Hello, and welcome to the Senti Biosciences Senti 202 Clinical Update Conference Call and Webcast. As a brief reminder, all participants are currently in a listen-only mode. If anyone requires operator assistance during the event, please press star zero on your telephone keypad. Following the presentation, there will be a question-and-answer session. Note that this webcast is being recorded at the company's request, and a replay will be made available on the company's website following the end of the event. At this time, I'd like to remind our listeners that remarks made during this webcast may state management's intentions, beliefs, expectations, or future projections. These are forward-looking statements and involve risks and uncertainties. Forward-looking statements on this call are made pursuant to the safe harbor provisions of the federal securities laws and are based on Senti Biosciences' current expectations, and actual results could differ materially. As a result, you should not place undue reliance on any forward-looking statements. Some of the factors that could cause actual results to differ materially from these contemplated by such forward-looking statements are discussed in the periodic reports Senti Biosciences files with the Securities and Exchange Commission. These documents are available in the investor section of the company's website and on the Securities and Exchange Commission's website. We encourage you to view these documents carefully. Additionally, certain information contained in this webcast relates to or is based on studies, publications, surveys, and other data obtained from third-party sources, and the company's own estimates and research. While the company believes these third-party sources to be reliable as of the date of this presentation, it has not independently verified and makes no representation as to the adequacy, fairness, accuracy, or completeness of, or that any independent source has verified any information obtained from third-party sources. Joining us on today's call from the Senti Biosciences leadership team are Dr. Timothy Lu, Chief Executive Officer and Co-founder, and Dr. Kanya Rajangam, President, Head of R&D, and Chief Medical Officer. I'd now like to turn the conference call over to Dr. Lu. Dr. Lu, please proceed. Thank you very much, Operator. Greetings, everyone. Thank you for joining us today. My name is Timothy Lu. I'm the CEO, Co-founder here at Senti. Senti was founded to create smarter medicines to treat difficult diseases, and we're very excited today to present an update and positive preliminary results in the treatment of relapsed refractory hemolignancies, including AML, in our ongoing phase one trial of Senti 202. Next slide. Before we get started, I would just refer you to our forward-looking statements on file with the SEC. Next slide. Senti is developing a potential best-in-class logic-gated cell therapy pipeline. Our first program initially targets AML and related hematological cancers and is called Senti 202. This is an off-the-shelf logic-gated CAR-NK cell therapy that contains the CD33 or FLT3 NOT endomucin logic. What we're going to discuss today is new data showing positive preliminary efficacy data of this product in our ongoing phase one trial for the treatment of relapse refractory AML. At AACR, we presented the fact that those findings have been completed. We are going to present our complete response and durability data along with correlative data supporting the logic-gating mechanism of action. Collectively, we are very excited about this data set, certainly for the Senti 202 product itself, but also for the ability to extend logic-gating to other liquid and solid tumors in the future, where it is going to be critical for us to effectively target cancer cells while sparing those healthy cells. I will note that this platform technology can be utilized across both NK and T cell therapies. Next slide. Before we jump into the clinical data, let's talk about what a logic gate is and why it has the potential to have such great impact in the treatment of cancer. First of all, what is a logic gate? Logic gate is a type of genetic circuit that we engineer into cell therapies to give them more precise targeting of cancer cells while being able to spare healthy cells. Existing drugs, such as commercially approved CAR T cell therapies or biologic drugs, such as ADCs or T cell engagers, are unable to incorporate this logical behavior. Typically, these drugs recognize a single target, which must be cleanly expressed on the cancer cell and not expressed on healthy cells in order to achieve a suitable therapeutic window. If those targets that they're recognizing are found on both cancer and healthy cells, what will happen is the product will kill both the cancer cells and the healthy cells at the same time. For a large number of tumors, including AML, a single clean target does not exist, and that's where our logic gate technology comes in. We can engineer two different types of logic gates that allow us to recognize multiple targets. The OR gate allows us to recognize multiple cancer antigens, and that allows us to achieve deeper killing of the cancer cell population, whereas the NOT gate allows us to recognize healthy tissue antigens that are expressed on the healthy cell but not on the cancer cells, and as a result, protect those healthy cells from being killed. This multi-antigen recognition system, as well as the ability for the cell to process this information and make a decision on whether to kill the cancer cell or spare healthy cell, is a unique part of our overall platform. I'm very happy now to pass it over to Dr. Kanya Rajangam, who's our President, Head of R&D, and our Chief Medical Officer, to share with you the latest updates in the use of our logic gate technology in our lead program, Senti 202. Kanya. Thank you, Tim. Next slide, please. We are developing Senti 202 in acute myeloid leukemia, or AML, as Tim indicated. AML is an aggressive leukemia with poor prognosis. It affects about 21,000 patients in the US every year, and about a little more than half experience relapse or unfortunately succumb to their disease within 12 months, even with aggressive upfront therapy. Once a patient's AML has either relapsed or is refractory, which means never responded to frontline therapy, the prognosis is even more dire, with a median survival of about five months. In fact, current standard of care produces responses in the rate of about 15-25% for a full CR, or about 20-33% for CR and CRh, which indicates both a complete remission or a complete remission with partial hematologic recovery. This is a high unmet need disease where we need multiple new effective anti-AML therapies. We've identified two key attributes of an anti-AML therapy which we believe is needed for it to be successful in treating this disease. First is the ability to target heterogeneous clones, including this niche population of cells called leukemia stem cells, or LSCs, which are thought to be responsible to repopulate the bone marrow with leukemia and decrease the durability of remission. Targeting these clones and the LSCs will allow us to achieve deep MRD negative CR. MRD stands for measurable residual disease, which leads to durable remissions and longer survival. The second key attribute Tim was alluding to is the ability to kill these AML blasts and LSCs but spare the healthy hematopoietic stem cells so that we can support normal blood cell count recovery, which also leads to improved prognosis and longer survival. The second part is especially key in terms because in AML, there are no clean targets as such. The ability to selectively achieve leukemia killing and sparing the healthy cells is important for a therapy to be effective. Next slide, please. That is where we designed Senti 202 to specifically address these two issues. Senti 202 is an intelligently designed CAR-NK, which has our unique logic gate, which constitutes a CD33 or FLT3 NOT endomucin gene circuit. I will walk you through each of the different components and what it does. First, looking at the schematic from left to right, the cellular backbone of Senti 202 is healthy NK or natural killer cells from selected adult donors. We chose NK cells for AML because they have some inherent anti-AML activity. We transduce these cells with our unique logic-gated gene circuit, which expresses three main proteins. The first protein imparts a kill function to Senti 202. It recognizes either CD33, which is found on bulk AML blasts, or FLT3, which is expressed on these leukemia stem cells. When Senti 202 sees either CD33 or FLT3 on these leukemia cells, it institutes a kill signal, giving rise to cytotoxicity of the leukemia. The second protein is our unique NOT logic gate, which protects healthy hematopoietic stem and progenitor cells, even if they express FLT3 or CD33. The way it does that is by virtue of an ICAR. What we did is we identified a protein called endomucin, or EMCN, which is found on the surface of the healthy HSCs, shown here in green, but not on the leukemia cells or LSCs commonly. When Senti 202 interacts with endomucin, the inhibitory CAR overrides the kill signal of the CD33 FLT3 CAR, resulting in protection of the HSCs. Pre-clinically, before we even came into the clinic, we spent a lot of time perfecting this balance so that we can get the balance just right in terms of selectively killing leukemia and sparing the healthy cells. The final protein, calibrated release IL-15, enhances Senti 202 and host immune cell activity and persistence. Next slide. Senti 202 is an off-the-shelf allogeneic CAR-NK. What that means is the two processes shown here, what happens in the manufacturing site and what happens to the patient, are decoupled from each other. We at Senti isolate NK cells from our healthy adult donors. We engineer them, expand them, cryopreserve, and store them, and keep them ready off the shelf such that when a patient enrolls into our trial, meets eligibility criteria, we are able to ship them the product right away the same day. We are also developing Senti 202 for future outpatient use based on the well-known safety profile of NK cells. Next slide. The phase one trial, or Senti 202 101, is a multicentral, multinational, open-label trial. In terms of key eligibility criteria, we enroll adult patients here between 18 and 75 years of age with a fairly good performance status. Patients have relapse refractory CD33 or FLT3 expressing heme malignancies. We require CD33 positivity by local assessment. Patients with AML can come on trial after one but no more than three prior treatments. They must have received targeted agents if they have the applicable mutations. The main objective of the study, being a phase one study, is to determine safety and the maximum tolerated dose, or MTD, and the recommended or the recommended phase two dose, or RP2D. We have standard DLT definition criteria. Other key objectives include efficacy based on ELN 2022 response criteria. That's a standard consensus criteria for assessing response and measurable residual disease, or MRD, assessment for local standard of care. We also measure PK. In terms of pharmacodynamics, or PD, we look at serial bone marrow samples and evaluate them by site-off. It's a 3 plus 3 study design with a dose finding phase followed by an expansion phase. We are looking at two dose levels, and two schedules are planned. We started our dosing with a dose that we anticipated was going to be biologically active. Next slide. This slide delineates the dosing schema in the center of the slide and the two different dose levels we were planning to evaluate in this trial. Both of these are either 1 billion cells or 1.5 billion CAR-NK cells per dose of the two dose levels. The two dose schedules are either three weekly doses of Senti 202 or five doses of Senti 202 on the days indicated in the dark blue in the center following lymphodepletion with fludarabine and cytarabine. On day 28, we do a bone marrow, and patients are allowed to get multiple cycles based on both safety and efficacy. As I said before, the opening dose was anticipated to be biologically active. We started with schedule one dose level one, enrolled three patients, and then we also enrolled three patients each in schedule one dose level two and schedule two dose level one. There were no DLTs or dose-limiting toxicities in any of the dose cohorts, so MTD was not reached. We identified schedule one dose level two as our preliminary RP2D based on the totality of clinical data. Next slide. Our study enrolled a high-risk relapse refractory AML population with multiple baseline adverse characteristics. Looking at all patients and the preliminary RP2D cohort in general, these patients failed prior therapies pretty rapidly. They enrolled on our trial within a year of diagnosis after having been exposed to multiple lines of prior therapy. The majority of patients on trial, in fact, all in the preliminary RP2D cohort, had adverse risk genetics at diagnosis by ELN 2022 criteria. Next slide. The study subjects had received multiple prior therapies. Across the study, patients had received a median of two lines before the study entry overall. All patients had received previous chemotherapy, including fludarabine and/or cytarabine, with four patients having received both agents. The majority of patients had also received venetoclax before entering trial. Next slide. In general, patients received a median of two cycles of Senti 202 therapy. The majority of patients who discontinued Senti 202 did so after having achieved a complete remission, with none discontinuing due to an adverse event. Next slide. Senti 202 preliminary safety data indicate that Senti 202 is very well tolerated. This table summarizes any grade 3 or higher AEs on study, regardless of relationship. In general, these grade 3, 4 AEs were hematologic events, unrelated to Senti 202, and consistent with relapse refractory AML patients receiving LD. No single type of serious adverse event was reported in more than one patient. There was no significant difference in AE profile across those cohorts, as you all can see. Finally, no grade 5 AEs were reported on study. Next slide. Senti 202 related AEs or adverse event of interest, AEIs, were generally low grade and manageable with standard of care. Three patients experienced grade 1 pyrexia, one each with either chills, hypotension, or hypoxia. These were noted typically within 24 hours of dosing of Senti 202 and rapidly resolved with standard of care. None were assessed as serious. They were reported as cytokine release syndrome by our investigators. We believe this likely represents delayed infusion reactions, which have been described with NK cell therapies. There were no other adverse events of interest or dose-limiting toxicities reported on study. Moving on now to efficacy on slide 15. We observed responses across all dose cohorts. Five of seven patients enrolled on trial achieved an ORR. The remaining two patients are continuing in cycle two after having seen some blast reduction in cycle one. The five ORR patients include four CCR and one MLFS patient. The four CCR, which stands for composite CR rate, includes three patients who achieved a full complete remission with full hematologic recovery, or CR, and one patient who achieved a CR with partial hematologic recovery, or CRh. Two of these CCR patients were in our preliminary RP2D cohort. All four CCR patients were MRD negative. All of these CR and CRh patient responses are ongoing as of the data cut, with a median duration of response that has not been reached. Next slide, please. This slide graphically depicts the patient's bone marrow blast burden at study entry and the best response they achieved on trial. We observed rapid bone marrow blast reduction across all dose cohorts. Indeed, the majority of patients, all except one, had some degree of blast reduction across all dose cohorts. Next slide, please. This slide depicts the individual patient's time on study and also provides information about their baseline demographic status on the table on the left. To orient you to the information on the slide, first, the table on the left looks at key adverse prognostic characteristics, such as primary refractoriness or if they had adverse risk cytogenetics by ELN 2022. It also looks at the exposure and refractoriness to fludarabine and/or cytarabine therapy before coming on trial. As you can see, many of our patients had multiple poor prognostic indicators or chemorefractoriness before they entered our trial, as shown with the red yes boxes. The swim lanes on the right depict the individual patient's time on study, with the preliminary RP2D cohort patients highlighted on the top. What the swim lane shows us is that patients did intensify their response with the second cycle, either converting from a PR to a CR or converting from MRD positive to MRD negative with the second cycle. Further, all of our CCR patients, that is, the three CR and the one CRh patient, continue in remission as of the time of the data cut, with the longest follow-up being eight months and continuing. Next slide. On this slide, what we are summarizing is our site-off bone marrow data. The data points on the left, the pie charts on the left look at the leukemia stem cells, or LSCs, in the bone marrow at baseline. We first gate for LSCs by gating them for CD34 positivity and CD38 low in our baseline bone marrow sample. We assess for the cell cycle status using Ki-67 and IDU. What you can see here in the pie chart is all of our patients, the majority of their LSCs are in G0 phase, which means they are quiescent, and they're not expected to be susceptible to chemotherapy. With Senti 202, which targets a cell surface marker, you would expect the cell cycle phase not to affect the activity of the therapy. As shown on the right, we are looking now on the right at LSCs over time at baseline, at the end of cycle one, and the end of cycle two for those who received two cycles. What we see with Senti 202 treatment is LSCs generally decrease, and they decrease more than tenfold in all patients who achieved a CCR. Next slide, slide 19. This slide looks at the peripheral blood cell count and the protection of bone marrow, hematopoietic stem and progenitor cells in patients who have achieved a CCR. On the left, both platelet counts, shown in black, and absolute neutrophil counts, shown in gray, decrease with lymphodepletion and recover rapidly by about day 14 of a treatment cycle. On the right, what we are showing you is the healthy hematopoietic stem and progenitor cell in the bone marrow at baseline, at the end of cycle one, and cycle two for those who get a second cycle. What you can see here is that the HSPCs were either maintained or increased in the bone marrow of patients who achieved a CR, consistent with the Senti 202 logic gate mechanism of action. Next slide, please. Finally, Senti 202 PK. This is peripheral blood PK, where we look at the transgene, Senti 202 transgene, in the peripheral blood of patients. We have the cycle one PK shown with the cycle two PK in the inset across all nine patients on study to date. The PK profile is consistent with allogeneic NK cell therapy profile, where we see a modest peripheral expansion in the first 14 days, consistent with NK biology and the safety profile of Senti 202, with it being cleared naturally by about 14 days from the periphery. There was no significant difference noted in exposure across patients who achieved CR or not across those cohorts or between cycle one and two. In conclusion, Senti 202 is a first-in-class, off-the-shelf, logic-gated selective CD33 or FLT3, NOT endomucin CAR-NK cell therapy, that's been designed to selectively kill the AML blasts and LSCs while protecting the healthy HSPCs. The trial enrolled a heavily treated relapsed refractory AML patient population with poor prognosis. Senti 202 is well tolerated, with the most frequent grade 3, 4 AEs being hematologic, consistent with relapsed refractory AML patients receiving lymphodepleting chemotherapy. The maximum tolerated dose was not reached, and the preliminary recommended phase two dose was identified as 1.5 billion cells per dose, given as three weekly doses over 28 days. Moving on now to the efficacy conclusions on slide 22. We saw promising preliminary efficacy with Senti 202 in relapse refractory AML patients. Overall, across the trial, five patients achieved an ORR, and four achieved a CCR, which includes three CR with full hematologic recovery and one CR with partial hematologic recovery, or CRh. Two out of the four CCRs were observed in the preliminary RP2D cohort. All four CCR patients were MRD negative, as assessed per local standard of care. All CCR patients are maintaining their remission with a longest follow-up of eight plus months. In terms of PK, Senti 202 transgene was detected in all treated patients, consistent with other allogeneic CAR-NK cell therapy PK profiles and the well-tolerated safety profile we've observed on study. Site-off analyses of bone marrow samples show that Senti 202 treatment decreases LSC frequencies and maintains or increases healthy HSPC frequencies in patients who achieved a CCR, consistent with Senti 202's logic-gated gene circuit design. Here at Chicago, we have two posters. One, which gives additional correlative data information that will be presented on Tuesday. The second one, which looks at the NOT endomucin logic-gated gene circuit and teases out its contribution to protection of the HSPCs in a humanized mouse model. That's going to be presented on Wednesday. I want to acknowledge all of our patients and their caregivers and all our enrolling sites, both in the U.S. and Australia, as well as SERM for partially funding the study. With this, operator, I believe you're ready for questions. Certainly. We'll now be conducting a question and answer session. If you'd like to be placed into the question queue, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you'd like to move your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing star one. One moment, please, while we pull up our questions. Our first question today is coming from Gula Lipchips from Shardan. Your line is now live. Good morning. Thanks for taking the questions and congrats on the data. On the bone marrow site-off analysis, could you maybe comment if there are any characteristics that are associated with the patients that did not have as deep a LSC reduction or the patients with incomplete hematologic recovery? Thanks. Morning, Gula. Thanks a lot for the question. I'll pass it to Kanya. You take that one. Thanks, Tim. Hi, Gula. To answer your question on site, I think there was a two-part question, right? Anything that was associated with the LSC reduction, not really beyond what we've shown. Obviously, the ones who achieved a CCR, their LSC went down more than tenfold. In terms of healthy hematopoietic cell recovery, it was generally maintained or increased in the patients who did achieve a CCR. We do have additional site-off data. That is part of what is being presented in our poster on Tuesday. Thank you. I do have a question that was pre-posted. What is next for the 202 trial? Kanya, you want to take that first, or just in broader context as to the additional programs? Yeah. Thank you for the question. We have now—we are at the phase in our trial where we have identified the preliminary RP2D. The next step is to put on more patients to confirm that and then move on to disease-specific expansion cohorts. We are primarily focused on AML, but the protocol also allows additional cohorts if we wanted to go in that direction. That will be next specifically for the trial. Thank you. Next question. Is it a canopy outpatient? Yes. NK cells, there's a huge body of clinical literature which has shown the excellent safety profile of NK cells in general. Our initial data supports that Senti 202 is very consistent with what has been noted for NK cells across literature. We are certainly planning on developing it for outpatient use where applicable. Thank you. Can you comment on the durability of cells? Is that what you expected? Yes. The PK profile is very consistent with what you would expect with allogeneic NK cell therapy, wherein you do see some modest expansion in the periphery for the first two weeks, which is the window of opportunity, so to speak, when a patient has received LD chemotherapy such as ours. It recovers. As the host cell recovers, we expect Senti 202 to be naturally cleared, which is one of the reasons there isn't as much of a concern for the long-term toxicities as you may have with some of the autologous products. Yes, this looks very consistent in what we were expecting to see going into the trial. I may add one other comment there. I think we do draw a distinction between the duration of the cells themselves as well as the duration of the response. From the duration of the cell perspective, building on what Kanya mentioned, through the ability to produce multiple doses of this product and be able to dose repeatedly as part of the strategy. For the patient, at the end of the day, the duration of response is what's most important. That's really where using allogeneic cell therapy, on one hand, is fine. We've done a lot of work to engineer the product to go after specifically the blasts plus leukemic stem cells, which typically form a really difficult-to-treat subpopulation of the cancer. As Kanya had mentioned in the ACR presentation, many of those LSCs are actually in that G0 state, unlikely to be effectively targeted by traditional chemotherapies. Part of the goal of this product is to drive as deep of a response as possible by targeting those leukemic stem cells and blasts together. I think there's clinical data prior to this trial supporting that those levels of LSCs can be potentially correlated with response durations. We hope to continue to explore that and hopefully engender that with the product here. Could you comment on the choice of LD? Yeah. Kanya, do you want to talk about that? Yeah. In our trial, we used fludarabine and cytarabine or Ara-C as lymphodepleting chemotherapy. We picked that for a couple of different reasons. One is flu and Ara-C. They have some debulking blast ability for AML. Our intention was to have this be a one-two treatment where you have some debulking from the chemotherapy followed by our Senti 202, which can get to the last of the disease, so to speak. The other reason was actually we presented this at AACR last year in 2024, where we showed pre-clinically that exposing AML cells to Ara-C, even if they have inherently low CD33 FLT3 expression, causes upregulation of those targeting proteins. That hints at potential synergy when you come in with flu Ara-C followed by cells, which is another reason we chose these two agents for our LD chemo. Thank you. Can you provide some information on patient three, who was the only one who had no blast reduction? Patient three—thank you, Tim. Patient three, their AML had a TP53 mutation, which is particularly hard to treat even with current approved standard of care. In addition, we've looked at some of their baseline tumor characteristics. We will be presenting that at our correlative poster. It appears that this patient has endomucin positivity as well in the tumors, which can happen very rarely in AML. Certainly something we are tracking. We have more of that information in our poster tomorrow. Thank you. Can you discuss the opportunities for logic gates beyond AML in liquid tumors? Yeah. I think one of the key things here at Senti is we want to try to develop products that are highly differentiated and solve an unmet need in the clinic in ways that current drugs don't do that adequately. I think, as I mentioned earlier on the slides, there's logic gate technology that's really meant to go after cancers where you can't find an easy single target. Many drugs, if that single clean target exists, many drugs exist or can be developed pretty easily. If you don't have that single target, then you really need a technology like the logic gates here to go after those tumors. We think AML certainly is a very high-met need that fits that criteria. There's also many solid tumors that could be addressed this way. We have built our logic gates so that they can be extended into other indications and actually function in both the T cell and NK setting. We look forward to sharing some of that in the future with the broader public. Thank you. Your current trial is for relapsed refractory AML. Can you discuss the opportunity to expand to frontline or other indications? Yeah. Maybe I will let Kanya handle that particular question on Senti 202 and other indications that might be addressable. Yeah. Senti 202 targets any malignancy which expresses either CD33 or FLT3. Obviously, we started with AML. Within our protocol, we also have the ability to go evaluate MDS, as an example. There are some other rarer malignancies as well which have CD33 expression or FLT3 expression. W e could go in that direction. We are also obviously evaluating at what point and how we look at Senti 202 upfront. I think we need a little bit more data for that, but certainly something we're actively considering. Thank you. What is the impact on the unmet need in AML from recent approvals, for example, Menin? Kanya, you want to take a shot? Sure. As we presented, AML is really a high-unmet-need disease, very low response rates once someone has relapsed or is refractory to frontline therapy. We need all sorts of therapies that can be approved for this terrible disease. The Menin inhibitors, which recently were approved, are approved for patients with a specific type of mutation. The response rates are in that range of about 19% CR. When you include CRh as well, about 25% or so. Further indicative of how AML is such a difficult-to-treat disease. We believe that for patients with AML, in order for their prognosis to continue to improve, we need multiple ways of addressing the disease, whether it be menin inhibitors or other targeted agents which are effective for maybe a subset of population with the right mutation or something like ours, where we are able to broadly target either CD33 or FLT3-expressing AML, which is in the vast majority, about 95% of AML. While these new therapies, it is great to see them coming on, more is needed, unfortunately, for these patients. Thank you. We have reached the end of our question-and-answer session. I would like to turn the floor back over to Dr. Lu for any further closing comments. Thank you, everyone, for taking the time to listen in. We're very excited about this most recent data update on the Senti 202 program and the future prospects of logic gating for cell therapies. We want to thank all the folks who joined us on this call, as well as the patients who've been participating in this study. Thank you, everyone. I hope you have a good morning. Appreciate it. Thank you. That does conclude today's teleconference webcast. You may disconnect or line out at this time. Have a wonderful day. We thank you for your participation today.