Pharma, my name is Michael Schmidt. I'm a biotech analyst with Guggenheim. It's my great pleasure to welcome Fred Schwarzer, CEO of IGM. Fred, welcome. Thanks for joining us. Thanks very much, and thanks for having us. Why don't we just jump right into the, you know, pipeline, some questions I've had, I have. Perhaps starting with IGM-8444, which is your DR5 agonist, which is in phase II right now. And so, yeah, maybe perhaps before we jump into it, just remind us, you know, what, what the mechanism of action is and, you know, what, you know, what do we know about the, the molecule so far? Sure. Well, in the mechanism of action, I mean, death receptor 5 has been a target that's been interesting to pharma for the last 20-some years. And, almost, well, most of the big players in the space have tried and failed. So you've had, Genentech try twice and failed. You've had, Human Genome Sciences, Daiichi, Amgen, a lot of failures. And they all tried with an IgG antibody. And the natural ligand to DR5 is TRAIL, which creates a trimer of 3 receptors on the surface bound together and cross-linked. You know, with an IgG antibody with the two binding sites, it doesn't do a particularly great job of creating a trimer, where we've shown that if we take the same binding units from an IgG, put them onto the IgM backbone, that we can increase the potency just with those same binding domains by more than 1,000 times. So we know we get much more potency. The world tried for 10-plus years with IgGs against this target and failed, primarily due to lack of efficacy. And so now the world has moved to multivalent approaches. And, among those multivalent approaches is the Genmab HexaBody to DR5, which failed due to liver toxicity, we believe due to liver toxicity, and has been pulled from development. And so the challenge with the multivalents has been, do you have liver toxicity? Because DR5 is expressed on normal human hepatocytes, we selected our lead candidate, IGM-8444, on the basis of some preclinical data that showed that we had a very wide therapeutic index, and we seemed to have almost no liver toxicity. So we think that the IgM is the perfect format for cross-linking the cell surface DR5 molecules and still maintaining safety. That's what we've seen to date. We've had an extensive single-arm study, where we showed significant increases in progression-free survival over what you would expect in those third- and fourth-line patients. We showed significantly greater response rates than what you would expect in those third- and fourth-line patients. Now we're trying to prove that in a randomized study in second-line colorectal cancer for patients who are irinotecan naïve, because preclinically we showed really good synergy between aplitabart and irinotecan treatment. It makes sense because the chemotherapy stresses the cell. The cell tends to upregulate DR5 under stress. And so the combination really makes sense. We see preclinically significant synergy there. So to bring us back to where we are today, we have a 110-patient randomized study testing aplitabart plus FOLFIRI plus bevacizumab against the current second-line standard of care, which is FOLFIRI plus bevacizumab. Our goal is to have that study fully enrolled by the end of this quarter. We hope to have progression-free survival data by the end of the year. That assumes that the control arm will have roughly six-month median progression-free survival. That's on the basis of historical data. There have been some recent studies that have sort of validated that the standard doesn't seem to have moved, that six months of PFS. So assuming that the control arm comes in at six months of PFS and we have this fully enrolled by the end of the first quarter, we should know what sort of signal we have by the end of the year. We should at least know if we have a better-than-control-arm signal by the end of the year. Right. And so is PFS the main outcome here? Are there other efficacy endpoints that you're trying to compare between the treatment and the control arm? Not really. PFS is the primary outcome here. Overall survival, obviously, is the gold standard for approval. But in colorectal cancer, PFS seems to be highly correlated with OS. Now, one of the things that we do allow in our study that will confound the overall survival signal to a certain extent is we allow a crossover. For what we saw in our single-arm study is that a number of patients who had previously been treated with FOLFIRI and had progressed on FOLFIRI, surprisingly enough, when you retreated them with FOLFIRI and aplitabart, they responded or had extended periods of progression-free survival. And so we want to see if we can see that same signal in this randomized study. It also helps with enrollment for the patients to know that they're going to get a shot at the drug even if, even if they progress on the control arm. Yeah. Is there an opportunity for an accelerated regulatory path based on this study? Or are there other trials that you will be, you know, starting if the data should be supportive? Well, the short answer to the question to the second part of the question is yes, absolutely. We expect that we will be starting a pivotal confirmatory study, assuming that the data are supportive. But we do think that with strong enough data that this could potentially form the basis for an accelerated approval. We do allow for randomized, blinded review of the scans in order to make sure that this would provide, you know, would support accelerated approval if the data so seem to indicate it. We expect that we will probably have to do a pivotal study with more patients, and that perhaps the endpoint there might be overall survival. Or there's some recent indications that perhaps progression-free survival might even be the basis for a final approval. But. Right. So there's been some other trials announced more recently that, you know, showed differential outcomes in patients that have liver mets or not. I think it's a negative prognostic marker, obviously. So, you know, how do you anticipate things like liver mets or perhaps KRAS status to, you know, affect potential efficacy of your drug? In our single-arm, patients to date, we've not seen an indication that those factors seem to have a significant bearing on the efficacy that we see. We have stratified for both of those two factors. But we think that, at least so far, we think there's a very good chance that this drug will work regardless of the liver mets. We've not seen any toxicity signal as a result of liver mets or any indication that the efficacy is particularly impacted. Same thing with KRAS status. So one of the huge benefits of this drug, if it does become a drug, if it is approved, is that it does seem to be broadly applicable across mutation status, across stage of treatment. And with the safety profile that we're seeing so far, it seems like it could be very, very broadly used. Right. And so, stepping back, how did you actually select colorectal as sort of this first lead indication? And if successful, you know, mechanistically, where else could this work? We selected it on the basis of some preclinical data that showed quite strong synergy in combination with irinotecan. We looked for places where irinotecan was being used. We looked for large markets, obviously. Colorectal cancer is a nice big market. We also looked for places where the standard of care was, the results of the standard of care did not present a particularly high bar to improve upon. We think colorectal cancer was perfect in that case. Because, as I just said, even in second-line colorectal cancer, progression-free survival is about 6 months. In third and fourth-line, progression-free survival is 2 months. You know, response rates are 1% or 2%. There was plenty of headroom there for us to improve on the standard of care. To the first part of your question, we've done a lot of preclinical work with other chemotherapies. We do see significant synergy with other chemotherapies as well. So assuming that we see a positive signal here, we would be looking very strongly at combining in other indications with other chemotherapies. Right. Okay, great. So, then looking forward to the data, the PFS data by the end of this year. Then, yeah, perhaps switching gears over to imvotamab, which is your CD20 bispecific antibody product, where you are now working in autoimmune diseases. And so perhaps, maybe just stepping back, you know, what are potential advantages or areas of differentiation of imvotamab sort of relative to these well-established CD20 antibodies like Rituxan and some of the next-gen products, as well as other perhaps other CD20 bispecifics like Roche, who's also doing studies in lupus? Yeah, I would separate those into two categories. The core CD20 drugs like Rituxan and Gazyva and all the follow-ons there, they're all ADCC-based drugs. So they rely on NK cells and complement for their activity. That's very different than any of the bispecifics, which rely on a much more potent mechanism of killing, the T-cell-directed cytotoxicity. And we've seen the benefits of that extra potency broadly in the heme/onc space, where the bispecifics are clearly just much more potent than the ADCC molecules. You see a lot of success in Rituxan refractory patients. So there's no question that, in general, the TDCC molecules, the T-cell engagers, are much more potent. There's a further factor here. Rituxan has had significant success in some autoimmune diseases, but not the kind of success that you've seen with the CAR-T molecules, even though it's small very small number of patients. We believe that that's because, given the mechanism of Rituxan, the ADCC mechanism of killing, it doesn't do a good job of killing reservoirs of pathogenic B cells that might be in various inflamed tissues, for example. And so while Rituxan or Gazyva or any of the CD20s will wipe out the CD20 cells in the bloodstream, they do a much less efficacious job at killing those, CD20 B cells out in the inflamed tissues and other, other tissues. So we think that, that because we rely on TDCC and the T cells, we a more potent mechanism, we know we believe we're quite confident the drug is going to get there. We've seen it going into solid tumors in the case of DR5 and so forth. We think that the T-cell-directed killing in those inflamed tissues will hopefully eliminate those reservoirs and provide us with an efficacy readout that looks more like what you're seeing with the CAR-Ts, somewhere at least between the Rituxan, ADCC molecules and the CAR-Ts. Right. And, you know, can you speak to your sort of, clinical trials that you're running in autoimmune indications with imvotamab? And, you know, how far are you into those studies? Well, we got IND clearance on those last year, on three we got three IND clearances last year, one in lupus, SLE, one in RA, rheumatoid arthritis, and one in myositis. We're currently actively enrolling in both the RA study and the SLE study. And the myositis study is in the process of being started up. So we should be enrolling there shortly. Right. And what are some of the insights, you know, gained from the lymphoma experience, with the molecule, perhaps relative to other drugs that are also being evaluated in lupus and in an autoimmune context? And, you know, to what degree does that data, you know, translate to possible, you know, positive outcomes in the autoimmune setting? Well, I think the most important data comparison from the oncology setting is the safety profile. We, we do believe that we have a best-in-class safety profile in terms of relatively quite low rate of cytokine release syndrome, relatively low in those small number of cases of CRS that we see. It's generally grade 1, just fever. We, we think that we have a better safety profile in terms of CRS. We also seem to have a much better safety profile in terms of ICANS, the immune cell-associated neurotoxicity, where we've seen none of that in roughly 100 patients that we've dosed in oncology. So first and foremost, we think we probably have a best-in-class safety profile. We've also seen from the oncology setting that we kill B cells. Even in the case of fast dividing tumor cells, we've had complete responses in all four of the major NHL subtypes. So we know we have an active molecule. We believe it has a best-in-class safety profile. We're using what we learned from the titration or step-up dosing that we used in the oncology setting. We want to make sure we really preserve that safety profile. And so, you know, it's easier to go a little more slowly in the autoimmune setting than it is in the oncology setting. It's not. You don't have rampant disease. It's just running away from you. So you can take your time. What we're doing is four doses, one dose each week, stepping up from a low dose up to a maximum dose. And then, at that point, the patient is followed after they've received those four doses. And we wait to see what we see in terms of biomarkers, B cell depletion, and autoantibodies, and a whole bunch of other biomarkers, clinical signs and symptoms. And then perhaps most importantly is when the B cells do start to come back, do those B cells look different than they looked when we first started treating the patient? And hopefully, we will change the ratio of those pathogenic B cells to the B cells that came up from being naive and are now non-pathogenic. This sort of fixed duration schedule is that just something you're looking at to, you know, as a pharmacodynamic, you know, evaluation of, of some of those markers in phase I? Or is it actually something that you could envision happening in, you know, as a commercial product? Yeah, we can definitely envision this as a commercial product. We don't know at this point whether more than four doses is going to be required. And so we believe the right thing to do is start with these four doses and see what impact we have on the B cells. We know it's going to knock down. We believe it's going to knock down the B cells. And then see what happens. It may well be that we need to treat for more than four doses. Maybe there's a window where you treat for four doses and then you come back in. It may be that ultimately there's some patient-to-patient variability in terms of retreatment. But one of the huge advantages we think we have with an off-the-shelf T-cell engager is the ability to easily retreat based on what the patient needs at the time. We think the right thing to do is try this initial, in you could call it an induction regimen, even. Try it, see what we see, and then figure out if we need to start with a longer induction regimen. Do we need, is this good enough, to start and then come back in some number of months later? These are the things we'll learn. Right. And then what's your current guidance for possible data disclosures from these initial trials in autoimmune? Well, one of the things that we've decided is we don't want to disclose data on a one-by-one patient sort of basis. And we want to get through, hopefully, a couple of these dose cohorts and have some follow-up time with those patients to see the B cells come back. So we would hope we'll get through a couple of these dose cohorts this year and have some follow-up. And at that point, it would make sense for us to disclose data. But we don't want to disclose bits and pieces of data. We'd rather we're not in any rush here. We'll get a good, robust data set that hopefully answers more questions rather than just raises more questions. Right. And have you disclosed which dose levels you're evaluating? We've seen, I think, the data for lymphomas. But you know. Yeah. Any, you know, shortcuts there as it pertains to dose escalation? Well, we certainly don't have to go back and start at MABEL's sort of doses. We, we get to what we think is going to be a clinically very active dose in the very first dose cohort. We start and move up. In the fourth dose is the final dose of the cohort. In the first dose cohort, that fourth dose is 100 milligrams, which you may recall from the NHL seemed to be a very effective dose in NHL. In the second dose cohort, we move up to 300. And so we will get, we are getting to what we hope will be clinically effective doses right away, right out of the right out of the box for the first patient. Okay, great. So keeping our eyes peeled for that data hopefully at some point later this year. And then maybe lastly, you do have a pretty broad collaboration with Sanofi around autoimmune products as well as agonist antibodies in general. So can you just update us on any activities you're undertaking as part of the Sanofi collaboration? I can just say generally, we feel that the Sanofi collaboration is going very well. We're excited about what we're seeing there in terms of the molecules that we're developing. We're not able to disclose even targets of those agonist molecules, let alone status in terms of timeline. But we feel we're making good progress. And from all indications, they seem to be very happy with what they're seeing that we're developing both on the oncology side and on the immunology side. Great. Well, with that, I think we can wrap up. Fred, thank you so much for the updates. And we'll look forward to seeing data probably in the second half of this year. Okay. Thanks for the opportunity.