so we're all focused on the randomized data, which, as we talked about earlier, we should see, you know, towards the end of this year, early next year, something like that. And so we haven't made any plans to talk anymore about the single-arm data at this point. So just haven't made any plans. We're just really focused on the randomized data, which is coming. Okay. With respect to timing of that randomized data, I know that you were hoping to complete patient enrollment by the end of last quarter. I guess, has that objective been met? And is the ability to provide a top-line disclosure before the end of the year, is that rate limited by the need to have a mature median progression-free survival statistic in hand? Yeah. The short answer to your last question is yes. It is, when do we have the PFS? We tend to update on enrollment with our quarterly updates. So I wouldn't be surprised with our first quarter update if you saw that we announced that we've completed enrollment in the study. And at that point, I think it's just a question of when do the PFS events come in? You know, given the assumptions on PFS of the control arm of roughly six months, and then we don't know what the PFS of the drug arm is going to be. It's, you know, probably towards the end of the year, beginning, you know, sometime in the first quarter is when at that point, it's just out of our control as to when those events come in. Okay. With respect to the phase 1B, can you maybe just speak to drug trial design briefly? And then, you know, what, if any, variables have you stratified for? Just out of curiosity. So it's a 1:1 randomization, with a target of 110 patients. It's second line. They have to be irinotecan naive. I mean, I assume it's going to—they have to be irinotecan naive. And we have a crossover so that patients who progress on the drug arm, if they wish, can cross over to the—or progress on the control arm, can cross over to the drug arm. We've stratified for KRAS, BRAF, and liver mets. So those are the only two stratification factors that we have, we have formally put in the protocol. Is the assumption here that all patients will have seen prior BEV as part of front-line therapy? Is that a requirement, or is that just an assumption? It's not an assumption that all patients will have seen prior BEV. It's an assumption that most, a majority of patients will have seen prior BEV. It's not a requirement that they have previously seen BEV. And we expect we'll have some, a minority that have not, for one reason or another, have not seen prior BEV, whether it's access or whatever. But we expect a majority will have seen BEV. Okay. And so in addition to the 3 mg/kg dose that you're evaluating in the randomized portion, I know you're still enrolling, a 10 mg/kg dose in, I think, a 20-patient dose expansion cohort, also with FOLFIRI/BEV. How will this data inform the strategic decision-making process around this asset, if at all? Yeah, I will have to wait and see. I think we would be surprised. We really like what we see at 3 mg/kg. I think we'd be very surprised if we saw something at 10 mg/kg that was so much better than 3 mg/kg that it would justify the longer infusion times, the potential for more infusion reactions. So I think we'll see at, you know, probably towards the end of the year, those data will come together at the same time that we see the randomized data. They'll be a little bit hard to compare because those will primarily be third- and fourth-line patients, where the randomized data will be second-line patients. But we do have a lot of data previously on third- and fourth-line patients. So we can look at that and see, does it look like there's such a significant improvement in efficacy that we want to further interrogate 10 mg/kg? But, you know, our current expectation is that 3 mg/kg looks good, and we're hopeful that that will be the dose that we go forward with. Okay. Maybe in the last few minutes, we can kind of stray off theme and get a couple of autoimmune questions asked, which I know are the centerpiece for a lot of investor interest right now. Your dose escalating in imvotamab and lupus and RA patients. Can you speak to how the pace of patient enrollment is progressing and provide a bit of an outline as to, you know, what it is you hope to be able to share before the end of this year? Yeah. So, with respect to lupus, we're seeing a surprising amount of screening. We're, to be honest, more, many more patients screen than we expected. But as we've discussed in the past, due to the FDA requirements on us in terms of the severity of those patients, a lot of them don't pass screening because they're not severe enough to fall into that category. So we're really looking forward to getting out of this severe patient group. And we think the level of screening is a really good indication of how patients and physicians feel about the attractiveness of this T-cell engager for treating autoimmune diseases, patients who are not at the very end of the line, but earlier patients. With respect to RA, things are going very well in terms of enrollment. So, you know, what we'd like to have, as we said, is we'd like to have a couple of dose cohorts, a couple of dose cohorts completed, and probably three months of follow-up on those patients in order to see, how do the B-cells look when they come back? Does it look like they have a different phenotype than, or at least the ratio of the phenotype is different when they come back as compared to pre-treatment? And, you know, we hope that those B-cells actually come back reasonably quickly. Long extended B-cell depletion is not good for patients. We hope they come back quickly, relatively quickly, and we hope they come back looking differently than, you know, looking different than before we treated them. Okay. I know the competitive landscape is kind of certainly tilted towards CD19. I think we just saw another company with a CD19/CD3 enter the competitive fray yesterday. I guess, do you have any in-house experience with a CD19-targeted format? And, you know, why do you believe, why does IgM believe that CD20 is the preferred antigen for this approach? We do. And we do have a CD19 in-house with multiple leads, multiple, yeah, we definitely have a CD19. However, I would say that we believe that for a T-cell engager, and I think you would probably say that most of the competitors, whether it's Roche with their two CD20s or Regeneron or Genmab and so forth, I think most competitors have viewed CD20 as a better target for T-cell engagers generally. I think there's a lot of interest in CD19 for autoimmune because of what's been done with the CD19 CAR-Ts. But we think that CD20 is just a better T-cell engager target. And we think that the combination of CD20 and CD38, whether in sequence or whatever, does a great job of covering the entire B-cell lineage and covers any parts that you want to cover that CD19 might not cover. We really don't want to get out on the left end of the B-cell lineage to the early pro-Bs and so forth. And I think, you know, the only CD19 T-cell engager that's out there is BLINCYTO, and, you know, it certainly has some challenges. So I think, you know, so short answer, we have a CD19. We're still not convinced, we're not convinced at all that CD19 is a better target for autoimmune T-cell engagers than CD20. Okay. Interesting. And then maybe just last question. You mentioned CD38. You know, when do you hope to initiate dose escalation with 2644? And can you speak to what diseases you're interested in in terms of dose escalation? I know we've seen some POC data from Dara and lupus. There's been other CD38 targeting formats and diseases like IgA nephropathy. Yeah. So I think what we hope to get this IND filed and approved this year, start treating patients this year, probably focus on diseases where they're purely autoantibody-driven, purely plasma cell-driven, just in order to get that signal that we're really looking for. You can think in terms of, as you mentioned, IgA nephropathy. You can think of MG as another place where it's very autoantibody-driven. And we think long-term, the combination or perhaps in sequence, not literally given at the same time, but in sequence of treatment with a CD20 and a CD38 might have broad applicability for more complicated autoimmune diseases like lupus. That has components, perhaps, of different aspects to the mechanism of action there. So maybe something broader would be very attractive there. Okay. That's all we have for time, I guess, in the context of there being an autoimmune presentation at ASH last year. I don't feel too bad asking a few autoimmune questions during an oncology event. So I appreciate the time, Fred. Good luck. Likewise. I'm sure we'll be in touch. Thanks, everyone, for listening. Thanks, Steve. Take care.