Good morning. My name is Eric Joseph. I'm one of the analysts on this mid-cap team at J.P. Morgan. It's my pleasure to introduce Stephen Hurly from LAVA Therapeutics. After the presentation, management will be joined with Stephen on the front. If you have questions, you can raise your hand. There's a mic going around. You can also ask questions through the portal, and I can ask management. Without further ado, Stephen. Thank you, Daniel, thank you to J.P. Morgan for the opportunity to participate in this wonderful conference. My name is Stephen Hurly. I'm the President and CEO of LAVA Therapeutics. I appreciate everybody's time today. Before I begin, this is our forward-looking statements. We'll be making forward-looking statements. Please read thoroughly before making any investment decisions. We at LAVA Therapeutics are focused on developing next-generation cancer therapeutics. I'm sure you're all quite familiar with the first generation of T-cell engagers, CD3 engagers, looking at a broad mixed bag of cells. Our approach is to utilize the same engager approach, but with a subpopulation of T-cells, Vgamma-9, Vdelta-2 family inside of the gammadelta T-cell population. We believe this approach keeps the precision of T-cell engagers, the conditional activation, maintains the cytotoxicity, but avoids some of the challenges of a narrow therapeutic window that the first generation of T-cell engagers are challenged from, including CRS on target, but off-tumor toxicity, activation of T-regulatory cells, et cetera. We are a clinical stage company, excited to have two programs in the clinic. Our lead program focused on hematological malignancies, CLL, MM, and AML, is focused on the tumor-associated antigen CD1d. Our lead solid tumor program focused on prostate cancer targeting PSMA is also in the clinic. Both of these programs are in dose escalation Phase I trials in the U.S. and in Europe. We have a nice pipeline supporting them, recently announced CD123. We recently announced in the fourth quarter of last year a partnership on our EGFR compound with Seagen. We also have an earlier stage collaboration with Janssen. We're a well-funded organization with $142 million pro forma. When you add in the Seagen capital at the end of third quarter of last year, we've guided this provides us beyond 24 months of cash runway. Here's the pipeline I mentioned. Lead program, CD1d. We announced early data at ASCO last year on this program in Chicago, additional data at ASH. We're gonna have additional data on this program as we continue to enroll mid this year. I'm excited to announce that our PSMA program will have initial data at ASCO GU next month here in San Francisco. We're excited to partner with Seagen on our EGFR collaboration, a world-class organization, and as I mentioned, recently announced our program, pipeline program on CD123. Fortunate to work with a great group of individuals with over 100 years of successful drug development. Let's get into the program. The T-cell engagers burst onto the scene with great enthusiasm years ago. You can see from this slide, as you look at the number of bispecifics, antibodies, and development has grown materially right now with many 200+ in the clinic, seven approved. The enthusiasm remains, but in many ways, these programs continue to suffer from some specific challenges. First, a very narrow therapeutic window. Just as you're seeing activity, you're seeing toxicity. You're dealing with cytokine release. You're dealing with, again, on target, but off-tumor toxicity. You're seeing the activation of those T-regulatory cells have shown to materially dampen clinical activity in these engagers. Certainly, the activity in solid tumors continues to pose a real challenge. There have certainly been efforts to open up that therapeutic window. They include looking for that perfect tumor-specific targets, step dosing, subcutaneous dosing, decreasing affinity of the T-cells, and using masking technology to try to open up that therapeutic window. More recent approach is to look for a different subset of cells. That's the camp that we're in, utilizing the gammadelta T-cells, specifically Vgamma-9, Vdelta-2, as a way to create a larger therapeutic window and avoid some of these challenges. Here's our approach on the upper left side. We have a T-cell engager, cross-links the T-cell receptor on the gammadelta T-cell with the targeted tumor-associated antigen on the cancer cell, selectively activates that gammadelta T-cell to kill the cancer cell. Importantly, we're an off-the-shelf therapies. We avoid all the cell therapy manufacturing challenges. It's a fully modular program, so we have a very broad toolbox to create new programs. Small size allows for better tumor penetration. It's a proven set of antibody technologies, and we have two programs that we have in the clinic, VHH format and in a VHH with an Fc domain as well. Why gammadelta T-cells? In one of our investor conferences this week, one of the investors used a term I really like called ready-to-kill cells, and I think that's exactly what they are. They sit between the innate and the adaptive immune system, the natural immunosurveillance cells of the body, looking for cancer cells, acting quickly, highly cytotoxic, and have a unique way to recognize these cancer cells versus healthy cells. Unlike MHC-restricted antigens, they use stress signaling, which we'll walk through a little bit more in the coming slides. Here's, on the left side, the natural activation mechanism of gammadelta T-cells. Phosphoantigens are upregulated in cancer cells. That causes a conformational change in the Butyrophilin receptor. That change allows the T-cell receptor on the gammadelta T-cells to recognize that as a cancer cell, bind to it, degranulate, and kill the cancer cell. Our approach is on the right side. You can see highlighted in yellow the targeted tumor-associated antigen. We cross-link with the T-cell engager with the T-cell receptor on the gammadelta T-cell. Once that happens, activation, degranulation, and kill the cancer cell. Importantly, this is conditional activation. Back in the nineties, when people started realizing that these gammadelta T-cells are highly correlated with favorable outcomes for patients, they started looking for ways to utilize them in anti-cancer therapies. A lot of these approaches use systemic activation. Systemic activation led to T-cell exhaustion. By only doing conditional activation, the team really engineered an elegant solution by once it's only activated locally, you're gonna avoid T-cell exhaustion. Importantly, it's not a fully blocking antibody, so we preserve this natural mechanism of the Butyrophilin receptor for the gammadelta T-cells. I'll tell you, this is one of my favorite parts of the platform, is that you see material differentiation of activity between cancer cells and healthy cells, and that allows us to go after some challenging targets, we believe, like EGFR, and I'll walk you through some data on this in some coming slides. What we have depicted here is what we call the cascade response. It begins, as I said, with the cross-linking of the cancer cell with the gamma delta T cell. Once that activation happens, you see very potent cell killing, EC50 in the low picomolar range. Importantly, we do not activate the T-reg cells, as I've said, and some data from blinatumomab, for example, has shown if in the presence of these T regulatory cells, a materially reduced anti-cancer activity. You get into the middle process here in our preclinical models. We've been able to show this mechanism, once activated, drives some pretty significant gamma delta expansion. You orchestrate an innate and adaptive immune response, you solicit and activate additional cells of the immune system into the anticancer fight. These gammadelta T cells have shown to present to provide an antigen-presenting function. You might not just get a rapid initial response, but there's the potential for a deep and durable response as well. Here's some data that kind of walks through the cascade response and provides some supportive data. On the left shows that expansion in a seven-day culture for CD1d and a CD40 Gammabody, we're able to show 10- to 70-fold expansion of the gammadelta T cells. In the middle is a cascade response I mentioned of additional immune cells. You see not just activation in the second bar of gammadelta T-cells, but you also see CD4, CD8, and NK cells activation into the anticancer fight. On the right, those bars show CD3 significant activation of T-regulatory cells and no activation by the EGFR CD3 Gamma body. This gets further into that characteristic I mentioned that I really like about the platform, outsized differentiated killing between cancer cells and healthy cells. Here on the left, in a C1R tumor cell line, you see very significant killing with the CD20 Gamma body of those cancer cells, at the bottom line, you see no impact on healthy cells, healthy B cells. On the right, in a prostate tissue, you see very significant killing of the prostate cancer cell line in the fourth bar by the gammadelta T-cell and no killing of the healthy cells. We completed significant non-human primate safety work to again investigate and validate this idea of avoidance of cytokine release. We completed programs with CD1d, CD20, and multiple clinical trials, non-human primate trials with our EGFR Gammabody. In all of these trials, all the way up to 28 milligrams, we had no evidence of cytokine release syndrome at all. In addition, this is a stark contrast to an EGFR CD3 EGFR BiTE that only at a 200-fold lower dose for three days infusion, they had to sacrifice the animals because of toxicity. A very significant safety window, at least in the non-human primate studies. In summary, the platform, if you look at it from this perspective, very selective with respect to tumor killing, low risk of on-target off-tumor toxicity, low risk of CRS, potentially very wide therapeutic window, high tumor killing, high tumor selectivity, no activation of those T-regulatory cells, and high tolerability. We're excited to be a clinical stage company. Our lead program targeting the cancer-associated antigen CD1d. Here is a pictorial of the program cross-linking with the T-cell engager between the CD1d on the cancer cell with the T-cell receptor on the gamma-delta T-cell to activate the gamma delta to kill the cancer cell. Importantly, this one also stabilizes interaction with iNKT cells and drives activation of those cells. In many ways, it's a bispecific with trispecific properties. Two effector cell populations into the anticancer fight. Here on the left, you see expansion of gammadelta T-cells. You see expansion of gammadelta T-cells as well as the iNKT cells versus control. On the right, you see lysis of patient tumor cells in both CLL, MM, and AML. Here's the schema for the clinical trial. We started with single patient dosing. We required MABEL dosing per regulatory, so very low dosing to start, but we took significant steps in single patient dosing to get us up to higher doses as quickly as possible. We are also investigating subcutaneous delivery as well. If you're looking at the data to date with respect to adverse events, we've reached 200 micrograms, 400 times the starting dose in MM and CLL. We'll begin the AML cohort once we get to higher doses. Most adverse events are suspected to be unrelated, and the severity and frequency is not correlated with increasing dosing. There's been no evidence of CRS or ICANS. No clinically relevant increase in CRS-related cytokine IL-6. Here you see activation marker CD25, CD69 showing the activation of gammadelta T-cells and receptor occupancy on the right side increasing with increasing doses. This linear PK is an attempt to show the progress we're making in comfort with the subcutaneous dosing. In this patient, you saw 74% availability with a subcutaneous dose. With other patients, we've gotten up to around 80%. Here in the swimmer plot, we show patients to the data cutoff date, six MM, six CLL of mix of men and women in a heavily pretreated population, and you see time on study in this slide. Two patients, we presented this back at ASCO last summer, had hints of activity. A CLL patient showed temporary enlargement and tenderness of involved lymph nodes accompanied with a grade two fever. This would be the characteristics of tumor flare. This patient was assessed of having stable disease, and the percent of clonal B-cells in peripheral blood dropped from 42% down to 9%. In addition, back to the idea I shared with you that we're able to differentiate activity against healthy cells versus cancer cells. Here, CD1d cells, monocytes that express CD1d were not impacted. On the right side, we show MM patient, four lines of prior therapy, refractory to last three lines after treatment, was able to get a 23% reduction in M protein. Two good signs of clinical activity. Unfortunately, both of these patients had to come off the trial due to COVID. In summary, next generation bispecific T-cell engager showing what we expected from our preclinical activity. These are continuing to enroll in the U.S. and Europe. We'll move now to our second program, our lead solid tumor program, LAVA-1207, targeting prostate cancer. The program is pictured on the right side. Again, a T-cell engager, but this time with an Fc domain for extended half-life, is shown cross-linking the gammadelta T-cell with the tumor cell. In the middle here shows a picture of significant activity against an LCA prostate cancer cell line and avoidance of healthy cells. This program is enrolling in the U.S. and Europe, dose escalation. Here is some data, preclinical data that supports the selectivity of these patients. On the left side, you see gammadelta T-cells degranulating with tumor infiltrating, and next to that, again, in PBMC. On the right, again, back to preferential lysis of the cancer cells here, prostate tumor cells, significant killing with the LAVA-1207 in PBMC, no killing of the normal tissue. Schema of the trial. Here we started with full 3+3, so we have three patients per cohort dose escalation. We are dosed every two weeks through IV. As I said earlier, we're very excited to partner with Seagen in our EGFR compound. Fourth quarter of last year, we announced that collaboration. This is our EGFR expressing Gammabody. Here we showed some very significant differentiated killing. EGFR is a challenging compound, one we think our program lends itself to tackle. Here you see very significant killing of tumor tissue and again, sparing of healthy tissue. We recently announced LAVA-123 as an addition to our pipeline. Here we showed some potent lysis of primary AML cell lines and differentiate killing on the right side of tumor cell lines and no killing against healthy cells. It's a really exciting year for us. I'm very proud of what the team accomplished in 2022, moving two programs forward, getting the collaboration done with Seagen. This year promises to be an even stronger, exciting year. We're going to have initial data for PSMA at ASCO GU next month here in San Francisco. As we continue to enroll these trials, we'll have more data mid-year for both programs and hopefully assist Seagen in any help they need to get that trial started as well. Janssen collaboration continues. We look for more news for that down the road. Thank you, everybody. I'm gonna welcome three of my team up to the front. Fred, our recently joined CFO, Benjamin, our CMO, and Hans, our Chief Science Officer, and Paul also, who sits in the front row, ran out of chairs. Thanks, everybody. As a reminder, you can ask questions to the portal, or there's a mic going around, so you can be able to, raise your hands and the mic will come to you. Maybe I'll start with the first question. From a high level, given I think investors' awareness of CRS as a potential marker of sort of efficacy even though it's a safety signal, why are we not seeing any CRS with LAVA zero five one? I think, Hans, would you like to answer that? I think it is to the point that Steve mentioned before. The characteristics of Gamma nine Delta two T-cells, their tumor preferential recognition, so it's a more restricted set of cytokines that will be produced in any case. We also think it is very well built on the earlier experience of Gamma nine Delta two T-cell-based therapies that systemically activated T-cells, which we don't anticipate to do because it's a conditional activation. Also in that worst case scenario, you could say no signs of high-grade CRS were observed. Can you give us some color on what we should expect to see with the next update from the dose escalation study? I guess how many patients worth of data should we expect to see? I see. Benjamin? Yeah. We last presented data at the ASH of the ongoing phase I program that's ongoing in U.S. and Europe, and obviously that study is continuing, so we think there's going to be significant additional data, both clinical, safety, pharmacokinetic, and pharmacodynamic towards the middle of the year. It's obviously difficult to predict exactly where the recommended dose is going to be established. Certainly good progress towards next towards the middle of this year. Continue. I guess you're currently enrolling in cohort six. Could we see an initial safety data but also anti-tumor activity as measured by response rate, but understanding that, you know, don't have a perfect crystal ball, but is there potential to see, you know, response rates from that cohort? Yeah. I mean, there are a couple of elements to that. We are enrolling right now CLL and multiple myeloma patients that are obviously very heavily pre-treated, have no other therapeutic option. We all know that there are multiple lines of effective therapy available for both of those diseases and patients as they come to this quote-unquote last line of therapeutic attempt. We have seen that in the swimmer plot that Steve showed, some of the patients are really at that stage where it's very, very difficult to catch the progressive disease. This is one thing to consider. I don't think we are talking about response rate, but we'll certainly have additional data on dose level six. Based on some modeling we try to do between in vitro concentrations and what we see in the clinic, we do reach at the present dose levels for 24-36 hours, the type of concentration that is relevant in vitro. Whether this is enough, clinically or we have to go to higher doses that gives you a longer exposure to these type of concentration, that obviously needs to remain to be seen. Should we expect to see, you know, you hit tolerability ceiling during the dose escalation? I mean, our working hypothesis, as you saw, is very much towards a broader therapeutic window, and we fully expect to identify the recommended phase II based on optimal pharmacological parameters, and not on a maximum tolerated dose. I mean, we have not seen so far any adverse events that become more frequent, that are observed more frequently or more severe with escalating doses. This is in most of the anti-cancer drugs, be it cytotoxic or be it immunologic, there is some kind of dose effect towards the target organs. We haven't seen any of this so far. Looking at all our preclinical data and the experience of systemic gammadelta T-cell, that Hans mentioned, we really don't expect to hit maximum tolerated dose. Question. Can you maybe outline for us the two different approaches, the subcutaneous and the prior approach? Why take two different approaches to administer LAVA-051? I mean, the small As Hans and, or as Steve showed, we have the two formats that we are presently producing molecules. The small format that we choose for the hematologic program based on Blincyto has a relatively short half-life of the free dar-drug, not of the active entity that sticks longer because we see very potent binding. We choose for the clinical study to start with a twice-a-week dosing. I'm not saying that's what we need eventually, but we said it's easier to dial the frequency back than to dial the frequency up. To have optionality here, we tried to understand what is SubQ bioavailability. We have analyzed the first three patient where we gave one dose IV, one dose SubQ. We see very, very good reproducibility between the three patients. SubQ could certainly be an option if we have to stay at twice-a-week dosing. Twice-a-week, subcutaneous obviously is much more pragmatic than twice-a-week intravenous. We leave that option open for us. Given the evolving therapeutic landscape, particularly multiple myeloma with introduction of CAR T-cells, upfront or at nearly upfront, is your plan still to explore all three indications, CLL, multiple myeloma, and AML, in the dose expansion cohorts? There you have a couple of questions in the same question. First question, expansion cohort. Obviously, we will look at each of the three diseases, the data from the dose escalation study, but conceptually, If we see the adequate data in the dose escalation part, we would plan to do dose expansion cohorts in each of these three diseases independently/separately. To the question of, is there room for it, or what was the word you used? I guess with evolving therapy. Right. I mean, we are having a new target. We're having a new novel approach. In a sense, yes, there are a number of new drugs available that are all active, but we know patients do progress, and at that point, the preference is to move to a different modality or a different target. That evolving landscape, if you want, is not really making much of a difference because most of the patients do progress, whether it's three lines or four lines or five lines. It doesn't make such a big difference. It's a new target, and at the point you show efficacy, you will eventually combine and move up in the line of therapies. I guess maybe to clarify a bit, as you're looking at the efficacy in this dose escalation study, what are you looking for to be able to choose a recommended phase II dose, you know, advance it and advance into those expansion cohorts? I mean, initially, we will look at identifying the recommended phase II dose, primarily on pharmacodynamic parameters. We are starting to get a good sense from our in preclinical data, but also seeing the same time of patterns in the clinic, we understand better which parameters to look for that could help us identify the recommended phase II dose. Yes, you would want to see some clinical activity in selected patients prior to moving forward. Like we said earlier, these are very heavily pre-treated patients, and sometimes, like you saw on the swimmer plot, there might not even be enough time to get to the point of observing clinical activity in these type of patients. Certainly, that would be a plus that you see clear activity in the one or the other patient. Okay. You know, given that timeline, is there potential to expect data from the expansion cohorts within 2023 then? I mean, it's difficult to predict when we will be at the point to identify the recommended phase II dose based on the fact that you don't have a maximum tolerated dose. Experience tells you're very often to overshoot and then go a step back and say, "I didn't reach much more with the dose going up." Certainly, in our plan, we foresee that towards the end of the year, we should be able to start one or the other of those expansion cohorts. Got it. Maybe moving to 1207, with data coming up soon. To begin with, maybe, you know, Hans, can you walk us through the difference or the molecular difference between 1207 and 051 that makes one better equipped for targeting solid tumors versus, you know, the heme malignancies? I'm not sure if the one format would be particularly better than the other for solid tumors. I think developing both formats also shows the versatility of the approach. We reasoned, so the difference for LAVA-051 is that it's a bispecific single domain antibody, binds with high affinity to the gammadelta T-cell and has a prolonged functional half-life as a result. The Fc containing format is developed in LAVA-1207, still a fairly small molecule. The size is about half the size of a conventional monoclonal antibody, and it's known that size matters with respect to infiltration of proteins and antibodies in tumors. It facilitates penetration into a solid tumor, and the reasoning was that it may also be beneficial to have the free compounds present for a longer period of time to push that infiltration into the solid tumor microenvironments further. The drug basically makes use of the two compartments where gamma nine delta two T-cells can be found both in circulation as well as in the tumor microenvironment. Okay. Regarding the phase I study, is there any color you could share regarding the characteristics of the metastatic, you know, castration-resistant prostate cancer patients you have enrolled into the study? For example, prior lines of therapy or mutation status of androgen receptor or baseline serum PSA levels, or we should just wait until next? No, I mean, the protocol clearly specifies the type of patients that can be enrolled in such a first-in-human study. We are collecting all the pertinent data on the patient, the comorbidities and the prior history, as well as the type of expressions of the tumor. Many of the patients will be order of magnitude 10 years after their original diagnosis. They have gone through multiple lines of hormonal therapy. They will have to have at least one of the novel class of anti-hormonal therapies, and in most cases, also one or more of a taxane, unless that was contraindicated for those specific patients. Again, very late-stage patients. We started the clinical study in, if I believe, in March of last year. That study has progressed very, very nicely, both in the U.S. and in Europe. We will have a good, data set to present, in a month from now, looking at clinical and safety, again, at PK and PD, a similar type of parameters that we showed for the LAVA-051. Obviously, prostate cancer, you do follow PSA as part of the surrogate marker for the disease. Okay. You've you also guided that, you know, you provide subsequent update, you know, in first half 2023. At that point, should we expect more of the same data, or is to expect something like anti-tumor activity besides the PK/PD and PSA levels? I mean, there have been a couple of bispecifics, specifically for PSMA, reporting clinical data. It's pretty clear where the expectation for our compound is. We'll have to show stabilization or reduction in PSA. In our case, we would expect to not have run into significant or serious adverse events at that point, defining the broader therapeutic window. Certainly, as the study is continuing, we are still in the dose escalation phase. Middle of this year, there should be quite some additional data to share. Yeah. I'll continue. Maybe this is similar to LAVA-051, how are we going to choose the recommended phase II to take, you know, when you think about the LAVA-1207? Right. It's a combination of the, what we expect the pharmacologically optimal dose. Here it's a little bit easier because you have the PSA marker that is easier and quicker to evaluate in some patients. An added quote-unquote "benefit" is that these solid tumor patients don't progress as quickly as the hematologic patients. There's a little bit more time for the compound to develop and show their immunological activity. Similar type of data. Okay. Maybe moving to the LAVA-1266 and LAVA-1278 programs. Maybe can you go over those two different programs, and what do you see as the unmet need in CD123, you know, tar positive tumors or CD40 targeted heme malignancies? CD123 targeted by LAVA-1266 is expressed by several indications, several tumor types like AML, MDS, BPDCN. There have been challenges in the development of CD123 engagers. We think as Steve also indicated, we may differentiate also from a safety point of view, maintaining efficacy. CD40 is targeted with LAVA-1278. Both of these engagers make use of the FC containing formats. CD40 is expressed by various indications, hematologic as well as several solid tumor indications like pancreatic cancer, renal cell cancer. We have good data sets for both programs, confirming preclinical anti-tumor activity, preferential activity against tumor cells expressing the targets, in vivo models. We are moving forward with LAVA-1266 expectation to submit a CTA RND about a year from now. Maybe one final question from me. I guess what's the current cash runway for the company, and how should we think about the potential financing options for LAVA in 2023? I think we're in very good position right now. You know, in the presentation, we had the pro forma number and the Seagen, the up to $50 million upfront allowed us to be at a pro forma of about $142 million at the end of the third quarter. You know, when we put out our year-end numbers, you'll see we still have the vast majority, over $130 million cash will be on the balance sheet as of the end of the year. We think that gets us, you know, greater than 24 months from where we are right now, at which point we'll have numerous milestones that will come through. We're not in any great need for any, you know, financing at this point. We do think that we're well capitalized. No further questions. I would like to thank Hans, Benjamin, Paul, and Steve. Thank you. We'll have a few minutes. All right. Thanks everyone. All right. Thank you.