Let's kick off this session. It's Michael Schmidt, Senior Biotech Analyst with Guggenheim. The next presenting company here is IGM Biosciences. With us today we have Fred Schwarzer, CEO. Fred, welcome, and thanks for joining us. I think, Fred, if you'd just like to give us a quick overview of the company, and then we'll dive into Q&A. Great. Well, thanks, Michael. Really appreciate the opportunity to talk about IGM, my favorite topic. We, as you might guess, name of the company is IGM Biosciences, and we do IGM antibodies. For those of you who aren't familiar with IGM antibodies, you can think of them as, you know, the IgG is the classic Y shape with the two binding domains. You can think of an IGM as roughly five IgGs in a circle bound into a with disulfide bonds to make a relatively rigid sort of structure. We are, to the best of our knowledge, the only significant effort anywhere in biotech or pharma that's doing IGM antibodies. We've been at this for 13 years now. In terms of why we think IGMs can be better, I'll only focus on two ways that we think they can be better and are relevant to our discussion today. One, with respect to agonism. We think that one of the basic principles of agonism, particularly the TNF receptor super family members, if you can cluster more receptors together, bind them and cluster them together, you send a stronger agonistic signal. We're gonna talk about death receptor five, which is a target that pharma and biotech have worked on for almost 30 years now and haven't had any success, and I think we've had some really interesting data. In the T-cell engager space, we think we have established a way of creating a best-in-class safety profile from T-cell engager, and we'll talk about how we think that's important in autoimmune disease as well as oncology. Great. Yeah, why don't we just touch upon some of those topics? For IGM-8444, which is your DR5 agonist antibody, you did recently disclose combination data in colorectal cancer that looked quite encouraging, relative to, you know, approved options in late line patients. Maybe just remind us of some of the key points from the data that supported your decision to advance the program into a randomized Phase II study. Sure. What we were really pleased to see was, a number of patients who had previously been treated with FOLFIRI, progressed after being treated with FOLFIRI, and yet when those patients were now treated with IGM-8444 plus FOLFIRI, a number of them achieved responses, had a lot of tumor shrinkage. You know, none of the patients who showed tumor shrinkage with FOLFIRI and 8444 had ever had a response in the past in FOLFIRI. You would normally expect when you re-treat a patient who's not responded to FOLFIRI, you're gonna see nothing on the re-treatment. Seeing that, seeing some really good progression-free survival data, we think very good progression-free survival data, where we showed in third line, among our third-line patients, 5.5 months of progression-free survival, where normally it's about two months, and the third-line response rate is 1%-2%. Seeing, you know, we saw four responses in our data that we released. That really encouraged us to move forward, and this trial will actually be in second line CRC, and one of the criteria is the patients will have never seen FOLFIRI previously. We're quite optimistic that the response that we're gonna see in these patients will be significantly better even than what we've seen, hopefully. You know, better than what we've seen to date. Yeah. You selected, I believe, the 3 milligrams per kgs dose for the antibody. You know, what drove that decision? You know, did you see dose response or any other markers of increased activity at that dose? Yeah. Yeah. let me say that part of what drove that decision was we saw really nice responses at 3 milligrams per kg, and we said, "Let's put the pedal to the metal here on 3 milligrams per kg." Now, that's a little bit glib, but we escalated, we started at 0.3 milligrams, and, you know, we didn't expect to see 0.3 milligrams any responses there. We didn't think that's a clinically relevant dose, but we just wanted to be safe from a liver toxicity standpoint. We went to 1 milligram per kg, and we did see a response at 1 milligram per kg, which we thought was, "Wow, that's really interesting." We moved to 3 milligrams per kg, we started to really like what we were seeing, we decided to expand 3 milligrams per kg in colorectal cancer and push as hard as we could there. We really liked what we saw, we're taking that into the randomized study. We will, as soon as we get the randomized study started, we are gonna run 10 milligrams per kg. We've only done three patients at 10 milligrams per kg to date, only one of whom was a colorectal patient. From a biomarker standpoint-I mean, three patients versus a much larger number, it's hard to make any real conclusions. We didn't see an obvious increase in activity as we went to 10 milligrams per kg versus 3 milligrams. The real test will be in the clinic. Do we see a even better response rate at 10 milligrams per kg than we're seeing at 3 milligrams? That's a very happy problem. In that case, we can swap the randomized study to start to focus on 10 milligrams rather than milligrams. Right. We like what we're seeing, we're not convinced that 10 mgs is going to be that much better to be worth it for the extra infusion time and cost of goods and so forth. Right. You did not see any, liver issues which had been seen with some of the other DR5 antibodies. I guess, is there an explanation for that or a mechanism? We think so, but it's a little bit of a hypothesis at this point. What we think the IgM antibody or what we know the IgM antibody allows you to do is to control how the receptors are clustered together because, as I said, the IgM is relatively rigid. When it sets down on the, i t's, it's planar when it's in your bloodstream. When it targets, when it binds to a cell surface target, it goes into what we call the crab or crouching position. It sort of comes in on itself like your fingers coming, closing a little bit. That controls where on the death receptor how the death receptor five death receptors are going to be clustered. What we've. Knowing that we have that controlled clustering as compared with like, other means that IgG-based means of clustering that don't really have that controlled structure, what that means is we can pick an epitope, and that we know with by picking a different epitope, we can control how the cluster works, the timing of the clustering. We think that we've tested different epitopes with IgMs, and we can create some liver toxicity with certain epitopes. If we cluster more quickly, we can create some liver toxicity. With the epitope that we've chosen, we did not see preclinically any liver toxicity, and we're really pleased that we didn't see any in the clinic. We think it's a function of the IgM structure together with the particular epitope you choose and also how quickly that epitope creates the cluster. We think if it creates the cluster more slowly, it allows the normal human hepatocytes time to upregulate the. Yeah. Their protective mechanisms. Okay, great. you know, will we see more data from this phase I study later this year, or are you focusing on the phase II at this point? Well, we're very much focused on the phase II. We think the randomized data that is truly the important, most important data. We are generating a lot of additional phase I data, we haven't made a decision as to when or how we would disclose that additional data. Right. Then can you just remind us where you are with your other combination course with Birinapant and Venetoclax? Those are behind, but we think right now we're just getting to doses of Birinapant that are comparable to what we were using in our preclinical models, where we saw very great synergy. We're hopeful that we will start to see some of that preclinical response reflected in the clinic there, and Venetoclax is just very, very early days on that one. Later this year, we should have a sense of how those are working. We're also focused preclinically on a lot of other chemotherapies, and so what we've seen, there was a recent Nature Cancer paper that talks about how if. You were the person who put out the great report on that paper. If you create senescence in these cells or cell cycle arrest, that they would become much more sensitive to DR5 agonism, thank you for that publication. Right. Just a reminder for folks, I guess the Birinapant combination in what types of cancers does that hold most promise? Preclinically, it works everywhere. Okay. Which is really remarkable. We think what you're doing there, birinapant is a SMAC mimetic. What you're doing there is you're hitting the extrinsic apoptosis pathway with the death receptor five antibody, and you're hitting the intrinsic pathway with the BCL-2 with Venetoclax or with the SMAC mimetic. Preclinically, we see remarkable synergy when you hit both of those at the same time. Right. Okay, great. We'll look out for updates there. On your CD20 bispecific, so that's been in phase I in the lymphoma setting. You have, you know, started this dose comparison bake-off study, so to speak. Could you just update us where you are with that and how we should think about the program at this point? Yeah. We're actively enrolling in that, 100 milligrams versus 300 milligrams, both in DLBCL and follicular lymphoma. We hope to have enough patients in that with scans that in the second quarter we'll be able to make a call as between 100 milligrams versus 300 milligrams. The standard here is just to make sure that we don't think that 300 milligrams is significantly better than 100 milligrams. As long as it doesn't look like it's significantly better, we'll go with the 100 milligrams obviously. We expect the safety profile to continue to be, You know, what we believe is best in class. We're hopeful that the DLBCL, complete response rate will be consistent with what we saw in our phase I, and so be in that, you know. I think the standard now is 39%. Hope we'll be, you know, right in that range somewhere. Right. Right. I know you've, a s we think about, you know, next steps, I mean, I guess there's three outcomes, I guess. It's either better, similar, or worse than 39%. Right. How would that determine your development, strategy for the antibody? Yeah. We, given current market conditions, FDA's recent guidance on accelerated approval and so forth, we've said we're really not very excited about third line monotherapy, and we haven't made a final decision yet, but not sure that we would decide to take this forward in third line monotherapy, regardless of whether it was any of those three, better, equal, or less good. What we're super excited about is, well, let me go to oncology. We think combinations is interesting there. We think that chemo-free combinations are the really interesting opportunity there. We're not. As we look at the combinations that other folks are doing, where they're adding to R-CHOP, and GEM-OX, and so forth, you know, those data just don't look that exciting, to us at least, and we're not sure that's a, that exciting an opportunity. We think chemo-free opportunities, like with ZYNLONTA that we're working on, is more interesting. If we can be competitive with CAR T in the second line setting, you know, hitting us in that 60% CR rate, durable CR rate, we think that's. Do that on an outpatient basis with, you know, in the community setting, we think that's interesting. We think what's even more interesting is taking a best in class, in terms of safety, T-cell engager into autoimmune diseases. We've announced recently that we're doing that. We're planning to file multiple INDs this year, the first of which will be lupus, following on the Georg Schett data with the CD19 CAR T. Okay. autoimmune disease, you know, the registration studies can be quite large. In some of the indications. Through that move into autoimmune, Has it changed or affected your, you know, partnering strategy around the asset? I think that you're absolutely right. Autoimmune disease can be very, very expensive to develop fully through all of the late stage trials. I think that using a T-cell engager in autoimmune for us would be a good opportunity to partner at some point, to find a partner who really has the muscle to take, and the muscle and the capital to take those programs forward. We think we have a very differentiated T-cell engager in terms of the safety profile. No ICANS, very low CRS, low neutropenia. We think there's a huge window of opportunity between the CD20 ADCC molecules, which have had some success, but, you know, not complete success in autoimmune disease, and a CAR T with lymphodepletion and everything else. We think there's this giant window there for a safe T-cell engager, and we think Well, we know there will be partners who are interested in sort of opportunity. Right. How do you track towards, you know, publishing, or presenting, or updating us on the dose selection study? Yeah. We hope that we have enough patients through scans, that in the second quarter we'll be able to have that answer and be able to share that in terms of 100 milligrams versus 300 milligrams, and probably what sort of response rate we're seeing in DLBCL. Right. As we think about your emerging pipelines beyond those two, I mean, which of your other antibody product candidates are you most excited about? Which child do I love best? I think that. Let me just pick on IGM-2644 right now, the CD38x3. We think that not only does that have oncology applications, we also are planning to take that into autoimmune disease, where you can move a little further down the B cell lineage with the, with the 38 target. We really like the fact that in multiple myeloma, we may well wind up being the only 38x3 T-cell engager there. We think that safety's gonna be critical in, you know, in 38. We think it's a very exciting opportunity. Great. On your Sanofi collaboration that you announced, you know, last year. Could you just remind us, you know, about some of the activities there and, you know, how this collaboration has been progressing? Sure. As a reminder, that was entirely based on the concept that an IgM can be a better agonist than an IgG. All six of those targets, three in oncology, three in autoimmune, all six of those are agonist targets. They're all early stage targets. They're all targets where we're assessing sequences, finding new sequences, doing antibody discovery. you know, we hope that lead selection is coming along well, but We're still in that lead selection period for-. Right. For all six of those targets. Right. How do you think about additional partnerships or collaborations to leverage your R&D platform? We think in particular that an easy one may be a T-cell engager partnership. We've just announced that we have a, we think, a very unique signal one, signal two format where we can put both a CD3 and a CD28, or a 4-1BB ligand onto the same molecule. Within the same T-cell synapse, you can get both of those signaling moieties in the same synapse. We think that's pretty unusual, and we think that something like that will be very interesting for solid tumors where, as you know, T-cell engagers have had very limited success to date. That is a, you know, a great opportunity for us to do perhaps our next collaboration. We'll have to think about collaborations for the existing pipeline programs. Right. More complicated decisions. Right. Okay. Well, with that, I think we can wrap up. Sounds like we're looking forward to seeing the CD20 dosing data soon. Is that right? Yeah. Q2 is our hope. Q2, and then perhaps more on the DR5 in the second half of this year. Yes. Perhaps. All right. Exactly. Great. Well, looking forward to that. Thank you, Fred. Really appreciate it. Thank you, Michael. Okay.