Legend Biotech Corporation (LEGN)

R&D Day 2021

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Oct 18, 2021

Hi, good morning and welcome. This is Jess Young, Head of Corporate Finance and Investor Relations at Legend Biotech. Thank you so much for joining us today on Legend's first Research and Development Day. Today, you will be hearing from our executive team highlighting the progress on a select numbers of therapeutic programs. After the presentations, we would like to hear from you and take your questions. I feel logistic before we get into the details. You can access our SEC filing highlighting the progress and updates announced this morning and see the presentation slides in the investor session of legendbiotech.com. Please note that today's presentation includes forward looking statements. We encourage you to review these cautionary statements regarding information and remarks included in today's presentation as well as the company's Form six ks, which identifies certain factors that may cause our actual results to differ materially from those projected. Next slide, please. Moving to today's agenda, our CEO, Doctor. Yin Huang, will have some opening remarks. Then during the next hour, Doctor. Lida Pugout, VP of Clinical Development and Steve Gavlo, VP of Commercial Development, will present clinical plan and commercialization strategy on the BCMA program. We will take a short break after the BCMA presentation at 11:20 a. M. After the break, we will hear from Doctor. Fan Fan, our Chief Scientific Officer for another hour. After all the presentations, we will have thirty minutes of Q and A before we conclude the event today. With that, I would like to welcome our CEO and CFO, Doctor. Ying Huang. Thank you, Jessie. Good morning and welcome. It's great to see so many friends in the room and also welcome everyone online as well. So it's a pleasure for me to welcome you to the Legend Biotech's first R and D Day. As some of you may know, Legend Biotech had the opportunity to ring the opening bell at NASDAQ a few weeks ago. And as I rang the bell, I was reflecting what and also we have accomplished since the founding in 2014. In 2016, the first in human study called Legend II was initiated. And based on the Phase I data, we entered into worldwide collaboration and licensing agreement with Janssen on sutacel. In August 2018, the first patient was dosed in the CARDIGH-one trial here in The United States. Just over three years later, we are here awaiting FDA approval with a PDUFA date of November 29. Among the many accomplishments we have made since 2014, some of the most exciting have taken place in our research pipeline, which is why we're here today. The company was built on foundation of innovative science and we remain committed to developing cell therapies that are paradigm shifting. This morning you'll hear from my colleagues on the BCMA program and also other exciting developments. Allow me to introduce you to speakers. First up, Doctor. Lita Pekkault, Vice President of Clinical Development and Steve Gavil, Vice President of Commercial Development will share updates related to our CAR T2 clinical programs and also updates on commercialization of ciforcele as we edge closer to that particular date of November 29. Lida is an experienced clinician who joined us from Novartis where she served as global clinical program lead and also executive medical director in the cell and gene therapy unit of Novartis. Prior to that, Lida worked at Roche and also Wyeth, where she was a medical lead on several clinical trials paving the way for regulatory submissions for Affinidol and Avastin. Steve Gabel is a longtime commercial and marketing specialist in the biotech industry. Steve came from Celgene, where he led The U. S. CAR T commercial development activities for the BB-two 121 program. Steve also led Velcade marketing, strategy and execution at Takeda Oncology and held multiple sales, marketing and market access leadership positions in companies including Johnson and Johnson, ImmunoX, Syntex and IMS Health. Doctor. Frank Fan, our Chief Scientific Officer and the inventor of SutureCell is a trained transplant surgeon and an expert in the field of human B cell tolerance. Before joining Legend, Frank helped identify the underlying mechanism of antibody generation in single B cells and developed one of the first anti HIV-one lentiviral vectors in the world. He has published more than 40 peer reviewed journal papers. Frank will take you through our research, technology platform and also R and D pipeline. As you will see today, Legend Biotech has a broad portfolio of research stage and also clinical stage programs. Before being a CAR T company, we were first antibody company at its core. We have in house antibody screening and also engineering capabilities. This is an important differentiation compared to our peers in this field. We frequently receive questions on why cilter cell has demonstrated better efficacy. Well, it's coming from this Dura Binder design. Since T cells are collected from patients in your autologous CAR T program, I hope you agree that we did not discover psuta cell by accident after this R and D day. Instead, it's crystallized from years of trial and error, end of an engineering effort. And we are also technology agnostic in how we develop the programs. Rather than drop one anchor to one technology, we explore different technologies including autologous CAR T, allogeneic CAR T, TCR T and NK. We don't pretend to know which technology will win the race of allogeneic cell therapy. And that's why we're investing in diverse allogeneic platforms, including non genetic alpha beta T cells, gamma delta T cells and natural killer cells. Our development strategy will be driven by science and only science. And we do believe that multiple armoring strategies will be necessary to overcome challenges to use T cells to treat solid tumors. So finally, I would like to close my introduction with why we do this here at Legend Biotech. You may remember that Legend II, the first in human study, is what catapulted Legend and helped us become who we are today. I would like to share a story of patient number six from Legend II study. Patient number six is a 61 year old gentleman who was diagnosed with multiple myeloma in April 2014. He had the type of lambda light chain myeloma with five prior lines of therapy including Revlimid. This patient was dosed with SutureCell in June 2016 with a total dose of 500,000 CAR positive cells per kilogram body weight. And you can see from this photo on the slide taken on the day of infusion on day one that this patient has a large number of plasmacytoma in the back. These are masses that look like solid tumor masses. Fortunately, he achieved MRD negative complete response twenty days after infusion of psuta cell. The plasmacytoma also disappeared over time, as you can see from day 19 through then the photo taken in March 2019. I'm very pleased to announce that he has been cancer free without the need for any additional maintenance treatment since then. As of last follow-up on 05/26/2021, patient number six remained in complete remission. This is just one example of five years of progression free survival for a patient who was dying from multiple myeloma before he was administered sutacil. And this patient is due for the next follow-up in November and we have not heard any progression as of today. Multiple myeloma has always been declared incurable. With SutaCell, we want to challenge that and we want to give this patient a fighting chance. Today, patient number six lives with his son, daughter-in-law, and also two grandchildren in China. He goes to market for grocery shopping, enjoys his favorite noodle dish, and sends his grandchildren to and from school every day. This last photo actually was patient number six in front of the second affiliated hospital of Xi'an Jiao Tong University Medical School where he was treated with tilta cell five years ago. He told Doctor. Zhao, the principal investigator and our staff that Siltacell gave me the second life. A company without a sense of purpose is a company without a soul. With the story of number six patient in Legend II, I hope you guys can also understand what inspires every team member of Legend Biotech here every day. Now please join me in welcoming Lida to discuss the BCMA targeted therapy, silt cell. Great. Thanks, Ying, and welcome everyone. So my name is Lida Pakauwd. I'm clinical lead at Legend for BCMA program as well as early stage pipelines. So today I would to Today I would like to give give updates updates on on siltacil siltacell clinical development program. I will start by reviewing new data for CARTITUDE I study, our registration study. I will also review CARTITUDE II. This is a multi cohort Phase II study. And lastly, I will cover our Phase three programs as we move siltacil in earlier line setting. So this will be two Phase three studies, CARTITUDE four and CARTITUDE five. So we have initially presented CARTITUDE I in 2020 with median twelve months follow-up. This year at ASCO we have shared median eighteen months follow-up data. We do continue to see unprecedented response rates in heavily pretreated multiple myeloma patients. This is overall response rate in this updated analysis is ninety seven point nine percent and responses are deep and durable. This is indicated by stringent CRs being 80.4 and also by MRD negative responses which are in ninety two percent of the patients. I also would like to note that what we see compared to previous analysis that we see deepening of responses. So some patients, like onethree of the patients who had VGPR became CRs and importantly CR patients became stringent CR's. So in previous analysis, stringent CR was only sixty seven percent of the patients and now stringent CR is eighty percent. Response rates seen in this trial is also translating in long term benefit for the patient and this is indicated by progression free survival. So what we see here in this eighteen months analysis is that the lower confidence interval indicates that minimum PFS benefit is twenty two point eight months. This curves will continue to mature and we will continue to report data in major clinical conferences. With that, we are very excited to provide such a potentially effective therapy to highly pretreated multiple myeloma patients. Response rates seen here is exceptional in oncology and in our careers and we are pleased to share this data with you. So now I would like to invite Steve to give you commercial perspective on this data. Thank you. Am I turned on? We good? Okay, good. Well, good morning, everybody. What's really a treat for me, during the IPO process, I've had we did not have the opportunity to meet face to face with many of the folks in this room. And when you IPO virtually, that's always an interesting experience. So it's always now very, very helpful for me and it's a personal type of connection to personally welcome you all and also thank you for your continued interest in Legend. So obviously the clinical data speaks for itself. And what I'd like to do with my piece of this presentation is give you a commercial perspective of what that means and the geographies that we will be launching into. So the take home message as it relates to our label assumptions are as follows. We are assuming that in all regions that we launch into that we will mirror the same indication statement as our competitor. So just to remind folks, in The United States, we're assuming that we will have a fifth line plus label. What you see up here on the parentheses, or just below that in the sub bullet I should say, around 12,000. What 12,000 represents, this is the eligible patient population in The United States that will meet this label requirement. It does not necessarily meet, this is not a treated population because there will have to be additional work on top of this twelve thousand that will account for fitness levels, etcetera, for these patients. But I just wanted to pull that out. And I'm going come back to The U. S. In a second. In Europe, we're assuming a fourth line plus indication. This is, again, this is in keeping what you saw earlier with ide cel, representing about a 6,000 or so patient population that would meet the eligibility criteria. And then in Japan, also a fourth line plus indication, again a population of around 4,000. Now let me take you back to The U. S. Because there's some interesting dynamics that's occurring right now in The States as it relates to payer coverage. Right now it's twelve thousand fifth line plus who meet the criteria. What we're starting to see, however, and this is a result of the NCCN clinical guidelines that were recently established, a bit of an interest in the private pay sector to look at potentially expanding the use beyond fifth line. So we're keeping our close eye on this because obviously with the ide cel launch just occurring, there's really has been, relatively speaking, kind of minimal experience yet in the marketplace, but we hearing loud and clear of an interest from the private payers to potentially broaden their coverage policies to incorporate potentially a fourth line patient population. For you guys who might be kind of jotting statistical notes, that represents 10,000 incremental patients in the fourth line setting. Obviously, from a promotional end, we would not be able to promote to that, obviously. This would be off label use. This is something that we are hearing today of an interest from the private insurers to potentially look to expand beyond fifth line. I'd like to spend a second, for those of you maybe who are not as familiar with our relationship with J and J as it relates to our co pro agreement. So we are co pro partners in The United States. It's a fiftyfifty partnership. They've been a tremendous asset for us as we've built out our commercial organization as well as our operational infrastructure to pull this exciting product through. What I did want to also bring out, I always get asked the question about, so how does the CoPRO work? What are you doing? What's your partner doing? So what we agreed to now a couple of years ago was that within the hospital setting that we will be selling into is where legend will play. So we have deliberately gone out and actively recruited and trained and hired folks from the industry who have a lot of gene and cell therapy experience as well as multiple myeloma experience. And a lot of these folks obviously have spent a lot of time in hospitals. We think that we've got a very nice relationship set up, Legend in the inpatient setting and largely Janssen in the outpatient setting. Let me just end, I guess, on my piece of this as it relates to the initial indication in terms of what we are also hearing in market in terms of how our customers, most importantly, are evaluating these CAR T drugs. And it's interesting now to watch for me, since working on my old program when I was at Celgene and where I am today, how that review has changed quite a bit over the last now for me it's about five years in total, five and a half years. So as we all know, it all starts with the data, right? The clinical data, safety and efficacy data of all these drugs, without question. And I think what you're hearing from Lita is from that perspective we have quite a hot product on our hands right now. So we're feeling very comfortable from our clinical profile for sure. But what we also know, and a really good example of this are some of the prior CD19 launches, is that just because you have hot cool technology doesn't necessarily mean that there are to be commercial successes, right? And one of the things that has been playing in market to us loud and clear, and this is an extension of safety profile, is how interested the market is in using silti cel and bridging patients into that hospital outpatient setting. That's been primarily the result of what you're seeing in the trials of our delayed CRS profile. This is very unique, and if you look at all CAR T products, to have a median delay of CRS of about seven days, that allows hospitals a lot of operational flexibility in terms of what to do with that patient and where to potentially administer this product. And that's more and more important for sites, especially as you're launching into large patient populations like multiple myeloma. Because when you do the math, and I've done it now a couple different times, in The United States in particular, and that's true globally, there are just not enough beds to treat all of these multiple myeloma patients and continue to do all the other work that you're involved in these hospitals, whether it be in transplant or in the clinical trial setting. So this is one of these operational aspects of this product that I truly did not appreciate until we got going with it. But this is something that is clearly resonating in market as an exciting also added feature of this program. And then finally, because of this combination of obviously safety and efficacy and operational flexibility, at the end of the day it enables these hospitals and providers to treat more patients. And one of my concerns as this product was picking up speed clinically because of the great work our clinic teams have been doing, not only here at Legend, but also our friends on the line from Janssen, we needed to ensure that everyone who was eligible to receive this drug will get it. And what I was getting worried about is the operational mechanism within these countries if they could pull it through. So the fact that, like I said, I think the CRS aspect is the enabler to actually treat potentially more patients in the outpatient setting. So I'll leave you with that and I'm sure during the Q and A we could get further into that. I'll turn it back to Lisa. Thank you, Steve. So next trial I would like to review is our Phase II CARTITUDE II study. So this is a multi cohort study which evaluates various multiple myeloma setting. We anticipate to enroll approximately 160 patients. And this so you see we have six cohorts right now and each cohort is 20 patients or more. We do this trial was designed and these cohorts are designed to support or inform our Phase III programs or they are designed to generate data which will be practice informing. So I will start by reviewing Cohort C. So I will start with later line setting. So Cohort C is a patient who are exposed to PI, EMIDS and CD38 agents but also exposed to BCMA targeting therapy except cell therapy. So this is basically called patient who had prior BCMA ADC or bispecifics. Next cohort is cohort A. So this is again relapsedrefractory setting, but patient with prior one to three lines of therapy done earlier than CARTITUDE And we have Phase III trial also ongoing in this population which I will come in a moment. So we have disclosed this cohort A 20 patient data and I will share that with you in a moment. So rest of the cohorts are also investigating silica cell in earlier line settings. So if we go to cohort B, these are patients who are early relapses after frontline therapy, patients who basically progress twelve months after induction therapy or autologous stem cell transplant. Next cohort is cohort D. Cohort D is patient who have suboptimal response to frontline therapy. So this is less than CR after frontline therapy. Court E is newly diagnosed patients who are not intended for autologous stem cell transplant. And these are high risk patients. And last cohort is also newly diagnosed patients with standard risk. And this last cohort F will investigate patients after induction of DVRD or similar quadruplet regimens. A silica cell will be given after induction as a consolidation. So this, as I mentioned, the Cohort A prior 123 line lenalidomide refractory data have been shared at ASCO this year. We are very encouraged to see high response rates consistent with CARTITUDE I. So we see ninety five percent of patients have overall response and the CR was seen in seventy five percent of the patients. So this data has median of five point eight months follow-up. And as I have mentioned from CARTITUDE I, we have learned that responses are going deeper over time. So we will look forward also to update this study in the future. I also would like to highlight safety profile in this earlier line setting. So we see a similar safety profile to CAR TIGIT-one in terms of targeted adverse events or some adverse events even numerically better. So this is very encouraging as well. So we see overall eighty five percent of patients with CRS, but vast majority are low grades. And in this subset, we did not see grades three and four neurotoxicity which also includes we did not see movement in neurocognitive type of neurotoxicity. And start of CRS and neurotoxic, I think to the point what Steve was mentioning, so we see like seven, eight day, seven for CRS and eight day median start for siltacen. Now I would like to introduce CARTITUDE IV Phase III study. So this is same patient population with prior one to three lines of therapy and refractory to lenalidomide. Patients should have had exposed to PI and EMIDS. And I would like to highlight daratumumab exposure was not required in this trial. So it means this trial will cover both populations with or without prior daratumumab. And I guess Steve will come to this point as well because we want to highlight in the context of we know there is KarMMa study which is ongoing, which is different. So KarMMa study has prior two to four lines. So this trial is one line earlier. And KarMMa trial, as we know, requires daratumumab exposure. But here both populations will be covered. This is trial schema. So trial is we'll enroll approximately 400 patients and we will give in control arm PVD or DPD standards of care regimen. PVD stands for Pomalidomide Velcade Dex and DPD is the DARZALEX Pomalidomide Dex. And patients are treated in control arm until disease progression. In siltacel arms, there will be bridging therapy one cycle or more, so maybe two if needed. And after this bridging therapy with the same regimen, patient will undergo silta cell infusion lymphodepletion and silta cell infusion. After silta cell infusion, there is no treatment, so there is observation treatment free period for patients. This trial has opened in June and we are very excited because we have seen very high interest from investigators in terms of recruitment, even better than we have forecasted. And this trial is clear was very priority for Janssen and Legend. So we hope to report on the progress of the trial very soon. And also to put this trial in the context, so just to highlight what is available standards of care right now and what benefits this can provide to this population. So we see as highlighted here nine, ten months is a benefit in lenalidomide refractory patients specifically which are studied in this study. Did we make the switch over? Can you guys hear me okay? Okay, great. Thank you, Leta. I love this study for the record for a number of different reasons. And thanks for the setup, Leta. So I won't go into the trial design, but as Lita does mention, this is the first phase III CAR T therapy in this patient population of one to three priors. A lot going on here, and Lita touched on a couple of them. So with this indication, fundamentally, this will be the first time that this program, cel, will now jump in front of ide cel. So that's one of the key points to the slide. The second piece, and jumping ahead, as you can see further down the slide, our competitive assumption, Lita mentioned this with our competitor in this two to four prior lines, the timing that we are estimating in terms of when they would get this indication would be the end of next year, early twenty twenty three. So that's the timeframe we're looking at. But again, with this indication, so we leap forward in front to the one to three prior. But the interesting aspect, and it's the reason why I love the trial design so much, is the fact that the lack of requirement for daratumumab. And as you can see in the sub bullet, it's probably hard to see here for the folks in the room, but based upon the data that we've been analyzing, about eighty percent of all patients in the second line setting do not or have not been exposed to daratumumab. So you can see the implications here. Most importantly for our patients and their providers who want to use CAR T upfront, for patients who have not seen dara, which is an overwhelming majority of them, this study now enables them to get involved in CAR T therapy early. I can't say that loud enough, right? That's probably the most important takeaway from the slide. And again, if you go further down in the sub bowl in terms of the patient opportunity, this is the total number here across all geographies. This is U. S. And Europe and Japan, is roughly about eighty thousand patients would fall meeting this criteria. So it's an extremely exciting study. I'm really excited about it for our patients because it's going to really open up where I believe our competitor went there but you're going to still have an issue with the early indication of the daratumumab requirement. Now you move forward with silt to sell earlier without this daratumumab requirement. So I'll pass it back to you. Okay. Thanks. So last trial is CARTITUDE V. So this is trial in newly diagnosed multiple myeloma. So to our knowledge, first newly diagnosed clinical trial for CAR T therapy in myeloma. So this trial will enroll patients who are not candidate, so not considered for stem cell transplantation. So there is two category of the patients. So one is patients who are not candidate because of age comorbidity organ function. And this is based on local institutional recommendations. So this is, as you can imagine, international trial and definition of transplant eligibility varies among countries. So one population will be transplant not eligible because of clinical conditions or age. And then there is population of patients who are deferring autologous stem cell transplant as a first line therapy. So this population emerged in last couple of years and these are patients, so there was actually the IMF studies, a clinical study which have shown that survival benefit is same if patient received transplant immediately in newly diagnosed setting or later in a treatment course of disease. So that led to investigate this population different transplant by physicians and patient choice. That was also investigated actually in three other Phase III trials of multiple myeloma, so non CAR T trials. So this is now becoming in last couple of like five or so years becoming a population which is treated together with transplant not eligible patients. And basically this trial will cover this patient as well. And I wanted to highlight also two references. So I looked to some references and half of the patients right now are deferring transplant and not undergoing it in first line setting based on literature. So trial schema is shown here. So this will be six fifty patient randomized clinical trial. Patient in investigation in control arm will undergo VRD regimen, Velcade Revlimid Dex. So as you can notice, all patients will have six cycles of induction. And after randomization, in both treatments arms, there are two cycles of this regimen. So this basically makes that in both treatment arms total, so equal number of cycles are given to the patient as induction. And in control arm, there will be RD maintenance or Revlimid Dex maintenance. And in investigational arms, will be silica cell infusion after lymphodepletion and there is no treatment after silica cell infusion. This trial opened, we announced in August and it will open approximately in more than 100 locations worldwide. And also to put again this trial in the context and patient population we tried to address here, so this is data from some literature which shows that median PFS in this patient population with current standards of care is around thirty six to forty months. Very good. Thank you, Vita. Again, just to reiterate, so now other than the questions we get commercially from many of our customers outside of the CARTITUDE I trial is when will you guys be in the front line, right? Because I think our providers are seeing the future and they obviously see that this potential asset of ours has a big place in the future in the up front patient population. So when you take a look again back here at some of our assumptions, if you look at some of the newly diagnosed patients, sixty four thousand, this is one thousand patients diagnosed across The U. S, Europe and in Japan. This transplant not intended eligible patient population, as you can see here, in The United States about fifteen thousand, in Europe about nine thousand, and in Japan sixteen or sixteen hundred patients. One of the things, I guess the only point I really want to make in this study, the economics really start to change here. The economics that I'm referring to is demonstrating success and all of that downstream cost avoidance, hopefully that we'll begin seeing, providing we're successful in this population. For any of you who've been following the myeloma space, I think would agree that there are a lot of different Thank God for these patients. The flip side of that argument is there's a lot of costs there associated in the treatment of multiple myeloma. So one of the key things that we are starting to model now is to model out what success would look like, not only obviously clinically for our patients, but also economically for all of us. As we are successful in earlier lines, you'll see a much larger economic input or impact on society, and we're very, very excited by that. Okay, great. So thank you, Lita and Steve, about the introduction on CAR T2 program. So as you can see from this slide, we have a very comprehensive clinical program, including the ongoing CARTITUDE I, which is registrational Phase onetwo trial in The U. S. That's serving as the basis for our application for BLA in U. S. And Europe as well as the ongoing Phase II program called CARDIFEN I in China, which will serve as a basis for BLA in China. Besides that, we also have an ongoing Phase II trial called CARTITUDE II that is evaluating pseudo cell in various settings, including frontline. And the Phase III CARTITUDE IV examines pseudo cell in patients with one to three prior lines of therapy, while the most recently initiated CAR TUNE V is our first Phase III trial in frontline patients. I'm also happy to report that based on these data, we have also submitted BLA to Switzerland, Brazil, South Korea, Australia and also Saudi Arabia by now besides the BLA in U. S. And EU. So let me provide a very quick summary of what you just heard from our CAR TAGE program. First of all, cell to cell has demonstrated potential best in class efficacy in relapsed and refractory multiple myeloma with eighty percent stringent CR rate. And most importantly, I want to emphasize that in the clinic we have seen that those CR rate achieved a durable CR. And the CR rates increased over longer time of follow-up. As you can appreciate, this has profound clinical implications and it's not necessarily what we have seen from our competition in the trend of CR. Secondly, we're also quite encouraged by the preliminary data from CAR T2, which shows early promise for Suture Cell in early line multiple myeloma. The Phase III CAR T2IV trial is enrolling very quickly and positions Suture Cell very well in second line and beyond multiple myeloma. Legend and our partner Janssen are determined to bring TUVASEL as the first BCMA CAR T in second line and beyond multiple myeloma by leapfrogging our competition. Lastly, the ongoing Phase III CAR T5 is the first pivotal Phase III trial for any BCMA targeting CAR T in frontline multiple myeloma. This very significant investment shows a strong commitment of Legend and G and J in advancing psutrocell as a potential frontline treatment for multiple myeloma. And now we will take a ten minutes coffee break, and we will resume at 10:50 a. M. Okay. Welcome back. And I now have the pleasure of introducing you to the man behind Suture Cell, who leads also our discovery research at Legend Biotech. So welcome Doctor. Frank Fan. Frank, you can take over. Thank you. Dear investors and your friends, thank you for your continuous support to our company. I'm the CSO and co founder of Legend Biotech. I'm an applied immunologist and a long term believer of cell and gene therapy. During twenty years of my academic career, I made some scientific breakthrough in transplantation immunology that impacted clinical practice. I returned to China in 2014 and supported by Jamescript, I founded Legend. I'm happy to witness that with the knowledge and the experience I gained in clinical, basic science and translational science being able to contribute to a key drug product for treatment of myeloma. Since I started to build the legend R and D team in early twenty fifteen, I strive to keep a robust R and D culture that a great passion, real innovation and a cooperation are the core sprints. When looking back to what we have achieved in the past seven years, I feel it was R and D culture, blessing the team to bring true miracle to the field. We may already set up an example for a startup biotech company that a true innovation and integrity will be fully rewarded. Today, I'm honored to be given this opportunity to update you our R and D activities. In the next one hour okay. In the next one hour, I will present you three parts of contents. In the first part, I will brief you about our core technologies and capabilities. Then I will introduce you three sodium cancer programs which are our current R and D focus. Then I would like to update you two of our allogeneic CAR platforms. Here I listed some core technologies I'm proud of. I believe we have expertise and insights to catch promising immunotherapy targets at a very early stage of the competition. We often started R and D activities for a promising target years before it become popular. For example, BCMA and claudium 18.2 is example. We have developed many technologies to help us efficiently obtain large amounts of protein at the least and identify, optimize the most promising least at a preclinical stage. We also own and apply our high value IP, for example, the multi specific CAR platform to enhance our product design. We also heavily invested in developing advanced allogeneic CAR T platforms which can simplify CMC and lower the cost of goods with enhanced safety and improved homogeneity. Legend's non genome editing allogeneic CAR T platform do not rely on any genome editing approach. We also have Legends unique CAR NK and the gamma data T CAR platforms in development. We have put enormous efforts into developing CAR Ts to treat high market value cancers such as gastric cancer, pancreatic cancers, HCC, non small cell lung cancer and small cell lung cancer and other indications. Because I have limited time today, I won't be able to report to you our gamma data team or TCR T platforms. I also don't have enough time to cover all our pipeline products. For example, the CD19, twenty twenty two, trispecific CAR T or other preclinical stage programs. Legend has our own in house 10x genomic single cell sequencing platform. Using in house high performance computer and AWS cloud computation, our bioinformatician team be able to analysis either internal data or public data set to support our pipeline development. Sometimes we use our NGS platform for target discovery and the validation at a single cell level such as target expression on tumor cells, on target off tumor risk analysis on normal tissues. When study tumor microenvironment, we'll be able to find a repressive cell type or signaling guiding the design of our ARMOR strategy. We have ever done in-depth analysis of clinical samples as well to characterize post infusion phenotype, gene expression, and the dynamical change of CAR T cells. We have multiple in house antibody development platforms including candidate VHH single domain antibodies, mutant antibodies and fully human antibodies. We usually will rely on multiple criteria for screening out the top antibody leads we want to proceed. LAMA produce highly diverse antibodies including a unique class of the VHH single domain antibodies that can have a high antigen binding potency compared to that of conventional antibodies which are composed of heavy and light chain domain. These smaller single domain VHH antibodies are also able to access antigenic sites that are close to the cell membrane which may not be physically accessible to larger conventional antibodies. Our technology has the potential to construct multiethyl antibodies targeting the same antigen or to enable designing multi antigen specific CAR constructs that is trispecific CAR products targeting CD19, CD20 and CD22 at the same time. As you know, one of the Legends current R and D focus is to conquering solid cancers. There are many challenges for CAR T cells to overcome in fighting with solid cancers. Critical barriers and the best regulated vasculature inside large cancer lesions block CAR T cells trafficking and infiltration. Our family tumor microenvironment including soluble and the cell membrane suppressive factors plus unfavorable metabolism in tumor all urge our CAR T cells to be able to act more strongly, smartly and more persistently. We never want to underestimate the challenges to overcome a solid cancer. That is why we always do our best at each single step in developing a pipeline product. We never cut an honor and usually when we kick off developing a new product, we start research projects from the preparation of target antigen to optimization of animal immunization regimen. By this step by step in house efforts, we've been able to obtain large amounts of high quality adipose leads. We polish our product by not only pursuing high specificity and affinity, but also optimizing individual car design by looking for ideal linker, right hinge and a robust transmembrane domain. Legend RNA team also proactively combine our complimentary suits of technologies at the early developmental stage. We have invented numerous armoring strategies and have fired many patent families to enrich our self IP toolbox. For each individual pipeline program, we will be able to swing out the most appropriate armoring strategy that can energize the pipeline CAR T cells when they fight with their corresponding target cancer. We were shy to claim any of our armored CAR T product as so called the first generation or fifth generation of CAR T. We care more about what our design can really help our CAR T cells in a very challenging mission. In some case, we enable our CAR T cells to transform negative signal to a robust positive signal that could motivate themselves. Some of our invention guided our CAR T cells to identify their specific cancer signals that facilitate the assembly of a needed ARMOR molecule like a self boosting mechanism. Armoring our CAR T cells with powerful tools on their battlefront frontline are important. But we want to further explore the possibility to improve their body fitness by regulating their intracellular signal molecules. By doing so, we may improve their metabolism or polarize their differentiation path towards desired phenotype. For both of CAR T cells and our CAR NK cells platform, we are making progress and we are accumulating our IP portfolio. With seven years of development, I believe legend R and D team already established as a combined force of different arms. We have more than 300 scientists distributed worldwide. Whether we can work as a one team in executing IND enabling studies or in a mission of a technical transfer to manufacture teams. We not only have efficient and talented discovery team, but also have professional and elastic development team skilled by our market experts and also have experienced early PD personnel. Our ambition is to keep advancing our knowledge in the area of cell therapy and to develop very competitive products in order to keep Legend leading the field. Although, our top cell therapies have gained tremendous success in the past decade, solid cancer remains the largest unmet clinical needs. Legend Biotech also heavily invests to explore new treatment options for solid cancers. In part two of my presentation, I would like to introduce three of our major solid cancer programs. The first program is autologous CAR T targeting claudium 18.2. The top two potential indication for claudium 18.2 are gastric cancer and pancreatic cancers. Gastric cancer is the most frequently diagnosed cancer worldwide and the second leading cause of cancer related deaths. Progatory cancers has extremely low five year survival and the second leading cause of cancer related deaths in The US. Because claudium 18.2 is a tetra transmembrane protein with very conservative extracellular domain across species, developing highly selective high affinity antibody to claudium 18.2 is very difficult. With years of efforts, we have successfully developed the high affinity claudium 18.2 VHH single domain antibodies that does not cross react into Cloudin 18.2 even at the very high concentration. We have already started the first in human clinical study with preliminary progress, which I would like to briefly report in this session. The family of clouding proteins comprise 27 tight junction proteins with four transmembrane domains and two extracellular groups. In human, clonidine 18 has two variants, eighteen point one and eighteen point two. They share highly similar protein sequence in extracellular loops with only eight amino acid difference in loop one. Chlorine 18.2 but 18.1 is selectively expressed abnormal lung. Chlorine 18.2 is restricted in differentiated short lived cells of the stomach epithelium. Therefore, highly selective claudium 18.2 antibody over 18.1 specifically extremely critical to assure the safety of claudium 18.2 target biologists, particularly important for CAR T cell therapy due to these live cells product could expand 100 times or even thousands of times in those patients and you don't want any of these cells to go attacking your lung tissues. Clogging as was reported summarized in the left panel in EU population, claudium 18.2 was detecting seventy percent gastric adenocarcinomas. The fraction of tumor cells expressing claudium 18.2 at any staining intensity is strongly correlated between primary tumors and the lymph node metastasis in matching price. Partly using the single domain antibody based CAR T platforms, Legend has successfully developed LB1908 or LCAR C18S product which is an autologous CAR T targeting 18.2 attached with four-1BB cytoplasmic domain as co stimulatory domains. The safety profile was featured by its high specificity by extensive characterization including in vivo binding, in vitro binding studies, human normal tissue profiling by IHC studies. And by comparing with benchmarks, LB1908 showed superior antigastric or anti pancreatic tumor activity in vitro in vivo. And I would like to show some of representative data for this program. The in vitro binding affinity and the specificity of the CAES CAR VHH to human Cloud 80.2 were assessed by two independent methods. That's as the PR and photocytometry using Pancubine cells. A human pancreatic cancer cell line just used to express Cloud 80.2. The CATS CAR VHH bond titrate to human calority 80.2 with a KD value of 17.15 picomolar by SPR. In the cell based flow cytometry acid, the clouding CAR VH is specifically interacted with cloud 18.2 expressed on the cell surface. In contrast, C18S VHH did not interact with 18.1 demonstrating the specific interaction between the C18S CAR VHH and the Cloud 18.2. We also use a real time lifestyle imaging culture assay to study the safety profile of LB1908 CAR T cells using a series of the primary cells. Here are some representative images. After overnight culture, this significant target cell lysis was noted by LB1908 on claudium 18.2 positive cells as indicated by yellow and green dyes and the cell aggregates suggesting non target recognition. Our product did not show significantly cytotoxicity in other Cloud 18.2 negative cells including types of cells from human primary normal lung cells. The assay control CD19 CAR T did not show cytotoxicity across these cells. Cloud 18.2 protein sequence are highly conservative among species. Human and mouse share identical extracellular loop one sequence of Cloud 18.2. Therefore, mouse is a highly relevant model to study the claudium 18.2 targeted biology, especially toxicology study. We performed in vivo studies using gastric tumor, then the graph models based on a highly immune incompetent NCG mouse spin. Gastric cancer cells were inoculated two weeks prior to the CAR T treatment followed by monitoring of tumor size, body weight, status and cardiac expansion and all. As you can see in figure A, the C18S showed significant tumor control in dose dependent manner. Tumor free can achieve seventy five percent of the one million group and all the 3,000,000 to 5,000,000 per mouse groups and no tumor relapse were noted. The expansion of CAR T cells was also dose dependent and no significant body loss was noted in these mice. In order to study the anti pancreatic cancer potency of LB1908 in vivo, we use similar xenograft approaches. Claudine implant to prostate cancer cells were inoculated three weeks prior to CAR T treatment. Our product showed significant anti pancreatic cancer cogences in vivo. All tumor were gone in each mice and the LB1908 expanded efficiently. Before we launch exploratory human trial, we also completed our comprehensive human tissue cross reactivity analysis of LV1908. Admitted by immunohistochemistry using frozen human TMA consisting of 30 different normal tissue in triplicate from three different individuals. Membrane staining of the VHH binder is restricted to gastric and mucosa epithelial cells. This result strongly supported the safety profile of LB1908 across human normal tissues. So early this year, we initialized an investigator initiated clinical trial in Shanghai East Hospital. Considering about safety, we initially restricted enrolling patients with previously total gastric ectomy and the sub total gastric ectomy. With more safety information collected for on target off tumor effects, we are now considering modifying our protocol to be able to enroll patients with full stomach. This is a prospective single arm, single center open label, single dose phase one study to evaluate the safety, tolerability, PK and antitumor efficacy profile of the LB1908 in subjects with claudiating point positive advanced gastric adenocarcinoma. This study was a dose finding study starting from zero point five million to nine million per kg. To date, four patients were dosed at levels ranging from 500,000 to 3,000,000 CAR positive cells per kg. Three patients completed the DLT observation and a no dose limiting toxicity DLT have been observed to date. The preliminary efficacy data shows anti tumor activities of nineteen oh eight. Since this study is still in its early stage and only the first dose patients have reached the time point of for evaluation at the day one hundred and eighty days for follow-up. So we decided to only briefing the first case for now and leave a full report to be re disclosed by PI in future academic meeting. The first subject we dose is a female patient bearing advanced stage of gastric adenocarcinoma expressing high level of a cloud 18.2. The patient previously received five prior lines of chemotherapy and bearing huge pelvic tumors and large amount ascites and pelvic infusion. Without effective bridging therapy available, the patient progress very fast before CAR T infusion. What is dramatic is due to the oppression of fast growing pelvic lesions. Before CAR T infusion, the patient developed acute bilateral ureteral obstruction leading to acute renal failure. Therefore, the investigator performed emergent bilateral palocectomy to relieve the critical condition. After careful consideration, the PRS still decided to proceed to the CAR T infusion at the lowest dose level zero point five million per kg. The patient was discharged from hospital on day fourteen post infusion and in the half year of a follow-up, about sixteen percent of tumors regressions were mirrored and the patient remained progression free at day one hundred and eighty. After CAR T infusion, this patient not just experienced the reduction of her lesion at roughly fifteen percent. Strikingly, her urination resumed and the periostomy catheters on both sides were removed. Before CAR T infusion, the patient has a large amount of ascites that need abdominal drainage. After CAR T infusion, ascites and pelvic infusion was significantly decreased. And by flow cytometry analysis, we see significant reduction of tumor cells and a large amount of the CAR T cells appeared in ascites. In each follow-up time points, the patient can walk on foot and her quality of life has been greatly and continuously improved. Progression free survival is already recorded for at least six months. This patient also experienced significant CAR T expansion. The CAR T cells were detected from day two with peak expansion noted on day twelve, reaching a level above 250,000 CAR T cells per male of blood. Based on my experience, I believe CAR T expansion reaching this high level is remarkable. The CAR T cells returned to low levels on day forty five and not detectable from day ninety two. Despite a very small dose of LB1908 CAR T cells being injected to the gastric cancer patient, the degree of CAR T expansion seems to be not inferior to what we have been observing in liquid cancer CAR T trials. So to summarize the program, we conclude, claudium eighteen point two is a very promising target for gastric cancer and the pancreatic cancer. But Cloud 18.2 is also a very challenging target for developing a safe and efficacious CAR T product because off target effects such as cross reactivity to Cloud eighteen point one could be fatal and on target of tumor defects could lead to severe injury to gastric mucosa. Despite the challenges and difficulties, Legend has successfully developed a robust clotting eighteen point two targeting CAR T program with high development potential. An investigator initiated clinical trial is currently ongoing and active activity was shown in the first dose DC patient. We have already escalated the dose level to three million per kg and no DLT were found so far. Based on the encouraging safety profile we got already, we are currently accelerating new patients enrollment and expanding the trial towards multi standard trials. We may expand the patient enrollments, cover gastric cancer with full stomach and also pancreatic cancer patients as well. We have added three additional sites recently and the preparation for filing the US IND in the first half twenty twenty two are currently ongoing. The second program I'm talking about is LCAR H903T CAR T targeting GPC3. GPC3 highly expressed in over seventy six percent of HCCC, fifty two percent LSCC and eighty percent of germ cell tumors. This target is specifically expressing these tumors but not in para tumor tissue. We developed the legend anti ATPG3 CAR T cells based on a highly selective, high affinity humanized single chain FV. We optimized the CAR backbone and the legends own customized CAR T armors technology has been applied. This next generation GPDC CAR T exhibit improved expansion and penetration persistence and excellent queuing in non clinical studies. GPD three overexpressed across a broad spectrum of tumor types with high positive percentage. CAR T therapy targeting GPC3 will cover large patient population indications including HCC liver cancer, LFCC, esophageal cancer, thyroid tumor and the germ cell tumors. The figure B show GPC3 staining hepatoblastoma. You can see GPC3 could well distinguish tumor cells and apparent tumor liver cells. The high specificity of GPD3 in tumor cells make it a safe target of a CAR T therapy. The anti GPD3 binders is a humanized antibody with affinity of 73 picomolar. Binder specificity has also been confirmed by TMA study with expected data. To assess the potency of legend anti GPC3 binder, we generated late CAR T cells when we call it H93 and two benchmarks. Using an aggressive Q7 xenograft model, our H93 CAR showed a superior efficacy at a very low dose response. In the past few years, we have put enormous efforts to develop various CAR T armoring strategies. Specifically for this GPC3 product, we developed our CAR T armoring technology with improved GPD3 CAR T expansion, infiltration, persistency and efficacy. Some of the highlights are the ARMOR is a membrane bound strategy with limited systematic effects. The ARMOR protein could transform a negative T TME signal to CAR positive signal. Furthermore, the ARMOR activation depends on both CAR activation signal and a TME signal. And the TME signal itself is not enough to activate ARMOR bio functions. Thus, it will not alter CAR T specificity to GPC3 positive tumor cells. So the GPC3 CAR T may not only resist to TME suppression, but even have more infiltration into tumor mass, expand well and exhibit a more potent tumor curing activities. This data suggests arming strategies improved CAR T in vivo functionalities. On the left figure, armored H93T CAR T cells showed complete tumor elimination since day 19. While naked CAR T obtained no antitumor efficacy at such a low dose. On the middle figure, selected armoring strategy markedly improved CAR T expansion potency. The CAR T cells decreased along with the tumor regression. On the right figure, body weight monitoring. No noted body weight loss or other in vivo toxicity were observed throughout the study. In summary, LB201 is a novel investigational CAR T therapy for the treatment of HCC, SCLC and potentially more broad indication. Due to LB2101 shows superior suppression of tumor growth compared to the benchmark based CAR T in the HCC model, the anti GPT-three CAR Ts may have great competitiveness. We plan to pursue China IND followed with more studies in other markets. In the future, the product may be used in combination with most legend allogeneic platforms. Next, I'm going to introduce a newly disclosed solid tumor program treating small cell lung cancer. The target molecule is ELL3. ELL3 is a very promising target for ACLC and other neuroendocrine tumors, highly expressed in about eighty percent of SCLC tumors on the plasma membrane. Lung cancer is the most common cancer worldwide. So most of our lung cancer accounts about fifteen percent of all lung cancer case with about thirty five thousand and one hundred and ten thousand newly diagnosed cases in US and China respectively. SCLC is also a very deadly cancer. The median OS for patients with extensive stage SCLC is less than ten months. Similar to the design of silica cell, we developed anti IL-three CAR T cells with a tandem humanized VHH single domain derived binder design, which has a high affinity and specificity against the DIL3 enabling the CAR T cells to respond potently and persistently to SCLC cells and to be competitive when compared with benchmark. The CAR T is further armored with a TME resisting element to overcome hostile tumor microenvironment. The ARMOR boost in vivo antitumor efficacy by improving CAR T cell proliferation resistance to TME inhibition and infiltration in the tumor next very well. The product is well tolerated both sub q tumor model and a pulmonary phosphatopic tumor model. DRL3 belongs to the delta like family protein. In SCLC tumors, DRL3 is a homogeneously express the high level of a cell membrane of tumor. In contrast, it is barely expressing normal tissues or very restricted in the cytosolic compartment. As shown in the IHC staining, DRL3 specifically overexpressed in SCLC and LCNEC. We have developed a DRL3 targeting autologous CAR T product with SCLC. The product is armored with a tumor microenvironment resistant element. In preclinical in vitro pharmacology studies, we have again demonstrated that similar to cell to cell tandem biparatopic single domain antibody derived CAR T outperformed monospecific ERL3 CAR T cells. Furthermore, as compared to the conventional tandem CAR T, LB2102, the armored TME resisting CAR T has superior persistency, proliferation and cytokine production in response to repetitive stimulation, particularly in a tumor microenvironment mimicking condition. More importantly, the increased proliferation is coupled with reduced exhaustion as analyzed by a set of exhaustion markers for T cells. Further in vivo pharmacology demonstrated superior anti tumor activity of the armored CAR T product in a sub q SCLC xenograft tumor model. In line with enhanced tumor suppressant activity, PK analysis of CAR T in peripheral blood as well as tumor infiltrated CAR T cells all demonstrated that improved infiltration into the proliferation with the vicinity of the tumor. Moreover, we have investigated the in vivo tolerance of Legend CAR T cells in both sub q and the isotopic tumor bearing model By infusion highest amount of CAR T cells into the mice, we demonstrated the high dose of CAR T cells can be well tolerated in vivo without causing any obvious histological damages. So the conclusion is that DLS3 is a promising target for SCLC leveraging bioparate topic tandem single domain derived binder and the TME resistant armor strategy. LV2102 has demonstrated a potent desatasticity improved proliferation, persistence, and infiltration and efficient in vivo tumor growth in vision. We are planning first in human study at the US IND. In part three of my presentation, I would like to present two allogeneic universal CAR platforms we have been developing. For the first CAR platform, I would say by spending years of efforts, our team have innovatively invented a distinct approach to disrupt TCR complex on T cell surface without the need of a genome editing. In past few years, the whole industry have been working hard to develop allogeneic CAR Ts with good progress despite the efficacy data still can't compete with leading autologous products. The mainstream allogeneic CAR T heavily rely on gene editing and a knockout strategies to prevent the risk of GVHD. However, multiple gene editing or knockout manipulations always come up with risk of off target and a potential genotoxicity. Also another important disadvantages is a multi step manufacturer will generate obliviously generate heterogeneity in the manipulated cell population and therefore require stringent depletion of unwanted or contaminated cells. This not just become challenging in CMC, but also lead to low manufacturer efficiencies and low yield of final drug products. Without any gene editing a knockout disruption, we aim to achieve silencing of TCR function while spare CAR T signal transduction. After five years of hard efforts by a big team, by a dedicated team, we managed to get this idea realized by co expressing immunomodulatory polypeptides to disrupt the TCR complex. The platform now is supported by a series of patent families and I'm very excited that we could have this initially impossible mission accomplished. Developing such a difficult to achieve approach via proteomic regulation of TCR is also driven by my hobby to pursue all in one solution. I love a simple step process that is clean, fast, efficient. Translating to the feature of the product, we can pretty much generate large amount of allogeneic CAR T cells by a very straightforward and a similar process to autologous product. Conventional allogeneic products exceptionally involve multi step gene manipulation including the CAR transduction and a multiple gene editing or gene knockout. This will generate about eight to 16 different population in the process that need complicated depletion process and a purification process for final DP. The most dangerous phenotype generated will be the CAR and TCR double positive cells which may cross GVHD after extensive on target expansion in vivo. So the quality control and the stringent releasing criteria will be critical to prevent the contamination of unwanted cells. In Legend's phone platform, the high heterogeneity of products was avoided by our simple all in one approach. Due to the TCR disrupting element is co expressed and tightly linked with CAR element in the all in one lentiviral vector used to generate universal CAR T cells. There are only two subtype of cells generated after the lentiviral transduction. All donor T cells either successfully transfused or not transfused. This strategy will assure all CAR positive cells are GvHD disarmed T cells that we need and unmodified T cells can be depleted. Even if small amount of unmodified T cells were contaminated in the final product, they will not have any risk to cause GVHD because they do not express CAR and will not survive very longer. To obtain proof of concept data for the novel non gene editing and a genetic platform, we chose a very well validated target CD20 and the construct CD20 CAR using a well characterized monoclonal antibody clone. As you can see on the left panel, flow cytometry analysis of the LU CAR 20S clearly demonstrated that the non gene editing CD20 CAR T cells are highly enriched in the final product after relatively simple process. CAR positive cells occupy 98.63% in the batch. While almost all these cells lost expression of TCR complex. In our MLR system to evaluate the allogeneic T cell response, our LU CAR 20S performed as good as TCR knockout T cells in terms of allo reactivities when encounter allogeneic stimulators lymphocytes. We proposed to test the platform step by step and our investigator collaborating with us also suggest that before we test the full version of the Allo CD20 CAR, we first test a basic version which only implemented GVHD solution in the first phase of the clinical study. So we did open an investigator initiated trial to mainly test the safety of the basic version LU CAR 20S. We have since obtained some initial data. Despite limited efficacy and CAR T expansion were found in the first few dosed patients, no GVHD or other ELT were found at the current three hundred million dose level. We are planning to study a full version of the product LUCAR 20 SD. For the whole allogeneic CAR T field, two immunological barrier need to be addressed in the long run are GvHD and HBV. The control of GvHD has been achieved by various approaches developed by different companies. However, rejection of allogeneic CAR T cells or so called HVT issue has not been perfectly solved in the field. The main bottleneck towards achieving comparable efficacy to autologous product is that to what extent an allogeneic product can address the HVG effects. Based on published data by leading allogeneic companies, it seems that the cardiac expansion, the majority of patients are quite limited and usually the allogeneic cells only persist for two to three weeks. This HBV issue mainly hamper the deepness of response for the current allogeneic products despite aggressive immunosuppression has already been used. So as I mentioned already, because I legend and the PI want to first test the anti GVHDF effects to address the safety of our non gene editing platform. So the basic version of the genetic C20 product, LU CAR 20S was taken to the first instrument study. It is an open label. Wait. So here, it is open label dose finding study to assess the safety and the tolerability of donor derived CD20 targeting CAR T cells administered with lymphodepletion and to obtain the preliminary efficacy in subjects who have been diagnosed with relapsed or refractory CD20 positive non Hodgkin lymphoma. Enrollment in the phase one study in China is ongoing. Five subjects were dosed at levels from 10,000,000 to 300,000,000 CAR T cells. The last that those patients received is 300,000,000 ALU CAR 20S in total. So far no dose limiting toxicity or GVHD were observed in these five patients and the three of the five dose patients achieved a partial response. This case showed one of PR patients who received 300,000,000 of allogeneic CAR T cells for prior life therapy including repeated use of anti CD20 monoclonal antibody rituximab. The patient experienced no GvHD, no SAE, no DLT and discharged from hospital at day fourteen post infusion. At day thirty, all target lesions and non target lesions regressed to normal or absent on CT scan. And a PET CT scan also showing complete metabolic response. But because of remaining cancer cells were found in bone marrow biopsy, So the overall efficacy assessment was determined to be PR. Besides the LUCAR 20S, which we already started in the clinical trial without finding GVHD and DLT, We also developed an upgraded modified full version which incorporated anti HVG function. We call it LUCAR 20SD. In the future clinical study, we wish to have this product used in combination with a small molecule drug to tackle the rejection of HVG issues. To confirm the upgraded version LUCAR20 SD still prevent GVHD. We also performed the full GVHD assessment in a specialized GVHD model. In experiment, our modified donor T cells are conventional CAR T cells all successfully rendered GVHD at animal loss. Our oligoCAR20 SD group labeled purple color remain staying safe without a GvHD band. Just like the group of conventional allogeneic CAR T cells. The blue lines in which the TCR knockout has been performed with CRISPR Cas9 technology. In a HVG mimicked MRR assay combined with the drug Y, we observed our anti HBV strategy did shift the balance between host T cells and the donor T cells in the system. We wish the fully armored version of LU CAR and the genetic platform can potently improve the deepness of clinical response by improving CAR T cell expansion and persistence without a need for heavy immunosuppression. By this way, the drug Y is a well studied, improved drug and we will only plan to use it for a short term post CAR T infusion. So Legend Biotech has developed a proprietary allogeneic CAR T technology using a non gene editing approach which reduce risk of off target activities and the general toxicities. Latin biotech also believe that this approach to the design of allogeneic programs potentially simplifies a process for chemistry manufacturing and controls and potentially improve product homogeneity. Based on this approach, we have developed allogeneic CAR T, LU CAR 20S targeting CD20. Our first human study was initiated for LU CAR 20S and the preliminary safety and efficacy were already observed. Legend has developed a modified version ALU CAR-20SD with an innovative armoring strategies to control host versus graft disease to further improve the CAR T persistence. An exploratory trial is being planned for LCAR TNSD. We're also interested in developing CAR NK platform to defeat cancers as we believe it possess unique advantages and as a genetic products. First of all, NK cells are major components of the innate immune system and are a fast killer of cancer cells. Second, CAR NK provide a promising solution to overcome PAA escape by multiple mechanisms including CAR dependent, CAR independent, ADCC mediated killing. Third, the key role of NK and ADCC support is combinational use with a therapeutic antibody drug to further enhance its response. Last but not the least, multiple NK trial have demonstrated the clinical benefit of CAR NK cells. One particularly attractive point is a superior effort, the safety profile observed across different type of CAR NK cells. There are multiple challenges in CAR NK fields. First NK cells are short lived in cells while persistency is a key for the success of a long duration response as we learn from autologous CAR T products. Second, the most powerful NK cell expansion methods is based on cancer cell lines such as K556-two feeder cells. These add a safety risk to the final products and also add a complexity to QC process. Third, NK cells are highly resistant to the lentiviral transduction. How to introduce gene of interest into NK is a technical challenge. Fourth, NK cells are more sensitive to cryopreservation than T cells while there are no commercial cryopreservation method is optimized to maintain NK viability. Legend has developed its multiple solutions to tackle these challenges. Legend developed the fetus cell free expansion system and a highly efficient way of NK transduction. Furthermore, we have developed a unique armor approach, LG kind to help NK persistency in vivo without a significant toxicity finding. Last but not the least, the cryopreservation methods that we develop is well suited for current product which maintains NK viabilities and a function after sorting. Let's have a closer look into the details of these unique features. The top row of this panel shows the highly pure NK product with high transduction rate. The middle row show the full expansion of current K across multiple batches of manufacture and representative of the vitro coding efficacy. The bottom row shows improvement of maintenance of viability by Legend's formulation in comparison to commercially available frozen formulation and the in vivo efficacy comparison between fresh and a frozen CAR NK product. This together show that Legend has a powerful manufacturing process CAR NK from end to end. We also developed a similar scalable cord blood NK platform with a feature of strong expansion, high purity, high transduction rate and a strong efficacy. When it comes to ARMOR approach for NK cells, one commonly used approach by this field is to armor NK with IL-fifteen into Leukine 15 to enhance persistency of NK cells. However, previous literature suggests secretion of IL-fifteen is associated with significant AE in preclinical animal models. To find a signaling proteins to armor our CAR NK cells, we leveraged our internal protein engineering platform to perform individually in vivo screening hundreds of rationally designed cytokine mutants. We successfully discovered a mutant we named LG kind which we found it can significantly improve the function of CAR NK while not adding any in vivo toxicity. Long term antitumor activity and extended animal survival were observed in animals treated with staldychine armored CAR NK cells. Therefore, I believe Legend has developed a robust NK manufacturing process with the following features, robust expansion and the CAR construction process, production of a highly pure current product with strong anti tumor activity, optimize the cryopreservation process to minimize the loss of viability and the functionality of the sorting. We further innovate our rational design NK cell armoring molecule called LGKIND which we found dramatically boost our current K cells. With seven years of development, Beta BioTek already evolved to be a leading cell therapy company. We have developed a multi technology platform with strong IP positions. Despite it, we haven't given lots of thoughts on giving them fancy names. We are ambitious to make breakthroughs in solid cancer treatment and to promote allogeneic platform in aim to improve patient accessibilities. For the R and D team, I'm proud of that. We have more than 300 scientists worldwide work as a highly integrated team in our mission to transform clinical oncology. We have passions and we believe in innovation and cooperation. While we keep a tradition of down to earth and the stay low key, we work together fearlessly to challenge the technical barriers and to we are world above transforming impossible to possible. Thank you for your attention and we are happy to take your any questions. Thank you very much. Thank you, Doctor. Fan. We will now take questions from the audience about our pipeline and BCMA program. Joining us to answer questions today, we have Doctor. Dong Gan, Head of Early Stage Drug Development I'm Steve Gavil, Doctor. Lita Pekkaud, Doctor. Fan Fan and Doctor. Ying Huang. If you are in the room today, my colleague, Tina, will come over to you after you raise your hand and give you the microphone. Please state your name and your company. If first year participants would like to ask a question, please submit your questions on the chat. Our executive will try to answer all of your questions in the time we have. Thank you. Hello. Thank you for taking my questions and congrats on the impressive progress. My name is Kelly Shu from Jefferies. So my first question is for Steve. You mentioned the late onset of CRS offers operational flexibility for patient treatment. And could you elaborate on this point? Does this refer to treat patients in outpatient settings or anything more? And also regarding exploration for siltacao treatment in outpatient settings, can you talk about the progress on that front? When are we going to expect data? And also what would be the meaningful data, for example, on the readmission rate? Thank you. And I have a follow-up. So I'll make sure you guys can hear me. Thank you for the question. So maybe for folks who maybe did not hear the question. So the question was specifically around outpatient, delayed CRS, kind of get into a little bit more detail around that and whether or not there's some data that would be forthcoming here around this program in the outpatient setting. So first of all, thanks for the question. So what we were getting at there is that one of the rate limiters in all these CAR T programs to date, and this is beyond BCMA, has been this multiple issues. One being the acute onset of CRS, whether it be in CD19 programs or, for example, our competitor's program. And that's problematic for many hospitals. And Lord knows, over the last five and a half years I've talked to a lot of administrators and physicians about this. What's problematic about this is that in the clinical trial setting, it's not as big a deal. But in the commercial setting, it's very problematic because of the types of volumes that we're talking about now, specifically around multiple myeloma. These are significant patient populations. You saw some of the numbers I was showing you in terms of the clinically eligible populations. It's staggering the size. What administrators in particular are asking themselves is, wow, there's this silti cell program that looks like it's unprecedented in terms of its clinical efficacy. So they're anticipating a lot of demand being driven in their facility. I make the analogy of a funnel where you have all these patients coming into a facility but that funnel becomes restricted pretty quickly just because of limitations that institutions have in terms of just pure bed capacity. And I'm not just talking about the general med type bed capacity, but more importantly, ICU bed capacity. They're looking at the future saying, how do I then pull through all of these patients that need this type of treatment? And can I do it in my current infrastructure? And the answer is no. That's very clear. So the workaround that many of them have been investigating is if I need to get this treatment to my patients as soon as I possibly can, from a mechanistically, what do I need to do? Logistically, what do I need to So they start moving down the road. Can I potentially administer these CAR T programs as a hospital outpatient? That would alleviate a lot of this pinch that these hospitals are forecasting to begin experiencing. So that's the first issue, is capacity, knowing these big volumes are coming out the site. So the question is then how do you do it? All right. So this is not a new issue, right? This is being investigated with CD19 when CD19 was being launched as well because those programs are also looking at fairly substantial populations. The problem these institutions ran with the CD19s, and I am predicting you're starting to see this now with our competitor, is that these CRS onsets are so acute they have to admit these patients, rightfully so, to ensure that they are not having a severe CRS type of reaction that may be considered to be life threatening. So you're kind of limited because of the toxicity profile, right? So that's the first kind of issue in the marketplace. I was mentioning to you all is, which is kind of really unique with this program, unique to any CAR T program, is that there's this delayed CRS, average onset or median onset around seven days. What we're hearing in the market, you're hearing about this more specifically with investigators that have been involved with us from the beginning in terms of the clinical trial, is they're seeing the opportunity here is to administer this in their hospital outpatient clinic, give cislta cel, knowing that cislta cel patients they're seeing in the clinical trials is delayed onset, so patients aren't spiking fevers. And basically, the protocol is very different by site to site because they'll treat different types of patients, right, in terms of where the patients live. But to keep these patients local, and that definition of local changes by hospital. Some folks have some hospitals have resources literally across the street. Some have resources within about a 10 mile radius to the hospital. So they could easily monitor these patients on an outpatient basis. So administer the product, monitor the patient, and then more extensively monitor that patient as they get closer to that median. And this is the examples that they give to me in terms of what they plan on doing moving forward. So in doing that, they are not immediately admitting patients. If you look at our clinical data in CARTITUDE I, and Lita could get more into that, you see that there's a very small percentage of patients that have severe CRS. The majority of them are considered to be fairly moderate. And again, the investigators who have been touching this product have been able to manage those patients quite easily outside the hospital. And I was just with an investigator last week in San Diego and he reminded me, he said, Steve, we're working in a COVID environment as well, continuing to be, right? So now do you really want to bring in immune compromised patients into a hospital today? I think not, right? It's a fortunate situation that we have because of delayed toxicity here. What the market is playing back to me is that that's a good thing because it allows me not to admit immediately but potentially later and in essence offsetting that length of stay that would have been, in essence beds and resources that would have been taken up, that patient is being monitored in the outpatient. That's the concept that the market is quickly going towards. And it's funny how the market has changed on that topic from five years ago when I started with these programs to where it is today. Very it was kind of very seldom, honestly, that you heard outpatient CAR T. I hear it all the time now. So the marketplace clearly understands that this is the future and they need to think through how to keep patients safe and treat them effectively outside the hospital. Do you want to talk about any of the data, though? Yeah. Question around the data. Our clinical trials include patients allow and we have kind of formulated what type of patients should be administered. Thank you very much. It's very helpful. I just have a very quick follow-up for Doctor. Frank Fan. This gene editing free allogeneic platform is very interesting. I'm curious, is the gene X blockage of endogenous TCR signaling is reversible process? And also what is the transduction efficiency of GeneX? And do you have to do the purification for the TCR positive cells for the manufacturing process? Thank you. Yes, thank you for your question. It was a very good question, I think. First, the mechanism is a reversible mechanism. That's in theory. But while we we have done tremendous experiment in setting up a very challenging environment to try to, you know, test the stability of these mechanisms. But even with very strong stimulations, majority of the CAR T cells, TCR will not come back to the cell membranes. And also we do incorporate this cell depletion process in the final form before the final formulations because even our CAR T lambda wire transduction efficiency is extremely high. We still need don't want those small amount of contaminated or modified T cells. By the way, for for the for one of your question, you asked about the transect efficiency. As I mentioned already, the CAR and the gene x has been stringently linked. It's an all in one solution. It's all it's in the same single vector and connected with with the two a peptide. So for any given cells that successfully can still so this is CAR, it for sure will overexpress the gene x as well. So the the PCR down modulation will also take place. So it is completely linked to the so called two two subtype scenarios. And we do do depletion to remove the amorphous cell. That's explain why we got 98% of 63%, 98.63% of CAR positivity. You really for autologous product in your formulations is a range of 30 to 50%. And the FDA don't like a 100% of the expression CAR T cells. But for autologous because we have that room and we after our enrichment, we can enrich to a very high percentage of the wanted cells but without additional risk. Yeah. Want to add on Frank's point and with the preliminary clinical data, Frank just presented, it actually does demonstrate that the hematurate MOA is actually very efficient even though actually that could be a potential reversal process. Great. Thank you. Thank you for taking my questions. My name is David Dye. I am an analyst at SMBC. So first question several questions are on BCMA actually for Steve. The first question is just around J and J is actually developing a few BCMA bispecific antibodies. So what are some thoughts around their strategy in terms of commercializing suta cel versus their bispecifics? And then the second question is around their the sort of neurotoxicity, the delayed onset of neurotoxicity with their the movement disorders you've seen so far. Any kind of any thoughts on latest mechanism around what's what causes those neurotox so far? And I have some follow-up questions after. Very good. Can you hear me okay? Okay. Maybe you'll take the neurotox question. So I'm not going to speculate in terms of J and J, in terms of the BCMA program, and the bispecific BCMA. But I will tell you this. Any new drug for the treatment of multiple myeloma count me in. So it's the best thing for patients, right? So we know, going into any of these endeavors, that no drug is a perfect drug for a specific patient. We know that there's different subtypes and so forth. And those numbers I was showing you earlier were eligible We knew and we know and continue to analyze that not every patient is going to be a silt to cell patient, rightfully so. So there's always room in the marketplace for bispecific BCMA programs as well. So think it's fantastic, whether it be at J and J or others, to bring out other options for patients and families. I'll kind of stop it for there. But we are, to be quite honest with you, we are having active conversations and we're beginning conversations with Johnson and Johnson as it relates to their other programs. It's one of the benefits to having a partner, quite honestly. Anyways, those conversations are ongoing, so I can't really speculate too much as it relates to their bispecific. We'll talk about the data. So David, I just want to add one more thing on top of Steve's comments about the J J's portfolio. So I have very frequent communication with the J and J Janssen leadership about this, and we did discuss a little bit of that. In fact, you probably will hear more on November 18 when JNJ hosts its Pharmaceutical Business Review for Anderson investors. But I can reiterate that there's very strong commitment from both Jensen and also Legend on our commitment that Suture Cell will become a cornerstone for the strategy for the portfolio because our intention and also ambition is to bring Suture Cell all the way to the front line. And we think that hopefully in the near future, every patient who is newly diagnosed with multiple myeloma will be treated with pseudo cell. And that's the cornerstone strategy. And then on top of that, of course, on cognitive JNJ will layer it up with DARZALEX and also the two bispecifics that they're developing. But that's a commitment from J and J and also from Legend. So for neurotoxicity question, so I think really mechanism of this delayed type of neurocognitive is not really clear right now. Like we have a lot of discussions with external experts as well. What I can say in siltasol programs, so we have identified what are risk factors for those events And also we implemented a strategy how to prevent like enhanced lymphodeplia enhanced bridging therapy, for example, which was not case in the initial CARTITUDE I study and some other management patient management basically strategies. And then what we have seen and we reported at ASCO at EHA, so those type of events significantly decreased. So we had five percent in CARTITUDE I and this is now around one percent. And last, what I would like to add that it emerged as maybe not something specific to SilvaCel but rather more class effects over BCMA or CAR T therapy because we know in Abecma label, they have a case of Parkinson like case and there is also case of myelitis. So it seems to be so it's indicated in a label. So it seems to be not only and maybe even CAR T specific because I can go on, on this, that there is French reporting CD19 CARs, French case series, which also reports this type of events for CD19 CARs. Great. Thank you so much. Just a follow-up on sort of pipeline program, especially on the claudin 18.2 program. Maybe a question for Frank. So did you do any biopsy on the patient that was presented? Did you see any kind of T cell infiltration and expansion within their tumors? And also can you just comment generally on claudin eighteen point two homogeneity within the gastric tumor and pancreatic tumor setting? Thank you. Yeah, as you know the patient is in critical conditions before the CAR T infusions. Unfortunately, I don't think we in the clinical studies we have chance to do any biopsies in the treatment course. So we don't know how many CAR T cells, despite we found extremely expanded CAR T cells in the peripheral blood, we don't know how many CAR T cells are in the tumor lesions. But while we we do have fast sample for from ascites, which we detect lots of CAR T cells. The model CAR T cell, the concentration is even higher than alpha blood. And the the cancer cells, if not all gone, are cell debris and then maybe dead cells of clogging compound two positive cells. So it's very good sign in the clinical setting. However, we can't do biopsies for ethical reasons. But since the patient has such huge pelvic lesions and based on I was a surgeon in my early career. So I can imagine there are necrosis, there are fibrosis, a lot of it. It's not a you know, huge tumor lesions is definitely not a hundred percent of cancer cells. Even it could even majority of the cells are the supporting tissues, fibro fibrosis and necrotic tissues. So we never expect that even with the best correlating point to CAR T cells, can shrink the tumor and the tumor completely gone within very short time. I don't think that's possible. So maybe based on my current hypothesis or my theory, fifteen percent of shrinkage of the tumor could be pretty remarkable already. And ultimately, very importantly, in the past six months, the lesion the CT scan, the so called tumors still not changed very much, remain stable. And the patient's conditions is very well. So I'm very happy with that. So if we got a chance, we would we would, you know, if I don't I'm not sure if the investigators will will be willing to convince the patient to do a biopsy in the future for follow-up. If we can do so, that would be great. I don't expect CAR T cells still there. But I do interesting to learn what's still inside of the tumor, the tumor vision, how many cancer cells are still left and can the tumor be further shrink? Yeah. Thank you. For the second question regarding to the CARD18.2 expression and the program was designed as a target therapy and we do have the pre screening of the patient for selected population. So there's a companion diagnostic has been developed associated with the treatment. Right. I apologize, I forgot your last question. Thank you, Don, for answering from my behalf. Yes, for I did look at immunohistochemistry analysis of many of these patients in enrollment procedures. As for majority of patients, no matter their expression level being rated as one plus, two plus, or three plus, my impression is most of the patients have a very high percentage of the claudium ionic expression. Lots of them, about 90% of expression area in the in the area of the immunohistochemistries, which consistent to what what we learned from the literature. The clobulin point two is highly expressed on gastric epithelial derived cells. And so it's it seems for the gastric adenocarcinoma, they they tightly bear these features, these lineage specific markers and protein secretions. They really lost this. And in lots of literature, I remember that one Japanese literature stated extensive study on this in this chemistries. When do the pair, I also presented that literature presentation. When you pair the primary tumor with metastasis and the lymph node, you see the clotting point to is there's almost no case of that claudium eight two being down regulated or lost. Instead, some of the patients you can see enhancement of the claudium 8.2 expression. So that's why we repeatedly, confidently say clonidine point two is a very promising target for gastric cancers and maybe pancreatic cancers. Thank you. I just want to add a little bit more on what Frank just said. If you and going back to the presentation and with the statistics actually Frank just presented and for the expression level of Guardant eighteen point two, it expressed more than fifty percent on both gastric and pancreatic cancers. However, the intensity of the expression could be very different patient by patient. But given the unique cell of our CAR T cells, it could target actually patient expression intensity at lower level. We believe actually the chances of the population for the treatment for this drug and it could be actually pretty wide. We are going to take a couple of questions from the online participants. So we have two questions from JPMorgan, Corey Kasimov. First for Steve, commercial. How should we think about potential labeling for psuta cell? Do you expect differentiation relative to other CAR T therapies are likely to be more similar than different? Hopefully. So you heard in my presentation earlier, our assumptions from a labeling perspective was consistent with what you're seeing in market today with ide cel. So we are planning around, in essence, the same label in all the geographies that we will be selling into. The one caveat, like I mentioned to you, that we're starting to observe in The United States is on the private pay interpretation of the label and also the interpretation that the private insurers are having with the NCCN guidelines, which are a little more liberal than what you see in market today in terms of that fifth line labeled indication. So we shall see, but I think hopefully that answers the question. We assume the same label as our competition. But I think in The U. S, I think you'll see further evolution of how that label or how the guidelines are interpreted actually expand the market a little bit in the fifth line setting. We have a follow-up question. So for Lida, regarding the potential of silder cell in the future frontline setting, why is that daratumumab being used in CARD2five, at least according to clinicaltrials.gov? Does this potentially impact the future opportunity? So, yes, thanks for the question. So I guess, yes, for CARTi2 V, so this is a global study and we have discussed this with health authorities. And health authorities, after this discussion, current standards of care was selected as it is shown in this study. So we've I mean, we had interest to go with data containing regimens, but the outcome of discussion with health authorities, we have current trial design. Okay. There's I want to take one more question from online before we go back to the room. So we have a couple of questions from Morgan Stanley, Matthew Harrison. So I think this is a question for Steve and Yang. Actually, for Yang. Can you talk about updates we look we can look forward to seeing this year from the CARD2 program? What is your view on AlloCAR given the data you have seen in the field recently, especially CRISPR and allergen? And do you think AlloCAR T can deliver durable responses? Okay. Thank you, Matthew, for the question. So I'll answer the first part, which is what we're looking forward to updating towards the end of this year. Legend and JNJ have already announced that we will provide another update likely for the CARTITUDE I data at a major medical meeting by end of this year. So that's something we plan to update with a longer follow-up of CARTITUDE I. And then potentially, we're also looking at the Cohort A, which is the data we presented at ASCO. But again, it's possible that we'll update with longer follow-up from CARTY-two Cohort A at a major medical meeting. And then lastly, it's possible also that we could also provide an update on additional new cohort from CAR T2. As you imagine, we actually enrolled those cohorts sequentially. So we started with Cohort A and then Cohort B. So that's something potentially you could look forward to by end of this year at a major medical meeting. That's what we plan to update on the CAR T2 program by end of this year. And then on the second question about AlloCAR, given the data we have seen in the field recently. So I'll start the answer and maybe Frank will add a little more. So I have two takeaways here. Number one is that like I emphasized in the takeaways slide from CAR TUDE, the CR rates we are observing, not only it's very high at eighty percent from CAR TUDE one, but also they're very durable, right? Durability is actually a very, very important key element from both regulators and also from physicians treating multiple myeloma. And I think if you look at the competition news from lately, you will see that not all the CRs are the same. And only the durable CR matters, right? That's the key takeaway from our program and also our data. Secondly, as you just heard from Doctor. Fan, we have chosen to use non genetic approach in our first allogeneic alpha beta T program. And there's a scientific rationale behind that, which Doctor. Feng will elaborate. But again, we don't believe that we're going to see a lot of abnormalities on chromosome or anything like that. So that's one of advantages of using non genetic technology. While if you use certain technologies in gene editing, you're bound to see some inaccuracies and also some infidelities from the process. So with that, I'm going to pass it to Frank to answer a little bit more about our lanolo strategy. Yeah. I think Ying, you already answered the question very well. The the actually we five to six years ago when we in our infancy of companies, we do realize that allogeneic will be the future of the cell therapy. It could be the future. So we have already invested. We form a dedicated team to explore the allogeneic platforms. But after our internal consideration and investigations, I I I still don't feel very comfortable going with the multiple gene editing approach. Let alone there's IP issues. And by that time we are, you know, it's unthinkable to to license so many IPs from from, you know, from different markets. So that's why our strategy is we decided to only go with non gene editing allogeneic platforms. No matter the upper right energy, gamma delta G, or current K. So that's why the other allogeneic CAR platforms I we we presented, disclosed are all non gene entities. It's not like we we, you know, we we really so basically, I don't feel that the current hurdles that would like a like a allergy encounter is not a solvable. I I do believe that there is still big room for improvement. I think maybe the FDA will find it clear their will resume their clinical trials and after, you know, the investigations. So I think the multi different approach by different development, different companies all have their pros and cons. We have already elaborate all the pros of our platforms. But still we are our program is not that that advanced in terms of a clinical stage. So we want to catching up. But we also wish the whole genome editing, whole gene therapy field will clear all these difficulties and can really proceed. Yeah. We also are a gene therapy company, believe. Were just doing ex vivo T cell gene therapies. So any, you know, we have to always aware all the risks that appear in for either gene the viral vector transduction or gene knockout. So we all need to have that positive attitude, but a very careful attitude to do to address all these issues. Thank you. Doctor. Fan Fan and Doctor. Dong Gan, we have a follow-up question from Morgan Stanley, Matthew Harrison. You didn't seem to dose limiting toxicities, DLT, in your early stage programs. Can you talk about how you are deciding on those in these programs? And when we could expect to see larger cohort data? Frank, would you like to take that first? So I want to Pardon. The question the point is, you know, we are still in the process of dose escalations. So we we we can't guarantee that with more patient being dosed at higher higher dose levels, we won't see DLTs. We can't guarantee that. But we wish may I answer your question? Sorry, maybe I missed your questions. Can you say that again? Yes. So it seems that Legend didn't dose to DLT, dose limiting toxicities level in our early stage program. Yes. I confirm that. How talk about how they I get can take from clinical perspective. So yes, that's true. And this trial, we have dose escalation and we will continue dose escalation in so I don't know which specific programs, but as soon as we don't see DLT or if we see DLT, will expand. So we will follow like route. Reporting of this data will depend, I guess, when we have meaningful number of patients with some indicative data. So we cannot comment on timing right now. We can see if we have any questions in the room. Thank you guys for taking my questions. This is Mikael Keiserman from BTIG. I've got two questions. Maybe, Steve, the first one for you, and this is related to sort of supply and capacity for the siltacell launch. Can you maybe touch on how you guys are thinking about having a steady supply for the sites that you do launch? And then secondly, just how you ensure a good patient and physician experience. Obviously, we've heard a competitor that has been very frustrating for a lot of physicians and patients based on their very long wait list. So how do you sort of ensure that experience? And the second question is just for Frank. If you can just touch on a little bit more on the claudin eighteen point two CAR T. Can you maybe compare just some of the specificity and the modality specifically you guys have selected versus some of the other clinical programs that are really more focused on bispecifics and antibodies, if you could just maybe compare those modalities? And then just on U. S. Strategy, are you expecting to take this beyond gastric, so looking at esophageal, looking at pancreatic tumors as well? You, guys. And do you want to take supply and I'll talk about go to market? Sure. So thank you, Mikael, for the question. So I'll talk about the supply and then maybe Steve will talk about the launch. So obviously, it's not in our position to comment or speculate on our competitive program in terms of the launch. But I can reassure you that Legend and also Janssen continue to place extremely strong emphasis and also on the both robust process and quality measures in the manufacturing discovery and delivery of Tutacil for both clinical and also commercial supply. As you're probably aware, due to COVID-nineteen outbreak, there are some global supply chain disruptions in stuff like kids, bags and also lentivirus. Lentivirus is a common, very important drug substance used in many CAR T therapies. And given what we're seeing in the market based on the first launch of BCMA CAR T, we do know that if you look at the patients who have been exposed with all three major classes of therapies including IMiD, proteasome inhibitor and CD38 antibody, they face very poor prognosis, right? So given the data you have seen from BCMA CAR T, it's not surprising to see a pent up demand based on the first launch experience. And if there's any potential supply issues here, JNJ and Legend are proactive in terms of enhancing our internal capabilities to supply LV. And that's our risk mitigation strategy. In fact, we're already implementing that now today in our supply chain. With that, I'm going to pass that to Steve about launch. Great. Thanks, Singh. Yes. So in terms of I think your question, we had a couple of questions commercially around how to manage the supply and making sure that things are running smoothly at the site level. So one thing that I think I discovered early in this process, in this space in particular, is the concept of transparency and predictability. So whatever the situation is, whether it be massive amounts of supplies or limited amounts of supplies, the need to be extremely transparent with our providers as well as predictable with those providers. So I think some of the issues that you've been referencing in the past by other companies, I think where they ran into problems was either they weren't clear themselves on what was going to happen in terms of supply and the impact that may have. But I think there was at least some degree of non transparency in the market. Again, I don't think that was a deliberate action at all. I think it was a matter of folks not knowing. And as Ing says, this is a pretty dynamic space when it comes to supply. So how we're approaching this, it's one of being very, very deliberate and very, very transparent with our customer group. Because of this patient population in particular, for everybody here I know in the room and on the phone realize the operational lift required and scheduling required to get drugs like this to patients. So you need to be as transparent as possible to our sites so they can begin the planning process in order to get drugs like this for their patients. So we're in the process right now, effective today actually, of having a lot of conversations with our sites in The United States to explain to them how we will be rolling this asset out to them. And we will continue that process for the next several weeks. But I can assure you this issue of transparency and predictability will be a cornerstone in terms of our go to market. I think the last question that you had was around just the operational sort of go between to ensure that nothing is lost in between. Yes, believe me, as a commercial person, I've learned way too much about operations and manufacturing over the last several years. But I think it's critical, obviously, to make these programs seamless to the customer. So we've been and this is where, honestly, Janssen has been an outstanding partner with us in developing an operational infrastructure that allows crosstalk with our sites, folks on the commercial team, our medical team and our manufacturing team to ensure that we have this predictability across one another to ensure that everyone is working from the same sheet of paper and ensuring that all these patients who should get silt to cell get silt to cell on time and there's no surprises. So anyways, there's a lot more behind that. I'm happy to go into with you maybe on the side, but that's what we're planning on doing. Thank you, Steve. We have a follow-up question from BTIG from Justin Salin. Will you be able to comment on on Legend manufacturing readiness? And also how would that compare to our competitor? Justin, thank you for the question. Again, just I'm not going to go into the detailed manufacturing capacity due to our contractual obligation with J and J on this. So I'm not going disclose the exact capacity. But suffice to say that both partners are working very hard, again, to ensure the robustness and also the delivery of the sutra cell once it's commercially launched. Frank, I think you can address the next question which is claudine CAR T versus biasesin Yeah. Regarding your claudine 80.2 questions, yes, obviously Clog 80.2 already evolved to one of the most popular immune therapy targets for salient cancers. And there are bispecific, there are ADCs, there are so many different modalities. All but all of them are antibody derived biologics including CAR Ts. I consider CAR T is also a derivative of antibody biologics. It just combines the gene therapy and T cell immunities. But if you want me to compare or comment, it's really difficult because it's kind of like to compare apples with oranges. It's still so different. In general, antibody drugs, bispecifics, and ADCs, I think the innovation of your modality, I mean, the development of new modalities is the, I think, in the past twenty years has been advanced of so much and quite immature, but maybe there is a limited room for for them to further evolve. But for CARP or CAR NK for those, basically, the nature is gene therapy. There's a virtually, there's no ceilings. So I think that for cell therapy company, they can always invent new armor strategies, you know, armor the CAR T cells with whatever tools they need. So probably so relatively so for cell and gene therapy, there are bigger rooms for for innovations, for further advancing the modalities to cope with whatever questions, whatever problems, barriers they will encounter. No matter is the infiltration, is expansion, barrier, whatever. So I that that that explains why I keep saying I'm a believer of gene gene cell therapy because they are viable drugs. We can and then we can energize them in in all sorts of different approaches. So we have a we can always keep improving it until we reach a goal to for cancer cure. And this is completely forward looking state of the I apologize for that. But since you asked, I have to show my comp I I still want to show my confidence. That's my personal opinion of representative pension. Thank you. So maybe I can add a little bit more on what Frank just said. Even though we do not know and what's the difference since we don't have data yet, what's the difference between bispecifics with CAR T for the treatment using CAR T18.2 as a target for the treatment of solid tumor. But for the existing data in the hematology actually field, and in general, and CAR T actually offer much more in advantage than by specific in terms actually, the overall and remission rate as well as the duration of the treatment because from the MOE perspective, it's of a more flexibility. I think in the same theory, probably will continue for the treatment of solid tumor as well. And as for CARDIN18.2 as a target, it already has actually proved to be a viable target from the existing antibody data as well as other data. And so we believe actually it is a validated target for the treatment for both gastric and pancreatic cancer. And we do have plan to pursue those two indications in the global wise. And Mikhail, if I may, I'll just add two things. Number one, the key difference between CAR T and the bispecific monoclonal antibodies that the CAR T express direct killing, right, instead of leveraging the patient's own T cells by using a bispecific monoclonal antibody for that matter, right? We actually take the T cell from the patient, yet we weaponize that with a CAR. So that's where the CAR T advantage is, right, compared to the endogenous CAR T cells from patient population. Secondly, I know we only have disclosed so far the first patient with the lowest dose so far. But if you compare it to our competition where I think the median PFS was about five point six months, that was actually with some chemo in the combination. This is actually data you see from monotherapy, one dosing only. And this is the lowest dose we have seen. We're seeing, like Frank was mentioning, already six month PFS and this patient still remains progression free. So that's the data telling us, right? So we have a question from Woodline Partners from Anish Kapoor, Ms. Solita. On CAR TIVO-four, given the fast enrollment, can you give us a rough sense of the timing of the data and whether it will allow you to leapfrog Adacel in terms of timeline. UNIDENTIFIED Well, so I guess I give good indication there. So we are happy with recruitment. But yes, I cannot comment more than that right now and we will share when it comes. So we have more questions on the Clotient 18.2 questions for FanFan and Dong. So next question is from Goldman Sachs and from Mike Liu. Will you test different preconditioning strategies for clotting eighteen point two CAR T? Do you think it will make a difference? No, I don't think so. Because due to the fact that our standard FC preconditioning already did very good jobs from seeing the first patient that we see extensive expansions. And, you know, at the peak level, 250,000 CAR T cells per male of peripheral blood. That's remarkable amount. And, you know, and we think we we don't want to read whether will. But maybe in the future, if we we see anything and and and we we want to, you know, reduce the the the the lymphodepletion. That's possible. But we need the data to support whether the lymphodepletion is really critical for solid cancer programs. There is not fully, not extensive study in this field. We all know that for hematologic malignancies, lymphodepletion preconditions are critical. But in the solid cancers, I remember some some investigators arguing that maybe for solid cancers, lymphodepletion is not that critical. But I don't know if I agree or disagree with it. I think that we need a data to support that. But at current stage, don't think we have a plan to vary this. We would rather put our energy on finding the optimal dose and whether we can re dose a patient and these kind of things. So the next question is from Li Rang from Diana Grisborsch. How are you thinking about multiple cycles of CAR T for your solid tumor programs? If necessary, when and how will you employ? So I guess, I mean, yes, we have to think about this. So in U. S. Clinical development plan is not yet established, so we are in the process of doing that and with also with health authorities. So I think we will do it depends on program by program. But in principle, I think we still try to achieve significant benefit to the patient with one infusion. So I don't know if Frank wants to comment but they are from CLIN. So we don't have any more questions online. Please raise your hand if you have any questions in the room. Well, if there's no further questions, I guess I'll just make some closing remarks here. As you can hear today, we do have a deep and wide pipeline of different programs in different technologies and also exploring different strategies to expand the field of cell therapy. And we're actually exploring multiple technologies to develop innovative cell therapy and bring them to the markets around the world. Together with our clinical development capabilities and also our global manufacturing facilities, we're building a fully integrated cell therapy platform. I hope that you have enjoyed today's presentations from my colleagues and also you share in our excitement about the future of Legend Biotech. We also would like to thank all of the investors and shareholders who have instructed us with precious capital to further our work. Thank you.

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