Hi, good morning and welcome. This is Jessie Yeung, 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'll 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. A few 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 presentations includes forward-looking statements. We encourage you to review the cautionary statement regarding information and remarks included in today's presentation, as well as the company's Form 6-K, 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, Dr. Ying Huang, will have some opening remarks. During the next 1 hour, Dr. Lida Pacaud, VP of Clinical Development, and Steve Gavell, 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 Dr. Frank Fan, our Chief Scientific Officer, for another 1 hour. After all the presentations, we will have 30 minutes of Q&A before we conclude the event today. With that, I would like to welcome our CEO and CFO, Dr. Ying Huang. Thank you, Jessie. Good morning and welcome. It's great to see so many friends are in the room, and also welcome everyone online as well. It's a pleasure for me to welcome you to Legend Biotech's first R&D Day. As some of you may know, Legend Biotech had the opportunity to ring the opening bell at Nasdaq a few weeks ago. As I rang the bell, I was reflecting what and also we have accomplished since the founding in 2014. In 2016, the first human study, called LEGEND-2, was initiated. Based on the phase I data, we entered into worldwide collaboration and licensing agreement with Janssen on cilta-cel. In August 2018, the first patient was dosed in the CARTITUDE-1 trial here in the U.S. Just over three years later, we're here awaiting FDA approval with a PDUFA date of November 29th. Among the many accomplishments we've 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, Dr. Lida Pacaud, Vice President of Clinical Development, and Steve Gavell, Vice President of Commercial Development, will share updates related to our CAR T clinical programs, and also updates on the commercialization of CARVYKTI as we edge closer to that PDUFA date of November 29th. 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 Afinitor and Avastin. Steve Gavel 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 bb2121 program. Steve also led development, marketing, strategy, and execution at Takeda Oncology and held multiple sales, marketing, and market access leadership positions in companies including Johnson & Johnson, Immunex, Syntix, and IMS Health. Dr. Frank Fan, our Chief Scientific Officer and the inventor of uniCell, 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-HIV1 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&D pipeline. Oops. 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're 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 uniCell has demonstrated better efficacy. Well, it's coming from this dual binder design. Since T cells are collected from patients in the autologous CAR T program, I hope you agree that we did not discover cilta-cel by accident after this R&D day. Instead, it's crystallized from years of trial and error and of an engineering effort. We're 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. 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. We do believe that multiple arming strategies will be necessary to overcome challenges to use T-cells to treat solid tumors. Finally, I would like to close my introduction with why we do this here at Legend Biotech. You may remember that LEGEND-2, 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-2 study. Patient number 6 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 cilta-cel in June 2016, with a total dose of 0.5 million CAR-positive cells per kilogram body weight. You can see from this photo on the slide, taken on the day of infusion on day 1, that this patient had a large number of plasmacytoma in the back. These are masses that look like solid tumor masses. Fortunately, he achieved MRD negative complete response 20 days after infusion of cilta-cel. The plasmacytoma also disappeared over time, as you can see from day 19 through 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 May 26th, 2021, patient number 6 remained in complete remission. This is just one example of 5 years of progression-free survival for a patient who was dying from multiple myeloma before he was administered cilta-cel. 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 cilta-cel, we want to challenge that, and we want to give this patient a fighting chance. Today, patient number 6 lives with his son, daughter-in-law, and also 2 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 6 in front of the second affiliate hospital of Xi'an Jiaotong University School of Medicine, where he was treated with cilta-cel 5 years ago. He told Dr. Zhao, the principal investigator, and our staff, that "cilta-cel gave me the second life." A company without a sense of purpose is a company without a soul. With the story of number 6 patient in LEGEND-2, 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 target therapy, cilta-cel. Thank you. Can I have the mic? Is it on? Okay, great. Thanks, Ying, and welcome everyone. My name is Lida Pacaud. I'm clinical lead at Legend for BCMA program, as well as early-stage pipelines. Today, I would like to give updates on cilta-cel clinical development program. I will start by reviewing new data for CARTITUDE-1 study, our registration study. I will also review CARTITUDE-2. This is a multi-cohort phase II study. Lastly, I will cover our phase III programs as we move cilta-cel in earlier-line settings. This will be 2 phase III studies, CARTITUDE-4 and CARTITUDE-5. We have initially presented CARTITUDE-1 in 2020 with median 12 months follow-up. This year at ASCO, we have shared median 18 months follow-up data. We do continue to see unprecedented response rates in heavily pre-treated multiple myeloma patients. This is our overall response rate in this updated analysis is 97.9%, and responses are deep and durable. This is indicated by stringent CRs being 80.4%, and also by MRD negative responses, which are in 92% of the patients. I also would like to note that what we see compared to previous analysis, that we see deepening of responses. Some patients, like third of the patients who had VGPR became CRs, and importantly, CR patients became stringent CR. In previous analysis, stringent CR was only 67% of the patients, and now stringent CR is 80%. Response rates seen in this trial is also translating in long-term benefit for the patient, and this is indicated by progression-free survival. What we see here in this 18 months analysis is that the lower confidence interval indicates that minimum PFS benefit is at 22.8 months. This course 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 heavily pre-treated 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. 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, we did not have the opportunity to meet face to face with many of the folks in this room. When you IPO virtually, that's always an interesting experience. It's always now 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. Obviously, the clinical data speaks for itself. What I'd like to do with my piece of this presentation is give you a commercial perspective of what that means in the geographies that we will be launching into. 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 indications statement as our competitor. Just to remind folks, in the U.S., 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 U.S. that will meet this label requirement. This is not a treated population because there'll have to be additional work on top of this 12,000 that will account for fitness levels, et cetera, for these patients. I just wanted to pull that out. I'm going to come back to the U.S. in a second. In Europe, we're assuming a fourth-line-plus indication. This is, again, in keeping what you saw earlier with ide-cel, representing about a 6,000 or so patient population that would meet the eligibility criteria. In Japan, also a fourth-line-plus indication, again, a population of around 4,000. Let me take it 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 12,000 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. We're keeping our close eye on this because obviously with the ide-cel launch just occurring and there's really has been, relatively speaking, kind of a minimal experience yet in the marketplace, but we are 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 about 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&J as it relates to our co-pro agreement. We are co-pro partners in the United States. It's a 50/50 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, how does the co-pro work? What are you doing? What's your partner doing? 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. 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. 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. 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 5 years in total, 5 and a half years. As we all know, it all starts with the data, right. The clinical data, safety and efficacy data of all these drugs, without question. I think what you're hearing from Leta is from that perspective, we have quite a hot product on our hands right now. We're feeling very comfortable from our clinical profile for sure. 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 that you're going to be commercial successes, right. One of the things that has been playing in market to us loud and clear, and this is an extension of our safety profile, is how interested the market is in using cilta-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. That's more and more important for sites, especially as you're launching into large patient populations like multiple myeloma. 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 in these hospitals, whether it be in transplant or in the clinical trial setting. This is one of these operational aspects of this product that I truly did not appreciate until we got going with it. This is something that is clearly resonating in market, as an exciting also added feature of this program. Finally, because of this combination of obviously safety, of efficacy, and operational flexibility, at the end of the day, it enables these hospitals and providers to treat more patients. One of my concerns as this product was picking up speed clinically, because of the great work our clinical 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 is eligible to receive this drug will get it. What I was getting worried about is the operational mechanism within these countries, if they could pull it through. The fact that, like I said, I think the CRS aspect is the enabler to actually treat potentially more patients in the outpatient setting. I'll leave you with that, and I'm sure during the Q&A, we could get further into that. Turn it back to Lia. Thank you, Steve. Next trial, I would like to review our Phase II CARTITUDE-2 study. This is a multi-cohort study which evaluates various multiple myeloma setting. We anticipate to enroll approximately 160 patients. You see we have six cohorts right now, and each cohort is 20 patients or more. 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. I will start by reviewing cohort C. I will start with later line setting. Cohort C is a patient who are exposed to PI, IMiDs, and CD38 agent, but also exposed to BCMA-targeting therapy, except cell therapy. This is basically cohort patient who had prior BCMA ADC or bispecifics. Next cohort is cohort A. This is again relapsed refractory setting, but patient with prior 1 to 3 lines of therapy done earlier than CARTITUDE-1. We have phase III trial also ongoing in this population, which I will come in a moment. We have disclosed this cohort A, 20-patient data, and I will share that with you in a moment. Rest of the cohorts are also investigating cilta-cel in earlier line settings. If we go to cohort B, these are patients who are early relapses after frontline therapy, patient who basically progressed 12 months after induction therapy or autologous stem cell transplant. Next cohort is cohort D. Cohort D is patients who have suboptimal response to frontline therapy, so this is less than CR after frontline therapy. Cohort E is newly diagnosed patients who are not intended for autologous stem cell transplant, and these are high-risk patient. Last cohort is also newly diagnosed patient with standard risk. This last cohort F will investigate patients after induction of DVRd or similar quadruple triplet regimens. cilta-cel will be given after induction as a consolidation. This, as I mentioned, the cohort A, prior 1 to 3 line lenalidomide refractory data have been shared at ASCO this year. We are very encouraged to see high response rates, and consistent with CARTITUDE-1. We see 95% of patients have overall response, and the CR was seen in 75% of the patient. This data has median of 5.8 months follow-up. As I have mentioned from CARTITUDE-1, we have learned that responses are going deeper over time. 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. We see a similar safety profile to CARTITUDE-1 in terms of targeted adverse events or some adverse events even numerically better. This is very encouraging as well. We see overall 85% of patients with CRS, but vast majority are low grades. And in this subset, we did not see grades 3 and 4 neurotoxicity, which also includes we did not see a major neurocognitive type of neurotoxicity. Start of CRS and neurotox, I think to the point what Steve was mentioning, we see 7 for CRS and 8-day median start for cilta-cel. Now I would like to introduce CARTITUDE-4 phase III study. This is same patient population with prior 1-3 lines of therapy and refractory to lenalidomide. Patients should have had exposed to PI and IMiDs. I would like to highlight daratumumab exposure was not required in this trial. It means this trial will cover both populations with or without prior daratumumab. I guess Steve will come to this point as well because, we want to highlight in the context of, we know there is KarMMa which is ongoing, which is different. KarMMa has prior 2 to 4 lines. This trial is 1 line earlier. KarMMa, as we know, requires daratumumab exposure. Here, both populations will be covered. This is trial schema. Trial will enroll approximately 400 patients, and we will give, in control arm, PVd or DPd standard of care regimen. PVd stands for pomalidomide, VELCADE, dex, and DPd is the DARZALEX, pomalidomide, dex. Patients are treated in control arm until disease progression. In cilta-cel arm, there will be bridging therapy, 1 cycle or more, so maybe 2 if needed. After this bridging therapy with the same regimen, patient will undergo cilta-cel infusion, lymphodepletion and cilta-cel infusion. After cilta-cel infusions, there is no treatment, so there is observation treatment-free period for patients. This trial has opened in June last year, we are very excited because we have seen very high interest from investigators in terms of recruitment, even better than we have forecasted. This trial is clear was very priority for Janssen and Legend. We hope to report on the progress of this trial very soon. Also to put this trial in a context. Just to highlight what is available standard of care right now and what benefit this can provide to this population. We see it's highlighted here, nine, 10 months is a benefit in lenalidomide-refractory patients specifically, which are studied in these studies. Did we make the switch over? Can you guys hear me okay? Okay, great. Thank you, Lida. I love this study for the record, for a number of different reasons. Thanks for the setup, Lida. I won't go into the trial design. As Lida does mention, this is the first phase III CAR T therapy, in this patient population of 1 to 3 priors. A lot going on here and Lida touched on a couple of them. With this indication, fundamentally, this will be the first time that this program, cilta-cel, will now jump in front of ide-cel. That's 1 of the key points to the slide. The second piece in jumping ahead, as you can see further down the slide, our competitive assumption, Lida mentioned this, with our competitor in this 2 to 4 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 2023. That's the timeframe we're looking at. Again, with this indication, we leap forward in front to the 1 to 3 prior. The interesting aspect, and it's the reason why I love the trial designs so much, is the fact that the lack of requirement for daratumumab. As you can see in the sub-bullet, it's probably hard to see here for the folks in the room. Based upon the data that we've been analyzing, about 80% of all patients in the 2nd line setting do not or have not been exposed to daratumumab. 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 a 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. Again, if you go further down in the sub-bullet 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 80,000 patients would fall, meeting this criteria. 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. You move forward with cilta-cel earlier without this dara requirement. I'll pass it back to you. Okay. Thanks. Last trial is CARTITUDE-5. This is trial in newly diagnosed multiple myeloma. To our knowledge, first newly diagnosed clinical trial for CAR T therapy in myeloma. This trial will enroll patients who are not candidate, so not considered for stem cell transplantation. There is 2 category of the patients. One is patient who are not candidate because of age or comorbidity, organ function, and this is based on local institutional recommendations. This is, as you can imagine, international trial and definition of transplant non-eligibility varies among countries. One population will be transplant not eligible because of clinical conditions or age. There is population of patient who are deferring autologous stem cell transplant as a first-line therapy. This population emerged in last couple of years, and these are patients. There was actually the IFM study. Clinical study which have shown that survival benefit is same if patient receive transplant immediately in newly diagnosed setting or later in a treatment course of disease. That led to investigate this population deferring transplant by physicians and patient choice. That was also investigated actually in 3 other phase III trials of multiple myeloma and non-CAR T trials. This is now becoming, in last couple of like 5 or so years, becoming a population which is treated together with transplant not eligible patients. This trial will cover this patient as well. I wanted to highlight this also to references. I looked to some references, and like half of the patients right now are deferring transplant and not undergoing it in first-line setting based on literature. Trial schema is shown here. This will be 650 patient randomized clinical trial. Patient in control arm will undergo VRd regimen, VELCADE Revlimid dex. As you can notice, all patients will have 6 cycles of induction, and after randomization in both treatment arms, there are 2 cycles of this regimen. This basically makes that in both treatment arms total, equal number of cycles are given to the patient as induction. In control arm, there will be RD maintenance or Revlimid dex maintenance. In investigational arms, there will be cilta-cel infusion after lymphodepletion, and there is no treatment after cilta-cel infusion. This trial opened, we announced in August this year, and it will open approximately in more than 100 locations worldwide. Also to put again, this trial in the context and patient population we try to address here. This is data from some literature, which shows that median PFS in this patient population with current standard of care is around 36-40 months. Very good. Thank you, Lida. Just to reiterate, other than the questions we get commercially from many of our customers outside of the CARTITUDE-1 trial is when will you guys be in the frontline? Right. 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 upfront patient population. When you take a look again back here at some of our assumptions, if you look at some of the newly diagnosed patients, 64,000, this is 1,000 patients diagnosed across the U.S., Europe, and in Japan. This transplant not intended eligible patient population, as you could see here, in the United States, about 15,000, in Europe, about 9,000, and in Japan, about 1,600 patients. One of the things, I guess the only point I would really want to make in this study, the economics really start to change here. The economics that I'm referring to is demonstrating success in an upfront population 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 treatment options, thank God, for these patients. The flip side of that argument is there's a lot of cost there associated in the treatment of multiple myeloma. 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 excited by that. Okay, great. Thank you, Lida and Steve, about the introduction on CARTITUDE program. Oops. As you can see from this slide, we have a very comprehensive clinical program, including the ongoing CARTITUDE-1, which is registrational phase I/II 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 CARTIFAN-1 in China, which will serve as a basis for BLA in China. Besides that, we also have an ongoing phase II trial called CARTITUDE-2 that is evaluating cilta-cel in various settings, including frontline. The phase III CARTITUDE-4 examines cilta-cel in patients with 1-3 prior lines of therapy. While the most recently initiated, CARTITUDE-5, is our first phase III trial in frontline patients. I'm also happy to report that based on this 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. Let me provide a very quick summary of what you just heard from our CARTITUDE program. First of all, cilta-cel has demonstrated potential best-in-class efficacy in relapse and refractory multiple myeloma with 80% stringent CR rate. Most importantly, I want to emphasize that in the clinic, we have seen that those CR rate achieve 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 CARTITUDE-2, which shows early promise for cilta-cel in early line multiple myeloma. The phase III CARTITUDE-4 trial is enrolling very quickly and positions cilta-cel very well in second line and beyond multiple myeloma. Legend and our partner Janssen are determined to bring cilta-cel as the first BCMA CAR T in second line and beyond multiple myeloma by leapfrogging our competition. Lastly, the ongoing phase III CARTITUDE-5 is the first pivotal phase III trial for any BCMA-targeting CAR T in frontline multiple myeloma. This very significant investment shows the strong commitment of Legend and J&J in advancing cilta-cel as a potential frontline treatment for multiple myeloma. Now we will take a 10-minute coffee break, and we will resume at 10:50 A.M. Thank you. Okay. Welcome back. I now have the pleasure of introducing you to the man behind Cilta-cel, who leads also our discovery research at Legend Biotech. Welcome, Dr. Frank Fan. Frank, you can take over. Hi. Thank you, Yin. Dear investors and 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 20 years of my academic career, I made some scientific breakthrough in transplantation immunology that impacted clinical practice. I returned to China in 2014, and as supported by GenScript, I founded Legend. I'm happy to witness that 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&D team in early 2016, I strive to keep a robust R&D culture that great passion, real innovation, and cooperation are the core spirits. When looking back to what we have achieved in the past seven years, I feel it was R&D culture blessing the team to bring true miracle to the field. We may already set up an example for a start-up 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&D activities. 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. I will introduce you three solid cancer programs, which are our current R&D focus. I would like to update you two of our allogeneic CAR platforms. Here I listed some core technologies and products. I believe we have expertise and insights to catch promising immunotherapy targets at a very early stage of the application. We often started R&D activities for a promising target years before it became popular. For example, BCMA and Claudin 18.2 are examples. We have developed many technologies to help us efficiently obtain large amounts of proteins, antibodies, and identify, optimize the most promising leads at the 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, which enhance the safety and improve homogeneity. Legend's non-genome editing allogeneic CAR-T platform does not rely on any genome editing approach. We also have Legend's unique CAR-NK and gamma delta T CAR platforms in development. I 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. I have limited time today, I won't be able to report to you our gamma delta T or TCR-T platforms. I also don't have enough time to cover all our pipeline products. For example, the CD19, CD20, CD22 tri-specific CAR-T or other preclinical stage programs. Legend has our own in-house 10x Genomics 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 the single-cell level, such as target expression on tumor cells, on target off-tumor risk analysis on normal tissues. When studying tumor microenvironment, we will be able to find a repressive cell type or signaling, guiding the design of our armor strategy. We have even 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 camelid VHH single domain antibodies, murine antibodies, and fully human antibodies. We usually will rely on multiple criteria for screening out the top antibody leads we want to proceed. Llama produce highly diverse antibodies, including a unique class of VHH single domain antibodies that can have high antigen binding potency compared to that of conventional antibodies, which are composed of a 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 multi-epitope antibodies targeting the same antigen or to enable designing multi-antigen specific CAR constructs, such as tri-specific CAR products targeting CD19, CD20, and CD22 at the same time. As you know, one of the Legend's current R&D focus is to conquering solid cancers. There are many challenges for CAR-T cells to overcome in fighting with solid cancers. Physical barriers and the dysregulated vasculature inside large cancer lesions block CAR-T cells trafficking and infiltration. Unfortunately, tumor microenvironment, including soluble and cellular immunosuppressive 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 any corner. Usually, when we kick off developing a new product, we start research projects from the preparation of target antigen to optimization of animal immunization regimens. By this step-by-step in-house efforts, we've been able to obtain large amounts of high-quality antibody leads and 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 R&D team also proactively combine our complementary suites of technologies at early developmental stage. We have invented numerous arming strategies and have filed 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 the 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 battle 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 the desired phenotype. For both our 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&D team already established as a combined force of different arms. We have more than 300 scientists distributed worldwide, but we can work as a one team in executing R&D enabling studies or in a mission of technical transfer to manufacture teams. We not only have efficient and talented discovery team, but also have professional and elastic development team, skilled biomarker 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 adoptive cell therapies have gained tremendous success in the past decade, solid cancer remain the largest unmet clinical needs. Legend Biotech also heavily invest to explore new treatment options for solid cancers. In part 2 of my presentation, I would like to introduce 3 of our major solid cancer programs. The first program is autologous CAR-T targeting Claudin 18.2. The top 2 potential indications for Claudin 18.2 are gastric cancer and pancreatic cancers. Gastric cancer is the 5th most frequently diagnosed cancer worldwide and the 2nd leading cause of cancer-related deaths. Pancreatic cancers has extremely low 5-year survival and the 2nd leading cause of cancer-related deaths in the U.S. Because Claudin 18.2 is a tetra transmembrane protein with very conservative extracellular domain across species, developing highly selective high affinity antibody to Claudin 18.2 is very difficult. With years of efforts, we have successfully developed the high affinity Claudin 18.2 VHH single domain antibodies that does not cross-react to Claudin 18.2, even at the very high concentration. We have already started the first human clinical study with preliminary progress, which I would like to briefly report in this session. The family of Claudin proteins comprise 27 tight junction proteins with 4 transmembrane domains and 2 extracellular loops. In human, Claudin 18 has 2 variants, 18.1 and 18.2. They share highly similar protein sequence in extracellular loops with only 8 amino acid difference in loop 1. Claudin 18.1 is selectively expressed of normal lung. Claudin 18.2 is restricted in differentiated short-lived cells of the stomach epithelium. Highly selective Claudin 18.2 antibody over 18.1 specificity extremely critical to assure the safety of the Claudin 18.2 targeting biologics. Particularly important for CAR T-cell therapy due to this live cells product could expand 100 times or even thousands of times in those patients. You don't want any of these cells to go attacking your lung tissues. Claudin, as was reported, summarized in the left panel in E.U. population, Claudin 18.2 was detected in 70%-100% primary gastric adenocarcinomas. The fraction of tumor cells expressing Claudin 18.2 at any staining intensity is strongly correlated between primary tumors and the lymph node metastasis in matched pairs. Harnessing the single domain antibody-based CAR T platforms, Legend has successfully developed LB1908, our LCAR-C18S product, which is an autologous CAR T targeting 18.2, attached with 4-1BB cytoplasmic domain as costimulatory 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. By comparing with benchmarks, LB1908 showed superior anti-gastric or anti-pancreatic tumor activity in vitro, in vivo. I would like to show some representative data for this program. The in vitro binding affinity and the specificity of the C18S CAR VHH to human Claudin 18.2 were assessed by 2 independent methods, SPR and flow cytometry using PANC-1 cells. A human pancreatic cancer cell line transduced to express Claudin 18.2. The C18S CAR VHH bound tightly to human Claudin 18.2 with a KD value of 17.15 picomolar by SPR. In the cell-based flow cytometry assay, the Claudin CAR VHH specifically interacted with Claudin 18.2 expressed on the cell surface. In contrast, C18S CAR VHH did not interact with 18.1, demonstrating the specific interaction between the C18S CAR VHH and the Claudin 18.2. We also use a real-time live-cell imaging coculture assay to study the safety profile of LB1908 CAR T-cells using a series of primary cells. Here are some representative images. After overnight culture, the significant target cell lysis was noted by LB1908 on Claudin 18.2 positive cells, as indicated by yellow and green dyes and the cell aggregates suggesting non-target recognition. Our product did not show significant cytotoxicity in other Claudin 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. Claudin 18.2 protein sequence are highly conservative among species. Human and mouse share identical extracellular loop 1 sequence of Claudin 18.2. Mouse is a highly relevant model to study the Claudin 18.2 targeted biologics, especially toxicology study. We performed in vivo studies using gastric tumor xenograft models based on a highly immune incompetent NCG mouse strain. Gastric cancer cells were inoculated 2 weeks prior to the CAR T treatment, followed by monitoring of tumor size, body weight, status, and CAR T expansion. As you can see in Figure A, the C18S showed significant tumor control in dose-dependent manner. Tumor-free can achieve in 75% of the 1 million group and all the 3 million-5 million per mouse groups, and no tumor relapse were noted. The in vivo 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 used similar xenograft approaches. Claudin 18.2 positive pancreatic cancer cells were inoculated three weeks prior to CAR T treatment. Our product showed significant anti-pancreatic cancer potencies in vivo. All tumor were gone in each mice, the LB1908 expanded efficiently. Before we launch exploratory human trial, we also completed our comprehensive human tissue cross-reactivity analysis of LB1908. Antibody by immunochemistry 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 mucosa and epithelial cells. This result strongly supported the safety profile of LB1908 across human normal tissues. 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 gastrectomy and subtotal gastrectomy. With more safety information collected for on-target off-tumor effects, we are now considering modify our protocol to be able to enroll patients with full stomach. This is a prospective single-arm, single-center, open-label, single-dose phase I study to evaluate the safety, tolerability, PK and antitumor efficacy profile of the LB1908 in subjects with Claudin 18.2-positive advanced gastric adenocarcinoma. This study was a dose-finding study starting from 0.5 million to 9 million per kg. To date, 4 patients were dosed at levels ranging from 0.5 million to 3 million CAR-positive cells per kg. 3 patients completed the DLT observation, no dose-limiting toxicity, DLT, have been observed to date. The preliminary efficacy data shows antitumor activities of 1908. This study is still in its early stage, and only the first-dose patients have reached the time point for evaluation at the day 180 days, for follow-up. We decided to only present the first case for now and leave a full report to be disclosed by PI in future academic meetings. The first subject we dosed is a female patient bearing an advanced stage of gastric adenocarcinoma, expressing high level of Claudin 18.2. The patient previously received 5 prior lines of chemotherapy and bearing huge pelvic tumors and large amount ascites and pelvic effusion. Without effective bridging therapy available, the patient progressed 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. The investigator performed emergent bilateral pelostomy to relieve the critical condition. After careful consideration, the PI still decided to proceed to the CAR-T infusion at the lowest dose level, 0.5 million per kg. The patient was discharged from hospital on day 14 post-infusion, and in the half year of follow-up, about 15% of tumors regressions were measured, and the patient remained progression-free at day 180. After CAR-T infusion, this patient not just experienced the reduction of her lesion at roughly 15%. Strikingly, her urination resumed, and the pelostomy catheters on both sides were removed. Before CAR-T infusion, the patient has large amount of ascites that need abdominal drainage. After CAR-T infusion, the ascites and pelvic effusion was significantly decreased. 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 6 months. This patient also experienced significant CAR-T expansion. The CAR-T cells were detected from day 2, with peak expansion noted on day 12, reaching a level above 250,000 CAR-T cells per ml 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 45 and not detectable from day 92. 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 cells. To summarize the program, we conclude Claudin 18.2 is a very promising target for gastric cancer and pancreatic cancer. Claudin 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 Claudin 18.1 could be fatal, and on-target on tumor effects could lead to severe injury to gastric mucosa. Despite the challenges and difficulties, Legend has successfully developed a robust Claudin 18.2 targeting CAR-T program with high development potential. An investigator-initiated clinical trial is currently ongoing, and antitumor activity was shown in the first dose DT patient. We have already escalated the dose level to 3 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-center trials. We may expand the patient enrollments to cover gastric cancer with full stomach, and also pancreatic cancer patients as well. We have added 3 additional sites recently, and the preparation for filing the U.S. IND in the first half of 2022 are currently ongoing. The second program I'm talking about is LCAR-H93T CAR T targeting GPC3. GPC3 highly expressed in over 76% of HCC, 52% of LSCC, and 80% of germ cell tumors. This target is specifically expressed in these tumors, but not in paracarcinoma tissue. We developed the Legend anti-GPC3 CAR T cells based on a selected high-affinity humanized single chain variable fragment. We optimized the CAR backbone, and Legend's own customary CAR T armor technology has been applied. This next-generation GPC3 CAR T exhibited improved expansion and infiltration, persistence, and excellent killing in non-clinical studies. GPC3 overexpressed across a broad spectrum of tumor types with high positive%. CAR T therapy targeting GPC3 will cover a large patient population in indications including HCC liver cancer, LSCC, esophageal cancer, thyroid tumor, and germ cell tumors. The Figure B shows GPC3 staining hepatoblastoma. You can see GPC3 could well distinguish tumor cells and a parent tumor-like liver cells. The high specificity of GPC3 in tumor cells make it a safe target for CAR T therapy. The anti-GPC3 binders is a humanized antibody with an 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 native CAR T cells, we call it H93, and two benchmarks. Using an aggressive Huh7 xenograft model, our H93 CAR showed a superior efficacy at a very low dose where 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 a CAR-T armoring technology with improved GPC3 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 TME signal to CAR-positive signal. Furthermore, the armor activation depends on both CAR activation signal and a TME signal. 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. The GPC3 CAR T may not only resist to TME suppression, but even have more infiltration into tumor mass, expand well, and exhibit more potent tumor killing activities. This data suggests armoring strategies improve 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 anti-tumor 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, LB21-01 is a novel investigational CAR T therapy for the treatment of HCC, SCLC, and potentially more broad indication. Due to LB2101 show superior suppression of tumor growth compared to the benchmark-based CAR-T in the HCC model, the anti-GPC3 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 DLL3. DLL3 is a very promising target for SCLC and other neuroendocrine tumors, highly expressed in about 80% of SCLC tumors on the plasma membrane. Lung cancer is the most common cancer worldwide. Small cell lung cancer accounts about 15% of all lung cancer case, with about 35,000 and 110,000 newly diagnosed cases in U.S. and China, respectively. SCLC is also a very deadly cancer. The median OS for patients with extensive stage SCLC is less than 10 months. Similar to the design of Cilta-cel, we developed anti-DLL3 CAR T cells with a tandem humanized VHH single domain-derived binder design, which has high affinity and specificity against DLL3, 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 boosts in vivo anti-tumor efficacy by improving CAR T cell proliferation resistance to TME inhibition and infiltration in the tumor nest very well. The product is well-tolerated in both subcutaneous tumor model and pulmonary orthotopic tumor model. DLL3 belongs to the delta-like family protein. In SCLC tumors, DLL3 is homogeneously expressed at high level on the cell membrane of tumor. In contrast, it is barely expressed in normal tissues or very restricted in the cytosolic compartment. As shown in the IHC staining, DLRC is specifically overexpressed in SCLC and LCNEC. We have developed a DLRC targeting autologous CAR T product with SC4 of SCLC. The product is armored with a tumor microenvironment-resistant element. In preclinical in vitro pharmacology studies, we have again demonstrated that similar to Cilta-cel, tandem bi-paratope single-domain antibody-derived CAR T outperformed monospecific DLRC 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 subcu SCLC xenograft tumor model. In line with enhanced tumor-suppressive activity, PK analysis of CAR T in peripheral blood as well as tumor-infiltrated CAR T cells all demonstrated that improved infiltration into and the proliferation with vicinity of the tumor. Moreover, we have investigated the in vivo tolerance of Legend CAR T cells in both subcu and orthotopic tumor-bearing model. By infusing 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. The conclusion is that DLRC is a promising target for SCLC. Leveraging a bi-paratope tandem single-domain-derived binder and the TME-resistant armor strategy, LB2102 has demonstrated potent cytotoxicity, improved proliferation, persistence, and infiltration, and efficient in vivo tumor growth inhibition. We are planning first-in-human study in the U.S. IND. In part 3 of my presentation, I would like to present two allogeneic, our universal CAR platform we have been developing. For the first platform, I would say by spending years of efforts, our team have innovatively invented a distinct approach to disrupt TCR complex from T-cell surface without the need of genome editing. In the 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 knockout strategies to prevent the risk of GvHD. Multiple gene editing or knockout manipulations always come up with risk of off-target and potential genotoxicity. Also, another important disadvantage is multi-step manufacture will obviously 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 manufacture efficiencies and a low yield of final drug products. Without any gene editing or gene knockout disruption, we aim to achieve silencing of TCR function while spare CAR T signal transduction. After five years of hard efforts 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 where proteomic regulation of TCR is also driven by my hobby to pursue all-in-one solution. I love 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 that are very straightforward in a similar process to autologous product. Conventional allogeneic products unexceptionally involve multi-step gene manipulation, including the CAR transduction and multiple gene editing or gene knockout. This will generate about 8-16 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 the TCR double positive cells, which may cause GvHD after extensive on-target expansion in vivo. The quality control and the stringent releasing criteria will be critical to prevent the contamination of unwanted cells. In Legend's own platform, the high heterogeneity of products was avoided by our simple all-in-one approach. Due to the TCR disruption 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 2 subtype of cells generated after the lentiviral transduction. All donor T cells either successfully transduced or not transduced. This strategy will ensure all CAR positive cells are GvHD disarmed T cells that we need, and unmodified T cells can be depleted. Even if small amount of the unmodified T cells were contaminated in the final product, it 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-edited allogeneic platform, we chose a very well-validated target, CD20, and then construct a CD20 CAR using a well-characterized monoclonal antibody clone. As you can see on the left panel, flow cytometry analysis of the LuCAR20-S clearly demonstrated that the non-gene editing CD20 CAR T-cells are highly enriched in the final product after the relatively simple process. CAR-positive cells occupy 98.63% in the batch, while almost all these cells lost the expression of TCR complex. In our MLR system to evaluate the allogeneic T-cell response, our LuCAR20-S 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 phase I of the clinical study. We did open an investigator-initiated trial to mainly test the safety of the basic version, LuCAR20-S. We have since obtained some initial data. Despite limited efficacy and the CAR-T expansion were found in the first few dosed patients, no GvHD or other GVHR were found at the current 300 million dose level. We are planning to study a full version of the product, LuCAR20-SD. For the whole allogeneic CAR-T field, 2 immunological barrier need to be addressed in the long run are GvHD and HVG. The control of GvHD has been achieved by various approaches developed by different companies. However, rejection of allogeneic CAR T cells or so-called HVG 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 CAR T expansion in the majority of patients are quite limited. Usually, the allogeneic cells only persist for 2-3 weeks. This HVG issue mainly hampers the deepness of response for the current allogeneic products despite aggressive immunosuppression has already been used. As I mentioned already, because Legend Biotech and the PI want to first test the anti-GvHD effects to address the safety of our non-gene editing platform. The basic version, allogeneic CD20 product, LuCAR20-S, was taken to the first in-human study. It is an open-label, dose-finding study to assess the safety and the tolerability of donor-derived CD20-targeting CAR T cells, administered with lymph depletion, 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 I study in China is ongoing. Five subjects were dosed at levels from 10 million to 300 million CAR T cells. The last of those patients received 300 million LuCAR20-S in total. Far, no dose-limiting toxicity or GvHD were observed in these five patients, and three of the five dosed patients achieved a partial response. This case showed one of PR patients who received 300 million of allogeneic CAR T cells. Four prior lines of 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 14 post-infusion. At day 30, all target lesions and non-target lesions regressed to normal or absent on CT scan. A PET/CT scan also showing complete metabolic response. Because remaining cancer cells were found in bone marrow biopsy, the overall efficacy assessment was determined to be PR. Besides the LuCAR20-S, 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 LuCAR20-S. 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-S, still prevent GvHD, we also performed the full GvHD assessment in a specialized GvHD model. In experiment, a modified donor T cells or conventional CAR T cells all successfully rendered GvHD and animal loss. Our LuCAR20-S group, labeled purple color, remain staying safe without a GvHD event, 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 mimic MR assay combined with the drug Y, we observed our anti-HVG strategy did shift the balance between host T cells and the donor T cells in the system. We wish the fully armored version of LuCAR allogeneic 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. Legend Biotech has developed a proprietary allogeneic CAR T technology using a non-gene-editing approach, which reduce risk of off-target activities and general toxicities. Legend Biotech also believe that this approach to the design of allogeneic programs potentially simplifies the process for chemistry, manufacturing, and controls, and potentially improve product homogeneity. Based on this approach, we have developed allogeneic CAR T LuCAR20-S targeting CD20. Our first human study was initiated for LuCAR20-S. The preliminary safety and efficacy were already observed. Legend has developed a modified version of LuCAR20-S 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 LuCAR20-S. We're also interested in developing CAR-NK platform to defeat cancers, as we believe it possess unique advantages as allogeneic products. First of all, NK cells are major components of the innate immune system and are fast killer of cancer cells. Second, CAR-NK provide a promising solution to overcome TA escape by multiple mechanisms, including CAR-independent ADCC-mediated killing. The key role of NK in ADCC supports its combinational use with a therapeutic antibody drug to further enhance depth of the response. Last, but not the least, multiple CAR-NK trials have demonstrated the clinical benefit of CAR-NK cells. One particularly attractive point is the superior effect, the safety profile observed across different types of CAR-NK cells. There are multiple challenges in the CAR-NK field. NK cells are short-lived cells, while persistency is a key for the success of a long duration response, as we learn from autologous CAR T products. The most powerful NK cell expansion methods are based on cancer cell lines such as K562 feeder cells. These add a safety risk to the final products and also add a complexity to QC process. NK cells are highly resistant to the lentiviral transduction. How to introduce gene of interest into NK is a technical challenges. Fourth, NK cells are more sensitive to cryopreservation than T cells, while there are no commercial cryopreservation method that is optimized to maintain NK viability. Legend has developed its multiple solutions to tackle these challenges. Legend developed a feeder cell-free expansion system and a highly efficient way of NK transduction. Furthermore, we have developed a unique armor approach, LGKINE, 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 CAR-NK product, which maintains NK viabilities and the 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 shows the folded expansion of CAR-NK across multiple batches for manufacture and a representative of the individual killing efficacy. The bottom row shows improvement of maintenance of viability by Legend's frozen formulation in comparison to commercially available frozen formulation, and the in vivo efficacy comparison between fresh and a frozen CAR-NK product. This together shows that Legend has a powerful manufacture process of CAR-NK from end to end. We also develop 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 armored approach for NK cells, one commonly used approach by this field is to armor NK with IL-15, interleukin 15, to enhance persistency of NK cells. Previous literature suggests secretion of IL-15 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 individual in vivo screening on hundreds of rationally designed cytokine mutants. We successfully discovered a mutant we named LGKINE, which we found it can significantly improve the function of CAR-NK while not adding any in vivo toxicity. Long-term anti-tumor activity and extended animal survival were observed in animals treated with LGKINE armored CAR-NK cells. Therefore, I believe Legend has developed a robust NK manufacture process with the following features. Robust expansion and a CAR transduction process. Production of a highly pure CAR-NK product with strong anti-tumor activity. Optimized cryopreservation process to minimize the loss of viability and the functionality after sorting. We further innovate our rational design NK cell armoring molecule called LGKINE, which we found dramatically boost our CAR-NK cells. With seven years of development, Legend Biotech already evolved to be a leading cell therapy company. We have developed a multiple technology platform with strong IP positions, despite 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&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 to stay low-key, we work together fearlessly to challenge the technical barriers. We are well above transforming impossible to possible. Thank you for your attention, we are happy to take your any questions. Thank you very much. Thank you, Dr. Fan. We will now take questions from the audience about our pipeline and BCMA program. Joining us to answer questions today, we have Dr. Dong Gan, head of early stage drug development, Steve Gavell, Dr. Lida Pacaud, Dr. Frank Fan, and Dr. 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 virtual participants would like to ask the questions, 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 Hsu from Jefferies. My first question is for Steve. You mentioned the late onset of CRS offers operational flexibility for patient treatment. Could you elaborate on this point? Does this refer to treat patients in all patient settings or anything more? Also, regarding the exploration for cilta-cel treatment in all patient settings, can you talk about the progress on that front? When are we going to expect data? Also, what would be the meaningful data, for example, on the re-admission rate? Thank you, and I have a follow-up. Just want to make sure you guys could hear me. Thank you for the question. Maybe for folks who maybe did not hear the question. 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. First of all, thanks for the question. 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. That's problematic for many hospitals. Lord knows over the last now 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 cilta-cel program that looks like it's unprecedented in terms of its clinical efficacy." 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 the limitations that institutions have in terms of just pure bed capacity. I'm not just talking about the general med-type bed capacity, but more importantly, ICU bed capacity, okay? They're looking at the future saying, "How do I then pull through all of these patients that need this type of treatment? Can I do it in my current infrastructure?" That answer is no. That's very clear. 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, Mechanistically, what do I need to do? Logistically, what do I need to do? They start moving down a 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. Okay, so that's the first issue is capacity, knowing these big volumes are coming at the site. The question is then how do you do it? All right. This is not a new issue, right? This was 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'm 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 reaction that may be considered to be life-threatening. You're kind of limited because of the toxicity profile, right? That's the first kind of issue in the marketplace. I was mentioning to you all, which 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, and 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 cilta-cel, knowing that cilta-cel patients they're seeing in the clinical trials, it's this delayed onset, so patients aren't spiking fevers. Basically, the protocol is very different by site to site because they all treat different types of patients, right, in terms of where the patients live. To keep these patients local, and that definition of local changes by hospital. Some hospitals have resources literally across the street. Some have resources within about a 10-mile radius to the hospital. They could easily monitor these patients on an outpatient basis. Administer the product, monitor the patient, and then more extensively monitor that patient as they get closer to that median. This is the examples that they give to me in terms of what they plan on doing moving forward. In doing that, they are not immediately admitting patients. If you look at our clinical data in CARTITUDE-1, and Leda 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. Again, the investigators who've been touching this product have been able to manage those patients quite easily outside the hospital. 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? 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've been, in essence, beds and resources that would've been taken up, that patient is being monitored in the outpatient. That's the concept that the market is quickly going towards. 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. You heard outpatient. It was kind of very seldom, honestly, that you would hear outpatient CAR T. I hear it all the time now. 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? Right. Yeah. A question around the data. Yeah, I can quickly comment on that. I think we shared in previous brief some of the data that we have actually trials to allow outpatient administration. We have CARTITUDE-2 study. We have reported the type of patients we recommend for outpatient, because this is the abstract we have reported. Yeah, 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'll just have very quick follow-up for Dr. Frank Fan. This gene editing-free allogeneic platform is very interesting. I'm curious, is the GeneX blockade of endogenous TCR signaling, is it reversible process? 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. Thank you for your question. It's a very good question, I think. First, the mechanism is a reversible mechanism. That's in theory. While we have done a tremendous experiment in setting up a very challenging environment to try to test the stability of these mechanisms. Even with very strong stimulations, the majority of the CAR T cells, the TCR will not come back to the cell membranes. Also, we do incorporate cell depletion process before the final formulations, because Although our transduction efficiency is extremely high, we still don't want those small amount of contaminated or modified T cells. By the way, for one of your question, you asked about the transduction efficiency. As I mentioned already, the CAR and the GeneX has been stringently linked. It's all-in-one solution. It's in the single vector and connected with the F2A peptide. For any given cells that successfully transduce with this CAR, it for sure will overexpress the GeneX as well. The TCR down modulation will also take place. It is completely linked, the so-called 2 subtype scenarios, and we do depletion to remove the amount of the cell. That explain why we got 98.63% of CAR positivity. Usually, for the largest product in your formulations is a range of 30%-50%. The FDA don't like 100% of the expression CAR T cells. For autologous, because we have that room, and after our enrichment, we can enrich to a very high percentage of the wanted cells, but without additional risk. Yeah. I want to add on Frank's point, and with the preliminary clinical data that Frank just presented, it actually does demonstrate that the hematologic MOA is actually very efficient, even though actually that could be a potential reversal process. Great. Thank you for taking my questions. My name is David Dai. I am an analyst at SMBC. First question, several questions are on BCMA actually for Steve. The first question is just around J&J's actually developing a few BCMA bispecific antibodies. What are some thoughts around their strategy in terms of commercializing cilta-cel versus their bispecifics? Second question is around the sort of neurotoxicity, the delayed onset of neurotoxicity with the movement disorders we've seen so far. Any thoughts on latest mechanism around what causes those neurotox so far? I have some follow-up questions after. Very good. Can you hear me okay? Okay. Maybe you'll take the neurotox question. I'm not going to speculate in terms of J&J in terms of their BCMA program, and their bispecific BCMA. I will tell you this, any new drug for the treatment of multiple myeloma, count me in. It's the best thing for patients, right? 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 that those numbers I was showing you earlier were eligible patient pools. We knew, and we know and continue to analyze that not every patient is going to be a cilta-cel patient, rightfully so. There's always room in the marketplace for bispecific BCMA programs as well. I think it's fantastic, whether it be at J&J or others, to bring out other options for patients and families. I'll kind of stop it there. We are, to be quite honest with you, we are having active conversations, and we're beginning those conversations with Johnson & 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. Want to talk about the data? David, I just want to add one more thing on top of Steve Gavel's comments about the J&J's portfolio. I have very frequent communication with the J&J Janssen leadership about this, and we did discuss a little bit of that. In fact, you probably will hear more on November 18th when J&J hosts its pharmaceutical business review for analysts and investors. I can reiterate that there's very strong commitment from both Janssen and also Legend on our commitment that cilta-cel will become a cornerstone for the strategy for the portfolio. Our intention and also ambition is to bring cilta-cel all the way to the frontline. We think that hopefully in the near future, every patient who is newly diagnosed with multiple myeloma will be treated with cilta-cel, and that's the cornerstone strategy. On top of that, of course, oncology J&J will layer it up with DARZALEX and also the two bispecific they're developing. That's a commitment from J&J and also from Legend. Data. For neurotoxicity, question, I think really mechanism of this, some delayed type of neurocognitive, is not really clear right now. We have a lot of discussions with external experts as well. What I can say in cilta-cel program, we have identified what are risk factors for those events, and also we implemented a strategy how to prevent enhanced bridging therapy, for example, which was not case in initial CARTITUDE-1 study and some other patient management, basically, strategies. What we have seen, and we reported at ASCO EHA, those type of events significantly decreased. We had 5% in CARTITUDE-1, and this is now around 1%. Last, what I would like to add that it's emerged as a maybe not something specific to cilta-cel, but rather more class effects of 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. It's indicated in the label, it seems to be and maybe even CARTITUDE specific because I can go on on this, but there is French report in CD19 CAR T, French case series, which also reports this type of events for CD19 CAR T. Great. Thank you so much. Just a follow-up on sort of pipeline program, especially on the CLDN18.2 program, maybe a question for Frank. Did you do any biopsy on the patient that was presented? Did you see any kind of T-zone infiltration and expansion within their tumors? Can you just comment generally on CLDN18.2 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 infusion. Unfortunately, I don't think in the clinical studies, we have a chance to do any biopsies in the treatment course. 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. We do have a biopsy sample from ascites, which we detect lots of CAR T cells. The amount of CAR T cells, the concentration is even higher than peripheral blood. The cancer cells, if not all gone, are cell debris and maybe dead cells of CLDN18.2 positive cells. It's a very good sign in the clinical setting. We can't do biopsies for ethical reasons. Since the patient has such two huge pelvic lesions and based on I was a surgeon in my early career. I can imagine there are necrosis, there are fibrosis, lots of For huge tumor lesions, it's definitely not 100% of cancer cells. It could even, majority of the cells are the supporting tissues, fibrosis, and the necrotic tissues. We never expect, even with the best CLDN18.2 CAR T cells, we can shrink the tumor, and the tumor completely gone within very short time. I don't think that's possible. Maybe based on my current hypothesis or my theory, 15% of a shrinkage of the tumor could be pretty remarkable already. Ultimately, very importantly, in the past six months, the lesion, under the CT scan, the so-called tumor still not changed very much. Remain stable. The patient, the condition is very well. I'm very happy with that. If we got a chance, we would I'm not sure if investigators 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 the CAR T cells still there, but I do interesting to learn what's still inside of the tumor lesion, how many cancer cells still left, and can the tumor can be further shrink? Yeah. Thank you. For the second question regarding to the CLDN18.2 expression, and the program was designed as a targeted therapy, and we do have the pre-screening of the patient for select the population. There's a companion diagnostic has been developed associated with the treatment. Right. I apologize. I forgotten your last question. Thank you, Dong, for answering on my behalf. Yes, I did look at the immunochemistry analysis of many of these patients in enrollment procedures. As for majority of the patients, no matter their expression level being rated as 1 plus, 2 plus, or 3 plus, my impression is most of the patients have a very high percentage of CLDN18.2 expression. Lots of them, about 90% of expression in the area of the immunochemistries, which consistent what we've learned from the literatures. That CLDN18.2 is highly expressed on gastric epithelial-derived cells. It seems for the gastric adenocarcinoma, they tightly bear these features, these lineage-specific markers and protein secretion, and they rarely lost this. In lots of literature, I remember that 1 Japanese literature stated extensive study on this immunochemistries. I also presented that literature in my presentation. When you pair the primary tumor with the metastasis and the lymph node, you see the CLDN18.2 is, there's almost no case that the CLDN18.2 being down-regulated or lost. Instead, some of the patients, you will see enhancement of the CLDN18.2 expression. That's why we repeatedly, confidently saying CLDN18.2 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 end going back to the presentation and with the statistic actually Frank just presented, and for the expression level of CLDN18.2, it express more than 50% on both gastric and pancreatic cancers. However, the intensity of the expression could be very different patient by patient. Given the uniqueness 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. Okay, we are going to take a couple questions from the online participants. We have two questions from JPMorgan, Cory Kasimov. First, for Steve, commercial. How should we think about potential labeling for cilta-cel? Do you expect differentiation relative to other CAR T therapies or likely to be more similar than different? Hopefully Mike. You heard in my presentation earlier, our assumptions from a labeling perspective was consistent to what you're seeing in market today with ide-cel. 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 U.S., 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. We shall see. 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 for Lida. Regarding the potential of cilta-cel in the future front-line setting, why is it Dara-Rd is being used in CARTITUDE-5, at least according to clinicaltrials.gov? Does this potentially impact the future opportunity? Yes, thanks for the question. I guess, yeah, for CARTITUDE-5, this is a global study, and we have discussed this with health authorities and health authority after this discussion, current standards of care was selected as it is shown in this study. We had interest to go with Dara-containing regimens, but the outcome of discussion with health authorities, we have current trial design. Okay. I want to take one more question from online before we go back to the room. We have a couple questions from Morgan Stanley, Matthew Harrison. I think this is a question for Steve and Ying. Actually for Ying. Can you talk about updates we can look forward to seeing this year from the CARTITUDE program? What is your view on allo CAR, given the data you have seen in the field recently, especially CRISPR and allogeneic? Do you think allo CAR T can deliver durable responses? Thank you, Matthew, for the question. I'll answer the first part, which is what we're looking forward to updating towards the end of this year. Legend Biotech and Janssen have already announced that we will provide another update, likely for the CARTITUDE-1 data, at a major medical meeting by end of this year. That's something we plan to update with a longer follow-up of CARTITUDE-1. Potentially, we're also looking at the Cohort A, which is the data we presented at ASCO. Again, it's possible that we'll update with longer follow-up from CARTITUDE-2, Cohort A, at a major medical meeting. Lastly, it's possible also that we could also provide an update on additional new cohort from CARTITUDE-2. As you imagine, we actually enroll those cohorts sequentially, we start with Cohort A and then Cohort B. 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 CARTITUDE program by end of this year. On the second question about allo CAR, given the data we have seen in the field recently. I'll start the answer, and maybe Frank will add a little more. I have 2 takeaway here. Number 1 is that like I emphasized in the takeaways slide from CARTITUDE, the CR rates we are observing, not only it's very high at 80% from CARTITUDE-1, but also they're very durable, right. Durability is actually very important key element from both regulators and also from physicians treating multiple myeloma. I think if you look at the competition news from lately, you will see that not all the CRs are the same. Only the durable CR matters, right? That's the key takeaway from our program and also our data. Secondly, as you just heard from Dr. Fan, we have chosen to use non-gene editing approach in our first allogeneic alpha beta T program. There's a scientific rationale behind that, which Dr. Fan will elaborate. Again, we don't believe that we're going to see a lot of abnormalities on chromosome or anything like that. That's one advantage of using a non-gene editing technology. While if you use certain technologies in gene editing, you're bound to see some inaccuracies and also some infidelities from the process. With that, I'm going to pass it to Frank to answer a little bit more about our allo strategy. I think Ying, you already answered the question very well. Actually, 5 to 6 years ago, in our infancy of companies, we do realize that allogeneic will be the future of the cell therapy. It could be the future. We heavily invested. We form a dedicated team to explore the allogeneic platforms. After our internal consideration and investigations, I still don't feel very comfortable going with the multiple gene editing approach, let alone the IP issues. By that time it's unthinkable to license so many IPs from different markets. That's why our strategy is, we decided to only go with non-gene editing allogeneic platforms, no matter if alpha beta T, gamma delta T or CAR NK. That's why the other allogeneic CAR platforms we presented, disclosed, are all non-gene editing. Basically, I don't feel that the current hurdles that would, like an allogeneic CAR hurdle, is not solvable. I do believe there is still big room for improvement. I think maybe the FDA will find it clear, we will resume their clinical trials and after the investigations. I think the different approach by development, different companies all have their pros and cons. We have already elaborated all the pros of our platforms. Still our program is not that advanced in terms of a clinical stage, so we want to catching up, but we also wish the whole gene editing, the whole gene therapy field will clear all these difficulties and can really proceed. Yeah. We also are a gene therapy company, I believe. We're just doing ex vivo T-cell gene therapies. We have to always aware all the risks that appear in for either gene, the viral vector transduction or gene knockout. We all need to have that positive attitude, but a very careful attitude to address all these issues. Thank you. Okay. Dr. Frank Fan and Dong Geng, we have a follow-up question from Morgan Stanley, Matthew Harrison. You didn't seem to dose to those 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? Lila? Yeah, go ahead. Which specific programs? Early-stage program in general. The any program? Yeah. Frank, would you like to take that first? So around- Pardon? The point is, we are still in process of those escalations. We can't guarantee that with more patient being dosed at higher dose levels, we won't see DLTs. We can't guarantee that. Am I answering your question? Sorry, maybe I missed your question. Can you say that again? Yeah. It seems that Legend didn't dose to DLT, those limiting toxicities level in our early-stage program. Yeah. I confirm that. Yeah. Can you talk about how? I guess, yeah, I can take from clinical perspective. Yeah, that's true. This trial, we have dose escalation. Totally We will continue dose escalation. I don't know which specific programs, but as soon as we don't see DLT, or if we see DLT, we will expand. We will follow the due routes. Reporting of this data will depend, I guess, when we have meaningful number of patients with some indicative data. We cannot comment on timing right now. We can see if we have any questions in the room, I think. Thank you guys for taking my questions. This is Mitchell Kapoor 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 cilta-cel launch. Can you maybe touch on how you guys are thinking about having a steady supply for the sites that you do launch? 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. How do you sort of ensure that experience? The second question is just for Frank, if you can just touch on a little bit more on the Claudin 18.2 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. Then just on U.S. strategy, are you expecting to take this beyond gastric? Looking at esophageal, looking at pancreatic tumors as well. Thank you guys. Ying, do you want to take supply, and I'll talk about go-to-market? Sure. Thank you, Mikhail, for the question. I'll talk about the supply, and then maybe Steve will talk about the launch. Obviously it's not in our position to comment or speculate our competitor's program in terms of the launch. I can reassure you that Legend, and also Janssen, continue to place extremely strong emphasis and also on both robust process and quality measures in the manufacturing, discovery, and delivery of cilta-cel for both clinical and also commercial supply. As you are probably aware, due to COVID-19 outbreak, there is some global supply chain disruptions in stuff like kits, bags, and also lentivirus. Lentivirus is a common, very important drug substance used in many CAR T therapies. 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 then our CD38 antibody, they face very poor prognosis, right? 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. If there's any potential supply issues here, J&J and Legend are proactive in terms of enhancing our internal capabilities to supply LV. 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, Ying. 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. One thing that I think I discovered early in this process, in this space in particular, is the concept of transparency and predictability. 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. 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. 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 just not knowing. As Ying says, this is a pretty dynamic space when it comes to supply. How we're approaching this, it's one of being very deliberate and 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. You need to be as transparent as possible to our sites so they could begin the planning process in order to get drugs like this for their patients. We're in the process right now, effective today, actually, of having a lot of conversations with our sites in the U.S. to explain to them how we will be rolling this asset out to them. We will continue that process for the next several weeks. I could 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. Believe me, as a commercial person, I've learned way too much about operations and manufacturing over the last several years. I think it's critical, obviously, to make these programs seamless to the customer. 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 cilta-cel get cilta-cel on time, and there's no surprises. Anyways, there's a lot more behind that I'm happy to go into with you maybe on the side, but that's how we're planning on doing this. Okay. Thank you, Steve. We have a follow-up question from BTIG, from Justin Zelin. Will you be able to comment on Legend manufacturing readiness, also how would that compare to our competitor? Justin, thank you for the question. Again, Justin, I'm not going to go into the detailed manufacturing capacity due to our contractual obligation with J&J on this. We're not going to disclose the exact capacity. Suffice to say that both partners are working very hard, again, to ensure the robustness and also the delivery of the cilta-cel once it's commercially launched. Frank, I think that you can address the next question, which is Claudin CAR T versus bispecific modality. Yeah. Regarding your Claudin 18.2 questions. Yes, obviously Claudin 18.2 already evolved one of the most popular immunotherapy targets for solid cancers. There are bispecific, there are ADCs, there are so many different modalities. All of them are antibody derived biologics, including CAR T. I consider CAR T is also a derivative of antibody biologics. It just combines the gene therapy and T cell immunities. If you want me to compare or comment, it's really difficult because it's like comparing apples with oranges. It's still so different. In general, antibody drugs, bispecifics, and ADCs, I think the innovation of their modality, the development of the new modalities is, I think in the past 20 years has been advanced so much and quite mature, but maybe there is limited room for them to further evolve. For CAR T or CAR-NK, basically, the nature is gene therapy. Virtually, there's no ceilings. I think for cell therapy company, they can always invent new armor strategies, armor the CAR T cells with whatever tools they need. Relatively, for cell and gene therapy, there are bigger rooms for innovations, for further advancing the modalities to cope with whatever questions, whatever problems, barriers they will encounter. No matter is it infiltration, is expansion, is barrier, whatever. That explains why I keep saying I'm a believer of gene and cell therapy, because they are viable drugs. We can energize them in all sorts of different approaches. We can always keep improving it until we reach a goal for a cancer cure. This is completely forward-looking statement, I apologize for that. Since you ask, I still want to show my confidence. Yeah. That's my personal opinion, not representative of Legend. Thank you. Maybe I can add a little bit more on what Frank just said. Even though we do not know, and since we don't have data yet, what's the difference between bispecific, what's the CAR T for the treatment using Claudin 18.2 as a target for the treatment of solid tumor. For the existing data in the hematology field, and in general, CAR T actually offer much more advantage than bispecific in terms of the overall remission rate, as well as the duration of the treatment. From an MOA perspective, it offer more flexibility. I think the same theory probably will continue for the treatment of solid tumor as well. As for Claudin 18.2 as a target, it already has actually proved to be a viable target from the existing antibody data as well as other data. We believe, actually, it is a validated target for the treatment for both gastric cancer and pancreatic cancer. We do have plan to pursue those two indications global-wise. Mikhail, if I may, I'll just add 2 things. Number 1, the key difference between CAR T and the bispecific monoclonal antibody is that the CAR T exhibits direct killing, right? Instead of leveraging the patient's own T cells by using a bispecific or monoclonal antibody for that matter. We actually take the T cell from the patient, yet we weaponize that with a CAR. That's where the CAR T advantage is, compared to the endogenous CAR T cells from patient population. Secondly, I know we only have disclosed so far the 1st patient with the lowest dose so far. If you compare to our competition, where I think the median PFS was about 5.6 months, that was actually with some chemo in the combination. This is actually data you see from monotherapy, 1 dosing only, and this is the lowest dose we have seen. We're seeing, like Frank was mentioning, already 6-month PFS, and this patient still remains progression free. That's the data telling us. Okay. We have a question from Woodline Partners, from Anish Kapoor. It's for Lida. On CARTITUDE-4, 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 ide-cel in terms of timeline? I guess I give good indication there. We are happy with recruitment, but I cannot comment more than that right now, and we will share when it comes. Okay. We have more questions on the Claudin 18.2 question for Frank Fan and Dong. Next question is from Goldman Sachs and from Ziyi Chen. Will you test different preconditioning strategies for Claudin 18.2 CAR T? Do you think it will make a difference? No, I don't think so, because given the fact that our standard Flu/Cy preconditioning already did very good job. From since the first patient, we see extensive expansions, and at the peak level, 250,000 CAR T cells per ml of peripheral blood, that's a remarkable amount. We don't want to reinvent the wheel. Maybe in the future, if we see anything and it emerge, we want to reduce the lymphodepletion, that's possible. Need data to support. The lymphodepletion is really critical for solid cancer programs. There is not extensively studied in this field. We all know that for hematologic malignancies, lymphodepletion precondition is critical. For solid cancers, I remember some investigators arguing that maybe for solid cancers, lymphodepletion is not that critical. I don't know if I agree or disagree with it. I think we needed data to support that. At current stage, I don't think we have a plan to vary this. We would rather put our energy on finding the optimum dose and whether we can re-dose a patient, and these kind of things. Yeah. The next question is from Liren, from Diana Grace Porch. How are you thinking about multiple cycles of CAR T for your solid tumor programs? If necessary, when and how will you employ? Thanks. We have to think about this. In U.S., clinical development plan is not yet established, so we are in the process of doing that, and also with health authorities. I think we will do it depends on program by program. In principle, I think we still try to achieve significant benefit to the patient with one infusion. I don't know if Frank wants to comment. From clinic. Okay. We don't have any more questions online. Please raise your hand if you have any questions in the room. Frank, you. Well, if there's no further questions, I guess I'll just make some closing remark 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. We're actually exploring multiple technologies, 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 entrusted us with precious capital to further our work. Thank you.