We're going to go ahead and get started. I'm Stephen Willey, one of the senior biotech analysts here at Stifel, and glad to have with us for the next session the new CEO of IGM Biosciences, Mary Beth Harler. We're going to have an informal discussion. If anyone has a question, feel free to raise your hand. We'll try to get your question asked and answered. Before we jump into Q&A, Mary Beth, is there any opening comments you want to make? I know you're fresh off of ACR. I'm sure we have a lot to talk about. Yes, we do indeed. And first of all, thank you for having us, Steve. This is an incredibly energizing time to be part of the autoimmune space right now, given the explosion of activity around B-cell depletion in particular. So I think it sets the stage very nicely for what we're trying to achieve. All right. So maybe we can just kind of reset the clock. A month or two ago, you guys made a pretty big announcement in terms of strategically pivoting to autoimmune disease exclusively. So I know when you made this decision, you obviously had open label aplitabart data at your disposal. You had a little bit of open label imvotamab data in lupus at your disposal. So should we take that decision to reflect anything about those two emerging data sets? I.e., is that decision part and parcel an indictment of aplitabart and maybe a vindication of imvotamab? I would say both. OK. All right. And I'll begin with aplitabart, which was our DR5 agonist. We were evaluating in colorectal cancer. We had set a high bar for progressing that molecule into phase II studies. And as we evaluated the emerging data, it became clear that the molecule was not going to meet those criteria. At the same time, as you note, we were already well underway in terms of the clinical development of imvotamab in a range of autoimmune disorders, including rheumatoid arthritis, lupus, and myositis. As you note, the lupus study is open label. The rheumatoid arthritis study is placebo-controlled, but suffice it to say we have some visibility to some of the biomarker data. And without getting into inappropriate discussions on emerging data, I'll just remind all of us that CD20 is a highly validated target in autoimmunity. We know we have an active molecule in imvotamab. The molecule was studied in about 100 patients with NHL, where we had a range of responses, including complete responses across all major subtypes of lymphoma. So we've got a solid target. We've got an active molecule. The question for us now is, how do we take this potential, do the hard work that is necessary from a drug development perspective, and really enable efficient, well-informed decision-making going forward? OK. And we'll certainly talk through some of that here over the next 25 minutes or so. So I guess the movement that you guys made away from oncology to autoimmunity, I mean, this kind of seems to be a pretty industry-wide trend right now, right? Both smaller companies like yourself, I think even your partner, Sanofi, has kind of reprioritized most of its development efforts into the autoimmune space. How do you think about just those two therapeutic arenas with respect to the opportunities for value creation that exist right now? And as you look at this migration to autoimmunity, what are your thoughts in terms of what the density of the competitive landscape may or may not look like in the next five or 10 years? So as you know, these two therapy areas oftentimes walk alongside one another in many, many companies. And this has been true for the last couple of decades. While many, many companies refer to the inherent synergies and the benefits of knowledge sharing and sort of translating insights from one to the other in practice, that can actually be quite difficult. I've lived in that scenario at least a couple of times. What I would say now on the biotech side, it's actually a lot easier to make that happen. As I think about where we are as this pendulum swings, yes, we are, whether it's peak activity or perhaps even a bit beyond peak activity, I don't know for autoimmunity. I do expect that pendulum to swing back towards oncology at some point with the appropriate data catalyst. When that occurs, I do not know. But it's sort of equal parts terror and validation, actually, to see all of the activity that has now funneled into this space. OK. So that activity that we've seen funneling into the space has been defined by a lot of different modalities. How do you think about the opportunity for T-cell engaging bispecifics? And then maybe more specifically, how do you think about the value proposition of an IgM-based T-cell engaging bispecific relative to the larger universe of IgGs that seem to be out there? Yeah. We see an important set of opportunities that reside across the range of B-cell mediated diseases that would benefit from deeper depletion than achievable through IgG ADCC-driven molecules, but without all of the burdens that come with a CAR-T approach. I do think there will be an important place for CAR-T, perhaps for the most severe of autoimmune disorders. But it's kind of difficult today to envision how CAR-T could be broadly applicable across many, many patients with autoimmune disorders, certainly not without a lot of, I guess, improvement in cost, feasibility, logistics, and so on. So again, I think if we envision an off-the-shelf product that does not require hospitalization, that delivers deeper control of disease activity than current therapies, allows intermittent therapy to enable that deep control of disease, we see that as an important set of opportunities. To your question on differentiation and why do we think we have a play with an IgM format, we would argue that, in fact, this multivalent structure, together with the engineering that has gone into imvotamab, so this is a 10-to- 1, 10 CD20 binders to a single non-detuned CD3 binder, that multi-armed structure enables great avidity. So the vision here is infuse the molecule. Again, this is currently IV. We have subQ in development. Infuse the molecule, enable sufficient concentrations to push the molecule into the tissues of interest. Once this thing lays down and binds, we believe that the off-rate is very, very low, perhaps even close to zero. So again, that's a feature that stems directly from this multivalent format. There is another aspect that I think is going to be critically important in the discussion around T-cell engagers. And this speaks to safety. At the end of the day, we believe that it's going to be that balance of safety to efficacy, otherwise known as therapeutic index, that will define the winners and the losers for T-cell engagers in autoimmunity. That 10-to-1 ratio on an IgM format inherently controls the level of T-cell activation through this molecule. We believe that is what is accountable for the CRS rates that we observed in NHL. It was a large part of our therapeutic hypothesis bringing the molecule into autoimmunity, where we knew that safety considerations were going to be of paramount importance. Okay. So maybe we can dig into imvotamab, your dose escalating in RA, lupus, myositis. Where do you stand right now in terms of enrollment? I know it's a question that we get a lot about. A lot of investors are asking the questions just because FDA is kind of making everyone step through these severe refractory patients first. But as you look across those three indications, can you maybe also just speak to any headwinds or tailwinds that you see within any one of those specifically? Yeah, so as I believe you know, Steve, we undertook the decision to pivot strategically for imvotamab a couple of years ago. In fact, it was in advance of the really sort of game-changing data that was published by Georg Schett and colleagues at the end of 2023. We rapidly implemented a multi-pronged clinical development program, and we've been very, very pleased with the execution on those studies, so at a time when I know many companies are literally just coming into this space, getting INDs filed and cleared, we, in fact, are already very well underway. The kinetics on each of these studies, RA, that program is doing exactly what we intended it to do. This is a more prevalent disease. We've been very, very pleased with our progress. We recently disclosed that we've cleared cohort three in the RA study. Lupus, as you know, has been the subject of great interest following the CD19 CAR-T data. A lot of competition for patients. Despite that, or perhaps even because of the attention now brought to this space, we have seen a lot of interest coming into our lupus program on behalf of patients, on behalf of investigators. We've screen-failed a fair number of patients with lupus because our focus today, as you said, is on patients with more severe disease, SLEDAI-2K of 10 and up. So suffice it to say that renders many patients ineligible for our study. It's where we're starting in terms of defining our profile as a foundation, not necessarily where we intend to end up. But we do think that these particular patients, i.e., those who have perhaps burned through a lot of the available options, they continue to have significant disease activity. For us, that could represent actually a very attractive opportunity, so we do not intend to overlook that. The myositis piece, again, that's unfolding. This is a much smaller, heavily translational effort we are conducting in collaboration with Stanford University, so we recently disclosed treatment of our first patient there, excited about how that data will complement that coming from RA and lupus. This study will enable biopsies, skin, and muscle to give us a sense of whether or not we are impacting local disease biology. So a lot going on, and we're pleased with where we're at today. Okay, so I know you were previously guiding to having an update by, I think, the end of this year, early next. That timeline was just pushed out to the middle part of next year. So can you just maybe expand a little bit on the decision-making process here and what this extension now means for the amount of indication-specific patient data that we should expect to see in the middle part of next year? Yeah, so again, another relatively recent disclosure that also coincided with my appointment in leading the company as we kind of stood back and evaluated where we were with our program and, frankly, what we want to achieve with these data, which is twofold. We felt that this was an appropriate next step in terms of setting expectations, and I do want to come back to what our goals are. They are, number one, to be able to come forward with a high-quality data set, a data package that will truly inform on what the future potential for imvotamab might be in an autoimmune setting. In our eyes, that means more than anecdotal-level data. It means having at least a couple of cohorts' worth of patient experience with enough follow-up in time to enable capture not only of the acute impact of B-cell depletion via imvotamab, impact on autoantibody titers, clinical disease signs and symptoms, importantly, the immunophenotype of those reconstituting B-cells, and possibly the opportunity to do that across diseases, as you mentioned. That seemed to be a really compelling opportunity for us. We also believe, because as you know, we've always approached this through a long-view lens, and to be able to come forward with data that not only speaks to future value, but also informs on next steps for an efficient phase II development program and in what diseases, we felt that was a good approach for our company. OK. I know you and I have had a discussion before around just whether or not the exposures that you're giving within the first couple of dose escalation cohorts would be sufficient to drive depletion of tissue-resident B-cells, and again, I think that's probably just largely based on my naive interpretation of non-human primate data, but does the extension say anything about those exposures that you have right now? What I would say is that, again, we are still accruing data. And very much through that same lens of how do we set ourselves up for the most informative data package and the most efficient progression to phase II, that's a question that we think a lot about. The follow-on to that line of thinking is, what do we need to do now in order to ensure that we have a good understanding of an optimal exposure, an optimal dose regimen to really deliver on the safety and efficacy profile that we believe is going to be necessary to succeed in this space? Dose and regimen optimization, we view as part and parcel of the current experiment. To the extent that pushing the data disclosure back a couple of months, for us, that's a good investment of time. OK. So how do you think about maybe interrogating regimen optimization? And I think we get questions around not necessarily the magnitude of the dose levels that you're escalating to, but also the duration of time for which you are dosing. So just four weekly administrations, I think you're probably stepping through a potential maybe one or two potentially subtherapeutic doses on your way there. So how do you think about trying to optimize regimen based upon this data that you're going to be generating? What could be the next steps that you look to implement to gain some insight there? Yeah. So again, important viewing this through the lens of delivering, hopefully, an optimized dose and regimen at the conclusion of these experiments, these studies, to enable a very efficient progression to next stage. This could include, absolutely, as we learn more and again, these are live studies. As we learn more, does the data begin to tell us that, in fact, we are hitting the target well? And now it's a matter of sustaining that level of activity. Is it a question of, well, perhaps we need to hit the target harder or more frequently? All of these are the kinds of questions that we are seeking to address now. We want to address the tough questions now, again, so that we not only understand what we have, but we can increase our confidence as we move into phase II. To defer those questions into phase II, while they might provide some short-term gratification, if we could come forward with some very interesting near-term data, but without addressing the harder development questions, we believe that that is a nearsighted approach. And as you know, our goal here is much more long-focused. Yeah. Presumably, you'll have at your disposal the ability to triangulate B-cell reconstitution data, clinical data, and maybe come to a conclusion that I might need to redose a patient after three months, four months, six months, if at all. That's exactly right. As you know, standard of care in the autoimmune setting is intermittent therapy. I think that's a very realistic way of viewing a B-cell depleter. And again, one that ideally offers deep control at the expense of intermittent treatment, based upon our discussions with clinicians and thought leaders, that's a very acceptable trade-off for that kind of advance. OK. You kind of inferred earlier that you're able to see biomarker data, I guess, on a blinded, blended basis coming out of the RA study. Can you maybe share what some of that biomarker data is and if there's anything on the directionality side that you could share as well? Yeah. So again, we have not disclosed any data yet. But again, I'll just again remind us, CD20 is a well-validated target. We've got an active molecule. The studies continue to accrue. We've got a highly invigorated investigator base. So I think sort of collectively, all of those considerations, they're going in the right direction. OK. I know we've talked about the BLINCYTO EAP experience in RA. I think Schett updated some of that data at ACR this past weekend. I know we've also discussed about maybe how the BLINCYTO data, in your opinion, is maybe not the competitive benchmark against which you should be held hostage to. And I guess along those lines, how do you think about not being held hostage to that? How is that driven by either differences in the trial design, the patient population, the safety tolerability profiles of the two agents, and/or just the differences in the target antigens that you guys are going after? Yeah. There's a lot in there, a lot packed in there. I'll start with the fact that CD19, as compelling as many of these emerging reports are, CD19 is not a validated target in RA or lupus. The only approved B-cell depleter in rheumatoid arthritis is rituximab. And there is a world of difference with regard to levels of evidence when we consider the data behind rituximab versus the emerging data on either CAR-T or a bispecific approach on CD19. We were gratified to see the BLINCYTO data. I think we've shared that position with you previously. Again, it helps substantiate the notion of taking a T-cell engager into rheumatoid arthritis. BLINCYTO itself may not be, in its current formulation and administration, may not be a good fit, certainly not for rheumatoid arthritis requiring in-hospital infusion over multiple days and some significant safety considerations that have emerged on the oncology front. So if we stand back and step away from the debate on whether or not a CD19 is substantially different from a CD20 approach with respect to deep B-cell depletion, we believe that much more important than CD19 versus CD20 is the depth of depletion any one modality can deliver. If we can deeply eradicate those tissue-resident B-cells that might otherwise serve as reservoirs for pathogenic B-cell drivers of disease, we believe we have an opportunity for a step change improvement here with imvotamab in RA. We're going to learn. We're going to learn more as these data come forward. I read with interest many of the comments coming from the clinicians who were managing the BLINCYTO program in RA. And I think they, too, are compelled by kind of the initial proof of concept, but also recognize that there will need to be an improvement in formulation, delivery, hopefully, safety, better safety than what is observed in the oncology setting in order to bring that forward as a feasible therapy in that setting. OK. I know the literature seems to suggest that the role of plasma cell biology across these different autoimmune disease states is likely different, whereby it may not be so pronounced in something like RA. It certainly has a role in the pathology of lupus or Sjögren's or something like that. Do you agree with that, I guess, and does that kind of give you a sense as to this notion that you might be more efficacious in something like an RA as opposed to a lupus, where maybe you need to go a little bit more downstream in terms of terminal B-cell depletion? So let's back up and remember that B-cells contribute to autoimmune disease through a variety of channels. First and foremost, B-cells are professional antigen-presenting cells critically important in initiating and driving autoimmune disorders. B-cells are prolific generators of pro-inflammatory cytokines. And then, of course, there's the third limb of this stool, or probably more, but the third limb of this stool that has received great attention recently, and that's around their role as precursors for future autoantibody-producing cells. So critically important that we not lose sight of the fact that where CD19 and CD20 and moving into the plasma cell space, the autoantibody space, that really starts to speak to a very specific disease biology, probably best codified by diseases such as myasthenia gravis or some of the autoimmune kidney diseases and so on. Many other diseases are driven by the earlier stages of B-cell subsets, and hence the reason that rituximab and other B-cell depleters that target CD20 are so effective there. I do think it's really important as we think about how these two approaches could complement one another. They do speak to differing B-cell biologies with respect to given diseases. And by definition, I believe they will also come with different safety implications. I don't think it's unreasonable to think that therapies that target plasma cells, long-lived plasma cells, which of course will also impact host immunity, protective immunity against infections, there may be some necessary funneling or narrowing of the kinds of patients that might be appropriate for such interventions. I think that will be quite different from the way that we think about patients who may be best candidates for a CD20 approach. So, a rather long-winded response, but I. It was a long-winded question. It was, like you usually do, but that's OK. We're even there. I do see these two approaches as complementary, but requiring a thoughtful approach to patient selection on both sides. OK. And you obviously have the ability to toggle that other group of patients via your CD38 biomarker, which is going into the clinic before the end of this year. So I think we've heard from physicians that there seems to be some correlation between the perceived burden of administration, safety tolerability, and then the efficacy benchmark that you're going to be held hostage to. So in the CAR-T space, that efficacy benchmark is 100% drug-free remission rate. Have you gotten any sense from your conversations with physicians what that efficacy benchmark is for a drug that is off the shelf, presumably has a clean safety tolerability profile like we saw in non-Hodgkin's? What are they telling you that that efficacy needs to look like? This is a very fluid conversation, as I think you probably know. The good news is there are a lot of conversations taking place. I think empirically, we know we have to do better than rituximab. We need to do better than the ADCCs. That goes without saying. I think the question is, how much better than the ADCCs, and how much, if any, of that CAR-T effect do we need to capture? That interval, the space between those two bookends, is actually quite broad. I have heard figures just in conversations with different individuals, treating clinicians, thought leaders, that range from at least a 30% to at least a 30%+ improvement, for instance, in a DAS28 score relative to rituximab. Again, this is very informal information that I'm sharing with you. We've also heard thoughts from thought leaders pertaining to how much they would like to see in terms of shifting that reconstituting immunophenotype for B-cells coming back. I do believe it's probably going to be more of a qualitative answer to this question. If we can deliver deep disease control, meaning we can drive a substantial number of patients down to remission or to low disease activity, ideally enable some tapering of concomitant medicines, ideally corticosteroids. We know that is very, very important to patients. Together with an improving immunophenotype for those reconstituting B-cells, I would argue that is a win. I do think, Steve, that as we get further into this data generation phase that we are in, there will be a closing of the gap between some of the aspirations, including multi-year drug-free remission goals, and perhaps what is realistically achievable through different modalities. Just looking from last year to this year, we've come miles. I expect by next year, we'll have a better read on that. OK. Maybe last question. I think we're going to be kicked out of here soon. So I guess if things go to plan with imvotamab, I think the opportunity set here is probably pretty big. Do you think that opportunity set is better captured by a better-resourced strategic partner? I know we moderated a lunch panel with Tim Opler yesterday. He's part of our banking team. And he said that the one thing that he's hearing unanimously from every single large pharma is that they want a T-cell engager for autoimmune disease. So I would imagine the demand is there if the data is there. But what is your preferred deal structure? Our preferred structure is whatever is going to maximize value. So that's commitment, breadth of CDP, alignment on philosophy. You're right. It's a hot space. So I think in our minds, even more reason to come forward with that high-value data package mid-2025. OK. That's all we have for time. Mary Beth, thank you very much. Thank you. Thank you, everyone.