Hello, and welcome to the IGM Biosciences conference call. At this time, all participants are in a listen only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during that session, you will need to press star one on your telephone. Please be advised that today's conference is being recorded. If you require any further assistance, please press star zero. I will turn the call over to Fred Schwarzer, Chief Executive Officer of IGM Biosciences. Fred? Thank you, operator, and welcome to all of you joining us on this call. We greatly appreciate your interest in IGM Biosciences. This presentation will contain certain forward-looking statements based on information available to IGM Biosciences as of today's date, and we must advise you that these forward-looking statements are subject to many factors which are beyond our control. Caution that these forward-looking statements should not be relied upon as predictions of future events. We also direct you to the risk factors described in our filings with the SEC. We are honored and pleased to have Dr. Elizabeth Budde of the City of Hope National Medical Center with us to present the data which she shared at the ASH conference earlier this afternoon. Dr. Budde is one of the world's leaders in the clinical development of T-cell engagers and CAR T therapies for the treatment of non-Hodgkin's lymphoma. After Dr. Budde's presentation, Dr. Chris Takimoto, our Chief Medical Officer, will discuss our plans for the clinical development of IGM-2323 and the role that we hope it will play in the treatment of non-Hodgkin's lymphoma and B-cell proliferative diseases. In particular, we will discuss the role that IGM-2323 may be well suited to play in earlier lines of treatment in combination with other therapeutic agents. We'll then offer a few concluding remarks and welcome your questions. We believe that IGM Biosciences is the global leader in the development of IGM antibodies. We also believe that there are many inherent advantages of engineered IGM antibodies over IgG antibodies, some of which may be reflected in the data we are presenting today. Building on our successes, we've taken important steps this year to expand our development of IGM antibodies beyond oncology to infectious diseases and to autoimmunity and inflammation. By the end of 2022, we expect to have five programs in the clinic and many more in the research pipeline. Our strategy continues to be to expand our leadership position in IgM antibodies. This includes extending our research and development efforts, building our pipeline, expanding our manufacturing capabilities, and building our broad intellectual property portfolio. IgM antibodies have a number of structural differences as compared with IgG antibodies, and we believe that these structural differences can be significant advantages in certain applications. If I were to focus on just one such inherent advantage, it is the greatly increased binding power that engineered IgM antibodies offer as compared to IgG antibodies. As illustrated in this graphic, the IgM antibody has 10 binding units, shown in yellow, as compared to 2 binding units for an IgG antibody. In simple terms, we describe this as the difference between trying to hold onto something with two fingers and grabbing it with two hands. With these preliminaries out of the way, it is my great honor and pleasure to introduce Dr. Elizabeth Budde and to thank her for her contributions to the clinical development of IGM-2323. On behalf of the study investigators, I'm delighted to present the updated results from IGM-2323, a phase I dose-escalation expansion study. IGM-2323 is an engineered high-affinity, high-avidity anti-CD20 pentameric IgM antibody. You have 10 anti-CD20 binding sites and one anti-CD3 single variable fragment fused to the joining chain and the pentamer. Pre-clinical study has demonstrated that IGM-2323 is able to kill tumor cells even with very low levels of CD20 expression through T-cell-dependent cellular cytotoxicity, the TDCC, and through complement-dependent cytotoxicity, CDC, which is quite unique to this IGM antibody. Compared to IgG or single chain-based bispecific antibodies, where the ratio of target to CD3 binding is quite low, IGM-2323 is designed to have a much higher ratio of target binding to CD3 binding, which translates into a more physiologic T-cell stimulation. In preclinical studies, IGM-2323 has been shown to induce strong tumor cell killing while minimizing cytokines associated with no adverse events such as cytokine release syndrome. IGM-2323-001 is an ongoing phase I dose-escalation expansion study enrolling patients with relapsed refractory non-Hodgkin's lymphoma including DLBCL, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma. Patients received IGM-2323 intravenously on a weekly basis with a 21-day cycle. If a CR is achieved, patient may choose to move to a every three-week weekly dosing cycle. Premedication with 10 mg dexamethasone was required starting with first infusion and continued until the plateau of dose is reached. The dose escalation part includes initial single patient cohorts until completion of 30 mg dose cohort, followed by titration dosing with a lower first dose and full dose starting on the second dose. Dose escalation with a maximum dose of 1000 milligrams has now been completed. The study is currently enrolling in the limited dose expansion cohort. As of September 10 data cutoff, 40 subjects have been enrolled and treated across all four histologies, with 45% of patients being DLBCL or 35% follicular lymphoma. Eight subjects have prior CAR T-cell therapy. Median prior lines of treatment was 3. Median time for last treatment was 3.4 months, and 63% were refractory to their last known treatment. The median duration of treatment was 3.2 months. 12 subjects, 30%, remain on treatment. Reason for treatment discontinuation include progression in 58% and patient or investigator decision in 13%, including patients who completed a protocol-defined treatment course. No patient discontinued treatment due to adverse event, and there was no treatment-related mortality. IGM-2323 was generally well-tolerated, with no DLTs observed in dose escalation. The most common AEs across all doses included infusion-related reaction and cytokine release syndrome at 30% and 25% overall, respectively. Treatment-emergent adverse events were generally transient and low-grade. A closer look at AEs of special interest reveals that when titration dosing strategies were employed, overall CRS rates were less than 20%, with only one case each of grade 3 and grade 2 cytokine release syndrome. The vast majority of CRS events occurred during cycle one and were transient. There have been no cases of ICANS and only one event of neutropenia grade 1 when titration dosing was utilized. No cases of treatment-emergent febrile neutropenia. Clinically meaningful tumor reduction and responses have been observed in this heavily pretreated population of lymphoma. Responses have been observed up to a dose of 600 milligrams. The most active dose across indications were 100 milligrams, with an overall response rate of 60% and CR rate of 50%. In relapsed refractory aggressive lymphomas, including DLBCL and MCL, rapid and durable responses were observed. Three of six patients with DLBCL achieved complete remission at the 100 milligram dose. All three patients remain CR at the time of data cutoff. IGM-2323 also elicited rapid and prolonged responses in indolent lymphoma subtypes. At the 100 milligram dose, two of three patients with follicular lymphoma achieved a response, both CRs. One subject with follicular lymphoma who achieved CR by week 12 at a dose of 100 milligrams went on to develop pseudoprogression, perhaps related to COVID vaccination at the time, and continued treatment with subsequent reduction in target lesions back to their remission baseline. Responses appear to be durable across all histologies. Of the 11 responders, five remain in remission beyond one year. Two patients have stopped dosing due to personal decision, and they all remain in follow-up. Five patients have moved on to every three-week dosing. All of these patients remain in remission. No anti-drug antibodies have been observed. PK analysis showed that sustained and dose-dependent drug levels were observed at doses at or above 100 milligrams. Preliminary estimated population half-life was 1.5 days. Shown here is a patient with follicular lymphoma who had two prior lines of therapy. The patient was treated with IGM-2323 and achieved CR by end of cycle four and remains in remission beyond a year. Biopsies taken prior to and during treatment showed a depletion of CD20-positive cells and persistent CD3-positive cells. Two additional subjects with matched pre- and on-treatment biopsies showed a decrease in CD20 positive cells and a corresponding increase in intratumoral CD3 positive T-cells. Notably, of four CR patients with baseline tissue samples, two had low levels of CD20 expression with H-scores of 15 and 30. IGM 2323 elicited an interferon gamma dominant cytokine response in nearly all patients. Repetitive transient cytokine elevations, peak around two to 12 hours, were observed over the course of multiple infusions. In contrast to observations with other T-cell engagers, IGM 2323 treatment resulted in higher levels of interferon gamma spike relative to other cytokines, including IL-6 and TNF alpha. This profile was maintained up to time points beyond cycle three. In patients without cytokine release syndrome, there's minimum to no detectable IL-6, TNF alpha, and/or other cytokines above baseline compared to interferon gamma. However, in patients that experience CRS, there was a polycytokine response, where in addition to interferon-gamma, high levels of all other cytokine testing are also observed. The timing of this polycytokine response corresponds with the onset and duration of cytokine release syndrome. In conclusion, this interim analysis of the phase I study for IGM-2323, the first anti-CD20 and CD3 engineered IgM T-cell engager, demonstrated that IGM-2323 is active in heavily pretreated NHLs, with evidence of prolonged duration of response as a single agent, including those who had received prior CAR T-cell therapy. IGM-2323 was generally well-tolerated, with low rates of cytokine release syndrome, especially grade 2 and 3. No ICANS and very low rate of neutropenia have been observed, supporting the evaluation of this molecule in combination studies in earlier lines of treatment. IGM-2323 demonstrated repeatable interferon-gamma-dominant T-cell activation due to a potentially more physiologic immune stimulation, which is in contrast to other T-cell engagers. Given the encouraging, rapid, and durable responses observed, two randomized cohorts, one in DLBCL and one in FL, have been initiated to select the optimal pivotal registrational dose. Further evaluation of every three-week dosing schedule is planned for 2022. As summarized by Dr. Budde, we are very excited about the observed activity and tolerability that we're seeing in our 2323 program. At the 100 mg dose level, we've observed complete responses in three of six DLBCL patients and two of three follicular lymphoma patients. Our safety profile over all titration dose cohorts is quite favorable, with an overall 18% CRS rate, the majority being grade 1. We saw no cases of either grade 2 or worse neutropenia, nor any immune neurotoxicity. Based on these emerging data, we are advancing the 2323 program forward into phase II studies in DLBCL and follicular lymphoma. We are very pleased with the level of activity we are seeing at 100 mg, and while our datasets are small for any single-dose cohort, higher doses have not been associated with greater degrees of efficacy. However, IgM antibodies are a new class of therapeutics, and we are just starting to understand their pharmacologic behavior by defining their exposure-response relationships. Based upon recent FDA guidelines recommending that sponsors perform more formal oncology dose evaluation studies, we have designed a randomized dose selection phase II study to select the optimal dose. This study will formally compare the efficacy of 100 and 300 milligram titration doses in two separate randomized phase II cohorts conducted in third-line plus DLBCL and in third-line plus follicular lymphoma patients. We have amended our current ongoing study to include these phase II arms, and we anticipate dosing our first randomized patient in the first quarter of 2022. This study approach was recently outlined by Rick Pazdur in the FDA in their October New England Journal of Medicine publication on oncology dose selection, and the agency has referred to this topic as Project Optimus in various scientific meetings. They've pointed out that a properly designed formal dose escalation trial could seamlessly expand into a pivotal registrational cohort after the dose is optimized. This provides a strong foundation for the further development of twenty-three twenty-three as monotherapy in advanced NHL patients. An important point to highlight is the broad potential of twenty-three twenty-three as a backbone therapy in these and other indications. Our current study is exploring twenty-three twenty-three as a monotherapy for late line NHL patients, but we believe our favorable safety profile also provides us with a competitive advantage for combining twenty-three twenty-three with other treatment regimens. This may allow us to move into earlier lines of therapy, thereby treating larger patient populations, potentially with even greater degrees of efficacy, because these will involve less heavily pretreated individuals. We see our safety profile as a critical factor for our success in expanding the use of 2323 in the treatment of B-cell malignancies. Dr. Budde has already described our very low levels of grade 2 CRS toxicity, as well as the absence of neurotoxicity, but we also want to highlight our exceedingly low rates of neutropenia of any grade in this heavily pretreated population. This is in contrast with the other bispecific agents in this class. Neutropenia is also very commonly observed with standard of care agents, especially cytotoxic chemotherapy, which is still a mainstay of lymphoma treatment. Thus, we think we may have the potential to become the backbone of choice for combination regimens used to treat patients earlier in their disease course. We are initiating a phase Ib study of IGM-2323 in combination with several standard of care regimens that may have the potential to unlock further development in earlier lines of therapy. The first arm is a combination with rituximab, gemcitabine, and oxaliplatin. This is the most commonly used second-line regimen for relapsed DLBCL patients who are ineligible for autologous stem cell transplantation. We anticipate that there would be limited overlapping toxicities, and the demonstration of additive or synergistic activity would define a very straightforward future development path. The second combination of interest is with the anti-CD19 antibody tafasitamab, which is approved in combination with lenalidomide in the second-line plus DLBCL patient population. This regimen is mechanistically very interesting in that it targets both CD19 and CD20 while modulating the immune system with lenalidomide. The third arm of interest is to combine IGM-2323 with rituximab and lenalidomide, which has the potential to expand further in the follicular lymphoma space. We are also evaluating other potential combinations where IGM-2323 could offer a clear advantage. These include combinations with antibody-drug conjugates, PI3K inhibitors, BTK inhibitors, and other agents as well. Our modular study design will allow for us to add additional arms to this trial as we deem appropriate. A key point in evaluating these combination regimens is to consider how we combine with other CD20 targeting agents, such as rituximab. This is a situation where our high avidity offers a clear advantage over other CD20 bispecifics, as shown in this preclinical experiment. Binding of IGM-2323 to target lymphoma cells is unaffected by the presence of rituximab, which is consistent with the relatively high binding avidity of IGM-2323 for CD20. This enables the continuation of T-cell-directed cell killing even in the presence of rituximab. However, for conventional CD20 bispecifics, their binding can be blocked by rituximab, potentially interfering with antitumor activity. Therefore, combinations of conventional CD20 bispecifics with rituximab carry the risk of interfering with their T-cell-mediated drug activity in ways that may not affect IGM-2323. This is an important consideration to keep in mind as you look at combination regimens involving this class of drugs. Finally, I'd like to highlight that IGM-2323 is our first IGM antibody product candidate. Clearly, it demonstrates that our platform can engage the intended target with promising activity and a favorable safety profile. We are very pleased with what we have learned thus far, and we feel that this bodes well for our plans to explore other IGM therapeutics. These include additional bispecific T-cell engagers against important validated hematologic antigens such as CD38 and CD123. Also, we are actively evaluating solid tumor targets, and more information will be forthcoming as these are developed. With that, I'd like to hand this back over to our CEO, Fred Schwarzer. Thank you, Chris. We are very pleased with the IGM-2323 clinical data we have presented today. We believe that we've shown a strong efficacy signal with a very good safety profile, and we believe that IGM-2323 may be able to play an important role in the treatment of non-Hodgkin's lymphoma and other B-cell proliferative diseases, including in earlier lines of treatment in combination with other standard of care and novel agents. We also believe that these clinical results for IGM-2323 may provide a positive read-through for our T-cell engager pipeline. The safety profile that we have shown with IGM-2323 may be particularly important for IGM-2644, our CD38 x CD3 T-cell engager for multiple myeloma, and IGM-2537, our CD123 x CD3 T-cell engager program for acute myeloid leukemia. In closing, I would like to thank all of the employees of IGM for their tireless work over the years, all of our principal investigators, their teams, and their institutions, and most importantly, the patients and their families, all of whom have made this day possible despite the ongoing challenges of COVID-19. All of us at IGM sincerely hope that today represents a significant step in the process of bringing new and important treatments to patients. At this point, we are pleased to open the floor to questions. Thank you. As a reminder, to ask a question, simply press star one on your telephone. To withdraw the question, press the pound or hash key. One moment while we compile the Q&A roster. Our first question comes from the line of Mike Ault with Morgan Stanley. Your question please. Yep. Hi, guys. Thanks for taking the question. Maybe just first off, looks like you're seeing some nice activity at the 100 milligram titration dose, but as you dose higher, you don't see quite the same effect. Maybe you can just, you know, comment on, you know, theories there. Is it just small patient numbers? Is there something unique about those patients? Chris, do you wanna take that question? Yeah. Thank you, Mike. Obviously, the data that we're seeing in terms of efficacy at 100 milligrams, we are very pleased with. But if you look at the 600 and the 1,000, the highest dose levels that we've looked at, there's nothing in those data sets that really suggest that we're seeing any greater levels of activity in those cohorts. Again, those numbers are small. We actually treated the most patients at 100 milligrams in the study thus far. But I think really it's these observations that make us confident to focus on 100 milligrams and 300 milligrams in the phase II study and really to analyze the impact of these dose cohorts on the overall efficacy. That's what we're exploring in the randomized phase II trial design. Gotcha. Maybe just one more question from me. You know, you highlighted moving into earlier lines of therapy in terms of combinations. Are you considering some partnerships there potentially, or how are you thinking about that at this point? Yeah. Thanks, Mike. We think that this may be an interesting data set for potential partners to take a look at in light of the strong safety signal that we're providing here, as well as the clear indications of efficacy. As Chris said, we believe that this may. Our 2323 may have some competitive advantages in becoming a backbone of choice in hematology. We think that we've created some really significant value here, and it will be interesting to see if potential partners are interested in working with us to develop this more, much more broadly and in earlier lines of treatment. Got it. Thank you. Thank you. Thank you. Our next question comes from Stephen Willey with Stifel. Your question please. Yeah. Thanks for taking the questions. Maybe just to follow up on Mike's question. Is there anything that you can speak to in terms of the magnitude of B-cell depletion that you're seeing in either this periphery or I guess maybe any evidence that you may have in the spleen or the lymph that would potentially explain this kind of disconnect in response rates that you're seeing at the 100 mg and then the higher doses? Chris, do you wanna take that? Yeah. Thanks for the question, Steve. You know, I think the one of the issues in terms of looking at the higher dose levels, where again, there's not a huge number of patients there, is to really understand what these data are telling us and what the magnitude is there. You know, I think that's something that we're thinking about how to explore. We do have correlative studies that are part of this trial. Dr. Budde presented some of those data, but we're obviously collecting a lot more and looking at that and really trying to understand in terms of how we could best characterize the relationships between dose and response. We do see falls in the peripheral B cells that seem to become more apparent as we go to the higher doses, but that's something that we start to see at doses around 30 or even 100. There's no real differences in the periphery as we get up to the higher doses. Obviously you asked the question about what's going on in the microenvironment, and I think that's really the most important area. Our data there are still limited. We have collected some on study biopsies from our patients. As we move into phase II, we plan on collecting more. We're building that in, actually on study biopsies as part of the phase II study. We hope to learn more about this, but those are some of the ways that we're approaching this. Okay. Maybe as kind of a tangential follow-up to that, is there anything that you can tell us about the responding patients in the 100 mg cohort, to give us, you know, some level of comfort that the discrepancy that exists here is not somehow just a byproduct of baseline patient characteristics? Are there some DLBCL patients in that cohort who are prior CAR T patients? Are those patients, you know, largely refractory to last therapy? Is there anything that you can say about the patients who you've seen respond to this regimen? One thing we can point to a patient that was treated at one of the lower doses was a DLBCL patient, a CAR T-cell patient. That was a patient that actually started at 30 but then had intrapatient dose escalation to 100 and was noted to have a complete response that is ongoing now for almost a year. That was a post-CAR T-cell patient that was treated at this lower dose range, including a plateau dose of 100 once they were escalated and had a very good response. You know, I think again, as we're treating more of these patients, we're pleased with what our drug is doing, particularly as we look at the patients in that dose cohort. Okay. Maybe just lastly, can you maybe just speak to the rationale behind the more measured step-up dosing regimen that you're taking into this kind of phase II bake-off trial between the 100 and the 300 mg doses? I know that you have a more gradual step-up dosing regimen that you've that you're now speaking to. Yes. Our current titration dosing regimen is starting at 15 mg in week 1, followed by 50 mg in week 2, and then 100 mg in week 3. Starting in week 4, we continue at the plateau dose. If that patient is at 100, they'll continue with 100 mg weekly, up to 12 weeks. If patients are responding, they can go to an every 3-week treatment. If they're going on to the 300 mg plateau dose and starting week 4, they get 300 mg weekly. This regimen really evolved over the course of the titration dose expansion part of the study. It was really designed to create a regimen that's well-tolerated, that can be administered in an outpatient setting. We're really very pleased with the overall tolerability of that approach. It is something that we've evolved to in the study. All right. I also wanted to remind people on the call that Dr. Budde is also here with us for Q&A. If there are any questions for her, please feel free. I'll hop back over to you. Thanks, Fred. Thanks. Thank you. Our next question comes from Michael Schmidt with Guggenheim. Your question please. Yeah. Hey, guys. Thanks for taking my questions. Yeah, perhaps one for the investigator then. You know, I didn't see the swim lane plot broken out by dose. I was just wondering, I mean, it looks like some of the CRs occurred, you know, pretty late subsequent to study initiation. I was just wondering if perhaps some of the patients at the higher doses, you know, might still have an opportunity to convert to CR with more follow-up. Just looking at the spider plots, it looks like most of the responders at least were continuing to trend down in terms of tumor size over time. Dr. Budde. Thank you for the question. You know, it's a different class of bispecific antibodies. We're trying to understand, you know, when is the best time, you know, for this drug to get to a complete remission. You know, we have seen different patterns. Also if you look at the spider plot, you know, that's really based on the size reduction. For aggressive lymphoma, to determine a CR, it's not really based on size, it's based on activity. So some of them can have residual mass, but the residual mass, you know, might be just full of dead cells or apoptotic cells, but they don't have activity then therefore they will be a CR. Now, which might not be reflected on the spider plot. They don't really go all the way down to, like minus 100%. Sometimes it can go down to 50%, but they're a CR. That's for aggressive lymphoma patients. Yeah. Maybe I'll ask the question differently. I guess the patients at higher doses were they predominantly stable disease, the non-responders? Or were they in fact progressing right out the gate? Chris, would you like to answer that question? It was a mix. The patients at the higher doses, we did see some of them have stable disease as their best response, and some obviously had progressive disease as well. It was kind of mixed in terms of those outcomes. Yeah. Okay. If I may add, this is a very early phase I clinical trial. Sometimes, you know, as long as a patient's eligible for the study, you know, we don't really cherry-pick patients. Some of the patients enroll on the studies, you know, they actually don't really have any other options, and they are on the study just because the study has a slot. They could have very aggressive disease and hard to control, very high, you know, tumor burden. Those are patients, in general, very difficult to manage. There certainly I think that patients on this study with aggressive B-cell lymphomas, you know, most of the ones in the category are very high risk with very poor prognosis. Yeah. Yeah. No, makes sense. Then, you know, one for Chris, and, you know, you touched on that already, but just thinking about, you know, the competitive environment, there's obviously a number of CD20 bispecifics moving ahead in development. You know, how do you see 2323 ultimately fit into the treatment paradigm? I know you mentioned the interesting observation with the Rituxan combination. I know some of your competitors are combining with GemOx without Rituxan, for example, in second-line DLBCL. Just curious, you know, how that might play out longer term, in your opinion. Yeah. Chris, go ahead. Yeah. Thanks for that question. Yeah, you know, I think this is really key, and we talked about this a little bit earlier in terms of we think that our really favorable safety profile, not just CRS, but things like neutropenia, really makes this well suited for these types of combination regimens. Then we really see this as an opportunity to move up into earlier lines of therapy. I think this is where we can really differentiate the competition. We saw today in the oral session that many of the other agents in this class have substantial neutropenia, particularly grade 3 and 4. We, at the titration dose levels, hardly see any neutropenia at all. Combining with cytotoxic chemotherapy, as well as other agents, we think there's an opportunity to differentiate. The other thing is the rituximab in these regimens, because the data that we showed you, we can displace that. It's not gonna impair the T-cell directed cell killing activity of our drugs. Again, this is why we think this has the potential to be the backbone of choice in combination therapies in these indications. Great. Thank you so much. Thank you. Our next question comes from Brian Abrahams with RBC Capital Markets. Your question please. Hi. Hello, it's Leo on for Brian. Thanks for taking our question. I guess maybe can you guys comment a little bit about how you're thinking of what the bar might be in the upcoming dose selection study? I guess how big of a difference are you looking for across the doses to, you know, decide which one to select? I guess is there a potential for you to, you know, go with a different dose in DLBCL versus follicular lymphoma? You know, if with a larger sample of patients, you start seeing, you know, slight differences in CRS rates, how is that gonna weigh against dose selection? Thanks. Chris? Chris, do you wanna take that question? Sure. I can address the second question first. The reason why we're doing two separate randomized dose selection studies, one in DLBCL and the other in follicular lymphoma, is because there is the potential that there might be differences. I'll say we I don't expect to see that, but that is a possibility. That's why we're treating them as two separate studies. In terms of how you select the design, these pick the winner designs, there is a fair amount of clinical trial study design literature here. The goal is, again, to pick the arm going forward that you have a high level of confidence that it's not inferior to the other arm. Now, that is different from a non-inferiority trial too different from a superiority trial. It's really just to give you the confidence that what you're taking forward is not worse than the other arm. This trial, I think, will give me a lot of confidence that the dose that actually is the winner here is the appropriate dose and that if we had and that we wouldn't have gained anything by taking the other arm that was dropped in that study forward. That's the thinking behind this type of study. Got it. Thanks. Maybe if I can ask one more sort of bigger picture. Given everything you've put together here, you know, pretty interesting data set, you know, can you maybe elaborate on how this is gonna apply to some of the other programs in the pipeline, whether that be on dosing, dose response or kinetics or the safety profile? I know you touched on this a little bit, but you know, I'm curious, you know, just if you can provide some more color on that. Yeah. Again, I'm happy to address that question. I think the biggest takeaway and read-through from this program is to recognize that this is our very first IgM therapeutic molecule to enter the clinic. W e're exceedingly pleased that we've demonstrated that we have a very favorable safety profile. Also that it is active, so it's hitting the target that it was designed to. And I think in terms of for the platform and specifically for the additional T-cell engager programs that are going after additional targets, this bodes very well given what we've seen here. I think for me, that's the biggest takeaway and read-through to our other programs. Does that answer your question, Mr. Leo? Yeah, thank you. I'll hop back in the queue. Thank you. Our next question is from Joel Beatty with Baird. Your line is open. Great. Hi. Congratulations on the data, and thanks for taking the question. First question is for the company or for Dr. Budde. What's the bar for efficacy for this agent when you think about the competitive landscape? R elated to that, how much does the safety profile you're seeing, such as the low rates of neutropenia, affect the bar for efficacy? You know, might there be some patients who can't tolerate some of the other agents but could, you know, be interested in this agent even if the efficacy does turn out to be a little bit lower? Yeah. Thank you for the question. I think the bar for aggressive lymphoma is very different than the bar for indolent lymphoma. I think somewhere around, you know, even a 30%-35% complete remission rate is a very reasonable bar. Now, if you look at some of the approved agents, for example, the Len+R, the complete remission rate only around less than 25%. Therefore, if you put this, you know, bispecific antibody, you know, in that category, treating similar patients, you know, a 30%-35% complete remission rate is very reasonable. Neutropenia. Well, neutropenia definitely is a concern. You know, I'm treating so many patients, you know, with lymphoma, with different intensity of regimens. You know, whenever the patient has neutropenia, you know, although on clinical trial maybe we don't see a consequence. You know, patient may be, you know, still doing okay. That might be because those patients are being actively watched because they are on clinical trial. You know, they're monitored, we monitor them all the time. Like, that translate into a day-to-day practice. You know, patient might not be followed up very closely. If a patient had neutropenia and you're not intervening, you're not giving them G-CSF, you know, or, you know, those patients, you know, they still have pretty high risk for infection. We know that for a fact. If they go down to 500 per microliter, then those patients need to be on antibiotics, you know, prophylaxis. We need to give them G-CSF, you know, to boost the white blood cell count. We need to hold off any treatment that can cause further lowering of the numbers. Definitely, I don't want to see neutropenia. As a practicing physician, someone has neutropenia, meaning that I need to see that patient more frequently in the clinic. It would be very nice to have a drug that have very minimal impact on the white blood cell count. It's also much easier to combine with other agents. I hope that answered your question. Yeah. Great. Thanks for that. Maybe one other question. Is you know anything from outside of the trial, you know, inspiring the company, either preclinical data or maybe data with other agents that could help make sense of the strong response you're seeing at the 100 milligram dose level that doesn't seem to be there at the higher doses? Chris, you wanna take that question? We're definitely looking at this question very closely. I think the best way for us to approach it is to think about how we can develop a comprehensive PK/PD and even a mechanistic model to really understand the relationship between dose, exposure, and response. You know, I would say at this point, we're still collecting these data and really trying to analyze the situation. You know, at this point, it's something that we're actively investigating. Can I just chime in? Sure. Based on my experience of working with other bispecific antibodies and other immunotherapies, agents, it's not really the higher the better. Sometimes it has to be just right 'cause they're really based on the receptor occupancy exposure curve. You know, we don't really see a linear dose-response relationship, even with the CAR T. You have to really weigh in. You know, you can go out further, but you can maybe more toxic without really giving you more benefit than by further going up. Just, you know, my own opinion, this is. Yeah. No, thanks for that perspective 'cause I think it's a very important one. As you know, as a medical oncologist who trained in the era well before Dr. Budde, there's this mindset that more is better and most is best. You know, these are immuno-oncology agents. They're very different from cytotoxic drugs. And so the types of causal relationships may be very different. In fact, we expect them to be different from other things like small molecules. I think that's part of what we're trying to understand better here. I think that's a great point to make. Thank you. Joel, does that answer your question? Yes. Thank you. My pleasure. Our next question comes from Asthika Goonewardene with Truist Securities. Your line is open. Hi, guys. Thanks for taking my question. I would like to ask Dr. Budde if she could build on what she just said and maybe perhaps give us from an immunological perspective, maybe, speculate on what might be going on at that 300, 600, and 1000 milligram dose as to why we didn't see any steep responses there. I have a couple of follow-ups. Yeah. Well, thank you for the question. Well, if I can speculate, you know, I think the higher dose, you know, we're really talking about how to stimulate the T cells, you know, make the T cell function optimally. You know, even a much higher dose, you know, possibly there could be more stimulation, which, you know, might not be a good thing for the T cells. If you give a higher dose, you know, and also possibly, you know, the drug, you know, because, you know, we look at the PK, the drug disappeared very fast, but it might be hanging in the tissue. Like, if you give too much drug, the T cell be, you know, constantly activating, and they might get exhausted. You know, this is another question for bispecific antibodies and also for CAR T-cell therapies. You know, some of the data looking at CAR T is, you know, a continuous activated CAR T cell. They don't cure that well as a CAR T that can go on and off. These are all need to be taken into consideration. Got it. Maybe for Dr. Chris. In the patients treated with the 300-, 600-, and 1,000-mg dose, did you still get elevated interferon-gamma on cycle 3 and after? Yes, we did. In patients that had elevated cytokines, we consistently saw interferon-gamma be the predominant one, and that was across essentially every subject that we could measure peripheral cytokines on. That was definitely true that those patients treated at the higher doses as well as at 100 in the month. Right. Can you just, sorry if I missed this earlier, what's the rationale for switching to a Q3W dose? Again, in our current study in phase II, we're switching those who are responding to every three weeks. I think that's just you know recognizing that these patients have undergone in some cases multiple regimens, many years of treatment, and that we feel that we can safely do this and still preserve the activity. Certainly in the five patients out of our 11 responders that we have switched to an every three-week regimen, we haven't seen anybody that has relapsed with progressive disease. That's that was the rationale for doing that. Now, we are also potentially exploring in a new cohort, every three-week dose after the initial three weeks of titration dosing, and that's something that we will explore just to see the level of activity there. In terms of our phase II study, and the cohorts that we prioritize, they are gonna continue to get treated weekly up until the 12-week point. Got it. Thanks for taking my question, guys. Thank you. Thank you. Our last question is from Stephen Willey with Stifel. Your line is open. Yeah. Thanks for the follow-up. I know that there were a couple of patients who had experienced CRS beyond cycle one, and was just wondering if you could maybe provide a little bit of color around each of those patients and whether or not they were treated at the higher doses, and just the kinetics of CRS, I guess, are of the most interest to me. Thanks. Yeah. You know what? It's very interesting when we talk about CRS. Now it's actually very different than the CRS you observe with CAR T-cells. It doesn't matter if it's this specific or other specific, you know. They always have a little bit of fever whenever they are exposed to the antibody. Now sometimes the fever, mostly the fever is very low-grade. Based on the definition, it may be of the grade one CRS definition. That's always captured as an adverse event. Does it really impact patients' whole life? Not really. You know, I have patients who have very low-grade fevers after several cycles, and sometimes they don't even tell me. They will come to clinic, and then they told me after the fact, just to a ti... You know, they take a Tylenol, fever went away. But it is an event, and we capture all the events. If you look at the overall CRS incidence, the majority of that's really just grade 1. There's only 1 grade 2, 1% of grade 2. Mechanistically, you know why those patients have every time they get exposure is that really a second CRS or really just truly infusional reaction to the antibody, which is a known common phenomenon to monoclonal antibody infusion? But as a clinician, I'm not that concerned. If a CAR T patient has fever, I'm very concerned. Maybe I can elaborate a little bit on those two patients that you're asking about because these were the ones that had the delayed CRS after cycle one, which is unusual. Majority of CRS patients experience in the first cycle. The two patients that had grade one CRS were both patients that were treated at our highest dose levels. One was at 600 and the other was at 1,000. The patient that was at 600, interestingly, had the grade one CRS, so as Dr. Budde explained, really just having a fever. That actually occurred with the first dose after several cycles of which the dexamethasone pre-medication was actually being weaned. In their first dose without any dexamethasone, they had this fever. The dexamethasone was reinstituted for the next one or two weeks of treatment and then was removed again, and there was no further events of CRS. It was really a very minor point, but it does get captured as CRS. The other patient that was at 1000 actually had the fever again outside of cycle 1, but they had that at the start of cycle 2 with the very first dose of 1000. Again, they had fever, so it was grade 1 CRS. In that patient, they increased the dexamethasone pre-medication for the next cycles. I believe they went from 10 to 20, and then they had no further evidence of fevers. They were both very, very transient cases and clinically were not very significant. Okay. Maybe just a quick follow-up for Dr. Budde. You know, we get a lot of different opinions with respect to CRS and, you know, what it means to be a prescriber and to treat patients that experience CRS, and obviously that's kind of a bifurcated answer between the community physicians and the academic physicians. Just wondering, you know, as you think about CRS, right? I mean, there's obviously magnitude, and then there's kind of the kinetics and predictability of CRS. When you think about your community prescriber peers, how important is the predictability of CRS? Then also, I guess, you know, the magnitude of CRS, right? How important do you think that grade two CRS is for a community prescriber in terms of, you know, potentially representing a rate-limiting step to prescribe it? Yeah, thank you for the question. It's something that I probably think of, you know, daily because, you know, I also oversee the CAR T program at City of Hope. You know, really, our way of managing CRS, you know, is very different, you know, for bispecific antibody treated patients versus CAR T patients. For CAR T patients, if they have CRS, even if it's a grade one fever, you know, they need to come to our urgent care immediately. Because if we don't intervene, there's a very high chance that it will evolve into a grade two or even higher. But for bispecific antibodies, you know, if someone very stable just had a fever, now we are really comfortable, so we don't even ask them to come in. You know, they will just take a Tylenol and, you know, call us back in a few hours to see whether the fever is still there. 'Cause majority of the CRS grade 1 associated bispecific antibodies, you know, usually, it's really self-limiting. It's very different than the CAR T relating CRS. For grade 2 CRS, which is extremely rare, you know, with IGM2323, but just speaking for bispecific antibody in general, a grade 2 CRS, you know, sometimes, you know, could be just a hypotension, you know, due to infusion reaction. With a little bit of fluid, that can be easily fixed. That's also very different than the CAR T patients with a grade 2 CRS. I think the management for grade 1 or grade 2 CRS, you know, due to a bispecific antibody versus, you know, due to CAR T-cell, both, you know, the management algorithms should be very different. I think here, I would be very comfortable for a community physician to manage CAR T patient. No. To manage bispecific antibody patients with grade 1, grade 2, but I will not be comfortable for them to manage a patient with even grade 1 CRS if it's because of CAR T-cells. I'm really hoping we can really dive, you know, deeper into, you know, really discussing the differences between CRS caused by bispecifics or by CAR T, 'cause they are very different. Unfortunately, they are under the same definition currently, the same ASTCT grading. Is that really the best, you know, grading system for bispecific antibodies? You know, my own opinion, you know, it's not. I think that grading needs to be revised, or we need to have a different grading system for this kind of event associated with, you know, bispecific antibodies. Great. Thanks for taking my question. You're welcome. Thank you. This concludes our Q&A session for today. I will turn the call back to Fred Schwarzer for his final remarks. Well, thank you very much for joining us this evening. We really appreciate your time, and we look forward to sharing our progress with you over the next year on the clinical development of IGM 2323, IGM 8444, IGM 6268, IGM 7354, and IGM 2354. Thank you very much, and good evening. Thank you. With that, we conclude our program. Thank you for your participation, and you may now disconnect.