IGM Biosciences, Inc. (NASDAQ:IGMS) Q4 2022 Earnings Call Transcript

IGM Biosciences, Inc. (NASDAQ:IGMS) Q4 2022 Earnings Call Transcript March 31, 2023

Operator: Good day, everyone, and welcome to the IGM Biosciences’ Fourth Quarter and Full Year 2022 Financial Results and Corporate Update Call. Today’s call is being recorded. At this time, I would like to turn the call over to Fred Schwarzer, Chief Executive Officer of IGM.

Fred Schwarzer: Thank you, operator. And thanks to all of you joining us on this call. On behalf of IGM, I’m joined today by Misbah Tahir, Chief Financial Officer; Dr. Chris Takimoto, Chief Medical Officer; Dr. Bruce Keyt, Chief Scientific Officer; and Dr. Mary Beth Harler, President, IGM Autoimmunity and Inflammation. Please note that we will be making forward-looking statements on this call including statements about IGM’s plans, expectations and forecasts and about future events. Actual results may differ materially as a result of various risks and uncertainties including those discussed in the Company’s most recent annual report on Form 10-K as well as its other filings with the SEC. Any forward-looking statements represent IGM’s views as of today, March 30, 2023 only, and the Company disclaims any obligation to update these statements, except as required by law.

Following this call, a replay will be available on the Company’s website, www.igmbio.com. I would like to start with a few introductory remarks and then I will turn the call over to Misbah to take you through our 2022 financial results. After Misbah’s update, Chris will update you on clinical development of IGM-8444, our death receptor 5 agonist antibody. Next, Mary Beth will update you on our development plans for Imvotamab and autoimmune diseases. We will then turn it back over to Chris to discuss the two most recent product candidates in our oncology pipeline, IGM-7354, our IGM targeted immunostimulatory IL-15 cytokine; and IgM-2644, our CD38/CD3 T cell engager, a next generation CD38 antibody for multiple myeloma. Looking back, 2022 was a transformational year for IGM.

At the end of the first quarter, we entered into an important collaboration with Sanofi to develop novel IgM agonist antibodies to address three oncology targets and three autoimmune targets. Throughout the year we also continued the clinical development of our death receptor 5 agonist antibody, IGM-8444, particularly in combination with FOLFIRI for the treatment of colorectal cancer. We are very pleased with the data we have seen from those clinical development efforts as we announced in January of this year. These data have provided the basis for our decision to immediately move into a randomized study of IGM-8444 in second-line, metastatic, colorectal cancer in combination with FOLFIRI and bevacizumab, which is the standard-of-care in second line colorectal cancer.

We are hopeful that this randomized study will show a significant improvement in progression-free survival relative to the standard-of-care chemotherapy control arm. As we announced today, we have now treated the first patient in this randomized study. We also made great progress during 2022 in developing and understanding of the potential role of our T-cell engagers such as imvotamab in treating autoimmune diseases. We are encouraged by the expanded safety and efficacy data for imvotamab at a 100 milligrams that we have developed through our clinical studies in non-Hodgkin’s lymphoma, and we believe that imvotamab safety profile may be an important differentiating factor in the exciting new field of T-cell engagers in autoimmune disease. Building on our success in 2022, we expect that 2023 will also be an important year for the expansion and validation of IGM’s platform.

Already this year, we have treated the first patients in our clinical study of IGM-7354, an IgM targeted immunostimulatory IL-15 cytokine, which could be used for the treatment of patients with solid and hematologic malignancies. We are particularly excited about the potential to use IGM-7354 in combination with cellular therapies such as CAR-T and CAR-NK cells. We are also initiating studies of IGM-2644, our CD38 x CD3 bispecific IgM antibody, which we hope will be a safe and more potent form of anti-CD38 therapy for multiple myeloma, including for patients who have previously been treated with daratumumab. We also plan to file investigational new drug applications and initiate clinical studies for imvotamab in multiple autoimmune diseases this year, beginning with lupus and rheumatoid arthritis.

At this point, I’d like to turn the call over to Misbah to review our financial results for 2022.

Misbah Tahir: Thank you, Fred. In addition to the brief financial overview, I will provide on the call today, you can read additional detail on our fourth quarter and year-end financial results in our press release issued prior to this call and in our 10-K, which was filed with the SEC. We are fortunate to be in a strong financial position. In the second quarter of 2022, we received an upfront payment of $150 million from Sanofi related to our collaboration agreement and raised gross proceeds of $230 million in a follow on public equity offering. As a result, our cash and investments totaled $427.2 million as of December 31, 2022. In the fourth quarter, our research and development expenses were $45 million. For the full year 2022, R&D expenses were $179.3 million.

General and administrative expenses for the fourth quarter of 2022 were $11.6 million and $49.7 million for the full year 2022. Collaboration revenues for the fourth quarter of 2022 were $0.4 million and $1.1 million for the full year 2022. Our net loss for the fourth quarter of 2022 was $52.6 million or a loss of $1.19 per share. For the full year 2022, our net loss was $221.1 million or a loss of $5.32 per share. Turning now to the financial guidance for 2023. We expect our full year 2023 GAAP operating expenses to be between $290 million and $300 million. This includes estimated non-cash stock-based compensation expense of approximately $50 million. For the full year 2023, we also expect to recognize approximately $3 million of collaboration revenue related to last year’s upfront payment from Sanofi.

Finally, we expect to end 2023 with a balance of approximately $200 million in cash and investments providing IGM with an expected cash runway into the second half of 2024. With that, I’ll now turn the call over to Chris, our Chief Medical Officer.

Chris Takimoto: Thank you, Misbah. As Fred mentioned, 2022 was a very important year for the clinical development of IGM-8444. I am pleased to announce that we have now dosed more than 100 patients with IGM-8444 in our broad multi-indication, multi-combination Phase 1 study, and we’re very excited about the safety and clinical activity profile that we’ve seen to date in our combination with the standard FOLFIRI chemotherapy regimen in colorectal cancer patients. In January, we shared our initial data from our FOLFIRI combination cohort, which is available in detail in our current corporate overview presentation. To summarize, these data showed an encouraging safety profile that was broadly comparable to that expected from chemotherapy alone.

Specifically, no signs of drug related clinically significant hepatotoxicity were observed, as only Grade 1 and Grade 2 transient drug related liver enzyme elevations were seen. The substantial majority of our patients with metastatic colorectal cancer have been treated with 3 milligrams per kilogram of IGM-8444 in combination with FOLFIRI and thus far we have seen promising activity at that dose level with multiple confirmed responses even in patients who had previously progressed on prior FOLFIRI. We also saw encouraging progression-free survival in third and fourth line patients with one patient continuing for over a year without progression. These data have encouraged us to start treating patients with FOLFIRI plus bevacizumab, which is the current standard of care treatment for second line colorectal cancer.

I am pleased to announce today that we have now treated nearly 20 patients in combination with bevacizumab and we’ve not seen any additional toxicity signals arising from the addition of bevacizumab to the combination. These early safety and efficacy observations have encouraged us to proceed immediately into a randomized clinical study of FOLFIRI and bevacizumab plus or minus IGM-8444 in second line colorectal cancer. We are pleased to announce today that we have now dosed the first patient in this randomized clinical trial. We’re also excited to announce today that our analysis of the cell death biomarker caspase-3 in patients treated with IGM-8444 across multiple dose levels both as monotherapy and in combination showed a consistent increase post-treatment in 60 of 64 patients analyzed.

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In addition, a dose-dependent increase was seen at the two highest dose levels tested of 3 and 10 milligrams per kilogram. A summary of these data is available in our current corporate overview slide deck available on our website. This biomarker signal has led us to add an additional 10 milligram per kilogram dose cohort to our randomized combination study. This protocol is currently being amended to randomized patients to three groups, either 3 or 10 milligrams per kilogram of IGM-8444 with FOLFIRI plus bevacizumab or standard of care chemotherapy alone. Our primary endpoint for this study will be progression-free survival with overall survival and response rate as secondary endpoints. We are exploring with the FDA potential randomized pathways to accelerated approval in accordance with their recently released guidance on this topic.

We also announced today that we are now treating patients in our fifth birinapant combination dose escalation cohort. To date, there have not been any observed dose limiting toxicities in combination with birinapant. We also announced today that we’ve treated the first patient in our IGM-8444 plus venetoclax and azacytidine combination in subjects with acute myeloid leukemia. Finally, we’ve also conducted extensive preclinical studies with other chemotherapeutic agents in combination with IGM-8444 in a variety of different cancer types. We plan to clinically evaluate one or more of these chemotherapy combinations with IGM-8444 as our development program expands. At this point, I’d like to turn the call over to Mary Beth Harler, our President of Autoimmunity and Inflammation.

Mary Beth will be leading our clinical development efforts for imvotamab in autoimmune diseases and as the clinical development in autoimmune diseases will be our focus going forward, she will be sharing today’s interim clinical updates about the imvotamab NHL program. Mary Beth?

Mary Beth Harler: Thank you, Chris. As you mentioned, we are announcing some encouraging safety and clinical activity data for imvotamab, which we think could offer a compelling and differentiated profile in the exciting new area of T-cell engagers in autoimmune disease. We think there is an important opportunity to bring forward a readily accessible therapy that offers deeper B-cell depletion than achievable with currently available anti-CD20 therapies. Also, you may recall hearing about some recent very encouraging data using CAR-T cells for B-cell depletion in lupus. We believe that imvotamab may have clear advantages over CAR-T therapies in autoimmune disease in terms of safety, cost and logistics. We announced today that as of our most recent data assessment, the incident of cytokine release syndrome was 9% overall safety evaluable patients treated with the 100 milligram titration dosing regimen in our Phase 1 and Phase 2 non-Hodgkin’s lymphoma studies, and it was 13% overall safety evaluable patients treated with either 100 milligrams or 300 milligram titration dosing in these Phase 1 and Phase 2 lymphoma studies.

All cases of CRS seen in the 100 milligram and 300 milligram titration dose cohorts were Grade 1 other than one Grade 2. We also announced today, although, the patient numbers are very small and additional patients currently on treatment may respond. As of the most recent data assessment, imvotamab has achieved a combined complete response rate of greater than 30% overall efficacy evaluable diffuse large B cell lymphoma or DLBCL patients in our Phase 1 and Phase 2 studies treated with the 100 milligram titration weekly dosing regimen, although, the patient numbers are too small to make a statistical assessment. Currently, the response rate in DLBCL continues to be appears €“ continues to appear to be lower at the 300 milligram dose. As you may recall, we have previously announced that we have seen complete responses with imvotamab in all four major NHL subtypes, diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma.

While it is not possible to directly extrapolate these encouraging efficacy data in NHL to what we might observe in autoimmune disease, it’s worth noting a couple of points. First, CD20 is a well-established target in multiple autoimmune diseases. And secondly, the imvotamab data in NHL clearly demonstrate that imvotamab effectively depletes B cells even rapidly growing lymphoma cells. In combination with these strong signs of clinical activity, we believe that imvotamab safety profile will be an important differentiating factor in the treatment of autoimmune diseases with T-cell engagers together with the potential to more effectively deplete pathogenic B-cell deep within tissues that may be refractory to current therapies. We believe there are significant unmet medical needs and commercial opportunities that imvotamab may address across a range of autoimmune diseases.

We have also announced today that we plan to file IND applications in the second quarter to begin clinical testing of imvotamab in both, severe systemic lupus erythematosus or SLE and in severe rheumatoid arthritis or RA. We are also evaluating a variety of additional autoimmune diseases for a potential third IND application later this year. With that I’ll turn the call back over to Fred.

Fred Schwarzer: Thank you, Mary Beth. We are pleased with the safety in clinical activity profile that we have seen with imvotamab at 100 milligrams in our non-Hodgkin’s lymphoma clinical studies to date, and we are excited to move forward aggressively in developing imvotamab for multiple autoimmune diseases. Given the relative size of the potential autoimmune markets and imvotamab’s potential competitive advantage in autoimmune disease resulting from its safety profile, we believe that the unmet medical needs and the commercial opportunities for imvotamab in autoimmune diseases are substantially greater than those in non-Hodgkin’s lymphoma, particularly those as monotherapy and relatively late lines of lymphoma treatment. As a result, we are announcing today that we are redirecting our clinical development efforts for imvotamab to autoimmune diseases and that we have decided to cease further monotherapy clinical development efforts for imvotamab in non-Hodgkin’s lymphoma.

We continue to believe that the safety and efficacy profile of imvotamab could position it well as a combination partner for the treatment of non-Hodgkin’s lymphoma, and we will be focusing our future efforts in NHL on evaluating combination opportunities and partnerships for imvotamab. With that I’d like to turn the call back to Chris to discuss our exciting early stage clinical development efforts in oncology.

Chris Takimoto: Thank you, Fred. As we announced in January we’re excited to have initiated a clinical trial exploring the safety, efficacy in pharmacodynamic activity of IGM-7354 and IgM targeted immunostimulatory IL-15 cytokine in the treatment of patients with solid tumors. We are announcing today that we’ve successfully dosed our first two patients with no drug related safety issues. We believe that IGM-7354 has the potential to be used in combination with a broad range of other drugs which rely on CD8 positive cells or NK cells for their activity, including combinations with CAR-T and CAR-NK cells. We are also announcing that the FDA has cleared our IND application for IGM-2644, a CD38 x CD3 IgM T-cell engager, which allows us to commence a Phase 1 dose escalation trial in patients with recurrent or refractory multiple myeloma.

This study will allow us to investigate the initial safety and efficacy of our next T-cell engaging IgM molecule. Our ultimate clinical development goal for IGM-2644 is to establish it as a safe and more potent anti-CD38 therapy, even for patients who have received prior daratumumab treatment. We are very excited by the potential for IGM-2644 to provide the next generation form of an anti-CD8 therapy. As you may recall in December of last year, we presented preclinical data at the 2022 ASH meeting showing that IGM-2644 achieved potent T-cell directed cellular cytotoxicity in multiple myeloma patient samples and in daratumumab resistance cell lines with minimal cytokine release. With that I’d like to turn the call back over to Fred.

Fred Schwarzer: Thank you, Chris. In closing, I’d like to thank all of the employees of IgM for their work over the past year. All of our principal investigators, their teams and their institutions and most importantly the patients and their families, all of whom have made the progress we’ve described today possible. We’re very excited about the progress that we hope to make in 2023 towards our goal of bringing new and important treatments to patients. We appreciate your interest in IgM and we look forward to keeping you all informed as to our progress. With that operator, I’d like to open the call for questions.

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Q&A Session

Operator: Thank you. And our first question is from Stephen Willey with Stifel. Your line is open.

Stephen Willey: Yes. Good afternoon, guys. Thanks for taking the questions. I guess a lot going on here. So the decision to add the 10 mg/kg dose to the randomized Phase 2. Can you maybe just €“ can you answer the question, I guess as to whether or not you’ve conducted any dose expansion with the 10 mg/kg dose in combination with Bev/FOLFIRI before you’re enjoying it into the randomized Phase 2. And then just any updated thoughts on when we might get a look at the remaining dose expansion patients, I guess those treated at the 3 mg/kg dose and any that you may have treated at the 10 mg/kg dose? And then I have…

Fred Schwarzer: Chris, would you like to take that one?

Chris Takimoto: Sure. Yes. Steve, thank you for the question. So the really the experience that we have with 8444 at 10 milligrams per kilogram, as you’re aware we explored a number of patients during the monotherapy dose escalation, and then when we started to combine with FOLFIRI. We did the expansion at 3 milligrams per kilogram, although we did treat three patients at 10 milligrams per kilogram with FOLFIRI. But it was really the biomarker data that we’re sharing with you now that really showed this increase in plasma caspase-3 levels that continued to increase as we went from 3 to 10 milligrams per kilogram, and that was one of the major factors that led us to incorporate and make the decision to add 10 milligrams per kilogram to the randomized study.

Plus we did get additional feedback from the FDA that was again very supportive of doing formal dose exploration and optimization in the study. So those were the things, the new biomarker data and that really prompted us to make this addition to the study.

Stephen Willey: Okay. And then I guess as a follow-up. Does the addition of the third arm to the randomized Phase 2 change your powering assumptions? And I know that you’re kind of guiding to potentially having a conversation with FDA regarding an accelerated approval pathway. So should we think about patient enrollment then as kind of a moving €“ a moving target?

Fred Schwarzer: Yes. So this study is built with a certain degree of flexibility, and again the study is really designed to confirm the signal that we have seen in our single arm experience in combining 8444 with FOLFIRI. But it’s also written so that when we can actually evaluate the impact of dose as well as looking at the primary endpoint, which is going to be progression free survival. And so we’ve left things somewhat open in terms of if we get a strong signal that allows us to pick a dose and also confirm the magnitude of the benefit over the control arm, there’s the potential that we can either stop this early and initiate a more formal registrational trial, or alternatively we could potentially with regulatory feedback expand this study to increase the number of patients on each of the arms and potentially use this as a randomized accelerated approval trial. So those possibilities are all things that we are considering as we move forward.

Stephen Willey: Okay. And then maybe just lastly, real quickly I know obviously imvotamab is getting prioritized for AI disease, but maybe for Mary Beth, can you just kind of speak to, I guess your interest in potentially looking at IGM-2644 in autoimmune disease as well? Thank you.

Mary Beth Harler: Yes. No, absolutely. Thanks Steve. As we are thinking about our T-cell engager assets morph through a portfolio lens than individual opportunities, and we are very excited about how these assets may come together to afford multiple therapeutic approaches to treating B-cell and plasma cell mediated diseases. As we discussed obviously CD20, a well-established target in autoimmune disease, CD38 some €“ there is a smaller, but very interesting data set particularly in the setting of diseases such as lupus to support the potential utility of CD38 targeting therapies. I think it is very important that we understand what the safety of our own CD38 x CD3 molecule looks like in multiple myeloma as we’ve discussed.

Steve, safety is clearly a very important consideration in the management of chronic diseases such as autoimmune disorders. I will note, however that even as we await those initial human data in multiple myeloma with 2644. We are in parallel performing preclinical studies to understand how this molecule could differentiate not only from imvotamab, but also other potential competitors in this space. So in summary, a lot of activity and we await that human data.

Stephen Willey: Great. Thanks for taking the questions.

Fred Schwarzer: Thanks Steven.

Operator: Thank you. And our next question is from Greg Harrison with Bank of America. Your line is open.

Greg Harrison: Hey, good afternoon. Congrats on the progress and thanks for taking the questions. First off maybe could you give some additional color on the transition towards autoimmune indications for imvotamab? What was the decision process that led to the choice of lupus and RA, and how broadly do you think imvotamab could be applied across autoimmune disease?

Fred Schwarzer: Well, Mary Beth, I think that’s probably a question for you. It’s one we spend a lot of time thinking about, and it’s very broad. So I’ll leave you to go at it Mary Beth.

Mary Beth Harler: Indeed, and thank you for that question. Again, the CD20 as a target in autoimmune disease well established and a very broad dataset out there in the literature with respect to how various approaches to CD20 and B-cell depletion may look in the management of different B-cell and auto €“ auto-antibody mediated diseases. As I think back to the conversations that were taking place, as our company contemplated the choice of continued investment in NHL versus beginning to invest in autoimmunity, you heard the key points of that rationale earlier in the presentation given the level of competition, given the change in the regulatory and therefore the commercial environment in the lymphoma space, right? The upside on the autoimmune front, again given that this is a well-characterized target and one that could absolutely benefit from deeper B-cell depletion.

Those are the things that really got us excited. If you have not seen the publication from Georg Schett at all from the University of Erlangen in September of 2022, looking at an anti-CD19 CAR-T in five patients with severe lupus that really catalyzed a deeper look at what is possible through deep B-cell depletion, right? And we think that imvotamab, which we believe will enable deeper B-cell depletion than currently available anti-CD20, because we are not dependent upon local complement and local NK cells. We know from our preclinical data that imvotamab will deplete in the spleen, in the lymph nodes, in the bone marrow, where reservoirs of pathogenic B-cells can sometimes hide and basically continue to drive autoimmune disorders. So our hope is that imvotamab will deliver that level of deep B-cell depletion that was suggested by the CAR-T data, but do so with an off-the-shelf product, with a better safety profile, clearly lower cost and fewer logistical considerations, so we’re quite excited and moving quickly.

Chris Takimoto: So I might add there that in terms of Greg, to your question, why lupus and RA as the first two indications and where might we go beyond that? Lupus obviously as Mary Beth mentioned you’ve got the proof of concept with Georg Schett and that paper of real immune modulation, that’s obviously a great place for us to start because we think we’ve got advantages over CD19 CAR-Ts there. RA is a place where we think we can get a signal very quickly in terms of biomarkers, and so forth. But in terms of where we go after those two, I think, you can think more broadly first any place where CD20 has shown signs of clinical activity or efficacy. Those are good places and any place across the entire landscape of autoimmune diseases where you got autoantibodies implicated in, in disease.

And as was mentioned earlier that includes not just B-cells that you might be able to take out with a CD20 T-cell engager, but also B-cells you might be able to take out with a CD38 or a combination of the two. So, our landscape is just really, really broad here in terms of what we might be able to do with a portfolio of T-cell engagers in autoimmune disease. And we think we’re in a €“ we have the potential to be in a real leadership position here. And we think our safety is perhaps the most important differentiating factor. Mary Beth, did you want to add to that?

Mary Beth Harler: Yes. No, thank you. I think, those are absolutely critical comments, right. We expect these initial studies in patients this year to inform on which development programs make the most sense for this particular mechanism, right. And I think for those of you who have been in the autoimmune space in the past, right, there is a lengthy list of potential diseases here. We could also think about in addition to the anti-CD20s and where the CAR-Ts are currently going in autoimmune disease, we could even contemplate perhaps, where the FcRns are going. So there is, as Fred indicated, there is a very broad range of opportunities. And I will come back to his last remark, right. We not only have a very active molecule, but we think we’ve got a safety profile that will define the bar for this new class of therapies around T cell engagers in autoimmunity. So it’s an exciting place to be.

Greg Harrison: Great. Great, that’s super helpful. Maybe just one other if I can a much narrower question. On IGM-8444 the biomarker data that you discussed looks encouraging, you are seeing in almost every patient. How would you expect that to correlate into a clinical response?

Fred Schwarzer: Chris, do you want to take that one?

Chris Takimoto: Yes. No, great question, Greg. So, obviously this is something that we’re looking at very carefully. I think though, when you first €“ when you think about caspase-3, it’s a cell death biomarker, it really is an indication of how well your agent is engaging the target and target pathway. And so, the most important information is that it’s telling us that the signal of engagement in modulating the extrinsic apoptotic product pathway is quite strong at 10 milligrams per kilogram. We’re obviously looking at how this correlates with other clinical parameters. And again, the data are still very early, so we can’t really draw any direct conclusions there. But again, in terms of a pharmacodynamic marker, we think it’s very, very positive and very informative.

Greg Harrison: Great. That helpful. Thanks again for taking the questions and congrats again on all the progress.

Fred Schwarzer: Thank you.

Chris Takimoto: Yes.

Operator: Thank you. One moment for our next question. And our next question is from Michael Schmidt with Guggenheim. Your line is open.

Michael Schmidt: Hey guys, thanks for taking my questions. I had two. Perhaps so, one on IGM-8444, you updated us on your combination arm with birinapant as well, it seems to be progressing in dose escalation. Could you just remind us which types of patients are likely to respond to that particular combination? Just curious how you think about that. And then on CD20 obviously, a large commercial opportunity across a huge number of indications here. Does that shift in development strategy affect how you think about partnerships for this program that, perhaps could maximize the opportunity if you have a large company on board for that? Thanks so much.

Fred Schwarzer: So, Chris, why don’t you take the first question and I’ll take the second one.

Chris Takimoto: Sure. Yes, so with regards to the birinapant combination, so, obviously we’re in a dose escalation part of the study. And just to be clear, we’re escalating the dose of birinapant in this study. And we’re conducting this in patients with all different types of solid tumors. So it’s a standard solid tumor Phase 1 dose escalation study that is continuing to go on. In terms of where we might take this, again our strong interest in birinapant in this combination was really built on the preclinical models that showed strong synergy as well as the scientific, mechanistic understanding of how a SMAC mimetic could obviously combine very well with a stimulator agonist of the extrinsic apoptotic pathway. And so we’ve seen activity in a range of different preclinical models. I know, Bruce, you want to comment a little bit to that in terms of where we think this is promising.

Bruce Keyt: Yes. Yes, Michael, thank you for the question. We have tested literally hundreds of different cell lines and patient samples in tumors. And we are, of course, always interested in any mechanism action type signals, but as well as prognostic indicators that might steer us. But what is really exciting is, as Chris mentioned, is we do see with the treatment of FOLFIRI, particularly 5FU and irinotecan, you get the synergy, but you also get upregulation of DR5, which may combine well and set us up for success with IGM-8444 treatment. Now, still having that we’ll, of course, have to do the studies, but the combination the clinical studies to show where and when, which patients result in the best therapy. But we €“ our preclinical data says that we’re going to see a broad spectrum response in this and other indications.

Chris Takimoto: And I think with respect to the specific question of birinapant, we think that that very much could be broadly applicable against a lot of different solid tumors. And hopefully with the combination of IGM-8444 and birinapant little or no additional toxicity. And so there may be multiple combinations here that are possible going forward. So

Bruce Keyt: Yes.

Chris Takimoto: Very encouraging, as Michael, as you know, with those two agents, we are hitting both the extrinsic apoptotic pathway and the intrinsic apoptotic pathway. And we think that’s a real important one to punch that could be if €“ with no seeming additional toxicity could be very, very helpful,

Bruce Keyt: Right. I mean, we clearly have quite a body of data showing that that we have high safety in both of these. And now pre-clinically we see again, a series of animal models and in vitro where the combination with birinapant intrinsic and IGM-8444 intrinsic really combine well.

Chris Takimoto: And thanks for your question about strategic partnerships for imvotamab, and I might expand it out to say imvotamab and our T cell engagers for autoimmune, perhaps more broadly. As you say, the opportunities there are large in number, large in size and could take a lot of money to pursue, but with a lot of potential upside at the end of the pathway. So, I think that strategically finding a partner that was looking to join us to explore this really new opportunity of T cell engagers and autoimmune disease, would be a really good thing for us as a company. Now exactly what the timing of that is, we’ll have to wait and see. But long term, I think, the opportunities are so large and so many different things we could do, I think, a partner would be a really good idea for that franchise if you will.

Michael Schmidt: Great. Thanks so much.

Operator: Thank you. One moment for our next question. And our next question is from Roger Song with Jefferies. Your line is open.

Roger Song: Great. Congrats on all the progress across broad IGM pipeline. So maybe two quick clarifications from us. One is for IGM-8444 DR5. As you are focused on the randomized trial for 3 mig and the 10 mig, would you keep renewing higher dose in your single-arm study, considering you may, maybe just test the safety and the PD marker? And also if or when you will report additional data from the single-arm trial? And also for the imvotamab, I noticed your €“ when you talk about the lupus in RA, we use the nomenclature severe form of the disease. Just curious as you position your T-cell engager for autoimmune disease, what is the real target population for each indication? It will be the last line of the therapy at the starting point, or you will potentially move into the early stage of the disease for those autoimmune disease, that’s two question we have. Thank you.

Fred Schwarzer: Sure. Well, Chris, do you want to take the first one and then hand off to Mary Beth to take the second one?

Chris Takimoto: Sure. So Roger, your question was really about the dose of 8444 now that we’re exploring 10 milligrams per kilogram in the randomized study. And as you’re probably aware, and we’ve talked about before in our monotherapy part of the study, we went as high as 10 milligrams per kilogram, but we did not go higher. There were no any safety signals that arose. We didn’t define dose limiting toxicities or a maximum tolerated dose, and that was also true going up to 10 milligrams per kilogram in combination with FOLFIRI chemotherapy. So there are really no safety issues there. But as we look across the program and the experience, particularly the preclinical experience the €“ in terms of the efficacy and exposures that that we’re achieving that that show activity in preclinical models, we feel that 10 milligrams per kilogram is a good dose, and we don’t feel that there’s a strong need to explore higher doses.

It is something we would potentially leave open, but at least in our thinking today, we’re really pleased with what we’re seeing at 3 milligrams per kilogram. We want to get more experience in combination at 10 milligrams per kilogram and really start to think about how we optimize the dose in that range.

Mary Beth Harler: And hi, Roger, this is Mary Beth. Sorry.

Fred Schwarzer: Well, I think there was the additional question of when we might show some of the monotherapy data there, and I think we just have not made a decision as to when and in what context we would produce additional monotherapy data. I think we’re very focused on the randomized data. We’re certainly not seeing anything in the monotherapy data that’s inconsistent with what we’ve seen to date that would cause us to question our decision to move forward into this randomized study so. But at some point, we will present those data. We just haven’t made a decision when Roger. And Mary Beth, you want to go the second question?

Mary Beth Harler: Yes. Yes. No, sure. Thanks, Roger, for the question. You’re absolutely correct. We are focusing initially on severe SLE and severe RA. Our intention is to establish initial safety and activity in those populations and then move into milder populations. So obviously a much more expansive group of patients on both fronts. This is true, particularly in light of the potential for disease modification through this approach as suggested by that CAR-T data from George . So thanks for the question.

Roger Song: Great. Thanks for the comment. Maybe just a quick follow-up maybe clarification for Fred. So what I meant is for the additional single arm data from the combination, also from the combination you have been doing now the monotherapy data, but I believe that the answer is similar. You haven’t decided that when you will produce.

Fred Schwarzer: Yes. We have not decided. We’ll €“ at some point, we’ll be presenting additional single arm data on the FOLFIRI combination. At some point, we’ll presenting additional €“ we’ll be presenting our initial single arm data on the birinapant combination. And at some point, we’ll be presenting our initial single arm data on the venetoclax combination. But we have not made a decision that on when those data disclosures might happen, where we’re still all in progress on all of those studies right now.

Roger Song: Excellent. Thank you, Fred. That’s it for now.

Fred Schwarzer: Thank you.

Operator: Thank you. And our next question is from Joel Beatty with Baird. Your line is open.

Joel Beatty: Great. Thanks for taking the questions. First one is on the DR5 randomized study. How would you define success from that study?

Fred Schwarzer: I think we’ll certainly know it when we see it, but I’m going to leave it to Chris to talk more about what we’ve got in mind.

Chris Takimoto: Yes. So thanks, Joel. Yes. So the study is designed with PFS as the primary endpoint. Obviously, we will be also looking at response rate and overall survival. The reason why we’re really focusing on PFS though is that one that’s much more strongly correlated with overall survival. And at least in the eyes of the FDA is a much more an endpoint, which is €“ has a much higher track record in terms of actually being a registration €“ potential registration endpoint. And as we start to think about now randomized data supporting accelerated approval, that’s really what has led us to design the study in the current way. In terms of what the success look like again, we don’t €“ I never like to give really specific targets, but we €“ our expectation is that if you look at historical second line colorectal cancer data will FOLFIRI control arms for large randomized studies, the PFS tends to be five, six months or so.

And in those studies and things in the not too distant past, so those that that kind of gives you a floor of what we think where we need to be better and where we expect to be substantially better. But that’s kind of the thinking that has gone into the design of the trial.

Fred Schwarzer: Yes. I mean we really are looking for hopefully a significant improvement on PFS over control here, something that’s clinically meaningful, so.

Joel Beatty: Got it. Okay. Sounds great. Thanks for all those details. And then also on the same agent now that you’re focusing more on the 10 milligram dose, is there a risk of seeing some of the liver issues that we’re seeing with other agents targeting €“ the target?

Chris Takimoto: Joel, what I would say is again, based on our monotherapy experience, we did not see any dose related issues. We didn’t see any issues around treatment related liver toxicity in general, and we certainly didn’t see anything that, that emerged at higher doses. So our expectation is that that would not be an issue and it hasn’t been, and we don’t expect it to be an issue in the future.

Fred Schwarzer: Yes. And we dosed, as we said, three patients in combination with FOLFIRI didn’t see anything there. We have dosed some patients in combination with birinapant 10 mg/kg too, and did not see any signal there. So we’re not expecting to see a safety signal a liver hepatotoxicity signal. But I guess that’s why you do the study, but not expecting it.

Joel Beatty: Great. Thank you.

Operator: Thank you. And our next question is from Noah Eisenberg with JPMorgan. Your line is open.

Noah Eisenberg: Hi guys, this is Noah on for Eric. Thanks for taking our question. Just kind of looking at the second line randomized trial for 8444 noticing that you’re stratifying by KRAS status. So based on that, we’re wondering is there any synergistic potential between DR5 activation and EGFR inhibition? And to what extent are you interested in evaluating EGFR combos or KRAS inhibitor combinations as part of the development strategy? Thank you.

Chris Takimoto: So maybe, I can start, obviously, the colorectal cancer space, there are €“ there we’re starting to see molecular profiling obviously have a big treatment impact on different treatment options. But one of the things that’s been very clear to us at least pre-clinically and also thus far in the clinic is that through our mechanism, we think we should work well in a variety of different molecular subtypes. So KRAS wild-type, KRAS mutant, we expect and what we’re seeing so far, again, small numbers and we’ll obviously look at this further, but we don’t expect to see really any differences in terms of just we expect to be active in all those subpopulations. That being said, as we think about really having a maximal impact on this disease and where do we go if we can confirm the signal and then where else do we go?

We would obviously be open to exploring other combinations in this space as we start to broaden the program. But at least the development and plans now is to try and go more broadly across different molecular subtypes. And I don’t know, there was kind of a mechanistic question there that maybe you can

Bruce Keyt: Yes. No, it’s a very good question. It’s a certainly an active area of research. We €“ as Chris mentioned, we haven’t seen differences due to KRAS positive or negative but there could likely we’d work in both, but the opportunity to combine is still a €“ is a good opportunity we’re investigating pre-clinically.

Noah Eisenberg: Thank you.

Operator: Thank you. And our next question is from Brian Abrahams with RBC Capital Markets. Your line is open.

Leonid Timashev: Hey, guys. Thanks. It’s Leo on for Brian. I had maybe a couple on the pipeline. So maybe starting with IGM-7354. Can you talk about given the initial clean safety data there in two patients? Is this a dose you think could be active? And then, I guess, when do you think we may get to doses where we’ll have more activity. And where’s the preclinical data steering you in terms of what doses you want to reach, what tumor types might be most active. And do you think you can also target low PD-1 expressing cells or is your strategy still going to be enrich? And then I had maybe a follow-up on IGM-2644 as well.

Fred Schwarzer: Chris, you want to take the €“ that question?

Chris Takimoto: Yes. So obviously, one of the things we do when we start a Phase 1 study is we €“ based on the preclinical data, make estimations of where we think efficacious exposure level is. And obviously for safety reasons and things in a dose escalation study, you generally start low and escalate. But I will say that €“ so in terms of our expectation going into the study, we would’ve that maybe in dose Cohort 3 or 4, we would be sort of entering the range that we saw clear actions in preclinical models. But I think the other factors that IL-15 is a potent agonist and we’ve shown certainly our molecules have been able to hit the target. So the safety we think is good, but we’re also through our biomarkers looking at pharmacodynamic effects even at the lowest dose levels.

And I think we’re off to a good start and we’ll have more to talk about in the future about this. But there is certainly the potential that we could start seeing evidence that we’re hitting the target even at the lowest dose levels in the study.

Leonid Timashev: Got it. Thanks. And then may be one on IGM-2644, obviously, there’s a few different bispecifics in multiple myeloma now, BCMA GPRC5D. How are you thinking about how IGM-2644 is going to play in the space and the advantages that you might have over some of the other offerings?

Fred Schwarzer: Maybe I’ll start with that and then let Chris take over. But we see IGM-2644 as pretty differential €“ at least the way we’re intending to develop it as hopefully quite differentiated from those other bispecifics. We would like to see this as a next generation CD38 molecule. And so we would like to assuming safety and efficacy. We’d like to randomize against dara as fast as we can in order to show that we can potentially work better than dara and some of those patients who may be seen dara previously and then maybe eventually moving up. So the focus here for IGM-2644 is a €“ hopefully a next generation CD38. Chris, you want to add to that?

Chris Takimoto: Yes. And it is a crowded space with bispecifics, but about 10 or 12 of those are all BCMA, CD3 bispecifics and then you have the BCMA CAR-T cells coming into the space. And I can tell you that, the fact that we’re not a BCMA bispecific is actually an important differentiating factor. There’s €“ obviously, there’s been reported cases of resistance to CAR T-cell therapy in multiple myeloma through lots of the BCMA antigen and things. And so it’s not necessarily clear, you’d want to use the BCMA targeting bispecific before you would use a CAR T-cell or that you could use it afterwards. So the fact, CD38 bispecifics, there are many fewer out there. There are a handful of other targets in multiple myelomas for bispecifics too, but it’s not anywhere near as crowded as BCMA.

So we think there’s a way to differentiate there. And then Fred has already outlined a major tenant to our strategy here, and that is to really think about this as potentially the best CD38 targeting agent in this class. So that’s really kind of driving our strategic thinking at this point.

Leonid Timashev: Got it. Makes a lot of sense. Thanks for the answers.

Operator: Thank you. And our last question is from Asthika Goonewardene with Truist. Your line is open.

Asthika Goonewardene: Hi, guys. Thanks for taking my questions. And I appreciate all the colors provided today. So Chris, I have a couple questions for you here. On your slide where you have the caspase-3 increase, what was the on-treatment €“ when was the on-treatment measurement made at which cycle, perhaps again, tell us that. And then do you expect a change in baseline to increase which subsequent cycles? And then related to that, do you had four patients that you profiled, the five patients had profiled, including four with PRs, and then one went on to curative surgery? What was the level of increase in caspase-3 that you noted in those profile patients? Then I got a couple of follow ups.

Chris Takimoto: Sure. Yes. Thanks for the questions. So just to be clear on our biomarker slide, what we’re doing this, so these are normalized data. So not surprisingly caspase-3 levels in the plasma can vary highly at baseline from our patients. So what we’ve done is taken the pre-treatment sample, normalize that to one and then show the relative change and actually the data that we’re showing you here. So we monitor the caspase levels during the first cycle, second cycle. And what we’re actually showing here is actually the maximum change that we see in the caspase-3 levels in patients who are on study. Now that could vary somewhat at different time points. So though, we do tend to see a very immediate rise in the caspase-3 levels with treatment. So it’s something that’s very consistent that we’re seeing across our patients. But there is some noise to the €“ in the timing of this, but in general it goes up in essentially all of the patients that are on treatment.

Asthika Goonewardene: Got it. And then

Fred Schwarzer: And then I’d also that we’ve looked at those specific patients.

Asthika Goonewardene: Oh, yes, yes. And then

Fred Schwarzer: How they’re relative fold increase in caspase

Chris Takimoto: Yes, so we have those data. We’ve looked at things in terms of those patients that have shown seem to see clinical benefit and things. And again, it’s just small numbers, so we really can’t draw any conclusions. So we don’t really have anything to share with you right now, although obviously we’re going to be looking at this pharmacodynamic biomarker and correlating that with all different sort of other clinical endpoints in this study, particularly as we move forward.

Asthika Goonewardene: Got it. Okay. And then Chris, I mean, the slide with the biomarkers suggests that there’s 17 patients or so who’ve been treated at 10 milligrams per kg. Could you maybe give us some color on that about what €“ how many of those patients had colorectal cancer? Or if you can’t tell us that, was the distribution similar the percentage of colorectal cancer patients? Was the distribution similar to that seen as a 3 mg/kg dose?

Chris Takimoto: Yes. Yes. So the answer to the last part of your question is no, it’s actually different. So the data that we’re showing you here is a combination of the monotherapy dose escalation patients, which were in all tumor types, as well as patients that were in the FOLFIRI combination arm. And we previously disclosed that we only treated three patients with at 10 milligrams per kilogram in combination with FOLFIRI, not only one of those was a colorectal cancer patient. And because of the expansion at 3 milligrams per kilogram with FOLFIRI, the majority of patients that were showing you with these biomarker changes in the 3 milligram per kilogram cohort are actually colorectal cancer patients that are being treated with in combination with FOLFIRI.

But that being said, one of the things obviously that is a key question is how much, particularly for the combination patients, how much of this biomarker change is being driven by our IGM-8444 molecule, and how much is being driven just by chemotherapy. And what we’ll say, again, with small numbers, but when we look at this in our dataset. We don’t see much of an effect of FOLFIRI chemotherapy on this marker. So we think it is likely more specific for the action of IGM-8444. But in our randomized study, we will have a control arm and we will obviously continue to measure this. We will have more definitive data to share with you to really address that question.

Asthika Goonewardene: Great. Thanks for the call there, Chris. Fred, I got one last for you. You said at some point, I’m using air quotes here for presenting data from the Phase 1 study on the different cohorts. Can I, easy to say at least one of them in some point this year.

Fred Schwarzer: What are you talking? The imvotamab study?

Asthika Goonewardene: No, IGM-8444.

Fred Schwarzer: IGM-8444. We have €“ I’m being really honest in saying we have not made a decision when we would do that. I would say that sometime this year is a €“ would be a reasonable hope, at least for some of those. But we honestly just have not decided. We’ve been so focused on getting the randomized study up and running and these new biomarker data that’s really been our focus. And we’ll turn to that question that you’ve asked shortly I think.

Asthika Goonewardene: Excellent. Thanks guys. I really appreciate the questions.

Fred Schwarzer: Okay. Thank you.

Operator: Thank you. And I would now like to turn the conference back to Fred Schwarzer, Chief Executive Officer for the closing remarks.

Fred Schwarzer: I’d like to thank you all for joining us on today’s call, and we greatly appreciate your support. Thank you.

Operator: And this concludes today’s conference call. Thank you for participating. You may now disconnect.