Morning, and welcome everyone to the 39th annual JPMorgan Healthcare Conference. My name is Felipe Velásquez, the Vice President on our Healthcare Investment Banking team. I'm here with our next presenting company, CEO Fred Schwarzer of IGM Biosciences. As a reminder to those watching the presentation, if you would like to ask a question afterwards, please submit one via the Ask a Question link found under the viewing panel of your screen. I'll now turn it over to Fred. Thanks very much, Felipe. It's my honor and pleasure to be able to present IGM Biosciences today. Second slide. This is our forward-looking statement disclosure, which basically advises you to take a look at our filings with the SEC, including the risk factor sections, and those will help explain that sometimes things can happen, and our best hopes and plans don't necessarily always work out as we expect or hope. Slide three. IGM is the global leader in the development of engineered IgM antibodies for therapeutic use. We've been working at this for about 10 years now. When we started, many folks said, "You really can't make IgM antibodies. You can't express them at high yields. You can't manufacture them. You can't formulate them." Well, we've spent the last 10 years proving that, in fact, you can do it if you work hard enough at it. Which is what we've done. Now, we are the global leaders in development of IgM antibodies. We have two programs in the clinic, CD20 by CD3, and a DR5 agonist, and we have a third program that we expect to file an IND on this year. Over the course of that 10 years, we've developed a really robust intellectual property portfolio encompassing 28 different patent families. Our strategy is to remain the global leaders in the development of IgM antibodies. Hopefully we'll come back 10 years from now, and we'll be able to tell you that we're still the global leaders, or even better, that you'll tell us we're the global leaders in the development of IgM antibodies. To the best of our knowledge, there is still no other significant commercial effort anywhere in biotech or pharma on IgM antibodies. We're still running as fast as we can, even though it seems like nobody is chasing us right now. We are developing our research programs. We're pouring money into research and development for both new products and to develop our pipeline. We are building our manufacturing capability, which will come online this year. We hope to participate in commercialization and of course, develop our intellectual property portfolio even further. We're in a great cash position right now. Here's a pipeline sketch. You'll see the two programs at the top that are in the clinic, CD20 by CD3 bispecific, and a DR5 agonist. The third program that will go into the clinic hopefully, we'll at least file an IND on it hopefully this year, is an IL-15 by PD-L1, targeted IL-15 delivery. Beyond those, we have a really strong pipeline of additional T-cell engagers, both for two other solid liquid tumor indications, CD123x3 and CD38x3, and multiple solid tumor indications. Following on the DR5 program that we'll talk about in a moment, we also have two other TNF receptor superfamily member agonist programs, OX40 and GITR. These are cases where, again, as with DR5, I think the results, we would probably say in the clinic so far on OX40 and GITR have not been particularly impressive. We think that that's as a result of the fact that IgG antibodies are being used rather than IgM antibodies. Here's a graphic illustration of an IgM antibody as compared to an IgG antibody. What you'll notice is the 10 binding domains in yellow of the IgM antibody, as compared with the two binding domains of the IgG. This gives us much greater binding power than the IgG antibody. The way I like to express it is, it's the difference between trying to hold onto something with two fingers or trying to hold onto something with two hands. It seems intuitively pretty clear that you probably can hold on a lot better if you're using two hands. I'd also draw your attention to the little red semicircle there. That's called the J chain or the joining chain. Of the five natural classes of antibodies, only two of them have a J chain, IgM, where the J chain makes it into a pentamer, and IgA, where the J chain creates a dimer. Now, we also work in IgA, and much of our intellectual property also applies to IgA, particularly around the J chain. We're not going to talk about IgA today because none of our near-term programs are primarily focused on IgA. Here's how we make a bispecific form of an IgM antibody. You see the 10 binding domains here. In our first program, the yellow is focused on binding CD20 on the surface of lymphoma cells. The green is a binding domain that targets CD3 on T-cells. This helps bring together the T-cell and the lymphoma cell in order to allow the T-cell to kill the lymphoma cell. As you see on the right-hand side, the IgM, we like to describe it as sort of a six-slice pizza, and the J-chain is where the one slice is missing. It gives plenty of room for the binding domain on the J-chain to bind to the T-cell or other targets. Here's how this works in the case of a T-cell engaging antibody. You see the IgM binds to the cancer cell, the T-cell binding domain, the CD3 binding domain, binds to CD3 on the T-cell. It brings the T-cell together with the cancer cell, the T-cell does something that's called degranulation. It sends out these chemical particles called perforins and granzymes that penetrate the cancer cell and kill it. It's a very potent killing mechanism known as T-cell directed cellular cytotoxicity or TDCC. We're very fortunate in that we can have a second mechanism of action as well using an IgM antibody. The IgG bispecifics have to disable their second mechanism of action, which is known as antibody-dependent cellular cytotoxicity or ADCC. Because if they didn't disable that, they would kill T-cells. We don't have to disable our second mechanism of action, which is complement, because it only takes effect when the IgM is bound to the cancer cell, so it won't kill any T-cells. What happens is the IgM binds to the cancer cell, as you see here, and then it does something called fixing complement. What that means is that the complement binds to the IgM, sits down on the IgM, and then goes and kills the cell. An IgM is inherently 100 times more potent in terms of fixing complement than an IgG. It's a very attractive natural mechanism of killing for an IgM antibody. You see on the right-hand side, you see the differences between the potency of these two mechanisms of action. In red, you see CDC alone, that's the complement alone. In blue, you see the combination of the TDCC and the complement. Obviously, the two together are more potent than one alone. Here's where we stand with respect to our clinical trial of what we call IGM-2323, which is our CD20 by CD3 engager. We started at 0.5 mg of fixed dose, a very low dose in order to establish safety. Moved up through four dose cohorts, 2.5 mg, 10 mg, 30 mg, and then we moved to a method we call titration dosing, where we give a first dose of 50 mg and then dose up to 100 mg. We have now moved up through 50 - 300 mg and we've completed clearing our dose-limiting toxicity window on 50-300 mg with three patients, and we are now enrolling to the 50-600 mg dose cohort. That's probably going to be our last dose cohort, but for 50-1000 mg. Probably two more dose cohorts that we'll go through here, 50-600 mg and 50-1000 mg, but we still need to see what the data shows at 50-600 mg and 50-1000 mg for that matter. Here's a quick snapshot of the data that we presented on December 5th at the time of the ASH conference. We saw what we thought was very encouraging efficacy. Nine of the 14 patients across those first five dose cohorts, starting all the way down at 0.5 mg, showed reduction in tumor size. There was evidence of activity across all the initial dose cohorts, even as low as 0.5 mg. We did allow intrapatient dose escalation after the next higher dose cohort had been cleared. In our highest dose cohort that we showed at the time of ASH, the 50-100 mg dose cohort, we have two follicular lymphoma patients, and of those, both turned into complete responses. We went two for two in the follicular lymphoma patients in that dose cohort. In the 30-mg dose cohort, we also had a response in a post-CAR T DLBCL patient, which was very encouraging. From the safety standpoint, we think we look to be establishing the potential for a best-in-class safety profile here with 2323. We had no dose-limiting toxicities. Three out of the 14 patients had CRS. Those were all at the 30-mg dose level, interestingly, but they were all Grade 1 transient and just some chills and fever. We had no CRS in the 50-100 mg dose cohort of three patients. We also saw no neurotoxicity and no anti-drug antibodies were observed. Very encouraging, both from a safety standpoint and from an efficacy standpoint. Here's a waterfall plot that shows the activity across four different types of non-Hodgkin's lymphoma, and you can see that we had responses in all of the different types of lymphoma, which again, we think is very encouraging. Here's an example of the extended duration of activity that we saw here in follicular lymphoma, where the activity deepened over time. In the patient on the top in blue, you see that they achieved their complete response at their 24-week scan, and the patient in black achieved their complete response at the 18-week scan. Very encouraging that the drug continues to act over time, and that responses seem to deepen over time. A subtle but very important aspect to what we saw is a very different cytokine release profile, and we think that this has implications both for safety and for efficacy. Unlike some of the IgG bispecifics, where they can have a very strong IL-6 component to their cytokine release, which can create very significant safety issues, our cytokine profile appears to be predominantly interferon gamma, which we think is very encouraging, both from a safety standpoint and from the standpoint of stimulating the immune system to greater activity over time, and potentially leading to endogenous immunity activity over time. We think this is very encouraging. In terms of what we hope to do this year, we hope to have a recommended phase II dose by roughly the middle of this year. We hope to expand into well-defined resistant refractory DLBCL and follicular lymphoma cohorts. We hope to also focus on some low CD20 indications, such as CLL and potentially multiple myeloma. Because of the extra binding power of the IgM antibody, we believe we're able to do much better against low CD20 leukemia cells, because we can just bind much better to those low-expressing cells. We think there's an opportunity for us in CLL, and we also think that our safety advantage, if it proves out, will be very important in CLL. We also intend to explore frontline combinations, where an advantage that we have is that we're able to compete effectively with Rituxan. With our 10 binding domains as compared to the two binding domains of Rituxan, we're able to compete quite effectively. We think that we can add to Rituxan, add to the standard of care right now, which is R-CHOP, which is a curative regimen. We think that that's a much more straightforward approval path than trying to initially replace Rituxan. We're very encouraged about what we're going to do this year in clinical development. It'll be a very big year for us, we hope. Moving on to DR5, our second clinical program. This is a really interesting application of an IgM antibody. Mother Nature has decided that if you're going to send a really important signal, like telling a cell to commit suicide, you need to make sure you really mean it. The way that Mother Nature has done that is it says that you need to bind three of these death receptor 5 ligands together closely in order to send this cell signal. Obviously, an IGG doesn't do a particularly great job of binding three, because it only has those two binding domains. An IgM does a great job of binding three and even clusters of three. If we look at the next slide here on slide 16, you'll see that we took five of the antibodies that pharma and biotech had taken into the clinic, DR5 antibodies, in order to target DR5. What we did was we took those same yellow binding domains from the IgG antibodies, and we converted them to IgM antibody. What you see here is that they are much more potent as IgM antibodies than they were as IgG antibodies, which provided us with a sort of confirmation of our rationale that our hypothesis that an IgM antibody would do much better than an IgG antibody against this particular target. On the next slide, you see some efficacy data using IGM-8444 as monotherapy in a gastric PDX model. On the next slide, you'll see the combination of using 8444 together with a common chemotherapy therapeutic, in this case, irinotecan. We think that the greatest patient need here is in combination of IGM-8444 with other agents, and we think that that's the way that we can make the greatest impact with patient health. While we will look for monotherapy applications for 8444, our primary focus is on combinations. If you go to the next slide, you see a combination with venetoclax, which, you may know, is a BCL-2 inhibitor, which makes intuitive sense that the combination of 8444 with venetoclax would be synergistic. The reason is DR5 8444 attacks a pathway known as the extrinsic apoptosis pathway, and that's a pathway, as we talked about earlier, that causes a cell to commit suicide. Mother Nature, as with many of these things, has a competing pathway, which is a survival pathway, and venetoclax addresses that survival pathway. There's a balance between the commit suicide pathway and the survival pathway. Intuitively, it makes sense that if you can address both of those pathways at the same time, the cell has a much lower chance of surviving. That's what you see here on this slide, is when we address both pathways at the same time with IGM-8444 and venetoclax, we get a very synergistic result. Now we'll go to the next slide. You may have seen that on Monday, we licensed exclusively worldwide commercialization and development rights to a compound called birinapant. This compound also addresses that second pathway. It's what's called a SMAC mimetic. I won't go into a lot of detail about the science here, but let me just say it also impacts that survival pathway. What you see here is remarkable synergy between the combination of 8444 and birinapant in this triple-negative breast cancer model. Now that we have exclusive rights to birinapant, we are planning to move this into the clinic, hopefully as soon as this year, in combination with 8444, and we're very excited about the potential of this. The next question you might ask is, this seems too good to be true. If you've got this molecule on the surface of a cell, and all you have to do is bind this molecule, and that will tell the cell to commit suicide. It just feels almost too good to be true. Isn't that molecule present on other cells? Well, it is present to some lesser extent on liver cells, and one of the challenges that other multivalent approaches have had in targeting DR5 has been liver toxicity. We very carefully selected our IgM antibody to have, apparently, in vitro and in our preclinical models, very, very low levels of liver toxicity. You see here that IGM-8444 shows a very large, on the right-hand side, what's called therapeutic window. In other words, the difference between the killing of the liver cells, the hepatocytes, that's in blue with 8444, it doesn't seem to kill any of them, versus the killing of the tumor cell, which is in red. In fact, on the left-hand side, you see the comparison of 8444 to the natural ligand to DR5. We actually even seem to be safer than the natural ligand here. We're very encouraged that the combination of this safety, plus the basic biologic mechanism, plus the combination synergy with birinapant or venetoclax or chemotherapy, will lead us to some very exciting clinical data later this year. On the next slide, you'll see our profile. This is slide 22, our clinical protocol. We have announced that we are currently dosing in our second monotherapy dose cohort, which is 1 mg per kg. As soon as we clear that dose cohort, we will start our third dose cohort, as well as our first combination dose cohort, where we give IGM-8444 in combination with a common chemotherapy regimen known as FOLFIRI. What we hope to do later this year as well, now that we've just signed the birinapant deal, is also start combination studies with birinapant, hopefully as early as sometime this year. In our remaining time, I want to move on to our third program, where we hope to file an IND later this year. This is a IL-15 delivery program. I think this is just a really beautiful application of the IGM technology. What you see here on the right-hand side is you see the IgM antibody which will bind to a PD-L1-expressing cell, whether that's a tumor cell or an antigen-presenting cell, and then it will display IL-15 to a passing natural killer cell or CD8 cell. In nature, the way that IL-15 is normally displayed is from one cell to another. Again, similar to what we do with the CD3 T- cell engaging mechanism, what we're doing with IL-15 is we're mimicking using an IgM antibody, a natural display of a natural biologic process. In this case, the display of IL-15. IGM is really well-suited for this application in the same way that it's really well-suited for T- cell engager applications, because once the IgM antibody binds to a cell, it never lets go. It has what we call essentially a zero off-rate. It can stay there for a long time, presenting either the CD3 binder to a T- cell, or in this case, presenting IL-15 to a passing NK cell or CD8 cell. If you move to the next slide, you'll see some of the in vitro results here that we had in terms of creating both cytotoxicity and stimulation of interferon gamma. If you move to the next slide, you'll see some of the in vivo efficacy that we've seen here, where treating with IL-15 here, we had eight of 10 mice tumor-free. Quite remarkably, when you take those same mice and you rechallenge them without drug with the tumor, eight of eight remain tumor-free. What we had done here is we've educated the immune system to fight this tumor, which I think is just remarkable and very encouraging. Let me briefly finish up here by talking about the potential for the IGM technology platform across a broad range of different applications. As we've talked about with T- cell engagers, this is slide 26, we think that there are a number of cases in addition to the CD20 application that make a lot of sense for our platform, both CD38 for multiple myeloma, CD123 for AML, and particularly for solid tumors. We think that the cytokine release profile and the extended duration of activity that we have are very encouraging with respect to solid tumors. With respect to receptor cross-linking, in addition to DR5, OX40 and GITR are natural targets there for us where we believe that we can have much improved efficacy as compared to IgG antibodies. Targeted cytokines, in addition to the IL-15, we think there are other cytokines that could be delivered in a similar mechanism. Another area that we intend to move into is antibody-drug conjugates. We think that IgM antibodies have some significant advantages there, both in terms of their ability to bind to low-expressing tumor cells, potentially their ability to separate in solid tumor cases, to separate tumor from normal by using what's called affinity tuning in order to adjust the antibody so that it binds only to those high-expressing cells and not low-expressing cells. Also IgM antibodies have some significant advantages in terms of internalization, and we can internalize more quickly against certain targets than IgG antibodies. From the standpoint of therapeutic areas, obviously, we're focused on oncology. We also think there's significant potential for IgM antibodies in infectious diseases and in autoimmune. In terms of catalysts that we expect to see coming, hopefully see this year, completion of enrollment in the phase I dose escalation study and establishment of that recommended phase II dose. We hope to release the initial clinical data from our phase I study of IGM-8444, and we hope to file an IND on IGM-7354, which is our IL-15 program. Importantly, we hope to be commencing operations at our newly constructed GMP manufacturing facility this year. I think I'm right about on time for Q&A. Thanks, Fred. Just a reminder to the audience, if you want to submit a question, please click on the link, Ask a Question, that's either below or next to your viewing panel. I'll just give a moment for questions to populate. First question we have. Fred, with no T- cell killing expected in 8444, would you expect a superior safety profile over IgG-based therapy, as in the case of a CD3, CD20 engager? The question is- maybe you could repeat the question. There is no T- cell killing in IGM-8444. That's absolutely true. It is simply an agonist. I think that it's safe to say that many of the cytokine release issues that you see with a T-cell engager, I would not expect that you would see those with IGM-8444. The primary safety issue with IGM-8444 appears to be liver toxicity with the other multivalent drugs that are in the clinic right now, and we do hope that we will not see any significant liver toxicity with IGM-8444. We've also tested in vitro the combination of IGM-8444 and birinapant, and we did not see any increased liver toxicity as a result of the combination of those two drugs. I don't know. Felipe, does that address the question? Yeah. I think the second part of the question was whether do you expect a superior safety profile over other IgG-based therapies? I think in the 8444 context, I think everyone's given up on IgG therapies, the remaining therapies that are in the clinic are various multivalent forms. You have Inhibrx, which has some single-domain antibodies on the end of an Fc. They have four single-domain antibodies on an Fc to get tetravalent. You have AbbVie, which has its TNF ligand display, again, multivalent. You have Genmab with its HexaBody. I guess that is an IgG-based drug, but it's a different form of an IgG-based drug there. What Genmab has done is they have engineered the Fc of those IgGs so that they're intended to form something like a hexameric structure on the surface of a cell. Our hope is that IGM-8444 will prove to have a lower degree of liver toxicity than either of those three competitive molecules, but we'll still have to prove that in the clinic. Got it. One quick follow-up for 8444. Does DR5 undergo polymerization upon binding? Well, polymerization between two DR5 IgMs, if that's the question, absolutely not. What 8444 will do is it will create clusters of DR5s on the surface, but we've never seen any polymerization of one IgM antibody with another IgM antibody. I'm not sure how that could even happen biomechanically. Okay. Yeah. We've not seen any anti-drug antibodies, and we've not seen any aggregation of one IgM naturally binding to another IgM. Got it. Next question. When will you release updated data from IGM-2323? What should we expect in terms of patient numbers or any other characteristics? Well, as I said, we hope that we'll establish a recommended phase II dose by the middle of this year, and I would expect that we would display, disclose the data that supports that decision on the recommended phase II dose. I can't tell you at this point exactly how many patients that would be. As you see from that clinical trial protocol slide, we are allowed to expand any of the 50-100 mg, 50-300 mg, and 50-600 mg dose cohorts. We would hope that we would have more than three patients in each of those dose cohorts, assuming that they're competitive dose cohorts from an efficacy and safety standpoint. Great. Thank you. There's been significant growth of bispecifics in the last couple of years. If you had to distill your platform's competitive advantages in a few key characteristics, what would they be? I think there'd probably be three key characteristics. I would start with what we hope is a significantly safer cytokine release profile. If we continue to see good results on the cytokine release side of things, then I think we may have a best-in-class safety profile there that will allow this drug to be used by community oncologists without concern. We also hope that because of the 10 binding domains, we'll be able to go after low-expressing CD20 cells, whether those are normal NHL cells that have become low CD20 as a result of multiple treatments with Rituxan, or if we have CLL, for example, where it is naturally a low CD20. The third, which still remains to be proven out but is very encouraging, is the interferon gamma-driven cytokine release profile, which we hope will allow us to have, in addition to better safety, better efficacy, both in terms of not desensitizing T- cells, but perhaps leading to a better endogenous immune response over time. Great. Thank you. To clarify the earlier question on DR5. The question is, is DR5 clustering as you had implied that was important for the efficacy of 8444? Yes. DR5 clustering. Being able to cluster engage DR5 receptors is critical to success. That's how you send a strong apoptosis signal. Great. I think that's the reason the IgGs didn't show success in the clinic. Mm-hmm. Have you seen any evidence of CRS in the 50 -300 mg patients? In the three 50- 300 mg patients that we dosed to date, we did not see any CRS. Got it. I think, do you expect to enter any potential partnerships with your lead assets in the coming year, or is that part of the corporate strategy going forward? I think we need to think about partnering. We are not committed to partnering any of these assets right now. I think we believe that as we continue to develop the assets, they greatly increase in value the further along that we develop them. What we would look for in a partnership is something that potentially adds value to the asset, the proverbial 1 + 1 = 3. I think, we would probably not do a partnership where the primary benefit to IGM was simply cash. That's probably not a scarce resource for us right now. I think it has to be something that really helps contribute to the long-term success of IGM and the long-term success of the particular product candidate. Great. Thank you. Again, there's only about two minutes left, so just to remind anyone who's viewing, if you have a question to submit, please do so via the Ask a Question link. I'll give it just a few more seconds to populate. Okay. Seeing none. Fred, thank you very much for presenting at our conference, and we really appreciate it. Oh, thank you. Appreciate the opportunity. All right. Have a great day.