Good day, and thank you for standing by. Welcome to IGM-8444 Clinical Update Conference Call. At this time, all participants are on a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to Fred Schwarzer, CEO of IGM Biosciences. Please go ahead. Thank you, operator. I would like to thank all of you for joining us during your very busy ASCO schedule. On behalf of IGM, I'm joined today by Dr. Chris Takimoto, Chief Medical Officer, and Dr. Eric Humke, Vice President of Clinical Development. Eric leads our IGM-8444 clinical development program. It is also our great honor and pleasure to have Dr. Susanna Ulahannan of the OU Health Stephenson Cancer Center with us on the call this evening. I will start with a few introductory remarks. I will turn the call over to Chris to provide some historical and scientific background on oncology therapeutic efforts directed at the Death Receptor 5 target. Chris will turn the call over to Dr. Ulahannan to provide an update on our recent IGM-8444 clinical data. After Dr. Ulahannan has provided a clinical data update, Eric will provide an update on our future clinical development plans for IGM-8444. 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 quarterly report on Form 10-Q, as well as its other filings with the SEC. Any forward-looking statements represent IGM's views as of today, June 2nd, 2023 only, 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. This slide provides an illustration of an IgM antibody as compared with an IgG antibody. As you may know, virtually all antibody-based therapeutic drugs approved to date are IgG-based. However, many of the protective antibodies in your body are IgM antibodies, and IgMs serve as our immune system's first antibody line of defense against infection. You will notice that IgM antibodies have 10 binding domains, as shown in red, as compared to two binding domains for an IgG antibody. We believe that having 10 binding domains provides a number of inherent advantages. For today's discussion, we'll focus on the advantage that having 10 binding domains provides when binding certain cell surface targets in order to send a signal to the cell. Death Receptor 5 is this type of cell surface target, and it is disproportionately present on tumor cells. When we properly engage Death Receptor 5 with an antibody, that sends a commit suicide signal to the tumor cell. Needless to say, that could be very helpful in treating cancer. As Chris will describe, an IgM antibody with its 10 binding domains has been shown to cause Death Receptor 5 to send a 1,000 or more times stronger commit suicide signal than the two binding domains of an IgG antibody in preclinical studies. As you can see on this slide, we have a broad pipeline of oncology and autoimmune product candidates, including a suite of IgM-based T cell engager antibodies, which we believe, based on our clinical experience in oncology with imvotamab, which is our CD20 by CD3 T cell engaging bispecific IgM antibody, have the potential to have very broad therapeutic indices as a result of the encouraging safety profiles we have seen to date, preclinically and in the clinic. As we announced earlier this week, we now have FDA clearance to begin testing imvotamab in systemic lupus erythematosus, otherwise known as SLE, and rheumatoid arthritis. We look forward to enrolling our first autoimmune patients for these phase I clinical trials next quarter. Similar to our approach to using the 10 binding domains of an IgM antibody to send a stronger intracellular signal with Death Receptor 5, we also have a very exciting collaboration with Sanofi to develop IgM antibodies against three oncology targets and three autoimmune targets. The goals for all of these targets will be to send a stronger intracellular signal with the 10 binding domains of an IgM antibody than can be sent with the two binding domains of an IgG antibody. Today, we're gonna focus our discussion on IGM-8444. At this point, I would like to turn the call over to Chris to provide some scientific and historical background on targeting Death Receptor 5 for purposes of treating cancer. Thank you, Fred. Death Receptor 5 is a member of the TNF superfamily that requires oligomerization to signal most potently. TRAIL, the ligand for DR5, is a preformed trimer that binds to DR5 and activates the extrinsic apoptotic pathway. This, in turn, triggers a downstream proteolytic cascade that generates activated caspase products, including cleaved caspases- 3 and 7. This ultimately leads to apoptosis or programmed cell death. DR5 was originally cloned in 1997. Soon after, it was recognized that tumor cells highly expressed DR5 relative to their normal tissue counterparts. Our own internal work, shown here on the right, demonstrates this increased expression of DR5, as assessed by IHC staining across different tumors. In contrast, in their normal tissue counterparts, expression is low or absent, consistent with DR5 being an attractive therapeutic target for the treatment of a variety of different tumor types. Clinical studies of agents targeting DR5 have been ongoing for almost 20 years. The earliest approaches used either recombinant TRAIL ligand or bivalent agonistic IgG antibodies, but their development was limited due to liver toxicity, modest antitumor activity, or because of poor pharmacologic properties. The second generation of molecules targeting DR5 have all employed multivalent approaches. This has generated greater antitumor potency, but all have shown a propensity for inducing serious liver toxicity. Our approach to activate DR5 uses an engineered IgM antibody with 10 binding sites, which allows for the orderly clustering of DR5 to trigger a potent apoptotic response. The contribution of the IgM framework is shown on the right, where the same epitope binding domain was examined in either an IgG or an IgM format. The IgM molecule results in a many thousand-fold greater killing of tumor cells compared to its IgG counterpart. This is due to the greater DR5 clustering induced by the multivalent IgM. IGM-8444 is a pentameric IgM DR5 agonist antibody. It was engineered to induce potent DR5 signaling, leading to tumor apoptosis, while simultaneously avoiding any toxic effects on normal hepatocytes. This impressive therapeutic index, shown on the right, results from the inherent IgM structure and from the kinetics of how it clusters DR5. It is also impacted by epitope selection and by affinity and avidity tuning. This has allowed us to design a molecule with the best-in-class therapeutic index. IGM-8444 demonstrated strong preclinical additivity and even frank synergy when combined with a broad range of different types of chemotherapy, including 5-FU, irinotecan, and other agents as well. Both 5-FU and irinotecan can upregulate the expression of tumor cell DR5, thereby enhancing pro-apoptotic signals that augment the activity of IGM-8444. Both drugs are important components of the FOLFIRI standard of care regimen for advanced colorectal cancer. Here are two in vivo models of colon cancer that demonstrate improved antitumor effects for the combination of either irinotecan or 5-FU with IGM-8444, compared to either agent alone. Now it is my pleasure to turn the call over to Dr. Ulahannan. Thank you, Chris. I am really pleased to have the opportunity to share with you the results so far from the IGM-8444/001 phase I trial. I have been involved with this clinical trial since it begun and have enrolled many patients, both to the single agent and combination cohorts, over the past three years. IGM-8444 went into the clinic in 2020, with a broad development plan from the beginning. Included in the protocol were single agent and combination dose escalations, along with multiple combination expansions. The single-agent dose escalation was a three plus three design in an all-comers solid tumor patient population, evaluating a range of doses. Each cycle consists of 28 days, with a dose of IGM-8444, given every two weeks. A limited number of patients were also given IGM-8444 on a weekly dosing schedule. Over the next four slides, I will share with you the clinical data from the single-agent dose escalation of IGM-8444, given every two weeks. The baseline patient characteristics and demographics of the single-agent dose escalation are summarized here. The median age was 61. Male and female enrollment was roughly balanced. Race was mostly white, and ECOG performance status was zero or one. Numerous different tumor types were enrolled, including 54% gastrointestinal, 27% soft tissue sarcomas, 9% non-small cell lung cancer, and 3% other tumor types. The single-agent dose escalation portion of the study was completed last year, with 33 total patients enrolled. The safety from the single-agent dose escalation was excellent, with no dose-limiting toxicities, no related grade three or higher adverse events, and no related serious adverse events. Most importantly, there was no significant liver toxicity, with only low grade one or two, liver function tests or bilirubin increases, which were transient with no clinical sequelae. This was of special interest because many therapies targeting DR5 have been hampered by the significant liver toxicity. Infusion-related reactions were dose-related and all low grade, either grade one or grade two, and manageable with premedication and longer infusion times. The pharmacokinetics of single-agent IGM-8444 exhibits a sustained exposure when given every two weeks at both three and 10 mg/ kg. For all doses at or above 3 mg/kg, given every two weeks, the concentrations at the end of the two week dosing period were above the projected preclinical effective concentration 90. There is no impact of the combinations on pharmacokinetics. The estimated half-life of IGM-8444 at three and 10 mg/kg is greater than two days. Anti-drug antibodies have been observed, but there is no clinical impact on the pharmacokinetics, and titers tended to diminish with continued dosing. Here, we are showing two paired biopsies collected from patients at baseline and on treatment with single-agent IGM-8444. The biopsies were stained for cleaved caspase-3, which is a downstream biomarker of DR5 activation. There are two main points I'd like to make with these paired biopsies. One, we have evidence of biologic activity of DR5 pathway activation after IGM-8444 treatment within solid tumors. Two, IGMs can penetrate deep within solid tumors. The single-agent swim lane plot is organized by cancer type. Soft tissue sarcomas are on top in light red, colorectal cancer in red, other gastrointestinal tumors in dark red, thymic in blue, and non-small cell lung cancer in light blue. Each bar represents an individual patient's time on study. In the phase I trial, we allowed patients to be enrolled with up to three prior residents in the metastatic setting. Most of the patients enrolled and treated with single-agent IGM-8444 had late-line metastatic cancers. We had numerous patients across multiple tumor types showing evidence of tumor reduction, along with prolonged progression-free survival. No patient showed more than a 30% reduction in their tumor size. Patients who had the longest time on treatment, approaching or surpassing one year, showed no evidence of any chronic toxicity with IGM-8444. Along with the single-agent dose escalation, IGM-8444 was evaluated in combination with FOLFIRI in dose escalation cohorts across multiple doses of IGM-8444. Once completed, two combination dose expansions were evaluated. IGM-8444 at 3 mg/kg, plus FOLFIRI without bevacizumab, and IGM-8444 at 3 mg/kg plus FOLFIRI with bevacizumab. Each combination expansion cohort enrolled approximately 20 colorectal cancer patients. The combination dosing cycle consists of 28 days, with doses given every two weeks. Over the next seven slides, I will share with you the clinical data from the combination dose escalation and expansion cohorts. The baseline patient characteristics and demographics of the combination patients are shown here. The median age was 54. Male and female enrollment was well-balanced, and ECOG performance status was zero or one. Both right and left-sided tumors were enrolled, with approximately 60% of patients having liver metastasis at baseline. KRAS and NRAS wild type and mutant and microsatellite instability, high and microsatellite stable tumors were enrolled. The median number of prior lines was two, so our patients were treated in a median third-line setting. Over 70% of patients enrolled had previously received irinotecan. IGM-8444, in combination with FOLFIRI, with or without bevacizumab, remains very well tolerated. Here we show the clinical safety profile on 51 patients treated with IGM-8444 plus FOLFIRI, with or without bevacizumab. All adverse events are shown on the left, and related adverse events are shown on the right. We had no dose-limiting toxicities, no related serious adverse events, and no grade three or higher adverse events related only to IGM-8444. Importantly, we continue to see no evidence of liver toxicity. Infusion-related reactions remain uncommon, low grade, and manageable with prolonged infusion time or premedication. The majority of patients treated in combination with FOLFIRI have had a time on study significantly longer than historical controls. This slide depicts the time on study for individual patients treated with IGM-8444 at 3 mg/kg plus FOLFIRI. Each bar represents an individual patient. Stars denote those patients previously treated with FOLFIRI. The length of the bar represents an individual patient's time on the study. Of the 24 patients treated at 3 mg/kg plus FOLFIRI, nearly half remain on treatment, with a current calculated median progression-free survival of 5.6 months. This patient population is median third line, which historically has a progression-free survival around two months, and an overall survival of about seven months in response to long-term chemotherapy. In colorectal cancer, the regulatory approval endpoint is overall survival. Progression-free survival is correlated with overall survival. This waterfall plot shows all patients in the single arm, non-randomized study, with at least two scans or progression, who have been treated with IGM-8444 at 3 mg/kg plus FOLFIRI, with or without bevacizumab. For the phase I study, we allowed metastatic colorectal cancer patients with up to three prior lines to be enrolled, and also allowed patients to have previously received FOLFIRI. Each bar represents an individual patient's best radiographic response. The bars are color-coded for whether patients received bevacizumab. Despite the late-line colorectal cancer patient population, median third line, with many patients having previously received FOLFIRI, we achieved numerous deep partial responses. One patient who nearly achieved a PR had a reduction in their tumor burden to the extent that they went on to receive curative surgery. Beyond the radiographic-defined RECIST response, additional patients had a decrease in their tumors, despite being late line and importantly, previously treated with FOLFIRI. For some patients that responded at 3 mg/kg, we put together a detailed view showing their baseline characteristics, mutational status, and colorectal cancer treatment history prior to coming on to our study. Many responders had prior FOLFIRI, and in the at least two of these cases, showed prior progression on FOLFIRI. three of the four patients shown here are mine. I'd like to walk through the details on two of them. The patient in the upper left previously received FOLFIRI plus bevacizumab, with a best response with stable disease, eventually progressing in five months. They went on to receive XELOX chemotherapy for just two months before progressing and enrolling into our study, where they received a partial response and continues to be on study now for over 16 months. Interestingly, this patient has not received much irinotecan due to toxicity of diarrhea. The patient in the lower right-hand had an NRAS mutation and had previously received FOLFOX, followed by FOLFIRI plus bevacizumab, with the best response of stable disease. They went on to receive IGM-8444 plus FOLFIRI, where they achieved a partial response and stayed on study for nearly six months. I have another patient who is not listed here on the slide, but is worth mentioning. This patient was experiencing significant toxicity with FOLFIRI, so we decided to hold the chemotherapy and continue them just on IGM-8444 plus bevacizumab, which they've been on now for nearly three months. The patient's energy has returned. They're back to gardening and mowing their lawn, and they have had a continued radiographic reduction over time. It's these individual patients' narratives that gives me hope that IGM-8444 is adding significant benefit to FOLFIRI. Typically, as you move to later treatment lines in metastatic colorectal cancer, the progression-free survival decreases by approximately half each time you move later in the line.... The median progression-free survival in first-line metastatic colorectal cancer is 12 months, in second line, about six months, and in third line, two months. The white bar represents an individual patient's time on FOLFIRI treatment without IGM-8444, given in the first or second-line setting. The adjacent blue bar represents the same patient's time on FOLFIRI treatment now with IGM-8444, given in a median third-line setting. Recall, in this setting, the median progression-free survival for standard of care is about 2 months. The majority of our patients have a time on FOLFIRI with IGM 8444 that is longer than, or at least equal to, the time on prior FOLFIRI without IGM 8444, suggesting that IGM 8444 is affecting how an individual patient is responding to FOLFIRI. A second expansion cohort, looking at 3 mg/kg of IGM 8444 in combination with FOLFIRI and bevacizumab, was opened in late 2022. Initial results for the evaluable population are shown here. We have much less follow-up for these patients, but remain encouraged by the prolonged duration of treatment we have observed. As of April 12th, 13 out of 17 patients, 76%, treated with IGM 8444 at 3 mg/kg in combination with FOLFIRI plus bevacizumab, remain on treatment. Colorectal cancer patients in this group were median third- line, and the median progression-free survival has not been reached. This waterfall plot shows all three patients treated with IGM-8444 at 3 mg/kg, plus FOLFIRI, plus bevacizumab, with at least two scans for prior progression. The median line for this group was three. As of April 12th, we had three responses out of nine patients. In conclusion, IGM-8444 demonstrates an encouraging safety profile as a single agent and in combination with FOLFIRI, with or without bevacizumab, with no clinically relevant hepatotoxicity across multiple doses and prolonged treatment. IGM-8444, in combination with FOLFIRI, with and without bevacizumab, shows promising activity in heavily pretreated metastatic colorectal cancer patients. Clinical responses and tumor shrinkage are observed in majority of patients, even in patients refractory to prior therapy. The overall response rate and progression-free survival is substantially higher than currently approved agents for a third-line treatment. There is longer duration of treatment in multiple patients compared with their prior FOLFIRI-based regimen. This is a patient population with a high unmet need, where we need better treatment. At this point, I would like to turn the call over to Eric. Thank you, Dr. Ulahannan. Encouraged by the clinical data you just heard from Dr. Ulahannan of IGM-8444 in combination with FOLFIRI and bevacizumab in a median third-line patient population, where the standard of care overall response rates are 1%-2% and the progression-free survival is two months, we will be moving development into the second-line setting, where we would expect to see even greater activity. FOLFIRI plus bevacizumab is the most common standard of care regimen for second-line colorectal cancer. The efficacy benchmarks for FOLFIRI plus bevacizumab in second-line colorectal cancer include: an overall response rate of 5%-20%, progression-free survival of six months, and an overall survival of 12 months. While the gold standard for regulatory approval remains overall survival, progression-free survival is correlated with overall survival, we believe it can form the basis for an accelerated approval. Based on the encouraging single-arm clinical data in median third-line patients that you heard about today, we've initiated a randomized clinical trial in second-line colorectal cancer. Patients will be randomized one to one to receive either IGM-8444 at 3 mg/kg, plus FOLFIRI, plus bevacizumab, or FOLFIRI plus bevacizumab alone. Those patients receiving the control arm will have the option to cross over at progression to receive IGM-8444 at 3 mg/kg plus FOLFIRI, plus bevacizumab. In March, we started making plans to include a 10 mg/kg dose as a separate arm in this randomized study. However, in light of our developing clinical data in late-line colorectal cancer at 3 mg/kg we have decided to move forward quickly with a 2-arm study to definitively evaluate the contribution of IGM-8444 at 3 mg/kg plus FOLFIRI plus bevacizumab as soon as possible. Nonetheless, given our encouraging safety profile, we remain committed to evaluating IGM-8444 at 10 mg/kg. In the interest of saving time, concurrently with our randomized study of 3 mg/kg we plan to begin generating additional data at 10 mg/kg in our ongoing non-randomized trial. As we determine the contribution of IGM-8444 at 3 mg/kg in the randomized study, we will evaluate the data we generate at 10 mg/kg in the single-arm study, to determine whether we wish to test 10 mg/kg in a subsequent randomized study. For the current randomized study, patients cannot have received prior FOLFIRI, and the study is agnostic to tumor mutational status and DR5 expression. While it is an open label study, we have included a blinded, independent radiographic review. The trial size will be approximately 110 total patients, which we believe is sized adequately to show a clinically significant improvement in progression-free survival, which is our primary endpoint. Secondary endpoints include overall response rate, overall survival, and safety. We hope to be fully enrolled in the randomized trial by first quarter 2024, have overall response rate data by mid-2024, and have progression-free survival data by the end of 2024. As we assess the magnitude of the clinical benefit of 3 mg/kg in the randomized study, we will discuss possible approval pathways with the FDA. These graphics highlight the best radiographic response on the left and the time on study on the right in all patients treated at 3 mg/kg plus FOLFIRI, with or without bevacizumab, who did not have prior FOLFIRI or irinotecan-based treatment. As compared with our patients who have received prior FOLFIRI or other irinotecan-based therapies, this group of patients is more similar to the population that we will be enrolling into our second-line randomized clinical trial. Encouragingly, all of the patients had a tumor reduction, and over half had either a partial response or a decrease in tumor burden that led to curative surgery. As of April 12th, all patients except one remain on treatment. In addition to our randomized clinical trial in second-line colorectal cancer plus FOLFIRI with bevacizumab, we have begun to consider additional development paths for IGM-8444. The encouraging safety profile that we have seen to date may enable us to move up in line within colorectal cancer to first line and the adjuvant setting, where safety is even more critical. Beyond colorectal cancer, there are other GI cancers, including pancreatic and gastric, that have a standard of care chemotherapy similar to colorectal cancer. We would also like to evaluate IGM-8444 in these indications. We are also currently exploring combinations that make mechanistic sense, such as venetoclax, an approved BCL-2 inhibitor, and novel agents such as birinapant and SMAC mimetic. Other interesting combinations we hope to test include antibody drug conjugates and drugs targeting senescence. With DR5 showing preclinical synergy with many classes of chemotherapies, the clinical data with FOLFIRI may also read through to additional chemotherapies, including taxanes and etoposide. In summary, we are very encouraged about what we've seen to date in combination with FOLFIRI and bevacizumab, and we are excited to get randomized clinical data as soon as possible. With that, I would like to turn the call back over to Fred. Thank you, Eric. In closing, I would like to thank Dr. Ulahannan and all of our principal investigators, their teams and their institutions, and most importantly, the patients and their families, for making the progress we've described today possible. We're very excited about the potential of IGM-8444 to make an important difference in the treatment of colorectal cancer and other malignancies. We look forward to updating you on our progress as we pursue our mission of developing this exciting new approach to targeting Death Receptor 5. With that, operator, I'd like to open the call for questions. Thank you, sir. As a reminder, to ask a question, you will need to press star one onec on your telephone. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. I show our first question comes from the line of Stephen Willey from Stifel. Please go ahead. Yeah, thanks for doing this, thanks for taking the question. Maybe just with respect to the decision, I guess, to deprioritize the 10 mg per kg dose as it pertains to the randomized study, I guess, what does that say about the, your perception around the biomarker data that was generated previously? I guess, how should we be thinking about some of the PD markers that I'm sure we're gonna be seeing with respect to trying to just get a sense of the magnitude of extrinsic apoptosis activation you're achieving? Well, maybe I'll start, Steve, thanks for the question. We do think the biomarker data certainly is indicative of how hard we are hitting the target. As we watch the median PFS data mature on 3 mg/kg we felt that it really made sense for us to try to get a definitive answer as quickly as possible on, to confirm the signal and to quantify the signal at 3 mg/ kg. At the same time, of course, we can test 10 mg/ kg in our single-arm study, we think that that will give us a good sense of whether 10 mg/ kg is going to add something to 3 mg/ kg. We felt that this was strategically the fastest way for us to get to a definitive answer. Okay. maybe I can. Is your target number? I'm sorry, Steve. Yeah, go ahead, sorry. I just wanted to elaborate, this is Chris Takimoto. That, you know, I wouldn't necessarily characterize it as deprioritizing, because I think after we discussed things, we realized that in a non-randomized setting, in more advanced third and fourth line patients, exploring 10 mg/kg in that combination, we would likely get more data more quickly by taking this approach. You know, we're fully committed to exploring 10, but this was actually a way we thought we could do it more efficiently. Okay. I guess just with respect to the 10 mg/ kg dose, how many patients are you looking to treat in order to just get some kind of determination as to whether or not it might be better than three from a clinical perspective? Chris? Yeah. Our plan is to, you know, gain more experience. You know, I think the initial expansion cohort that really showed us the signals with 3 mg/kg were about 20 patients in expansion, and we would start with an evaluation of about a similar number at 10 mg/kg. That would be our plan. Is there just anything that either you or Dr. Ulahannan can say about the kinetics of response? Are these rapid in nature, or should we expect there to be some potential deepening of responses over time from some of these patients that are sitting in stable disease? Would just be curious as to how the responses are kind of manifesting in the clinic. That's my last question. Maybe I can address that first and then ask Susanna to comment. You know, we see responses, both in the first set of scans, and then we've also seen some patients have deepening of their response as they stay on therapy. You know, I think we've seen both, but Susanna. Yeah. Yeah, I agree with that. I've had a patient, for example, the one that we showed there with the 60%, that was the first scan. That was a 60% PR that she has maintained, and that patient is actually preparing to go to surgery. I've had another patient, so the one that, I don't think it was one of the four, but where we've seen over a longer period of time where each scan is better, with I think it's third or fourth scan, going into a PR. I think just looking at the PR, most of the patients actually have had their PR pretty quickly, quicker than I would have anticipated, but there are also some that have been, more, gradual at PR. Okay, that's helpful. Thanks for taking the questions. Thank you. I show our next question comes from the line of Greg Harrison from Bank of America. Please go ahead. Hey, guys. Congrats on the update, and thanks for taking the question. I was wondering, can you make any general conclusions as to how the second-line patients responded relative to later-line patients? And, and what does that imply for your expectations in the randomized trial in second line? Eric, do you want to take that one? Yeah, happy to do that. We have not done that analysis looking at second-line patients as a subset of the group that we've treated. You know, it's a relatively small group. I think probably more interesting to us is the group of patients that would be most similar to the patients we'd be enrolling in the second-line setting. That would include this FOLFIRI naive group that we shared with you. That's a mix across lines. A number of them were second line, a lot of were late line as well. That's the group that we ultimately decided to just evaluate to do this small subset. Again, with more patients, the data will be more robust, so it's hard to always quantitate. Got it. Thanks for taking the question, and again, congrats. Thank you. I show our next question comes from the line of Michael Schmidt from Guggenheim. Please go ahead. Hey, this is Paul in for Michael. Thanks for taking our question. I guess first, could you talk a little bit about your decision to move forward with PFS as the primary endpoint of the phase II, as to opposed to pursuing maybe a response rate and duration of response for accelerated approval? You've highlighted some current benchmarks in the 2nd-line setting. Is surpassing those sufficient, or do you have a different bar for potential accelerated approval? Chris, do you wanna take that one? Yeah. You know, I think the decision to focus on PFS is because, you know, I think when you actually look at what parameters, efficacy parameters are best correlated with overall survival, PFS is much more strongly correlated with survival than response rate is in colorectal cancer. We think that there's a much more straightforward path in terms of taking this compound forward by focusing on PFS. That being said, we are gonna look at all of these endpoints, including overall survival, so we will be collecting data there. That was really what was driving our decision to focus on PFS. Got it. Okay. Then for Dr. Ulahannan, just maybe a quick one on maybe giving us a sense of what% of your patients get FOLFIRI up front as opposed to FOLFOX? Yeah. maybe how much impact does prior FOLFIRI have on patient responses, in your opinion, to the combination? Thank you. Yeah. I mean, in U.S., I think most of our patients do get FOLFOX up front. You know, FOLFIRI goes in the second-line, whereas in Europe, you see much more of the FOLFIRI in the front-line setting. I think, you know, if you look at my patients, the majority have had FOLFOX, and that's what you can see here, too. Those who've had, you know, more of a second-line setting, they've all had FOLFOX in front-line, and then they get the FOLFIRI here on study. I think the second part of the question was... Oh. What impact of prior FOLFIRI do you think has, prior treatment with FOLFIRI has on... On adding- Yes. the new drug? No, I mean, the patient having previously been treated with FOLFIRI and then coming onto the study. I think that's the most interesting part of the study, is really seeing these responses, deep responses in patients who progressed on FOLFIRI. In a standard of care clinical setting, you would never retreat with FOLFIRI. I mean, that's nothing we do. We don't expect to see something in that population. Here we are actually seeing a response, PRs in those patients who've already progressed on FOLFIRI. I think that's what, that's what made me mostly excited about this drug, is really to see that you're, you know, you're getting responses in patients who've already been exposed to FOLFIRI. I think that's an important part also, because we see in colorectal cancer, a lot of the treatment is also going into front-line FOLFIRINOX, and so even more important to see that this drug actually is making the FOLFIRI work even when it's been exposed previously. Very helpful. Thank you. Thank you. I show our next question comes from the line of Roger Song from Jefferies. Please go ahead. Great. Congrats for the data, thanks for taking the question. Question maybe just focusing on this bev combo triplets. Since you have thre PR out of nine patients evaluable with two scans, that's pretty encouraging. Just any kind of a detail around those patient baseline in terms of the second versus third- plus line and the prior FOLFIRI plus, minus bev experience, that would be helpful. Also in terms of the mechanism, maybe can elaborate on a little bit how you think IGM-8444 may have some synergy with bev? Seems that this the signal is stronger than just FOLFIRI alone as the combo. I have a one follow-up after that. Thank you. Maybe I could address the first part of your question, Roger. In terms of the responses, you know, we're seeing a really good tumor shrinkage and responses across patients with multiple different lines of therapy, including some of them, you know. ... third and fourth line, as well as, some in earlier lines as well. You know, I think that's part of the reason why we were so excited about these data. I think the second part of your question was the mechanism? In terms of the mechanism, you know, very clearly, we've now shown that IGM-8444 is a potent agonist of DR5, triggering the extrinsic apoptotic pathway. We know that things like chemotherapy, and certainly irinotecan and 5-FU, can enhance pro-apoptotic signals in tumor cells, and that was really the basis for the strong synergy that we saw pre-clinically. I think that mechanism is being borne out in the clinical data that we've generated thus far. The other part, I'll just add, Chris, this is Eric. The other thing I'll add is that the addition of bevacizumab to FOLFIRI now with IGM-8444. Certainly what we know is that when you add bevacizumab to FOLFIRI, that you get improvement in PFS and overall survival in colorectal cancer. We have preclinical data that suggests that IGM-8444 with bevacizumab, you get an added boost to the efficacy, if not synergy. Now that triplet is really the one that we're interested most to test, not only because it's second-line standard of care, but also because we have this compelling preclinical data. Great, thank you. Since Eric, you mentioned adding bevacizumab to the FOLFIRI, the PFS OS improves. Given you have set up this two-month PFS for the third plus line, so maybe just give some color around what is the standard of care efficacy for bev plus FOLFIRI in second line versus the third plus line? Thank you. I can take that. I'm happy to take that. Recall, let me start with the third line plus first. Recall that standard of care here, the approved standard of care agents are regorafenib and Lonsurf, here, progression-free survival is around two months. Response rates are 1%-2%. That's really the benchmark for third line as of today. The approval for bevacizumab is in second-line colorectal cancer in combination with FOLFIRI, the benchmarks are the ones that we've listed as part of the presentation. Here, the PFS is right around six months, OS is right around 12 months. Those are the benchmarks that we would expect to be going up against in now those second-line colorectal cancer. Great. Thank you. Thank you. I show our next question comes from the line of Joel Beatty from Baird. Please go ahead. Hello, this is Benjamin Paluch for Joel Beatty. Thanks for taking the questions. The first one we had was how much does bevacizumab add to the caspase-3 on treatment effect? Does it add anything on top of FOLFIRI and then 8444, perhaps you're able to hit the pathway harder? I'm happy to take that one as well. We don't have that data. We haven't done that analysis yet. understood. Yeah, that makes understandable. Perhaps for Dr. Ulahannan, can you maybe put the context of getting patients to surgery? What's the significance of that? Yeah, I mean, that's really the win here. We know in colorectal cancer that that's our goal. Colorectal cancer was one of the first cancer types where when we realized the importance of getting patients to NED and getting them to surgery, that's the only curative paradigm we have in colorectal cancer. These are patients who went to tumor board, were deemed non-resectable, not having a surgery pathway, then having such good response that they now became surgical candidates. That's really the ultimate goal to get these patients to surgery. Remembering that when we look at colorectal cancer, there is really a difference in where the metastasis is. Is it in the lungs? Is it in the liver? Is it in the abdomen? We know that patients who have peritoneal disease have the poorest outcome. What's interesting is that we've seen several patients have really remarkable responses with peritoneal disease, where one of our patients went to surgery, and we have another patient with a 85% PR. That's really remarkable and very impactful for these patients, because how these patients die and how they go in, where there is most morbidity, is because they go into bowel obstructions, and it is just very difficult to treat those patients. I think that's one of the points that I've noted in my patients has been very important. Thanks so much for that. Really much appreciate that. Last question for us, any sense of was there a difference in patient compliance or dropout from the combination of FOLFIRI and 8444 versus the combination of FOLFIRI, 444, and then bevacizumab? I'm happy to take that one again. This is Eric. No difference whatsoever. Dose intensity was extraordinarily high. You know, as we presented, the addition of 8444 with either backbone chemotherapy, with or without bevacizumab, does not add to the safety issues with FOLFIRI alone. Got it. Yep. Thank you so much. Appreciate it. Thank you. I show our next question comes from the line of Mike Ulz from Morgan Stanley. Please go ahead. Hey, guys. Thanks for taking the question. You highlighted a couple additional opportunities for 8444. Just curious if you could maybe comment on how you're prioritizing those other opportunities in terms of the combos you're looking at or indications? Thanks. Sure. Chris, do you wanna take that one? Well, I think our highest combination priorities beyond FOLFIRI are the ones that we're actively exploring now in a treated patient. As we've alluded to, the combination with birinapant, the small molecule SMAC mimetic, strongly synergistic in preclinical studies. Mechanistically, it makes a lot of sense to combine these agents, so that's an ongoing part of the study where we're treating patients with that combination. The other combination that mechanistically we think is very interesting is combining the BCL-2 inhibitor, venetoclax, and 8444 with azacitidine in AML patients, and that's an active arm of the study that we've treated patients. I think those are two of the highest priorities as well as the other options that we've talked about. I think as we look at additional chemotherapies, we're going to look for opportunities that look similar to FOLFIRI in second line colorectal cancer, where there's a well-established standard of care of approved drugs. The progression-free survival is not particularly good, the response rate is not particularly good, and where we think we may be able to improve, particularly progression-free survival, with the addition of 8444 to that well-established standard of care. That appears to us, such as venetoclax, as the easiest path forward to demonstrate value and to hopefully get to a regulatory approval. Got it. Thank you. Thank you. I show our next question comes from the line of Brian Abrahams from RBC Capital Markets. Please go ahead. Hey, good afternoon. Thanks for taking my questions. I had one question on the future path and then one question on the data. Maybe just starting with the future path, can you talk a little bit more about the potential opportunity for accelerated approval? Has there been any sort of initial informal FDA discussions around that or any precedent to that might guide the use of PFS in an open label randomized study here, and then, you know, in this indication? I guess along those lines, are there any... I know you laid out timelines for potential data availability. Are there any opportunities just being an open label trial for earlier looks or interims that could potentially enable an earlier filing? I have one follow-up. Yeah. Thanks, Brian, for your question. You know, we have actively engaged with the FDA about this program. We expect those interactions to continue. To be clear, you know, we designed this current randomized study really to focus on confirming the strong PFS signal that we're seeing with 3 mg/kg in this colorectal cancer population. That's really the intent of the study. Obviously, we've designed that study with the potential to do blinded reads of the data. I think if the data are looking strong, we're obviously gonna have discussions with the agency about how we could carry that forward. That is very much part of our strategic thinking. Great. No, that's super helpful. Just maybe on the combo arms, can you just remind us how many patients you enrolled? I, and I realize this is in the escalation, not the expansion portion, but how many patients you had enrolled with doses higher than 3 mg/ kg? Three. Only three, only one was colorectal. That was disclosed in January. We've not dosed any patients since, other than those 3- 10 mg patients. Got it. No, that's really helpful. I wasn't sure if any additional patients had been added with colorectal. Great. Then maybe just one more really quick question. It did seem like there was a, maybe a slight change amongst the four patients you called out in the duration on therapy. Just wanted to see. It looked like for one of them, it was maybe shorter. Just wanted to understand the change there. Just more of a housekeeping question there. That's it for me. Thanks. Maybe I can address that one. You know, previously, we've reported time on study, and now we report an even more conservative way to present the data, and that's the so-called duration of treatment. The swim lanes that are presented are so-called duration of treatment. That is the time from first their first dose until either their current date or their last dose, if they progress. There can actually be some erosion of time on study, and we thought this is the most conservative way to present the numbers. That could be what you're seeing in terms of any erosion. Yeah, that would, that would explain it. Thanks, Chris. That's really helpful. Thanks again. That was Eric, but thank you. You're welcome. Thank you. I show our last question comes from the line of Eric Joseph from JP Morgan. Please go ahead. Hi, this is Noah on for Eric. Thanks for taking our questions. Our first question is, in the data that you've presented today, have you noticed if there is an impact from a liver mets or a KRAS status on efficacy in these patients? This is Eric. I'm happy to take that question. We see very nice responses in patients with or without liver mets, as well as KRAS mutant, KRAS wild type. For us, this is another piece that makes it very exciting because this now is an all-comers patient population that we'll enroll into this second line randomized study. Got it. Great, thank you. Just wanted to also ask on, in the non-randomized study, when do you plan to... Do you have plans to resume dosing in the 10 mg-kg arm, this year? Yeah, I can take that one as well. Yes, we do. We, as Chris, and others have mentioned, we think we can, because we are gonna be enrolling in the non-randomized arm for the 10 mg/ kg, FOLFIRI with Bev, with, without Bev, we think we can enroll this really quickly. We expect to see patients enroll this year into those non-randomized arms. Got it. Great. Thank you. Thank you. That concludes the Q&A session. At this time, I'd like to turn the conference back over to Fred Schwarzer, CEO of IGM Biosciences, for closing remarks. Well, thanks very much to all of you for taking your time on a Friday evening. We really appreciate it, and we appreciate your support, and don't hesitate to get in touch if you have additional questions. Thank you. Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.