Okay, we are ready to get started. I'd like to welcome everyone back, and thank you for joining us for another Virtual Investor Closing Bell segment. My name is Jenene Thomas. I am CEO of JTC IR, and I will be the moderator for today's event. Today we are featuring Senti Bio, and I am very pleased to be joined by Dr. Timothy Lu. He is co-founder and Chief Executive Officer, as well as Dr. Kanya Rajangam. She is President, Head of Research and Development, and Chief Medical Officer. Welcome to our Virtual Investor platform. Thank you. Happy to be here. Travis. We're so happy to have you, and we are excited to showcase Senti today on our platform and share your story with our audience. Before we get started, I just want to remind our audience that Senti Bio is publicly listed on NASDAQ and trades under the ticker SNTI. During today's discussion, the company will be making forward-looking statements, and I encourage you to view the company's website at sentibio.com for the latest filings and information. All right, we're going to dive right in, Tim. To start, can you provide an overview of Senti Bio for those that are new to the story? Sure. Thanks again for being here and giving us the opportunity to share the story. Senti was really founded as a company to advance the types of drugs that we have available to treat difficult and intractable diseases. I'll share with you guys an overview today and happy to discuss more about what Senti is up to. Just a disclaimer and forward-looking statement slide before we get started. Here at Senti, we are laser-focused on solving one of the central challenges in oncology. If we think about the challenge of treating cancer, the fundamental problem is how do we distinguish cancer cells from healthy cells? If we can do that, we can focus our firepower on killing those cancer cells while not affecting the rest of the body. Many of the drugs we have today are unable to give you this fine-grained discrimination, leading to side effects as well as the inability to fully clear out cancer. We believe we have the technology to overcome this central challenge by leveraging what we call logic gates. Logic gates allow us to recognize multiple targets on the cancer cell and to try to kill those cancer cells more effectively, but also to recognize healthy cells and to protect those healthy cells from being affected. That is very different from many of the current drugs that we have available that rely on a single target to give you that discrimination between cancer and healthy. We have implemented our logic gate technology into our lead program, SENTI- 202, which is designed to address this problem for patients with acute myeloid leukemia or AML. As we'll talk about, AML, disease heterogeneity, is a big challenge. To overcome that, we actually attack two well-validated targets called CD33 as well as FLT3. By addressing both of those targets, we may have the potential to suppress the tumor to a greater extent. The other big problem in AML is that none of these targets are clean on their own. They are expressed on healthy tissues. We can recognize and spare those healthy tissues by recognizing a different target antigen called EMCN. We've been very excited last year at the end of 2024 to present promising initial clinical data at the first dose level and the first dose schedule with this program, where we saw two out of three of our relapsed refractory AML patients achieve a complete response or CR. These CRs were both MRD negative in terms of their responses with ongoing durability that continues to look very exciting. If we're successful here, we can demonstrate that our logic gates work not just in AML, but also can be expanded into solid tumors and opens up a big universe of additional applications for the space. As a company, first and foremost, we've built these logic gates, and we're going to focus on that today. The way the logic gating technology works is we can engineer a cell therapy that recognizes both cancer targets and healthy targets and basically discriminate between whether to kill or to protect cells based on which targets are present. We also do have other technologies, which we won't cover in detail today, but I just want to highlight here. Our multi-arming technology allows us to enhance the overall therapeutic activity of our cell and gene therapies by engineering additional mechanisms into a single product. We have something called the regulator dial that allows us to control on or off what the cell or gene therapy is doing in vivo. We have different smart sensors that can allow us to program our cell and gene therapies to turn on or turn off at the right time and the right place in the body. As I mentioned, we have focused our lead program on treating diseases like acute myeloid leukemia. This is a significant and aggressive disease, especially in patients that have failed current frontline therapy. The median survival rate in these patients is quite low, about 5.3 months. The existing drugs are not basically able to treat the heart of the disease. For effective AML therapies, we really need two things which SENTI- 202 is designed to address. The first is the ability to hit heterogeneous clones and AML leukemic stem cells. AML is a heterogeneous disease. You have multiple different AML cell types that constitute the disease, both AML blasts as well as leukemic stem cells, which are this more rare population of cells that can repopulate the tumor burden. In order to achieve longer-lasting and durable remissions, we need to be able to hit both of those cell populations. The challenge number two, though, is in addition to selectively killing these AML blasts and leukemic stem cells, they actually look very similar to healthy cells, including what we call HSCs or hematopoietic stem cells. These hematopoietic stem cells are really important. They basically are responsible for generating our blood and our immune system and other key cell types. If you can't protect those cells from being killed, you're never going to be able to hit the cancer as far as you can. That is a really essential challenge that SENTI- 202 was designed to address. We are very excited to introduce SENTI- 202 today. This is a first-in-class off-the-shelf cell therapy. It uses our logic gate to recognize two different cancer targets, CD33 and FLT3. Both of these are validated targets expressed in about 95% of AML patients. What we did with this product is we engineered the cell therapy, which is a natural killer cell. We engineered the cell therapy to recognize either CD33 or FLT3 or both. When that happens, it triggers killing. Our cell therapy goes in and kills AML blasts as well as AML leukemic stem cells based on these targets. However, as I mentioned earlier, both these targets are also found on healthy cells, CD33 and FLT3. One of the key things that we had to engineer into this product is a way to protect those healthy cells from being killed. This is what we call our NOT gate or NOT logic gate. It basically involves a receptor called an inhibitory CAR receptor. It recognizes this protein called EMCN, which is found on healthy cells, but not found at high levels on the cancer cells. When this recognition happens, which is illustrated here by this purple receptor, what happens is it binds to endomucin and it delivers a do-not-kill signal into the product, basically keeping the product from affecting these healthy hematopoietic stem cells. The third portion here is something called Calibrate Release IL-15, which serves to enhance overall SENTI- 202 persistence and activity. All of these three proteins that we engineer into our product constitute our gene circuit, and they are delivered and engineered into our NK cells through a single genetic engineering step. We source our product from selected adult donors. These are healthy adults that basically provide these NK cells. We take them to our manufacturing facility with our partners, and we can genetically modify these cells. We can freeze the cells and make this an off-the-shelf product for AML patients. As I mentioned earlier, in 2024, we're very excited to release initial clinical data at that first dose level and schedule. As of December 2024, when we put out this update, two out of two of the complete response MRD negative patients continue to be in durable response. In summary, SENTI- 202 is designed to integrate sort of well-known disease mechanisms in AML into one single solution and to solve those key outstanding problems in AML. We're very excited about this product and happy to dive into this more detail with Janine. Great overview, Tim. Appreciate that. What a great way to set the stage for this discussion. All right, Kanya, on to you. Can you expand on the lead indication and explain the setting relapse or refractory AML and the unmet need? Sure, happy to. Tim, if you don't mind going to slide five, we can dive a bit deeper and add more color to what Tim mentioned. Acute myeloid leukemia or AML is essentially, it's an acute leukemia, so it moves very quickly, and it originates from myeloid cells, which are a type of cells in the bone marrow. There are about 21,000 newly diagnosed patients in the U.S. every year. It's a disease of the elderly. Not all of them can actually even tolerate the very intensive therapy you need to get rid of the leukemia. Even in those who do, it's about less than half who have the complete response, if you will. The remaining, either they relapse or they never respond, which is called refractory. The disease is refractory to upfront therapy, or some of them even succumb to the disease right up with the first line of treatment very quickly. Those patients who do relapse or are refractory to that frontline treatment, their survival and prognosis is even more dire. The median survival for this group of patients is about five months. Current standard of care is either you recycle chemotherapy or those patients who have specific driver mutations, as it's called, and for which there are targeted agents, they can get those targeted agent therapies as well. Even that, it's a minority of patients who respond, about 20% or so, complete remissions. It really is a disease with a very high unmet need. Appreciate that background, Kanya. What are some of the challenges associated with developing a drug to treat these patients? As Tim mentioned, there's a few different challenges with developing therapies for patients with AML. Just from the, in terms of the disease per se, as mentioned here, there's two ones. There are additional challenges which come in from the fact that these are all elderly frail patients, so you need to have therapies which can be well tolerated. To dive a bit deeper into what we've come up with as a way to overcome these challenges is, one is the heterogeneity of the disease. AML is notoriously heterogeneous, and there's these bulk blasts, which are these myeloid cells which have transformed into leukemia and have kind of overtaken the bone marrow, to put it simplistically. There's a niche population called leukemia stem cells or LSCs, which are thought to drive the short duration of remission. These LSCs are not often susceptible to chemotherapy for a variety of different reasons. What happens is even if the bulk blasts are gone, the LSCs are kind of there in their niche, and then they come back and repopulate the marrow. It is really important to get rid of those LSCs as well to achieve a deep response. The depth of response then translates to its durability. The second problem is AML comes from myeloid cells. The markers on an AML cell surface, often the healthy myeloid cell population or the hematopoietic stem cells, they overlap. There is not an ability to remove all of the AML cells without also causing serious damage to the healthy hematopoietic stem cells, which is needed to repopulate and give rise to the normal blood cells, which do a lot of important things for us in the body. Those are among the two main challenges in terms of scientifically designing a drug. Of course, we do need therapies to be well tolerated because a lot of these patients are elderly. They have other comorbidities, cardiac disease, and so on. You need to have products which can also be well tolerated and do not add to the toxicity, which can affect these patients. Extremely helpful. I know this is the first live event that Senti is participating in. You'll have to forgive me. I have a bunch of questions because we do want to educate our audience on the Senti Bios story. I'm going to keep going at it, Kanya. Investors might be familiar with CAR-T, but what is CAR-NK, and how does this differ from CAR-T? Great question. Currently, all the CAR-T products that are approved, their origin is obviously a T cell, which is a type of lymphocyte which is involved in killing different cells in the body, which has been engineered to express this CAR. The other thing to remember is all of the approved therapies are autologous, which means that they are taken from the patient's own body, engineered to fight the patient's cancer, and then reinfused into the patient, which takes a period of time for you to do the manufacturing and bring it back to the patient. NK cells are another type of lymphocyte. They are part of what is known as the innate immune system. All of us have NK cells. The name NK actually stands for a natural killer cell. Inherently, their job in all of us is to go around and surveil for any malignantly transformed cell or virally infected cell and then kill them. NKs do this killing by a balance of activating and inhibitory receptor. At any given time, there are a whole set of kill proteins and a don't kill protein. Depending on what the balance is, that's how they have the cell-to-cell direct cytotoxicity. That's what NKs do. Some of the advantages for using NKs for AML, and Senti as a company, we are a logic gate company. We do look carefully at not only what is the engineering we need to put into a cell, but which cell works best for which indication. For AML, we feel NKs are inherently better suited than T cells for a couple of different reasons, and I'll highlight two of the main ones. One is NKs have inherent anti-AML activity. When you take one person's NK cell, put it in a healthy NK cell, put it in a patient with AML, there are responses. The issue with those is they are not long-lasting, which goes back to the point that Tim and I were making about you need to be able to target the leukemia stem cells. That then increases the durability. The second advantage is AML, as I said, it's an acute leukemia, so it moves pretty rapidly. There often is not the time to take a patient's cell, engineer it, and infuse it back. Patients don't have the time. Our approach is get healthy donors, pre-make the cell, keep them ready to go and off the shelf. When a patient with AML comes on our trial, once they meet eligibility, we ship product out within hours of us confirming eligibility. That's a big advantage. There's one final point I'll make. Patients with AML, inherently, there's some level of dysfunction of their T cells as well. They often are not good cellular backbones to make these sort of therapies. Extremely helpful, Kanya. Appreciate that. I'd like to dive a little deeper into the mechanism of SENTI- 202. Kanya, what specific targets does it go after and why? Yeah. Tim mentioned this at a very high level. Maybe what I'll do is walk through. There's a lot going on here. The nice thing is all of this elegant design is something that Senti does. All the patients see is really a vial of cells, right? Let me walk you through from left to right what is going on with SENTI- 202. First of all, the cellular backbone is a healthy NK cell. We screen donors, and then we recall donors with favorable manufacturing attributes in their NK cells to make SENTI- 202. What we do is we insert a single gene circuit which expresses three proteins. That's fundamentally why it's a logic gated gene circuit. You alluded to the CAR-T cells. They express one protein, go find a cell or a cancer which expresses a target CD19 or something and kill. Whereas ours, we call it logic gated because it's not just a kill when you see the target, but kill in certain contexts and protect in other contexts, right? That's the logic gating. The three proteins are the first one is what we call our kill signal or the odd logic gate. This also addresses the heterogeneity of AML. What's shown in the cartoon there is an AML blast cell expressing CD33. They tend to do that. Then there's leukemia stem cells, that niche population expressing a target called FLT3. What Senti 202 is designed to do is kill when it sees either CD33 or FLT3. That's the odd logic gate. Now, the issue is these targets, CD33 and/or FLT3, can also be expressed on the healthy hematopoietic stem cells shown in the green in the center. What we've done is first, we identified a protein called endomucin, which is found only on the healthy cells, but not on the leukemia cells. We engineered in this iCAR or a NOT gate so that when SENTI- 202 finds endomucin, it doesn't kill endomucin expressing healthy cells, even if they express CD33, FLT3. We spent a lot of time perfecting that preclinically before we went into the clinic. We do these cell-cell assays, and we get 70%-80% protection, very selective. We also did a lot of optimization of these constructs so that there isn't the spillover killing, but there's also not tonic inhibition. We get it just right. It only kills the cancer cells and protects the cells we want it to protect. The third protein is an enhanced protein. All of these immune cells, cytokines can augment their activity. What we've done is we've attached IL-15, which is a cytokine that's important for NK cells, and that can also serve to augment host immune cell activation persistence as well. Okay. You touched on this, but I'm going to ask a little bit further. You mentioned that there's no great universal target for AML, but you've picked two that seem to cover most patients. Aren't these also expressed on healthy cells? They are. That is really the reason for our approach is very unique. This is some of the foundational work that Tim did when he was at MIT. What honestly attracted me to come and join Senti to work on a product like this, where it is not just about, hey, there is CD33, FLT3, let's kill, but this NOT gate that comes in where, yes, the healthy cell also may have CD33, FLT3, but there is this other protein that is found on healthy cells, very rarely on leukemia, but pretty universally on healthy cells, which stops and overrides the kill function. Because AML does not have a clean target, what we have done here is we have engineered in that cleanliness to decrease the off-tumor on-target effects potentially. Fascinating. Okay. The company has shared initial data from three patients showing two of the three achieve CR or complete response, with both achieving MRD negative. Can you help investors understand what a CR means and how important MRD negative is for survival? Great question. Thank you for that. In AML response, there's essentially two components. With all cancers, one component of the response is how much is the tumor cleared, right? CR or complete remission means that the AML blasts are completely eliminated from the bone marrow by conventional methods of detecting them. In addition to that, CR also includes measurement for recovery of normal blood cell levels, two of them specifically, neutrophils, which are important to fight off infection, and platelets, which can help to make sure that patients don't have bleeding issues. It helps forming blood clots and stopping bleeding. CR is not only elimination of AML blasts below 5% because there is some level of healthy blasts, and sometimes it's difficult to distinguish a leukemic from a healthy blast just morphologically, and also recovery of both neutrophils and platelets to a level where it's considered that the side effects like infection and bleeding largely are not an issue anymore. That is CR. You come to what is known as measurable residual disease or MRD negative. Now, typically, when a pathologist looks at the bone marrow, they look at it through immunohistochemistry or flow and what we call conventional methods. More and more, there are more and more sensitive methods of detecting that one stray leukemic blast that's kind of hidden somewhere in a niche. These are often multiparametric flow, or sometimes they're mutational analysis where you look at all the DNA in the bone marrow to see if there's any mutations which are more often found in leukemia than in healthy. Those often have sensitivities of up to one to 10 to the minus four. What that means is if there's one leukemic cell in 10 to the power of four cells, this technology can detect those. The key to prolonged remissions is to have that deep remission. That's why MRD negativity is getting more and more importance. To date, there's no product which has been approved with MRD negativity on its label. To a large extent, it is still very much in the research arena. We hope that a product, hopefully SENTI- 202, which can consistently achieve that sort of MRD negativity, will help us incorporate that into a regular assessment for patients' AML. Yeah. Certainly exciting. Wow. Thanks for explaining that. Appreciate it. All right, Tim. Before we open up for Q&A, Senti will be presenting an update at AACR this coming weekend. In line with the conference's embargo policy, I understand you're not able to share actual data that'll be presented. With that said, what should investors look for from the company at this important cancer conference? Yeah. I'm happy to give an overview and certainly pass it over to Kanya as well. I think at AACR, we are looking at more patients beyond what we disclosed at the end of 2024, as well as a longer duration of looking at those patients that we've already reported on. Both of those, certainly with the passage of time and as we enroll this trial, will be available at that point. Kanya, do you want to add anything? Maybe what I'll add is for an early phase trial like ours, I really like our abstracts that have been accepted at AACR because I feel it paints a nice picture with the trifecta. We have the primary clinical data, which is in oral. We also have correlative analyses where we look in some detail at what is happening in the bone marrow before and after treatment, among other analyses. That is a correlative poster also from our patients' bone marrows. Finally, we have a preclinical humanized mouse model where in a mouse model, you can do things like switch out different parts of the component of the gene circuit to really isolate what is contributing to which effect. Putting all of that together, I think it's going to be a nice story of how SENTI- 202 is working and the mechanism, in addition to, of course, just the clinical data and what sort of results we are seeing in these patients with a high unmet need. Excellent. For the audience, stay tuned for results from this conference this coming weekend at AACR. Thank you both. That was a great overview. Appreciate you answering all those questions. You did a great job. Now I think we're going to turn to the live Q&A. I know our audience has questions. As a quick reminder to our audience, if you have a question, click the Q&A button at the bottom of your screen, type in your questions, and we will get to as many as time allows. All right. Let's see here. Our first question, how many patients are you enrolling total in your phase one, and when do you expect to have final results? You want me to take that, Tim? Yeah. Kanya wants you to take it. Our phase one has a dose-finding component, and then we have different dose expansions where we can look at AML, MDS, and others, and so on. As the study is contemplated, we have some flexibility in terms of the number of patients we put on. What we've said publicly is this year, we are hoping to have about 20 or so patients put on by the end of the year in our phase I, which I think will give us really good insights into not only what is the baseline activity, if you will, but what sort of patients perhaps we should be looking at and so on. That's our target for the year. Great. Okay. Our next question, in the current phase one setting, are patients being treated in the outpatient setting, or is this something that you plan to move to for later studies or the commercial setting? That's a terrific question. A key difference between NK and T cells is really its excellent safety, NK cells' excellent safety, I mean, because biologically, unlike T cells, when NKs see their stimulus, they don't explosively divide and have this outpouring of cytokines, which often gives rise to a lot of the side effects of CAR-T cells. Our intention absolutely is that NKs, that SENTI- 202 be given in an outpatient setting. Having said that, for a first-in-human trial, I think our understanding is that the FDA requires all first-in-human cell therapy trials to start inpatient, get that safety data, and then move into an outpatient setting. We have built that into our protocol, and we are pretty confident that this will eventually be used outpatient. Okay. Our next question, you mentioned AML is a very unmet medical need. What made you go after that target first? Kanya, do you want to start, and then I can talk about other things? Yeah. Yeah. A couple of different reasons. One is when you look at AML, for the reasons that I think what Tim and I alluded to, this is when you think of our logic-gated technology, this is a blood cancer, high unmet need, where clearly this issue of not having a clean target is a big driving factor for why we are not able to really bring on new products. That makes AML a pretty attractive way to look at how our logic gates perform. Beyond that, it's a high unmet need. I mean, all of us, what we are trying to do here is come up with something which hopefully can make a difference to these patients. With a median survival of about five months or so, any sort of responses we can get, and especially if we can make it durable, can be quite meaningful for these patients. Yeah. The only thing I'll add to that is beyond AML, we are very excited about the potential of the logic gate technology. If you look at solid tumors, there's a significant amount of, I would say, crowding in the space right now if you think about ADCs, T-cell engagers, or other products around the same targets, things like HER2 and others, where there are targets that have been identified that are clean enough for those sort of conventional strategies. There is a large number of patients out there where, again, there's not a single clean cancer target. We are focused very much on advancing the SENTI- 202 clinical programs, our top focus, but at the same time, with increasing validation of our logic gates with SENTI- 202, the ability to extend this into the solid tumor setting, certainly exploring both NK cells as well as T cells is something well within our plans. Great. Okay. Our next question, this does, you just answered it, which is great. It says, are you able to go after other cancers beyond just AML? That is excellent. Okay. We do have another question that just came in, and it's basically asking for an update on the data that you had provided earlier. With that, just according to embargo, I'm going to answer that for you guys. Stay tuned to our participant because they had mentioned that they will be providing data at AACR. Do you want to talk about how you would prioritize while we're waiting for other questions to come in, how you would prioritize maybe looking at other indications and other cancers? Maybe that's with your important technology. I'll take a first stab, but then, Kanya, if you want to weigh in as well from the clinical perspective. I think there have been actually quite a lot of, so let me step back here. The way we go about identifying good applications for the logic gate technology is by looking at, number one, the clinical unmet need, identifying targets, ideally ones that are known to be good targets for the cancer of interest, but have a challenge in terms of the therapeutic window because of their expression away from the tumor, and then being able to look into that specific off-target population of cells and identify a protective antigen that we can recognize in order to protect those healthy cells from being killed. That's the approach we actually did in AML, where we took patient samples, did a lot of bioinformatics work to identify the use of CD33 and FLT3 to go after AML blasts and leukemic stem cells, but also the use of endomucin to protect those healthy cells from being affected. We can replicate that analysis internally. There's also, I would say, been some really interesting academic work that's come out looking at what combinations of targets are available. We can leverage that third-party research as well. Based on that, in addition to AML, I think there are many additional target combinations, including in solid tumors, that we think are valuable here. We certainly intend with this technology not to be just looking at AML. I think being able to expand into those other targets where the logic gates can make a big input, and frankly, where there's not much other competition out there is how we're prioritizing our pipeline. Yeah. I I mean, if you think about AML alone is a great opportunity, and to be able to have an impact there would be tremendous. To go beyond that would be wonderful for patients. Okay. If you think about our next question comes in, do you have a commercialization strategy? Are you looking to partner? Yeah. I think our strategy currently is that we can continue to push this program forward. We have a clear roadmap in terms of being able to continue to advance the program as well as bring this product from a manufacturing perspective into pivotal and commercial. Certainly, if there are opportunities along the way to team up with another group, we will be open-minded to that. It has got to make sense for the patients and for the company. That is our current approach. Great. Awesome. Okay. It looks like that's it for the questions. We did go a little bit over, so we have had some good interest today. Tim, before we close, you talked about a lot of great things with respect to the company, data coming soon, and then additional data before the end of the year. If you think through the line of questioning that we had today, are there any questions that we've missed? Is there something that you'd like to share with investors as far as why they should continue to pay attention to Senti and why you think Senti is a good investment opportunity? I think we covered most of it here. I would just make one more plug in that we are going typically after indications and targets where we think other modalities just can't play because they don't have access to the logic gate approach here. And so we're really excited about that. More data to come certainly at AACR and beyond, and more programs that we'll disclose in due time. Excellent. Great job, both of you. Appreciate your time today. You shared an exciting story with the virtual investor audience, so we thank you for that. This does conclude our virtual investor closing bell segment featuring Senti Bio. As a reminder, Senti trades on NASDAQ under the ticker SNTI. If you like what you saw today, I encourage you to visit senti-bio.com for more information on the company, to sign up to follow the company to receive their alerts, as well as follow their social channels on X and LinkedIn to stay current on the latest information. You can also visit virtualinvestorco.com for a replay of today's event, as well as our latest segments and events calendar. Thank you, Tim. Thank you, Kanya. Thank you to our audience. I wish you a great rest of your day. Thank you.