All right, great. Welcome to this fireside chat with IGM Biosciences. I'm very pleased to welcome Misbah Tahir this morning, CFO, as well as Lisa Decker, Chief Business Officer. Welcome and thanks for joining us this year. And so, as some of you may know, IGM obviously recently announced a strategic pivot to focus entirely on autoimmune diseases. Could you just briefly provide an overview of where the company is right now and what the main value proposition for T-cell engagers perhaps is in autoimmunity? Michael, thanks for having us here today. You referenced some pretty big announcements that we recently made. IGM is now focused exclusively on autoimmunity, and we believe we're a leader in the development of T-cell engagers in autoimmunity. We are a clinical stage company. We have three active phase one studies underway and one soon to be initiated phase one study in autoimmune indications of large unmet medical need. All those candidates are wholly owned by IGM, and then we also have an important research collaboration with Sanofi, where we're focusing on the development of agonist antibodies using the IGM platform and are eligible for over $3 billion of milestones, so that's where the company is today. With respect to the value proposition of TCEs in autoimmunity, I think the value proposition is fourfold. There's an opportunity to achieve greater B-cell depletion in tissue. Our CEO, Mary Beth Harler, will tell you that's where the game is going to be won. And with IGM, we have clinical experience with one of our legacy programs, which shows that we can get the IGM drug into tissue. And we also have some encouraging preclinical cyno data, which shows deep B-cell depletion from Imvotamab in tissues and organs of interest. Second, there's an opportunity to deplete where the target is expressed at very low levels. And this could be a key point of differentiation vis-à-vis existing drugs in the autoimmune landscape, specifically Rituxan. We have some encouraging preclinical data on our corporate deck showing that at very low target expressing levels, CD20 expression levels, specifically with memory B-cells, Imvotamab is more potent than Rituxan in depleting. So that could give us an advantage in that space. Third, there's potentially a wide therapeutic window. So as you know, Michael, we started testing Imvotamab first in NHL some years ago, and we dosed nearly 100 patients, and we benefit from that experience, particularly from a safety perspective in the sense that we were able to dose up to 1,000 milligrams with no DLTs. And because of the geometry and size of the IgM, we believe that affords us a more controlled level of T-cell activation, which in turn could be leading to lower CRS rates. So across all of our NHL patients at all doses, our CRS rate was around 15%, predominantly grade 1 CRS. So a wider therapeutic window potentially. And then finally, there's the opportunity for a more convenient method of administration. And this is more specific to vis-à-vis CAR-T therapies in autoimmunity. With a bispecific T-cell engager, it's off the shelf. You don't have the burden of a preconditioning regimen or lymphodepletion. You also don't have to deal with hospitalization. And there's the opportunity for retreatment, which you don't necessarily have with CAR-T therapies. So that in summary is what we think the value proposition is for TCEs in autoimmunity. Right. And so you already mentioned some of the sort of takeaways for Imvotamab, CD20 asset, from some of the lymphoma studies as it pertains to safety, CRS, and side effects. Any read-through or learnings in terms of its activity profile that could be applied to future studies in the autoimmune disease setting? Yeah, absolutely. And even taking a step back further, we've learned quite a bit about just our platform in general. Going back to our IPO, and I'm sure you remember these days, the questions we received most often back five years ago was, could you manufacture IGMs? Could you safely dose it to patients? There were concerns about immunogenicity. And at this point in time, we've dosed over 200 patients with an IGM candidate. And with respect to manufacturing, we feel very comfortable and confident in our ability to manufacture these drugs at scale. We've had multiple GMP runs across multiple numerous IGM candidates. And then from a safety perspective, we've referenced some of the low rate of CRS, as well as encouraging safety across multiple programs. Specifically with Imvotamab, because we were able to dose so many patients and go up as high as we did, we learned quite a bit, and that gives us the opportunity to hit the ground running in autoimmunity with Imvotamab, so we learned quite a bit in terms of what a good step-up dosing regimen looks like to help de-risk the potential for CRS, and that experience in NHL also allowed us to start at what could be a therapeutically active dose. We didn't have to start our RA SLE studies at MABEL. We could start on our very first cohort, go all the way up to 100 milligrams that we showed was an active dose in NHL, and then the other thing we learned about Imvotamab from the NHL days is that we know it's an active drug. We saw complete responses across all major NHL subtypes and really encouraging levels and rates of complete responses. Right. And so there's obviously a lot of clinical data available supporting targeting CD20 in autoimmune diseases, including data on Rituxan, obviously. There's approvals of Gazyva. There's data in lupus as well. And so what do we know about, I think you mentioned earlier, but the ability of a CD20 T-cell engager to perhaps achieve even higher activity in those settings? Lisa? Yeah, happy to address that question. So we very much view the potential of bringing in another mechanism of action above and beyond what the classical monoclonal antibodies have been used in that space, Rituxan, for example, which really relies on ADCC mechanism in order to deplete. And we are aware of the limitations of the approach of using just ADCC. It's been published and known that you don't achieve the same type of deep tissue depletion just with that mechanism alone. So with a T-cell engager, you have the ability to bring in subsequent activity through T-cell engagement to drive for deeper overall B-cell depletion. And as Misbah indicated, with Imvotamab, we are encouraged by the results that we got in NHL and through some of our preclinical experience to really see the depths of the type of B-cell depletion that we hope to be able to recapitulate in the clinic through our autoimmune studies. Right. And then the other discussion at the moment is what's better targeting CD19 or CD20. There's an antibody approach pursuing both targets in lupus and other autoimmune diseases right now. So where do you stand on that? And how relevant do you think is the slightly different expression of both targets for autoimmune conditions? No, it's a really good question and one that we have been getting for a while. What is going to be better, CD19 or CD20? The way that we really view it, there are multiple levers to consider. For CD20, it is a highly validated target in autoimmunity, in particular when it comes to rheumatologic indications, and that's really anchored by the experience of using Rituxan in RA. We also know that if you just go to basic B-cell biology, CD19 and CD20 are largely co-expressed across the lineage, with the exception of towards the tail end of the lineage where CD19 expression continues on activated plasma blasts and then really drops off at the plasma cell level, but if you focus on that active plasma blast population, we know biologically those cells are very, very short-lived. So we feel that for conditions in which are multifactorial and involve multiple mechanisms, not just autoantibody production, a CD19 or a CD20 will likely be a non-issue. It really speaks to the depth of depletion that you're able to achieve. If you want to go after an indication that is very heavily autoantibody producing, you wouldn't use a 19 or even a 20 for that matter. You would go after a different target, such as a 38 or a BCMA. We feel very fortunate that in our portfolio, we also have a CD38 x CD3, IGM-2644, which we are going to be initiating clinical studies on in MG later this year to really test the hypothesis about breaking down the immunologic conditions a little bit more finely to those that have multiple mechanisms of action, such as lupus, versus those that are largely more heavily autoantibody driven, such as in the MG context. Right. So I'll come back to that in a minute. But maybe first, so there has been some clinical data generated with Blincyto recently in RA. And so yeah, I guess what are takeaways from that sort of clinical experience and how does that perhaps compare or read through to other conditions you just talked about, lupus perhaps, or the CD20 approach? Yeah. So again, we are happy to see the validation of taking a T-cell engager into autoimmunity and having that initial experience. What I can say is that given how Blincyto is dosed and the safety profile, we don't think that's going to be a molecule that's going to move forward in that way in autoimmunity because of the liabilities associated with it. So from an IGM perspective, we really look to Rituxan as a benchmark, as an approved molecule for what we're hoping to beat and achieve with Imvotamab. Again, it was reassuring to see the ability to put a T-cell engager in autoimmunity. And we remain laser-focused on bringing forward that informative data for our CD20 x CD3, hopefully by mid-year next year. Then, yeah, I know you recently updated sort of the status of that trial on the most recent earnings call. But can you just remind us of where you are with your phase one study in autoimmune diseases in the various cohorts? Yeah, happy to. So as Lisa mentioned, our guidance is for data disclosure. Initial data disclosure is by middle of 2025. We're making very good progress across all of our programs. In RA, we announced on Friday that we cleared the third dose cohort in RA. In lupus, we've cleared the first dose cohort and are currently enrolling in the second cohort. And with myositis, we just dosed our first patient that was announced on Friday. So data disclosure by middle of next year. And I think the primary reason for that timing is we want to make sure we come to folks with a fairly robust data set, multiple cohorts, and be able to answer the questions that people have that we really have internally. So starting with safety is what we're seeing on the safety side, aligning with our expectations for Imvotamab in terms of B-cell depletion. What does the depth of B-cell depletion look like and how long does it last? And then we also want to be able to answer the questions around what do the B-cells look like when they come back? What do the reconstituted B-cells look like? So those are the questions we have for ourselves that we want to answer over the coming months. And we want to make that part of our update by middle of next year. What does an optimum B-cell depletion profile look like in terms of depth and duration? Sort of what are the goalposts for that in your opinion? Are there any benchmarks for that? Yeah, I mean, I think these are questions we're trying to answer with these studies. I mean, that's probably the biggest question. And for us, it's really about the depth within tissue. In these initial studies in RA and lupus, we're not necessarily going to be able to answer directly that question of tissue penetration. We can look at peripheral B-cell depletion. We can look at the reconstituted B-cells. We can look at various disease severity scores and try to triangulate on are we getting into tissue. With myositis, actually, we have the opportunity for skin and tissue biopsies where we're able to complement the data we're getting from lupus and RA. So I think that is literally the question we're trying to answer. Right. And what are some of the other outcomes or biomarkers perhaps that you're planning to assess in a study that we could see early results on next year? Yeah, Lisa, did you want to take that? Yeah, so as Misbah mentioned, we are going to be looking at peripheral depletion of B-cells in addition to duration of depletion, what that reconstituted phenotype looks like, and other key biomarkers to show whether we are getting that deep depletion in the tissue, such as autoantibody production and other relevant biomarkers associated with disease activity in the relevant patient populations. Okay. And will you be assessing clinical outcomes or ACR scores for the RA study or outcomes for the lupus cohorts? Yeah, for sure. So as part of the studies, we are looking for RA at ACR 28 scores and, excuse me, DAS28 scores, apologies. And for lupus, the disease index that we're looking at are the SLEDAI-2K scores and improvement in disease measures there. Correct. And I think I may be mistaken, but for the lupus cohorts, my understanding is that the enrollment criteria are a little bit more stringent than what has been done in other studies with a higher SLEDAI-2K cutoff. Is that true? And if so, what was the reason for using sort of this higher cutoff? Yeah, it is true. Our SLEDAI-2K cutoff score for enrollment is 10, which is certainly geared toward a more severe patient population. I think that's more a reflection of where we were with the FDA back when we submitted these INDs and were having discussions towards the end of 2022, early 2023. The FDA was certainly at that time taking a very cautious approach toward T-cell engagers in the autoimmune disease setting. We've certainly seen that. And so our protocol and our cutoff criteria are reflective of that. Despite that cutoff, we certainly have had a high number of screen fails as a result of that cutoff. But despite that, we're pleased with where we are in enrollment. And there's continued interest, strong interest from investigators and patients. And we've seen over time the FDA become a little bit more comfortable with T-cell engagers. That's reflected in our myositis study. That IND came a little bit later, and they allowed us to increase the number of doses from four to two optional doses on top of that. And we see with some of the other biotechs that are pursuing T-cell engagers in lupus that they're entering with lower, slightly lower cutoff scores. So certainly, there's an evolution of thought at FDA that we're seeing. Makes sense. So then you mentioned sort of the myositis cohorts started a little later than the RA and lupus cohorts. It's also a more rare condition. So can you just review the design of that cohort here and how you're thinking about enrollment in that particular study? Yeah, very excited about this study. As I mentioned earlier, we just announced our first patient in. This is a study that we're conducting in collaboration with Stanford University, and we're targeting five to 10 patients for weekly doses, building up to 300 milligrams as that top dose, with the option for two additional doses. Those doses can be given at the discretion of the treating physician. What's really nice about this study is that it gives us the opportunity for some deep translational data. We're going to have the opportunity for skin and tissue biopsies. Again, it should be a nice complement to the data we're receiving from SLE and lupus. Great. So then maybe switching gears to CD38, where you mentioned already opportunity in myasthenia gravis. Yeah, remind us again where you are with your phase one study and perhaps talk about the various metrics you're planning to evaluate in the study. Yeah, I'm happy to take that one. So as we believe, we're the only company that has a CD38 x CD3 T-cell engager that we're looking to apply in the autoimmune context. And we think that really speaks to the potential to deliver a mechanism to go after B-cells later in the lineage, such as plasma cells. MG is a canonical autoantibody-driven disease. So it was a natural place to go to really investigate whether depleting those plasma cells could have a disease impact. That study is initiating later this year in MG, as you have indicated. We are very much in the same vein with the MG study as with the lupus and RA studies, going to be assessing depletion and autoantibody production. But in this particular molecule, we're keenly aware to look at the safety profile. We don't have the same amount of clinical data with CD38 x CD3 that we did with Imvotamab. So there's going to be a very large focus on the safety component in that particular study. We also are keenly aware that MG is a smaller indication with a lot of competition in the space. So we're also evaluating other ways in which we could potentially accelerate development in that area. Okay. And yeah, so no, it's early. But when we think about MG, there's obviously the sort of complement inhibitors. There's the FcRn antibodies, which have gained a lot of share at this point in time. And then recently, we saw positive data from Amgen's Uplizna, which is a CD19 antibody. And so yeah, just if you had to project from a clinical perspective, where could your CD38 antibody sort of fit in relative to those other classes of therapies? Again, we think that CD38 as a target really just lines up very well with myasthenia gravis as an indication because you're taking out the plasma cells, which really are generating the pathogenic autoantibodies. We also think that we have the ability to achieve the type of deep depletion that could result in an immune reset that would really differentiate a T-cell engager approach versus some of the other approaches, like you mentioned, for example, Uplizna, which is a CD19 approach. And as a reminder, CD19 is not expressed on plasma cells. So we think there's inherent differentiation in the target in and of itself. Yeah. Okay, great. And then any other opportunities outside MG for CD38? What else is interesting for that? Yeah, I think that once we start getting that initial experience in MG, again, taking the same type of playbook as we are doing from the lupus and the RA studies with Imvotamab, it really has the potential to ungate a lot of other types of indications that we could consider going after that are very largely autoantibody production focused. Great. And then before we wrap up, I just wanted to touch on the Sanofi collaboration. Sort of any updates on that front that you can share? And as you sort of shifted your focus onto autoimmune diseases in-house, has that affected the partnership in any way or perhaps overlap in opportunities that you're pursuing there? Yeah, I'm happy to take that question as well. We are really pleased with the level of engagement that we have from our collaborators at Sanofi. As Misbah mentioned earlier, we are working with them on three targets in autoimmunity to drive agonism using the IGM platform. The collaboration continues to go well, and we really think that our pivot aligns very, very nicely with the pivot that Sanofi announced earlier in the year as well to focus on autoimmunity. Great. Well, thank you. Well, with that, I think it's time to wrap up. So we're really looking forward to the Imvotamab data next year. And with that, I'd like to thank you for being here. Thank you, Michael. Thank you.