All right, good afternoon, everyone. I'm very happy to have with us here, as part of this Stifel I&I Summit, CEO of IGM Biosciences, Fred Schwarzer, and with him is Mary Beth Harler, who heads up the autoimmune development efforts at IGM. Fred, not sure if you wanna make any opening statements here before we get into Q&A? Sure. First, thanks very much for inviting us, Steve. We really appreciate the opportunity, and I think the only opening comments I would make is that we're very excited about the potential for our T-cell engager platform in autoimmune. As you know, we've got two programs that we're in the clinic or heading into the clinic, and we have additional programs that we're developing, and we think that our safety profile, in conjunction with the efficacy certainly that we've shown with imvotamab in oncology, makes us very well-suited to be a successful T-cell engager in addressing autoimmune diseases. With that, I'll let you get into the details with Mary Beth. All right. Very well. Thank you. So Mary Beth, let's start with imvotamab. You know, this is the CD20/CD3 bispecific you're currently dose-escalating in RA, lupus, myositis. I know you guys provided an enrollment update last month. Maybe you can just kinda remind us where you stand on enrollment at this point. Are there any updates to provide? And then, what, if anything, has been rate-limiting in terms of patient enrollment kinetics into each of these indications? We continue to be very pleased with our progress in recruiting both the SLE as well as the lupus studies, despite the highly competitive trial environment for the latter in particular. Note also that both studies have a global footprint. We have recently announced clearance of the first two cohorts in RA, and clearance of the first cohort in lupus. To your question on you know, any potential barriers, our focus, our current focus on patients with more severe disease has led to a number of patients being screened out, but we continue to be encouraged by the level of interest that we are seeing coming from investigators as well as patients. We believe that speaks to the unmet need for more effective therapies in these diseases. Myositis, which is much more rare than lupus, and certainly more rare than RA, was more recently initiated. Although this is a somewhat smaller study, we believe it's going to contribute some very helpful translational information, including biopsy data, sophisticated imaging, and so on, to really complement the datasets coming out of RA and lupus. Mm-hmm, and I think we've seen lupus become really competitive as a function of all the different CAR T modalities pursuing patients. It seems like there's been maybe a little bit of a shift in some of those CAR T development efforts towards myositis in some cases. I think that's becoming a little bit more of interest to some of these companies. Do you think that myositis, given that it's rarer than lupus, could become even more challenging of an enrollment mandate? It could be. You know, the good news here, again, the way we have fashioned this particular study is, you know, we don't, we're not gonna need a whole lot of patients, right? Because our intent is not patient volume, but rather depth of information, right? So, we'll evaluate, you know, the readiness of the data as we move along, but it really is another leg of a multi-legged table or stool, so it's really through that lens of bringing complementary data that we view this particular study. Okay. So I know that you've suggested previously the need to have a requisite amount of data in hand before you're comfortable providing any kind of initial disclosure to the street. What should we be expecting in terms of patient numbers, duration of follow-up, and then how does all of that inform disclosure timelines, for each of these indications? Our goal is to come forward with enough data to inform on the future potential of imvotamab in autoimmune disease. For us, that means a couple cohorts' worth of patients with at least three months of follow-up, rather than anecdotal reports of small, uncontrolled experiences. At this point, we continue to plan for either the end of twenty twenty-four or early twenty twenty-five for this initial data disclosure. Okay. And then, as we think about what that disclosure might look like, what are some of the specific data points that you want to be able to communicate to investors when you actually make these disclosures? And should we assume that these disclosures will look similar across all of these trials, or could we actually see some indication-specific variability with respect to what you disclose? ... So not surprisingly, we are going to be evaluating depth and duration of B-cell depletion, impact on autoantibodies, clinical signs and symptoms, and importantly, the phenotype of those reconstituting B-cells. Are we starting to see a shift towards more, a more naive B-cell phenotype rather than predominantly memory B-cells coming back? Those are the kinds of things that we're gonna be watching for. We will also be speaking to the safety of imvotamab in this setting. Given the increasing interest in T-cell engagers in autoimmunity, we continue to believe this is going to be a very important consideration for treating clinicians, and we believe further it will be a key differentiator for imvotamab in autoimmunity. To your last question, on the potential for differing outcomes across different diseases, I think we need to remain open to that possibility, given differences in disease drivers, differences in the ways that we measure disease activity, differences in baseline immune status, and so on. So, I think it's a salient question, and, you know, I think we're maintaining open minds on that. Okay. Maybe we can dig into RA specifically. I think there's obviously, you know, a lot of interest here following the publication of data from the Blincyto expanded access program earlier this year. How does that Blincyto data, you know, both in terms of B-cell depletion and reconstitution, immunophenotyping, and clinical benefit, how does all of that inform what you're hoping to show with this initial imvotamab disclosure, maybe particularly as it pertains to some of the clinical efficacy metrics we saw in that manuscript, like DAS28? And maybe just to further complicate the question, should we also be thinking of the Blincyto data as kind of an appropriate benchmark for you guys? So we see the Blincyto compassionate use data as providing initial validation for a T-cell engager in rheumatoid arthritis, and of the types of analyses that we see in the Blincyto report, I think are very similar to the way that we will be evaluating imvotamab in RA, including the immunophenotyping work, as well as DAS28. I think the data do speak to the power of a T-cell engager as part of an induction regimen, at least for the Blincyto experience. Having said that, I think it's premature to view the Blincyto data as a benchmark. Remember, this is an uncontrolled, very small experience, six patients in total, five of whom received Orencia as maintenance therapy. The benchmark here is Orencia, which is approved for use in rheumatoid arthritis. A number of important questions do remain, including what a regimen optimized for exposure, response, and safety over time would look like. And I think it's important to remember, RA is a chronic disease, right? What could be the role of a T-cell engager as part of a long-term maintenance regimen, right? Can intermittent dosing actually maintain remission or low disease activity over time? The reality is that Blincyto is not able to address many of these questions, you know, because of the associated safety profile, the need for continuous infusion and hospitalization, and so on. But we believe imvotamab does have that potential for chronic administration over the long term, so we're setting out to answer these questions. Okay. So your perspective on Blincyto as a benchmark then is... seems like it's geared perhaps more just based upon the smallness of the data that's been generated to date, and not necessarily the targeting of CD20 versus CD19. This is not an antigen-specific- No, this is a depth thing. Okay. I guess along those lines, with respect to twenty versus nineteen, you know, obviously the competitive landscape here is pretty heavily tilted towards CD19, although that does seem to be changing here a little bit, which is interesting. I know a lot of the questions that we typically field about this asset, you know, are asked in the context of being able to recapitulate some of the CD19 targeting data that we've seen to date, by going after an antigen that is, you know, that has expression lost on some of these pathological autoantibody-secreting cells. So I guess the question here is, you know, are you, are you still confident that you can generate a competitive efficacy profile in these autoimmune disease settings with a CD20 targeting modality? Based upon our in vitro and in vivo cyno data, we do believe that imvotamab has the potential for a differentiated and competitive profile in autoimmune disease. There are a number of reasons that we believe CD20 is a robust target for a T-cell engager in autoimmunity. I'll note that, again, CD19 and CD20 are co-expressed on 95% plus of B-cells. The vast majority of the short-lived plasmablasts, in which we start to see CD20 expression coming down as those B-cells mature into future autoantibody-producing cells, we know that the vast majority of those cells die within five to seven days. Last but not least, just evaluating, you know, the full body of evidence out there. CD20 is a well-established therapeutic target in autoimmunity, with multiple approved drugs, unlike CD19. That probably relates to both mechanistic as well as clinical reasons. On the mechanistic side, we know that CD19 is a rapidly internalized receptor, making it challenging for a T-cell engager platform. And on the safety side, we know that the you know the CRS and the ICANS associated with currently available CD19 therapies in oncology probably render many of those molecules unacceptable in an autoimmune setting. I think it's also important to remember that B cells drive autoimmune disease through multiple actions, not just autoantibody production, right? So that includes you know being B cells are professional antigen-presenting cells. They generate prolific amounts of pro-inflammatory cytokines. So the contribution of any one or more of these pathways to autoimmune disease may in fact differ across diseases. Example, RA is heavily driven by the antigen presenting activities of a B cell whereas lupus, on the other hand, is driven by all three. I think the bigger question is, which of these B-cell-depleting therapies will actually yield the best overall net impact by addressing all of these levers according to the drivers of a given disease? Okay. And I know you just mentioned the cyno data, and I want to ask a question on that in a minute, but maybe just kind of honing in on the RA protocol specifically, right? So I guess when you look at the Blincyto manuscript, I think four of six patients were allowed to stay on background methotrexate at time of study entry. I think per protocol, right, they reintroduced abatacept or Orencia at week 16. Yep. I know the imvotamab protocol allows for continued use of background oral corticosteroids if it's less than a certain amount and stable, but is background methotrexate also allowed, and is there gonna be any kind of protocol-specified introduction of maintenance therapy at any time point here? So methotrexate is permitted as background therapy in our RA study, and I think it's important to note that's conventional in clinical trials of RA patients with more severe disease. It's important to note that these patients continue to have severe disease activity, despite the presence of methotrexate and background steroids and so on. Our current protocol does not call for the introduction or withdrawal of any of these medicines. Okay, that's helpful. And then this is probably gonna overlap into lupus a little bit, but I know, you know, this concept of a drug-free remission objective here has been probably talked about mostly in the context of lupus. So maybe I'll ask it from a lupus point of view. You know, your lupus trial protocol, I think not only allows for stable background therapy, but also seems to not allow for any tapering of that therapy to occur until after week eight. So I guess, what background therapy in lupus are you allowing for at time of study entry? And then does this delayed tapering impact, i.e., you can't do this until after week eight, does that impact the duration of follow-up that you'd want to have represented in any initial data disclosure, given the fact that you're probably gonna want to try, or maybe you don't want to try to taper these patients off of background meds? Yeah. So let's start with your initial comment, right, around the gold standard, and we agree that, you know, ultimately, a future gold standard should enable the withdrawal of concomitant medications. But we would argue we're not yet there. We need to see reproducibility. We need to understand how generalizable these effects are with regard to a broader, more heterogeneous set of patients with autoimmune disease, and I do think that deep B-cell depletion is one important step along the way, and we do believe that imvotamab could play a very important role in helping to define what good looks like for these future therapies. Now, with respect to the ongoing RA study, we are not tapering off any background meds, as I mentioned a moment ago. We're focused first and foremost on ensuring that we optimize the B-cell depletion, after which we will start to refine the overall regimen in order to maintain longer-term control of the disease, while hopefully, in the future, starting to reduce the burden of concomitant medications. So step one, optimize the depletion. Step two, then start refining that treatment regimen for long-term use. Okay, and then just with respect to the background therapy that is allowed in lupus, have you specified what that background therapy is? ... Yes, yes. So, very, you know, I would argue conventional for a lupus trial. And again, I'll just remind our audience that, you know, much of what we've seen come forward thus far has actually not been in the context of a clinical trial. It's been in a compassionate use, sort of uncontrolled setting, certainly from the CAR T perspective. For our ongoing study, yes, we are permitting stable doses of anti-malarials, as well as immunomodulators, such as MMF and background corticosteroids. And again, very consistent with what one would expect for a severe lupus population. As I noted a moment ago in the discussion on RA, at this point in time in the development stage that we are with imvotamab, we're really focused on answering those key foundational questions. Are we... Are we optimizing the B-cell depletion to the extent possible with imvotamab? Are we starting to see, you know, some key PD markers respond as anticipated? And are we starting to see evidence of clinical signs and symptoms begin to correlate with those biologic drivers? You know, I do think that answering these questions in a systematic, but efficient fashion, nail the B-cell depletion, and make sure you're impacting the biology, and then refine the regimen over time, such that we are in good position to initiate mid to later stage development. I think that is ultimately a winning playbook, right, you know, to produce medicines. Mm-hmm. Okay. Maybe just going back to the cyno data for a minute, you know, how confident are you that these initial imvotamab doses that you're escalating to will achieve the necessary depth of B-cell depletion that's needed in tissue specifically? And I guess going back to the cyno data, right, you showed reductions in CD20 positive B-cells, I think of around 85%-90% in the lymph and spleen at a cyno dose of 5 mg per kg administered, I think four times over the course of 10 days. I guess my math would suggest that that kind of translates to a flat imvotamab dose that needs to be kind of north of 100 mg to get to that same level of depletion. So, do you think that you're gonna be achieving kind of sufficient exposure levels in these first two cohorts to get that desired level of benefit that you think you could achieve? I think the data from these first couple of cohorts will inform on how much exposure is needed to deliver deep B-cell depletion, certainly to the extent that we are seeking. You know, and again, as I mentioned a moment ago, you know, how that starts to correlate with, you know, proximal PD markers and clinical outcomes. You know, if the emerging data start to suggest that we need to hit the, you know, the target harder or for longer, I can assure you, we will be adapting our protocols to enable that. Example, right? If we believe that patients will benefit from additional doses of imvotamab, right, when compared with the challenges of administering either a Blincyto or a CAR T, we believe that kind of trade-off would be very acceptable in the setting of a very significant and clinically meaningful treatment effect. So again, kind of coming back to yet another differentiator that we see for imvotamab, that off-the-shelf outpatient ability to administer as needed in order to maintain deep control of disease, we view as a key differentiator in this exploding space. Okay, so it kind of sounds like the next development steps here will be dictated by the exposure data and the clinical- That's right that you're able to extract out of these first two or three cohorts. Okay. That is correct. So safety, I think obviously, you know, seems to be a competitive advantage for this asset, specifically with respect to CRS. I think we've talked before about how there may be some aspirations with respect to maybe moving this into an earlier line of therapy with less severe patients. How much data do you think you need to have in hand to kind of have that population expanding discussion with regulators, and do you need to have that discussion with regulators on an indication-by-indication basis? Yeah. We do see our safety profile as a competitive advantage in the autoimmune space, and a key differentiator, again, relative to other T-cell engagers. In terms of when and to which populations we extend into, you know, there remains very significant unmet need in patients who have failed multiple treatment options, exactly the kinds of patients that we are currently studying in both RA as well as SLE. So we want to ensure that we are paying adequate attention to these populations, which are underserved with today's currently available therapies, even as we consider who and when to pivot to other kinds of patient populations, including those with less severe disease. In terms of your question on regulatory discussions, yes, we absolutely do anticipate that these conversations will be indication by indication with FDA and other health authorities. Okay. Maybe just a couple more imvotamab questions. The myositis protocol allows for this potential retreatment or the potential administration of a couple of extra doses. I guess, why is retreatment only allowed in this trial? Why wasn't that kind of built into the RA and lupus protocols? And then, what dictates the administration of additional doses? Is that kind of predefined, objective clinical criteria, or is that really just left to the investigator's subjective decision? Mm-hmm. So one of the important goals of the myositis study is to understand whether two additional doses at 300 milligrams will offer deeper or more sustained B-cell depletion. It's notable that at the time that we submitted the INDs for lupus and RA, which was relatively shortly after the initial publication by Georg Schett in Nature Medicine on the first cohort of SLE compassionate use patients. At that point in time, FDA was clearly very cautious in their thinking about the use of T-cell engagers in autoimmune patients. Of note, by the time that we submitted the myositis IND several months later, they were much more receptive to the notion of additional doses beyond the 4 currently specified in our RA and SLE studies. So I think, you know, in short, right, their exposure to multiple efforts focused on deep B-cell depletion does appear to have had some impact on their receptivity to dosing over longer periods of time and with more therapy than what they had been initially. With respect to, you know, what will trigger the use of those two or the administration of the two additional doses, the protocol allows the PI to make that call based upon what he or she is seeing in the patient, so we are not pre-specifying the criteria. Okay, okay. I know we're running out of time here, but I don't want to leave you without asking a question about IGM-2644- Yeah ... which is the CD38, CD3 bispecific. So you're guiding to dose escalation occurring here in generalized MG before the end of the year. What are those patients gonna look like, just from a severe refractory perspective? Are these gonna be patients who have failed prior complement inhibitors? Are they gonna have to be FcRn experienced? Do you have to kind of take that same severe refractory phenotype and apply it to this indication as well? Yeah, we're very excited about this, this particular program. We think 26-44 has potential across a broad range of autoantibody-driven cells, and, you know, we think this will be a much more direct approach to those types of diseases, offering a very nice complement to imvotamab, the CD20 by CD3. We are indeed targeting a moderate to severe MG population, that has failed at least one standard of care therapy. So, we are not pre-specifying what that standard of care therapy must have been, but this is the protocol that we're currently moving forward. Okay. And then maybe just last question: Should we think of gMG as just kind of a surrogate indication here, where you'd want to get an initial read on what efficacy looks like? Or should we expect to see more of these diseases where you kinda wanna target that more terminally differentiated B cell? Do you wanna see more of those diseases come online, whether it's stuff like ITP or IgAN? Yeah. Yeah, again, we see a lot of potential here. gMG offers, you know, a couple of key advantages. The first is the relatively tight correlation between autoantibody titer and clinical disease activity. The second point, clearly there is an attractive market opportunity here, as demonstrated by a number of other molecules. Having said that, we also think there are additional ways that we could generate informative data, that go beyond gMG, and we are, at present, thinking through what the most efficient of those approaches might look like. So more to follow. All right. That's it for time. Mary Beth, thank you for all the insight. Fred, always appreciate the time. Thank you very much. Thank you. Looking forward to what should be a very interesting next few months here for IGM, so thank you. Agree. Thank you.