Hi, everyone. Welcome. It's great to have everyone back in person. My name is Raji Gunasekera. I'm an associate here in the healthcare investment banking team. It's my absolute pleasure to introduce Jaume Pons, CEO and President of ALX Oncology. Thank you. After the customary disclaimers, let's move to CD47 as a target and evorpacept, our clinical candidate as a CD47 blocker. Here in the lab you have the expression of CD47 in cancer cells in red and normal cells in black. As you can see, CD47 is very highly overexpressed in tumors, but also it's like highly expressed in normal tissues. Therefore, if you want to use CD47 as a tumor target and kill all CD47 positive cells, you will be producing a lot of toxicity. What's interesting to us about CD47 is its function as a myeloid checkpoint. It functions very similarly to PD-1, PD-L1, but instead of T cells, we are here talking about macrophages and dendritic cells in the innate immune system. Here on the left and the right, you have... see a macrophage expresses SIRPα. That's the receptor for CD47, and that's an inhibitory receptor. Cancer cells display positive signals that we call eat me signals, and these eat me signals will allow macrophages to eat the cancer cells. To protect itself, cancer cells will upregulate CD47, sending a don't eat me signal, inhibiting macrophages. One of the most known positive signals is actually the binding of an antibody to the cancer cell and the interaction of the Fc of this antibody with Fc-gamma receptors on the macrophage side. Molecules like Herceptin should be able to kill cancer cells by macrophages, but it's not happening because macrophages upregulate CD47. What's important here that, like in the case of PD-1, blocking CD47 SIRPα is not sufficient to activate macrophages. The positive signal, the interaction between the Fc and the Fc-gamma receptors, for example, is absolutely required for a macrophage to get activated and kill cancer cells. This is important because other agents, our competition, has decided to make molecules that block CD47, at the same time contain an active Fc that interact with Fc-gamma receptors on the macrophage side. What is happening there, as I showed you before, CD47 is expressed everywhere, so all these molecules have shown in the clinic hematological toxicity, anemia, thrombocytopenia, neutropenia. These toxicities has limited dosing of these molecules and therefore they cannot dose high enough to completely block the mechanism, and in the combination setting, they cannot get the maximum activity of the combination drug. Because these molecules have been tuned down to have a weak Fc, because the very active Fc are very toxic, they cannot be developed, these molecules do not have single agent activity. They have to be developed in combination. They just carry over the toxicity that they built in in the design of the molecule. What we decided to do is designing a molecule that only blocks CD47. It does not provide the required positive signal. Therefore, despite binds normal cells, it does not kill normal cells. Then in the combination setting, we can dose very high and when the other molecule provides the required positive signal, kill cancer cells. Basically we had gained a specificity by removing the effector function. Let me introduce you to evorpacept, our clinical candidate. We usually will paint it like an antibody, but it's not an antibody. What it is the extracellular domain of the receptor for CD47 SIRPα that has been highly modified to have very high affinity. It's a picomolar binder of CD47. We've used that to completely inactivate the Fc in terms of Fc-gamma receptor binding, yet it still contains the same binding for FcRn. It has the same decay as a regular antibody. We have a half-life of 30 days in the clinic. This molecule also has half the molecular weight of an antibody, therefore we have twice the number of binding sites per gram of protein. Our 10 mgs per kg is equivalent to 20 mgs per kg of an antibody. This smaller molecular weight also may allow better tumor penetration. Manufacturing is completely antibody standard. In this table, I compare ALX molecule, evorpacept with the main competition, Gilead and Pfizer molecule and also I-Mab. You can see that evorpacept is the highest affinity of all the molecules that now are showing the clinic. Also, the only one that does not have any effector function. All the other ones are mostly IgG4s and one IgG1. That has resulted that evorpacept is the only of these molecules that does not have hematological signal in the clinic, and is the only one that has shown proof of principle in solid tumors. For example, magrolimab from Gilead did fail a couple of studies in solid tumors. In the heme area, we have shown activity as well as magrolimab has done. Here I'm showing the development plan of evorpacept, and we look at this development plan in terms of mechanisms. In one part, we have combination with checkpoint modulators. In this bucket, we are doing now 2 phase 2 randomized studies, one in combination with Keytruda, another one with Keytruda chemotherapy, both in first-line head and neck. We have Fast Track designation for these 2 indications, and we're working with Merck in this study. In the bucket of anti-cancer antibodies, we have a randomized phase 2 in combination with Herceptin, Cyramza, paclitaxel, and it has a Fast Track designation in collaboration with Lilly. In the same bucket, we are doing multiple phase 1s, for example, with Nectin-4 ADC for urothelial cancer. zanidatamab design was molecule, but now it's just therapeutics molecule, a bispecific HER2 molecule for breast, high HER2 breast and low HER2 breast. Within HER2 ADC from the Daiichi Sankyo AstraZeneca, also in breast. We have another bucket in hematological malignancies in combination with azacitidine or azacitidine, venetoclax or rituximab. In addition, we also have extensive IST trials, for example, in ovarian with Keytruda, colorectal with Keytruda plus Erbitux, and NHL rituximab, lenalidomide. Altogether, this class of molecules represent almost half of the sales of cancer agents in U.S., just showing the potential of use of this molecule when our randomized study is rolled out. Focusing first on safety, it's one of the slides that I find more boring, and it's because it's actually not much to talk about. You can see that the most frequent side effect is fatigue, low-grade, some rash, low-grade, and everything else is low incidence and mostly low-grade. If you compare that with the other CD47 molecules, you will see a very strong difference. In terms of efficacy, I want to talk first about gastric trials. In this case, we are combining with Herceptin by HER2 on the cancer cell, and then the FC of Herceptin interacts with Fc-gamma receptors, providing the required positive signal. Because cancer cells upregulate CD47, this positive signal is actually not working. We block CD47, and we enable a new mechanism of Herceptin that is usually not in use. The first study that we did was in second line and later, gastric patients that had progressed after one or more HER2 treatments, and also half of them had been actually progressed after PD-1 treatment. It's a very advanced, very difficult patient population. In this study, we pick it because it was not expected that Herceptin had any activity in this set, in this setting. There's a publication from Makiyama et al, that in a prospective way showed that Herceptin after Herceptin did not add anything on top of paclitaxel. When we combined evorpacept and Herceptin, we saw a 21% response rate that is very similar to a chemotherapy treatment in this setting. It actually shows a very nice activity in a very difficult patient population. However, Herceptin is not approved in this second-line setting because not shown to work. Therefore, we have to go into study on what is standard of care. We picked this active doublet, Herceptin plus evorpacept, and we went on top the standard of care, Cyramza, paclitaxel. In this setting, we saw a 72% response rate and OS at 70 months. That data is very compelling if we compare it with what is our benchmark in this indication. Our regulatory benchmark for this would be Cyramza, paclitaxel is 28% response rate and less than 10-month OS, to which we have a big gap between what is the standard of care and our results. The other relevant data point is actually in HER2, that has been recently been approved in second-line or third-line gastric cancer, where we see a response rate in the 41%, also with shorter OS. There is one study, single institution, single arm in Korea, where we have our trastuzumab ramucirumab, so our control arm, with a 52% response rate. In either case, we have a big gap between our results and the potential results that we can use as a benchmark. Of course to prove the efficacy of this treatment, we have to go to randomized studies. That is where we are now. The first study is a phase 2 randomized with a control arm of Herceptin, Cyramza, paclitaxel versus our arm of evorpacept, Herceptin, Cyramza, paclitaxel. The goal here is to define the contribution of evorpacept on top of the triplet. If this study is positive, we're going to go phase 3 against the regulatory benchmark, which is Cyramza, paclitaxel. Therefore, if the phase 2 is positive, the phase 3 is very likely to be positive. I want you to note the dosing of the study, 30 mgs per kg every other week. You will see that all our studies are a multiple of 15 mgs per kg weekly. So if we combine with our agent, that is dosed weekly, we use 15 mgs per kg weekly. With Herceptin, in this case, every other week, we're using 30 mgs per kg every other week. In other studies will be 45 every 3 or 60 every 4. That shows that our safety profile is allowing us to dose higher and expand the dosing interval to be able to combine well with the combination agent. That is actually not possible with the other CD47 blockers, because they have to start with a priming dose of 1 mg/kg, then they have to go higher to 30 mg/kg, they have to go lower, et cetera. I want to remind you that this 30 mg/kg, for example, is equivalent to 60 mg/kg of antibody. Actually dosing much higher than the molecule of the competition. The other mechanism that we're testing is combination with checkpoint modulators. Here, the interaction between CD47, SIRPα is the same. Everolimus also blocks the same pathway, but the cell of interest is another myeloid cell, dendritic cells. Dendritic cells are constantly inhibited by cancer cells by the interaction of CD47 with SIRPα. If we block this interaction, dendritic cells get activated, are able to pick antigens from the cancer cells, cross prime T cells. T cells that are trained to see these antigens in cancer cells get unleashed by the combination with the T-cell checkpoint, PD-1. These T cells will be able to kill cancer cells. To look at our data in this setting, first we have to understand how PD-1 works in the head and neck setting. Here you have the two studies that got the approval of Keytruda in head and neck, KEYNOTE-048 for the first line and KEYNOTE-040 for the second line. In the first line, in the top you see the Keytruda pembrolizumab plus 5-FU platinum versus EXTREME atezolizumab, 5-FU platinum. You can see that the response rate is basically the same between the both arms. Keytruda was not approved based on response rate. If you look at the PFS, actually went the wrong direction. The control arm is actually better than the Keytruda arm. Keytruda was approved by OS, overall survival. You can see that the only early parameter that you can use to predict this overall survival is overall survival at 12 months, where Keytruda's 53% is better than the control arm. The same happened in the second line, in KEYNOTE-040. Response rate in absence of chemotherapy is a little bit better for the Keytruda arm, 4% better. PFS is the same. Keytruda was approved by OS endpoint, and the only parameter that we use early in the study to predict the OS is actually OS at 12 months. KEYNOTE-048, 53%, KEYNOTE-040, 37% OS at 12 months. We have two studies in our head and neck, one in the second line, equivalent to KEYNOTE-040, and one in the first line, equivalent to KEYNOTE-048. Similar to what it was seen for the KEYNOTE series, the response rates didn't change much. In the case of the first line, 38% versus 36% in the KEYNOTE-048. In the OS at 12 months, where it was 50%, we have 87%. In the second line, equivalent to KEYNOTE-040, we do see an improvement in response rate, 40% versus 15%. Again, our OS at 12 months is 80%, that compares very well to the 30 something% that KEYNOTE-040 had. Of course, this is 1 number of patients. It's 10, 15 patients. Like in the previous case, we have to go to a randomized study to prove the efficacy of our molecule. In this case, we're taking the full label of Keytruda in the first line, head and neck. One study is Keytruda versus Keytruda, evorpacept. The other one is Keytruda chemotherapy versus Keytruda chemotherapy, everolimus. The first case is for patients who have PD-1 score greater than 1. In the other case, for patients that are diagnostics of any PD-1 score. Moving to hematological malignancies, which is another mechanism. In this case, combining with azacitidine, with azacitidine does is upregulate galectin-9, which is a known positive signal that cancer cells display. Galectin-9 interacts with LRP in the macrophage site, providing the required positive signal. Everolimus blocks CD47, unleashing the activity of macrophages. In this case, we have 2 studies, 1 in MDS and 1 in AML. We put them kind of in the same bucket because they're related diseases. In both cases, we have done so far the doses, the dose escalation safety study. That we start at 20 mg/kg every other week, to 30 mg/kg every other week, and 60 mg/kg every 4 weeks. In both cases, the same. In both cases, we have been able to reach the maximum dose. Our... We didn't get maximum dose. Our maximum dose is the maximum administered dose. Remember that is equivalent to 120 mgs per kg of antibody in terms of binding sites. Focusing first in MDS, you see that we saw blast reductions. Something we're going to point out in this study is that in both studies we have refractory patients and newly diagnosed patients. Refractory patients are not expected to respond much, and the ones that you really want to focus going forward is the newly diagnosed. It is a phase 1, most of our patients are refractory patients. If you look at the results on the right, you see blast reductions in most patients. We have CRs in the naive, newly diagnosed patients, and very interestingly, we have marrow CRs in the refractory patients. Similar study is seen in the case of AML in combination with azacitidine and venetoclax. In this case, we see blast reduction in all patients. Again, we only have 3 newly diagnosed patients, but with CRs, and also see refractory activity in the ven-naïve refractory patients. From here, what we're running now is dose expansions, dose optimization study, where we're comparing 40 mg per kg versus 60 mg per kg of evorpacept in combination with azacitidine. This is for the patients. After that we pick one dose to start a randomized phase 2. That will be a pivotal study. In the case of AML, we have finished the first part as well. We are waiting to have the results from the dose optimization in MDS to also move into a shorter, hopefully shorter and smaller dose optimization before going to a randomized study. Here are the upcoming milestones for 2023. I'm not going to read them all. You can download them from our website. I just want to point out a couple of them. At the second half of the year, we are going to show data from the gastric study, our randomized phase 2. That will be for sure the first solid tumor randomized data for the CD47 pathway, and maybe the first randomized data that we'll see for any CD47 agent, as yesterday Gilead changed their guidance for when they're going to show data for their phase 3 MDS. In the second half of the year, we'll show the dose optimization data for our MDS study. In the first half of this year, we're going to start the... We're going to file IND for our second compound that I didn't have time to talk about it, but you can see information about that in our website. Going into 2024, very importantly, we're going to have the randomized data for the two phase 2s in head and neck. Also randomized, also it will be the first time that any combination randomized with checkpoint modulators show data. In terms of financial information, we are in a good situation. As of last September, we had $293 million in cash or cash equivalents. We have access to a $100 million loan facility, 50 of those at our own discretion, 40 based on milestones, and we have taken the minimum, that is 10. With that, we expect to have a cash runway through mid-2025, which includes, the readout of all these phase 2s and all the phase 1s I've been talking about. As a summary, we believe that, evorpacept is a very differentiated design of a molecule that has translated in a very differentiated clinical profile. Hopefully, the phase 2 will prove this statement. Also we have other compounds that we'll be talking in the future. With that, thank you for your attention. Thank you very much for the presentation. We can now open it up for Q&A. Sorry. I think they'll bring the mic to you. Thank you. Very interesting. It always works with, in combination with another agent, so that it enhances the efficacy of the other agent. Can we use it in several lines, which means if a patient is failed the second line and now he's moving with another agent to the third line, can it be also associated in several lines for the same patient? I would say yes. I would say that this mechanism, we have never seen any situation of downregulation of this mechanism, right? I think that it just depend on the mechanism of the combination agent. Okay. If you do in 1 line with, let's say with carfilzomib and another 1 we use it with claudin, let's say, I would expect to be able to transport. You didn't see any resistance on the compound by itself? We don't have enough data in the clinic to prove that yet. Okay. It's not expected. When do you anticipate approval? In like 2, 3 years? I mean, I know that you have been granted Fast Track, when you anticipate the NDA? Yeah. That really depends. Obviously, all these are phase IIs, so it's a conversation with FDA at the end of the end of the study. The two phase IIs for head and neck are designed to be substitute for standard approval- Okay ... because we are doing in comparison with the standard of care. In the case of gastric, because our control arm is not a standard of care. It may be less likely, but again, we have orphan designation for that indication. It's possible that the conversation will bring us there, right? When it will be, so the most optimistic will be 2 years after we finish the study, right? That it will be in cash in 2025, but of course, that is a completely guess. Thank you. I had a question as well. You mentioned the competitive landscape. I was wondering if you could speak a little bit more in detail about that, given that you identified the big players as competitors, but also you do collaborations as well. I was kinda wondering what the team's thought process there is, as well as do you see any smaller players coming into the CD47 space or SIRPα there? Yeah. Well, initially was a lot of activity. Most of the companies that were not yet in the clinic, they have been dropping out. There's actually a lot less competition now than a year ago. What we see as a pure CD47 blockers, that is actually a molecule that only blocks CD47, and the mechanism of action is actually blocking CD47. I would say that the main players is the ones I mentioned. There's a new wave of molecules that are bispecifics against CD47 plus something. Many of those molecules, I do not consider them truly blockers of CD47. Some of them use CD47 as a way to localize the other's hand, the other molecule into the tumor microenvironment, and their properties are not going to be good to be a strong blocker. No, we have to go 1 by 1. If you have a specific one, just let me know which one to actually say what is difference with respect to this one to other one. There's some that are trying to build specificity by using a low affinity CD47 blocker with a high affinity binding antigen, for example, CD20, right? It is a very difficult play to do, but it may work. That is that you have to have the both antigens to be expressed at similar levels in a similar location on the cell, and that will not always happen. Even in the case that that would work, that would be actually just limited to one antigen. We have the advantage that actually we can combine with any of these molecules that are already available, already approved, and they are already standard of care. Put it on top of that and get approval instead of having to do a head-to-head against those molecules, right? That's why strategically we pick this approach. You ask about SIRPα. SIRPα, the other side of the interaction, you could go against SIRPα as well. In that case, it will be very similar to the case of evorpacept. It will require a second molecule to be added because you are actually targeting the macrophage. There's a lot of expression of SIRPα in neutrophils. The molecules that are now in development for SIRPα actually have shown neutropenia as a side effect. In terms of what is known so far, I think our molecule is the safest and the one with wider, potential combination. Thank you. Any other questions? Yeah. I'm also curious about the financial profile a little bit, if you can go a little more in depth. Obviously, the company is well capitalized. You have cash runway into 2025. I was wondering if there's any plans to extend that. Just kind of a little more detail about the financial metrics. We don't need money right now, right? Obviously, any biotech company will raise money when the market is allowing to do it properly. We have multiple good milestone this year that we hope it will make the stock higher and will be a good opportunity for us to raise more cash. Of course, we're moving to do a phase 3 after that, right? We'll have to raise money for our phase 3 studies. Of course, getting ready for commercial. Right. No, no questions came in online. If there's anything you would like to go more in depth in or emphasize, we could use the time for that, but... Maybe we can talk about our second molecule, Lucas. If you really want to know. We have a second molecule that will be IND the first half of the year. In that case, we're actually focused on the other side of the interaction, but with a very interesting twist. SIRPα, as the receptor for CD47, is expressed in dendritic cells, as I told you before, which are the master orchestrator of the study in the immune system. We have designed a molecule that targets SIRPα and at the same time delivers a strong agonist for dendritic cells. It's a CpG. It's a very unique agonistic of TLR9 that will bind dendritic cells and activate the dendritic cells to jumpstart the immune system. The clinical data is actually super strong. This molecule with just one or two injections produces tumor eradication. It's a, it's kind of the opposite of evorpacept. We designed evorpacept to be combined with everything. We designed ALT002 to be used as a single agent later, in later lines of therapy. I'll have data, I guess, 1 year from now, 2 years from now. Okay. I just wanna thank you, thanks again for the presentation, for the Q&A. One more round of applause.